Detection of Barrett s Esophagus in Patients Without Gastroesophageal Reflux Disease (GERD) Symptoms
Phase: NA
Conditions: Barrett's Esophagus
Sponsor: Case Comprehensive Cancer Center

1
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
Study Number: CASE 1221
Protocol Date: 14AUG2023
Study Title: Detection of Barrett’s Esophagus in Patients without GERD symptoms
PRINCIPAL INVESTIGATOR:
Amitabh Chak, M.D.
Department of Gastroenterology
University Hospitals Cleveland Medical Center
Case Western Reserve University
CO- INVESTIGATORS:
John Dumot, D.O.
Department of Medicine/Gastroenterology
University Hospitals Cleveland Medical Center
University Hospitals Ahuja Medical Center
Ashley Faulx, M.D. 
Department of Medicine/Gastroenterology 
University Hospitals Cleveland Medical Center
Sanford Markowitz, M.D.
University Hospitals Cleveland Medical Center
Case Western Reserve University
Joseph E. Willis, M.D.
Department of  Pathology
University Hospitals Cleveland Medical Center

2
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
Case Western Reserve University
                                                Helen Moinova, PhD
Case Comprehensive Cancer Center
Case Western Reserve University
DATABASE ADMINSTRATORS: 
Apoorva Chandar – Database Administrator 
Rajesh Gupta – Database Administrator
STATISTICIANS:
Jennifer Cullen, PhD
 
SPONSOR: 
Case Comprehensive Cancer Center
FUNDING SPONSOR:
NCI BETRNet and SPORE grants
CLINICAL FACILITIES: 
University Hospitals Cleveland Medical Center, University 
Hospitals Ahuja Medical Center, University Hospitals Westlake 
Surgery Center, University Hospitals North Ridgeville Medical 
Center, University Hospitals St. John Medical Center 
   
LEAD STUDY COORDINATOR:
Wendy Brock, R.N.
Department of Medicine/Gastroenterology
University Hospitals Cleveland Medical Center
Case Western Reserve University 
STUDY COORDINATORS:
Rajesh Gupta, R.N., M.S.N.
Department of Medicine/Gastroenterology
University Hospitals Cleveland Medical Center
Case Western Reserve University
Apoorva Chandar, MBBS
Digestive Health Institute

3
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
University Hospitals Cleveland Medical Center
Case Western Reserve University
Beth Bednarchik, R.N., CCRP
Department of Medicine/Gastroenterology
University Hospitals Cleveland Medical Center
Case Western Reserve University

4
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
TABLE OF CONTENTS
       
1.0
Background and Rationale
2.0
Objectives
3.0 
Selection of Patients
4.0
Registration Procedures
5.0
Data Safety Monitoring Plan
6.0
Study Calendar
7.0 
Study Conduct
8.0
Drug Information
9.0
Statistical Considerations
10.0
Patient Consent and Peer Judgment
11.0
Records to be Kept
12.0 
References

