Effect of Aspirin on Biomarkers of Barrett's Esophagus After Successful Eradication of Barrett's Esophagus With Radiofrequency Ablation
Phase: PHASE2
Conditions: Barrett Esophagus, Esophageal Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

DCP Protocol Number: MDA2013-02-02 
Protocol Version, dated 5/3/2019 
 
DCP Protocol Template Version 8.3 
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DCP Protocol #: MDA2013-02-02 
 
Local Protocol #: 2015-0819 (MDACC); 15-1171 (UC-Denver); 15-2673 (UNC); 824385 (UPenn); 
00914/PS0083 (KC-VA); 15-007099 (Mayo-Rochester); STU00202495 (NWU); 15-
314 (St. Michael’s); 16-000628 (UCLA); H-39447 (Baylor-Houston).  
 
Effect of Aspirin on Biomarkers of Barrett’s Esophagus After Successful Eradication of Barrett’s 
Esophagus with Radiofrequency Ablation 
 
 
Consortium Name: 
 
University of Texas MD Anderson Early Phase Clinical Research 
Consortium 
 
Name of Consortium Principal  
Powel H. Brown, M.D., Ph.D. 
Investigator: 
 
Professor and Chair, Department of Clinical Cancer Prevention 
 
 
University of Texas MD Anderson Cancer Center 
 
 
1515 Holcombe Boulevard, Unit 1360 
Houston, TX 77030-4009 
Telephone: (713) 792-4509 
Fax: (713) 794-4679 
 
 
phbrown@mdanderson.org 
 
MD Anderson Consortium 
 
Lana A. Vornik, M.H.A., M.S. 
Administrative Director: 
 
Associate Director, Research Planning and Development 
 
 
Department of Clinical Cancer Prevention 
 
 
University of Texas MD Anderson Cancer Center 
 
 
1515 Holcombe Boulevard, Unit 1360 
Houston, TX 77030-4009 
Telephone: (713) 792-9594 
Fax: (713) 745-4230 
 
 
lavornik@mdanderson.org 
 
 
Organization Name: 
 
 
University of Texas MD Anderson Cancer Center  
Protocol Principal Investigator: 
Robert S. Bresalier, M.D. 
 
 
 
 
 
Department of Gastroenterology, Hepatology and Nutrition 
 
 
 
 
 
The University of Texas MD Anderson Cancer Center 
 
 
 
 
 
1515 Holcombe Boulevard Unit 1466 
 
 
 
 
 
Houston, Texas 77030 
713-745-4340 
713-745-9295 
rbresali@mdanderson.org  
 
Organization Name: 
 
 
University of Texas MD Anderson Cancer Center  
Investigator:  
 
 
Marta Davila, M.D. 
15151 Holcombe Boulevard Unit 1466 
Houston, Texas 77030-4900 
Tel: 713-563-8906 
mdavila@mdanderson.org 
 
 
 

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Organization Name: 
 
 
University of Texas MD Anderson Cancer Center  
Investigator:  
 
 
PeiyingYang, Ph.D. † 
Integrative Medicine Research 
1515 Holcombe Boulevard Unit 1414 
Houston, Texas 77030-4009 
Tel: 713-563-7531 
pyang@mdanderson.org 
 
Organization Name: 
 
 
University of North Carolina School of Medicine 
Protocol Co-Principal  
 
Nicholas Shaheen, M.D.* 
Investigator: 
CB#7080, 130 Mason Farm Rd, Suite 4150 
Chapel Hill, NC  27599-7080 
(919) 962-9791 
nicholas_shaheen@med.unc.edu 
 
Organization Name:  
Mayo Clinic Rochester 
Protocol Co-Principal   
Navtej S. Buttar, M.D.*  
Investigator: 
Mayo Clinic Department of Gastroenterology and Hepatology 
200 First Street SW 
Rochester, MN 55905 
Tel: 507-284-2511 
Fax: 507-255-7612 
Email: buttar.navtej@mayo.edu 
 
Organization Name:  
Mayo Clinic Rochester 
Investigator:   
Prasad G. Iyer, M.D. 
Mayo Clinic Department of Gastroenterology and Hepatology 
200 First Street SW 
Rochester, MN 55905 
Tel: 507-284-6930 
Fax: 507-255-7612 
Email: iyer.Prasad@mayo.edu   
 
Organization Name:  
Kansas City VA Hospital 
Protocol Co-Principal  
Prateek Sharma, M.D.* 
Investigator: 
Gastroenterology 
4801 E. Linwood Blvd. (111) 
Kansas City, MO 64128 
Tel: 816-861-4700, ext 57456 
Fax: 816-922-3362 
E-mail: psharma@kumc.edu 
 
Organization Name:  
Baylor College of Medicine 
Investigator:   
Hashem B. El-Serag, M.D. 
Michael E. DeBakey VA Medical Center  
2002 Holcombe (152) 
Houston, Texas 77030  
Tel: 713-794-8640 
Email: hasheme@bcm.tmc.edu  
 

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Organization Name: 
Baylor College of Medicine 
Investigator: 
G. Avinash Ketwaroo, M.D. MSc 
Michael E. DeBakey VA Medical Center  
(Mail code: 111-D) 
2002 Holcombe Boulevard 
Houston, Texas 77030  
Tel: 713-791-1414 (work) 
617-955-7517 (cell) 
Fax: 713-794-7472 
Email: gyanprakash.ketwaroo@bcm.edu 
 
Organization Name:  
Northwestern University 
Investigator:  
Srinadh Komanduri, M.D. 
Feinberg School of Medicine 
Chicago, Ill 
Tel: 312-933-4873 
sri-komanduri@northwestern.edu 
 
Organization Name:  
St. Michael’s Hospital 
Investigator:  
Norman Marçon, M.D. 
30 Bond Street – Suite 16-062 
Toronto, Ontario, Canada  M5B 1W8 
Tel: 416- 864-3092 
norman.marcon@utoronto.ca 
 
Organization Name:  
University of California, Los Angeles 
Investigator:  
V. Raman Muthusamy, M.D. 
Gastroenterology/Interventional Endoscopy 
200 UCLA Medical Plaza, Room 330-37 
Los Angeles, CA 90095 
Tel: 310-825-1892  
Fax: 310-825-5492 
raman@mednet.ucla.edu 
 
Organization Name:  
University of Colorado Anschutz Medical Campus 
Investigator:  
Sachin Wani, MD 
Medical Co-Director Esophageal and Gastric Center 
Therapeutic and Interventional Endoscopy 
1635 Aurora Ct, Rm 2.031 
Aurora, CO 80045 
Telephone Academic: 720-848-2786 
Clinical: 720-848-2746  
Fax: 720-848-2749 
E-mail sachin.wani@ucdenver.edu 
 
Organization Name:  
University of Pennsylvania 
Investigator:   
Gary Falk, MD, MS 
Gastroenterology 
1 Convention Avenue 
9th Floor Penn Tower Building 

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Division of Gastroenterology 
Philadelphia, PA 19104 
Tel: 215-662-7655 
Fax: 215-615-3756 
Email: gary.falk@uphs.upenn.edu 
 
Organization Name:  
Baylor University Medical Center at Dallas 
Investigator:  
Rhonda F. Souza, MD, AGAF, FASGE † 
Investigator/Professor 
Co-Director, Center for Esophageal Research 
Baylor Scott & White Research Institute 
Baylor University Medical Center 
Center for Esophageal Research 
2 Hoblitzelle, Suite 250 
3500 Gaston Avenue 
Dallas, TX 75246 
Office phone: 214 865-2243 
Email: Rhonda.Souza@BSWHealth.org 
 
MD Anderson Consortium 
 
University of Texas MD Anderson Cancer Center 
Statistician: 
 
J. Jack Lee, Ph.D. 
 
 
1515 Holcombe Boulevard, Unit 447 
Houston, TX 77230 
 
 
Telephone: (713) 794-4158 
 
 
Fax: (713) 563-4242 
 
jjlee@mdanderson.org  
 
*Protocol Co-Principal Investigators 
†Biomarker Laboratories 
 
Sponsor: 
 
NCI/Division of Cancer Prevention  
9609 Medical Center Drive, Rm 5E-536 
Rockville, MD  20850 
(240) 276-7050 
 
IND#  
 
N/A 
 
Agent(s)/Supplier: 
NCI DCP 
 
NCI Contract # 
HHSN261201200034I 
 
Protocol Version Date: 
5/3/2019 
 
Protocol Revision or   
Amendment #  
Version 12 

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SCHEMA 
 
Effect of Aspirin on Biomarkers of Barrett’s Esophagus After Successful Eradication of Barrett’s 
Esophagus with Radiofrequency Ablation 
 
Study Population: Participants who have received radiofrequency ablation for Barrett’s Esophagus (BE) and have 
documentation of complete ablation on at least 2 occasions 3 months apart (second demonstration of ablation may 
be qualifying exam) 
↓ 
Screening to determine initial eligibility (see inclusion/exclusion criteria) Chart review and telephone interview: 
No invasive cancer, no contraindication to aspirin use (bleeding diathesis, platelet disorder, history of GI or 
intracranial bleed on aspirin, previous UGI surgery, renal insufficiency), inability to tolerate aspirin, no regular 
aspirin/NSAID use for 1 month, no medical contraindications) 
↓ 
Consent / Registration: Followed by qualifying endoscopic exam. This exam will be clinically indicated second 
clearing or subsequent surveillance exam to document complete eradication of BE (completion of ablation should 
have occurred no greater than 36 months prior to randomization). Clinically indicated biopsies (Seattle protocol) 
will be taken and sent to local Pathologist. Baseline study biopsies 1 cm above GE junction, midway through area 
defined by length and location of previous Barrett’s segment, 2 cm above extent of original Barrett’s segment: 2 
biopsies in each of 4 quadrants at each location (1 processed for immunohistochemistry, remainder snap frozen) 
 
