Diagnosis and Monitoring of Eosinophilic Esophagitis Using the Cytosponge
Phase: NA
Conditions: Eosinophilic Esophagitis, EoE
Sponsor: University of North Carolina, Chapel Hill

 
Diagnosis and monitoring of eosinophilic esophagitis using the Cytosponge 
 
NCT02114606 
 
Protocol Version Date: 
 
25 September 2020 
 
 
 
 
 

 
CONFIDENTIAL 
CLINICAL RESEARCH 
P
 
 
 
 
 
DIAGNOSIS AND MONITORING OF EOSINOPHILIC 
ESOPHAGITIS USING THE CYTOSPONGE 
 
 
 
Principal Investigator 
Evan S. Dellon, MD, MPH 
Assistant Professor of Medicine and Epidemiology 
University of North Carolina School of Medicine 
130 Mason Farm Road, Ste 4140 
Chapel Hill, NC 27599 
(919) 843-9618 
 
Co-Investigators 
David A. Katzka, MD 
Mayo Clinic Rochester 
Rochester, MN 
 
Rebecca C. Fitzgerald, MA, MD 
Cambridge University 
Cambridge, U.K. 
 
Nicholas J. Shaheen, MD, MPH 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Funding Sponsor: 
CURED (Campaign Urging Research for Eosinophilic 
Disease) Foundation 
UNC IRB Number: 
13-3521 
Protocol Version: 
4.0 
Protocol Version Date: 
25 September 2020 
 
 
 
 
 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date:  
 
Name:  
 
Title:  

Cytosponge EoE Protocol (IRB# 13-3521) 
 
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Summary of Changes 
 
 
Version 4.0 dated 25Sep2020 
Study Summary 
Objectives and methodology updated according to changes 
made to these sections of the protocol. 
2.0 Study Objectives 
Aim 2 removed as the scope of the study was limited by 
device availability and aim 2 was unable to be evaluated 
with available data. 
3.1 General Design 
Reference to Aim 2 removed. 
3.4 Secondary Outcomes 
Added “agreement between cytosponge and endoscopic 
biopsy as measured by kappa.” Revised secondary outcome 
to clarify measures used to assess acceptability. 
6.1 Sample Size Determination 
Removed reference to Aim 2. 
6.2 Statistical Methods 
Removed reference to Aim 2. 
Administrative Changes 
Administrative changes to protocol version and version 
dates throughout. 
Version 3.0 dated 05Sep2017 
3.1 General Design 
Additional analyses on samples has been added. 
Administrative Changes 
Administrative changes to protocol version and version 
dates throughout as well as updating table of contents and 
section numbers. 
Version 2.0 dated 05Oct2016 
 
Study Summary 
6.1 Sample Size Determination 
Increased enrollment from 100 to up to 150 to account for 
any potential issues with sample quality and additional 
safety assessments. 
Administrative Changes 
Administrative changes to protocol version and version 
dates throughout as well as updating table of contents and 
section numbers. 
 
Version 1.0 dated 24Nov2015 
Initial Protocol 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 3 
1.1 
KEY ROLES AND PERSONNEL.......................................................................................................... 3 
1.2 
BACKGROUND ................................................................................................................................ 3 
1.3 
RATIONALE .................................................................................................................................... 5 
1.4 
DEVICE DESCRIPTION ..................................................................................................................... 6 
1.4.1 
Prior Utilization ........................................................................................................................ 6 
2 
STUDY OBJECTIVES ......................................................................................................................... 7 
3 
STUDY DESIGN ................................................................................................................................... 7 
3.1 
GENERAL DESIGN .......................................................................................................................... 7 
3.2 
PROTOCOL MAP ............................................................................................................................. 9 
3.3 
PRIMARY OUTCOMES ................................................................................................................... 10 
3.4 
SECONDARY OUTCOMES .............................................................................................................. 10 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 10 
4.1 
INCLUSION CRITERIA .................................................................................................................... 10 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 10 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 10 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 10 
5 
STUDY PROCEDURES ..................................................................................................................... 12 
5.1 
SCREENING/ENROLLMENT ............................................................................................................ 12 
5.1.1 
Assessments ......................................................................................................................... 12 
5.1.2 
Consenting Procedure ........................................................................................................... 13 
5.1.3 
Cytosponge Administration ................................................................................................... 13 
5.1.4 
Routine Care Endoscopy with Biopsy ................................................................................... 14 
5.1.5 
Adverse Event Assessment .................................................................................................. 14 
5.2 
FOLLOW-UP PHONE CALL ............................................................................................................ 14 
5.2.1 
Assessments ......................................................................................................................... 14 
5.2.2 
Impact of Events Scale .......................................................................................................... 14 
5.2.3 
Procedure Preference and Acceptability Questionnaire ....................................................... 14 
5.2.4 
Follow-up Phone Call Adverse Event Assessment ............................................................... 14 
5.3 
FOLLOW-UP CYTOSPONGE ADMINISTRATION ................................................................................. 14 
5.3.1 
Assessments ......................................................................................................................... 15 
5.4 
FOLLOW-UP PHONE CALL ............................................................................................................ 15 
5.5 
SUBJECT PARTICIPATION COMPLETION ......................................................................................... 15 
6 
STATISTICAL PLAN ......................................................................................................................... 15 
6.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 15 
6.2 
STATISTICAL METHODS ................................................................................................................ 15 
6.3 
SUBJECT POPULATION FOR ANALYSIS ........................................................................................... 16 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 16 
7.1 
DEFINITIONS ................................................................................................................................ 16 
7.2 
REPORTABLE ADVERSE EVENTS ................................................................................................... 17 
7.2.1 
Reporting Timeline ................................................................................................................ 18 
7.2.2 
Recording of Adverse Events ................................................................................................ 18 
7.2.3 
Reporting Adverse Events to Lead Site ................................................................................ 18 
7.2.4 
Reporting Adverse Events to Local EC/IRBs ........................................................................ 19 
7.2.5 
Notifying the FDA .................................................................................................................. 19 
7.2.6 
Lead Site Reporting to Participating Investigators ................................................................ 19 

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7.3 
MEDICAL MONITORING ................................................................................................................. 19 
8 
DATA HANDLING AND RECORD KEEPING ................................................................................... 19 
8.1 
CONFIDENTIALITY ......................................................................................................................... 19 
8.2 
SOURCE DOCUMENTS .................................................................................................................. 20 
8.3 
CASE REPORT FORMS.................................................................................................................. 20 
8.3.1 
Case Report Form Completion Table ................................................................................... 20 
8.4 
RECORDS RETENTION .................................................................................................................. 20 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 20 
9.1 
AUDITING AND INSPECTING ........................................................................................................... 20 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 21 
11 
STUDY FINANCES ............................................................................................................................ 21 
11.1 
FUNDING SOURCE ........................................................................................................................ 21 
11.2 
CONFLICT OF INTEREST ................................................................................................................ 21 
12 
PUBLICATION PLAN ........................................................................................................................ 21 
13 
REFERENCES ................................................................................................................................... 22 
 

