Advanced Angle-Resolved Low Coherence Interferometry (a/LCI) Systems for Improved Clinical Utility: An a/LCI-Optical Coherence Tomography (OCT) Pilot Study
Phase: NA
Conditions: Barrett Esophagus
Sponsor: Duke University

 
 
 
 
 
Advanced a/LCI Systems for Improved Clinical Utility: 
An Optical Coherence Tomography (OCT) Pilot Study 
(OCT Pilot) 
 
 
Principal Investigators: 
 
Nicholas J Shaheen MD, MPH 
Professor of Medicine 
Chief, Division of Gastroenterology & Hepatology 
University of North Carolina at Chapel Hill 
 
Adam P Wax, PhD 
Professor and Director of Graduate Studies 
Department of Biomedical Engineering 
Duke University 
 
IDE Sponsor: Dr. Adam Wax, Duke University 
 
Funded by: National Cancer Institute (NCI) 
Award No.: R01CA210544 
 
ClinicalTrials.gov Identifier: NCT03434834 (cohort A) 
ClinicalTrials.gov Identifier: NCT04392167 (cohort B) 
 
Version Number: 4.0 
 
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Summary of Changes 
The table below summarizes changes from protocol version 3.0, 10Oct2019. 
 
Description of Change  
Section(s) 
Impacted 
Brief Rationale 
Added dual modality a/LCI-OCT probe  
Entire document  
Addition of a/LCI engine aids in 
detection of dysplasia by 
measuring nuclei within the 
epithelium. 
Added “Cohort B” defined as the cohort who will 
be administered the dual modality a/LCI-OCT 
probe 
Entire document 
To allow for a combined modality 
a/LCI-OCT probe to be studied in 
parallel with the current probe.   
Increased study duaration to 24 months 
Section 1.1 
To allow for phase II/Cohort B. 
Added collection of research-specific biopsies for 
Cohort B only and associated risks 
Sections 1.2, 1.3, 
2.3, 2.3.1, 2.3.3, 
8, 8.1.2.1, 
8.1.2.3, 10.2 
Conconcurrent biopsies at 
imaging site to validate imaging 
with current standard of 
detecting dysplasia. 
Added Inclusion criteria specific to Cohort B: 
Current dysplastic or non-dysplastic Barrett’s 
Esophagus of any length OR, History of dysplastic 
or non-dysplastic Barrett’s Esophagus after 
treatment with endoscopic eradication therapy 
(EET) OR, Normal asymptomatic controls without 
any history of dysplastic Barrett’s Esophagus 
Section 5.1 
To specify inclusion criteria for 
Cohort B. 
Modified Inclusion criterion 2.1.3 for Cohort A to 
clarify subjects previously ablated with current 
neosquamous tissue are allowable 
Section 5.1 
Clarification. 
Added Exclusion criteria specific to Cohort B: 
Uncontrolled coagulopathy 
Section 5.2 
To specify exclusion criteria for 
Cohort B. 
Modified section title from “Optical Probe” to 
“OCT Optical Probe”  
Section 6.1.1 
To clarify section is referencing 
OCT optical probe 
Added A/LCI Engine Section 
Section 6.1.3 
To provide specifications on the 
a/LCI engine probe components. 
Added A/LCI Optical Probe Section 
Section 6.1.4 
To provide specifications on the 
a/LCI optical probe components. 
Added A/LCI-OCT Engine Section 
Section 6.1.5 
To provide specifications on the 
dual modality a/LCI-OCT probe. 
Added section referencing use of clincial 
pathology reports and slide acquisition from 
clinical biopsies in this study 
8.1.2.3 
To aid in evaluation of device 
performance. 
Amended statistics section to increase sample 
size  
Section 9.2, 9.3, 
9.4  
Statistics amended for larger 
sample size required to 
accommodate Cohort B.  
Administrative changes to table of contents, 
protocol version date, and number 
Entire document 
Administrative. 

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................ 2 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Background........................................................................................................................................... 5 
2.2 
Study Rationale .................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 7 
2.3.1 
Known Potential Risks ..................................................................................................... 7 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND OUTCOMES ................................................................................................................ 9 
4 
STUDY DESIGN ............................................................................................................................................. 9 
4.1 
Overall Design ...................................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design.............................................................................................. 10 
4.3 
End of Study Definition ..................................................................................................................... 10 
5 
STUDY Population ....................................................................................................................................... 10 
5.1 
Inclusion Criteria ................................................................................................................................ 10 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 12 
5.4 
Screen Failures .................................................................................................................................. 12 
6 
STUDY INTERVENTION ............................................................................................................................ 12 
6.1 
Device Description ............................................................................................................................. 12 
6.1.1 
aCI/OCT Optical Probe ................................................................................................. 13 
6.1.2 
OCT Engine .................................................................................................................... 14 
6.1.3 
a/LCI ENGINE ................................................................................................................ 15 
6.1.4 
A/LCI OPTICAL PROBE ............................................................................................... 16 
6.1.5 
a/LCI-oct engine ............................................................................................................. 16 
6.1.6 
Computer ......................................................................................................................... 17 
6.1.7 
Physical Enclosure and Power Bus ............................................................................. 17 
6.2 
Non-Significant Risk (NSR) .............................................................................................................. 17 
6.2.1 
NSR Justification ............................................................................................................ 17 
6.2.2 
NSR compliance............................................................................................................. 18 
6.3 
Preparation/Handling/Storage/Accountability ................................................................................ 19 
6.3.1 
Acquisition and accountability ...................................................................................... 19 
6.3.2 
Device Labeling .............................................................................................................. 19 
6.3.3 
Device Storage ............................................................................................................... 20 
6.3.4 
Preparation ...................................................................................................................... 20 
6.4 
Concomitant Therapy ........................................................................................................................ 20 
6.4.1 
Rescue Medicine ............................................................................................................ 20 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 20 
7.1 
Strategies for Recruitment and Retention ...................................................................................... 20 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 21 
7.3 
Lost to Follow-Up ............................................................................................................................... 21 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 22 
8.1 
Schedule of Activities (SOA) ............................................................................................................ 22 
8.1.1 
Screening ........................................................................................................................ 22 

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8.1.2 
Enrollment ....................................................................................................................... 22 
8.1.3 
7 Day Follow-Up ............................................................................................................. 24 
8.2 
Adverse Events and Serious Adverse Events ............................................................................... 25 
8.2.1 
Definition of Adverse Events (AE) ............................................................................... 25 
8.2.2 
Definition of Serious Adverse Events (SAE) .............................................................. 25 
8.2.3 
Unanticipated Adverse Device Effect .......................................................................... 25 
8.2.4 
Classification of an Adverse Event .............................................................................. 25 
8.2.5 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 27 
8.2.6 
Adverse Event Reporting .............................................................................................. 27 
8.2.7 
Other Safety Reporting.................................................................................................. 28 
8.2.8 
Reporting Events to Participants ................................................................................. 28 
8.2.9 
Events of Special Interest ............................................................................................. 28 
8.2.10 
Reporting of Pregnancy ................................................................................................ 28 
8.3 
Unanticipated Problems .................................................................................................................... 28 
8.3.1 
Definition of Unanticipated Problems (UP) and Unanticipated adverse Device 
Effect (UADE) 
28 
8.3.2 
Unanticipated Problem (UP) Reporting ...................................................................... 29 
8.3.3 
Unanticipated Adverse Device Effect (UADE) Reporting ......................................... 29 
8.3.4 
Reporting Unanticipated Problems (UPs) and Unanticipated Adverse Device 
Effects (UADEs) to Participants ...................................................................................................................... 30 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 30 
9.1 
Statistical Hypotheses ....................................................................................................................... 30 
9.2 
Sample Size Determination .............................................................................................................. 30 
9.3 
Populations for Analyses .................................................................................................................. 31 
9.4 
Statistical Analyses............................................................................................................................ 31 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 31 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 31 
10.1.1 
Informed Consent Process ........................................................................................... 31 
10.1.2 
Study Discontinuation and Closure ............................................................................. 32 
10.1.3 
Confidentiality and Privacy ........................................................................................... 33 
10.1.4 
Future Use of Data ......................................................................................................... 33 
10.1.5 
Key Roles and Study Governance .............................................................................. 34 
10.1.6 
Safety Oversight ............................................................................................................. 34 
10.1.7 
Clinical Monitoring .......................................................................................................... 34 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 35 
10.1.9 
Data Handling and Record Keeping ............................................................................ 35 
10.1.10 
Protocol Deviations ........................................................................................................ 36 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 36 
10.1.12 
Conflict of Interest Policy .............................................................................................. 37 
10.2 
Abbreviations ...................................................................................................................................... 37 
11 
REFERENCES ............................................................................................................................................. 39 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the National 
Cancer Institute Terms and Conditions of Award. The Principal Investigator will assure that no deviation 
from, or changes to the protocol will take place without prior agreement from the Investigational New 
Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) 
to the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent using a previously approved consent form. 
 