↓ 
Eligibility Confirmation 
Participants have no residual BE (biopsy documented) 
Laboratory tests (CBC, platelets, creatinine, pregnancy test in persons of childbearing potential) WNL and normal 
physical exam 
↓ 
Randomization 
↓ 
Intervention 
Duration 12 months (+/-30 days) 
Aspirin 325 mg/day or 
Placebo 
↓ 
Scheduled Visits 
At Month 1: Interview by phone regarding somatic symptoms, illnesses, doctor’s visits, medication, over-the-
counter medications, compliance with study medications. 
Every 3 months during entire course of study: Interview by phone or mail regarding somatic symptoms, illnesses, 
doctor’s visits, medication, over-the-counter medications, compliance with study medications.  Dispensation of 
study agent by mail. 
At one year: As above plus SF-36 Health Survey and Interval Questionnaire plus follow-up exam 
Toxicity Assessment at Months 1,3,6,9 by follow-up phone calls or mail and in person at 1 year and 18 months 
↓ 
Post-Treatment EGD and Tissue Acquisition at 12 and 18 months after randomization 
EGD will be performed and clinically indicated biopsies (Seattle protocol) will be taken at scheduled surveillance 
exam  and sent to local Pathologist. Study biopsies 1 cm above GE junction, midway through area defined by length 
and location of previous Barrett’s segment, 2 cm above extent of original Barrett’s segment: 2 biopsies in each of 4 
quadrants at each location (1 processed for immunohistochemistry, remainder snap frozen) 
Physical exam and laboratories at 12 months 
 
↓ 
 
 

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1. Primary Endpoints: 
a) Difference in the change of tissue CDX2 mRNA levels in esophageal mucosa between participants taking aspirin 
and placebo at 12 months 
2. Secondary Endpoints 
a) Safety Profile (Toxicity Assessment) and tolerability of aspirin at 12 months. 
b) Difference in the change of tissue CDX2 mRNA levels in esophageal mucosa between participants taking aspirin 
and placebo at 18 months 
c) Differences in activation of NF-ĸB between groups by assessing levels of total and phospho-p65 and cytoplasmic 
to nuclear translocation of phospho-p65 
d) Differences at 12 and 18 months in prostaglandin E2 levels 
e) Differences in the expression of proinflamatory cytokines TNFα, Il-1β, Il-6, IL-10, Il-17A, IL-23 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
COVER PAGE.............................................................................................................................................. 1 
 
SCHEMA ...................................................................................................................................................... 5 
1. 
OBJECTIVES ................................................................................................................................ 10 
1.1 
Primary Objectives ..................................................................................................................................... 10 
1.2 
Secondary Objectives ................................................................................................................................ 10 
 
2. 
BACKGROUND ........................................................................................................................... 10 
2.1 
Study Disease: Barrett's Esophagus (BE) ................................................................................................... 10 
2.2 
Study Agent: Aspirin 325 mg/day for 12 months ....................................................................................... 11 
2.3 
Rationale ...................................................................................................................................................... 11 
 
3. 
SUMMARY OF STUDY PLAN ................................................................................................... 12 
 
4. 
PARTICIPANT SELECTION ....................................................................................................... 14 
4.1 
Inclusion Criteria ........................................................................................................................................ 14 
4.2 
Exclusion Criteria ....................................................................................................................................... 14 
4.3 
Inclusion of Women and Minorities ........................................................................................................ 16 
4.4 
Recruitment and Retention Plan ............................................................................................................... 16 
 
5. 
AGENT ADMINISTRATION ...................................................................................................... 16 
5.1 
Dose Regimen and Dose Groups ............................................................................................................. 16 
5.2 
Aspirin Administration .............................................................................................................................. 16 
5.3 
Run-in Procedures ...................................................................................................................................... 17 
5.4 
Contraindications ........................................................................................................................................ 17 
5.5 
Concomitant Medications ......................................................................................................................... 17 
5.6 
Dose Modification ...................................................................................................................................... 17 
5.7 
Adherence/Compliance ............................................................................................................................. 18 
 
6. 
PHARMACEUTICAL INFORMATION ...................................................................................... 18 
6.1 
Study Agent (IND #, IND Sponsor) ........................................................................................................ 18 
6.2 
Reported Adverse Events and Potential Risks ....................................................................................... 19 
6.3  
Availability .................................................................................................................................................. 19 
6.4 
Agent Distribution ...................................................................................................................................... 19 
6.5  
Agent Accountability ................................................................................................................................. 19 
6.6 
Packaging and Labeling ............................................................................................................................ 20 
6.7 
Storage ......................................................................................................................................................... 20 
6.8 
Registration/Randomization ..................................................................................................................... 20 
6.9 
Blinding and Unblinding Methods ........................................................................................................... 20 
6.10 
Agent Destruction/Disposal ...................................................................................................................... 21 
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ................................................................... 22 
7.1 
Schedule of Events ..................................................................................................................................... 22 
7.2 
Baseline Testing/Prestudy Evaluation ..................................................................................................... 23 
7.3 
Evaluation During Study Intervention ..................................................................................................... 26 
7.4 
Evaluation at Completion of Study Intervention ................................................................................... 25 
7.5 
Post-intervention Follow-up Period ......................................................................................................... 26 

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7.6 
Methods for Clinical Procedures .............................................................................................................. 27 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ........................................... 28 
8.1 
Primary Endpoint........................................................................................................................................ 28 
8.2 
Secondary Endpoints ................................................................................................................................. 28 
8.3 
Off-Agent Criteria ...................................................................................................................................... 30 
8.4 
Off-Study Criteria....................................................................................................................................... 30 
8.5 
Study Termination ...................................................................................................................................... 30 
 
9. 
CORRELATIVE/SPECIAL STUDIES ......................................................................................... 30 
9.1 
Rationale for Methodology Selection ...................................................................................................... 30 
9.2 
Comparable Methods ................................................................................................................................. 33 
 
10. 
SPECIMEN MANAGEMENT ...................................................................................................... 33 
10.1 
Laboratories ................................................................................................................................................. 33 
10.2 
Collection and Handling Procedures ....................................................................................................... 34 
10.3 
Shipping Instructions ................................................................................................................................. 36 
10.4 
Tissue Banking ........................................................................................................................................... 37 
 
11. 
REPORTING ADVERSE EVENTS ............................................................................................. 37 
11.1 
Adverse Events ........................................................................................................................................... 38 
11.2 
Serious Adverse Events ............................................................................................................................. 39 
 
12. 
STUDY MONITORING ............................................................................................................... 41 
12.1 
Data Management....................................................................................................................................... 41 
12.2 
Case Report Forms ..................................................................................................................................... 41 
12.3 
Source Documents ...................................................................................................................................... 41 
12.4 
Data and Safety Monitoring Plan ............................................................................................................. 41 
12.5 
Sponsor or FDA Monitoring ..................................................................................................................... 42 
12.6 
Record Retention ........................................................................................................................................ 42 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA)42 
 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................... 43 
13.1 
Study Design/Description ......................................................................................................................... 43 
13.2 
Randomization/Stratification .................................................................................................................... 43 
13.3 
Accrual and Feasibility .............................................................................................................................. 43 
13.4 
Primary Objective, Endpoint(s), Analysis Plan ..................................................................................... 43 
13.5 
Secondary Objectives, Endpoints, Analysis Plans ................................................................................. 45 
13.6 
Reporting and Exclusions .......................................................................................................................... 46 
13.7 
Evaluation of Toxicity ............................................................................................................................... 47 
13.8 
Evaluation of Response ............................................................................................................................. 47 
13.9 
Interim Analysis ......................................................................................................................................... 47 
13.10 Ancillary Studies ........................................................................................................................................ 47 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 47 
14.1 
Form FDA 1572 .......................................................................................................................................... 47 
14.2 
Other Required Documents ....................................................................................................................... 48 
14.3 
Institutional Review Board Approval ...................................................................................................... 48 
14.4 
Informed Consent ....................................................................................................................................... 48 
14.5 
Submission of Regulatory Documents .................................................................................................... 49 

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14.6 
Other ............................................................................................................................................................. 49 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ................................................................... 49 
 
REFERENCES ........................................................................................................................................... 50 
 
APPENDIX A ............................................................................................................................................. 52 
 
APPENDIX B ............................................................................................................................................. 53 
 
 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives – We plan to conduct a randomized, double blind, placebo-controlled Phase 
II chemoprevention trial, investigating whether supplementation with aspirin 325 mg/day for 12 
months is safe and reduces the expression of CDX2 mRNA (a biomarker which has been associated 
with the risk of developing Barrett’s Esophagus [BE]) in comparison to placebo after successful 
radiofrequency ablation (RFA). 
 
1.2 
Secondary Objectives – Secondary endpoints will assess safety at 12 months.  Secondary 
endpoints will also assess differences in the expression of CDX2 at 18 months, activation status of NF-
kB by assessing levels of total and phospho-p65 and cytoplasmic to nuclear translocation of phospho-p65 
which is likely to be affected by aspirin.  Additional secondary endpoint markers will be the prostanoid 
marker, prostaglandin E2, and prostaglandin synthases, which are known to respond to aspirin and to 
correlation with clinicopathological factors in the esophageal cancer PGE2 was previously shown to be 
reduced in Barrett’s mucosa in response to a combination of acid inhibition and high-dose (but not low 
dose) aspirin. Furthermore, differences in the expression of proinflammatory cytokines known to induce 
activation of NFkB, i.e., TNFα, IL-1β, IL-6, IL-10, IL-17A, IL-23 will be measured. These 
inflammatory mediators have been implicated in the pathogenesis of Barrett’s Esophagus and esophageal 
adenocarcinoma.  Recurrent Barrett’s Esophagus (at 12 and 18 months) will be ascertained completely 
and accurately.  While we will not have sufficient power to assess differences in histological 
recurrence of BE during the short course of the study, we will examine this as an exploratory 
secondary endpoint. This study will generate data designed to lead to the submission of an adequately 
powered multi-center prospective chemoprevention trial with histologic recurrence of BE after RFA as 
the clinically relevant primary endpoint.  
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease: Barrett's Esophagus (BE) 
The incidence of adenocarcinoma of the esophagus (EA) has increased dramatically over the past three to 
four decades in western countries. This increase has occurred in all race and gender groups, most 
dramatically in white males. According to data from the National Cancer Institute's Surveillance, 
Epidemiology and End Results (SEER) program, the incidence of esophageal adenocarcinoma (EAC) in 
white males rose from 0.8 per 100,000 in 1973 to 5.4 per 100,000 in 2002, a near-annual increase of 8% . 
Barrett's esophagus (BE) is being increasingly recognized in western countries and is widely considered 
the major risk factor for EAC (1). Activation of signaling pathways may facilitate the healing of reflux-
damaged squamous cells through metaplasia (manifested as BE).  Identifying these pathways could 
provide molecular targets for chemoprevention to prevent Barrett’s Esophagus from recurring in patients 
who have undergone endoscopic ablation of Barrett’s epithelium.  Molecular, biochemical, and 
immunohistochemical studies have focused on potential pathways and markers that may result in Barrett's 
metaplasia and subsequent transformation and progression to adenocarcinoma (1-4). Cancers are believed 
to arise through the development of genetic instability and clonal expansion driven by selection for 
mutations in cancer genes. A combination of genetic instability and clonal expansion is associated with 
progression to adenocarcinoma in BE. Chronic exposure to both acid and bile in the gastroesophageal 
refluxate promotes damage and inflammation in the esophageal epithelium which may trigger these 
changes (3). Within the epithelial cells, the combination of reactive oxygen species (ROS) damage, 
alterations in DNA methylation, activation of the NFΚB signaling pathway by cytokines and the acid/bile 
refluxate contribute to activation of target genes that further amplify inflammation and promote intestinal 
differentiation (5-7).  These changes are associated with biological and morphological changes which are 
manifested as “biomarkers” which are associated with disease progression. Cdx homeotic genes of the 

