Patient Acceptance and Preference Among Screening Modalities for Detection of Barrett's Esophagus
Phase: NA
Conditions: Barrett Esophagus, GERD
Sponsor: University of North Carolina, Chapel Hill

STUDY PROTOCOL 
 
 
Patient Acceptance and Preference Among Screening Modalities for Detection of 
Barrett's Esophagus 
 
 
NCT number NCT04301986 
Document Date 16Jul2021 
 

 
PATIENT ACCEPTANCE AND PREFERENCE AMONG 
SCREENING MODALITIES FOR DETECTION OF 
BARRETT'S ESOPHAGUS 
 
Principal Investigator 
Swathi Eluri, MD, MSCR 
Assistant Professor of Medicine 
Division of Gastroenterology and Hepatology 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Phone: (919) 843-6686 
Fax: (919) 966-6842 
Email: swathi@med.unc.edu 
 
Co-Investigators 
Nicholas J. Shaheen, MD, MPH 
 
Funding Sponsor: 
American Gastroenterological Association 
Protocol Number: 
18-3290 
Protocol Version: 
4.0 
Protocol Version Date: 
16Jul2021 
 

AGA TNE Preference 
 
Version 4.0 
Protocol # 18-3290 
 
16Jul2021 
 
 
PROTOCOL 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 U.S. federal regulations and ICH guidelines. 
 
 
______________________________ 
Investigator Name (Printed) 
______________________________ 
 
______________________________ 
Investigator Signature 
 
 
 
 Date 
 
 
 
 
 
 
 
 
 

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0 
Protocol Version 3.0 Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Version 4.0 
16Jul2021 
Version 3.0 
Version 2.0 
Version 1.0 
04Mar2021 
02Sep2020 
23Sep2019 
Version 0.8 
19Sep2019 
 
Version 4.0 (16Jul2021) 
 
Overall Rationale for Version 4.0: 
This summary includes changes made to Protocol AGA TNE Preference from Version 3.0 (dated 
04Mar2021). The purpose of Protocol Version 4.0 is to communicate changes made to the 
Protocol to revise the inclusion/exclusion criteria. Updates will not impact the safety 
assessment of administration of Cytosponge or Transnasal Endoscopy (TNE) nor will they alter 
the risk-benefit ratio for study participants.  
 
The following is a summary of context-oriented changes that were made. Strikethrough text 
denotes text removed, and bolded text denotes added text. Additional administrative edits 
were also made but not specifically noted (e.g., corrected spelling, punctuation, grammar, 
abbreviation, and style errors), including edits required for consistency. 
 
Section 
Description of Change 
Rationale 
Section 1 Protocol 
Synopsis, Section 
6.1 Inclusion 
Criteria 
Amended inclusion criteria to include all eligible patients 
undergoing upper endoscopy 
 
To increase enrollment by 
including all eligible patients 
Section 1 Protocol 
Synopsis, Section 
6.2 Exclusion 
Criteria 
6. Inability to hold use of anti-coagulation medications or 
non-aspirin anti-platelet agents (APAs) for the 
recommended clinically indicated duration Current use of 
blood thinners, such as warfarin, clopidogrel, heparin 
and/or low molecular weight heparin (requires 
discontinuation of medication five (5) days prior to and five 
(5) days after esophagogastroduodenoscopy [EGD] and 
Cytosponge administration; aspirin use is OK)  
To provide clarity. 
Discontinuation of blood 
thinners per standard of care is 
acceptable 
Section 1 Protocol 
Synopsis, Section 
6.2 Exclusion 
Criteria 
1. Cohort B only: History of pre-existing esophageal 
stenosis/stricture , esophageal diverticulum or significant 
esophageal anatomic abnormalities (masses, obstructive 
lesions, etc.) with active symptoms of dysphagia 
To clarify that patients with 
active symptoms of dysphagia 
will be excluded  
Section 5.1 Study 
Population 
We will recruit adults at least 18 years of age with Barrett’s 
esophagus (BE) or Gastroesophageal Reflux Disease (GERD) 
who are presenting for routine clinically indicated upper 
endoscopy (EGD) at UNC presenting for routine outpatient 
upper endoscopy 
To clarify that enrollment 
includes all eligible patients 
undergoing upper endoscopy 

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TABLE OF CONTENTS 
PATIENT ACCEPTANCE AND PREFERENCE AMONG SCREENING MODALITIES FOR DETECTION OF 
BARRETT'S ESOPHAGUS ................................................................................................................................ 1 
0 
Protocol Version 3.0 Summary of Changes ........................................................................................... 3 
1 
PROTOCOL SYNOPSIS ............................................................................................................................ 7 
2 
BACKGROUND AND JUSTIFICATION ...................................................................................................... 9 
3 
STUDY AIMS ........................................................................................................................................ 11 
3.1 
Primary Objective ........................................................................................................................ 11 
3.2 
Secondary Objective ................................................................................................................... 11 
4 
SCHEDULE OF EVENTS ......................................................................................................................... 12 
5 
SAMPLE SIZE ........................................................................................................................................ 13 
5.1 
Study Population ......................................................................................................................... 13 
6 
ELIGIBILITY CRITERIA ........................................................................................................................... 13 
6.1 
Inclusion Criteria ......................................................................................................................... 13 
6.2 
Exclusion Criteria ......................................................................................................................... 13 
7 
STUDY PROCEDURES ........................................................................................................................... 14 
7.1 
Screening and Recruitment ......................................................................................................... 14 
7.2 
Written Informed Consent .......................................................................................................... 14 
7.3 
Baseline Visit ............................................................................................................................... 15 
7.3.1 
Cytosponge Administration ................................................................................................ 15 
7.3.2 
TNE Administration ............................................................................................................. 16 
7.3.3 
Clinically Indicated Routine Care Endoscopy ...................................................................... 16 
7.3.4 
Visual Analog Scale .............................................................................................................. 16 
7.4 
Follow-Up Phone Call .................................................................................................................. 17 
7.4.1 
Impact of Events Scale ........................................................................................................ 17 
7.4.2 
Procedure Preference and Acceptability Questionnaire .................................................... 17 
7.5 
Study Exit..................................................................................................................................... 17 
8 
RISK AND BENEFIT ASSESSMENT ........................................................................................................ 17 
8.1 
Assessment of Safety .................................................................................................................. 17 
8.2 
Patient Confidentiality ................................................................................................................ 19 
8.3 
Minimization of Risk .................................................................................................................... 19 
8.4 
Potential Benefits ........................................................................................................................ 19 