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List of Abbreviations  
  
Item 
Definition 
AE 
Adverse Event 
CRF 
Case Report Form 
EC 
Ethics Committee 
EGD 
Esophagogastroduodenoscopy 
EoE 
Eosinophilic Esophagitis 
IES 
Impact of Events Scale 
IRB 
Institutional Review Board 
VAS 
Visual Analog Scale 
 
 
 
 
 
 
 

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Study Summary 
Title 
Diagnosis and monitoring of eosinophilic esophagitis using the Cytosponge 
Methodology 
This will be a prospective cohort study, with patient enrollment conducted at UNC and 
Mayo Clinic by Drs. Dellon and Katzka, and further sample analysis performed by Dr. 
Fitzgerald. In Aim 1, patients with eosinophilic esophagitis (EoE) or suspected EoE will 
be enrolled, tissue will be obtained from both the Cytosponge and routine care 
endoscopy, and the methods will be compared for a single time point to determine 
accuracy of Cytosponge for quantifying esophageal eosinophil counts. The patients 
who are being treated will be followed and tissue will be assessed over time with both 
Cytosponge and routine care endoscopy to determine the utility of Cytosponge for 
monitoring treatment response in patients with EoE. For all patients, safety will be 
monitored and subjects will complete a survey about the acceptability of Cytosponge 
(Aim 2). 
Study Duration 
2 Years 
Study 
Center(s) 
University of North Carolina, Chapel Hill, NC 
Mayo Clinic, Rochester MN 
Objectives 
Aim 1: To determine the accuracy of Cytosponge for quantifying esophageal eosinophil 
counts in patients with active EoE, as compared to endoscopy with biopsy as the gold 
standard.   
 
Aim 2: To determine the safety and acceptability of Cytosponge for patients with EoE.   
Number of 
Subjects 
150 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion Criteria: 
1. Able to read, comprehend, and complete the informed consent form 
2. Male or female subjects, age 18-80 years, 
3. Suspected EoE or has a diagnosis of EoE with current active disease, 
 
Exclusion Criteria: 
1. History of esophageal stricture precluding passage of the endoscope or sponge, 
2. Pregnancy, or planned pregnancy during the course of the study, 
3. Any history of esophageal varices, liver impairment of moderate or worse severity 
(Child’s- Pugh class B & C) or evidence of varices noted on any past endoscopy, 
4. Any history of esophageal surgery, except for uncomplicated fundoplication 
5. History of coagulopathy, with INR>1.3 and/or platelet count of <75,000. 
6. Current use of blood thinners such as coumadin, warfarin, clopidogrel, heparin 
and/or low molecular weight heparin (requires discontinuation of medication 7 days 
prior to and 7 days after esophagogastroduodenoscopy [EGD] and Cytosponge 
administration, aspirin use is OK). 
7. Are allergic to local anesthetics such as lidocaine (these subjects may opt not to 
receive the optional lidocaine gargle prior to the Cytosponge administration and 
still be eligible). 
8. Have not fasted the night before administration of the Cytosponge. 
9. History of perforation. 

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Statistical 
Methodology 
Aim 1: To test the hypothesis that the Cytosponge accurately quantifies esophageal 
eosinophil counts in patients with active EoE, the maximum eosinophil counts from the 
Cytosponge and endoscopic biopsy will be compared by calculating the Pearson 
coefficient of correlation.  In addition, patients will be categorized as having an 
eosinophil count either above or below 15 eos/hpf (the current diagnostic threshold).  
Agreement between patients above and below this threshold for Cytopsponge and 
endoscopic biopsy will be measured using the kappa statistic. If eosinophil counts are 
not normally distributed, non-parametric methods will be used.   
 
Aim 2: Summary statistics will be calculated to describe adverse events and the 
tolerability of the Cytosponge.  The proportion of subjects who prefer the Cytosponge 
will be calculated. 
 
 

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1 Introduction 
This document is a protocol for a human research study. The study will be conducted in accordance with 
the International Conference on Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code 
of Federal Regulations on the Protection of Human Subjects (45 CFR Part 46), and applicable federal 
regulations and institutional policies. All personnel involved in the conduct of this study have completed 
human subjects protection training. 
1.1 Key Roles and Personnel 
Principal Investigator:   
Evan S. Dellon, MD, MPH 
Assistant Professor of Medicine and Epidemiology 
University of North Carolina School of Medicine 
130 Mason Farm Road, Ste 4140 
Chapel Hill, NC 27599 
(919) 843-9618 
 
Clinical Site 
Investigators: 
David A. Katzka, MD 
Mayo Clinic Rochester 
Rochester, MN 
 
Rebecca C. Fitzgerald, MA, MD 
Cambridge University 
Cambridge, U.K. 
 
Institutions: 
Enrolling sites: 
University of North Carolina at 
Chapel Hill 
130 Mason Farm Road 
Chapel Hill, NC 27599 
 
Site PI: Evan S. Dellon, MD, MPH 
Phone: (919) 843-9618 
Fax: (919) 843-2508 
Email: evan_dellon@med.unc.edu 
 
Mayo Clinic Rochester 
200 1st St SW 
Rochester, MN 55905 
 
Site PI:  David A. Katzka, MD 
Email: Katzka.David@mayo.edu 
 
 
Laboratories: 
Mayo Clinic Rochester 
200 1st St SW 
Rochester, MN 55905 
 
MRC Cancer Unit 
University of Cambridge 
Hutchison/MRC Research Centre 
Box 197  
Cambridge Biomedical Campus 
CB2 0XZ 
T. 01223 761085 / 01223 763994 
1.2 Background 
Eosinophilic esophagitis (EoE) is an emerging disease defined by the abnormal presence of eosinophils 
in the esophageal lining, leading to trouble swallowing (dysphagia), esophageal narrowing (stenosis), and 
food impaction.1-3  The incidence and prevalence of EoE have risen dramatically,4-7 and EoE is now the 
most common cause of food impaction in patients presenting to emergency rooms.8, 9  In order to 
diagnose and monitor EoE, upper endoscopy with esophageal tissue biopsy is currently required.  Two 
upper endoscopies are needed to diagnose EoE, the first one to evaluate symptoms and the second one 
to confirm the diagnosis after treatment with a proton pump inhibitor (anti-acid) medication.3  If a patient is 
treated with a swallowed (“topical”) steroid medication such as budesonide or fluticasone, they undergo a 
third endoscopy to determine whether the medication was effective.10-14  If they are treated with an 

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elimination diet, they will require an endoscopy 6 weeks after the initial elimination, and then another one 
every 4-6 weeks after each food is added back.15-17  In some cases this can add up to more than 8-10 
endoscopies in a single year.  This is costly, inconvenient, and the repeated procedures add risk.  New 
diagnostic methods for EoE are urgently needed. 
 