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para-homoeobox family appear to direct the formation of simple columnar epithelia, and the metaplastic 
epithelium of BE express CDX messenger RNA and protein (5, 8). Existing data from our group (see 
below) suggest that acid and bile salts induce CDX2 in esophageal squamous cells from patients 
with BE, but not from GERD patients without BE (8). These differences may underlie the 
development of BE and could serve to predict development of metaplasia both de novo and after ablation.  
 
2.2 
Study Agent: Aspirin 325 mg/day for 12 months 
Endoscopic ablative techniques such as radiofrequency ablation (RFA) have provided an alternative to 
surgery in treating high-risk lesions including high grade dysplasia associated with BE (9,10).  Long-term 
follow-up has, however demonstrated recurrence of BE after RFA ranging from 8% to 25% (9-12). Long-
term use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, has been associated in 
observational studies with a decreased risk of EAC (OR 0.54 in one pooled analysis) and a decreased risk 
of neoplastic progression in BE (13). NSAIDs may be especially associated with decreased EAC risk in 
individuals with high-risk markers predictive of conversion to EAC (4).  Aspirin may play a protective 
role against the development of EAC by inhibiting chronic inflammation and NFkB-dependent 
transcriptional induction of CDKN2A and prostaglandin biosynthesis genes which have been shown to 
contribute to carcinogenesis (4, 5,13).  Aspirin-induced suppression of NF-KB target genes is significant, 
because acid and bile salts activate NF-kB to induce CDX2, which has been recently linked to the 
development of Barrett’s metaplasia (8). Using PGE2 concentrations as a surrogate for NF-KB activation 
levels, aspirin (325 mg/day) in combination with acid inhibition significantly reduces NF-KB activation 
in esophageal tissue from  individuals with BE (14) Moreover, aspirin has been used extensively in 
chemoprevention trials of gastrointestinal and other forms of neoplasia with an acceptable safety profile 
(15). 
 
2.3 
Rationale 
 
CDX2 and the Development of Intestinal Metaplasia: Metaplastic conditions like BE are associated with 
a high rate of cell turnover that may be stimulated by chronic inflammation (16). The continuous cycle of 
injury and repair that accompanies chronic inflammation predisposes to alterations in the pattern of gene 
expression by the epithelial cells.  Metaplasias occur when such alterations affect homeotic genes, like 
CDX2, that control tissue phenotypes. In one study of esophageal biopsy specimens taken from patients 
with BE, CDX2 expression levels were approximately 400 times higher in the Barrett’s metaplasia than in 
the normal esophageal squamous epithelium, in which the levels were almost undetectable (17). In fact, 
CDX2 has been implicated as the “master switch” in the formation of Barrett’s metaplasia. In a rat model 
of reflux esophagitis and intestinal metaplasia, basal cells in the esophageal squamous epithelium begin to 
express CDX2 prior to the development of intestinal metaplasia suggesting that CDX2 expression 
precedes the development of Barrett’s metaplasia and that GERD may initiate the development of 
intestinal metaplasia by increasing CDX2 expression in esophageal stem cells (18,19).  
Reflux Esophagitis and the Induction of 
CDX2: There are at least two ways in which 
GERD might induce CDX expression in the 
esophagus:  1) Certain components of the 
refluxed gastric juice (e.g. acid, bile salts) 
stimulate CDX expression by esophageal 
stem cells or 2) Esophageal inflammation 
(reflux 
esophagitis) 
stimulates 
CDX 
expression 
by 
esophageal 
stem 
cells. 
Following 
ablation 
of 
BE, 
re-
epithelialization by squamous cells is 
favored in the setting of acid suppression 

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whereas recurrent Barrett’s epithelium occurs when acid suppression is inadequate (20,21).  Thus, it is 
recommended that patients with BE should take PPIs as a means to prevent recurrence in the setting of 
ongoing reflux (22).  However, PPIs do not correct the underlying reflux diathesis and Barrett’s patients 
who take PPIs still have frequent reflux of weakly acidic (pH 4-7) material (including bile acids) (23). 
Perhaps this is why a substantial proportion of patients with BE have recurrence of intestinal metaplasia 
following RFA. Differences in gene expression profile within the regenerated squamous epithelium may 
predict which Barrett’s patients recur and subsequently require recurrent endoscopic intervention.  We 
have previously shown that esophageal squamous epithelial cells from GERD patients with BE increase 
the expression and activation of CDX2 in response to exposure to acid, bile salts, and the combination of 
both.  In contrast, esophageal squamous cells from patients who have GERD without Barrett’s 
Esophagus fail to induce CDX2 expression in response to any of these exposures (8).  Our 
preliminary data demonstrate that compared to squamous cells from Barrett’s patients, squamous cells 
from GERD patients exposed to acid and bile salts exhibit less phosphorylation of IKKα/β and IΚB, and 
less nuclear translocation of p50. Unlike the squamous cells from Barrett’s patients, furthermore, the 
GERD squamous cells show no nuclear translocation of p65, and p50 does not bind their CDX2 
promoter. In squamous cells from Barrett’s patients, knockdown of p65 by siRNA inhibits the induction 
of the CDX2 promoter suggesting that nuclear translocation of p65 is functionally relevant for the 
induction of CDX2 in response to acid and bile salts. These data suggest that phenotypic differences 
among patients in how the NF-ΚB pathway in their esophageal squamous cells responds to gastric reflux 
might determine whether they develop Barrett’s metaplasia. We propose to investigate the 
chemopreventive potential of aspirin, which has been shown to affect the expression and activation of 
NF-ΚB related pathways in the esophagus. CDX2 expression will serve as a surrogate marker of 
recurrence of Barrett’s metaplasia after RFA.  
 
3. 
SUMMARY OF STUDY PLAN 
 
3.1 
Target Population 
• 
Age ≥ 18 years 
• 
Known diagnosis of histologically-confirmed BE with or without dysplasia (as defined 
by the presence of specialized columnar epithelium anywhere in the tubular esophagus 
with ≥ 1 cm of circumferential or non-circumferential involvement of specialized 
columnar epithelium) requiring radiofrequency ablation. 
• 
Documentation of complete ablation of BE after radiofrequency ablation on two 
endoscopic examinations at least 3 months apart (including no evidence of BE on 
surveillance and biopsies). Completion of ablation should have occurred no greater than 
36 months prior to randomization. 
 
3.2 
Sample Size and Duration of Accrual 
This is a randomized, double-blind placebo controlled study with 2 intervention arms.  We plan to enroll 
up to 20 participants per group.  
 
3.3 
Intervention Arms 
Participants who have successfully completed radiofrequency ablation for BE with or without dysplasia 
and who have been histologically-confirmed to be free of Barrett’s will be randomly assigned to a 12 
month intervention with: 
    
Arm A - aspirin 325 mg PO QD  
Arm B – aspirin placebo QD  
 
All participants will take proton pump inhibitor in the FDA approved healing dose as clinically 

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indicated (omeprazole or S-omeprazole 40 mg twice daily, lansoprazole 30 mg twice daily or 
equivalent). 
 
Participants will continue study agent up to the day of the 12-month endoscopic assessment (see 
below). 
 
Study Assessments 
Endoscopic examination of the esophagus will be performed as part of a clinically prescribed 
protocol for patients undergoing radiofrequecy ablation for BE.  Participants who have 
documentation of complete ablation on at least 2 separate occasions 3 months apart will be 
eligible to participate in the study.  An endoscopy performed for a second demonstration of 
ablation may serve as a qualifying exam. Clinically indicated biopsies will be performed using 
the Seattle protocol and sent for local Pathology assessment.  Additional study biopsies will be 
performed at baseline and at 12 and 18 months in locations 1 cm above the gastroesophageal 
junction, midway through an area defined by the length and location of the pre-ablation Barrett’s 
segment, and 2 cm above the upper extent of the original Barrett’s segment. Standardization of 
endoscopic techniques, assessment of landmarks and tissue procurement methods across 
Participating Organizations will be achieved through a series of pre-trial discussions with the 
Protocol Lead Investigators.  Details of the biopsy protocol are provided in Section 7.6.1 and 
7.6.2. 
 
All participants will have a telephone interview at Month 1 regarding symptoms possibly related 
to the agent, illnesses, doctors’ visits, hospitalizations, mediations (including over the counter 
medications), and compliance with study tablets. Adherence with the study medication will be 
discussed and reinforced; pill diary will be reviewed. 
 
All participants will have a telephone interview and/or be contacted by mail every 3 months 
regarding symptoms possibly related to the agent, illnesses, doctors’ visits, hospitalizations, 
mediations (including over the counter medications), and compliance with study tablets. 
 
Participants will undergo a clinically indicated surveillance EGD at 12 months following 
randomization at which time clinically indicated surveillance biopsies and research biopsies will 
be obtained.  End of treatment questionnaires and SF-36 Health Surveys, physical exam and 
laboratories will also be performed. 
 
