Conditions: Barrett's Esophagus
Keywords: Barrett's Esophagus Acetic Acid Chromoendoscopy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
Neoplasia in Barrett's esophagus could be missed during routine random biopsies. We propose a study using chromoendoscopy with Acetic Acid to increase the yield of biopsies in detecting neoplasia.

Detailed description:
Neoplasia in Barrett's esophagus is often focal and can be missed by nontargeted biopsies alone. In recent years, various advanced endoscopic techniques have been utilized, but with varying success rates. Narrow-band imaging, trimodal imaging, spectral imaging and i-scan are technologies that are manufacturer dependent with limited varying success rates and have financial implications. At our institution, narrow band imaging is routinely utilized as a diagnostic tool for detecting Barrett's esophagus. Acetic acid is a commonly available dye that has been used in the detection of neoplasia in Barrett's esophagus.

This study is aimed to prove the effectiveness of acetic acid chromoendoscopy in our Barrett's esophagus surveillance population. The goal is to compare the neoplasia yield of acetic acid chromoendoscopy with that of standardized random biopsy protocol. The sensitivity and specificity for neoplasia detection by these two methods will also be analyzed.

Investigators plan to conduct this prospective randomized study for a period of one and a half years (beginning August 1, 2015, ending February 29, 2016). Based on data from 2014, we anticipate to enroll approximately 185 patients. All gastroenterologists (with privileges at Doctors Hospital at Renaissance) will participate in this study. Patients will be randomized to either acetic acid chromoendoscopy or current standard of care (standardized random biopsy protocol utilizing narrow band imaging). Random biopsies from both protocols and targeted biopsies (if identified) will be obtained and submitted to pathology department. These will be reviewed independently by two pathologists. Any discordant results will be reviewed by an outside expert pathologist. Statistical data analysis will be performed utilizing Datadesk XL software.

Arms:
arm 1: Patient will have endoscopic examination of esophagus. Esophageal mucosa sprayed with 5cc solution of Acetic Acid 2.5% one time only. Esophageal mucosa examined again. Biopsies are obtained. Abnormal areas identified by Acetic Acid 2.5% will be submitted on separate containers for pathology review. If no abnormalities seen, random biopsies taken as per standard recommendations for Barrett's esophagus. Samples submitted for pathology review. arm 2: Patient will have endoscopic examination of the esophagus. Esophageal mucosa will not be sprayed with Acetic Acid 2.5%. Random biopsies taken as per standard recommendations for Barrett's esophagus. Samples submitted for pathology review.

Interventions: intervention 1: Chromoendoscopy using Acetic Acid 2.5% intervention 2: Standard random esophageal biopsies
Intervention descriptions: intervention 1: Spraying esophageal mucosa during random biopsies for Barrett's esophagus intervention 2: Random esophageal biopsies performed as per protocol

Protocol document:
Prot_SAP_000.pdf: 
Acetic Acid Chromoendoscopy 
Page 1 
Version 1.3, Dated 17Nov 2016 
 
 
 
 
 
 
TITLE PAGE 
 
TITLE:  Acetic acid chromoendoscopy in Barrett’s esophagus surveillance is superior to the 
standardized random biopsy protocol in detecting neoplasia: A prospective randomized trial. 
 
 
 
Coordinating Center: 
Doctors Hospital at Renaissance 
 
Principal Investigator 
Ingrid M Chacon, MD 
5520 Leonardo Da Vinci Ste. 100  
Edinburg, Texas 78539 
(956) 207-9844 
(956) 362-3636 
I.chacon@dhr-rgv.com 
 
Study Coordinator: 
Lana Yamba, MD 
2609 Michael Ángelo Drive 
Edinburg, Texas 78539 
(956) 362-2379 
l.yambal@dhr-rgv.com 
 
Data Manager: 
Vanessa Benavidez 
2609 Michael Angelo Drive 
Edinburg, Texas 78539 
(956) 362-2384 
v.benavidez@dhr-rgv.com 
 
 
 
CTRC/CTMS# 16-0087  
IND#: 129137PROTOCOL V 1.3 
DATE: 17 Nov 2016 


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INVESTIGATOR’S AGREEMENT 
 
I have read and understand the contents of this clinical protocol for Protocol UTHSCSA CTMS# 16-
0087 and will adhere to the study requirements as presented, including all statements regarding 
confidentially. In addition, I will conduct the study in accordance with current international conference 
on harmonization (ICH) guidance, Good Clinical Practice (GCP) guidance, the Declaration of Helsinki, 
US Food and Drug Administration (FDA) regulations and local IRB and legal requirements. 
 