5
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
1.0 
BACKGROUND AND RATIONALE 
Whereas the rate of many common cancers has declined, the incidence of esophageal 
adenocarcinoma (EAC) has increased greater than six-fold over the past 3 decades.(1)  
Furthermore, the outcome of this cancer remains poor, accounting for over 1 in 50 adult male 
cancer-related deaths.(2) Although Barrett’s esophagus (BE), a precursor of EAC, can be easily 
recognized at endoscopy, current clinical strategies of endoscopic screening and surveillance 
based on the close association of BE with chronic Gastroesophageal Reflux Disease (GERD) in 
adults are woefully inadequate. Nearly 40% of patients who develop EAC have no preceding 
symptoms of GERD(3, 4) and less than 5% of EAC’s are diagnosed in patients whose BE was 
recognized prior to cancer diagnosis.(5) In recognition of the burden of morbidity and mortality 
caused by EAC and the clinical need to develop more effective screening, surveillance, and 
ablative strategies for BE, EsoCheck and EsoGuard (“EC/EG”) have been developed to offer an 
alternative to endoscopic screening,  to improve the detection, prognostication, and treatment of 
BE, with the ultimate goal of reducing the mortality associated with EAC. 
There has been a startling rise in the incidence of esophageal adenocarcinoma (EAC) in the 
United States during the past three decades, especially in white males where the incidence has 
gone up more than six fold.(1, 6-8) National statistics estimate 16,980 new cases of esophageal 
cancer, mainly adenocarcinomas, in 2015.(9) Although there have been advances in 
chemotherapy, radiotherapy, and surgical therapy, the prognosis remains poor with a dismally 
low five year survival of less than 20%.(9) Most EACs originate in Barrett’s epithelium, a pre-
malignant condition in which normal squamous epithelium is replaced by metaplastic specialized 
intestinal type columnar epithelium.(10-17) Despite endoscopic screening and surveillance 
efforts,(18) less than 5% of EAC are diagnosed in individuals with previously detected BE.(5) 
Gastroesophageal reflux disease (GERD) is closely associated with BE and is present in about 
10% of patients who have endoscopy for GERD(16, 18-20) but even if esophago-gastro-
duodenoscopy (EGD) was recommended in all adults with GERD, studies show that this strategy 
would only be partially effective at preventing EAC or detecting it early.(3, 4) The reason for 
limited effectiveness is that nearly 40% of adenocarcinomas occur in individuals without GERD 
symptoms.(3, 4) Other risk factors for BE and EAC include older age, male gender, white race, 
obesity, family history, and smoking.(17, 21, 22) We propose to use these risk factors to help 
detect BE in those without GERD symptoms.
Screening for BE is recommended in men with chronic GERD with two or more risk factors for 
BE or EAC.(21) Risk factors include age >50 years, White race, central obesity (waist 
circumference >102 cm or waist–hip ratio >0.9), smoking, and a family history of BE or EAC. 
Screening can be considered in women with multiple, four or more, risk factors for BE or EAC. 
Our studies of the Explorys database has shown that these risk factors are independent predictors 
of risk of BE and patients who do not have GERD and have three or more risk factors have a risk 
for BE that is similar to patients with GERD who have two risk factors. Using EC/EG we 
propose to expand screening to patients without GERD who have three or more risk factors for 
BE. This will enable the detection of BE in a group that is at risk for developing EAC but are 
currently not offered EGD.  
Endoscopy is the gold standard for diagnosis of BE, as biopsies obtained during endoscopy are 
the only means by which to identify intestinal metaplasia (as well as dysplasia). A more efficient 
use of diagnostic endoscopy in the setting of BE screening, whereby the “hit rate” were to 

6
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
increase for finding disease, and the rate of negative endoscopy were to decrease, would be 
advantageous.  EC/EG offers a means by which to achieve this goal. Using EC/EG as a triage 
step to suggest who, among those at risk of BE, should have an endoscopy, may be expected 
both to increase positive endoscopies and to decrease negative ones, due to the known high 
sensitivity, specificity, negative predictive value and useful positive predictive value of EG on 
samples collected via EC. EC/EG would also enable the screening of patients without GERD 
symptoms who are currently do not undergo EGD, expanding the detection of BE and prevention 
of EAC. The goal of this study is to demonstrate the ability to detect BE in a non-GERD 
population that is at risk for BE and demonstrate an improvement to the utilization of endoscopy 
when it is performed on those with a positive EC/EG result.  
2.0 
OBJECTIVES
We study whether using EsoCheck/EsoGuard (EC/EG) can detect BE in patients at risk for BE 
who are currently not being detected and are not undergoing routine EGD.
AIM 1.  Assess whether EC/EG can identify BE in a population at risk for BE
Estimate the positive predictive value of EC/EG in a non-GERD population that has three or 
more non-GERD risk factors for BE. Patients who are at risk will be offered EC/EG. Those who 
are positive will undergo subsequent EGD. 
 
AIM 2.  Confirm that patients who are negative as assessed by EC/EG do not have BE. 
Estimate the proportion of patients negative via EC/EG who subsequently are proven negative 
via EGD. This would be measured by offering EGD to a proportion of patients who are EC/EG 
negative.
 
