Non-Endoscopic Surveillance for Barrett's Esophagus Following Ablative Therapy
Phase: NA
Conditions: Barrett's Esophagus
Sponsor: University of North Carolina, Chapel Hill

 
CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
NON-ENDOSCOPIC SURVEILLANCE FOR BARRETT’S 
ESOPHAGUS FOLLOWING ABLATIVE THERAPY 
 
 
 
 
 
Principal Investigator 
Nicholas J. Shaheen, MD, MPH 
Professor of Medicine and Epidemiology 
Director, Center for Esophageal Diseases and Swallowing 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Phone: (919) 966-7047 
Fax: (919) 843-2508 
Email: nicholas_shaheen @med.unc.edu 
 
Co-Investigators 
Rebecca C. Fitzgerald, MA, MD 
Cambridge University 
Cambridge, U.K. 
Funding Sponsor: 
National Institutes of Health (NIH) 
Covidien GI Solutions now part of Medtronic 
UNC IRB Number: 
13-2618 
Protocol Version: 
1.0 
Protocol Version Date: 
 
National Clinical Trial 
Number: 
08 December 2015 
 
 
NCT02106910 
 
 
 
 
 
 
 

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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: Nicholas Shaheen, MD, MPH 
 
Title: Principal Investigator, Professor of Medicine and Epidemiology 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 3 
1.1 
BACKGROUND ................................................................................................................................ 3 
1.2 
RATIONALE .................................................................................................................................... 4 
1.3 
DEVICE DESCRIPTION ..................................................................................................................... 7 
1.3.1 
Prior Utilization ........................................................................................................................ 7 
2 
STUDY OBJECTIVES ......................................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................................... 8 
3.1 
GENERAL DESIGN .......................................................................................................................... 8 
3.2 
PROTOCOL MAP ........................................................................................................................... 10 
3.3 
PRIMARY OUTCOMES ................................................................................................................... 11 
3.4 
SECONDARY OUTCOMES .............................................................................................................. 11 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 11 
4.1 
INCLUSION CRITERIA .................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 11 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .............................................................................................. 12 
5 
STUDY PROCEDURES ..................................................................................................................... 13 
5.1 
SCREENING/ENROLLMENT ............................................................................................................ 13 
5.1.1 
Assessments ......................................................................................................................... 13 
5.1.2 
Consenting Procedure ........................................................................................................... 14 
5.1.3 
Cytosponge Administration ................................................................................................... 14 
5.1.4 
Routine Care Endoscopy with Biopsy ................................................................................... 14 
5.1.5 
Adverse Event Assessment .................................................................................................. 15 
5.2 
FOLLOW-UP PHONE CALL ............................................................................................................ 15 
5.2.1 
Assessments ......................................................................................................................... 15 
5.2.2 
Impact of Events Scale .......................................................................................................... 15 
5.2.3 
Procedure Preference and Acceptability Questionnaire ....................................................... 15 
5.2.4 
Follow-up Phone Call Adverse Event Assessment ............................................................... 15 
5.3 
REPEAT CYTOSPONGE ADMINISTRATION ....................................................................................... 15 
6 
STATISTICAL PLAN ......................................................................................................................... 15 
6.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 15 
6.2 
STATISTICAL METHODS ................................................................................................................ 16 
6.3 
SUBJECT POPULATION FOR ANALYSIS ........................................................................................... 16 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 16 
7.1 
DEFINITIONS ................................................................................................................................ 16 
7.2 
REPORTABLE ADVERSE EVENTS ................................................................................................... 18 
7.2.1 
Reporting Timeline ................................................................................................................ 18 
7.2.2 
Recording of Adverse Events ................................................................................................ 18 
7.2.3 
Reporting Adverse Events to Lead Site ................................................................................ 19 
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 ................................................................ 20 
7.3 
MEDICAL MONITORING ................................................................................................................. 20 
8 
DATA HANDLING AND RECORD KEEPING ................................................................................... 20 
8.1 
CONFIDENTIALITY ......................................................................................................................... 20 

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8.2 
SOURCE DOCUMENTS .................................................................................................................. 20 
8.3 
CASE REPORT FORMS ................................................................................................................. 20 
8.3.1 
Case Report Form Completion Table ................................................................................... 21 
8.4 
RECORDS RETENTION .................................................................................................................. 21 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 21 
9.1 
AUDITING AND INSPECTING ........................................................................................................... 21 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 21 
11 
STUDY FINANCES ............................................................................................................................ 22 
11.1 
FUNDING SOURCE ........................................................................................................................ 22 
11.2 
CONFLICT OF INTEREST ................................................................................................................ 22 
12 
PUBLICATION PLAN ........................................................................................................................ 22 
13 
REFERENCES ................................................................................................................................... 23 
 