 
Principal Investigator: 
 
 
________________________________  
Print/Type Name 
 
 
 
Signed: 
 
 
_____________________________________ Date: ______________  
Signature 
 
 

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PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
Advanced a/LCI Systems for Improved Clinical Utility: An Optical 
Coherence Tomography (OCT) Pilot Study (OCT Pilot) 
 
Study Description: 
This is a pilot study to test the operating characteristics of a newly 
developed dual modality probe including optical coherence 
tomography (OCT) and angle-resolved low-coherence interferometry 
(a/LCI) in human subjects, and to collect data for further 
optimization of the a/LCI-OCT device. Phase I will incorporate the 
single modality OCT probe. Phase II will consist of a dual modality 
probe to include both OCT and a/LCI components. 
 
Potential subjects will be presenting to a UNC Endoscopy unit for 
routine upper endoscopy (EGD) for clinical signs or symptoms.  If 
eligible, informed consent will be obtained prior to undergoing this 
routine care upper endoscopy.  During the endoscopy, and prior to 
taking any biopsies, the probe will be attached to the end of the 
endoscope and passed with the endoscope into the esophagus. The 
probe will make contact with the epithelium of the esophagus, and 
data will be collected as part of this research study to identify 
operating characteristics of the new OCT device and the a/LCI-OCT 
combined device. Esophageal images and pictures will be obtained 
during the procedure and will be used in this study.  If biopsies are 
taken for routine care (clinical biopsies), then results from those 
biopsies will be used in this study. For a subset of subjects, 
participating in the combined-modality probe, study-specific 
biopsies will be taken at the same location the probe is deployed, to 
allow comparison of data from the imaging modalities to “gold-
standard” biopsy data. Additionally, slides may be requested from 
clinical biopsies for use in this study after they have yielded their 
results for routine care. 
 
Objectives: 
 
To test a newly developed imaging device in human subjects to 
determine 1) whether adequate tissue contact can be attained to 
acquire high quality images, and 2) to identify if these images can 
discern whether the imaged tissue is squamous or Barrett’s 
Esophagus (BE) epithelium. 
 
Endpoints: 
None  
 
Study Population: 
Patients of UNC Healthcare undergoing routine care endoscopy with 
or without Barrett’s Esophagus. Target enrollment includes two 
cohorts, with an approximate enrollment of up to 82 subjects. 
Cohort A will consist of 14 subjects in each of 3 groups; normal 
asymptomatic controls, non-dysplastic Barrett’s Esophagus, and 

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history of or current dysplastic Barrett’s Esophagus (High Grade 
Dysplasia (HGD) or Low Grade Dysplasia (LGD)). Cohort B will consist 
of 20 patients in each of the two groups; current dysplastic Barrett’s 
Esophagus of either High Grade Dysplasia (HGD) or Low Grade 
Dysplasia (LGD)) and normal controls (with or without history of 
previous successful esophageal ablation).  Classification of patients 
will occur based on medical history and clinical pathology obtained 
during the EGD. 
 
Description of Sites/Facilities 
Enrolling Participants: 
UNC Chapel Hill (Enrolling Site) 
Duke University (Device Manufacture) 
 
Description of Study 
Intervention: 
The purpose of this instrument is to obtain optical measurements 
from the esophageal mucosa via an endoscopic probe.  The 
modalities used by this probe are angle-resolved low-coherence 
interferometry (a/LCI) and Optical Coherence Tomography (OCT); 
depth-resolved optical imaging technology.  These optical readings 
provide indications of subsurface tissue architecture and will assist 
in the detection and diagnosis of metaplastic and dysplastic 
conditions such as Barrett’s esophagus. 
 
The probe is designed to be used in conjunction with the visual 
guidance provided by a commercial endoscope.  The probe has 
mechanical features similar to a radiofrequency ablation (RFA) 
“paddle”, which is externally attached to an endoscope to provide 
ablative therapy under visual guidance of the endoscope. 
Once inserted into a patient’s esophagus and placed against the 
tissue surface, the probe will acquire 2D OCT images of the tissue 
surface at operator-selected locations.  Some of the optical data 
received will be displayed in real-time.  All optical data will also be 
stored on a computer for post hoc analysis.  
During Phase I the OCT instrument will be used alone. The 
components of the OCT device are grouped into the following 
modules: 1) Optical probe, 2) OCT engine, 3) computer system and 
4) physical enclosure. Phase II of the study will consist of a dual 
modality a/LCI - OCT combined probe. The combined probe will 
consist of the following modules: 1) Optical probe, 2) OCT engine, 3) 
a/LCI engine, 4) computer system and 4) physical enclosure. See 
section 6.1 for detailed device descriptions. 
 
Study Duration: 
24 Months 
 
Participant Duration: 
7 days 
 
 
 

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1.2 
SCHEMA 
 
 
 
 
 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures7 
Screening1 
Enrollment1 
Post-EGD 
7 Day Follow-
Up (+/-3 days) 
Informed consent 
X 
 
 
 
Eligibility Assessment 
X 
X 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Urine Pregnancy Test 
 
X2 
 
 
Routine Care EGD 
 
X3 
 
 
Esophageal Images 
 
X 
 
 
Research Biopsies 
 
X6 
 
 
Administer Probe 
 
X5 
 
 
Collection of 
Pathology Results 
 
 
X4 
 
Adverse event review 
and evaluation 
X 
X 
 
X 
Complete Case Report 
Forms (CRFs) 
X 
X 
X 
X 
 
1Screening and enrollment can occur on the same day 
2Urine pregnancy tests will be performed on females with reproductive potential. 
3EGD is performed as part of routine care.  Subjects would be receiving this EGD regardless of participation in the study.  
4Only if biopsies are taken for routine clinical care during the procedure. If biopsies are taken for routine clinical care during 
this procedure, then pathology results will be collected as part of this study, and slides may be requested from clinical 
biopsies for use in this study after they have yielded their results for routine care. 
5 Probe utilized can be either the OCT probe (Cohort A) or the combined a/LCI-OCT probe (Cohort B), based on Investigator 
discretion at time of enrollment.  
6 Research biopsies may be taken for participants in Cohort B, per discretion of principal investigator. 
7 Both cohorts (A and B) will follow the same schedule of activities, unless specifically mentioned otherwise. 
 
 
2 
INTRODUCTION  
 
 
2.1 
BACKGROUND  
 
Barrett’s esophagus (BE) is a metaplastic change where the normal squamous epithelium of the 
esophagus is replaced by intestinal columnar epithelium, typically in response to chronic gastro 
esophageal reflux.1, 2 BE is a known risk factor for esophageal adenocarcinoma (EAC)3, a cancer with a 
high mortality rate and rapidly increasing incidence in developed countries.4, 5 The increased risk of 
cancer in BE patients leads to a need for surveillance, via endoscopy with random biopsies scattered 
across the affected tissue, using a biopsy pattern termed the “Seattle protocol”.6 However, this pattern 
samples <5% of BE tissue, leading to substantial sampling error. In spite of evidence that endoscopic 
surveillance does not substantially impact cancer mortality,7 it is still the recommended management 
tool for in BE patients, due to a lack of proven alternatives.8 
 

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Because of this problem with sampling error, many optical techniques have been proposed for 
improving detection of pre-cancerous, dysplastic BE tissues but none have yet been widely adopted for 
routine use,8 due primarily to limited performance. While high resolution methods, such as confocal 
microscopy, have shown good sensitivity and specificity, the need to manually move a point probe to 
scan large areas of epithelium limits clinical utility. In comparison, wide area imaging approaches, such 
as autofluorescence imaging, view more tissue area but offer lower sensitivity and specificity. Recently, 
Thekkek and Richards-Kortum advocated a multi-modality approach for optimal cervical screening.9 
Similar approaches have been suggested for BE screening as well.10  The Investigators seek to create a 
novel imaging platform embodying this approach. This platform combines wide area imaging, using 
optical coherence tomography (OCT) to visualize esophageal epithelial regions, with high resolution, 
depth-resolved measurements of nuclear morphology, using angle-resolved LCI (a/LCI) to provide highly 
sensitive and specific detection of dysplasia. 
 