3.0 
PATIENT SELECTION
3.1
Inclusion Criteria 
Patients who are undergoing colonoscopy are considered a reasonable representation of the 
population. Signed permission will be obtained from physicians who are performing 
colonoscopy to contact and recruit their subjects for this research. Patients who are at risk for BE 
but do not have chronic GERD and have not had a prior EGD will be accrued at time of their 
colonoscopy (21). Those eligible will be:
1. Adults > 50 who have no prior EGD and are able to provide informed consent
2. No known coagulopathy, no known esophageal varices.
3. No significant dysphagia or odynophagia
4. Absence of chronic GERD, defined as five or more years of heartburn or regurgitation 
with symptoms at least once a week when not on medications for GERD symptoms. 
5. Subjects to qualify must meet criterion 4, be over age 50, and have two additional risk 
factors for BE (white race, central obesity defined as waist size > 35 inches for women and > 40 

7
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
inches for men, male gender, current smoker or smoking history > 10 pack years, confirmed 
family history in at least two members with one being a first degree relative). 
3.2 Exclusion Criterion 
1. History of prior EGD procedure 
2. Inability to provide written informed consent
3. History of weekly of more frequent heartburn or regurgitation for five or more years
4. On anti-coagulant drug(s) that cannot be temporarily discontinued or coagulopathy with INR 
> 1.5
5. Known history of esophageal varices or esophageal stricture
6. Any contraindication, as deemed in Investigator’s medical judgment, to undergoing the 
EsoCheck procedure, undergoing the EGD procedure, and/or having biopsies taken, 
including but not limited to due to comorbidities such as coagulopathy or a known history of 
esophageal diverticula, esophageal fistula and/or esophageal ulceration 
7. History of difficulty swallowing (dysphagia) or painful swallowing (odynophagia), including 
swallowing pills
8. Oropharyngeal tumor
9. History of esophageal or gastric surgery, with exception on uncomplicated surgical 
fundoplication procedure
10. History of myocardial infarction or cerebrovascular accident within past 6 months
4.0 
 REGISTRATION PROCEDURES
Subjects will be identified through prescreening in the Electronic Medical Record (EMR) of 
patients scheduled for screening colonoscopy or other endoscopy procedures.  All endoscopy 
patients will receive a Clinical Research Opportunity Flyer with their endoscopy prep 
instructions which allows for a potential subject to opt-out of research.  After the patients report 
for their scheduled colonoscopy or other endoscopic visit, they will be additionally exposed to 
the research opportunity flyer in the endoscopy waiting room. If they do not “opt-out”, and are 
found to be agreeable for study inclusion, the informed consent process and a signed informed 
consent form will be obtained by a study nurse or non-conflicted study investigator not 
performing said scheduled procedure. 
5.0
DATA SAFETY MONITORING PLAN 
This multicenter investigation employs two diagnostic assessments (EsoGuard and both EGD 
visualization as well as pathologic assessment of EGD biopsies), both of which make use of 
marketed medical devices which have obtained FDA 510(k) clearances (EsoCheck and 

8
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
endoscopies). As well, the EsoGuard test is offered as an LDT at a CLIA/CAP certified facility 
(ResearchDx, Irvine, CA). It will perform non-endoscopic sampling of the esophagus. 
Endoscopy with biopsy sampling of the esophagus will be performed subsequently as needed 
when EsoCheck is positive or if those with a negative EsoCheck volunteer for a research 
endoscopy. The recruitment, non-endoscopic sampling, upper endoscopic screening protocols 
and collection of biospecimens pose minimal risk to participants.  Because of this low risk status, 
the data safety monitoring (DSM) plan for this trial focuses on close monitoring by the principal 
investigators in conjunction with a safety officer, along with prompt reporting of any serious 
adverse events to the NIH and to the IRB at the respective institution.
  
The frequency of data review for this study is shown in the following table:
Table 2 Data Safety Monitoring Plan
Data type
Frequency of review
Subject accrual (adherence to protocol regarding 
demographics, inclusion/exclusion)
Quarterly 
Adverse event rates (injuries) related to 
endoscopic procedures
Quarterly 
Qualifications and responsibilities of the Safety Officer
The safety officer for this trial will be Jeffry Katz, M.D. who is independent and is not 
participating in this clinical trial.  Dr. Katz is board certified in gastroenterology and has 
experience running epidemiological studies. He understands the types and severity of injuries 
commonly experienced as a result of upper endoscopy.  As Safety Officer, Dr. Katz will review 
the reports sent by the study coordinator (at the frequency outlined above) and determine 
whether there is any corrective action, trigger of an ad hoc review, or stopping rule violation that 
should be communicated to the study investigators, UH Cancer Center IRB, the University 
Hospitals Case Medical Center IRB, and the NCI.  
Measurement and reporting of subject accrual, adherence to inclusion/exclusion criteria
Review of the rate of subject accrual, adherence to inclusion/exclusion criteria occurs every 3 
months during the study.  Because BE and EAC predominantly affect Caucasian males we 
expect to see a lower recruitment of women and other ethnic groups.
Measurement and reporting of adverse events
We plan to collect injury data from the endoscopic procedures quarterly.  We plan to present 
unblended adverse events data to the principal investigators and the safety officer throughout this 
trial. Any adverse event will also be reported to the Quality Assurance Committee of the 
institution where it occurs and the IRB. Adverse event forms that meet the goals of this data 
safety monitoring plan already exist and will be used by the study staff to report injuries or other 
adverse events caused by endoscopic procedures. The risks of routine diagnostic upper 
endoscopy are minimal and include a risk of bleeding, aspiration, and adverse reaction to 
sedative medications. The complication rate for routine sedated upper endoscopic diagnostic 
procedures is 0.1 to 0.5%(23). The complication rate for balloon detection study is expected to 