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List of Abbreviations  
  
Item 
Definition 
BE 
Barrett's Esophagus 
eCRF 
Electronic Case Report Form 
EAC 
Esophageal Adenocarcinoma 
EC 
Ethics Committee 
EGD 
Esophagogastroduodenoscopy 
EMR 
Endoscopic Mucosal Resection 
HGD 
High grade dysplasia 
IMC 
Intramucosal Carcinoma 
IRB 
Institutional Review Board 
LGD 
Low grade dysplasia 
PDT 
Photodynamic Therapy 
RFA 
Radiofrequency Ablation 
 
 
 
 
 
 
 
 

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Study Summary 
Title 
Non-Endoscopic Surveillance for Barrett’s Esophagus Following Ablative Therapy  
Methodology 
This is a cross-sectional study of subjects with dysplastic Barrett’s Esophagus (BE) 
who have undergone successful endoscopic ablation with radiofrequency ablation 
(RFA), to assess the utility of the Cytosponge assay as a non-endoscopic method for 
monitoring the post-ablation patient. In addition, we will enroll a small cohort of up to 
50 subjects with a current diagnosis of BE to collect pilot data for a larger scale study.  
 
Subjects presenting to UNC Hospitals for routine endoscopic examinations for current 
BE or after successful ablation will be offered enrollment in the study. After informed 
consent, and the same day as the endoscopic procedure, the subject will undergo 
administration of the Cytosponge assay and complete a questionnaire. The subject will 
then undergo routine endoscopic surveillance, using a standard Seattle biopsy 
surveillance protocol. The Cytosponge will be placed in fixative and shipped to the 
Fitzgerald laboratory for processing according to their established protocols. If the 
Cytosponge tissue specimen is inadequate, the patient will be recalled for a repeat 
sponge procedure (not endoscopy) 30 days later. Routine care tissue biopsies will 
undergo standard processing and H&E staining, with assessment by expert 
gastrointestinal pathologists.  Subjects will be contacted via phone 7 days (+/- 2 days) 
after Cytosponge administration to complete additional questionnaires. 
Study Duration 
5 Years 
Study 
Center(s) 
University of North Carolina, Chapel Hill, NC 
Objectives 
Primary objective: 
To assess the acceptability of a novel, minimally invasive esophageal mucosal 
sampling technique, the Cytosponge, in subjects undergoing surveillance after 
radiofrequency ablation. Based on previous data, we hypothesize that the sponge-
based sampling technique will be associated with low levels of patient distress, and will 
be preferred by patients, when compared to standard sedated upper endoscopy, for 
surveillance of their esophageal mucosa. 
 
Secondary objective: 
To assess the operating characteristics of this technique against a gold standard of 
upper endoscopy with biopsies for endoscopic surveillance in subjects with a history of 
successful radiofrequency ablation for dysplastic BE. We hypothesize that the assay 
will demonstrate both a sensitivity and specificity of >90% in the detection of recurrent 
BE following radiofrequency ablation. Further, we expect higher accuracy in those with 
a larger burden of recurrent disease. 
Number of 
Subjects 
374 (324 Post-ablation, 50 BE) 

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Diagnosis and 
Main Inclusion 
Criteria 
Inclusion Criteria: 
1. Male or female subjects, age 18-80 years, 
2. Meets the following: 
2.1. Previous diagnosis of BE with dysplastic LGD or HGD, as evidenced by both 
classical endoscopic appearance of salmon-colored mucosa in the tubular 
esophagus, as well as endoscopic biopsies from the involved areas 
demonstrating columnar metaplasia with goblet cells. The diagnosis of 
dysplasia must have been confirmed by a second expert pathologist. Previous 
EMR of focal nodular HGD or superficial intramucosal cancer (IMC) is 
allowable, as long as the EMR specimen shows complete resection of any 
IMC with clear margins, and biopsies following ablation confirm excision of the 
lesion, AND 
2.1.1. A history of complete eradication of both dysplasia and intestinal 
metaplasia by radiofrequency ablation. Complete eradication is defined 
as a normal endoscopic appearance of the tubular esophagus, and 
histologic confirmation by biopsies in 4 quadrants every cm from 
throughout the length of the previous BE (post-RFA cohort).OR 
2.2. Current diagnosis of BE, presenting for routine care endoscopy (BE cohort). 
3. Good general health, with no severely debilitating diseases, active malignancy, or 
condition that would interfere with study participation. 
 