 
 
Name of Clinical Investigator: Ingrid Chacon, MD 
 
Institution: Doctors Hospital at Renaissance 
 
 
___________________________________________  
___________________________ 
Investigator Signature 
 
 
 
 
 
 
 
Date 
 
 
 
 


Acetic Acid Chromoendoscopy 
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 ABBREVIATIONS (sample list – please only use those that are relevant to your protocol) 
 
 
AA 
 
 
 
Acetic Acid 
AE 
 
 
 
Adverse Event 
DHR  
 
 
Doctor’s Hospital at Renaissance 
DSM  
 
 
Data Safety Monitoring 
DSMB  
 
 
Data Safety Monitoring Board 
DSMC 
 
 
Data Safety Monitoring Committee 
 
DSMP  
 
 
Data Safety and Monitoring Plan 
FDA  
 
 
Food and Drug Administration 
 
GCP  
 
 
Good Clinical Practice 
IIS 
 
 
 
Investigator Initiated Protocol 
IND 
 
 
 
Investigational New Drug 
IRB 
 
 
 
Institutional Review Board 
NIH 
 
 
 
National Institutes of Health 
ORA  
 
 
Office of Research Administration 
PI 
 
 
 
Principal Investigator 
PRC  
 
 
Protocol Review Committee 
PRF  
 
 
Protocol Review Form 
PRMS  
 
 
Protocol Review and Monitoring System 
SAE  
 
 
Serious Adverse Event 
UTHSCSA 
 
 
University of Texas Health Science Center at San Antonio 
SBP                                    Standardized random Biopsy Protocol 
AAC                                    Acetic Acid Chromoendoscopy      
ICF                                     Informed Consent Form 
BP                                      Blood Pressure 
HR                                      Heart Rate 
BMI                                     Body mass index 
BX 
 
 
 
Biopsy 
SOC  
 
 
Standard of Care 
 
 


Acetic Acid Chromoendoscopy 
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Table of Contents 
TITLE PAGE .......................................................................................................................................................................... 1 
INVESTIGATOR’S AGREEMENT ...................................................................................................................................... 2 
ABBREVIATIONS ................................................................................................................................................................ 3 
PROTOCOL SYNOPSIS ........................................................................................................................................................ 6 
1. 
OBJECTIVES ........................................................................................................................................................ 7 
1.1 Primary Objective ............................................................................................................................................................. 7 
2. 
BACKGROUND ................................................................................................................................................... 7 
2.1 Study Disease .................................................................................................................................................................... 7 
2.2 Investigational Agent or Device ....................................................................................................................................... 7 
2.3 Rationale ........................................................................................................................................................................... 7 
3. 
PATIENT SELECTION ........................................................................................................................................ 8 
3.1 Inclusion Criteria .............................................................................................................................................................. 8 
3.2 Exclusion Criteria ............................................................................................................................................................. 8 
4. 
PROCEDURES ..................................................................................................................................................... 9 
4.1 General Guidelines ............................................................................................................................................................ 9 
4.2 Informed Consent Process ................................................................................................................................................ 9 
4.3 Randomization Procedures ............................................................................................................................................... 9 
5. 
RESEARCH PLAN ............................................................................................................................................... 9 
5.1 Research Plan Administration ........................................................................................................................................... 9 
5.2 General Concomitant Medication and Supportive Care Guidelines ............................................................................... 11 
5.3 Duration of Therapy ........................................................................................................................................................ 11 
5.4 Duration of Follow Up .................................................................................................................................................... 11 
5.5 Criteria for Removal from Study .................................................................................................................................... 11 
5.6 Alternatives ..................................................................................................................................................................... 11 
5.7 Compensation ................................................................................................................................................................. 11 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................................................. 12 
6.1 Procedure Related ........................................................................................................................................................... 12 


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6.2 Definitions ....................................................................................................................................................................... 12 
6.3 Recording and Reporting of Adverse Events .................................................................................................................. 12 
6.4 Adverse Events based on signs and symptoms ............................................................................................................... 13 
6.5 Causality collection ......................................................................................................................................................... 13 
6.6 Adverse Events Characteristics ....................................................................................................................................... 13 
7. 
INVESTIGATOR RESOURCES ........................................................................................................................ 13 
7.1 Qualifications .................................................................................................................................................................. 13 
7.2 Use of Facilities .............................................................................................................................................................. 14 
8. 
STUDY CALENDAR ......................................................................................................................................... 14 
9. 
DATA/REGULATORY CONSIDERATIONS & PROJECT MANAGEMENT ............................................... 14 
9.1 Data Management ........................................................................................................................................................... 14 
9.2 Study Monitoring ............................................................................................................................................................ 15 
9.3 Data Safety Monitoring Committee ................................................................................................................................ 15 
Serious Adverse Event Definition: is any adverse event that: ..................................................................................... 16 
10. 
STATISTICAL CONSIDERATIONS ................................................................................................................ 19 
REFERENCES ..................................................................................................................................................................... 21 
 
 
 


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PROTOCOL SYNOPSIS 
 
PROTOCOL TITLE: Acetic acid chromoendoscopy in Barrett’s esophagus surveillance is superior to the standardized 
random biopsy protocol in detecting neoplasia: A prospective randomized trial. 
STUDY PHASE: 3 
INDICATION:  Barrett’s esophagus undergoing chromoendoscopy surveillance for neoplasia. 
PRIMARY OBJECTIVE: To compare the neoplasia yield when using acetic acid chromoendoscopy versus the 
neoplasia yield from standardized random biopsy protocol in Barrett's esophagus surveillance population at Doctor’s 
Hospital at Renaissance.   
SECONDARY OBJECTIVE: N/A 
HYPOTHESIS: Acetic acid chromoendoscopy will be able to detect more neoplasias in comparison to standard, 
random biopsies in Barrett’s esophagus surveillance population.  
STUDY DESIGN: Prospective randomized study 
PRIMARY ENDPOINTS AND SECONDARY ENDPOINTS: Percent (%) neoplasia detection in 2 groups:  
Random Biopsy Protocol (control) and Acetic Acid Chromoendoscopy (treatment group)  
SAMPLE SIZE BY TREATMENT GROUP:  104 patients randomized into two groups with 1:1 ratio. 
SUMMARY OF SUBJECT ELIGIBILITY CRITERIA: Patients 18 years and older with a previous diagnosis of 
Barrett’s esophagus, confirmed by pathology. 
INVESTIGATIONAL PRODUCT DOSAGE AND ADMINISTRATION: 10cc of 2.5% Acetic Acid 
CONTROL GROUP: Standard Random Biopsies 
PROCEDURES: Acetic Acid Chromoendoscopy Guided Biopsies 
 