9
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
be much lower as no complications have been noted in over 600 cases performed to date. Any 
adverse event rate over 0.5 % in 12 months will be reported to all institutional IRBs and the NIH.  
Stopping rules
In this minimal risk trial it is unlikely that excess adverse events will occur and require stopping 
the trial.  However, as outlined, we will monitor injury rates in all participants and the safety 
officer, together with the study investigators, will alert the IRB and the NIH if a larger than 
reasonably expected injury rate (> 0.5%) should occur.  
6.0
STUDY CALENDAR
Study Team will:

Ensure IRB approved DHI Clinical Research Opportunity Flyers are provided to 
endoscopy patients with their endoscopy prep instructions sent by central scheduling

Identify a potential subject in Soarian or Provation the day before the colonoscopy.

Complete HIPAA approved pre-screening of potential subject for inclusion/exclusion 
criteria in EMR

Check that potential subject is not listed on the DHI Research “Opt Out” List.

Obtain treating gastroenterologist permission to approach patient on day of procedure and 
if yes,

Ensure DHI Clinical Research Opportunity Flyers (openly available to patients in the 
general waiting area of the GI suite), which contain research contact “opt out” 
procedures, are provided.

Once the potential subject has completed their standard of care (SOC) admission process, 
and has been assigned to their pre-procedure station, the study coordinator will ask the 
admitting nurse the following questions: 
1. Did the patient ask to not be contacted for research?
2. Does the patient speak and understand English?
3. Has the patient been administered sedative medication?

If the subject meets the criteria listed above (answers “no” to questions #1, #3, and “yes” 
to question #2) the patient will be approached by the study coordinator.  The study 
coordinator will use the Research Introduction Script  (below) to determine if the subject 
is interested in participating in research as follows:
“Hi, I am _____________________________.  I am a research nurse with the GI 
department.  I would like to talk to you about a research study.  Would you be interested 
in hearing about a study that you may qualify for?  If you are feeling too distracted or 
anxious because of your procedure, or you aren’t interested, it’s okay to say no.”
If the potential subject answers “yes”, proceed with the study description and consenting 
process using IRB approved ICF.
If the potential subject answers “no”, the potential subject will be thanked for their time 
and the research nurse will walk away. “Thank you for your time”.

10
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
Timepoint
Procedures
Informed 
Consent
ROI 
signature
Questionnaire 
completion 
with 
coordinator
EsoCheck
EsoGuard
Upper 
Endoscopy 
Tissue 
Samples 
Collected 
Day of scheduled 
procedure
X
X
X
X
Send samples and  
receive results
X
If positive, 
subject requested 
to complete SOC 
upper endoscopy
X
X
If negative, 100 
volunteers to 
complete 
research upper 
endoscopy
X
X
7.0
 STUDY CONDUCT 
  Patients are sent to screening colonoscopy and other endoscopic procedures through open 
access scheduling where they see their treating gastroenterology endoscopist on the day of the 
endoscopic procedure in the UH endoscopy suite locations. Ensuring the patient understands 
their scheduled procedure, consent is obtained by their treating gastroenterologist/team at that 
time.
Patients who are scheduled for a screening colonoscopy and other endoscopic procedures with a 
UH gastroenterologist will receive endoscopy prep information by mail or email. A copy of the 
DHI Clinical Research Opportunity Flyer will be included with this endoscopy prep information.  
This will allow patients to independently review their opportunity for research and determine if 
they are interested in participating in research. They can choose to “opt-out” of the opportunity 
by calling the designated study coordinator listed on the flyer. 
 Scheduled endoscopy patients wait in the pre-op waiting room in their UH endoscopy suite 
location. While they are waiting, they will openly be exposed to copies of the DHI Clinical 
Research Opportunity Flyer located in the waiting room for their review.  The flyer will offer the 
potential research subject an “opt-out” option for research.  This will allow patients to 
independently review their opportunity for research and determine if they are interested in 