A novel, minimally invasive a simple, non-endoscopic device, termed the Cytosponge, has been 
developed for endoscopic screening of subjects at risk 
for Barrett’s Esophagus (a precancerous condition 
that is a complication of reflux disease),18  by 
investigators at the University of Cambridge in the 
U.K. and is readily applicable to EoE.  Cytosponge 
consists of a foam sponge which is contained within a 
dissolvable capsule and attached to a string (see 
Figure 1). The capsule is swallowed, dissolves in the 
stomach, the sponge expands into a sphere, and after 
5 minutes is retrieved by pulling the string.  As the 
sponge is withdrawn, cells along the whole length of 
the esophagus are collected by the foam sphere; this 
amounts to obtaining an esophageal biopsy tissue 
sample, but without doing the endoscopy. The foam 
sphere, 
now 
containing 
cells, 
is 
placed 
into 
preservative fluid and processed using standard 
pathology methods readily available everywhere. Our team has published data about the safety, 
acceptability, and accuracy of this technique in Barrett’s,18-21 and we have preliminary data in EoE 
patients.  Of note, Cytosponge differs substantially from the Esophageal String Test (EST), which is also 
under development for EoE.22  The EST uses a dissolvable capsule and a string to collect fluids secreted 
from the esophageal lining, but does not capture tissue.  Moreover, the EST requires a specialized lab to 
run advanced tests to measure factors secreted from eosinophils.  In contrast, because Cytosponge 
obtains tissue, it can be used anywhere with existing and inexpensive pathology techniques. 
  
 
Medtronic, formerly Covidien GI Solutions, has 
developed 
a 
more 
refined 
version 
of 
the 
Cytosponge 
I 
(referred 
hereafter 
as 
the 
CytospongeTM or “Cytosponge”).  The Cytosponge 
was developed from the Cytosponge I specification 
and design, with the additional priority of a more 
reproducible 
manufacturing 
process, 
standardization of dimensions, and other quality 
related features (Figure 2).  Because we seek to 
assess a tool for widespread clinical usage, this 
study will use the Cytosponge which will be 
purchased from Covidien GI Solutions (now part of 
Medtronic).   
 
The current endoscopic methods for diagnosing 
and monitoring treatment response in EoE are 
costly, inconvenient, and risky.  Novel diagnostic 
methods are needed, and the minimally-invasive 
Cytosponge holds great promise.  It has been shown to be safe and accurate in Barrett’s esophagus, it 
has the advantage (over the string test) of obtaining a true tissue sample, and our preliminary data 
supports its further study in EoE.  The proposed prospective cohort study, conducted by experts in 
esophageal diseases and EoE, will assess the accuracy of Cytosponge compared to endoscopy and 
biopsy in EoE, and determine the safety and acceptability of this technique.  Use of the Cytosponge 
would fundamentally change the paradigm for clinical management of EoE by allowing collection of non-
Figure 2 CytospongeTM (left) and Cytosponge I
(right) for comparison 
Figure 1:  The Cytosponge.  The left image 
shows the expanded sponge. The right image 
shows the capsule.  Both have the string in place. 

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endoscopic esophageal biopsies, thus minimizing the need for invasive testing.  It would also facilitate 
future genetic, mechanistic, and pathogenesis research in EoE. 
 
The specific goals of this study are to assess the safety, acceptability, and accuracy of Cytosponge for 
diagnosis and monitoring of EoE in comparison to endoscopy and biopsy as the gold standard.  To 
achieve these goals, we will recruit subjects with EoE from both the University of North Carolina (Dr. 
Dellon) and from the Mayo Clinic in Rochester where Cytosponge has already been used for EoE (Dr. 
Katzka).  Our central hypothesis is that the tissue obtained using Cytosponge will show an eosinophilic 
infiltrate similar to that seen on endoscopic biopsies in patients with active EoE, will have utility to monitor 
tissue eosinophilia in patients being treated for EoE, and will be safe, acceptable, and preferable for 
patients when compared with endoscopy.  This research will impact clinical practice by fundamentally 
changing the way EoE is diagnosed and monitored, decreasing the need for costly and invasive 
endoscopic procedures.  Moreover, because this technique readily obtains esophageal tissue, it could 
greatly facilitate genetic, mechanistic, and pathogenesis research in EoE. providing less invasive and 
more cost-effective surveillance of this large and growing patient population. 
1.3 Rationale 
PRELIMINARY RESULTS 
Our research team has extensive experience with EoE diagnosis, treatment, and Cytosponge 
Drs. Dellon (from UNC) and Katzka (from Mayo Clinic) are recognized experts in diagnosis and treatment 
of EoE.  At both centers, their clinical practice and research endeavors focus on esophageal diseases 
and EoE in particular.  They each have a large EoE patient population and have demonstrated the ability 
to recruit patients for EoE studies.  Dr. Fitzgerald (from Cambridge, UK), also a Gastroenterologist who is 
expert in esophageal diseases, has developed the Cytosponge, shown its great utility in diagnosis and 
surveillance of Barrett’s esophagus (see below), and is committed to extending its application into EoE. 
 
Cytosponge has been shown to be safe and have great diagnostic utility in Barrett’s esophagus 
The safety, feasibility, and acceptability of 
using Cytosponge in a primary care setting to 
screen for Barrett’s esophagus has been 
shown by Dr. Fitzgerald’s group.18-21  In the 
largest published study to date,18 99% of the 
504 subjects successfully swallowed the 
Cytosponge and there were no serious 
adverse events.  In an interim analysis of 751 
patients in a follow-up study, it is similarly 
well-tolerated.21  The tissue samples obtained 
from these patients were more than adequate 
to evaluate for Barrett’s esophagus, and the 
Cytosponge 
gave 
very 
similar 
results 
compared with endoscopy and biopsy as the 
gold standard.18, 21  Moreover, the tissue that 
was obtained was readily amenable to 
standard 
pathologic 
analysis 
techniques, 
including regular hematoxylin and eosin 
(H&E) staining and immunohistochemistry 
(IHC).18, 19, 21  These data show that in a large 
cohort of patients, Cytosponge was safe, well-
tolerated, 
effective 
for 
obtaining 
tissue 
samples that are easily processed, and 
effective for diagnosis and surveillance of Barrett’s esophagus compared with endoscopy and biopsy. 
 