Exclusion Criteria: 
1. 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). 
2. Known bleeding disorder 
3. For the post-RFA cohort, prior ablative therapy of the esophagus other than 
radiofrequency ablation (RFA), including photodynamic therapy (PDT), more than 
one session of spray cryotherapy, and any other ablation therapies is exclusionary. 
However, prior endoscopic mucosal resection (EMR) is acceptable and up to two 
prior treatments of thermal/coagulation therapy (other than RFA) for focal residual 
disease following otherwise successful RFA therapy is acceptable. The BE cohort 
must be treatment naive and have no history of ablation, but prior EMR is 
acceptable. 
4. History of esophageal stricture precluding passage of the endoscope or sponge, 
5. Pregnancy, or planned pregnancy during the course of the study, 
6. 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, 
7. Any history of esophageal surgery, except for uncomplicated fundoplication, and, 
8. History of coagulopathy, with INR>1.3 and/or platelet count of <75,000. 
9. Planned ablation therapy within 3 days of Cytosponge administration (endoscopic 
mucosal resection and submucosal dissection is OK). 

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Statistical 
Methodology 
For the primary objective, to assess the acceptability of the novel mucosal sampling 
technique in subjects after successful ablation, we will assess the distribution of Impact 
of Events Scale scores, and the intrusiveness and avoidance subscales. We will 
generate measures of central tendency and distribution of these data. Bivariate 
analysis will be performed to assess for predictors of low tolerance of Cytosponge 
surveillance, and a logistic regression model created to assess these factors while 
controlling for potential confounders. Data will be compared to population norms using 
parametric statistics.  VAS scores will be calculated, and measures of central tendency 
and distribution reported. 
 
Subjects’ preferences for Cytosponge vs. endoscopic surveillance, as well as 
willingness to undergo the procedure again, will be measured as proportions, with 
bivariate and multivariate analyses for predictors of preference performed. 
 
For the secondary objective, to assess the operating characteristics of Cytosponge 
against a gold standard of upper endoscopy, initially 2x2 tables will be constructed 
demonstrating Cytosponge and the gold standard findings (Y/N for BE). Sensitivity, 
specificity, positive predictive value, negative predictive value and accuracy will be 
calculated. Because Cytosponge positivity may vary based on the burden of BE, we 
will perform sensitivity analyses, defining “positive” cases as those with recurrent BE of 
≥1 cm in length, and then ≥2 cm in length, to assess impact of disease burden on 
operating characteristics. Multivariate models controlling for age, sex, period of time 
from last ablation, burden of residual disease, and other potential confounders will be 
constructed, to assess the impact of these factors on test accuracy. Although we do 
not expect to see an association between the degree of dysplasia and Cytosponge 
positivity, exploratory analyses will be performed using degree of dysplasia as a 
predictor variable, and Cytosponge positivity as the outcome variable. 
 
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 Background 
Barrett’s esophagus (BE) is a premalignant condition associated with the development of esophageal 
adenocarcinoma (EAC). BE is an extremely common condition, and 1-2% of the general adult population 
harbor this lesion. In the majority of such subjects, the condition will be indolent, and EAC will not 
develop. However, in <5% of these subjects, BE will progress to EAC. If BE does progress, it is thought to 
do so through worsening degrees of dysplasia, from no dysplasia, to low-grade dysplasia (LGD), to high-
grade dysplasia (HGD) and on to EAC. The prognosis of EAC is dismal, with a <15% five year survival. 
For that reason, endoscopic intervention is suggested in the setting of dysplastic BE to avert the 
development of cancer. 
 
Radiofrequency ablation (RFA) is a safe and effective method for inducing reversion of BE to 
neosquamous epithelium. RFA is associated with a >90% risk reduction of EAC in the setting of 
dysplastic BE. However, BE recurs in as many as a quarter of subjects by 36 months following successful 
RFA. For this reason, surveillance endoscopy is recommended following RFA with complete eradication 
of intestinal metaplasia. Because this surveillance endoscopy is performed at frequent intervals (every 3-
12 months), these procedures obligate the patient to recurrent risks associated with sedation and upper 
endoscopy, and the inconvenience of these exams. Importantly, the costs associated with this effort 
greatly impact the cost-effectiveness of RFA treatment. 
 

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A minimally-invasive, sponge-based technique for sampling the esophageal mucosa, the Cytosponge, 
has recently been described. This simple device is comprised of an abrasive sponge encapsulated in a 
gelatin coating, which is attached to a string. The subject ingests the capsule, which dissolves after a 
short exposure to gastric secretions. The sponge, now freed from the capsule, is drawn back through the 
hiatus and distal esophagus and out of the mouth by the string, sampling cardiac and esophageal 
epithelium. The resulting sample is immunostained for trefoil factor 3, a marker both sensitive and specific 
for the presence of BE. Preliminary work from collaborators in the U.K. demonstrates high sensitivity and 
specificity of this assay for detecting BE. 
 