The Investigators seek to implement and test advanced optical systems for detection of dysplastic tissue 
in BE patients. The a/LCI technique is based on examining the angular distribution of light scattering to 
determine structural features in a biological sample.11 The approach can be used as a diagnostic of early 
pre-cancerous changes (dysplasia) by measuring the size of cell nuclei in the basal layer of the 
epithelium.12 In a preliminary in vivo study, a/LCI nuclear morphology measurements were shown to be 
an effective biomarker for detecting dysplastic tissues in BE patients,13 achieving 87.8% accuracy. 
Significantly, this biomarker has 100% negative predictive value (NPV), a strong justification for clinical 
use. The Investigators seek to improve the clinical utility of a/LCI by covering wider tissue areas and 
incorporating the visual guidance of OCT. 
 
Angle-resolved LCI (a/LCI) and OCT are two imaging technologies that will be integrated into one probe. 
The purpose of the first phase of this pilot study is to utilize optical coherence tomography (OCT) 
technology alone. In the second phase of the study, the optical coherence tomography (OCT) technology 
will be combined with the angle-resolved LCI (a/LCI) into a multimodal device developed by investigators 
on a small population of patients in an effort to gather information necessary for continuing 
development as a screening tool described above.   
 
 
2.2 
STUDY RATIONALE  
 
Esophageal adenocarcinoma (EAC) is a deadly disease which has been rapidly increasing in incidence.14  
The rate of mortality from this cancer has remained above 80%,14 even as mortality and incidence of 
other types of gastrointestinal cancers, such as colon cancer15, have been decreased through improved 
screening programs.16 The leading risk factor for EAC is Barrett’s esophagus (BE), a very common 
metaplastic tissue condition arising from gastroesophageal reflux disease (GERD)3 which is thought to be 
the precursor to this cancer.  BE can progress to EAC through dysplastic changes,17 transitioning from 
non-dysplastic BE to low grade dysplasia (LGD), high grade dysplasia (HGD), and eventually EAC.18 The 
increased risk of EAC in BE patients justifies periodic surveillance via endoscopy with biopsy3. The 
difficulty of accurate identification of dysplasia in the epithelium requires clinical guidelines to 
recommend frequent surveillance endoscopy8.  However, the endoscopic surveillance protocol is 
laborious,8 and nearly half of surveillance procedures do not adhere to guidelines.19  The net result is 
that current surveillance approaches are not particularly effective at preventing mortality.7  The need for 
more effective tools for preventing esophageal cancer in the setting of BE is urgent, especially given that 
2-3 million Americans harbor this lesion. 

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Investigators seek to create a multimodal screening tool that combines in situ measurements of nuclear 
morphology, a proven biomarker of dysplastic progression20, with an imaging modality that gives visual 
representation of the architecture of BE tissues.21-24 Angle-resolved LCI (a/LCI) obtains accurate, high 
resolution nuclear morphology measurements using depth-gated light scattering measurements11,25. 
Investigators have shown that a/LCI nuclear morphology measurements can detect dysplastic lesions in 
vivo in the esophagus26 and ex vivo in other types of epithelia such as colon27 and trachea28 with high 
sensitivity and specificity.  As a standalone modality, a/LCI is somewhat limited for clinical screening of 
BE tissues in that it has only been implemented as a point modality to date.  To address this limitation, 
investigators propose to expand a/LCI to cover more tissue area with each measurement and to 
incorporate image guidance using optical coherence tomography (OCT), as a “red flag” to help target 
abnormal tissue for closer interrogation.  OCT provides micron scale, cross-sectional tissue images.   It 
can discriminate BE tissues from typical squamous epithelium but has lesser accuracy in detecting 
dysplasia compared to a/LCI.21-24 By combining these two imaging modalities, investigators seek to 
provide a more incisive, clinically useful tool to aid physicians in diagnosis and monitoring of BE patients.   
 
Angle-resolved LCI (a/LCI) and OCT are two imaging technologies that will be integrated into one probe. 
The purpose of this pilot study is to first utilize optical coherence tomography (OCT) technology alone, 
delivering it in a form factor that is conducive to upper endoscopy. In the second phase of the study, the 
optical coherence tomography (OCT) technology will be combined with the angle-resolved LCI (a/LCI) 
into a multimodal device developed by investigators on a small population of patients in an effort to 
gather information necessary for continuing development as a screening tool described above.   
 
 
2.3 
RISK/BENEFIT ASSESSMENT 
 
2.3.1 KNOWN POTENTIAL RISKS  
 
There are no known complications due to application of either a/LCI or OCT imaging techniques. Similar 
approaches have been previously approved by the UNC and Duke IRBs as non-significant risk device 
studies, and there were no safety issues in that study (UNC IRB# 07-1860).   
 
Although the technique is not invasive, the probe itself will come in contact with esophageal tissue. For 
the dual modaility probe (a/LCI-OCT) a small invagination in the surface of the instrument will mark the 
mucosa of the eosphagus applied at the same location images are taken. This will aid in co-localization 
of research biopsies, to allow comparison of optical and histological diagnoses.   We have used similar 
methodology in a previous study26, with no adverse events noted. However, there is a theoretical risk of 
infection.  To guard against this, the probe will be cleaned per current clinically approved methods for 
disinfecting endoscopy equipment which will utilize Cidex and/or Revital-Ox. Disinfection methods for 
this study have been reviewed and approved by the UNC Hospitals outpatient care and instrument 
reprocessing group. Refer to study standard operating procedures for additional information. 
 
To date, there have been no adverse effects reported from exposure to the spectrum of light used in 
this device. Additionally, the device does not generate thermal injury, and because it is placed on the 
epithelial surface, and does not penetrate the tissue, no epithelial trauma is experienced. There is no 
risk of radiation from this device because the device uses only light waves. 
 

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Because the device is administered in conjunction with an upper endoscopy, there are a number of 
potential risks associated with the endoscopy that will be reviewed with subjects as part of their clinical 
care.  There are also adverse events subjects may experience as a result of the endoscopy in which the 
contribution of the device may not be able to be ruled out.  However, these events will be considered 
expected unless the nature, severity, or frequency implies the event is possibly related to the device 
itself (>50% likelihood that the event is related to the device or study procedures).  These events include 
but are not limited to: throat irritation including scratchy or sore throat, esophageal pain, bloating, 
bleeding or tearing (perforation) of tissue in the esophagus, allergic reaction to the medication used for 
the endoscopy procedure (nausea, vomiting, fever, hypoxia (reduction in oxygen to tissues), pneumonia, 
adverse drug reactions, urine retention, clumsiness, drowsiness, blurred vision, and death), or aspiration 
of contents into the lungs. This may require the use of antibiotics, hospitalization and sometimes a 
surgery to repair. 
 
The number of biopsies taken for this study is within the spectrum of routine clinical practice for 
esophageal diseases and Barrett’s Esophagus in particular. Nevertheless, there is a very small risk of 
perforation or significant bleeding that would require a blood transfusion or other measures to stop the 
bleeding. To minimize this risk, subjects will be monitored for any bleeding during the biopsy portion of 
the procedure, and if bleeding is heavy, clinically indicated actions to stop the bleeding will be 
performed, and further biopsy procurement will be stopped.   In the performance of esophageal 
research biopsies in greater than 5,000 patients previously, the investigators have not either had to 
perform endoscopic therapy to halt bleeding, nor has any patient experienced esophageal perforation. 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
This study will not likely result in immediate direct benefit to its participants.  Because standard-of-care 
endoscopy will be performed regardless of imaging results, and because the imaging results from this 
trial will not be clinically actionable, immediate benefit in participation is not anticipated.  However, 
should these imaging approaches be found to be an accurate, safe, and well-tolerated means of 
monitoring this patient population, several potential benefits would accrue to both study participants 
and others who undergo upper endoscopy.  These individuals would have the option of a more efficient 
surveillance method. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
There are no known complications due to application of the a/LCI or OCT imaging techniques, with 
similar approaches having been previously approved by the UNC and Duke IRBs as a non-significant risk 
device.  The new instruments will again be evaluated by the IRB for application in this study. 
 