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9 
STATISTICAL CONSIDERATIONS ........................................................................................................... 19 
9.1 
Statistical Plan & Sample Size Calculation .................................................................................. 19 
10 STUDY MANAGEMENT ........................................................................................................................ 20 
10.1 
Institutional Review Board (IRB) Approval .................................................................................. 20 
10.2 
Required Documentation ............................................................................................................ 21 
10.3 
Data Management ...................................................................................................................... 21 
10.4 
Data Collection ............................................................................................................................ 21 
10.5 
Adherence to the Protocol .......................................................................................................... 21 
10.6 
Noncompliance ........................................................................................................................... 22 
10.7 
Unanticipated Problems Involving Risks to Subjects or Others .................................................. 22 
10.7.1 
Definition ............................................................................................................................ 22 
10.7.2 
Reporting ............................................................................................................................. 22 
10.8 
Definition of Adverse Events (AE) ............................................................................................... 22 
10.9 
Adverse Event Assessment ......................................................................................................... 22 
10.10 
Severity of Event ......................................................................................................................... 22 
10.11 
Relationship to Study Intervention ............................................................................................. 23 
10.12 
Expectedness .............................................................................................................................. 24 
10.13 
Unexpected Adverse Event ......................................................................................................... 24 
10.14 
Time Period and Frequency for Event Assessment and Follow-Up ............................................ 24 
10.14.1 
Serious Adverse Event (SAE) ........................................................................................... 24 
10.14.2 
Adverse Event Documentation and Reporting ............................................................... 25 
10.15 
Amending the Protocol ............................................................................................................... 25 
10.16 
Privacy and Confidentiality ......................................................................................................... 25 
10.17 
Record Retention ........................................................................................................................ 26 
10.18 
Criteria for Terminating the Study .............................................................................................. 26 
10.19 
Investigator Responsibilities and Compliance ............................................................................ 26 
10.20 
Adherence to the Protocol .......................................................................................................... 27 
10.21 
Emergency Modifications ........................................................................................................... 27 
11 PUBLICATION ...................................................................................................................................... 27 
12 ASSESSMENTS ..................................................................................................................................... 28 
12.1 
Visual Analog Scale (VAS) ............................................................................................................ 28 
12.2 
Procedure Preference and Acceptability Questionnaire ............................................................ 29 

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12.3 
Impact of Events Scale (IES) ........................................................................................................ 30 
13 REFERENCES ........................................................................................................................................ 31 
14 ABBREVIATIONS .................................................................................................................................. 33 
 
 
 

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1 
PROTOCOL SYNOPSIS 
Title 
 
Patient Acceptance and Preference Among Screening Modalities for Detection of 
Barrett's Esophagus 
Purpose 
To assess patient acceptance and preference among screening modalities, 
Esophagogastroduodenoscopy (EGD), Transnasal Endoscopy (TNE), and Cytosponge 
for Barrett’s esophagus (BE). 
Population 
Patients with Barrett’s esophagus or gastroesophageal reflux disease (GERD). 
Design 
Single-center, prospective, single arm, non-randomized study 
Sample Size 
40 patients 
Primary 
Outcome 
To assess acceptability of the three modalities: traditional upper endoscopy, TNE and 
Cytosponge. 
Secondary 
Outcomes 
Patient preference and willingness to perform procedure again. 
Inclusion 
Criteria 
1. At least 18 years of age at time of consent 
2. Able and willing to provide written informed consent 
3. Able and willing to comply with required study procedures and follow-up 
schedule 
4. Presenting to UNC Hospitals for outpatient routine care upper endoscopy  
Exclusion 
Criteria 
1. Cohort B only: History of pre-existing esophageal stenosis/ stricture, esophageal 
diverticulum or significant esophageal anatomic abnormalities (masses, 
obstructive lesions, etc.) with active symptoms of dysphagia 
2. History of head and neck malignancy or anatomical abnormalities of the 
nasopharynx 
3. Any history of Ear, Nose and Throat (ENT) surgery within three (3) months before 
the screening visit. Past medical history of ENT surgery altering the anatomy of 
the nasopharynx is exclusionary 
4. History of significant epistaxis or hereditary hemorrhagic telangiectasia (HHT) 
5. Sinus or pulmonary infection in the last 4 weeks 
6. Inability to hold use of anti-coagulation medications or non-aspirin anti-platelet 
agents (APAs) for the recommended clinically indicated duration 
7. Known bleeding disorder 
8. Pregnancy, or planned pregnancy during the course of the study 
9. 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 
10. Any history of esophageal surgery, except for fundoplication 
11. History of coagulopathy, with international normalized ratio (INR)>1.3 and/or 
platelet count of <75,000 
12. General poor health, multiple co-morbidities placing the patient at risk, or 
otherwise unsuitable for trial participation 

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13. Subject has any condition that, in the opinion of the investigator or sponsor, 
would interfere with accurate interpretation of the study objectives or preclude 
participation in the trial 
Study 
Summary 
Potential subjects will be identified via protocol and Institutional Review Board (IRB) 
methods prior to obtaining written informed consent. Once written informed 
consent is obtained and baseline demographic and medical history is collected, 
subjects will undergo administration of Cytosponge and Transnasal Endoscopy (TNE) 
prior to their scheduled clinically indicated upper endoscopy performed per routine 
standard of care. Following the procedure, a follow-up phone call will be made 
during which an impact of events scale related to the subjective distress of each 
procedure, a preference and acceptance questionnaire, and adverse events related 
to study participation will be collected.  
Funder 
American Gastroenterological Association Research Scholar Award 
Principal 
Investigator 
Swathi Eluri, MD, MSCR 
Co-
Investigator 
Nicholas J. Shaheen, MD, MPH 
NCT Number 
NCT04301986 
 
 
 
 

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2 
BACKGROUND AND JUSTIFICATION 
The incidence of esophageal adenocarcinoma (EAC) is increasing in the western world. In 2017, 
it is estimated that there will be 16,940 new cases of esophageal cancer in the US and an 
estimated 15,690 people will die of this disease.1 Survival outcomes in EAC are dramatically 
improved with early stage diagnosis.2, 3 However, only 8% of EAC cases annually are diagnosed 
through current methods of cancer prevention (Figure 1),4 indicating that high-risk patients are 
ineffectively screened. We know that gastroenterologists (GI) are highly likely to perform EGD in 
symptomatic or chronic GERD patients5 with one study6 showing trigger for EGD in 51/100 GERD 
episodes by GI compared to 6/100 by primary care providers (PCP), indicating that understanding 
and optimizing screening practices at the patient or primary care level is critical to improve EAC 
detection.  
 
One strategy for early detection of EAC is 
identification of Barrett’s esophagus 
(BE), a known precancerous lesion of EAC 
with a long latent stage, in high-risk 
GERD patients. BE with dysplasia can be 
effectively eradicated with endotherapy 
to prevent progression,7,8 which can 
improve EAC outcomes and associated 
mortality.9 Currently, nearly 70% of 
patients with BE go undiagnosed.10 
Considering 
that 
3-6% 
of 
the 
approximately 87 million people with 
GERD in the US are estimated to have 
BE,11,12 it is a significant public health 
concern, and represents an unexploited opportunity to stem the remarkable rise in deaths from 
EAC.  
 