11
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
participating in research. They can choose to “opt-out” of the opportunity by telling their 
admitting nurse they do not want to be approached for research.
The study coordinator will review the potential study subject’s scheduled procedure  and will 
identify patients with age of > 50 years who have no chronic GERD and have at least two other 
factors for BE/EAC (male gender, white race, smoking history, central obesity, or family 
history). Eligible colonoscopy  patients who have not expressed their desire to “opt-out” of 
research , with permission from the physician performing their procedure (whom patient will 
meet on the day of the scheduled procedure), will be approached by a member of the study team 
to acquaint them with the following: an introduction to the study using the research informational  
flyer, the privacy and quiet of the enclosed area, given adequate time to consider their 
participation and ask and have questions answered, with possible family around, and before any 
scheduled sedation. They will be asked questions to confirm their eligibility.
 The study team member will initially and purposefully allow the potential subject to “opt-out” 
of being approached for study inclusion.  The study team member will assure the subject that 
they will not need to participate in the study to receive their scheduled clinical care and they will 
receive their prescribed medical care whether they decide to participate in the research, or not.  If 
the potential subject is agreeable and found to be eligible, they will be presented with the 
consenting process by the Human Research Protections Certified member of the research team.  
If they agree to participate and have signed and dated the approved informed consent form, they 
will then be asked to complete the study Questionnaire, Release of Medical Information Form 
with the study team and then undergo the EsoCheck procedure prior to their scheduled 
endoscopic procedure.
Once eligibility has been established the study will be explained in detail by one of the study 
team.  Specifically, it will be explained that participation requires the following:
1. Written informed consent to participate in the study.  
2. Donation of biofluids or tissue collected during non-endoscopic sampling (EsoCheck 
Procedure).
3. Signature of “Authorization for Release of Medical Information” form (Appendix G) by 
affected subjects or their authorized representative to allow researchers to obtain surgical 
reports, pathology reports, chart summaries, and/or paraffin-embedded tumor blocks and 
matching H & E slides related to the diagnosis of BE and/or EAC.
4. Completion of a Study Questionnaire that asks questions about reflux symptoms and 
patient’s attitudes toward non-endoscopic screening. 
5. Performance of an EsoCheck procedure; the EsoCheck sample will subsequently be tested 
with the EsoGuard assay.
6. Patients whose EsoGuard assay results comes back positive, suggesting that they may have 
BE, will be recommended an EGD and contacted to undergo EGD. This will be a standard of 
care billable EGD. EsoGuard assay results may take up to two weeks from the date when the 
sample is obtained. Patients will be contacted by phone and results will be discussed with 
them. The patient will then have the opportunity to schedule an EGD at their convenience.

12
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
7. Selected patients whose EsoGuard assay comes back negative will also be offered a research 
EGD if they consent. . EsoGuard assay results may take up to two weeks from the date when 
the sample is obtained. Patients will be contacted by phone and results will be discussed with 
them. If the patient chooses, they will then have the opportunity to schedule an EGD at their 
convenience.  This will be a research EGD.
8. Patients who participate in the research study and undergo EC/EG will be provided $20 as a 
token of appreciation along with a parking pass. In addition, those who are EC/EG negative 
and undergo a research EGD will be offered $60 as an additional token of appreciation along 
with a parking pass. 
The study Questionnaire obtains details regarding GERD symptoms, environmental exposure 
history, family history, height, weight, and prior upper endoscopy along with attitudes toward 
non-endoscopic screening. The questionnaire will take approximately 5 to 15 minutes to 
complete.  The gastroesophageal reflux questionnaire (GERQ) is a validated measure of reflux 
symptoms and environmental exposure history developed by the Mayo Clinic(24).  
The EsoCheck procedure is performed according to its Instructions for Use (Appendix 1). 
Samples collected are sent by study coordinators to ResearchDx/PacificDx, a licensed 
CAP/CLIA Laboratory, 5 Mason, Suite 100, Irvine CA 92618 where the EsoGuard assay will be 
performed.  The EsoGuard test extracts DNA from the esophageal samples.  DNA is reduced 
with bisulfite and then assayed for methylated Vimentin and methylated CCNA1 using specific 
primers. % methylated Vimentin > 2% or % methylated CCNA1 > 0.5% is considered positive.
 