This is a comparative effectiveness study to assess the utility of this technique in endoscopic surveillance 
of patients with BE following successful RFA. The central hypothesis of this work is that this novel 
surveillance tool could supplant upper endoscopy in subjects having undergone RFA for BE, providing 
less invasive and more cost-effective surveillance of this large and growing patient population. 
1.2 Rationale 
Esophageal adenocarcinoma is a lethal cancer with a rapidly increasing incidence.  In stark contrast to 
recent progress in other solid tumors, incidence and death rates from esophageal adenocarcinoma 
continue to rise rapidly in the U.S. There has been a 500% increase in the incidence of esophageal 
adenocarcinoma (EAC) from the 1970’s to 
the 1990’s,1 and a near-parallel increase in 
mortality (Figure 1),  underscoring the need 
for more effective prevention and treatment 
for 
this 
lethal 
cancer. 
Esophageal 
adenocarcinoma is thought to develop 
through a series of metaplastic, then 
dysplastic, changes of the mucosa.2 Chronic 
gastroesophageal reflux (GERD) precipitates 
a metaplastic change from the normal 
squamous epithelium, to a more acid-
resistant columnar histology.3 When this 
columnar epithelium contains goblet cells, it 
is 
termed 
specialized 
or 
intestinalized 
metaplasia. When endoscopically evident, 
columnar metaplasia with goblet cells in the 
esophagus is termed Barrett’s esophagus 
(BE).4,5 
 
 
Barrett’s esophagus is the strongest risk factor for esophageal adenocarcinoma. BE is associated with a 
risk of esophageal adenocarcinoma that is 40-120 times that of the general population.6,7 Furthermore, 
BE is an extremely common condition, present in approximately 10% of subjects with chronic GERD,8 
and 1-2% of the general population.9 Since 10- 20% of adult Americans have at least weekly symptoms of 
GERD,10,11the number of cases of BE in the U.S. is thought to be >2 million.22 BE does not generally 
spontaneously regress; barring an intervention, the patient will have BE for life. Most subjects harboring 
BE will not progress to EAC. However, in a proportion (0.2-0.5%/year,)2,12 the metaplastic tissue will 
progress from low-grade dysplasia (LGD) to high-grade dysplasia (HGD), culminating in EAC.13,14 Given 
the poor prognosis of cancer diagnosed symptomatically,15,16 current effort is directed toward early 
detection and treatment. Current strategies for prevention of EAC focus on endoscopic screening and 
surveillance.17 In the approach most commonly used in the U.S., subjects with chronic heartburn are 
offered a screening endoscopy to assess for BE. Patients found to have BE are then enrolled in 
endoscopic surveillance, consisting of periodic endoscopy at intervals governed by the presence of 
dysplasia.24 In current American College of Gastroenterology guidelines,4 subjects with BE and no 
dysplasia undergo endoscopy every 3 yrs. Subjects with BE and LGD have endoscopy yearly. Subjects 
with BE and HGD are effectively managed with endoscopic therapy,18 but may also opt for 
esophagectomy or continued surveillance. Endoscopic exams for GERD and BE are common and costly, 
Figure 1 Incidence (top curve) and mortality 
(lower) from esophageal adenocarcinoma33 
Incidence 
Mortality 

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with over 330,000 exams/year in Medicare patients alone,19 and an average total cost in ambulatory care 
centers of >$2,000/exam,20 making for $660M in endoscopy costs in the Medicare population alone 
annually. 
 
Endoscopic ablation induces reversion of Barrett’s Esophagus and decreases progression of disease. 
Due to the increasing incidence of EAC and the poor prognosis once cancer has developed, endoscopic 
ablative therapies are commonly employed in subjects with dysplastic BE. In the most commonly used 
approach, radiofrequency ablation (RFA), high radiofrequency waves, are delivered by an endoscopic 
balloon covered with an electrode array, to cause 
epithelial destruction (Figure 2). Because of the regular 
spacing of the electrodes, and the delivery of a pre-set 
amount of energy, the depth of injury is well-controlled 
and reproducible. Data from our center and others 
demonstrates that RFA is highly effective in inducing 
reversion to squamous epithelium in subjects with 
dysplastic BE.21–23 Additionally, data suggest that 
subjects with dysplastic BE who have undergone 
ablative therapy with RFA are less likely to progress to 
either more severe dysplasia or adenocarcinoma.24 For 
these 
reasons, 
the 
newest 
societal 
guidelines 
recommend endoscopic ablative therapy for subjects 
with HGD.18 Further, RFA is cited as a preferred 
endoscopic ablative therapy for these subjects. Not 
surprisingly, RFA has become the predominant method for ablation of BE in the U.S., and to date, over 
100,000 of these procedures have been performed in the U.S. (personal communication, D. Utley, CMO, 
GI Solutions). 
 