We know that 60% of EACs occur in GERD patients over the age of 40 in the United States,4 and 
as a result it makes sense to target this group for BE and EAC screening. Screening for BE/EAC is 
currently done by sedated upper endoscopy with endoscopic and histologic assessment. Most 
recent guidelines13 recommend screening in men with more than 5 years of GERD or more than 
weekly symptoms, who have at least two other risk factors. Risk factors include age >50, 
Caucasian race, central obesity, smoking history, and family history of BE or EAC in first-degree 
relative. Additive risk factors appear to increase the risk of developing BE and EAC. For example, 
an obese, white, male, smoker with GERD, has more than three times the relative risk of 
developing EAC compared to a white male with GERD.14 
150millionofUSpopula on
>40yearsofage
80%haveno
GERD
20%have
GERD
90%
havenoEGD
10%
haveEGD
Diagnosed
EACcases
40%

*52%

8%

*52%ofEACcasesarediagnosedin90%ofGERDpa entswhohave
neverhadanEGD
Figure 1: Proportion of EAC cases diagnosed annually in the US 

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However, since a large proportion of the population has GERD, it 
is neither practical nor cost-effective to screen everyone with 
GERD with traditional upper endoscopy. Therefore, risk-
stratification tools18 and alternate screening methods to EGD with 
both endoscopic and non-endoscopic approaches have been 
explored (Figure 2). Of the endoscopic approaches, Transnasal 
Endoscopy (TNE) is as sensitive as EGD for BE diagnosis, well 
tolerated, and less expensive.15-18 TNE uses a small caliber scope 
that is inserted into the nares after application of local anesthetic, 
and can be performed without sedation. Of the non-endoscopic 
screening techniques, the most studied is an ingestible sponge 
attached to a string, Cytosponge. Cytosponge is a minimally 
invasive, sponge-based technique for sampling the esophageal 
mucosa. It is an abrasive sponge encapsulated in a gelatin coating, 
which is attached to a string. After ingestion, the capsule dissolves 
upon exposure to gastric secretions. It is then withdrawn 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 markers, which have been sensitive and specific for 
the presence of BE. Cytosponge has also been shown to have good acceptability and tolerance 
by patients.19,20  
 
These alternate screening modalities, while demonstrated to be effective, have not been 
implemented in clinical practice. There are prior studies comparing the clinical effectiveness 
and patient acceptability measures between EGD and TNE,21,22 and more recently EGD and 
Cytosponge.19 To date, however, no study has simultaneously evaluated all three available 
modalities.  Given that we have more available screening tools, it is vital to understand patient 
acceptability in utilizing these new modalities. Therefore, the goal of the study is to compare 
patient acceptance and preference between three screening modalities for BE: traditional 
upper endoscopy (EGD), Transnasal Endoscopy (TNE), and Cytosponge.  
 
 
Figure 2: (a) Transnasal 
Endoscopy (b) Cytosponge 
b
a

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3 
STUDY AIMS 
 
3.1 
Primary Objective 
The primary objective is to assess patient acceptance of each screening modality (Cytosponge, TNE, and 
EGD) using Impact of Events (IES)23 score evaluated at approximately seven (7) days post-EGD. 
3.2 
Secondary Objective 
The secondary objectives are: 
Secondary objective 1:  Assess patient comfort pertaining to each screening modality (Cytosponge, TNE, 
and EGD) using VAS acceptability score at baseline. 
Secondary objective 2: Assess willingness to repeat each screening modality (Y, N) evaluated ~7 days 
post-EGD. 
Secondary objective 3: Determine ranking of preferred screening modality (1,2,3) evaluated ~7 days 
post-EGD. 
Secondary objective 4:  Identify factors that influence preference rankings or preferred choices among 
the 3 methods. 
 
 
 

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4 
SCHEDULE OF EVENTS 
Study Period 
Screening2 
Follow-Up 
Visit Title 
Baseline Visit2 
~7 Days Post-
Endoscopy 
Informed Consent 
x 
  
Inclusion/Exclusion Criteria 
x 
  
Pregnancy Test 
x3 
 
Medical History 
x 
  
Demographics 
x 
  
Endoscopy  
(per SOC guidelines) 
x 
  
Cytosponge Administration 
x1 
  
Transnasal Endoscopy 
Administration 
x 
  
Procedure Preference and 
Acceptability Questionnaire 
  
x 
Visual Analog Scale (VAS) 
x 
  
Impact of Events Scale (IES) 
 
x 
Enrollment Case Report Form 
(eCRF) 
x 
  
Adverse Event Assessment 
x 
x 
1 Subjects who have previously undergone Cytosponge as a part of the UNC IRB study #13-2618 will 
not repeat Cytosponge.  
2 Screening and baseline visits can occur on the same day or on separate days. 
3 Performed on females with reproductive potential. The urine pregnancy test does not need to be 
repeated if already performed as part of routine care during the visit. 
 
 
 

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5 
SAMPLE SIZE 
To satisfy enrollment for the primary objectives, it is estimated approximately 40 subjects will need to 
be enrolled into the study (please refer to section 9.1 for additional details pertaining to sample size 
determination).  
 
5.1 
Study Population 
We will recruit adults at least 18 years of age who are presenting for routine clinically indicated upper 
endoscopy (EGD) at UNC. Since the primary objective is to compare patient acceptance and preference 
between EGD, Cytosponge, and TNE, patients will have to undergo all three procedures. The ideal study 
design would have subjects undergo all three procedures the same day. However, this could potentially 
be cumbersome to the patients. To have Cytosponge testing prior to EGD, patients need to present at 
their EGD appointment more than 2 hours ahead of time. This is because Cytosponge administration 
requires patients drinking sips of water to swallow the Cytosponge. Following this, patients must wait at 
least 2 hours prior to undergoing sedated EGD per standard NPO guidelines. Therefore, in an attempt to 
decrease individual patient burden, we primarily plan to recruit patients from a prior study conducted 
by our group (IRB #13-2618) who have already undergone Cytosponge and EGD testing and are 
returning to have a clinically indicated EGD.  A significant proportion of these patients, given that they 
have a history of BE, will undergo routine EGD for BE surveillance. Patients recruited through this 
pathway (Cohort A) will be approached to only undergo TNE right before their clinically indicated EGD. 
 
If we have difficulty recruiting patients through this path, we will plan to recruit subjects who are 
presenting for a clinically indicated routine endoscopy and recruit them to undergo Cytosponge and TNE 
prior to their EGD (Cohort B).  
 
Cohort A: Participants from IRB# 13-2618 
- 
Subjects will undergo: TNE, clinically indicated EGD 
Cohort B: Cytosponge-naïve  
- 
Subjects will undergo all procedures: Cytosponge, TNE, clinically indicated EGD 
After administration, follow-up procedures for both cohorts are the same. Since subjects from Cohort A 
have already undergone Cytosponge, data from those administrations will be used for VAS, IES, and 
adaptability of Cytosponge procedures.  
6 
ELIGIBILITY CRITERIA 
6.1 
Inclusion Criteria 
1. At least 18 years of age at time of consent 
2. Able and willing to provide written informed consent 
3. Able and willing to comply with required study procedures and follow-up schedule 
4. Presenting to UNC Hospitals for routine care upper endoscopy  
6.2 
Exclusion Criteria 
1. For Cohort B only: History of pre-existing esophageal stenosis/ stricture, esophageal 
diverticulum or significant esophageal anatomic abnormalities (masses, obstructive lesions, 
etc.) with active symptoms of dysphagia 
2. History of head and neck malignancy or anatomical abnormalities of the nasopharynx 

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3. Any history of Ear, Nose and Throat (ENT) surgery within three (3) months before the 
screening visit. Past medical history of ENT surgery altering the anatomy of the nasopharynx 
is exclusionary 
4. History of significant epistaxis or hereditary hemorrhagic telangiectasia (HHT) 
5. Sinus or pulmonary infection in the last 4 weeks 
6. Inability to hold use of anti-coagulation medications or non-aspirin anti-platelet agents 
(APAs) for the recommended clinically indicated duration 
7. Known bleeding disorder 
8. Pregnancy, or planned pregnancy during the course of the study 
9. 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 
10. Any history of esophageal surgery, except for fundoplication 
11. History of coagulopathy, with international normalized ratio (INR)>1.3 and/or platelet count 
of <75,000 
12. General poor health, multiple co-morbidities placing the patient at risk, or otherwise 
unsuitable for trial participation 
13. Subject has any condition that, in the opinion of the investigator or sponsor, would interfere 
with accurate interpretation of the study objectives or preclude participation in the trial 
7 
STUDY PROCEDURES 
All procedures will be documented on study-specific electronic case report forms that are provided in 
addition to this protocol. Refer to Schedule of Events in section 4 for a summary of study procedures.  
 