In a pilot study, Cytosponge shows great promise for use in EoE 
Given the success of Cytosponge in Barrett’s esophagus and the need for esophageal biopsy tissue for 
diagnosis and to monitor treatment response in EoE, Drs. Katzka and Fitzgerald conducted a pilot study 
Figure 3:  Examples of esophageal tissue samples from 
EoE patients using Cytosponge.  Low power (A) and high 
power (B) views from the same patient show multiple bright 
red eosinophils that are easy to see on routine exam.   
Examples from two other patients are seen in (C) and (D). 

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of Cytosponge in EoE.  A total of 20 EoE patients, some with active disease and some with disease in 
remission to provide a range of disease severity and esophageal eosinophilic infiltration, swallowed the 
Cytosponge for tissue sampling prior to undergoing standard endoscopy and biopsy.  All patients, even 
those with esophageal strictures, were able to swallow the Cytosponge without problems, and there were 
no serious adverse events.  The first main result was that the tissue samples were adequate for analysis 
with standard pathology H&E staining (a stain on which eosinophils are bright pink in color; see Figure 3).  
The second main result was that Cytosponge performed very well compared with endoscopy and biopsy, 
with a sensitivity of 100% (the Cytosponge picked up all of the cases of EoE that were also found by 
endoscopy) and a specificity of 70% (there were some cases felt to be EoE on the Cytosponge that were 
not felt to be EoE on endoscopy).  These preliminary data show that the Cytosponge holds great promise 
for diagnosis and monitoring of treatment in EoE.  If tissue can be obtained with this minimally invasive 
technique, it would fundamentally change the paradigm for clinical management of EoE by minimizing the 
need for invasive endoscopies. 
1.4 Device Description 
The Cytosponge™ Cell Collection Device (Cytosponge) is intended to collect surface cells from the 
esophagus.  The device consists of a swallowable 
capsule, which dissolves in the body cavity, releasing a 
self-expandable sponge.  The sponge is then retrieved 
from the esophagus using an attached cord. During the 
retrieval process, the sponge collects cells from the 
most superficial layer of the esophageal mucosa.  
Once removed from the body cavity, the sponge and 
cells are retained for investigation and/or testing.  
 
The 
Cytosponge™ 
Cell 
Collection 
Device 
(Cytosponge) received 510(k) clearance from the FDA 
on November 26, 2014 (K142695). The Cytosponge ™ 
Cell Collection device is a Class II product under 21 
CFR 874.4710 esophagoscope (flexible or rigid) and 
accessories.  This study uses the Cytosponge in 
accordance with its labeling and is therefore exempt 
from an IDE. 
1.4.1 Prior Utilization 
Dr. Fitzgerald and colleagues administered Cytosponge I to 504 patients in a primary care setting and 
found it to be safe and well-tolerated. Of these patients, 501 (99%) were able to successfully swallow the 
capsule.  Unsurprisingly, given pill-swallowing difficulty in the general population, 3 patients were unable 
to swallow the pill, feeling it was too large. No adverse events were noted, and patients demonstrated a 
low level of anxiety associated with the test. These 504 administrations are documented in a report in the 
British Medical Journal30.  These investigators have, since this investigation, administered the 
Cytosponge to an additional 831 patients as part of the BEST2 study (a multicenter, prospective study to 
determine whether BE patients can be risk stratified using the Cytosponge) and an interim data analysis 
shows similarly excellent safety and tolerance profile, with no adverse events reported. 31   Overall, to 
date, there have been 1,335 documented administrations of the sponge, with no adverse events.  Several 
hundred additional uses of the device have occurred in Cambridge, UK, without adverse event (personal 
communication, Dr. Fitzgerald), but have not yet been reported in the peer-reviewed literature.  
 
Cytosponge is extremely similar to Cytosponge I.  Although no major complications have been reported 
with this device, there are several risks associated with the administration of this device. There is the 
possibility of aspiration whenever instrumentation of the esophagus or stomach is performed. Because 
the device does not render the upper esophageal sphincter incompetent, this risk is expected to be 
minimal. Additionally, although the sponge is soft and non-abrasive, subjects could bleed from any 
mucosal surfaces of the mouth, stomach or esophagus which come in contact with it, and/or experience a 
sore or irritated throat following administration. Finally, to date there have been >1,000 administrations 
Figure 4 Cytosponge with planned packaging 
and retrieval cord 

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and detachment of the sponge from the string has occurred in less than 1% of cases. Should the sponge 
detach from the string, it will be retrieved during the routine care upper endoscopy immediately following 
administration.  
 
The current study has been designed to minimize occurrence of these theoretical risks. Specifically we 
plan to exclude those patients who: 
• Are unable to discontinue clopidogrel, and/or warfarin for 7 days prior and 7 days after procedure, 
• Have a history of esophageal stricture that precludes passage of an adult endoscope,  
• Have any history of esophageal varices, liver impairment of moderate or worse severity (Child’s-
Pugh class B & C), or evidence of varices noted on any past endoscopy, 
• Have any history of esophageal surgery (except uncomplicated fundoplication), and history of 
coagulopathy, with INR >1.3 and/or platelet count of <75,000. 
 
 
Cytosponge administration will occur after an overnight fast to minimize the possibility of aspiration of any 
gastric contents. Every administered sponge will be assessed post-procedure for signs of fracture or 
incomplete retrieval of the sponge. In the unlikely case of incomplete retrieval, the sponge will be 
retrieved with a Roth net at the standard of care endoscopy which will routinely immediately follow the 
administration of the sponge per the study protocol. Any bleeding noted, either clinically following the 
sponge administration or due to blood on the sponge itself, will be similarly investigated, and, as 
necessary, treated during the subsequent endoscopy. Because study inclusion/exclusion criteria are 
designed to exclude those at highest risk for a bleeding complication, the risk of bleeding in this study 
should be extremely low. 
2 Study Objectives 
Aim 1: To determine the accuracy of Cytosponge for quantifying esophageal eosinophil counts in patients 
with active EoE, as compared to endoscopy with biopsy as the gold standard.   
 
Aim 2: To determine the safety and acceptability of Cytosponge for patients with EoE, all patients who are 
enrolled in both Aims 1 and 2 will be monitored.   
3 Study Design 
3.1 General Design 
This is a prospective longitudinal cohort study, with patient enrollment conducted at UNC and Mayo Clinic 
by Drs. Dellon and Katzka, and further sample analysis performed by Dr. Fitzgerald.  In Aim 1, patients 
with EoE will be enrolled, tissue will be obtained from both the Cytosponge and endoscopy, and the 
methods will be compared for a single time point.  For all patients, safety will be monitored and subjects 
will complete a survey about the acceptability of Cytosponge (Aim 2).  
 