Participants will be followed off aspirin or placebo for an additional 6 month period (with an 
interval phone interview at 13 months post-randomization). Participants will undergo a clinically 
indicated surveillance EGD at 18 months following randomization at which time clinically 
indicated surveillance biopsies and research biopsies will be obtained. 
 
Expression of CDX2 mRNA and differences in the activation status of NF-ĸB will be analyzed in 
the laboratory of Dr. Rhonda Souza at the Center for Esophageal Research, Baylor Scott & White 
Research Institute, Dallas, TX.  Prostaglandin E2 levels and expression of pro-inflammatory 
cytokines will be assessed in the laboratory of Dr. Peiying Yang Ph.D. at the University of Texas 
MD Anderson Cancer Center. 
 
 
 
 
 

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4. 
PARTICIPANT SELECTION 
 
4.1 Inclusion Criteria 
4.1.1 
Age ≥ 18 years  
4.1.2 
Known diagnosis of histologically-confirmed BE with or without dysplasia (as defined 
by the presence of specialized columnar epithelium anywhere in the tubular esophagus 
with ≥ 1 cm of circumferential or non-circumferential involvement of specialized 
columnar epithelium) requiring radiofrequency ablation. 
4.1.3 
Documentation of complete ablation of BE after radiofrequency ablation on two 
endoscopic examinations at least 3 months apart (including no evidence of BE on 
surveillance biopsies) as determined by the pathologist at each site. Completion of 
ablation should have occurred no greater than 36 months prior to randomization. 
4.1.4 
The effects of the candidate chemoprevention agents on the developing human fetus 
remain incompletely defined.  For this reason, persons of childbearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  Should a 
participant become pregnant or suspect she is pregnant while participating in this trial, 
she should inform the research personnel and her clinical care provider immediately.   
4.1.5 
Willingness to provide tissue samples for research purposes. 
4.1.6 
No chronic use of aspirin or NSAIDs or selective COX-2 inhibitors during one month 
prior to randomization.  Chronic use is defined as any aspirin or NSAID use on ≥ 7 days 
during one month preceding the beginning of randomization.    
4.1.7 
Normal organ and marrow function, as defined below, based on laboratory studies 
obtained ≤ 45 days prior to randomization:   
• 
Hemoglobin .......................................       >10 g/dL or Hematocrit > 30 % 
• 
Leukocyte count .............................................................. ≥3,000/microliter 
• 
Platelet count .............................................................. ≥100,000/microliter 
• 
Absolute neutrophil count ............................................... ≥1,500/microliter 
• 
Creatinine ............................................................. ≤2.5 x institutional ULN 
• 
OR GFR ....................................................................... >30ml/min/1.73m2  
• 
Total bilirubin ......................................................... ≤2 x institutional ULN 
• 
AST (SGOT) ........................................................≤2.5 × institutional ULN 
• 
ALT (SGPT) ........................................................≤2.5 × institutional ULN 
4.1.8 
A negative serum pregnancy test at Baseline, but within 21 days of Randomization, for 
persons of childbearing potential only. 
4.1.9 
ECOG performance status ≤ 2 (see Appendix A). 
4.1.10 Ability to understand and the willingness to sign a written informed consent document.  
A Legally Authorized Representative (LAR) may sign Informed Consent for persons who 
do not have the capacity to legally consent to take part in the study.  
 
4.2 
Exclusion Criteria 
4.2.1 
Inability to abstain from NSAID (including aspirin) and selective COX-2 inhibitor 
therapy at the time of randomization through the completion of the study (the study 
period is defined as baseline to exit endoscopy at 18 months after randomization which 
defines the completion of the study).  Participants may take Tylenol and Non-NSAID 
pain relievers. 
4.2.2 
Current or planned use of anticoagulant drugs such as: warfarin, heparin, low molecular 
weight heparin, Plavix, or Aggrenox throughout the course of the study. 
4.2.3 
Individuals taking the drugs listed below may not be randomized unless they are willing 
to stop the medications (and possibly change to alternative non-excluded medications to 

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treat the same conditions) no less than 1 month prior to starting aspirin or placebo on this 
study.  Consultation with the participant’s primary care provider will be obtained prior to 
stopping any agent.  The use of the following drugs or drug classes is prohibited during 
aspirin/placebo treatment: 
 
 
 
 
NSAIDs: such as aspirin, Naprosyn, ketorolac and others NSAIDs 
 
COX-2 inhibitors: such as Celecoxib, Rofecoxib  
 
Valproic acid 
 
Sulfinpyrazone 
 
Probenecid 
 
Corticosteroids (other than short-term use defined as less than 2 weeks or prn 
use of an inhaler less than twice per month) 
 
Platelet aggregation inhibitors, except in a monitored antithrombotic regimen 
 
Methotrexate (MTX) 
 
Vaccines containing live viruses 
 
Gingko 
 
4.2.4 
Individuals with uncontrolled renal insufficiency or renal failure.  
4.2.5 
Participants with fundoplication within the past year, bariatric surgery or any other major 
upper GI surgery. Fundoplication more than one year ago will not be grounds for 
exclusion. Cholecystectomy will not be grounds for exclusion. 
4.2.6 
History of invasive cancer diagnosis ≤ 12 months prior to randomization, excepting non-
melanoma skin cancer. Patients with T1a adenocarcinoma of the esophagus arising in the 
setting of Barrett’s esophagus are eligible for enrollment in the trial. 
4.2.7 
History of cancer treatment ≤ 12 months prior to randomization, excepting hormonal 
therapy (except treatment for non-melanoma skin cancer or carcinoma-in-situ of the 
cervix). 
4.2.8 
Receipt of any other investigational agents ≤ 3 months prior to randomization, except 
innocuous agents with no known interaction with the study agents (e.g., standard dose 
multivitamins or topical agents for limited skin conditions), at the discretion of the 
Protocol Lead Investigator at each Participating Site. 
4.2.9 
History of allergic reactions attributed to aspirin or compounds of similar chemical or 
biologic composition to the study agent. 
4.2.10 History of endoscopically or radiographically diagnosed peptic ulcer disease with upper 
GI bleeding during the past 5 years or history of endoscopically or radiographically 
diagnosed peptic ulcer disease with upper GI bleeding any time while taking aspirin. 
4.2.11 Uncontrolled intercurrent illness including, but not limited to: ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, bleeding disorder, vitamin K deficiency, alcohol abuse (defined as ingestion 
of 3 or more drinks per day) or psychiatric illness/social situations that would limit 
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4.2.12 Pregnant women. Note: because the teratogenic or abortifacient effects of the study 
agents remain incompletely defined. 
4.2.13 Breast feeding women.  Note: because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with the study agents, 
women who are breast-feeding will be excluded. 
4.2.14 Surveillance biopsies demonstrating residual BE at qualifying exam. 
4.2.15 Presence of an esophageal stricture defined as “any recognizable change in esophageal 
luminal caliber that is accompanied by symptoms of dysphagia, or any asymptomatic 
narrowing that either will not allow any adult endoscope to pass or allows passage with 
resistance.”  
4.2.16 Patients with human immunodeficiency virus (HIV) infection.  
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
However, BE is more common among Caucasian males and we expect our recruitment to reflect 
the known demographics of this condition.  There is no information available regarding 
differential effects of the study agents in population subsets defined by race, gender, or ethnicity, 
and there will be no reason to expect such differences exist. Therefore, although the planned 
analysis will look for differences in intervention effect based on racial and gender groupings, the 
sample size is not increased in order to provide additional power for these subset analyses.  
 
4.4 
Recruitment and Retention Plan 
See Document A for details. 
 
 
5. 
AGENT ADMINISTRATION 
 
Intervention agents will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 6.2.   
 
5.1 
Dose Regimen and Dose Groups 
 
Doses of the study agents will be either  
(a) Aspirin 325 mg PO QD or  
(b) Matching placebo PO QD 
 
Agents will be administered for 12 months after randomization.  
 
5.2 
Aspirin Administration  
 
Aspirin or aspirin placebo will all be administered once in the morning with a meal.  All study 
agents will be self-administered by the participants.  Participants will be given sufficient agent 
supplies to last for a 3 month period (between phone interviews or mail contacts) plus a short 
time period beyond their scheduled interview to account for unavoidable scheduling delays. 
 
First Randomized Pill Bottle: Participants who continue to be eligible based on qualifying 
endoscopy and biopsies and interested in study participation will receive a supply of study pills. 
The supply will be the randomly assigned study agent.  Participants will be instructed to start this 

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new bottle immediately upon receipt and to record the date that the bottle is started.   The study 
agent may be dispensed to the participant at the randomization visit or shipped directly to the 
participant.  
 
Subsequent Randomized Pills: Participants will be instructed to take at least 3 months of pills 
from each bottle prior to starting their new one and to record the date that the new bottle is 
started.   Bottles containing randomized pills will be mailed in approximately three month 
intervals adjusting for the previous pill bottle start date.  Special shipments will also be made 
upon request, if, for example, a participant loses their bottle or does not receive their new bottle 
of pills.   
 
5.3 
Run-In Procedures  
 
This trial will not include a placebo or active agent run-in period 
 
5.4. 
Contraindications  
 
Exclusions as outlined in Section 4.2 
 
5.5 
Concomitant Medications  
 
Concurrent use of aspirin with valproic acid has been reported to increase the plasma 
concentration of valproic acid and induce valproic acid toxicity (see exclusions).  Concurrent use 
of aspirin with high-dose corticosteroids may increase the risk of gastrointestinal side effects (see 
exclusions).  Concurrent use with platelet aggregation inhibitors is prohibited, except in a 
monitored antithrombotic regimen, because the risk of bleeding may be increased.  
Sulfinpyrazone and probenecid may decrease renal clearance and increase plasma concentrations 
and toxicity of salicylates (see exclusions).  Aspirin may block excretion of methotrexate (MTX) 
and increase MTX toxicity (see exclusions).  No vaccines containing live viruses can be 
administered during the study due to an increased risk of Reye’s syndrome (see exclusions). 
Gingko may be associated with increased risk of bleeding; patients will not be allowed to use 
gingko on this study.  All medications (prescription and over-the-counter), vitamin and mineral 
supplements, and/or herbs taken by the participant will be documented on the concomitant 
medication CRF and will include: start and stop dates (if known; if unknown, will be marked 
“unknown” in the database), and dose.  Medications taken for a procedure (e.g., biopsy) will also 
be included. 
 