Patients who have a positive EsoGuard assay will then be offered and undergo standard of care 
EGD. They will be informed that this endoscopy will be billed to insurance. EsoGuard is an 
approved laboratory developed test. Up to 100 patients who have a negative EsoGuard assay will 
also be offered a research EGD free of charge if they choose to participate further in research. 
Patients with BE or EAC at EGD will have standard of care screening and diagnostic biopsies. 
Biopsies from BE and EAC will be directed by using high definition narrow band imaging. 
Biospecimens will also be snap frozen at bedside and stored for future research assays. 
In patients found to have BE, biopsy specimens for routine histology will be obtained at 2-cm 
intervals along the entire length of the Barrett's epithelium following standard of care “Seattle” 
protocol.  In patients with a normal esophagus or BE, additional brushings or biopsies will be 
obtained for research purposes from areas of columnar appearing mucosa and also from normal 
squamous mucosa at least 3cm proximal to the squamocolumnar junction, normal gastric 
mucosa, or normal duodenal mucosa for control purposes. A total of up to 12 additional research 
brushings or biopsies will be obtained. 
8.0
DRUG INFORMATION
Patients may be offered Cetacaine, a topical anesthetic spray and/or viscous lidocaine applied 
to the pharynx to minimize gag reflex for the balloon capsule procedure.

13
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
9.0
STATISTICAL CONSIDERATIONS
EsoCheck/EsoGuard positive will mean the reporting of a “positive” result for an EsoGuard test 
run on a sample obtained via EsoCheck. EGD positive will mean a result of BE (whether or not 
dysplasia is also present) and/or EAC based on the visualization of salmon-colored mucosa on 
EGD as well as the reported pathologic finding of intestinal metaplasia, dysplasia and/or 
neoplasia.  
A two by two table will be constructed comparing results from EC/EG and result from EGD 
histology.
EGD Positive
EGD Negative
Total
EsoCheck/EsoGuard Positive
PP
PN
PP+PN
EsoCheck/EsoGuard Negative
NP
NN
NP+NN
Total
PP+NP
PN+NN
n
where 
PP is the number of patients who test positive via EsoCheck/EsoGuard then positive via EGD, 
PN is the number of patients who test positive via EsoCheck/EsoGuard then negative via EGD, 
NP is the number of patients who test negative via EsoCheck/EsoGuard then positive via EGD, 
NN is the number of patients who test negative via EsoCheck/EsoGuard then negative via EGD.  
n = PP+PN+NP+NN  and represents the total sample size.
Primary Aim 1.  Calculate positive predictive value for patients who have EC/EG then 
undergo EGD.
For patients who are predicted to be positive via EsoCheck/EsoGuard to undergo EGD.  The 
estimated EGD positive rate for Strategy B is B = PP/(PP+PN).
B will be calculated and reported with 95% confidence intervals. 
Primary Aim 2.  Calculate proportion of patients who have negative EC/EG and are also 
confirmed to be negative for BE when they undergo EGD.
Study population and justification of sample size: 
The prevalence of BE in male patients with chronic GERD symptoms who have two other risk 
factors is 7-10%.(21) A study that performed EGD on 822 men undergoing colonoscopy reported 
that up to 7% of those without GERD who met criteria similar to what we will use for this study 
had BE.(25) Furthermore, using the M-BERET BE risk prediction model developed at the 
University of Michigan, we tested various scenarios that fit our inclusion criteria and found the 
prevalence of BE for the proposed study population would be expected to be between 4-6%. To 
be conservative, we have estimated the PPV using a sample size of 500 subjects for the lower 