Subject recruitment will be from consecutive eligible patients presenting for endoscopy as part of their 
routine care.  Potentially eligible subjects will be contacted by telephone in advance of their procedure 
and their interest in study participation assessed. Subjects interested in participating will be asked to 
present to the endoscopy unit prior to their scheduled procedure. At that time, inclusion and exclusion 
criteria will be reviewed, and eligible subjects will give informed consent. Subjects will then undergo the 
Cytosponge assay.  
 
After the Cytosponge has been removed, the patient will undergo standard upper endoscopy and biopsy, 
as clinically indicated.  During this exam, endoscopic features of EoE will be recorded, including rings, 
furrows, white plaques, decreased vascularity, and strictures.  The severity of the endoscopy findings will 
be measured using the recently validated EREFS scoring system.23  Four esophageal biopsies will be 
taken both from the distal (5 cm above the gastro-esophageal junction) and proximal (15 cm above the 
gastro-esophageal junction) esophagus.  This number of biopsies has been shown to maximize the 
diagnostic sensitivity for EoE.24 

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Enrolled subjects will be administered the Cytosponge during the enrollment visit.  After enrollment, if 
subjects receive treatment for their EoE and return to the enrolling site for an upper endoscopy as part of 
their standard of care, then subjects will be asked to repeat the Cytosponge procedure prior to each 
follow-up standard of care endoscopy. 
 
Histology and eosinophil counts 
All tissue samples from the Cytosponge and endoscopy will be coded with a subject’s ID number, but will 
otherwise be masked for all clinical data, including EoE activity, symptoms, patient characteristics, and 
treatments prescribed.  Using the paraffin blocks, pathology slides will be cut and the tissue processed 
with routine H&E staining.  The slides will then be digitized, and using the Aperio ImageScope (Aperio 
Technologies, Vista, CA), the maximum eosinophil density (eosinophils/mm2 [eos/mm2]) will be 
determined using our previously validated protocol.25  For purposes of comparison to previous studies, 
eosinophil density will then be converted to eosinophil counts (eos/hpf) for an assumed hpf size of 0.24 
mm2, the size of an average field as reported in the literature.26  The study pathologists from UNC and 
Mayo Clinic will review the specimens from their sites, and the study pathology from Cambridge will 
provide a second review of all specimens to ensure the most accurate quantification of eosinophil counts 
possible. Importantly, no record of the results of the standard endoscopy and biopsies will be provided to 
those assessing the Cytosponge results and these individuals will be masked to all clinical data. Similarly, 
the pathologists interpreting the histological specimens from the endoscopy will have no knowledge of the 
outcomes of the Cytosponge assay. Only the study biostatistician will have access to these data. 
 
In addition, we would plan to perform special staining and analysis of the existing biopsy and sponge 
samples with the goal of determining if the diagnostic accuracy of this test can be improved. In particular 
we will examine markers of eosinophil function, activation, and inflammation, such as eosinophil 
peroxidase (EPX), a granule protein that clearly identifies intact eosinophils, as well as extracellular EPX 
deposition suggestive of degranulation. This can be detected with immunohistochemistry.  
 
Safety and accessibility assessments 
Patients will be assessed at multiple points to determine the safety of the Cytosponge in EoE.  Research 
staff will assess for any symptoms or events as soon as the sponge capsule is swallowed, as well as 
immediately after the expanded sponge is removed.  Subjects will also be contacted 7 days after the 
endoscopy to assess for adverse events. 
 
Primary assessment of acceptability will be via the Impact of Events Scale. This widely used scale was 
developed to assess the distress associated with a specific life event. It includes measures of both the 
intrusiveness of the event, and any avoidance responses by the subject in response to the event. Final 
scores are between 0-75, with low scores demonstrating a low impact of the event. The scale will be 
administrated 7 days after the sampling in order to allow the subjects to have time to reflect on the 
experience and to compare with the EGD. Secondary acceptability outcomes will include a visual analog 
scale of acceptability of the Cytosponge, performed immediately after the Cytosponge is administered 
and again 7 days after. Also, the subject will be asked whether he/she would be willing to repeat the 
assay, and, assuming similar accuracy between Cytosponge and upper endoscopy, whether he/she 
would rather undergo surveillance by Cytosponge or standard EGD with biopsies. 
 

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3.2 Protocol Map 
Patient 
Enrolled
Administration of 
Cytosponge
Standard of care clinical 
biopsies taken during 
standard of care EGD
Cytosponge shipped to 
Mayo Clinic Rochester 
for initial processing
Questionnaire administered 
immediately following Cytosponge:
• Visual Analog Scale
Mayo Clinic Rochester 
ships sponges to 
University of Cambridge 
for additional analysis
Questionnaires administered 7 days after 
procedure:
• Visual Analog Scale
• Impact of Events Scale
• Procedure Preference and 
Acceptability Questionnaire
All questionnaire and study 
Case Report Form (CRF) 
data transmitted  to UNC
Cytosponge assay results 
communicated to UNC 
biostatisticians
Subject returns to enrolling site for 
additional standard of care EGD 
following therapy?
No
Subject 
participation 
complete
Yes
 

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3.3 Primary Outcomes 
The primary outcome variables will be sensitivity and specificity of the cytosponge, as compared against 
the gold standard of the presence of EoE as detected by upper endoscopy with biopsies.  
3.4 Secondary Outcomes 
1. Agreement between cytosponge and endoscopic biopsy as measured by kappa. 
2. Acceptability of cytosponge compared to endoscopy, as rated on visual analog scale. 
3. Acceptability of cytosponge as measured by the Impact of Events Scale. 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Able to read, comprehend, and complete the informed consent form 
2. Male or female subjects, age 18-80 years, 
3. Suspected EoE or has a diagnosis of EoE with current active disease, 
4.2 Exclusion Criteria 
1. History of esophageal stricture precluding passage of the endoscope or sponge, 
2. Pregnancy, or planned pregnancy during the course of the study, 
3. Any history of esophageal varices, liver impairment of moderate or worse severity (Child’s- Pugh 
class B & C) or evidence of varices noted on any past endoscopy, 
4. Any history of esophageal surgery, except for uncomplicated fundoplication 
5. History of coagulopathy, with INR>1.3 and/or platelet count of <75,000. 
6. Current use of blood thinners such as coumadin, warfarin, clopidogrel, heparin and/or low molecular 
weight heparin (requires discontinuation of medication 7 days prior to and 7 days after 
esophagogastroduodenoscopy [EGD] and Cytosponge administration, aspirin use is OK). 
7. Are allergic to local anesthetics such as lidocaine (these subjects may opt not to receive the optional 
lidocaine gargle prior to the Cytosponge administration and still be eligible). 
8. Have not fasted the night before administration of the Cytosponge. 
9. History of perforation. 
 