 
 
SCHEMA 
 
 
 
 
Barrett’s Esophagus Surveillance Patients  
Undergoing Planned Endoscopy 
Standard Random 
Biopsy Protocol 
(Control) 
Acetic Acid  
Chromoendoscopy 
Guided (Intervention) 
Neoplasia detection at 
threshold of 142 
seconds 
Pathology Report 


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1. OBJECTIVES 
1.1 Primary Objective 
 
The objective of this study is to compare the neoplasia yield when using acetic acid 
chromoendoscopy versus the neoplasia yield from standardized random biopsy protocol in our 
Barrett's esophagus surveillance population.   
 
2. BACKGROUND  
2.1 Study Disease 
 
Barrett's esophagus is the single most important precursor lesion and risk factor for 
esophageal adenocarcinoma.  It develops when the squamous esophageal epithelium is 
replaced by columnar epithelium (resulting in intestinal metaplasia) during the process of 
healing after repetitive injury, and is typically associated with gastro esophageal reflux disease. 
Intestinal metaplasia can be detected in most patients with esophageal adenocarcinoma. 
Patients diagnosed with Barrett's esophagus are followed at established intervals with 
surveillance endoscopy. These intervals are based on American College of Gastroenterology 
Clinical Guidelines for the diagnosis and management of Barrett’s esophagus. Endoscopic 
examination of the esophageal mucosa and random biopsies may help to find neoplasia at an 
early stage. Patient’s found to have earlier neoplasia have the best prognosis (Shaheen, Falk, 
& Iyer, 2016). 
 
2.2 Investigational Agent or Device 
 
Acetic acid is a commonly available dye that has been used in the detection of neoplasia of the 
uterine cervix and in Barrett's esophagus. Several studies have been performed using acetic 
acid as a chromoendoscopy agent to increase the yield of biopsies on Barrett’s esophagus 
surveillance. Few studies, mostly retrospective cohort studies, utilizing this detection modality 
have been reported in literature. (Curvers, W Gastroenterology 2010) (Pohl J Endoscopy 2007) 
 
 
2.3 Rationale 
 
Neoplasia in Barrett's esophagus is often focal and can be missed by no targeted biopsies 
alone. Meta-analysis of 24 studies involving patients with Barrett’s esophagus revealed a 25% 
missing rate of esophageal neoplasia after index endoscopy (Visrodia, Singh 2016). 
 
Despite of current knowledge and recommendations by national societies, the adherence of 
biopsy protocol guidelines in the US community setting is not ideal. A review of 2245 Barrett’s 
esophagus cases showed 51.2% adherence to guidelines. Non-adherence to guidelines is 
associated to decreased neoplasia detection (Abrams, Kapel, & Linberg, 2009). In recent 
years, various advanced endoscopic techniques have been utilized, but with varying success 
rates. Narrow-band imaging, trimodal imaging, spectral imaging, confocal laser 
endomicroscopy and i-scan are technologies that are manufacturer dependent with limited 
varying success rates and have financial implications (Pohl J, May 2007) (Curvers, Wallace 
2010) ( Gupta A, Attar 2014). Narrow band imaging is routinely utilized as a diagnostic tool for 


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detecting Barrett's esophagus at Doctors Hospital at Renaissance. Acetic acid is a commonly 
available dye that has been used in the detection of neoplasia in Barrett's esophagus. Few 
studies, mostly retrospective cohort studies, utilizing this detection modality have been 
reported in literature. A large retrospective cohort study compared neoplasia detection rate in 
627 patients with Barrett’s esophagus undergoing surveillance.  Patients had spray of 
esophageal mucosa with acetic acid before biopsies. Targeted biopsies were taken at areas 
with lack of acetowhitening or abnormal surface patterns. Pathology results were compared 
retrospectively with surveillance patients who had standard biopsies in the past.  In the acetic 
acid cohort there was a 14.7 fold increase in neoplasia detection compared with the standard 
random biopsy protocol group.  (Shareef Tholoor… Bhandari, Gastrointestinal endoscopy).  A 
prospective cohort study of 132 patients with Barrett’s esophagus reported also increased 
sensitivity for neoplasia after acetic acid spray. Patients were given acetic acid spray before 
esophageal biopsies. Targeted biopsies of any neoplasia and quadrantic 2-cm biopsies of 
residual Barrett's area were then taken. Using a threshold of 142 seconds after spray yielded a 
sensitivity for neoplasia of 98 % (95 % confidence interval [95 %CI] 89 % - 100 %) and 
specificity of 84 % (74 % - 91 %) (Bhandari 2013).  Current guidelines don’t recommend the 
use of these modalities in lieu of random biopsy protocol. (Shaheen, Falk & Lyer 2016)  
 
Recent meta-analysis of 24 cohort studies concluded that among patients with non dysplastic 
Barrett’s esophagus (or BE with low grade dysplasia) at their index endoscopy, 25% of 
esophageal adenocarcinoma was diagnosed within a year. These cases are considered 
missed esophageal carcinoma by definition. A more sensitive technique for Barrett’s 
esophagus surveillance should be allocated to decrease the incidence of missed esophageal 
adenocarcinoma. 
 