14
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
estimated prevalence of 4% and 5%. Our goal is to develop a screening test with a minimal 
threshold PPV of 20%. 
We propose to recruit 500 patients for EC/EG based on the following analysis. If we assume a 
5% prevalence of BE in the study population, with a 90/90 sensitivity/specificity for the 
EsoGuard assay(26), then 70 would undergo endoscopy, of whom 22 would be true positive (true 
PPV 32% with 95% CI of 26.3-39.1%). If we assume a 4% prevalence of BE in the study 
population, with a 90/90 sensitivity/specificity for the EsoGuard assay(26), then 66 patients 
would undergo  endoscopy, of whom 18 would be true positive (true PPV 27% with 95% CI of 
21.6-33.7%). 
The majority of these patients will have a negative EsoGuard assay. Of those with a negative 
EsoGuard assay, we will recruit up to 100 patients for a research EGD. 
Assuming that the sensitivity of EsoGuard is 90% and the prevalence of BE in our population is 
5%, the expected rate of missed BE will be 0.5% in EsoGuard negative patients. If we perform 
EGD on 100 patients then we will be able to estimate a miss rate of 0.5% with a 95% confidence 
of + 1.4%. Even if we assume that the sensitivity of EsoGuard is only 80%, then the expected 
rate of missed BE will be 1% in EsoGuard negative patients. If we perform EGD on 100 patients, 
then we will be able to estimate a miss rate of 1% with a 95% confidence of + 2%, i.e. a positive 
test result defines a population with a 27-fold enrichment for BE versus a test negative 
population.
The research EGD procedure will be billed to research; therefore, patients will not have to pay 
for EGD costs if they have a negative EsoGuard assay result. The performance of research EGD 
on 100 patients with negative EsoGuard assays will allow us to estimate the proportion of BE 
patients that are missed by an EC/EG strategy in these patients. 
400 subjects will be recruited at UH locations. We plan to extend enrollment for this study to 
other sites by 100 subjects to obtain a planned final enrollment of 500.
10.0
PATIENT CONSENT AND PEER JUDGEMENT
All institutional, NCI, FDA, state and Federal regulations concerning informed consent and peer 
judgment will be fulfilled. 
11.0
RECORDS TO BE KEPT
To ensure confidentiality for patients participating in the study, numbers will be assigned to each 
subject. Each study coordinator and PI has access to participant identifiers and the assigned 
numbers at their respective institutions.  Questionnaire information will be identified by a code 
number.  All subject records (hard copy) will be stored in locked file cabinets at the institution 
where the patient was enrolled.  All coded information (questionnaire data, pathology reports, 
surgical reports, endoscopy reports and lab analysis results) collected about a participant will be 
entered into Labmatrix and Veeva Vault, secure electronic databases.  The information stored in 
these databases is protected under HIPAA and all individuals with access to the information 
follow government regulations to protect the privacy of research study subjects. 

15
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
If participants are patients at the institution where they are recruited, results from research and 
other information obtained during the study will not be placed in the patient’s medical record.  If 
standard of care lab test results are confirmed in a CLIA laboratory it is appropriate to include 
those results in the patient’s medical record.  Esoguard and possible research EGD results will be 
shared with research participants and their physician.  Esoguard results will be placed in EMR by 
study investigators and copied to the primary physician.  Patients will also be called by phone 
with results.