Recurrence of BE following ablative therapy. Early enthusiasm for endoscopic ablative therapy was 
stoked by the hope that, in addition to being an effective anti-neoplastic measure, successful ablation 
might allow elimination of surveillance upper endoscopy afterward. Because periodic upper endoscopy is 
used frequently in these subjects (every 3-12 months, depending on the baseline degree of dysplasia),24 
omission of these examinations would result in substantial healthcare savings, and would reduce risk and 
inconvenience to patients. Unfortunately, data demonstrate a risk of recurrence of BE following 
successful eradication. Recent data published by the candidate and colleagues from the AIM Dysplasia 
study demonstrate that approximately 25% of subjects who experience successful eradication of 
dysplastic BE will develop recurrent BE, almost all in the first year following successful therapy (Figure 
3).24 While most of these recurrences are non-dysplastic BE, dysplastic BE and even adenocarcinoma 
have been noted to occur after endoscopic ablative therapy.25 Therefore, following successful endoscopic 
ablation, patients receive ongoing endoscopic surveillance. Current post ablation surveillance practices 
are governed by expert opinion, but reported intervals are frequent (every 3-12 months), and involve a 
copious number of biopsies. The cost and frequency of these examinations impacts the cost-
effectiveness of ablative therapy 
for BE.26 Additionally, each of 
these examinations imparts a 
small, but real risk to the 
patient.27 There is substantial 
inconvenience 
and 
negative 
impact 
in 
quality 
of 
life 
associated with enrollment in 
endoscopic 
surveillance 
programs,28 especially since the 
center performing the ablation 
may be far removed from the 
patient’s home, and because 
currently most exams are done 
Figure 2 Circumferential Ablation Catheter 
Figure 3 Durability of Eradication of IM34 

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under sedation, requiring both a day missed from work and an accompanying driver for transportation 
home. Because the number of subjects having undergone RFA in the U.S is now large, and continuing to 
rise, this is a substantial and growing healthcare cost. 
 
A novel non-endoscopic technique as a potential surveillance tool after successful endoscopic ablation. 
Given the large number of patients with chronic GERD and BE, and the expense and inconvenience of 
endoscopic examinations for BE, investigators have sought less expensive, non-endoscopic modalities of 
assessing patients for BE. Early attempts using a non-endoscopic balloon demonstrated inadequate 
sensitivity, in part due to inadequate cytological samples.29 More recently, a simple, non-endoscopic 
device, termed the Cytosponge, has been developed for endoscopic screening of subjects at risk for BE 
by investigators at the University of Cambridge in the U.K. The Cytosponge is an ingestible gelatin 
capsule enclosing a compressed spherical mesh 
of 3 cm diameter, the center of which is attached 
to a string (Figure 4). The capsule and string are 
swallowed with water. The string is held at the 
mouth without tension, allowing the capsule to 
move into the stomach. After 5 minutes (during 
which the gelatin capsule dissolves and the 
sponge is liberated), the sponge is withdrawn by 
gentle traction on the string. The sponge is placed 
in fixative for 48 hours, then the cells are pelleted, 
and processed into paraffin blocks. The pellets 
are immunostained with trefoil factor 3, which is 
interpreted simply as either positive or negative by 
the presence of any staining. In a recent study of 
504 subjects with chronic GERD symptoms in the 
U.K. who underwent both Cytosponge analysis 
and 
upper 
endoscopy, 
the 
Cytosponge 
demonstrated a sensitivity of 90% and a 
specificity of 94% for the detection of BE (Prague 
classification C2 or more).30 Follow-up work with an additional 334 subjects (186 controls, 148 BE) 
demonstrated similar results, with a sensitivity of 84% and a specificity of 92% (data courtesy of Rebecca 
Fitzgerald, MA(Cantab),MD). These results suggest that the Cytosponge may have suitable operating 
characteristics to serve as a surveillance tool in subjects with BE or dysplastic BE who have undergone 
ablative therapy. 
 
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 5).  Because we seek to assess a tool for 
widespread clinical usage, this study will use the 
Cytosponge provided by Covidien GI Solutions 
(now part of Medtronic).   
 
 
 
Figure 4 Cytosponge 
Figure 5 CytospongeTM (left) and Cytosponge I 
(right) 
for 
comparisonCytospongeTM 
(left) 
and 
Cytosponge I (right) for comparison 

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1.3 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 per 21CFR812.2. 
 