The endoscopy referenced in this pilot study is performed as routine clinical care for patients and not 
specific to participation in this study, meaning subjects would undergo this procedure regardless of 
participation in this study. 
 
Serious risk of endoscopic biopsies is very uncommon in subjects without known bleeding disorders and 
in those who do not regularly take blood thinning medications (such as aspirin, nonsteroidal anti-
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heparin). This is because the biopsies are very small (2-3 mm) and are obtained with blunt tipped 
forceps under direct vision of the physician 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. The additional time necessary to complete biopsies for this 
study will be less than 2 minutes. 
 
The Seattle biopsy protocol is used for standard of care (SOC) which includes taking 4 quadrant biopsies 
every one to two centimeters throughout the area of interest. Because we generally take these biopsies 
every two centimeters, up to 10 research biopsies in addition to SOC biopsies would generally be within 
the total number of biopsies advocated as the standard of care (give our mean BE segment length of 4-5 
cm). It should also be noted that no higher incidence of complications has been documented by taking 
biopsies by the more aggressive biopsy protocol (4 biopsies every one cm) than the less aggressive (4 
biopsies every two cm) protocol. 
 
Given the excellent safety profile of these imaging techniques, the risks and costs inherent in the current 
standard of care, the potential benefits of this investigation outweigh the risks. 
 
 
3 
OBJECTIVES AND OUTCOMES 
 
The purpose of this pilot study is to use the angle-resolved Low-Coherence Interferometry (a/LCI) and 
optical coherence tomography (OCT) technologies, developed by investigators on a small population of 
patients in an effort to gather information necessary for continuing development as a screening tool 
described above.  Specifically, the study is designed to test the newly developed a/LCI-OCT device in 
human subjects to determine 1) whether adequate tissue contact can be attained to acquire high quality 
images, and 2) to identify if these images can discern whether the imaged tissue is squamous or BE 
epithelium. 
 
 
4 
STUDY DESIGN 
 
4.1 
OVERALL DESIGN 
 
This is a pilot study to test the operating characteristics of a newly developed optical coherence 
tomography (OCT) device in human subjects, and to collect data for further optimization of the OCT 
device. 
Phase II of the study will consist of a combined probe consisting of angle-resolved Low-Coherence 
Interferometry (a/LCI) with developed optical coherence tomography (OCT).  
 

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Potential subjects will be presenting to a UNC Endoscopy unit for routine care endoscopy for clinical 
signs or symptoms.  If eligible, informed consent will be obtained prior to undergoing routine care upper 
endoscopy.  During the endoscopy, and prior to taking any routine care biopsies, the probe will be 
attached to the end of the endoscope and passed with the endoscope into the esophagus. The probe 
will make contact with the epithelium of the esophagus, and data will be collected as part of this 
research study to identify operating characteristics of the new device. Esophageal images and pictures 
will be obtained during the procedure and will be used in this study.   
 
In Cohort A, if biopsies are taken for routine care, then results from those biopsies will be used in this 
study. Slides may be requested from clinical biopsies for use in this study, after they have yielded their 
results for routine care.  
 
In Cohort B, co-localized research biopsies may be taken at the same location the probe is deployed. The 
indentation on the surface of the probe leaves a transient raised area of mucosa, which will aid in 
endoscopic identification of the site and allow for targeted concurrent biopsies.  
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This is a pilot study to test the operating characteristics of a newly developed optical coherence 
tomography (OCT) and angle-resolved Low-Coherence Interferometry (a/LCI) imaging technologies in 
human subjects.  
 
 
4.3 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial. 
 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Subjects must meet all of the following criteria to be eligible for this study: 
 
1. Presenting to UNC for routine care upper endoscopy 
2. Meet one of the following criteria: 
2.1. Cohort A  
2.1.1. Presenting to UNC for upper endoscopy of GI conditions without esophageal 
symptomology  with no history of gastroesophageal reflux disease (GERD) or other 
esophageal condition affecting the epithelium (asymptomatic controls). Esophageal 

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symptomology includes, but is not limited to, heartburn, globus, chest pain, dysphagia, 
and odonophagia OR, 
2.1.2. Current dysplastic or non-dysplastic Barrett’s Esophagus of any length OR,  
2.1.3. History of dysplastic or non-dysplastic Barrett’s Esophagus after treatment with 
endoscopic eradication therapy (EET) 
OR 
2.2. Cohort B 
2.2.1. Current dysplastic or non-dysplastic Barrett’s Esophagus of any length OR,  
2.2.2. History of dysplastic or non-dysplastic Barrett’s Esophagus after treatment with 
endoscopic eradication therapy (EET) OR, 
2.2.3. Normal asymptomatic controls without any history of dysplastic Barrett’s Esophagus 
AND 
3. Aged 18 to 80 
4. Able to read, comprehend, and understand the informed consent document. 
 

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5.2 
EXCLUSION CRITERIA 
 
Subjects meeting any of the exclusion criteria below will not be eligible for this study: 
 
1. Prior esophageal surgery (uncomplicated nissen fundoplication OK) 
2. Pregnant women 
3. Unable to provide written informed consent 
4. History of esophageal stricture or prior esophageal dilation 
 
Additionally, subjects meeting any of the exclusion criteria below will not be eligible for Cohort B of this 
study: 
5. Uncontrolled coagulopathy 
 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable. 
 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements, and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
 
6 
STUDY INTERVENTION 
 
6.1 
DEVICE DESCRIPTION 
 
The purpose of this instrument is to obtain optical measurements from the esophageal mucosa via an 
endoscopic probe.  The imaging modalities used by this probe are angle-resolved Low-Coherence 
Interferometry (a/LCI), a technology that measures the depth- and angle-dependent scattering of light 
by tissue and Optical Coherence Tomography (OCT), a depth-resolved optical imaging technology.  These 
optical readings provide indications of subsurface tissue architecture and will assist in the detection and 
diagnosis of metaplastic and dysplastic conditions such as Barrett’s esophagus. 
 
The probe is designed to be used in conjunction with the visual guidance provided by a commercial 
endoscope.  The probe has mechanical features similar to a radiofrequency ablation (RFA) “paddle”, 

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which is externally attached to an endoscope to provide ablative therapy under visual guidance of the 
endoscope.  This form is advantageous because it is known to be well-tolerated and easily passed when 
mounted on the endoscope.  It will also eventually allow the development of a single paddle that could 
both image and treat diseased mucosa. 
 
Once inserted into a patient’s esophagus and placed against the tissue surface, the probe will acquire 2D 
OCT images of the tissue surface at operator-selected locations.  Some of the optical data received will 
be displayed in real-time.  All optical data will also be stored on a computer for post hoc analysis. 
 
The components of the combined probe system a/LCI-OCT instrument are grouped into the following 
modules: 1) Optical probe, 2) OCT engine, 3) a/LCI engine, 4) computer system, and 5) physical 
enclosure. 
 
6.1.1 aCI/OCT OPTICAL PROBE 
 
The optical probe is similar in form to a RFA “paddle,” with a length of approximately 23 mm, width of 
14 mm, and a thickness of 4 mm. The paddle housing is fabricated by a 3D printing process known as 
stereolithography (SLA).  A miniature optical assembly for both a/LCI and OCT imaging is contained 
within the paddle, composed of silica and borosilicate glass, optical fiber, and optical adhesives.  These 
components are fully enclosed within the paddle, except for the optical fiber, which extends from the 
paddle through a hollow sheath to the optical engine.  The paddle and sheath are sealed against air and 
moisture to isolate the internal optical components from the patient environment.  A transparent region 
of the paddle housing allows the beam to exit the paddle.  Figure 1 below illustrates the general concept 
of the paddle probe attachment to the endoscope.  Figure 2 depicts the probe layout within the paddle.  
(This figure is schematic and not to scale.) 
 