 
 
3. PATIENT SELECTION 
3.1 Inclusion Criteria 
 
o Patients 18 years and older  
o Previous diagnosis of Barrett’s esophagus, confirmed by pathology. 
 
3.2 Exclusion Criteria 
 
o Patients diagnosed with any level of dysplasia on previous esophageal biopsies. 
o Patients who had esophageal therapy with Halo radiofrequency ablation in the past, or 
esophagectomy. 
o History of allergy to Acetic Acid 
o History of esophageal dysplasia or cancer  
o Esophageal ulcerations  
o Esophageal Candida 
o Esophageal Varices 
o Patients who cannot provide a valid consent 
o Patients who are currently pregnant 
 


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4. PROCEDURES 
4.1 General Guidelines 
 
All DHR employed gastroenterologists will participate in the study.  All procedures will be 
performed by trained and experienced Endoscopists. DHR Research Institute will ensure that 
all participating Gastroenterologists and pathologists are instructed on consenting, source 
documentation requirements, Good Clinical Practice (GCP) guidelines and additional study 
related topics.  Dr. Chacon, the Study Principal Investigator will be responsible for training 
Gastroenterologists and Endoscopists on the technique. She will ensure that all 
Gastroenterologists and Endoscopists are qualified to perform the technique in a standardized 
fashion. All key study personnel will sign a training affidavit attesting to their knowledge of study 
processes. 
 
Eligible subjects will be randomly allocated to either the intervention arm of acetic acid 
chromoendoscopy or the non-intervention arm of standardized random biopsy protocol. 
Source documentation verifying eligibility, along with the eligibility checklist and consent will be 
verified by Dr. Chacon and kept in subject’s chart. 
 
4.2 Informed Consent Process 
 
Study candidates will be identified through DHR’s Barrett’s surveillance program. Research 
staff and Gastroenterologists who are permitted to consent patients will describe the trial in 
detail. All patients will be made aware that they are under no obligation to participate, that 
failure to participate will not adversely affect their care, and that they may decline 
participation at any time. They will be given an opportunity to ask questions and have these 
answered to their satisfaction.  The informed consent will then be signed and dated by both 
the patient and the principal Investigator. In general, patients who are deemed competent to 
sign an informed consent for their procedure will be deemed competent to evaluate whether 
or not they wish to participate in this trial. If there are any questions regarding competence, 
the trial will not be offered to the patient. Patients who have agreed to participate and have 
signed the informed consent will participate. 
 
4.3 Randomization Procedures 
 
Prior to the initiation of the study, the DHR Research Institute will create a randomization list. 
Patients will be randomized to one of the two treatment arms and assigned randomization # 
with a 1:1 allocation ratio. Prior procedure, the delegated research associate will assign the 
patient to a treatment arm and the Gastroenterologist will then be instructed to perform 
procedure according to the randomization group. 
5. RESEARCH PLAN 
5.1 Research Plan Administration 
 
Study candidates will be identified through DHR’s Barrett’s surveillance program. Patients 
who have agreed to participate and have signed informed consent will participate. Patient's 
eligibility information will be verified by the Principal Investigator.  The patient will then be 
randomized prior to their scheduled endoscopy. For the control group, the 


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Gastroenterologist will follow routine procedure. For the intervention group, acetic acid 
chromoendoscopy will be performed.  All Gastroenterologists participating in the study will 
be educated on the application and documentation of this procedure.  Patients will 
receive routine follow up care as per DHR policy. 
 
Pre-Procedure: 
Gastroenterologists will provide the following information to Dr. Chacon to verify 
eligibility. 
 
1. History and physical notes 
2. Eligibility checklist 
3. Informed consent form 
 
Delegated Research Associate will assign a number and allocation to the gastroenterologist. 
 
Procedure: 
 
Control group:  Random biopsy protocol 
- 
Patients assigned to no intervention arm will have a random biopsy consisting of 4 
quadrant biopsies every 2 cm of Barrett's esophagus (from proximal to distal).  
- 
If abnormality is seen such as mucosal ulceration, mucosal nodularity, abnormal 
vessels, additional biopsy will be taken and identified as targeted. 
                          Samples collected will be labeled as random or targeted. 
 
 
Intervention group:  Acetic Acid protocol 
 
Acetic Acid will be pre-prepared by DHR Pharmacy  
Patients assigned to AA arm will be given spray of the mucosa with 10 cc of 2.5% of AA 
via scope. Physician will allow 142 seconds for the acetowhitening effect to happen.  
- 
If no abnormal mucosa seen, physicians will biopsy the mucosa according to the 
random biopsy protocol; meaning the physician will take 4 quadrant samples every 2 
cm of Barrett's Esophagus (from proximal to distal).  
- 
If abnormality is seen (lack of acetowhitening effect) physician will take biopsies on 
target (abnormal mucosa) plus random biopsy as per protocol. Targeted biopsies will 
be labeled as such.  
 