1.3.1 Prior Utilization 
Dr. Fitzgerald and colleagues administered Cytosponge 
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 complications have been reported with this 
device, there are several theoretical 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 
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,  
• 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. 
Figure 6 Cytosponge with planned packaging 
and retrieval cord 

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Importantly, all patients enrolled in this study will have previously and recently received an upper 
endoscopy during which absence of findings putting the subject at higher risk for these theoretical 
concerns (conditions such as varices and stricture) will be documented.  
 
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 
Primary objective: 
To assess the acceptability of a novel, minimally invasive esophageal mucosal sampling technique, the 
Cytosponge, in subjects undergoing surveillance after radiofrequency ablation. Based on previous data, 
we hypothesize that the sponge-based sampling technique will be associated with low levels of patient 
distress, and will be preferred by patients, when compared to standard sedated upper endoscopy, for 
surveillance of their esophageal mucosa. 
 
Secondary objective: 
To assess the operating characteristics of this technique against a gold standard of upper endoscopy with 
biopsies for endoscopic surveillance in subjects with a history of successful radiofrequency ablation for 
dysplastic BE. We hypothesize that the assay will demonstrate both a sensitivity and specificity of >90% 
in the detection of recurrent BE following radiofrequency ablation. Further, we expect higher accuracy in 
those with a larger burden of recurrent disease. 
3 Study Design 
3.1 General Design 
This is cross-sectional study of subjects with dysplastic BE who have undergone successful endoscopic 
ablation with RFA, to assess the utility of the Cytosponge assay as a non-endoscopic method for 
monitoring the post-ablation patient. In addition, we will enroll a small cohort of up to 50 subjects with a 
current diagnosis of BE to collect pilot data for a larger scale study. Subjects presenting to UNC Hospitals 
for routine endoscopic examinations for current BE or after successful ablation will be offered enrollment 
in the study. After informed consent, and the same day as the endoscopic procedure, the subject will 
undergo administration of the Cytosponge assay. The patient will then undergo routine endoscopic 
surveillance, using a standard Seattle biopsy surveillance protocol. The Cytosponge will be placed in 
fixative and shipped to the Fitzgerald laboratory for processing according to their established protocols. 
Tissue biopsies will undergo standard processing and H&E staining, with assessment by expert 
gastrointestinal pathologists at UNC. The primary outcome variables will be sensitivity and specificity of 
the novel assay, compared against the gold standard of the presence of recurrent BE as detected by 
upper endoscopy with biopsies. Secondary outcomes include acceptability of the nonendoscopic assay to 
the patient (assessed by a standardized tool, the Impact of Events Scale, as well as a visual analogue 
scale), and likelihood of assay positivity as a function of amount of residual disease (as measured by 
Prague criteria). 
 

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If the initial administration of the Cytosponge demonstrates an inadequate sample, defined as a sample 
that does not demonstrate at least one columnar cell on hematoxylin & eosin staining, repeat Cytosponge 
administration will be performed at 30 days (+/- 10 days) from the initial administration. 
 
Subject recruitment will be from consecutive eligible patients presenting for routine care surveillance 
endoscopy of current BE or following endoscopic ablation of BE.  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 one hour 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. Following Cytosponge 
assay, subjects will complete the procedure acceptability measures described below. Subjects will then 
attend their usual surveillance endoscopy session. Upper endoscopy will be performed and biopsies 
taken as part of routine care. 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. 
 
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 
analogue scale of acceptability of the Cytosponge, performed after the Cytosponge is administered. 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. 
 
There are no plans for repeat testing or duplicate enrollment. Enrolled subjects will be administered the 
cytosponge one time, on the date of an endoscopy scheduled for routine care, prior to the endoscopy. 
Subjects can only participate one time. The only exception is for subjects who have an inadequate 
sample on the initial Cytosponge.  These subjects will be asked to return for repeat Cytosponge 
administration 30 days (+/- 10 days) after the initial administration. 

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3.2 Protocol Map 
 
Patient Enrolled
Administration of 
Cytosponge
Routine care clinical biopsies 
taken during EGD
Cytosponge 
shipped to Lab
Questionnaire administered immediately 
following Cytosponge:
•
Visual Analogue Scale
Cytosponge assay 
results communicated 
to UNC biostatisticians
Questionnaires administered 7 days after procedure:
•
Impact of Events Scale
•
Procedure Preference and Acceptability Questionnaire
All data will be entered 
via web-based data 
capture
Pathology results collected 
from routine care EGD
Sample 
adequate?
Yes
Lab contacts site to 
request repeat 
administration
No
Site contacts subject 
to request repeat 
Cytosponge 
administration
 

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3.3 Primary Outcomes 
The primary outcome variables will be sensitivity and specificity of the novel assay, compared against the 
gold standard of the presence of recurrent BE as detected by upper endoscopy with biopsies.  
 