5.6 
Dose Modification 
 
There will be no dose modification.  Participants with Grade 4 adverse events possibly, probably 
or definitely related to study agent, or Grade 3 adverse events possibly, probably or definitely 
related to study agent will be taken off study and followed off study agent for at least 30 days or 
for the remainder of the planned intervention period (whichever is longer). Participants with 
Grade 2 adverse events possibly, probably or definitely related to the study agent can be taken off 
study agent for up to 1 week.  If the adverse event resolves, the study agent may be resumed.  If 
the adverse event continues, participants will be taken off study.  Participants with any Grade 1 
adverse event may continue the study agent at full dose, unless either the participant or the 
investigator finds the adverse event to be intolerable.  In this instance, the study agent can be 
stopped and restarted as described for participants with Grade 2 adverse events.  Rechallenge of 
participants who experience Grade 2 or intolerable Grade 1 adverse events with the study agent 

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will be instituted only after the adverse event has been resolved to the satisfaction of the Protocol 
Principal Investigator.  If the Grade 2 or intolerable Grade 1 adverse event recurs after re-
challenge, the participant will be withdrawn from the study and followed off study agent for at 
least 30 days or for the remainder of the planned intervention period (whichever is longer).     
 
5.7 
Adherence/Compliance 
 
Although drug concentration will not be measured in the blood, compliance will be monitored in 
the following ways: 
 
 
 Pill diary completion:  Compliance will be monitored by a pill diary that all participants will be 
asked to complete (see Appendix B).   Participants will be asked to mail back their pill diary and 
their unused agent supplies after each phone call at Month 3, 6, and 9 visits and to bring both 
their pill diary and their unused agent supplies to the Post-Intervention evaluation at Month 12 
visit.   
 
Dose count: Randomized participants will receive their initial 3 month (90 pills plus 10 additional 
pills) supply of study agent at the randomization visit.   At Month 3, 6, and 9 visits the 
participants will be asked to return all full and empty bottles by mail, and to start taking pills from 
their new 3 month (90 pills plus 10 additional pills) supply that has been mailed to them. After 
each visit at Months 3, 6, 9 and 12 compliance will be measured as follows: 
 
number of tablets taken (i.e., number of tablets given - number of tablets returned) / number of 
tablets that should have been taken during that period of time x100   = % compliance. 
 
Compliance (acceptable adherence to study agent) will be defined as ingestion of ≥ 80% of the 
planned agent doses for the purposes of secondary data analyses. In cases where the tablets are 
not returned, the compliance has to be calculated from the calendar.  In cases of non-compliance 
with the study agent, the participant will be reinstructed.  The research nurse or study coordinator 
and the physicians will provide education for participants, indicating when and how should the 
tablets be administered. 
 
In case of concomitant medications, subjects are asked to contact the study staff in order to check 
whether any potential interference is expected. Data on drug suspension or interruption will be 
reported in the CRFs. 
 
 
6. PHARMACEUTICAL INFORMATION 
 
6.1 
Study Agent  (IND #, IND Sponsor) 
 
This study will not be conducted under an IND.  
 
Aspirin (325 mg enteric coated tablets) and placebo will be supplied by NCI, DCP. Aspirin is an 
odorless white, needle-like crystalline or powdery substance.  When exposed to moisture, aspirin 
hydrolyzes into salicylic and acetic acids, and gives off a vinegary-odor.  It is highly lipid soluble and 
slightly soluble in water. The 325 mg aspirin tablet contains 325 mg aspirin and the following 
excipients: carnauba wax, cellulose, D&C Yellow #10 Aluminum  Lake, FD&C Yellow #6 Aluminum  
Lake, hypromellose, iron oxides, methacrylic acid copolymer, polysorbate 80, propylene glycol, 
shellac, sodium lauryl sulfate, starch, titanium dioxide, triacetin. 
 

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6.1.1 
Rescue Medication: 
Participants will be allowed to take acetaminophen in clinically indicated doses for headache or 
pain, but will not be allowed to take aspirin or other NSAIDS during the entire study period 
(baseline to 18 months after randomization). 
 
6.2 
Reported Adverse Events and Potential Risks 
 
Aspirin has been associated with gastrointestinal (GI) side effects. GI side effects include stomach 
pain, heartburn, nausea, vomiting, and gross GI bleeding. Minor upper GI symptoms, such as 
dyspepsia, are common and can occur anytime during therapy. Aspirin has also been associated 
with an increased risk of hemorrhagic stroke. Aspirin has also been associated with elevated hepatic 
enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged 
bleeding time.  High-dose aspirin has been associated with tinnitus. 
 
6.3 
Availability 
 
Aspirin and aspirin placebo are investigational agents supplied to investigators by NCI, DCP. 
 
6.4 
Agent Distribution 
 
Agents will only be released by NCI, DCP after documentation of IRB approval of the DCP-approved 
protocol and consent is provided to DCP and the collection of all Essential Documents is complete (see 
DCP website for description of Essential Documents).  
 
NCI, DCP-supplied agents may be requested by the Investigator (or their authorized designees) at each 
Organization. DCP guidelines require that the agent be shipped directly to the institution or site where the 
agent will be prepared and administered. DCP does not permit the transfer of agents between institutions 
(unless prior approval from DCP is obtained). DCP does not automatically ship agents; the site must 
make a request. Agents are requested by completing the DCP Clinical Drug Request form (NIH-986) (to 
include complete shipping contact information) and faxing or mailing the form to the DCP agent 
repository contractor: 
 
John Cookinham 
MRIGlobal 
DCP Chemoprevention Agent Repository 
425 Volker Blvd. 
Kansas City, MO 64110 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
Email: NCI.DCP@mriglobal.org 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP using the NCI Drug Accountability Record 
Form (DARF) or an institutionally-approved accountability system. The Investigator is required to 
maintain adequate records of receipt, dispensing and final disposition of study agent. Include on receipt 
record from whom the agent was received and to whom study agent was shipped, date, quantity and batch 
or lot number. On dispensing record, note quantities and dates study agent was dispensed to and returned 
by each participant.  The protocol site PI(s) or their representative will be responsible for study agent 
accountability for participants at his/her participating site. 
 

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6.6 
Packaging and Labeling 
Aspirin and aspirin placebo will be packaged by NCI, DCP.  
 
6.7 
Storage 
Study drug will be stored in a secure location, at controlled room temperature (59°F and 86°F) under 
low humidity. All agents should be kept in a secured storage area. 
 
6.8 
Registration/Randomization 
 
Screening and Registration into the DMI Database:  
Once informed consent has been signed, participants will be registered into the DMI database.  The DMI 
database will assign a participant’s ID upon completion of the registration process. 
 
Randomization:  
Participants will be assigned a randomization number once the following has been accomplished: 
eligibility has been verified at the site level, eligibility has been confirmed by the site PI, and eligibility 
CRF has been entered into the DMI web application.  The randomization number will be generated by the 
database and assigned to the participant. Refer to Section 13.2 for details of randomization.  
 
Screening/Registration/Randomization into site-specific databases: 
The DMI is the database of record for the study. Registration and randomization should occur per the 
procedures outlined above. If the site staff need to enter study data into site-specific electronic databases 
per their institutional requirements, they should do so in accordance with their institutional policies and 
procedures. 
 
Appropriate CRFs must be completed for any participant who signs an informed consent. If a consented 
participant is a screen failure and deemed ineligible, the following CRFs must be completed: 1) the 
Registration CRF; 2) the Randomization CRF with the eligibility box checked “no”, 3) the Inclusion and 
Exclusion CRFs showing why the participant is ineligible, 4) the Off-Study CRF, 5) the Adverse Event 
CRF, 6) the Concomitant Medication CRF and 7) the Verification CRF. If no Adverse Event and/or 
Concomitant Medications were assessed by the time the participant is deemed ineligible, the “NONE” 
box will be checked to complete both CRFs.  All participants who sign an informed consent must 
formally go off study. All participant registration information will be entered into DMI. If a participant 
experiences a serious adverse event during the screening process, an SAE form must be completed. 
 
6.9 
Blinding and Unblinding Methods 
 
6.9.1 
Participants will be blinded to aspirin or placebo. 
6.9.2 
The Statistician and the Site Study Pharmacist will not be blinded to aspirin or placebo. 
6.9.3 
All other Investigators will be blinded to aspirin or placebo and to the dose level. 
6.9.4 
All participants will take one 325 mg tablet per day of aspirin or an identical-appearing 
placebo tablet.  
6.9.5 
Study assignments will be unblinded to the Study Investigators and Site Coordinators 
after all of the data are collected and the study database has been locked.  Unblinding will 
also occur if the participant’s physician deems that unblinding is necessary, such as in the 
case of unacceptable toxicity thought to be related to the study agent or progressive 
disease, or if the participant becomes pregnant.   
6.9.6 
The Data and Safety Monitoring Board will also be blinded unless unblinding is 
warranted (if the participant’s physician deems that unblinding is necessary, if the 

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participant becomes pregnant, or after all of the data are collected and the study database 
has been locked). 
6.9.7 
Unblinding will only take place after consultation with the NCI, DCP Task Order 
Monitor (Medical Monitor).  Unblinding will be conducted as follows: 
1) The Site PI contacts the Protocol Chairman (the Protocol Principal Investigator) and 
requests the participant’s treatment status be unblinded. 
2) The Protocol Chairman (the Protocol Principal Investigator) contacts the NCI, DCP 
Task Order Monitor (Medical Monitor) and requests the participant’s treatment status 
be unblinded.  The Protocol Chairman then conveys the Task Order Monitor’s 
decision to the Site PI.  The Site PI then proceeds with unblinding as written out 
below.  
3) If the NCI Task Order Monitor cannot be reached and the participant requires 
emergency care, the Protocol Chairman (the Protocol Principal Investigator) may 
authorize the site PI to break the blind. 
4) If the Site PI is unable to reach the Protocol Chairman and the participant requires 
emergency care, then the Site PI must proceed with unblinding as written out below.  
5) The Site PI requests the participant’s treatment status be unblinded by the research 
pharmacist (or designated individual responsible for dispensing drug). 
6) The Site PI officially takes the participant off-study.  
7) The date and reason for breaking the blind must be submitted by the Site PI to the 
Protocol Chairman, Robert Bresalier, MD, as soon as possible.  
8) It is the responsibility of the Study Chairman to report the date and reason for 
breaking the blind to the NCI Task Order Monitor, Gary Della'Zanna, DO as soon 
as possible after receiving this information from the Site PI. 
NCI Task Order Monitor: 
Gary Della'Zanna, DO, MSc  
National Cancer Institute  
Division of Cancer Prevention 
Gastrointestinal and Other Cancers  Research Group 
9609 Medical Center Drive, MSC-9782 
Rockville, MD 20850 
Phone: 240-276-7042 
Fax (with cover sheet, Attn: Dr. G. Della'Zanna): 240-276-7848 
Email: gary.dellazanna@nih.gov 
9) The date and reason for breaking the blind must be submitted by the Study Chairman 
to the MD Anderson Consortium Principal Investigator, Powel H. Brown, MD, PhD, 
or designee as soon as possible via email to phbrown@mdanderson.org. 
10) The date and reason for breaking the blind will be reported by the Study Chairman to 
the MD Anderson DSMB as soon as possible. 
 