Biopsies will be labeled and sent to pathology as per Doctors Hospital at Renaissance 
protocol.  Samples will be identified with patients name, medical records number, and 
research identification number. Pathologist will be blind to patient's participation arm.   
 
Patient is given information in writing and contact numbers in case s/he experiences 
symptoms. 
 
Post-Procedure, Pathology:   
 
All specimens will be sent to pathology.  These specimens will be reviewed by a pathologist 
who will be blinded to patient's participation arm.  Any discordant results will be reviewed by 
an outside expert pathologist.  
 
All biopsies will be obtained in appropriate biopsy containers, properly labeled and 
submitted to pathology department. Biopsies are fixed for a minimum fixation time of 6 


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hours. They are properly identified and transferred to appropriate cassettes. In order to 
identify these cases, cassettes will be color coded. The cassettes are placed in a tissue 
processor wherein the steps performed include fixation, dehydration, clearing and wax 
infiltration. After this process, tissue cassettes are removed embedded with proper 
orientation. 3-5 micron thick serial sections (6) are obtained with a sharp clean knife and 
transferred on to a glass slide. These slides are stained, utilizing Hematoxylin and Eosin 
automated stained and cover slipped.  
 
Two pathologists independently review the slides, and record their diagnosis. If there is 
discordance, slides will be sent to independent outside pathologist with gastrointestinal 
expertise for review. Final results will be recorded on an excel document and will be made 
available for statistical analysis. 
 
Gastroenterologists will provide the following to Dr. Chacon: 
 
1. Copy of the procedure note 
2. Copy of the pathology report which includes the following 
a. Data regarding specimen and 
b. Other clinicopathologic data. 
 
5.2 General Concomitant Medication and Supportive Care Guidelines 
 
All of the procedures described in this study are standard of care (SOC). There is no 
additional substantive risk associated with Acetic Acid. 
 
5.3 Duration of Therapy 
 
Treatment is limited to the surgical intervention.  Routine adjuvant care will be given. 
 
5.4 Duration of Follow Up 
 
N/A.  No follow up period. 
 
5.5 Criteria for Removal from Study 
 
Patients will remain in the study unless there is an intraprocedure catastrophe that 
mandates an incomplete procedure; or if they choose to withdraw. 
 
5.6 Alternatives 
 
Chromoendoscopy is a commonly accepted procedure and there is no increased risk with the 
addition of acetic acid to this procedure.  All precautions will be taken to minimize overall 
procedural risk.  Alternatives to the study would be to have standard of care in which patients 
will be informed of.   
 
5.7 Compensation 
 
Patients will not be paid for participating in this study. 


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6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
6.1 Procedure Related 
 
Expected adverse effects for this study include an allergic reaction to the acetic acid.   
 
6.2 Definitions 
 
The definitions of adverse events (AEs) and serious adverse events (SAEs) are listed below. 
 
Adverse Event (AE) Any untoward or unfavorable occurrence in a human research subject 
(physical or psychological harm) temporally associated with the individual's participation in the 
research (whether or not considered related to participation in the research). 
 
Related: There is a reasonable possibility that the incident, experience or outcome may have 
been caused by the procedures involved in the research. The term AE is used to include both 
serious and non-serious AEs. 
 
Serious adverse event: A serious adverse event is an AE occurring during any study phase (ie, 
run-in, treatment, and washout, follow-up), that fulfills one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above? 
 
6.3 Recording and Reporting of Adverse Events 
 
Non-serious adverse events and SAEs will be collected throughout the study period. Only 
Serious unexpected adverse events will be collected and reported to the Institutional Review 
Board. Adverse events should be reported to the IRB within 5 days of discovery of the adverse 
event.  
 
The following variables will be collected for each AE: 
• AE (verbatim) 
• The date when the AE started and stopped 
• Whether the AE is serious or not 
• Investigator causality rating 
• Outcome. 
 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of serious AE 
• AE is serious due to 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 


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• Date of death 
• Autopsy performed 
• Description of AE 
• Causality assessment in relation to Study procedure(s) 
• Causality assessment in relation to other medication 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Definitions. An AE of severe intensity 
need not necessarily be considered serious. For example, nausea that persists for several 
hours may be considered severe nausea, but not a SAE. On the other hand, a stroke that 
results in only a limited degree of disability may be considered a mild stroke but would be a 
SAE. 
 
6.4 Adverse Events based on signs and symptoms 
 
When collecting AEs, the recording of diagnosis is preferred to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
 
6.5 Causality collection 
 
The causality of SAEs (their relationship to study procedures) will be assessed by the PI and 
reported to the IRB. 
 
6.6 Adverse Events Characteristics 
 
'Expectedness': AEs can be 'Unexpected' or 'Expected' for expedited reporting 
purposes only. 
 
Attribution of the AE: 
Definite -The AE is clearly related to the study treatment  
Probable -The AE is likely related to the study treatment  
Possible- The AE could be related to the study treatment  
Unlikely -The AE is doubtfully related to the study treatment 
Unrelated -The AE is clearly NOT related to the study treatment 
 
 
7. INVESTIGATOR RESOURCES 
7.1 Qualifications 
 
Multiple Gastroenterologists at Doctors Hospital at Renaissance and the DHR Research 
Institute will conduct this study. All study personnel will be required to complete the requisite 
Human Subjects Protection Training by CITI. Documentation of training will be kept on file. 
 