7.1 
Screening and Recruitment 
Patients will be screened for potential eligibility according to UNC IRB approved screening methods.  
Potential subjects will be approached prior to routine care endoscopy by research staff to explain the 
study and obtain informed consent.  
 
Since the study population involves recruitment from the population who would be receiving EGD 
clinically as part of SOC, this will be the main recruitment strategy. This can include prescreening the 
clinic and procedure schedule for potential subjects, and referrals from UNC providers (PCP or GI). 
 
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 provide 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 medical history. The consent process will be documented by the coordinator in the 
patient’s study file. 
 
7.2 
Written Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks will be provided to 
the participant and written documentation of informed consent is required prior to performing any 

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study procedures. In obtaining and documenting informed consent, the investigator must comply with 
applicable regulatory requirement(s) (e.g., 45 CFR Part 46) and should adhere to International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) and to ethical principles that have their origin in the 
Declaration of Helsinki. 
 
 
Before any study procedures are performed, the patient will be given a full explanation of the study and 
will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by federal regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. The 
informed consent process will be documented by the study team. A copy of the signed and dated 
informed consent form will be retained by the study team and a copy of the signed and dated informed 
consent will be provided to the subject. 
 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations.  The IRB should approve the consent form and protocol. 
 
7.3 
Baseline Visit 
Potential subjects who agree to participate and provide written informed consent will be enrolled. 
Eligibility will be based on the inclusion and exclusion criteria.  
 
The following will be completed during the screening/enrollment visit: 
• 
Eligibility review 
• 
Informed consent 
• 
Cohort A: TNE administration only if subjects are participants of previous Cytosponge 
study (UNC IRB # 13-2618) 
OR 
Cohort B: Cytosponge followed by TNE administration  
• 
Routine care upper endoscopy with biopsy 
• 
Visual Analogue Scale (VAS) to measure pain 
• 
Adverse event assessment 
• 
Enrollment Case Report Form (eCRF):  This captures demographics including race, 
ethnicity, gender, and year of birth, relevant medical history including documentation of 
endoscopic procedures received to date as well as pathology findings and endoscopic 
history related to current diagnosis. It will also capture date of TNE and Cytosponge 
administration and associated exam findings. 
 
7.3.1 
Cytosponge Administration 
The Cytosponge will be supplied by Medtronic. 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). An investigator, study coordinator, or other 
trained and qualified personnel will perform the Cytosponge administration and retrieval. Our clinical staff 

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will be members of the Center for Esophageal Diseases and Swallowing (CEDAS) and are all well versed in 
the administration and collection of the Cytosponge, due to previous studies our group has conducted 
(15-0332; 13-2618).  
 
Subjects will undergo administration of the Cytosponge 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]). 
 
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”. 
Subjects who are unable to swallow the Cytosponge will continue to participate in the remainder of the 
study.  
 
7.3.2 
TNE Administration 
Prior to the scheduled upper endoscopy, Transnasal Endoscopy will be performed using the neonatal 
(ultrathin) endoscope (Olympus America Inc). The TNE will be performed by qualified trained 
investigator or sub-investigators. While it would be ideal to have one provider perform all cases, in an 
effort to be cognizant of the patient’s time and clinical workflow demands in the endoscopy units, it 
would be impractical to have the same operator perform all cases. Prior to the procedure, a 
combination of a topical decongestant (oxymetazoline hydrochloride, 0.05%, Afrin, Schering-Plough 
Healthcare Products, Inc., Memphis, Tennessee) and topical anesthesia with 4% lidocaine, or another 
topical anesthetic based on the discretion of the physician performing the procedure, will be used to 
anesthetize the nares and posterior pharynx. The exam will be performed with the participant in the 
upright position. The posterior pharynx, esophagus and proximal stomach will be examined with the 
Transnasal Endoscopy approach. No biopsies will be obtained. The scope will be withdrawn from the 
nares following completion of the exam.   
 
7.3.3 
Clinically Indicated Routine Care Endoscopy 
After examination with both Cytosponge and TNE is completed, subjects will undergo routine care upper 
endoscopy, with assessment of BE or GERD, 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.  
 
7.3.4 
Visual Analog Scale 
Acceptability outcomes will include a Visual Analogue Scale (VAS) of acceptability of the Cytosponge, 
TNE, and EGD. Also, the subject will be asked whether he/she would be willing to repeat the assay, and, 

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assuming similar accuracy between modalities, whether he/she would rather undergo surveillance by 
Cytosponge, TNE, or standard EGD with biopsies. 
 
7.4 
Follow-Up Phone Call 
Subjects will be contacted approximately seven (7) days after successful administration of the device via 
phone or other IRB approved method. The following data will be collected from subjects during the 
follow-up phone call: 
• 
Impact of Events Scale (IES) 
o Cohort A: IES for EGD and TNE only (IES data has been previously collected for Cytosponge 
in the prior study) 
o Cohort B: IES for EGD, TNE, and Cytosponge 
• 
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. 
7.4.1 
Impact of Events Scale 
The Impact of Events Scale (IES) will be completed with the subject during the follow-up phone call and 
measures subjective distress related to the administered procedures. 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. IES has been used to measure 
acceptability of Cytosponge in prior studies.25,26 In addition the previous study referenced here UNC IRB 
#13-2618, used the IES instrument and therefore we have utilized the same instrument in this protocol so 
the data is comparable.  
 
For Cohort A subjects, we plan to use existing IES data pertaining to Cytosponge which was collected 
seven (7) days after Cytosponge administration in the prior study. Since a period of time has passed since 
the patients in Cohort A underwent Cytosponge, using the already collected data will help minimize recall 
bias. Therefore, Cohort A subjects will only have IES collected for TNE procedure and EGD during this 
current proposed study.  
7.4.2 
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 vs. traditional 
upper endoscopy vs. TNE, as well as willingness to undergo the procedure again. 
 