6.10 
Agent Destruction/Disposal 
 
At the completion of investigation, all unused study agent will be returned to NCI, DCP Repository 
according to the DCP “Guidelines for AGENT RETURNS” and using the DCP form “Return Drug List”.  
 
The guidelines and the form are available on the DCP website.  
 

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7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
 
SCHEDULE OF EVENTS 
Evaluation/ 
Procedure 
Screening 
Baseline 
Visit/ 
Eligibility 
Verification 
 
 
Randomization 
(within 45 days 
of 
qualifying 
endoscopy)b 
Month 
1 (+/- 7 
days) 
Phone 
contact 
Months 
3,6,9 
(+7 
days) 
and 
Month 
15 (+/- 
14 
days) 
Phone 
or mail 
contact 
Month 12 
(+/- 30 days) 
EGD 
with 
biopsies. 
End 
of 
treatment 
Month 18 
(+/- 30 days) 
EGD 
with 
biopsies. 
Study 
termination 
Informed Consent 
 
X 
 
 
 
 
 
Assess Eligibility 
X 
X 
 
 
 
 
 
Baseline 
History 
Assessment 
X 
X a 
 
 
 
 
 
 
Symptom 
Assessment 
Questionnaire 
X 
 
 
 
 
 
 
Symptom 
Assessment 
 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
X 
X 
Vital Signs/ Height 
and Weight c 
 
X 
 
 
 
X 
X 
Laboratory Tests  
 
X 
 
 
 
X 
 
Pregnancy Test d 
 
X 
X 
 
 
 
 
Qualifying EGD with 
Biopsies 
 
X g 
 
 
 
X h 
X h 
Biomarkers 
 
X 
 
 
 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Dispense 
Study 
Agent 
 
 
X 
In person or by 
mail 
 
X 
Mail e 
 
 
Collect Study Agent 
 
 
 
 
X f 
X 
 
Review 
Pill 
Diary/Record 
 
 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Telephone Contact 
X 
 
X b 
X 
X 
 
 
Interval questionnaire 
 
 
 
 
X 
X 
 
Your 
Health 
and 
Well-Being (SF-36) 
survey 
 
X 
 
 
 
X 
 
a Do not repeat the Baseline History Assessment Questionnaire at Baseline. If participant is registered to study, enter 
Baseline History Assessment Questionnaire captured at Screening. 
b  In person or by phone. 
c  Do not repeat height measurement after Baseline Testing. 
d In persons of childbearing potential a serum pregnancy test must be done at the baseline visit.  If positive at that 
baseline visit that participant is a screen failure. Randomization may occur within 21 days from the baseline visit 
negative pregnancy test without repeating the test.  For randomization to occur after this 21 day window from the 
baseline visit negative pregnancy test date a repeat pregnancy test must be done and must be known to be negative 
prior to randomization and medication dispensing. 
e Study medication is distributed after randomization and at 3, 6, and 9 months only. 

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f Study medication is collected at 3, 6, 9 and 12 months. 
g Qualifying endoscopy. 
h A clinically indicated surveillance endoscopy. 
 
 
7.2 Baseline Testing/Prestudy Evaluation 
 
7.2.1 Screening 
 
Eligible participants will be identified from patients undergoing or who have undergone radiofrequency 
ablation for BE and are participating in or will participate in an ongoing surveillance program.  
Potentially eligible participants will be identified through database/charts/clinic lists prior to Baseline 
Visit.  A letter may be mailed to potentially eligible participants introducing the study to the patients.  If 
the Site chooses to utilize a letter, the letter will be signed by the Site PI who is familiar to the patient as 
the doctor following their medical condition.  If the Site PI is not the patient’s physician who is treating 
their BE, the letter will be co-signed by the physician who is familiar to the patient.   To facilitate 
screening, the Study Coordinators are advised to call potential participants and introduce the study over 
the phone, as well as administer the screening questionnaires.  However, the study team may choose to 
administer the questionnaires in person when the participant is seen at the clinic.  Screening to identify 
potentially eligible participants takes place prior to obtaining Informed Consent.  The following 
questionnaires will be administered during Screening: 
• 
Baseline history assessment questionnaire, to include a review of cancer history and previous 
medical history, previous surgery, chemotherapy, radiation, and other cancer-directed therapy 
history, family history, demographic information, including age and race, history of allergies 
or intolerance to aspirin, aspirin containing products or NSAIDs. 
• 
Symptom Assessment Questionnaire, to include a review of the following symptoms: 
gastrointestinal bleeding, hematemesis, hematochezia, melena, abdominal pain/cramping, 
heart burn, irregular heart rate/palpitations, chest pain, shortness of breath, edema, itching, 
constipation, diarrhea, headache, dizziness, drowsiness, lightheadedness, vertigo, easy 
bruising/bleeding.   
• 
Use of concomitant medications will be collected. 
 
If the participant is found to be potentially eligible for the study, a Baseline visit will be scheduled. 
 
7.2.2 Baseline Testing/Eligibility Verification: Consent; Registration; Qualifying EGD with biopsies  
The following procedures will be conducted at the Baseline Testing/Eligibility Verification Visit  
• 
Informed consent must be obtained prior to starting any further study procedures. 
• 
Registration: Registration will be completed during the screening period once informed 
consent has been signed. All consented participants will be assigned a PID number pre-
generated by the electronic database. All participants will be entered with the Data 
Management Initiative (DMI) database and Participating Organizations registry databases as 
applicable. Participants will also be registered into site-specific registry databases as 
applicable. 
• 
Enter Baseline history assessment into the DMI. 
• 
Symptoms assessment. 
• 
Participants will be given a “Your Health and Well-Being (SF-36)” survey. If the survey 
cannot be completed during the visit due to time constraints, the participant may be asked to 
complete the survey at a later date, but prior to randomization.  
• 
Use of concomitant medications will be collected. 
• 
Physical examination will be performed (to include assessment of vital signs, height and 

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weight)  
• 
Laboratory tests: CBC (must include hemoglobin, leukocyte count, platelet count) with 
differential (must include absolute neutrophil count), Creatinine, electrolytes (must include: 
sodium, potassium), AST/SGOT, ALT/SGPT, TBILI. Standard of care labs are acceptable for 
use to confirm eligibility if done within 30 days of Qualifying Visit.  
• 
In persons of childbearing potential a serum pregnancy test must be done as part of the 
baseline visit/eligibility verification and must be negative.  If positive the participant is a 
screen failure. A participant with a negative pregnancy test at that baseline visit maybe 
randomized up to 21 days from that negative pregnancy test without repeating the test. If 
randomization occurs after that 21 day period a repeat negative pregnancy test must be done 
and must be known to be negative prior to randomization and medication dispensing.  If 
pregnancy is found at any time after randomization such participants are not considered 
screen failures and the proper procedure for taking a participant off study should be followed. 
See Notes below.  
• 
Esophagogastroduodenoscopy and biopsies will be performed as part of a clinically indicated 
surveillance exam to document complete eradication of BE and absence of Barrett’s 
metaplasia or associated dysplasia. 
• 
At the time of qualifying and subsequent EGDs standard of care mucosal biopsies will be 
performed according to the Seattle protocol (4 quadrant biopsies every 2 cm in individuals 
with a history of metaplasia or low grade dysplasia, every 1 cm in those with a history of high 
grade dysplasia) 
• 
Additional research study biopsies will be performed as follows: 4 quadrant biopsies 1 cm 
above the gastroesophageal junction, at a site mid-way through an area defined by the length 
and location of the original Barrett’s segment, and normal-appearing squamous mucosa 2 cm 
above the upper extent of the original Barrett’s segment (2 biopsies in each of 4 quadrants to 
be snap frozen plus 1 biopsy for formalin fixation and paraffin embedding, or 9 biopsies in 
each segment, at 3 separate segments, for a total of 27 additional research biopsies). 
• 
Eligibility will be determined by absence of residual Barrett’s metaplasia or dysplasia at this 
qualifying exam as determined by the local Pathology reading. 
 
Notes: 
• 
Any screen failed participant who is deemed ineligible based on medical history, physical 
exam,  laboratory values, pregnancy test or persistence or BE at qualifying exam after 
consent is obtained will need to have a screen failure case report form completed.  
Information will be recorded on the appropriate CRF(s) up until the point at which the 
participant was found ineligible and screen failed.  
• 
Participants who are ineligible due to regular aspirin or NSAID use at the time of screening 
may be reevaluated after refraining from aspirin or NSAID use for one month.  
• 
If a pregnancy is discovered after Randomization, instruct the participant to stop taking drug, 
take participant off-study, complete the Off-Study CRF, follow the pregnancy to term and 
complete the Outcome of Pregnancy CRF. 
 