The OCT modality components will rotate on command to sweep a beam across the tissue surface to 
generate 2D images, as well as translate longitudinally on command to generate 3D volumes.  The speed 
of OCT rotation will be 40 rotations per second (2,400 rotations per minute) or less.  The speed of OCT 
translation will be 2 mm per second or less.  
 
 
 
 
 
 
Paddle probe 
Endoscope body 
Figure 1: 3D concept rendering of probe paddle attached to endoscope 

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To transduce its linear and rotational motion, a wound steel torque coil encloses the OCT optical fiber, 
which transmits force from motors mounted on the OCT engine to the OCT optical components within 
the paddle. 
 
A flexible tether containing the OCT driveshaft and optical fiber protrudes from the proximal end of the 
probe, runs alongside the endoscope until it exits the body where it is connected to the OCT engine. The 
probe contains no electrical components or wires. 
 
 
 
 
6.1.2 OCT ENGINE 
 
The OCT engine contains the optical, electrical, and mechanical components related to the acquisition of 
OCT images from the esophagus. 
 
The OCT system includes a light source (superluminescent diode, Exalos AG) emitting at approximately 
1300 nm, a spectrometer composed of lenses and a diffraction grating, a sensor (linear array camera, 
Sensors Unlimited Inc.), a rotary motor system including a motor driver and belt assembly, a fiber-optic 
rotary junction (FORJ, Princetel), a translational motor system including a motor driver and translating 
stage, and various optical fibers, connectors, and controllers. 
Figure 2: Schematic for placement of optical probe components within paddle.  Right, 
schematic of OCT optical component layout within OCT probe 
Figure 3: 3D drawing of paddle probe housing. This housing will contain miniature optics and 
will be attached to the tip of an upper GI endoscope via a silicone cuff (gray cylinder). 

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In brief, the OCT light source transmits light that is simultaneously divided among two paths: a static 
reflector within the OCT engine (“reference” light) and a path directed towards the patient tissue via the 
probe (“sample” light).  The FORJ allows the probe fiber to rotate relative to the stationary fiber while 
remaining optically connected.  The light from both sample and reference paths are recombined by a 
fiber coupler, resulting in an interference pattern that encodes the depth of reflective objects and 
surfaces in the sample.  This interference is detected by a spectrometer, which divides the interference 
signal into its constituent wavelengths that are individually detected by pixels of a linear camera.  Figure 
4 below depicts the block diagram of the OCT engine. 
 
 
 
Each such measurement produces a column of data, or “A-scan,” which represents the depth-resolved 
reflectance profile of the tissue where the OCT beam intersects it.  To produce 2D OCT images, the 
miniature optics in the probe are rotated by the rotary motor and FORJ system, which are mechanically 
linked by a belt system and the wound-steel torque coil within the probe sheath.  To produce 3D OCT 
images, a stage is translated by a stepper motor such that the entire fiber optic assembly moves 
longitudinally during its rotation, resulting in a spiral scan. 
 
The maximum permissible exposure (MPE) for exposures greater than 10 seconds on skin is 1.0 W/cm2 
at the principal OCT wavelength of 1300 nm and a defined limiting aperture of 3.5 mm diameter (ANSI 
Z136.1).  The OCT beam focus falls entirely within the 3.5 mm (0.35 cm) aperture, and thus is the power 
limit is 1.0 W/cm2 * 3.14 * (0.175 cm)2 = 96.2 mW.  The total power of OCT beam on the tissue is less 
than 20 mW. 
 
6.1.3 A/LCI ENGINE 
 
The a/LCI engine contains the optical, electrical, and mechanical components related to the acquisition 
of a/LCI images from the esophagus. a/LCI, uses the pattern of scattered light to measure the size of 
nuclei within the epithelium, which is a known biomarker for dysplasia. 
 
Figure 4: Block diagram of OCT engine components 

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The a/LCI engine is very similar to the OCT engine in terms of the diagrammatic modules that compose 
the system, operating in parallel with the OCT engine. 
 
The a/LCI engine includes a light source (superluminescent diode, Superlum) emitting at approximately 
830 nm, a spectrometer composed of lenses and a diffraction grating, a sensor (area camera, FLIR 
Imaging), and various optics that compose the interferometer.  The interferometer sends light to the 
probe via an optical fiber, collects the scattered light returning from the probe’s optical fiber bundle, 
and combines that sample light with reference light to be detected on the camera. 
 
The maximum permissible exposure (MPE) for exposures greater than 10 seconds on skin is 3.6 
mW/mm2 at our principal wavelength of 830 nm (ANSI Z136.1).  Our imaging region in the tissue is 
approximately 100 µm, smaller than the minimum limiting aperture given in ANSI Z136.1 of 3.5 mm. Our 
total permissible power is thus 3.6 mW/mm2 x 3.14 x (1.75 mm)2 = 34.6 mW.  Our maximum power of 
10 mW is much lower than the ANSI MPE. 
 
6.1.4 A/LCI OPTICAL PROBE 
 
The optical probe is similar in form to a RFA “paddle,” with a length of approximately 23 mm, width of 
14 mm, and a thickness of 4 mm. The paddle housing is fabricated by a 3D printing process known as 
stereolithography (SLA).  Miniature optical assembly for a/LCI is contained within the paddle, composed 
of silica and borosilicate glass, optical fibers, and optical adhesives.  These components are fully 
enclosed within the paddle, except for the optical fibers, which extend from the paddle through a 
hollow sheath to the a/LCI optical engine.  The paddle and sheath are sealed against air and moisture to 
isolate the internal optical components from the patient environment.  Transparent window regions of 
the paddle housing allow the a/LCI beam to exit the paddle.   
 
Upon identification of an area of interest on the esophagus, based on video endoscopy and/or the OCT 
images, an a/LCI acquisition will be initiated. This component does not entail moving parts in the probe, 
but engages a series of optical acquisitions lasting less than 10 seconds while the probe is held in place. 
A flexible tube containing the OCT driveshaft and optical fiber protrudes from the proximal end of the 
probe, runs alongside the endoscope until it exits the body where it is connected to the OCT engine. A 
second tube containing the a/LCI illumination and detection fibers runs parallel to the first.  Both tubes 
are tethered together in a single outer tubing, composed of polyolefin.  The probe contains no electrical 
components or wires. 
 
6.1.5 A/LCI-OCT ENGINE 
 
The combined a/LCI-OCT engine will operate both systems in tandem. Individual components have been 
previously described in Section 6.1.2 and 6.1.3. Figure 5 below depicts the block diagram of combined 
a/LCI-OCT engine. 
 

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6.1.6 COMPUTER 
 
A computer workstation performs the data acquisition and control through a custom application.  
Software control of the data acquisition sequence is provided.  Real-time display of the OCT and a/LCI 
data is shown on a monitor.  Raw and/or processed OCT image data and a/LCI data are saved to the hard 
drive. Storage of patient data on the computer is protected by encryption (Bitlocker). 
 
6.1.7 PHYSICAL ENCLOSURE AND POWER BUS 
 
The a/LCI and OCT engine and computer are contained within a painted and grounded aluminum 
enclosure.  An isolated 120V power bus is connected through a medical isolation transformer, which 
provides power to all electrical components. 
 
 
6.2 
NON-SIGNIFICANT RISK (NSR) 
 
6.2.1 NSR JUSTIFICATION 
 
The FDA defines an NSR device as one which does not meet the definition of a significant risk (SR) 
device. Per 21 CFR 812.3(m), a Significant Risk Device is an investigational device that: 
 
a. Is intended as an implant and presents a potential for serious risk to the health, safety, or 
welfare of a subject;  
Figure 5: Block diagram of combined a/LCI and OCT engine components. 

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b. Is purported or represented to be for use supporting or sustaining human life and presents a 
potential for serious risk to the health, safety, or welfare of a subject;  
c. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or 
otherwise preventing impairment of human health and presents a potential for serious risk to 
the health, safety, or welfare of a subject; or  
d. Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.  
 
This device is (a) not intended as an implant, (b) is not used to support or sustain life, (c) is not for a use 
of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing 
impairment of human health and presents a potential for serious risk to the health, safety, or welfare of 
a subject; and (d) does not otherwise present a potential for serious risk to the health, safety, or welfare 
of a subject.   
 