3.4 Secondary Outcomes 
Secondary outcomes include acceptability of the non-endoscopic assay to the patient (assessed by a 
standardized tool, the Impact of Events Scale, as well as a visual analogue scale), and likelihood of assay 
positivity as a function of amount of residual disease (as measured by prague criteria). 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Male or female subjects, age 18-80 years, 
2. Meets the following: 
2.1. Previous diagnosis of BE with dysplastic LGD or HGD, as evidenced by both classical 
endoscopic appearance of salmon-colored mucosa in the tubular esophagus, as well as 
endoscopic biopsies from the involved areas demonstrating columnar metaplasia with goblet 
cells. The diagnosis of dysplasia must have been confirmed by a second expert pathologist. 
Previous EMR of focal nodular HGD or superficial intramucosal cancer (IMC) is allowable, as 
long as the EMR specimen shows complete resection of any IMC with clear margins, and 
biopsies following ablation confirm excision of the lesion, AND 
2.1.1. A history of complete eradication of both dysplasia and intestinal metaplasia by 
radiofrequency ablation. Complete eradication is defined as a normal endoscopic 
appearance of the tubular esophagus, and histologic confirmation by biopsies in 4 
quadrants every cm from throughout the length of the previous BE (post-RFA cohort).OR 
2.2. Current diagnosis of BE, presenting for routine care endoscopy (BE cohort). 
3. Good general health, with no severely debilitating diseases, active malignancy, or condition that 
would interfere with study participation. 
 
Exclusion Criteria: 
4.2 Exclusion Criteria 
1. 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). 
2. Known bleeding disorder 
3. For the post-RFA cohort, prior ablative therapy of the esophagus other than radiofrequency ablation 
(RFA), including photodynamic therapy (PDT), more than one session of spray cryotherapy, and any 
other ablation therapies is exclusionary. However, prior endoscopic mucosal resection (EMR) is 
acceptable and up to two prior treatments of thermal/coagulation therapy (other than RFA) for focal 
residual disease following otherwise successful RFA therapy is acceptable. The BE cohort must be 
treatment naive and have no history of ablation, but prior EMR is acceptable. 
4. History of esophageal stricture precluding passage of the endoscope or sponge, 
5. Pregnancy, or planned pregnancy during the course of the study, 
6. 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, 
7. Any history of esophageal surgery, except for uncomplicated fundoplication, and, 
8. History of coagulopathy, with INR>1.3 and/or platelet count of <75,000. 
9. Planned ablation therapy within 3 days of Cytosponge administration (endoscopic mucosal resection 
and submucosal dissection is OK). 
 

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4.3 Subject Recruitment and Screening 
Potential subjects will be identified during their GI clinic or procedure visits at their treating 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 of Barrett’s Esophagus and ablation therapy.   
 
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 
• 
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) 
Repeat 
Cytosponge 
(30 days +/-10 
days after 
Enrollment) 
Informed Consent Form   
X 
 
 
Demographics 
X 
 
 
Medical History  
X 
 
 
Inclusion/Exclusion Criteria  
X 
 
 
Cytosponge Administration 
X 
 
X1 
Visual Analogue Scale 
X2 
 
 
Routine Care Endoscopy with 
Biopsy 
X3 
 
 
Impact of Events Scale 
 
X 
 
Procedure Preference and 
Acceptability Questionnaire 
 
X 
 
Adverse Events4 
X 
X 
X 
1If the initial Cytosponge sample is inadequate, sites will be notified and subjects will be asked to return for repeat 
Cytosponge administration 30 days (+/- 10 days) after the initial Cytosponge administration.  Only the Cytyosponge 
administration will be repeated.  Questionnaires and the endoscopy procedure will not be repeated on these patients. 
2VAS should be administered immediately following completion of the Cytosponge and prior to the upper endoscopy. 
3Routine 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. 
4Only those events that are 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 
• 
Informed consent 
• 
Cytosponge administration 
• 
Visual Analogue Scale 
• 
Routine care upper endoscopy with biopsy 
• 
Adverse event assessment 
• 
Enrollment Case Report Form (eCRF):  This captures demographics including race, 
ethnicity, gender, and year of birth, relevant BE medical history including documentation 
of endoscopic procedures received to date as well as pathology findings and endoscopic 

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history related to current diagnosis. This will also capture the date the Cytosponge was 
sent to the Fitzgerald Lab for analysis 
5.1.2 Consenting Procedure 
If a subject is screened eligible and interested in the study, 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, 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 Fitzgerald Lab in Cambridge.  On arrival at the Fitzgerald 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 for trefoil factor 3, where any staining is considered positive for the 
assay. 
 