16
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
12.      REFERENCES
1.
Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase 
of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005;97(2):142-6.
2.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin.60(5):277-
300.
3.
Chak A, Faulx A, Eng C, Grady W, Kinnard M, Ochs-Balcom H, Falk G. 
Gastroesophageal reflux symptoms in patients with adenocarcinoma of the esophagus or cardia. 
Cancer. 2006;107(9):2160-6.
4.
Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux 
as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340(11):825-31.
5.
Dulai GS, Guha S, Kahn KL, Gornbein J, Weinstein WM. Preoperative prevalence of 
Barrett's esophagus in esophageal adenocarcinoma: a systematic review. Gastroenterology. 
2002;122(1):26-33.
6.
Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal 
and gastric carcinoma in the United States. Cancer. 1998;83(10):2049-53.
7.
Blot WJ, Devesa SS, Kneller RW, Fraumeni JF, Jr. Rising incidence of adenocarcinoma 
of the esophagus and gastric cardia. JAMA. 1991;265(10):1287-9.
8.
Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence 
of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology. 
1993;104(2):510-3.
9.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-
29.
10.
Cameron AJ, Lomboy CT, Pera M, Carpenter HA. Adenocarcinoma of the 
esophagogastric junction and Barrett's esophagus. Gastroenterology. 1995;109(5):1541-6.
11.
Haggitt RC, Tryzelaar J, Ellis FH, Colcher H. Adenocarcinoma complicating columnar 
epithelium-lined (Barrett's) esophagus. Am J Clin Pathol. 1978;70(1):1-5.
12.
Hameeteman W, Tytgat GN, Houthoff HJ, van den Tweel JG. Barrett's esophagus: 
development of dysplasia and adenocarcinoma. Gastroenterology. 1989;96(5 Pt 1):1249-56.
13.
Hirota WK, Loughney TM, Lazas DJ, Maydonovitch CL, Rholl V, Wong RK. 
Specialized intestinal metaplasia, dysplasia, and cancer of the esophagus and esophagogastric 
junction: prevalence and clinical data. Gastroenterology. 1999;116(2):277-85.
14.
Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS. Flow-
cytometric and histological progression to malignancy in Barrett's esophagus: prospective 
endoscopic surveillance of a cohort. Gastroenterology. 1992;102(4 Pt 1):1212-9.
15.
Ruol A, Parenti A, Zaninotto G, Merigliano S, Costantini M, Cagol M, Alfieri R, 
Bonavina L, Peracchia A, Ancona E. Intestinal metaplasia is the probable common precursor of 
adenocarcinoma in barrett esophagus and adenocarcinoma of the gastric cardia. Cancer. 
2000;88(11):2520-8.
16.
Sharma P, McQuaid K, Dent J, Fennerty MB, Sampliner R, Spechler S, Cameron A, 
Corley D, Falk G, Goldblum J, Hunter J, Jankowski J, Lundell L, Reid B, Shaheen NJ, 
Sonnenberg A, Wang K, Weinstein W, Workshop AGAC. A critical review of the diagnosis and 
management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology. 
2004;127(1):310-30.
17.
Spechler SJ. Clinical practice. Barrett's Esophagus. N Engl J Med. 2002;346(11):836-42.
18.
Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and 
therapy of Barrett's esophagus. Am J Gastroenterol. 2008;103(3):788-97.

17
BNET_2017_Balloon_subprotocol 
CASE 1221 Version: 14AUG2023
19.
Cameron AJ, Lomboy CT. Barrett's esophagus: age, prevalence, and extent of columnar 
epithelium. Gastroenterology. 1992;103(4):1241-5.
20.
Shaheen N, Ransohoff DF. Gastroesophageal reflux, barrett esophagus, and esophageal 
cancer: scientific review. JAMA. 2002;287(15):1972-81.
21.
Shaheen NJ, Falk GW, Iyer PG, Gerson LB. ACG Clinical Guideline: Diagnosis and 
Management of Barrett's Esophagus. Am J Gastroenterol. 2015.
22.
American Gastroenterological A, Spechler SJ, Sharma P, Souza RF, Inadomi JM, 
Shaheen NJ. American Gastroenterological Association medical position statement on the 
management of Barrett's esophagus. Gastroenterology. 2011;140(3):1084-91.
23.
Poynton AR, Walsh TN, O'Sullivan G, Hennessy TP. Carcinoma arising in familial 
Barrett's esophagus. Am J Gastroenterol. 1996;91(9):1855-6.
24.
Locke GR, Talley NJ, Weaver AL, Zinsmeister AR. A new questionnaire for 
gastroesophageal reflux disease. Mayo Clin Proc. 1994;69(6):539-47.
25.
Rubenstein JH, Morgenstern H, Appelman H, Scheiman J, Schoenfeld P, McMahon LF, 
Jr., Metko V, Near E, Kellenberg J, Kalish T, Inadomi JM. Prediction of Barrett's esophagus 
among men. Am J Gastroenterol. 2013;108(3):353-62. PMCID: PMC3903120.
26.
Moinova HR, LaFramboise T, Lutterbaugh JD, Chandar AK, Dumot J, Faulx A, Brock 
W, De la Cruz Cabrera O, Guda K, Barnholtz-Sloan JS, Iyer PG, Canto MI, Wang JS, Shaheen 
NJ, Thota PN, Willis JE, Chak A, Markowitz SD. Identifying DNA methylation biomarkers for 
non-endoscopic detection of Barrett's esophagus. Sci Transl Med. 2018;10(424). PMCID: 
PMC5789768.