In fact, the FDA guidance document titled “Information Sheet Guidance for IRBs, Clinical Investigators, 
and Sponsors: Significant Risk and Nonsignificant Risk Medical Device Studies,” specifically cites 
gastroenterology and urology endoscopes and accessories as examples of non-significant risk devices 
(Section X, subpart A, page 8). 
 
6.2.2 NSR COMPLIANCE 
 
The device used in this study may be deemed a non-significant risk (NSR) device by the IRB or FDA.  If 
deemed an NSR, this means the device qualifies for an abbreviated investigational device exemption 
(IDE).  To qualify as an NSR, the FDA or IRB must determine the device does not pose a serious risk to the 
health, safety or welfare of a subject and does not otherwise meet the definition of a significant risk 
device according to 21 CFR 812.3(m). If deemed non-significant risk (NSR); the sponsor and investigator 
must comply with "abbreviated IDE requirements" described in 21CFR812.   
 
Subpart A--General Provisions  
   § 812.1 - Scope.  
   § 812.2 - Applicability.  
   § 812.3 - Definitions.  
   § 812.5 - Labeling of investigational devices.  
   § 812.7 - Prohibition of promotion and other practices.  
   § 812.10 - Waivers.  
   § 812.18 - Import and export requirements.  
   § 812.19 - Address for IDE correspondence.  
Subpart B--Application and Administrative Action  
   § 812.20 - Application.  
   § 812.25 - Investigational plan.  
   § 812.27 - Report of prior investigations.  
   § 812.30 - FDA action on applications.  
   § 812.35 - Supplemental applications.  
   § 812.36 - Treatment use of an investigational device.  
   § 812.38 - Confidentiality of data and information.  
Subpart C--Responsibilities of Sponsors  
   § 812.40 - General responsibilities of sponsors.  

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   § 812.42 - FDA and IRB approval.  
   § 812.43 - Selecting investigators and monitors.  
   § 812.45 - Informing investigators.  
   § 812.46 - Monitoring investigations.  
   § 812.47 - Emergency research under 50.24 of this chapter.  
Subpart D--IRB Review and Approval  
   § 812.60 - IRB composition, duties, and functions.  
   § 812.62 - IRB approval.  
   § 812.64 - IRB's continuing review.  
   § 812.65 - [Reserved]  
   § 812.66 - Significant risk device determinations.  
Subpart E--Responsibilities of Investigators  
   § 812.100 - General responsibilities of investigators.  
   § 812.110 - Specific responsibilities of investigators.  
   § 812.119 - Disqualification of a clinical investigator.  
Subpart F [Reserved]  
Subpart G--Records and Reports  
   § 812.140 - Records.  
   § 812.145 - Inspections.  
   § 812.150 - Reports.  
 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812 
 
6.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
6.3.1 ACQUISITION AND ACCOUNTABILITY 
 
The devices listed in this protocol will be manufactured by the co-PI, Dr. Adam Wax, at Duke University 
and provided to UNC Chapel Hill for use in this pilot study.   Accountability logs will be maintained by 
both Duke University and UNC Chapel Hill.  
 
 
6.3.2 DEVICE LABELING 
The device will be labeled with a serial number, and in accordance with 21CFR812.5 (below): 
(a) Contents. An investigational device or its immediate package shall bear a label with the following 
information: the name and place of business of the manufacturer, packer, or distributor (in accordance 
with §801.1), the quantity of contents, if appropriate, and the following statement: “CAUTION—
Investigational device. Limited by Federal (or United States) law to investigational use.” The label or 
other labeling shall describe all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings, and precautions. 
(b) Prohibitions. The labeling of an investigational device shall not bear any statement that is false or 
misleading in any particular and shall not represent that the device is safe or effective for the purposes 
for which it is being investigated. 

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(c) Animal research. An investigational device shipped solely for research on or with laboratory animals 
shall bear on its label the following statement: “CAUTION—Device for investigational use in laboratory 
animals or other tests that do not involve human subjects.” 
(d) The appropriate FDA Center Director, according to the procedures set forth in §801.128 or §809.11 
of this chapter, may grant an exception or alternative to the provisions in paragraphs (a) and (c) of this 
section, to the extent that these provisions are not explicitly required by statute, for specified lots, 
batches, or other units of a device that are or will be included in the Strategic National Stockpile. 
 
 
6.3.3 DEVICE STORAGE 
 
The device(s) will be stored in a secure location with access limited to research personnel. 
 
 
6.3.4 PREPARATION 
 
Prior to each use, the device will be cleaned per current clinically approved methods for disinfecting 
endoscopy equipment which will utilize Cidex and/or Revital-Ox. Disinfection methods for this study 
have been reviewed and approved by the UNC Hospitals outpatient care and instrument reprocessing 
group.  Refer to study standard operating procedures for additional information. 
 
 
6.4 
CONCOMITANT THERAPY 
 
There are no medication restrictions to participate in this study other than the standard of care 
medication discontinuation instructions patients receive in preparation for an upper endoscopy. 
 
 
6.4.1 RESCUE MEDICINE 
 
Not applicable. 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
All participants will be screened and enrolled using IRB-approved and HIPAA compliant methods.  
IRB approved site personnel will obtain consent prior to completion of 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.  After the subject 
signs the consent, a copy of the signed consent will be provided to the subject.  The consent process will 
be documented. 
 

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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
This is a pilot study involving one-time collection of data during a routine care endoscopy.  Participants 
are free to withdraw from participation in the study at any time upon request.  
 
An investigator may discontinue or withdraw a participant from the study if the participant is deemed 
ineligible based on findings from the endoscopy, or other reason. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are withdrawn may be replaced.  
Withdrawn or terminated subjects will be excluded from the study.  If data were collected, then they 
will not be used. 
 
 
7.3 
LOST TO FOLLOW-UP 
 
This pilot study involves a one-time visit with data collection.  However, if for some reason a subject 
needs to be contacted for follow-up, then a participant will be considered lost to follow-up if he or she 
fails to return for a scheduled visit and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening1 
Enrollment1 
Post-EGD 
7 Day Follow-
Up (+/-3 days) 
Informed consent 
X 
 
 
 
Eligibility Assessment 
X 
X 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Urine Pregnancy Test 
 
X2 
 
 
Routine Care EGD 
 
X3 
 
 
Esophageal Images 
 
X 
 
 
Research biopsies 
 
X6 
 
 
Administer Probe5 
 
X 
 
 
Collection of 
Pathology Results 
 
 
X4 
 
Adverse event review 
and evaluation 
X 
X 
 
X 
Complete Case Report 
Forms (CRFs) 
X 
X 
X 
X 
 
1Screening and enrollment can occur on the same day 
2Urine pregnancy tests will be performed on females with reproductive potential. 
3EGD is performed as part of routine care.  Subjects would be receiving this EGD regardless of participation in the study.  
4Only if biopsies are taken for routine clinical care during the procedure. If biopsies are taken for routine clinical care during 
this procedure, then pathology results will be collected as part of this study, and slides may be requested from clinical 
biopsies for use in this study after they have yielded their results for routine care. 
5 Probe utilized can be either the OCT probe (Cohort A) or the combined a/LCI-OCT probe (Cohort B), based on Investigator 
discretion at time of enrollment.  
6 Research biopsies may be taken for participants in Cohort B. 
 
 
 
8.1.1 SCREENING 
 
The following procedures will be performed during the screening visit: 
1) Identification of potential subjects via IRB approved methods 
2) Informed consent (see section 10.1.1 for details regarding the informed consent process) 
3) Collection of data including demographics and medical history 
4) Complete CRFs and data entry 
 
 
8.1.2 ENROLLMENT 
 
The following procedures will be performed during the enrollment visit: 
1) Re-assess eligibility 

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2) Completion of urine pregnancy test on women with reproductive potential 
3) Administration of OCT-probe for Cohort A or combined a/LCI-OCT probe for Cohort B and 
completion of esophageal images during routine care upper endoscopy 
4) Collection of data from endoscopy 
5) Collection of co-localized research biopsies (Cohort B) 
6) Adverse event assessment 
7) Complete CRFs and data entry 
 
For this study, an enrolled subject is defined as a subject who was successfully administered the OCT 
device and for whom we have evaluable data. 
 