4.3 Subject Recruitment and Screening 
Potential subjects will be identified prior to or during their GI clinic or procedure visits at their enrolling 
institutions.  All subjects will be screened and enrolled using EC/IRB-approved and HIPAA compliant 
methods.  
 
An investigator, study coordinator, or other qualified personnel will obtain written informed consent prior to 
any study procedures.   Potential subjects will have an opportunity to carefully review the consent form.  
The details of the study will be reviewed verbally, and all questions will be answered to the satisfaction of 
the patient.  Only adults with the ability to consent will be eligible for enrollment in this study.  After the 
subject signs the consent, a copy of the signed consent will be provided to the subject.  Once written 
consent has been obtained, the coordinator will collect demographic and historical information from the 
patient pertaining to history esophageal conditions and procedures received.   
 
The consent process will be documented by the coordinator in the patient’s study file. 
4.4 Early Withdrawal of Subjects 
Subjects will be considered to have completed the study after completion of the last study visit (follow-up 
phone call).  Subjects may be withdrawn prior to this for any of the following reasons: 
• 
Death, or 
• 
Lost to Follow-Up, or 

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• 
Withdrawal of consent, or 
• 
Discontinuation by the investigator. 
 
Documentation must be maintained at the site for any subject withdrawals.  Subjects unable to complete 
Cytosponge administration will be withdrawn from the study (discontinued by investigator).  Three 
attempts at contact using two different methods are required prior to determination that the subject is lost 
to follow-up. Attempts at contact must be with certified letters OR documented telephone contact.  If a 
subject is withdrawn prior to completion of the study, the site should complete and submit a change of 
status case report form.  See section 8.3 for additional information on case report forms.  Subjects who 
withdraw after completion of the initial Cytosponge administration will not be replaced.  Withdrawn 
subjects will not be followed, unless they have an active adverse event (AE) at the time of withdrawal.  
Subjects withdrawn while experiencing an adverse event will be followed until resolution of the AE.   

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5 Study Procedures 
Assessment 
Screening/Enrollment 
Visit 
Follow-Up 
Phone Call 
(7 days +/- 
2 days after 
Enrollment) 
Follow-Up 
Cytosponge 
Administration1 
Follow-Up 
Phone Call 
(7 days +/- 2 
days after 
each follow-
up 
Cytosponge) 
Informed Consent 
Form   
X 
 
 
 
Demographics 
X 
 
 
 
Medical History  
X 
 
 
 
Inclusion/Exclusion 
Criteria  
X 
 
 
 
Cytosponge 
Administration 
X 
 
X 
 
Routine Care 
Endoscopy with 
Biopsy 
X2 
 
X2 
 
Visual   Scale 
X3 
X 
X3 
X 
Impact of Events 
Scale 
 
X 
 
X 
Procedure 
Preference and 
Acceptability 
Questionnaire 
 
X 
 
X 
Adverse Events4 
X 
X 
X 
X 
1 After enrollment, if subjects receive treatment for their EoE and return to the enrolling site for an upper endoscopy 
as part of their standard of care, then subjects will be asked to repeat the Cytosponge procedure prior to each follow-
up standard of care endoscopy. 
2Routine care biopsies should be taken during the endoscopy following the Cytosponge as this is considered 
standard of care for the target population.  No research-specific biopsies will be obtained during the procedure. 
3 The VAS should be administered immediately following completion of the Cytosponge and prior to the upper 
endoscopy. 
4Only those events potentially related to participation in this research study must be reported.  See section 7.2 for 
definition of a reportable adverse event. 
 
5.1 Screening/Enrollment 
During screening/enrollment, eligibility is assessed and those eligible and interested in participating are 
consented on the study.  Once consent is obtained, subjects will undergo administration of the 
Cytosponge, complete a questionnaire and proceed with routine care upper endoscopy immediately 
following completion of the Cytosponge in which biopsies are taken for clinical purposes and sent to 
pathology.  
5.1.1 Assessments 
The following will be completed during the screening/enrollment visit: 
• 
Eligibility review 

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• 
Informed consent 
• 
Cytosponge administration 
• 
Visual Analog Scale 
• 
Adverse event assessment 
• 
Routine care upper endoscopy with biopsy 
• 
Enrollment Case Report Form (CRF):  This captures demographics including race, 
ethnicity, gender, and year of birth, relevant EoE medical history including documentation 
of endoscopic procedures received to date as well as pathology findings and endoscopic 
history related to current diagnosis.  
5.1.2 Consenting Procedure 
If a subject is screened eligible and interested in the study, then the subject will be consented on the 
study prior to any study procedure. Written informed consent will be obtained by qualified study 
personnel.  Documentation of the consent process will be maintained in the subject’s research record. 
 
Subjects will be given ample time to review the consent document and ask any questions they may have.  
A copy of the written consent form will be provided to the subject and the original maintained in the 
subject’s research record.   
 
If subjects meet all inclusion and none of the exclusion criteria and consent to the study, then they will be 
enrolled in the study. Subjects will be assigned a unique subject code.  Each institution will be provided a 
list of subject codes to use.   
5.1.3 Cytosponge Administration 
The CytospongeTM  device (referred to hereafter as the “Cytosponge”) will be supplied by Covidien GI 
Solutions to the participating sites. Study sites will be responsible for storage and accountability of the 
device. The Cytosponge lifetime/use by date will be confirmed on the product packaging. The device 
received FDA 510(k) clearance on November 26, 2014 (K142695).  The Cytosponge device consists of a 
spherical 3.0 cm diameter reticulated polyester foam compressed and encapsulated in a standard 
vegetarian capsule (size 00).  
 
Subjects will undergo administration of the CytospongeTM according to the IFU.  Briefly, subjects will be 
placed in the seated position and will swallow the capsule with 150 – 250 mL of water.  Additional water 
may be used if necessary. The sponge is attached to a length of suture material which passes out 
through the capsule. The suture is affixed to a retainer card which is held by the subject or administrator 
to prevent inadvertent swallowing of the suture.  The string is to be held without tension as peristalsis and 
gravity advance the capsule into the stomach.  
 
The capsule dissolves in the stomach, allowing the sponge to expand to its full size. Seven minutes and 
30 seconds to ten minutes after ingestion, the sponge is then withdrawn by gentle traction on the suture, 
collecting cells from the lining of the esophagus in passing.  
 