Once this study has completed all regulatory requirements including the following; IRB 
approval of protocol, completion of all required Human Subjects Protection Training (HSPT), 
CV's and Medical Licenses for participating gastroenterologists, Confidential Disclosure 


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Agreements (CDA) and other regulatory documents as required, there will be a protocol 
training meeting to ensure that all Gastroenterologists, pathologists and study staff are trained 
in the protocol, procedures, and their responsibilities. Should there be any questions that arise 
during the study, all investigators and research staff will be provided with the PI's, and PM's 
contact  information  and encouraged  to contact them with any questions. 
 
7.2 Use of Facilities 
 
All study procedures will be performed at Day Surgery at Doctors Hospital at Renaissance 
according to local policy and procedures. 
 
8. STUDY CALENDAR 
 
Pre-Study 
Visit 
Procedur
e day 
Informed  Consent 
X 
 
Demographic Data 
X 
 
Medical History 
X 
 
Concomitant Medication 
Review 
X 
 
Physical Exam 
X 
 
Weight (lbs.) 
X 
 
Height (in) 
X 
 
BMI 
X 
 
Inclusion/Exclusion Criteria 
X 
 
Randomization 
X 
 
Chromoendoscopy or SOC Bx 
 
X 
Collection of AE’s* 
 
X 
Procedure Report 
 
X 
Pathology Report 
 
X 
*Adverse Event information related to the biopsy will be collected at the time of 
procedure and during routine follow-up with the subject.   
 
9. DATA/REGULATORY CONSIDERATIONS & PROJECT MANAGEMENT 
9.1 Data Management 
 
Data (source documentation) will be collected at the site and stored at DHR Research Institute 
in a locked, limited access room. De identified data will then be downloaded in either Excel or 
SPSS format for statistical analysis, which will be done on a HIPAA compatible, password 
protected encrypted   computer at DHR Research Institute. A separate file that contains the 
code to link patients Study IDs to their identifiable information will be kept in a locked, limited 
access room at DHR Research Institute. All data entry will be performed by the study Project 
Manager. 


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9.2 Study Monitoring 
 
The DHR Research Institute will support the PI with site management aspects of this trial. This 
includes but is not limited to study start-up, regulatory assistance (IRB submissions, 
amendments, and renewals), provision of template study forms (tracking and eligibility 
checklists, etc.), training, and overall project management. The DHR Research Institute will be 
available to provide tools to assist the study team in conducting the trial appropriately and 
according to GCP Standards. 
 
Monitoring will be performed by DHR Research Institute by conducting routine monitoring visits 
throughout the life of the protocol.  Following each routine monitoring visit, a visit report will 
be generated containing information on site activities, and a summary of pertinent points and 
action items together with a copy of the follow-up letter will be available in investigator site file. 
 
During these monitoring visits, some of the items that will be reviewed are: 
• Training of the study staff 
• Site personnel qualifications to participate in the trial 
• That study related documents are current 
• That regulatory compliance is accomplished 
• That each subject has signed the informed consent 
• That the current and approved protocol is complied with (including reporting and logging of all 
protocol deviations) 
• That all SAEs and AEs have been reported to the local regulatory and Ethics/IRB 
Committees, as appropriate 
• That source documentation matches data entry. 
 
9.3 Data Safety Monitoring Committee 
 
Data and Safety Monitoring Oversight 
A Data and Safety Monitoring Plan (DSMP) is required for all protocols conducted at CTRC. All 
protocols conducted at CTRC are covered under the auspices of the CTRC Institutional Data 
Safety Monitoring Plan.   
 
The CTRC Institutional DSMP global policies provide individual trials with:  
 
institutional policies and procedures for institutional data safety and monitoring,  
 
an institutional guide to follow, 
 
monitoring of protocol accrual by the CTRC Protocol Review Committee, 
 
review of study forms and orders by the Forms Committee, 
 
tools for monitoring safety events, 
 
monitoring of UPIRSO’s by the Director of Quality Assurance and DSMC, 
 
determining level of risk (Priority of Audit Level Score – PALS) ,  
 
oversight by the Data Safety Monitoring Committee (DSMC),  and 
 
Verification of protocol adherence via annual audit for all Investigator Initiated Studies 
by   the   
CTRC Quality Assurance Division. 
 
Monitoring Safety: 
Due to the low risk associated with participation in this protocol, the Principal Investigator will 
perform primary assessment of adverse events, adverse event trends and treatment effects on 


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this study.  The PI will conduct independent quarterly review and report findings to the CTRC 
Data Safety Monitoring Committee (DSMC) and the UTHSCSA IRB.  
 
Baseline events and adverse events will be captured using the CTRC Master Adverse Events 
Document for each patient using CTCAE V4.03 for the grading and attribution of adverse 
events. Usage of the CTRC Master Adverse Events Document centrally documents: 
 
the event and grades the seriousness of it,  
 
if the event was a change from baseline,   
 
determines the relationship between the event and study intervention,  
 
if the event was part of the normal disease process, and  
 
What actions were taken as a result of the event?  
 