 
7.2.3 Randomization 
 
Subjects meeting the criteria outlined above and whose standard of care surveillance biopsies 
document absence of residual Barrett’s metaplasia or dysplasia will be eligible for randomization 
which will take place within 45 days of the qualifying endoscopy. The randomization visit may 
be in person or by phone.  
 

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• 
Randomization: Once registration is complete, eligibility has been confirmed and eligibility 
CRF is entered into the web application, participants will be assigned a randomization 
number pre-generated by the database. Participants will be randomized to receive either 
active agent (aspirin 325 mg) or placebo.  Both the participant and the investigator will be 
blinded to the agent. 
• 
Symptom assessment. 
• 
Concomitant medications.  
• 
Randomized participants will receive a 3-month supply of study agent (90 pills plus 10 
additional pills).  The drug supply may be mailed to the participant or given to the participant 
in person.  
• 
Review pill diary and pill intake instructions with the participant. Participants must be 
instructed to take at least 3 months of pills from their first bottle prior to starting the next 
bottle and to record the date that the new bottle is started.  
• 
Assess adverse events.  
 
 
7.3 
Evaluation During Study Intervention 
 
Month 1 (+/- 7 days) Phone contact 
• 
All participants will have a telephone interview at Month 1 (+/- 7 days) regarding symptoms 
possibly related to the agent, illnesses, doctors’ visits, hospitalizations, mediations (including 
aspirin, NSAIDs and over the counter medications), adverse events, and compliance with study 
tablets. Adherence with the study medication will be reinforced. 
• 
Adverse Events assessment. 
• 
Concomitant medications assessment.  
• 
Symptom assessment.  
• 
Review pill diary.  
 
Months 3, 6, and 9 (+7 days) Phone or mail contact 
• 
All participants will have a telephone or mail interview every 3 months (+7 days)regarding 
symptoms possibly related to the agent, illnesses, doctors’ visits, hospitalizations, mediations 
(including aspirin, NSAIDs and over the counter medications), adverse events, and compliance 
with study tablets.   
• 
After documentation of continued eligibility and compliance, participants will be instructed to 
return any unused study agent at this time. Prior to Months 3,6, and 9 (+7 days) visit the site 
coordinator should mail to the participant their next 3-month supply of study agent or placebo (90 
pills plus 10 additional pills). The participant is instructed to take at least 3 months of pills from 
each bottle before switching to the next bottle.  
• 
Interval questionnaire. 
• 
Adverse Events assessment. 
• 
Concomitant medications assessment.  
• 
Symptom assessment.  
• 
Review pill diary.  
 
 
7.4 
Evaluation at Completion of Study Intervention (12 months from randomization +/- 30 
days) 
A clinically indicated surveillance endoscopy exam will be performed at 12 months (+/- 30 days) 
from randomization.  This will also serve as the end of treatment exam. At this time the following 

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will be performed: 
• 
Symptom assessment. 
• 
Physical examination will be performed (to include assessment of vital signs and weight).  
• 
Laboratory tests: CBC (must include hemoglobin, leukocyte count, platelet count) with 
differential (must include absolute neutrophil count), Creatinine, electrolytes (must include: 
sodium, potassium), AST/SGOT, ALT/SGPT, TBILI.  
• 
Esophagogastroduodenoscopy and biopsies will be performed as part of a clinically indicated 
surveillance exam to document complete eradication of BE and absence of Barrett’s 
metaplasia or associated dysplasia. 
• 
Standard of care mucosal biopsies will be performed according to the Seattle protocol (4 
quadrant biopsies every 2 cm in individuals with a history of metaplasia or low grade 
dysplasia, every 1 cm in those with a history of high grade dysplasia). 
• 
Additional research study biopsies will be performed as follows: 4 quadrant biopsies 1 cm 
above the gastroesophageal junction, at a site mid-way through an area defined by the length 
and location of the original Barrett’s segment, and normal-appearing squamous mucosa 2 cm 
above the upper extent of the original Barrett’s segment (2 biopsies in each of 4 quadrant to 
be snap frozen plus 1 biopsy for formalin fixation and paraffin embedding in each segment, 
or 9 biopsies in each segment, at 3 separate segments, for a total of 27 additional research 
biopsies). 
• 
Interval questionnaire. 
• 
SF-36 health survey. 
• 
Any unused study medication will be returned (participants will also have returned unused 
study medications at 3, 6 and 9 months). 
 
7.5 
Post-intervention Follow-up Period 
 
A phone and/or mail interview to track adverse events and medication use (including aspirin and NSAID 
use) will be performed at Month 15 (+/- 14 days). Refer to the schedule of events for study procedures at 
Month 15 (+/- 14 days) visit.  
 
A clinically indicated surveillance endoscopy exam will be performed at 18 months (+/- 30 days) from 
randomization.  At this time the following will be performed: 
• 
Symptoms assessment. 
• 
Adverse events assessment. 
• 
Concomitant medications assessment. 
• 
Physical examination will be performed (to include assessment of vital signs and weight).  
• 
Esophagogastroduodenoscopy and biopsies will be performed as part of a clinically indicated 
surveillance exam to document complete eradication of BE and absence of Barrett’s 
metaplasia or associated dysplasia. 
• 
Standard of care mucosal biopsies will be performed according to the Seattle protocol (4 
quadrant biopsies every 2 cm in individuals with a history of metaplasia or low grade 
dysplasia, every 1 cm in those with a history of high grade dysplasia). 
• 
Additional research study biopsies will be performed as follows: 4 quadrant biopsies 1 cm 
above the gastroesophageal junction, at a site mid-way through an area defined by the length 
and location of the original Barrett’s segment, and normal-appearing squamous mucosa 2 cm 
above the upper extent of the original Barrett’s segment (2 biopsies in each of 4 quadrant to 
be snap frozen plus 1 biopsy for formalin fixation and paraffin embedding in each segment, 
or 9 biopsies in each segment, at 3 separate segments, for a total of 27 additional research 
biopsies). 

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Subsequent to study participation, the patients will be followed through routine clinically indicated 
surveillance endoscopy exams and biopsies performed at 6 to 12 month periods.   
 
 
7.6 
Methods for Clinical Procedures 
 
Clinically indicated surveillance esophagogastroduodenoscopy (EGD) will be performed at 
qualifying exam, 12 months (+/- 30 days) from randomization and 18 months (+/- 30 days) from 
randomization. Standard of care mucosal biopsies will be performed according to the Seattle 
protocol (4 quadrant biopsies every 2 cm in individuals with a history of metaplasia or low grade 
dysplasia, every 1 cm in those with a history of high grade dysplasia) 
 
Additional research study biopsies will be performed as follows: 4 quadrant biopsies 1 cm above 
the gastroesophageal junction, at a site mid-way through an area defined by the length and 
location of the original Barrett’s segment, and normal-appearing squamous mucosa 2 cm above 
the upper extent of the original Barrett’s segment (2 biopsies in each of 4 quadrant to be snap 
frozen plus 1 biopsy for formalin fixation and paraffin embedding in each segment, or 9 biopsies 
in each segment, at 3 separate segments, for a total of 27 additional research biopsies) 
 
Surveillance Mucosal Biopsies 
 
Kits are required for research biopsies.  The kit contains supplies and instructions for 
collecting, processing, and shipping research biopsy specimens.  Participating Sites may obtain 
specimen collection kits by faxing the Fax Supply Order Form to the number provided (found in 
the Forms Packet).  At least two weeks should be allowed to receive the kits.  Kits will not be sent 
to the Participating Sites by FedEx ®.  Because charges are incurred for all outgoing kits, a small 
but sufficient supply of the specimen collection kits should be ordered prior to participant entry. 
Endoscopic research biopsies will be obtained with the Boston Scientific Radial Jaw  
 RJ4 large capacity  biopsy forceps (provided by coordinating center) from  1 cm above the level 
of the lower esophageal sphincter, just above the proximal margin of the gastric folds, in a zone 
corresponding to the middle of the former Barrett’s segment, and a zone 2 cm above the upper 
extent of the former Barrett’s segment.  
 
 
 

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8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 
The primary endpoint of the study will be differences in the change of CDX2 mRNA levels from 
baseline to 12 months post-randomization in esophageal squamous tissue between participants 
taking aspirin supplementation versus those taking placebo.  CDX2 mRNA levels will be compared 
at baseline versus at 12 months within each participant, and the change in CDX2 mRNA levels 
compared between participants taking aspirin participants taking placebo (similar comparisons 
will be made for differences in the change of secondary biomarkers-see below).  Our rationale to use 
this biomarker is based on the direct link between aspirin, chronic inflammation, and the downregulation 
of NF-kB-induced downstream target genes among which is CDX2 (4,5,8).Total RNAs will be isolated 
from squamous and neosquamous mucosal biopsy specimens using Trizol (Invitrogen, Carlsbad, CA) and 
quantitated by spectrophotometry.  Reverse transcription will be performed using QuantiTect Reverse 
Transcription kit (Qiagen, Valencia, CA) per manufacturer’s instructions. Real-time PCR for CDX2 
mRNA will be carried out using rapid cycling with the StepOnePlus Real-Time PCR System and SYBR 
mix (Life Technologies, Carlsbad, CA) using previously published CDX2 primer sequences (8). 
 
8.2 
Secondary Endpoints 
8.2.1 
Safety will be assessed by comparison of adverse events using the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. AEs will be assessed 
according to the CTCAE grade associated with the AE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading 
used in the CTCAE v4.0. as stated in Section 11.1.3.1. We will closely monitor the toxicity 
profile and tolerability in each group.  Safety will be assessed by monitoring routine clinical 
parameters at baseline and at each visit throughout the trial (including Month 1, every 3 
months by phone calls and/or mail interviews and in person at 12 and 18 months), and by 
monitoring laboratory parameters at baseline and at 12 months.  All AEs will be recorded and 
graded during clinical visits, whether or not they are considered drug-related.  All participants 
will be monitored for toxicity from the time of randomization.  Each treatment arm will be 
monitored separately for severe toxicities (grade 3 and 4 and SAEs).  We will be especially 
vigilant about the incidence of gastrointestinal (gastric and duodenal ulcers, gastritis, 
gastrointestinal bleeding or perforation, hematemesis) and hematological (anemia, 
thrombocytopenia) events.  Toxicity will be considered drug-related based on clinical 
assessment. In addition, at the completion of the study, the frequency of toxicities will be 
compared between the placebo and aspirin groups. 
 