After retrieval, the string is cut and the retrieved foam sphere containing the cytological specimen is 
immersed in fixative and stored refrigerated (1° to 12°C [34° to 54°F]) until shipped.  Samples will be 
shipped in batches to the Mayo Clini for initial processing, then batch shipped to the Fitzgerald lab in 
Cambridge for additional analysis.  On arrival at the lab, the fixative is spun in a centrifuge, and the 
pelleted cells are embedded in paraffin using standard techniques. The blocks are sectioned and stained 
and processed with routine H&E staining. 
 
If a subject fails to swallow the Cytosponge, the subject will be asked to swallow again. Subjects who are 
willing to try again will be asked to wait 5 minutes before the Cytosponge is presented to them again. 
Subjects will be able to try up to three times before they are classified as “Cytosponge swallowing failure” 
and discontinued by the investigator. 

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5.1.4 Routine Care Endoscopy with Biopsy 
After Cytosponge administration is complete, subjects will undergo routine care upper endoscopy, with 
assessment of EoE, and biopsy.  During this exam, endoscopic features of EoE will be recorded, 
including rings, furrows, white plaques, decreased vascularity, and strictures.  The severity of the 
endoscopy findings will be measured using the recently validated EREFS scoring system.23  Four 
esophageal biopsies will be taken both from the distal (5 cm above the gastro-esophageal junction) and 
proximal (15 cm above the gastro-esophageal junction) esophagus as part of their standard of care for 
EoE. The clinical tissue biopsies will undergo standard processing and H&E staining at the home 
institution, with assessment by expert gastrointestinal pathologists. 
5.1.5 Adverse Event Assessment 
Subjects should be assessed for any adverse events that occur before, during, or after Cytosponge 
administration.  Only those events that are potentially related to participation in this research study must 
be reported to the lead site.  See section 7.2 for the definition of a reportable adverse event.  Sites are 
responsible for following local IRB/EC guidelines for reporting adverse events to their local IRB/EC. 
5.2 Follow-Up Phone Call 
Subjects will be contacted 7 days (+/- 2 days) following the Cytosponge and upper endoscopy 
procedures.  During this phone call, adverse events will be assessed and subjects will complete 
questionnaires.   
5.2.1 Assessments 
The following data will be collected from subjects during the follow-up phone call: 
• 
Visual Analog Scale 
• 
Impact of Events Scale 
• 
Procedure Preference and Acceptability Questionnaire 
• 
Adverse event assessment 
• 
Follow-Up Case Report Form (CRF):  This captures relevant information for questionnaire 
completion and assessment of adverse events. 
5.2.2 Impact of Events Scale 
The impact of events scale will be completed with the subjected during the follow-up phone call and 
measures subjective distress related to administration of the Cytosponge.  
5.2.3 Procedure Preference and Acceptability Questionnaire 
The procedure preference and acceptability questionnaire will be completed with the subject during the 
follow-up phone call.  This assessment collects subject preference for the Cytosponge or traditional upper 
endoscopy as well as willingness to undergo the procedure again. 
5.2.4 Follow-up Phone Call Adverse Event Assessment 
During the follow-up phone call, subjects should be assessed for any adverse events that have occurred 
since administration of the Cytosponge.  Only those events that are potentially related to participation in 
this research study must be reported.  See section 7.2 for the definition of a reportable adverse event.  
Sites are responsible for following local IRB/EC guidelines for reporting adverse events to their local 
IRB/EC. 
5.3 Follow-Up Cytosponge Administration 
After enrollment, if subjects receive treatment for their EoE and return to the enrolling site for an upper 
endoscopy as part of their standard of care, then subjects will be asked to repeat the Cytosponge 
procedure prior to each follow-up standard of care endoscopy. 
 

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Patients will be followed and tissue will be assessed over time with both Cytosponge and routine care 
endoscopy; samples will be taken at up to 6 time points. 
 
5.3.1 Assessments 
The following will be completed during each follow-up Cytosponge administration 
• 
Re-affirmation of consent 
• 
Cytosponge administration 
• 
Visual Analog Scale 
• 
Adverse event assessment 
• 
Routine care upper endoscopy with biopsy 
• 
Follow-Up Case Report Form (CRF):  This captures demographics including race, 
ethnicity, gender, and year of birth, relevant EoE medical history since enrollment 
including documentation of endoscopic procedures received,  pathology findings and EoE 
treatment(s) received since enrollment.  
5.4 Follow-Up Phone Call 
Subjects will be contacted 7 days (+/- 2 days) after the follow-up Cytosponge and upper endoscopy 
procedures.  During this phone call, adverse events will be assessed and subjects will complete 
questionnaires.  The same assessments are completed during the follow-up phone call following a follow-
up Cytosponge administration as were completed during the initial Cytosponge administration.  See 
section 5.2 for details. 
5.5 Subject Participation Completion 
Subject participation is considered complete when the subject no longer returns to the enrolling site for 
clinical care of their condition, or prior to that time if the subject withdraws for any reason (see section 
4.4). 
 
6 Statistical Plan 
6.1 Sample Size Determination 
With 60 subjects enrolled for Aim 1, we will be able to detect a correlation between the Cytosponge and 
endoscopy eosinophil counts as low as R = 0.40 with a power of 0.9 and an alpha of 0.05.  This sample 
size would also have a power of 0.8 to detect an agreement (kappa) of as low as 0.7 (compared to a null 
of 0.4). 
 
We will allow for enrollment up to 150 subjects across both sites to account for any potential issues with 
sample quality and additional safety assessments. 
6.2 Statistical Methods 
Aim 1:  To test the hypothesis that the Cytosponge accurately quantifies esophageal eosinophil counts in 
patients with active EoE, the maximum eosinophil counts from the Cytosponge and endoscopic biopsy 
will be compared by calculating the Pearson coefficient of correlation.  In addition, patients will be 
categorized as having an eosinophil count either above or below 15 eos/hpf (the current diagnostic 
threshold).  Agreement between patients above and below this threshold for Cytopsponge and 
endoscopic biopsy will be measured using the kappa statistic. If eosinophil counts are not normally 
distributed, non-parametric methods will be used.  Separate analyses will be performed for patients with 
active EoE and patients undergoing treatment. 
 
Aim 2:  Summary statistics will be calculated to describe adverse events and the tolerability of the 
Cytosponge.  The proportion of subjects who prefer the Cytosponge will be calculated. 
 