7.5 
Study Exit 
Study participation is complete when the participant has completed the follow-up phone call.  
 
8 
RISK AND BENEFIT ASSESSMENT 
8.1 
Assessment of Safety  
All endoscopies and standard of care biopsies referenced in this protocol are consistent with current 
standard of care, so subjects would be receiving these endoscopies regardless of participation in the 
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clinical care. However, subjects should be reminded of endoscopy risks as part of the consent process 
for the study. The endoscopy is a well-established procedure with a very low rate of complications. 
Subjects may experience mild discomfort due to gagging while the tube is passed down the throat. 
Subjects may also experience mild sore throat, chest pain or discomfort, abdominal pain, or discomfort, 
or painful or difficult swallowing following the procedure. Medicines may ease these problems. Rare 
risks from an endoscopy include bleeding and infection. There is a very small risk (about 3 in 10,000) of 
esophageal perforation that could require surgery to repair and a similarly small risk (8 in 10,000) of 
aspiration that could cause pneumonia. If clinical biopsies are taken, there is a very small risk of 
perforation or significant bleeding that would require a blood transfusion or other measures to stop the 
bleeding. Subjects could also have an adverse reaction to the anesthetic or medication used. These 
reactions may require treatment. There may be inflammation of the vein through which medication is 
given. If subjects have asthma, they may have an increased risk for problems with the anesthesia. An 
adverse reaction to the medications used for the endoscopy can include difficulty breathing, respiratory 
depression, hypotension, bradycardia, excessive sweating, spasms in the larynx, or an allergic reaction, 
such as hives and itching or anaphylaxis. These risks are indicative of the procedure itself and are not 
added risk of participating in the study. 
 
The Seattle biopsy protocol is used for standard of care (SOC) which includes taking four (4) quadrant 
biopsies every one  to two centimeters throughout the area of interest.  
 
Serious risk of endoscopic biopsies is very uncommon in subjects without bleeding disorders and in 
those who do not regularly take blood thinning medications (such as aspirin, nonsteroidal anti-
inflammatory medications, Coumadin (warfarin), Plavix, Lovenox, heparin, and low molecular weight 
heparin). This is because the biopsies are very small (2-3 mm) and are obtained with blunt tipped 
forceps under direct vision of the doctor performing the endoscopy. Possible serious complications 
include excess bleeding from the biopsy sites causing the blood pressure to drop and/or the need for 
blood transfusion or esophageal perforation (tear) due to trauma. More common, but not serious, is 
minor bleeding which requires no treatment or responds to treatment with oral antacids. The risk of 
bleeding secondary to endoscopic biopsies is less than 1/1,000 and there is an even smaller risk of 
perforation or infection. When bleeding does occur, adequate medical staff and equipment are on hand 
to abate any long-term damage that could result from this risk. These participants will often already be 
undergoing biopsies as part of their standard of care, so the incremental risk is expected to be minimal. 
These risks are indicative of the procedure itself and are not added risk of participating in the study. 
 
Cytosponge risks: There are several risks associated with the administration of the Cytosponge. These 
include risk of bleeding or aspiration. In addition, discomfort from either the string when the device is in 
the stomach, or when the sponge is retracted from the body, or mild soreness or irritation in the throat 
following the procedure which is common in patients receiving an endoscopy, but the Cytosponge may 
also cause soreness or irritation in the throat.  
 
To date there have been >1,000 administrations and detachment of the sponge from the string has 
occurred in less than 1% of cases. Detachment of the sponge from the string could block the intestines. 
Should the sponge detach from the string, it will be retrieved during the routine care upper endoscopy 
immediately following administration. 
 
To reduce the likelihood of these risks, Cytosponge administration will occur after an overnight fast, to 
minimize the possibility of aspiration of any gastric contents. Patients’ throats may be sprayed with a 
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administered sponge will be assessed post-procedure for signs of fracture or incomplete retrieval of the 
sponge, and in the unlikely case such incomplete retrieval occurs, the sponge will be retrieved during 
the routine care endoscopy which is scheduled to immediately follow administration of the sponge. If 
any potential bleeding is noted due to administration of the sponge, this will also be investigated, and, 
as necessary, treated during the routine upper endoscopy. 
 
Transnasal Endoscopy (TNE) potential risks share the same risks as a conventional endoscopy (reported 
above). These include nasal discomfort; gagging (mild); discomfort during insertion; aspiration (drawing 
matter into the lungs along with the breath); bleeding; epistaxis (nosebleed); sinus infection; choking; 
nausea; retching or vomiting; anxiety; severe pain. A rare risk includes esophageal perforation (occurring 
in <0.1% of people, or less than 1 out of 10,000 people) which could possibly require surgery to repair.  
 
The equipment for small-caliber endoscopy is FDA approved, and all study procedures will be carried out 
with trained and/or licensed qualified staff. In the case of procedural complications, the participating 
investigators will refer the patient for the appropriate care.  
 
8.2 
Patient Confidentiality  
There is a risk that subjects’ confidential medical information could be compromised because of 
participation in this study. Precautions will be taken to protect confidential information including 
assigning each subject a unique identifier for study records and restricting access to research records. In 
addition, study case report forms (CRFs) will collect minimal protected health information. 
 
There may be uncommon or previously unknown risks. Study participants should be instructed to report 
any problems to the study team for additional reporting per protocol. 
 
8.3 
Minimization of Risk 
All efforts will be made to minimize risk to subjects who participate in this clinical study. 
• 
Investigators participating in this study are licensed, experienced, and skilled in endoscopic 
procedures at their institution.  
• 
Treatment and follow-up are consistent with current medical practice. 
• 
Patients will be closely monitored during the procedure and at regularly scheduled intervals for 
the duration of the study. 
• 
The protocol clearly defines eligibility criteria to ensure that only the appropriate patients are 
enrolled. 
• 
Investigators agree to maintain the highest level of confidentiality, including conducting 
appropriate training for site staff prior to study initiation. 
  
8.4 
Potential Benefits 
It is not expected for participants to benefit directly from participating in this study. Subjects will receive 
standard of care (SOC) treatment regardless of study participation. There is, however, the potential for 
researchers and patients to benefit in the future as a direct result of what is learned from this study. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Plan & Sample Size Calculation 
The acceptability of each screening modality will be assessed with the Impact of Events Scale (IES) 
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Since the same subject will undergo treatment with each of the screening modalities, we anticipate that 
the scores generated will be correlated.  We assume each pair of scores will have the same correlation.  
For the planned analysis, each IES score will be classified as low or high. High score will be defined as 
total IES score >38.25 A low score will be defined as a total IES score less than or equal to 38. 
 
To compute power, for each of the three devices we specified the proportion of high scores as well as 
the correlation between observations within a subject.  Estimating that 1% of the subjects undergoing 
sedated EGD group, 5% of those undergoing Cytosponge,25 and 20% of those undergoing TNE will 
experience a high IES score, using a correlation of 0.3, and a sample size of 40, we specified a trivariate 
Binomial distribution.  Random data were generated from such a distribution and Fishers Exact Test was 
computed from the data.  This was done 10,000 times.  The percentage of the 10,000 trials in which the 
Fishers Exact Test p-value was less than 0.05 provided our power estimate of 80% for a sample size of 
40. 
 
We will compare the median IES score for each modality using Kruskal-Wallis testing as well comparing 
the proportion of subjects with high IES scores for each modality using Pearson’s chi-square testing. For 
the secondary objectives: 
- Secondary objective 1: Median VAS score will be compared between the three modalities using 
Kruskal-Wallis testing 
- Secondary objective 2: The proportion of subjects willing to repeat each test will be computed. 
- Secondary objective 3: Subjects’ preferred screening modality ranked highest will be measured as 
proportions. The proportion of the highest ranked screening modality will be computed. 
- Secondary objective 4: Bivariate and multinomial logistic regression analyses will be used to identify 
factors such as patient discomfort, sex, and EGD indication influencing screening preference among the 
three modalities. 
 