***Screening and enrollment can occur on the same day. 
 
8.1.2.1 PROBE ADMINISTRATION, ESOPHAGEAL IMAGES, AND RESEARCH BIOPSIES 
 
Subjects will proceed with routine care EGD, during which esophageal landmarks will be identified, and 
the OCT or a/LCI-OCT device administered.  In brief, the probe will be affixed to the end of the 
endoscopy using a plastic band, in a manner similar to that used to deliver other devices into the 
esophagus.  The device and endoscope tip will be passed through the posterior pharynx and the upper 
esophageal sphincter under direct endoscopic visualization.  Areas of normal squamous epithelium can 
be easily identified endoscopically, as can areas of columnar mucosa in the esophagus, based on the 
endoscopic appearance.  The OCT or a/LCI-OCT combined device will be apposed to both normal and 
columnar (Barrett’s) tissue, by deflection of the endoscope tip.  Images will be acquired by the device, as 
detailed below, and subjects enrolled in cohort B will also receive research-specific biopsies as detailed 
below. The indentation on the tip of the probe will create a transient tissue bump  that is visible 
endoscopically to allow for concurrent research biopsies after images are taken.After acquisition of 
these images and research biopsies (as applicable), the remainder of the study will be performed as per 
the standard of care.  
 
Erosions, erosive disease, and areas of inflammation will be avoided when placing the paddle for probe 
administration.  Adequacy of device-to-epithelium contact will be measured based on the quality of the 
OCT image. In images with poor contact, esophageal mucosal layers are poorly defined.  In this situation, 
the probe will be repositioned in an effort to improve image quality. A good image is that in which 
esophageal mucosal layers are clearly defined in the OCT image. 
 
COHORT A:  
During the procedure, the OCT device will be administered, and at least one white light image and at 
least one narrow band image will be taken from the following locations of the esophagus: 
1) 3 centimeters above the top of the gastric folds (TGF-3) 
2) 5 centimeters above the top of the gastric folds (TGF-5) 
3) Any planned clinical biopsy locations 
 
COHORT B: 
During the procedure, the a/LCI-OCT device will be administered, and at least one white light image and 
at least one narrow band image will be taken from the following locations of the esophagus: 
1) 3 centimeters above the top of the gastric folds (TGF-3) 
2) 5 centimeters above the top of the gastric folds (TGF-5) 

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3) Co-localized research-specific biopsies will be taken at the imaging location 
4) Any planned clinical biopsy locations 
 
Variations to the imaging protocol (location and number of images obtained) are allowable and are not 
considered protocol deviations. 
 
Device images will not be used to diagnose or categorize participants. Participants will be categorized 
based on endoscopy, clinical pathology and medical history, as per usual clinical practice.  If no biopsies 
are taken for clinical care, and the subject is presenting for upper endoscopy for GI conditions without 
esophageal symptomatology, then the epithelium will be assumed to be normal squamous epithelium 
per the endoscopic imaging. 
 
8.1.2.2 PATHOLOGY REPORTS AND SLIDES ACQUISITION 
 
If clinical biopsies are obtained during the enrollment upper endoscopy, then results from those clinical 
biopsies will be obtained for this research study after they have yielded their results for routine care. 
 
Slides may be requested from clinical biopsies and used as part of this research study. 
 
8.1.2.3 RESEARCH BIOPSY COLLECTION AND ANALYSIS 
 
For participants enrolled in cohort B, research biopsies will be obtained from the location of device 
imaging. Research biopsies are taken only if the additional biopsies do not significantly increase the 
patient’s risk or interfere with routine care procedures. The research biopsy protocol may be modified 
by the physician performing the procedure if necessary. During the procedure up to 10 research biopsies 
may be taken for use in this study. The total number of research biopsies may vary based on 
presence/absence of nodularity but will not exceed 10 research-specific biopsies. This number of 
esophageal biopsies is within the standard of care for biopsying the esophagus. Biopsies will be 
immediately placed in formalin for processing and histopathological analysis by Dr. Goldblum. 
 
Variations to the biopsy protocol (location and number of specimens obtained) are allowable and are 
not considered protocol deviations. 
   
 
8.1.3 7 DAY FOLLOW-UP  
 
Enrolled subjects will be contacted 7 days (+/-3 days) after administration of the device via phone or 
other IRB approved method. Subjects who do not meet the definition of enrolled will not be contacted. 
During the 7 day follow-up, the following procedures will be performed: 
1) Assess for adverse events 
2) Complete eCRF and data entry 
 
No additional follow-up is anticipated. 
   
 
 

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8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.2.1 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)). 
 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
1) Death,  
2) A life-threatening adverse event,  
3) Inpatient hospitalization or prolongation of existing hospitalization,  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
5) A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.2.3 UNANTICIPATED ADVERSE DEVICE EFFECT 
 
According to 21 CFR 812.3(s), an “unanticipated adverse device effect means any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.” 
 
8.2.4 CLASSIFICATION OF AN ADVERSE EVENT 
8.2.4.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, 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.  

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• 
Grade 2 (Moderate) – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• 
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. 
 
8.2.4.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by an investigator 
who evaluates the event 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.  
 
• 
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 associated with 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 
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• 
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.] 
8.2.4.3 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. 
 
8.2.5 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. 
 
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 occurring while on study must be documented 
appropriately regardless of relationship. 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. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded 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. 
 
Research staff will record all adverse events with start dates occurring any time after informed consent 
is obtained until completion of study participation.  At each study visit, the investigator will inquire 
about the occurrence of AE/SAEs since the last visit.  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 completion or termination of the clinical investigation. This includes AEs that are not 
device or procedure related. 
 
8.2.6 ADVERSE EVENT 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 
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Events will be described using the NCI Common Terminology Criteria for Adverse Events (CTCAE).  
 
8.2.7 OTHER SAFETY REPORTING 
 
Sites may have additional safety reporting requirements or reporting requirements that differ from 
those outlined in this protocol.  Sites are responsible for complying with requirements outlined in this 
protocol, as well as any local reporting requirements and definitions. 
 
8.2.8 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable.  Participation involves a one-time visit.  Safety information will be reviewed as part of 
the initial consent process, and consent will be obtained with new safety information as applicable. 
 
8.2.9 EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.2.10 REPORTING OF PREGNANCY  
 
Not applicable. 
 
 
8.3 
UNANTICIPATED PROBLEMS 
8.3.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) AND UNANTICIPATED ADVERSE 
DEVICE EFFECT (UADE) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“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 
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• 
Serious or suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
According to 21 CFR 812.3(s), an unanticipated adverse device effect means  any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
8.3.2 UNANTICIPATED PROBLEM (UP) REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and other study investigators. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
Unanticipated problems must be reported to participating investigators within 48 hours of learning of 
the event, and to local IRBs per local IRB reporting policies.    
 
Participating sites are responsible for ensuring compliance with local IRB policies and procedures on 
safety reporting, which may differ from those outlined in this protocol. 
 
8.3.3 UNANTICIPATED ADVERSE DEVICE EFFECT (UADE) REPORTING 
 
Unanticipated adverse device effects (UADEs)  must be reported to participating investigators within 48 
hours of learning of the event, and to local IRBs per local IRB reporting policies. 
 
Per 21 CFR 812.46, a sponsor shall immediately conduct an evaluation of any unanticipated device 
effects.  A sponsor who determines that an unanticipated adverse device effect presents an 
unreasonable risk to subjects shall terminate all investigations or parts of investigations presenting that 
risk as soon as possible. Termination shall occur not later than 5 working days after the sponsor makes 
this determination and not later than 15 working days after the sponsor first received notice of the 
effect.  
 
A sponsor who conducts an evaluation of an unanticipated adverse device effect under 812.46(b) shall 
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within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall 
submit such additional reports concerning the effect as FDA requests 21 CFR 812.150(b)(1)).    
 
Participating sites are responsible for ensuring compliance with local IRB policies and procedures on 
safety reporting, which may differ from those outlined in this protocol. 
 