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We predict that the Cytosponge will be safe and well-tolerated in patients with EoE, and that they will 
prefer this minimally invasive method to endoscopy with biopsy.  We also predict that the eosinophil 
counts obtained with Cytosponge will strongly correlate with the counts from endoscopy with biopsy in 
both patients with active EoE. 
6.3 Subject Population for Analysis 
The population whose data will be subjected to the study analysis will include all subjects enrolled in this 
study that completed the Cytosponge administration and have pathology results available from the 
subsequent routine care endoscopy with biopsy. 
7 Safety and Adverse Events 
7.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research, 
• Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.  They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 

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The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following completion of the biomarker panel.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
7.2 Reportable Adverse Events 
For this study, only those events that are related to participation in the study must be reported.  This 
includes events related to: 
• 
Cytosponge administration 
• 
Questionnaire administration 

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• 
Any adverse event that may be related to participation in this study or use of the Cytosponge 
device (possibly, probably, or definitely related)  
• 
Any adverse event in which the Cytosponge may have caused or contributed to the event. 
• 
Any event required to be reported to the FDA and/or manufacturer per 21CFR803 including: 
o 
Device-related deaths; 
o 
Device-related serious injuries. 
 
***Deaths due to the expected progression of disease do not need to be reported as adverse events but 
should be reported as an outcome for the patient. 
7.2.1 Reporting Timeline 
Serious adverse events (meeting the definition of a reportable AE) or unanticipated problems involving 
risk to subjects or others must be reported within 24 hours of learning of the event.  To report such 
events, sites must complete the Reportable Event case report form.  In addition to completion of the CRF, 
sites must also fax or email the form to +1 919 843-2508 or cedas@med.unc.edu. If for any reason the 
form cannot be completed within 24 hours, a phone call should be made to the lead site +1 919 966-7655 
to meet the reporting timeline. In the case of a telephone report, sites must still complete the reportable 
event form at the earliest possible opportunity, and no later than 72 hours following learning of the event.   
 
All other reportable events should be reported within 15 days of learning of the event. 
7.2.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events possibly related to the study that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the study procedures 
or study participation should be recorded and reported immediately. 
7.2.3 Reporting Adverse Events to Lead Site 
All adverse events that meet the criteria of a “reportable” adverse event as described in section 7.2 above 
must be reported by completing the reportable event form and entering in the study database. 
 
All events will be reported using the National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  A quick reference guide can be accessed from the following website: 
http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf 
7.2.3.1 
Initial Report 
If a patient experiences an event that should be reported as described in section 7.2 the site should 
complete and submit a reportable event form. 
 
If a patient experiences more than one event, sites should report each event using a separate reportable 
event form.   
7.2.3.2 
Follow-Up Reports 
All reported adverse events should be followed until resolved or a reason documented if resolution will not 
occur.  Any new information or updates to a previously reported event should be reported as a follow-up 

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to the event.  To report a follow-up to an event, sites will update the previously completed electronic 
reportable event CRF.  
7.2.4 Reporting Adverse Events to Local EC/IRBs 
Investigators must conform to the adverse event reporting timelines, formats and requirements of the 
various entities to which they are responsible.  All investigators are responsible for safety reporting to 
their local institutional review board (IRB) or ethics committee (EC).  Investigators are responsible for 
complying with their local EC/IRB’s reporting requirements, though must submit the required reports to 
their IRB no later than 10 working days.  Copies of each report and documentation of IRB notification and 
receipt will be kept in the investigator’s files.  The definition of a reportable event for a local EC/IRB may 
not be the same as the definition used for this pilot study. 
7.2.5 Notifying the FDA 
The facility/institution and device manufacturer are required to report events to the FDA as defined per 
21CFR803 (medical device reporting).   
1. Reports of death. Facilities must submit a report to the FDA as soon as practicable but no more 
than 10 work days after the day that you become aware of information, from any source, that 
reasonably suggests that the device has or may have caused or contributed to the death of a 
patient of your facility.  Facilities and institutions must report the following to the FDA via an FDA 
MEDWATCH Form 3500A (this form can be completed on paper or submitted electronically. You 
may obtain this form from http://www.fda.gov/medwatch/getforms.htm. 
2. Reports of serious injury. Facilities must submit a report to the manufacturer of the device no later 
than 10 work days after the day that you become aware of information, from any source, that 
reasonably suggests that a device has or may have caused or contributed to a serious injury to a 
patient of your facility. 
Facilities and manufacturers are responsible for all other FDA reporting requirement per 21CFR803 
including semi-annual reporting. For additional guidance on reporting to the FDA including where to send 
reports please visit:  
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm. 
 
To review 21CFR803 please visit: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=803&showFR=1   
7.2.6 Lead Site Reporting to Participating Investigators 
It is the responsibility of the lead site (UNC) to notify all participating investigators of any adverse event 
associated with the study that is both serious and unexpected.   
7.3 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. 
8 Data Handling and Record Keeping 
8.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 

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• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
8.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
8.3 Case Report Forms  
This study will utilize paper case report forms (CRFs).  The study case report form (CRF) is the primary 
data collection instrument for the study.  All data requested on the CRF must be recorded.  All missing 
data must be explained.  If a space on the CRF is left blank because the procedure was not done or the 
question was not asked, this should be documented in the comments field.   
8.3.1 Case Report Form Completion Table 
Form 
Screening/Enrollment 
Follow-
Up 
PRN  
(As 
Needed) 
Enrollment CRF   
X 
 
 
Follow-Up CRF  
 
X 
 
Reportable Event CRF 
 
 
X 
Change of Status CRF 
 
 
X 
8.4 Records Retention 
The data compiled in this study will be stored for a period of at least 2 years following study termination. 
9 Study Monitoring, Auditing, and Inspecting 
9.1 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC, IRB, the sponsor, 
the lead site, government regulatory bodies, and University compliance and quality assurance groups of 
all study related documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.).  The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 

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10 Ethical Considerations 
This study is to be conducted according to the International Conference on Harmonisation Good Clinical 
Practice (ICH/GCP) as well as US federal  regulations (21 CFR parts  803, 812, and 45CFR46), as well 
as all applicable local and state government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor-investigator, 
Dr. Evan Dellon, before commencement of this study.  The investigator should provide a list of EC/IRB 
members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  Sample 
consent forms will be provided by the lead site.  These consent forms include a consent for the study as 
well as a consent for storage of samples for future use. All consent forms will be submitted with the 
protocol for review and approval by the EC/IRB for the study.  The formal consent of a subject, using the 
EC/IRB-approved consent form, must be obtained before that subject undergoes any study procedure.  
The consent forms must be signed by the subject or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.  
11 Study Finances 
11.1 Funding Source 
This study is funded by the CURED (Campaign Urging Research for Eosinophilic Disease) 
Foundation. 
11.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study.  All University of 
North Carolina investigators will follow the University conflict of interest policy. 
12 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the lead investigator, Dr. Evan Dellon.  Any investigator 
involved with this study is obligated to provide the lead investigator with complete test results and all data 
derived from the study. 

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