 
Safety Definitions: 
 
For this study, the following safety definitions will be applicable: 
 
Adverse Event Definition: An adverse event (AE) is defined as any untoward or unfavorable 
medical occurrence in a human subject, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in the research, whether or not considered related to the subject’s 
participation in the research  For this study, all adverse events will be documented starting with 
the beginning of the endoscopy and ending with the routine follow up patients have after their 
procedure.   
 
Serious Adverse Event Definition: is any adverse event that: 
1. Results in death; 
2. Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
3. Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; 
5. Results in a congenital anomaly/birth defect; or 
6. Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition  
 
Unanticipated Problems Involving Risks to Subjects or Others Definition: Unanticipated 
problem involving risk to subjects or others includes any incident, experience or outcome that 
meets all of the following criteria: 
 
A. 
unexpected (in terms of nature, severity, or frequency) given  
 (a) the research procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and  
 (b) The characteristics of the subject population being studied (note: the unfounded 
classification of a serious adverse event as “anticipated” constitutes serious  non-
compliance); 
B. 
definitely related or probably related to participation in the research; and 
C. 
suggests that the research places subjects or others at a greater risk of harm (including 
physical,  
psychological, economic, or social harm) than was previously known or 
recognized 
 
Reporting Requirements 


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For this study, all Master Adverse Events Documents collected on patients for this protocol will 
be reviewed by the Principal Investigator on an annual  basis to determine if a serious safety 
problem has emerged that result in a change or early termination of a protocol such as: 
 dose modification, 
 suspending enrollment due to safety or efficacy, or 
 termination of the study due to a significant change in risks or benefits.   
 
As per the CTRC DSMP, any protocol modifications, problematic safety reports, unanticipated 
problems, and suspension or early termination of a trial must be reported to all members of the 
research team. Suspension and early termination of a trial must also be reported immediately 
to the Director of Quality Assurance (DQA) who will promptly notify the UTHSCSA IRB.  
 
The PI will review the Master Adverse Events documents to determine the significance of the 
reported events and will file the Investigator Initiated Study Annual DSMB Report Form on an 
annual basis with the CTRC DSMB. The Investigator Initiated Study DSMC Report Form 
includes information on adverse events, current dose levels, and number of patients enrolled, 
significant toxicities per the protocol, patient status (morbidity and mortality), dose adjustments 
with observed response, and any interim findings.  Any trend consisting of three or more of the 
same event will be reported to the CTRC DSMB for independent review outside of the 
reporting cycle, which begins three months following protocol start up. Conflict of interest is 
avoided by the independent review of the CTRC DSMB and by ongoing independent review of 
adverse events trends reported to the Director of Quality Assurance.  
 
 
 
 
 
 


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All SAE and UPRISO’s will be reported following CTRC and UTHSCSA institutional guidelines. 
UTHSCSA SAE/UPRISO REPORTING REQUIREMENTS 
Type Event 
Report to 
Timeframe 
All AE, SAE and 
UPIRSO 
Regulatory Affairs 
and DQA 
Same as other notification timeframes 
except for SAE/AE which should be 
reported on Monday for the prior week 
SAE 
CTRC DQA 
within 24 hours 
AE/SAE 
UTHSCSA IRB 
Annually 
UPIRSO - all 
CTRC DQA 
within 24 hours of the PI determining a 
UPIRSO exists 
UPIRSO - life 
threatening 
UTHSCSA IRB 
within 48 hours of the PI determining a 
UPIRSO exists 
UPIRSO - non-life 
threatening 
UTHSCSA IRB 
within 7 days of the PI determining a 
UPIRSO exists 
 
AE’s and SAE events that occur during clinical trials with or without an Investigational New 
Drug (IND) application are mandatory reports submitted to FDA via Medwatch FDA F3500A 
within 15 days for events that have at least a possible relationship with the drug. 
 
 
Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at CTRC, the PI has ultimate responsibility for ensuring protocol 
compliance, data accuracy/integrity and responding to recommendations that emanate from 
monitoring activities.    Source verification of data will be performed every six weeks by DHR 
Research Institute. Protocol compliance, data accuracy and reporting of events is further 
ensured by an annual audit conducted by the Data Safety Officer, whose audit report is shared 
with the PI, the research team, and will be reviewed by the CTRC DSMC.  
 
 


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10. 
STATISTICAL CONSIDERATIONS 
 
Sample Size and Power 
 
This will be a randomized balanced two-arm clinical trial of the effect of acetic acid relative to 
random biopsy.  The primary end point will be the proportion (p) of patients with detectable 
neoplasia, denoted as pic in the random biopsy control arm and PA in the acetic acid arm.  Based 
on historical data, it is assumed that pic=0.04.  It is further assumed that PA=0.24.  Based on these 
assumptions, two-sided testing of the null hypothesis Ho: PA=pic with Fishers Exact test and 
alpha=0.05, this study will attain 80% power for testing Ho with n=52 subjects per arm. Assuming 
no losses, a total of 104 patients will be required. [PASS Version 11, NCSS Kaysville UT 2011]. 
 