Since we are recruiting patients from two separate pathways (described in Section 5.1), we plan to 
account for the differences by analyzing the two groups separately as well as the entire cohort as a 
whole to see if there is a statistically significant difference in results between the groups. In addition, we 
acknowledge that the results may be affected by carryover effect for subjects recruited via Pathway 1, 
but recruiting via this strategy makes this study feasible, and we will acknowledge this as one of the 
limitations. 
 
All hypothesis tests that are deemed to be not statistically significant will be reported as being 
inconclusive. 
 
All statistical estimates of population parameters will be tabulated along with corresponding standard 
errors, or confidence intervals (CI) to convey levels of precision and imprecision. 
 
10 STUDY MANAGEMENT 
10.1 Institutional Review Board (IRB) Approval 
IRB approval will be obtained prior to subject recruitment and enrollment.  Research staff are 
responsible for maintaining IRB approval throughout the duration of the study, including submission of 
continuing review and modifications when appropriate per local IRB reporting requirements. In addition, 
research staff must ensure timely submission of any protocol amendments and obtain IRB approval 
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10.2 Required Documentation 
Before the study can be initiated, the following documentation must be placed on file. 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list 
• 
CVs and medical licensure for the principal investigator and any sub-investigators who will be 
involved in the study 
• 
Investigator’s signature documenting understanding of the protocol and providing commitment 
that this trial will be conducted according to all stipulations of the protocol  
 
10.3 Data Management 
The study principal investigator and study team will be responsible for study conduct and analysis. The 
study monitor will be responsible for source data verification.  
 
10.4 Data Collection 
Data collection is the responsibility of the study personnel at the site under the supervision of the 
principal investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. 
 
Hardcopies of study visit worksheets may be used as source document worksheets for recording data for 
each participant enrolled in the study. Data recorded in the electronic case report form (eCRF) derived 
from source documents should be consistent with the data recorded on the source documents. If source 
documentation is maintained in an electronic medical record, then electronic source is allowable if the 
system is 21 CFR 11 compliant, and access is provided to the monitor for clinical monitoring. 
Study data (including adverse events, AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by UNC Chapel Hill. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Study data will be entered directly from the source documents. Missing data will be noted in 
the database and the study team will provide reasons for missing data.  
 
10.5 Adherence to the Protocol 
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance may be 
either on the part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly. 
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations in a timely manner after identification of the protocol deviation, or prior to the scheduled 
protocol-required activity. All deviations must be addressed in study source documents and reported to 
the reviewing Institutional Review Board (IRB) per their policies. The principal investigator is responsible 
for knowing and adhering to the reviewing IRB requirements. 
 
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10.6 Noncompliance 
Noncompliance is defined by the UNC IRB as intentional or unintentional failure to follow applicable 
federal regulations, the requirements or determinations of the IRB, the IRB-approved study protocol, or 
University policies. Noncompliance can occur as a result of performing an act(s) that violate(s) 
requirements. Noncompliance can also occur as a result of failing to act when required.   
 
10.7 Unanticipated Problems Involving Risks to Subjects or Others 
10.7.1 Definition  
As defined by UNC’s IRB, unanticipated problems involving risks to study subjects or others (UPIRSO) 
refers to any incident, experience, or outcome that: 
• 
Is unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the subject population being 
studied; 
• 
Is related or possibly related to a subject’s participation in the research; and  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) related to the research than was previously known or 
recognized. 
 
10.7.2 Reporting  
Any UPIRSO that occurs during the conduct of this study and that meets the criteria must be reported to 
the UNC IRB using the IRB’s web-based reporting system. 
 
10.8 Definition of Adverse Events (AE) 
An adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)).  
 
10.9 Adverse Event Assessment  
A member of the study team will be present during all in-person visits during which Cytosponge, TNE 
and EGD will be administered to monitor safety and adverse event assessment. Participants will be 
assessed for adverse events during all in-person visits. All documented AEs will be addressed and 
followed until resolution and their resolution documented in the participant’s research record. Local IRB 
guidelines for reporting adverse events will be followed. Only those AEs that meet UNC IRB criteria for 
reporting will be reported to the UNC IRB.   
 
 
 
10.10 Severity of Event  
For adverse events (AEs) the following guidelines will be used to describe severity.  
 
• 
Grade 1 (Mild) – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Grade 2 (Moderate) – Events result in a low level of inconvenience or concern with the 
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• 
Grade 3 (Severe) – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious.” 
• 
Grade 4 (Life-Threatening) – Life-Threatening consequences; urgent intervention indicated. 
• 
Grade 5 (Death) – Death related to AE. 
 
10.11 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect. Only those events that are definitely related or possibly related 
to participation in this research study will be reported.   
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Possibly Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
“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. Reasonable 
possibility means that the event is more likely than not related to participation in the research 
or, in other words, there is a >50% likelihood that the event is related to the research 
procedures. 
• 
Somewhat Likely to be Related – There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events), so there is a <50% likelihood that the event is related to 
the research procedures. Although an AE may rate only as “somewhat likely to be related” soon 
after discovery, it can be flagged as requiring more information and later be upgraded to 
“possibly related” or “definitely related”, as appropriate. 
• 
Unlikely to be Related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 

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10.12 Expectedness 
The investigators will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
10.13 Unexpected Adverse Event 
An unexpected adverse event is defined by the UNC IRB as any adverse event occurring in one or more 
subjects participating in a research protocol, the nature, severity, or frequency of which is not consistent 
with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol-related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for 
the adverse event. 
 
10.14 Time Period and Frequency for Event Assessment and Follow-Up  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor.  
 
Only those events that are definitely related or possibly related to participation in this research study 
will be reported.  All AEs will be captured on the appropriate case report form (CRF). Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship to 
study device (assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Events will be followed for outcome information until resolution or stabilization. 
 
All new or worsening adverse events (AEs) will be collected for all subjects from the time of subject 
enrollment through study completion or termination of the clinical investigation.  
10.14.1 Serious Adverse Event (SAE) 
An SAE is any adverse event temporally associated with the subject’s participation in research that 
meets any of the following criteria: 
• 
Death; 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization;* 
• 
Results in congenital anomaly/birth defect; 

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• 
Results in a persistent or significant disability/incapacity; 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition. For reporting purposes, also consider the occurrences of 
pregnancy as an event, which must be reported as an important medical event. 
 
*Hospitalization for anticipated or standard of care specified procedures such as administration of 
chemotherapy, central line insertion, metastasis interventional therapy, resection of primary tumor, or 
elective surgery, will not be considered serious adverse events. 
 
10.14.2 Adverse Event Documentation and Reporting  
Research staff will maintain records of all adverse events and report them in a timely manner via 
completion of the Adverse Event Case Report Form.  The form should be updated with any changes 
including updates to severity, relatedness, and resolution. Adverse events will be reported to the UNC 
IRB per UNC IRB reporting requirements. 
 
Events will be described using the NCI Common Terminology Criteria for Adverse Events (CTCAE).  
 
10.15 Amending the Protocol 
Should amendments to the protocol be required, amendments will be originated and documented by 
the Principal Investigator at UNC. Changes only go into effect after it has been approved by appropriate 
regulatory IRB. Non-significant changes that do not impact subject safety or scientific integrity of the 
study may be communicated via protocol clarification memo in lieu of a formal amended protocol. 
 