8.3.4 REPORTING UNANTICIPATED PROBLEMS (UPS) AND UNANTICIPATED ADVERSE 
DEVICE EFFECTS (UADES) TO PARTICIPANTS  
 
Not applicable.  Participation involves a one-time visit.  Safety information will be reviewed as part of 
the initial consent process, and the consent will be obtained with new safety information as applicable. 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
No hypothesis tests will be performed. All statistical estimates (e.g., proportions, incidence rates, 
sensitivity, specificity, means, correlations, etc.) will be tabulated with 95% confidence intervals (CIs). 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Cohort A will be imaged with OCT.  Previous data on OCT demonstrate that established systems are 
sensitive with respect to detecting Barrett’s mucosa.  For instance, Poneros et al (2001) found a 97% 
sensitivity rate using OCT in 38 patients29.  At this stage of development, if we can achieve at least 70% 
sensitivity, then the device will pass initial testing.  If optimal sensitivity is 95%, and the lowest 
acceptable sensitivity is 70%, then we will require at least 14 patients with evaluable data in each group 
(42 total in Cohort A) to assess whether the device adequately meets this threshold with 85% power.   
 
Cohort B will be imaged with a/LCI.  Our group previously conducted and published a study in 2011 using 
single-point a/LCI to measure nuclear diameter as an indicator of dysplasia in the esophagus.13  The 
primary differentiating characteristic between dysplastic and normal tissue was nuclear diameter 
(measured by a/LCI).  For dysplastic tissue, the mean nuclear diameter and standard deviation was 13.0 
± 1.1 μm, and for normal tissue, the same respective values were 10.3 ± 1.7 μm.  This difference was 
highly statistically significant, and we rejected the null hypothesis (no difference between normal and 
dysplastic nuclear diameters) with a p-value of 0.0001. 
 
To determine the number of targeted patient enrollments in Cohort B, we conducted a statistical power 
analysis based on our previous results.  For a sample size of 20 patients with dysplasia and 20 patients 
with normal esophageal tissue, and targeting the same p-value of 0.0001, we expect a robust statistical 
power of 97% when conducting a two-sample t-test for nuclear diameter distributions matching our 
observations from the 2011 study.  We would therefore expect a 97% chance of validating our previous 
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of 10 patients in each category, our power would be only 36%, far too low; for a sample size of 30 
patients in each category, our power would be greater than 99.9%, which is unnecessarily high.  
Therefore, for Cohort B, we will target 20 patients with dysplasia and 20 normal patients to achieve a 
strong statistical power without an undue excess in patient enrollment. 
 
To accommodate Cohort B, which will be receiving the dual modality a/LCI-OCT probe, we have 
therefore changed the sample size to be a total of 82 (42 in Cohort A, and 40 in Cohort B). 
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All subjects who were administered the probe, regardless of enrolling cohort, will have data included for 
optimization unless withdrawn per section 7.2. For this study, an enrolled subject is defined as a subject 
who was successfully administered the device and for whom we have evaluable data. 
 
 
9.4 
STATISTICAL ANALYSES 
 
This is a pilot study collecting data for OCT and a/LCI-OCT device optimization.  This study will provide 
initial images for the investigational device, and depending on the device’s accuracy in discerning tissue, 
these data will help form the basis for further investigations. Data analysis will consist of simple bivariate 
analysis, with endoscopy results being compared to a/LCI-OCT image results.  Specifically, 2 x 2 tables of 
OCT, a/LCI-OCT, and endoscopy results will be constructed, with each imaging site being categorized as 
columnar versus squamous.  Sensitivity will be defined as the proportion of sites correctly categorized 
by OCT, or a/LCI-OCT, using endoscopy results as the gold standard.  Measures of variability of sensitivity 
results will be generated using non-parametric statistics.   
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
In obtaining and documenting informed consent, the investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should adhere to ICH 
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Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator or designee will explain the research study to the participant and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigators, funding agency, the Investigational 
Device Exemption (IDE) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping    
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
This is a pilot study with very low risk, therefore it is not anticipated the study will be terminated or 
suspended.  However, the data safety monitor (DSM) will monitor the trial for unanticipated adverse 
events on regular (3 month) intervals, as well as performing interim assessments of the performance 
characteristics of the imaging devices, which may merit consideration of premature termination of the 
study should the device prove inadequately accurate for clinical use, or conversely be so highly accurate 
that further enrollment would not be likely to change the results of the trial.   
 
 

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10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, 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 sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or company supplying study product 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 pharmacy 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 each 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. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the University of North Carolina at Chapel Hill and Duke University. This 
will not include the participant’s contact or identifying information other than date of birth and 
procedure dates (limited data set). Rather, 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 and Duke University 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 and Duke University.  One master list linking subjects to their 
code will be maintained securely by the PI, and separate from the research data. 
 
10.1.4 FUTURE USE OF DATA  
 
Data collected for this study will be analyzed and stored at the University of North Carolina at Chapel Hill 
and Duke University. After the study is completed, the coded, archived data will be stored at the 
University of North Carolina at Chapel Hill and Duke University, for use by other researchers including 
those outside of the study.  
 
When the study is completed, access to study data and/or samples will be provided through 
investigators at the University of North Carolina at Chapel Hill and Duke University. 
 
 
 
 
 

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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Principal Investigator and IDE 
Sponsor 
Data Safety Monitor  
Nicholas J Shaheen, MD, MPH 
Professor of Medicine and 
Epidemiology Director 
Chief, Division of 
Gastroenterology & Hepatology 
Adam P Wax. PHD 
Professor and Director of Graduate 
Studies 
Department of Biomedical 
Engineering  
Evan Dellon, MD, MPH 
Associate Professor of 
Medicine, 
Gastroenterology 
UNC Chapel Hill  
Duke University 
UNC Chapel Hill  
130 Mason Farm Road, Ste. 4150 
Chapel Hill, NC 27599-7080 
2571 CIEMAS, Box 90281 
Durham, NC 27708-0281 
130 Mason Farm Road, Ste. 
4140 
Chapel Hill, NC 27599-7080 
(919) 955-2513 
(919) 660-5143 
(919) 966-2511 
Nicholas_shaheen@med.unc.edu a.wax@duke.edu 
Evan_dellon@med.unc.edu 
 
Dr. Wax is responsible for programming and computations for data management. 
Dr. Shaheen is responsible for statistical computations for analyses of the data. 
 
10.1.6 SAFETY OVERSIGHT 
 
Monitoring for the trial will occur at several levels.  On a daily basis, the clinical study PI will monitor any 
adverse events in subjects enrolled in the trial.  In addition to performing the endoscopies, and, in 
conjunction with other study personnel, the clinical study PI will supervise other study-related activities 
and be well-positioned to evaluate the safety of the intervention.  Additionally, the study will comply 
with all monitoring regulations of UNC and Duke’s IRBs.  The study will also have a formal Independent 
Safety Monitor (ISM), Evan Dellon, MD, MPH.  Dr. Dellon is a faculty member at UNC who has extensive 
experience in the care of subjects with Barrett’s esophagus, and no connection to the trial.  Dr. Dellon 
will perform review of any reported adverse event within a week of occurrence or within a week of the 
study team’s knowledge of the event, whichever is applicable. As events occur, the monitor will 
characterize each event in terms of relatedness, expectedness, severity, and seriousness.  These AEs will 
be reported to the IRB and the NIH according to their specified reporting time frames. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
 
 

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10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
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 as long 
as the system is 21 CFR 11 compliant, and access is provided to the monitor for clinical monitoring. 
 
Clinical data (including adverse events (AEs)) 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. Clinical data will be entered directly from the source 
documents. Data collected directly from the OCT device will be stored on the OCT’s computer. Data will 
stored and transmitted between UNC and Duke using secure IRB-approved methods. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 

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formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. 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.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
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, reported to the 
NCI Program Official and UNC Chapel Hill and Duke University. Protocol deviations must be sent to the 
reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
  
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 3 years after the 
completion by contacting Duke University.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 

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nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the NCI has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
 
 
10.2 ABBREVIATIONS 
 
a/LCI 
Angle-resolved Low Coherence Interferometry 
AE 
Adverse Event 
BE 
Barrett’s Esophagus 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHHS 
Department of Health and Human Services 
EAC 
Esophageal Adenocarcinoma 
eCRF 
Electronic Case Report Forms 
EET 
Endoscopic Eradication Therapy 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GERD 
Gastroesophageal Reflux Disease 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HGD 
High Grade Dysplasia 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 

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ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
LGD 
Low Grade Dysplasia 
MOP 
Manual of Procedures 
NCI 
National Cancer Institute 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NSE 
Neosquamous Tissue 
OCT 
An Optical Coherence Tomography 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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