 
Statistical Methods 
 
Patients will be randomized to acetic acid or random biopsy in permuted blocks of size 2.  
Continuously distributed outcomes will be summarized with the sample size, mean, standard 
deviation, median, minimum and maximum and binary and categorical outcomes will be 
summarized with frequencies and percentages.  The number screened, the number of screen 
failures by reason, the number randomized, lost to follow-up by reason and treatment arm, and 
the number completing the study by treatment arm will be tabulated.  The significance of variation 
the proportion of patients with detectable neoplasia will be assessed with Fishers Exact test.  
Treatment arms will be contrasted with regard to mean age, BMI, gender, ethnicity, and medical 
history.  The significance of variation in treatment group with regard to mean age and BMI will be 
assessed with T tests or Wilcoxon tests as appropriate and variation in gender, ethnicity and 
medical history will be assessed with Fishers Exact tests.  Adverse events, if any, will be tabulated 
by treatment arm.  The significance of variation the occurrence of adverse events with treatment 
arm will be assessed with Fishers Exact tests.  All statistical testing will be two-sided with a 
significance level of 5%.  R or SAS Version 9.4 for Windows [SAS Institute, Cary, North Carolina] 
will be used.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 2: Clinical Investigator Tools for Recruitment of Minorities       
 
 
** - 
It is 
rec
om
me
nde
d to 
sub
mit 
any 
pati
ent 
mat
eria
ls 
to 
the 
IRB 
as 
an 
am
end
me
nt 
afte
r 
the 
initi
al 
IRB 
app
rov
al 
has 
bee
n 
gra
nte
d 
 
Tool included 
in study 
LIST OF TOOLS AND ACTIONS FOR INCREASING MINORITY ACCRUAL TO 
CLINICAL TRIALS 
For assistance with submitting IRB documents, developing materials in English 
and Spanish, and scheduling public service announcements, please contact 
MAtools@uthscsa.edu 
Yes     No 
1.  Include Clinical Trial information on CTRC website in both English and Spanish 
(Please notify MAtools@uthscsa.edu). 
Yes     No 
2. Use of Bilingual Research Team Member or Translation services 
Yes     No 
3. Identification of bilingual Patient Navigator representative of the Target Population 
Please Specify:  
Yes     No 
4.  Informed Consent available in Spanish 
Yes     No 
6.  Information Brochures in English and Spanish** (IRB approval required)  
Yes     No 
7.  Flyers in English and Spanish (two sided, printed in English on one side and 
Spanish on the other).** (IRB approval required) 
Yes     No 
8.  Public Service Announcements (PSAs) or Advertisements- Spanish Radio** (IRB 
approval required) 
Yes     No 
9.  PSA’s or Advertisements -Spanish newspapers (e.g., La Prensa)** (IRB approval 
required) 
Yes    No 
10.  PSA’s or Advertisements -Spanish Television (e.g., Univision)** (IRB approval 
required) 
Yes     No 
11. Patient Friendly Fast Facts in English and Spanish ** (IRB approval required) 
Yes     No 
12.  Outreach to advocacy or community organizations (including presentations or 
awareness campaigns). Please specify:  
 
Yes     No 
13. Other. Please Specify:  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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REFERENCES 
1. Abrams, J. A., Kapel, K. C., & Linberg, G. M. (2009). Adherence to biopsy guidelines for Barrett's 
esophagus surveillance in the community setting in the United States. Clinical Gastroenterology and 
Hepatology, 736-742. 
2. Bhandari , P., Longcroft-Wheaton, G., Brown, J., Basford, P., Cowlishaw, D., & Higgins , B. (2013). 
Duration of acetowhitening as a novel objective tool for diagnosing high risk neoplasia in Barret's 
esophagus: a prospective cohort trial. Esophagus. 
3. Curvers, W. L., Herrero, L. A., & Wallace, M. B. (2010). Endoscopic tri-modal imaging is more 
effective than standard endoscopy in indentifying early stage neoplasia in Barrett's esophagus. 
Gastroenterology, 1106-1114. 
4. Pohl, J., & May, A. (2007). Comparison of computed virtual chromoendoscopy and conventional 
chromoendoscopy with acetic acid for detection of neoplasia in Barrett's exophagus. Endoscopy, 594-
598. 
5. Shaheen, N. J., Falk, G. W., & Iyer, P. G. (2016). ACG Clinical Guideline: Diagnosis and Management 
of Barrett's esophagus. American Journal of Gastroenterology, 30-50. 
6. Thoolor, S., Bhattacharyya, R., & Bhandari, P. (2014). Acetic Acid Chromoendoscopy in Barrett's 
esophagus surveillance is superior to the standarized random biopsy protocol: results from a large cohort 
study . Gastrointestinal Endoscopy, 417-424. 
7. Visrodia, K., & Singh, S. (2016). Magnitude of missed esophageal adenocarcinoma after Barrett's 
esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology, 599-607. 
8. Gupta, A.; Attar, BM et al. (2014) Utility of confocal laser endomicroscopy in identifying high-grade 
dysplasia and adenocarcinoma in Barrett's esophagus: a systematic review and meta-analysis. Eur J 
Gastroenterol Hepatol 369-77 
 
 
 
  
 
 
 
 


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APPENDICES 
 
Appendix A:  English Informed Consent Form + HIPAA 
Appendix B:  Spanish Informed Consent Form + HIPAA 
Appendix C:  Adverse Event Log 
Appendix D:  Concomitant Medication Log 
Appendix E:  Medical and Surgical History Log 
Appendix F:  Patient Demographic Form