10.16 Privacy and Confidentiality 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their institutions. This confidentiality is extended to cover testing and 
storage of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, biological specimens and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the Principal 
Investigator. 
 
All research activities will be conducted in as private a setting as possible. 
 
Authorized representatives of UNC Chapel Hill, representatives of the Institutional Review Board (IRB), 
regulatory agencies, or funding sponsor may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and other applicable study records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 

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Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored at the University of North Carolina at Chapel Hill. Individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by the University of North Carolina at Chapel Hill will be secured and 
password protected. At the end of the study, all study databases will be coded and archived at the 
University of North Carolina at Chapel Hill. Study participant identifiers will be documented in a master 
list; the master list will be maintained securely by the site investigators and kept separate from the 
research data. 
 
10.17 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source documents, Sponsor-
Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to the 
conduct of a clinical trial must be retained by the study investigator.  In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two years 
after the last approval of marketing application in an International Council for Harmonisation (ICH) 
region.  In all other cases, study documents should be kept on file until three years after the completion 
and final study report of this investigational study. 
 
10.18 Criteria for Terminating the Study 
The principal Investigator reserves the right to terminate the study but intends only to exercise this right 
for valid scientific or administrative reasons and reasons related to protection of subjects. Appropriate 
authorities including study funder and the IRB will be notified in writing in the event of termination. 
 
10.19 Investigator Responsibilities and Compliance 
The Principal Investigator is responsible for the conduct of the study at the site in accordance with 
ethical principles originating from the Declaration of Helsinki. The Principal Investigator must assure that 
all study site personnel, including sub-investigators and other study staff members, adhere to the study 
protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion.  
 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of 
the data 
 
This study will be conducted in full accordance all applicable UNC Policies and Procedures and all 
applicable Federal and state laws and regulations including 45 CFR 46, and the HIPAA Privacy Rule. Any 
episode of noncompliance will be documented. 
 

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The investigators will perform the study in accordance with this protocol, will obtain consent and assent 
(unless a waiver is granted), and will report unexpected problems in accordance UNC IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be accurate 
and will ensure the privacy, health, and welfare of research subjects during and after the study. 
 
10.20 Adherence to the Protocol  
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, the study shall be conducted exactly as described in the 
IRB-approved protocol.   
 
10.21 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior UNC or their respective institution’s IRB approval/favorable 
opinion.   
 
For any such emergency modification implemented, this occurrence will be reported to a UNC’s IRB as 
required by current UNC IRB reporting procedures.  
11 PUBLICATION 
Authorship of publications will abide by the criteria established by the International Committee of 
Medical Journal Editors: Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (August 2013). Procedural details including rights of review and 
timing will be governed by the terms listed and agreed to by both parties in a separate clinical research 
agreement. 
 
 

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12 ASSESSMENTS 
12.1 Visual Analog Scale (VAS)  
 
Date: 
-- 
(YYYY-MMM-DD) 
 
 
 
 
Please place an “X” on the line below to indicate the worst pain you felt with 
administration of the [Cytosponge/Transnasal Endoscopic Procedure 
(TNE)/Traditional Upper Endoscopy (EGD)]. 
 
 
 
No Pain   
    
     Worst pain imaginable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Internal Use Only: 
 
VAS score: mm  
 
Verified by: 
 
 
 

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12.2 Procedure Preference and Acceptability Questionnaire 
 
1. On a scale of 0-10, please rate your experience with the Cytosponge procedure:  
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
      
 10 
| 
 
 
 
 
 
| 
 
 
 
 
 
| 
Unacceptable,  
 
 
Tolerable as a necessary 
 
 
 
Not an issue, 
very difficult even 
 
 
 
medical test 
 
 
 
would take 
for a medical test 
without hesitation 
 
2. On a scale of 0-10, please rate your experience with the transnasal endoscopic procedure 
(TNE):   
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
      
 10 
| 
 
 
 
 
 
| 
 
 
 
 
 
| 
Unacceptable,  
 
 
Tolerable as a necessary 
 
 
 
Not an issue, 
very difficult even 
 
 
 
medical test 
 
 
 
would take 
for a medical test 
without hesitation 
3. On a scale of 0-10, please rate your experience with the traditional upper endoscopic 
procedure (EGD): 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
      
 10 
| 
 
 
 
 
 
| 
 
 
 
 
 
| 
Unacceptable,  
 
 
Tolerable as a necessary 
 
 
 
Not an issue, 
very difficult even 
 
 
 
medical test 
 
 
 
would take 
for a medical test 
without hesitation 
4. Would you be willing to repeat the Cytosponge procedure if your physician indicated it was 
medically necessary? 
Yes 
 
No  
 
5. Would you be willing to repeat the transnasal procedure (TNE) if your physician indicated it 
was medically necessary?  Yes 
 
No 
 
6. Would you be willing to repeat the traditional upper endoscopic procedure (EGD) if your 
physician indicated it was medically necessary?  Yes 
 
No 
 
7. Which procedure would you prefer to undergo again if your physician indicated it was 
medically necessary? 
 Traditional Upper Endoscopy (EGD) 
Cytosponge 
 
Transnasal Endoscopy (TNE) 
 
8. What factors, if any, influenced your decision (select all that apply)? 
Discomfort/Pain  Time (needed for preparation)   Cost   Need for Sedation  
 Other; Describe: ______________________ 
 

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12.3 Impact of Events Scale (IES) 
 
Below is a list of comments made by people in connection with their [Cytosponge/TNE/EGD] screening 
test. Please check each item, indicating how frequently these comments were true for you during the 
past seven (7) days. If they did not occur during that time, please mark the ‘not at all’ column. 
 
 
Not at all 
Rarely 
Sometimes 
Often 
 I thought about it when I did not mean to. 
 
 
 
 
I avoided letting myself get upset when I thought 
about it or was reminded of it. 
 
 
 
 
I tried to remove it from my memory. 
 
 
 
 
I had trouble falling asleep or staying asleep, 
because of pictures or thoughts about it that came 
into my mind. 
 
 
 
 
I had waves of strong feelings about it. 
 
 
 
 
I had dreams about it. 
 
 
 
 
I stayed away from reminders of it. 
 
 
 
 
I felt as if it wasn’t happening to me, or wasn’t 
real. 
 
 
 
 
I tried not to talk about it. 
 
 
 
 
Pictures about it popped into my mind. 
 
 
 
 
 
Other things kept making me think about it. 
 
 
 
 
I was aware that I still had a lot of feelings about it, 
but I didn’t deal with them. 
 
 
 
 
I tried not to think about it. 
 
 
 
 
Any reminder brought back feelings about it. 
 