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. 
5.1.4 Routine Care Endoscopy with Biopsy 
After Cytosponge administration is complete, subjects will undergo routine care upper endoscopy, with 
assessment of BE (where applicable), and biopsy per accepted surveillance or screening 
recommendations.  Routine care tissue biopsies will undergo standard processing and H&E staining at 
the home institution, with assessment by expert gastrointestinal pathologists. 
 

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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.  Participation in the study is complete when subjects have completed the follow-up phone 
call. 
5.2.1 Assessments 
The following data will be collected from subjects during the follow-up phone call: 
• 
Impact of Events Scale 
• 
Procedure Preference and Acceptability Questionnaire 
• 
Adverse event assessment 
• 
Follow-Up Case Report Form (eCRF):  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 Repeat Cytosponge Administration 
If the initial Cytosponge sample is inadequate, sites will be notified and subjects will be asked to return for 
repeat Cytosponge administration 30 days (+/- 10 days) after the initial Cytosponge administration.  Only 
the Cytyosponge administration will be repeated.  Questionnaires and the endoscopy procedure will not 
be repeated on these patients.  See section 5.1.3 for details on the Cytosponge administration procedure. 
The Repeat Administration eCRF should be completed. 
6 Statistical Plan 
6.1 Sample Size Determination 
Previous data suggest a sensitivity of Cytosponge analysis for detecting BE ranging from 84-90%, and a 
specificity of 92-94%, using upper endoscopy as a gold standard. It is unlikely that this technique will be 
appropriate for surveillance if the true sensitivity is much lower than 80%, given the unacceptably high 
rate of false negatives. Previous data document a rate of recurrent BE of 13-38% in subjects assessed 
with surveillance endoscopy. If we wish to assess the accuracy of the Cytosponge compared to upper 
endoscopy, assuming a baseline sensitivity of 87%, we will need to enroll 81 subjects with recurrent BE to 

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yield a 95% confidence interval of 10% or less. If we further assume a rate of recurrent BE of 25% in the 
post-ablation population, a total of 324 post-ablation subjects will need to be enrolled in the trial.  
6.2 Statistical Methods 
For the primary objective, to assess the acceptability of the novel mucosal sampling technique in subjects 
after successful ablation, we will assess the distribution of Impact of Events Scale scores, and the 
intrusiveness and avoidance subscales. We will generate measures of central tendency and distribution 
of these data. Bivariate analysis will be performed to assess for predictors of low tolerance of Cytosponge 
surveillance, and a logistic regression model created to assess these factors while controlling for potential 
confounders. Data will be compared to population norms using parametric statistics.  VAS scores will be 
calculated, and measures of central tendency and distribution reported. 
 
Subjects’ preferences for Cytosponge vs. endoscopic surveillance, as well as willingness to undergo the 
procedure again, will be measured as proportions, with bivariate and multivariate analyses for predictors 
of preference performed. 
 
For the secondary objective, to assess the operating characteristics of Cytosponge against a gold 
standard of upper endoscopy, initially 2x2 tables will be constructed demonstrating Cytosponge and the 
gold standard findings (Y/N for BE). Sensitivity, specificity, positive predictive value, negative predictive 
value and accuracy will be calculated. Because Cytosponge positivity may vary based on the burden of 
BE, we will perform sensitivity analyses, defining “positive” cases as those with recurrent BE of ≥1 cm in 
length, and then ≥2 cm in length, to assess impact of disease burden on operating characteristics. 
Multivariate models controlling for age, sex, period of time from last ablation, burden of residual disease, 
and other potential confounders will be constructed, to assess the impact of these factors on test 
accuracy. Although we do not expect to see an association between the degree of dysplasia and 
Cytosponge positivity, exploratory analyses will be performed using degree of dysplasia as a predictor 
variable, and Cytosponge positivity as the outcome variable. 
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 

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• 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 
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. 

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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 
• 
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 electronic case report form.  In addition to completion 
of the eCRF, 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 electronic 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 electronic 
case report form (eCRF).  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 

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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 electronic reportable event form 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 
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:  

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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 
• 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 electronic case report forms (eCRFs).  The study case report form (eCRF) 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.   

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8.3.1 Case Report Form Completion Table 
Form 
Screening/Enrollment 
Follow-
Up 
PRN  
(As 
Needed) 
Enrollment CRF   
X 
 
 
Follow-Up CRF  
 
X 
 
Repeat Administration 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. 
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  11, 50, 56, and 312,  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 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.  

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11 Study Finances 
11.1 Funding Source 
This pilot study is funded by the National Institutes of Health (NIH) and Covidien GI Solutions now part 
of Medtronic. 
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. Nicholas Shaheen.  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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