 
 
 
 
 
 

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13 REFERENCES 
 
1. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2013, National Cancer 
Institute. Bethesda, MD. 2016. 
2. 
Wani S, Drahos J, Cook MB, et al. Comparison of endoscopic therapies and surgical resection in 
patients with early esophageal cancer: a population-based study. Gastrointest Endosc. 2014;79(2):224-
32.e1. Epub 2013/09/26. 
3. 
Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) 
esophageal adenocarcinoma in Barrett's esophagus. Gastroenterology. 2009;137(3):815-23. Epub 
2009/06/16. 
4. 
Vaughan TL, Fitzgerald RC. Precision prevention of oesophageal adenocarcinoma. Nat Rev 
Gastroenterol Hepatol. 2015;12(4):243-8. Epub 2015/02/11. 
5. 
Rubenstein JH, Saini SD, Kuhn L, et al. Influence of malpractice history on the practice of 
screening and surveillance for Barrett's esophagus. Am J Gastroenterol. 2008;103(4):842-9. Epub 
2007/12/14. 
6. 
Halpern R, Kothari S, Fuldeore M, et al. GERD-related health care utilization, therapy, and 
reasons for transfer of GERD patients between primary care providers and gastroenterologists in a US 
managed care setting. Dig Dis Sci. 2010;55(2):328-37. Epub 2009/08/22. 
7. 
Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett's esophagus with 
dysplasia. N Engl J Med. 2009;360(22):2277-88. Epub 2009/05/29. 
8. 
Phoa KN, van Vilsteren FG, Weusten BL, et al. Radiofrequency ablation vs endoscopic 
surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. 
JAMA. 2014;311(12):1209-17. Epub 2014/03/29. 
9. 
El-Serag HB, Naik AD, Duan Z, et al. Surveillance endoscopy is associated with improved 
outcomes of oesophageal adenocarcinoma detected in patients with Barrett's oesophagus. Gut. 
2016;65(8):1252-60. Epub 2015/08/28. 
10. 
Jung KW, Talley NJ, Romero Y, et al. Epidemiology and natural history of intestinal metaplasia of 
the gastroesophageal junction and Barrett's esophagus: a population-based study. Am J Gastroenterol. 
2011;106(8):1447-55; quiz 56. Epub 2011/04/13. 
11. 
El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology of gastro-oesophageal 
reflux disease: a systematic review. Gut. 2014;63(6):871-80. Epub 2013/07/16. 
12. 
Cameron AJ, Zinsmeister AR, Ballard DJ, et al. Prevalence of columnar-lined (Barrett's) 
esophagus. Comparison of population-based clinical and autopsy findings. Gastroenterology. 
1990;99(4):918-22. Epub 1990/10/01. 
13. 
Shaheen NJ, Falk GW, Iyer PG, et al. ACG Clinical Guideline: Diagnosis and Management of 
Barrett's Esophagus. Am J Gastroenterol. 2016;111(1):30-50. Epub 2015/11/04. 
14. 
Coleman HG, Xie SH, Lagergren J. The Epidemiology of Esophageal Adenocarcinoma. 
Gastroenterology. 2017. Epub 2017/08/07. 
15. 
Blevins CH, Iyer PG. Who Deserves Endoscopic Screening for Esophageal Neoplasia? Gastrointest 
Endosc Clin N Am. 2017;27(3):365-78. Epub 2017/06/05. 
16. 
Peery AF, Hoppo T, Garman KS, et al. Feasibility, safety, acceptability, and yield of office-based, 
screening transnasal esophagoscopy (with video). Gastrointest Endosc. 2012;75(5):945-53.e2. Epub 
2012/03/20. 
17. 
Jobe BA, Hunter JG, Chang EY, et al. Office-based unsedated small-caliber endoscopy is 
equivalent to conventional sedated endoscopy in screening and surveillance for Barrett's esophagus: a 
randomized and blinded comparison. Am J Gastroenterol. 2006;101(12):2693-703. Epub 2007/01/18. 
18. 
Saeian K, Staff DM, Vasilopoulos S, et al. Unsedated transnasal endoscopy accurately detects 
Barrett's metaplasia and dysplasia. Gastrointest Endosc. 2002;56(4):472-8. Epub 2002/09/26. 

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19. 
Kadri SR, Lao-Sirieix P, O'Donovan M, et al. Acceptability and accuracy of a non-endoscopic 
screening test for Barrett's oesophagus in primary care: cohort study. BMJ. 2010;341:c4372. Epub 
2010/09/14. 
20. 
Benaglia T, Sharples LD, Fitzgerald RC, et al. Health benefits and cost effectiveness of endoscopic 
and nonendoscopic cytosponge screening for Barrett's esophagus. Gastroenterology. 2013;144(1):62-
73.e6. Epub 2012/10/09. 
21. 
Jobe BA, Hunter JG, Chang EY, et al. Office-based unsedated small-caliber endoscopy is 
equivalent to conventional sedated endoscopy in screening and surveillance for Barrett's esophagus: a 
randomized and blinded comparison. Am J Gastroenterol. 2006;101(12):2693-703. Epub 2007/01/18. 
22. 
Saeian K, Staff DM, Vasilopoulos S, et al. Unsedated transnasal endoscopy accurately detects 
Barrett's metaplasia and dysplasia. Gastrointest Endosc. 2002;56(4):472-8. Epub 2002/09/26. 
23.  
Briere J, Elliott DM. Clinical utility of the impact of event scale: psychometrics in the general 
population. Assessment. 1998;5(2):171-80. Epub 1998/06/17 
24.  
Chang AO, Cotton CC, Eluri S, et al. Acceptability of Tissue Collection by Cytosponge in US 
Patients with Barrett's Esophagus. Gastroenterology. 2017;152(5):S457 
25.  
Kadri SR1, Lao-Sirieix P, O'Donovan M, Debiram I, Das M, Blazeby JM, Emery J, Boussioutas A, 
Morris H, Walter FM, Pharoah P, Hardwick RH, Fitzgerald RC. Acceptability and accuracy of a non-
endoscopic screening test for Barrett's oesophagus in primary care: cohort study. BMJ. 2010 Sep 
10;341:c4372. 
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Katzka DA, Smyrk TC, Alexander JA, Geno DM, Beitia RA, Chang AO, Shaheen NJ, Fitzgerald 
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14 ABBREVIATIONS 
 
AE  
Adverse Event  
ANOVA 
Analysis of variance 
BE  
Barrett's Esophagus  
Bx 
Biopsy 
CFR  
Code of Federal Regulations  
CRF  
Case Report Form  
Cyto 
Cytosponge 
EAC 
Esophageal Adenocarcinoma 
eCRF  
Electronic Case Report Form  
EGD  
Esophagogastroduodenoscopy  
EMR  
Endoscopic Mucosal Resection  
FDA  
US Food and Drug Administration  
GCP 
Good Clinical Practice 
GEJ  
Gastroesophageal Junction  
GERD 
Gastroesophageal Reflux disease 
GI 
Gastroenterologists 
H&E 
Hematoxylin and Eosin  
ICH 
International Council for Harmonisation 
IES 
Impact of Events Scale 
IMC  
Intramucosal Cancer  
INR 
International Normalized Ratio 
IRB  
Institutional Review Board  
NBI  
Narrow Band Imaging  
NCT 
National Clinical Trial Number 
PCP 
Primary Care Provider 
SAE  
Serious Adverse Event  
SOC 
Standard of Care 
TGF  
Top of Gastric Folds  
TNE 
Transnasal Endoscopy 
Tx  
Treatment  
UNC  
The University of North Carolina at Chapel Hill  
UPIRSO  
Unanticipated Problem Involving Risk to Subjects or 
Others  
VAS 
Visual Analogue Scale