The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale 
profile of functional health and well-being scores as well as psychometrically-based physical 
and mental health summary measures and a preference-based health utility index. It is a 
generic measure, as opposed to one that targets a specific age, disease, or treatment group. 
Accordingly, the SF-36 has proven useful in surveys of general and specific populations, 
comparing the relative burden of diseases, and in differentiating the health benefits produced 
by a wide range of different treatments.  Since a secondary endpoint of our study is to 
determine safety in a specific clinical setting (use of aspirin following radiofrequecy ablation, 
we wish to compare measures of health and well-being between those receiving aspirin and 
those receiving placebo.  Bivariate analyses will be performed on study entry and completion 
of the on-drug period. Multivariate analyses will be performed between groups after 
controlling for potential confounders. 

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8.2.2 
Differences in the change of CDX2 mRNA levels from baseline to 18 months post-
randomization in esophageal squamous tissue between participants taking aspirin 
supplementation versus those taking placebo. Total RNAs will be isolated from squamous 
and neosquamous mucosal biopsy specimens using Trizol (Invitrogen, Carlsbad, CA) and 
quantitated by spectrophotometry.  Reverse transcription will be performed using QuantiTect 
Reverse Transcription kit (Qiagen, Valencia, CA) per manufacturer’s instructions. Real-time 
PCR for CDX2 mRNA will be carried out using rapid cycling with the StepOnePlus Real-
Time PCR System and SYBR mix (Life Technologies, Carlsbad, CA) using previously 
published CDX2 primer sequences (8). 
8.2.3 
Differences in the activation status of NF-kB by assessing levels of total and phospho-
p65 and cytoplasmic to nuclear translocation of phospho-p65 which is likely to be 
affected by aspirin (baseline, 12 and 18 months).  Fractionation and Western blot for the p65 
NF-kB family member: Using esophageal  squamous and neosquamous mucosal biopsies 
taken before and after treatment with aspirin, levels of phospho-p65 and total p65 will be 
determined by Western blot and quantitated by densitometry.  We will then evaluate the 
cytoplasmic to nuclear translocation of phospho-p65 protein as previously described by us. 
Nuclear extracts will be isolated from tissues using the NE-PER Nuclear and Cytoplasmic 
Extraction kit (Thermo Fisher Scientific, Rockford, IL) per manufacturer’s instructions.  
Blots will be probed with antibodies to phospho-p65 and total p65. Tubulin and transcription 
factor IIB (TFIIB) antibodies will be used to assure the purity of the cytoplasmic and nuclear 
subcellular fractions, respectively.  
8.2.4 
Differences in the prostanoid marker, prostaglandin E2, and prostaglandin synthases 
(baseline, 12 and 18 months), which are known to respond to aspirin and to correlation with 
clinicopathological factors in the esophageal cancer (14, 24).  PGE2 was previously shown to 
be reduced in Barrett’s mucosa in response to a combination of acid inhibition and high-dose 
(but not low dose) aspirin. Endogenous eicosanoids will be extracted from snap frozen 
biopsies and analyzed as we have previously described (25).  Immediately following 
isolation, biopsies will be placed in individual vials containing 5 µg/mL aqueous 
indomethacin, instantly snap frozen in liquid nitrogen and maintained in liquid nitrogen.  
Using this regimen, measured PGE2 reflects the actual concentration in vivo (26). 
8.2.5 
Differences in the expression of proinflammatory cytokines known to induce activation 
of NFkB, i.e., TNFα, IL-1β, IL-6, IL-10, IL-17A, IL-23 will be measured (baseline, 12 and 
18 months). These inflammatory mediators have been implicated in the pathogenesis of BE 
and esophogeal adenocarcinoma. Snap frozen biopsies will be homogenized in lysis buffer 
and endogenous IL-1β, IL-6, IL-10, IL-17A, IL-23, and TNFα will be simultaneously 
measured utilizing a human Bio-Plex customized multiplex kit (Bio-Rad) and the Bio-Plex 
200 System as we have previously described (27). 
8.2.6 
Recurrent Barrett’s Esophagus (at 12 and 18 months) will be ascertained completely and 
accurately.  While we will not have sufficient power to assess differences in histological 
recurrence of BE during the short course of the study, we will examine this as an exploratory 
secondary endpoint. This study will generate data designed to lead to the submission of an 
adequately powered multi-center prospective chemoprevention trial with histologic 
recurrence of BE after RFA as the clinically relevant primary endpoint. At all endoscopic 
examinations after randomization, all raised mucosal lesions, and all flat lesions suspicious 
for neoplasia, will be biopsied and excised by EMR, their location and size noted, and 
pathology material reviewed by the study pathology center for confirmation of diagnosis.  For 
each participant, the surface area of recurrent BE will be estimated along with its Prague 
classification, histological characteristics, and location.  A designated study pathologist will 
review all pathology specimens without knowledge of treatment assignment. Each biopsy 

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will be classified (using standard criteria) as normal, Barrett’s metaplasia, BE with low- or 
high-grade dysplasia, neoplasia, indefinite for dysplasia, intramucosal or invasive carcinoma.  
 
8.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, noncompliance, 
concomitant medications, medical contraindication.  Participants will continue to be followed, if possible, 
for safety reasons and in order to collect endpoint data according to the schedule of events.   We plan to 
enroll up to 20 participants per group.  
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/serious adverse event, lost to follow-up, non-
compliance, concomitant medication, medical contraindication, withdraw consent, death, determination of 
ineligibility (including screen failure), pregnancy. 
 
8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
 
Methodology employed is based on existing literature and previously generated data from the biomarker 
laboratories and investigators involved in this study. 
Preliminary Data to Justify Primary Endpoint CDX2 and Assessment of Differences in the 
activation status of NF-kB by assessing levels of total and phospho-p65 and cytoplasmic to nuclear 
translocation of phospho-p65 which is likely to be affected by aspirin: 
In Esophageal Squamous Cells Derived from GERD Patients with and without Barrett’s Esophagus, 
There Are Differences in NF-κB Activation after Acid and Bile Salt Exposure. In human esophageal 
squamous cell lines derived from GERD patients with BE, we have shown that acid and bile salts cause 
nuclear translocation of both the p50 and p65 subunits of NF-ΚB, but only p50 binds the CDX2 promoter 
to induce CDX2 expression. In contrast, esophageal squamous cells from patients who have GERD 
without BE fail to induce CDX2 expression in response to any of these exposures (8).  To further explore 
this mechanism, esophageal squamous cells from GERD patients with (NES-B3T & NES-B10T) and 
without (NES-G2T & NES-G4T) BE were exposed to acidic media (pH5.5), neutral bile salt media (pH 
7.2), and acidic bile salt media (the same bile salt solution at pH5.5) and activation of NF-κB pathway 
proteins were determined. Compared to the Barrett’s squamous cell lines, the GERD squamous cell lines 
exhibited less phosphorylation of IKKα/β and IΚB after exposure to all three test media; levels of 
phospho-IKKα did not differ among the cell lines (Figure 1 and data not shown). 
 
 
 
 
 
 
 
Figure 1.  NES-G2T and NES-G4T exhibit 
less phosphorylation of IKK α/β and IκB than 
NES-B3T and NES-B10T in response to 
exposure to acid, bile salts, or the 
combination of both. C, non-treated control 
cells; A, acidic media alone; B, bile salt 
media alone; A&B, acidic bile salt media. 

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Compared to Barrett’s squamous cell lines, the GERD squamous cell lines exhibited more cytoplasmic 
binding of p65 to IΚB after exposure to all three test media (Figure 2).  
 
 
 
 
 
 
 
 
 
 
The NES-G lines also exhibited less nuclear translocation of p50, and there was no apparent nuclear 
translocation of p65 (Figure 3); these results were confirmed with immunofluorescence (data not shown).   
 
 
 
 
 
 
 
 
 
 
 
 
Using ChIP, we determined whether p50 and/or p65 bound to the CDX2 promoter. We observed no 
increase in binding of the p65 subunit to the CDX2 promoter in response to any of the test media in the 
squamous cells from GERD patients with and without BE. Following exposure to our test media, 
squamous cells from GERD patients with BE has a marked increase in DNA binding of p50, whereas 
squamous cells from patients without BE demonstrated no DNA binding of p50 to the CDX2 promoter 
(Figure 4). These data suggest that although p65 does not bind directly to the CDX2 promoter that nuclear 
translocation of p65 may be necessary to allow for p50 to bind the CDX2 promoter.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.  NES-G2T and NES-G4T 
exhibit more cytoplasmic binding of p65 
to IκB than NES-B3T and NES-B10T in 
response to exposure to acid, bile salts, or 
the combination of both. C, non-treated 
control cells; A, acidic media alone; B, 
bile salt media alone; A&B, acidic bile 
salt media. 
Figure 3.  NES-G2T exhibits less nuclear 
translocation of p50 and no apparent 
translocation of p65 compared to NES-
B3T in response to exposure to acid, bile 
salts, or the combination of both. C, non-
treated control cells; A, acidic media 
alone; B, bile salt media alone; A&B, 
acidic bile salt media. 
Figure 4.  NES-G2T and NES-G4T have no 
apparent binding of p50 to the CDX2 promoter 
whereas as NES-B3T and NES-B4T 
demonstrate a marked increase in DNA binding 
of p50 in response to exposure to acid, bile 
salts, or the combination of both. None of our 
cells demonstrated p65 binding to the CDX2 
promoter. C, non-treated control cells; A, acidic 
media alone; B, bile salt media alone; A&B, 
acidic bile salt media. 

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To determine whether nuclear translocation of p65 was required for p50 to bind to CDX2 promoter, we 
transfected NES-B10Tcells with p65 siRNA and with a CDX2 promoter-reporter construct and exposed 
the transfected cells to acidic bile salt media. As expected, acidic bile salt media significantly increase 
CDX2 promoter activity in NES-B10T cells containing the control siRNA. In contrast, acidic bile salt 
media did not increase CDX2 promoter activity in NES-B10T cells containing p65 siRNA (Figure 5).  
 
 
 
 
 
 
 
 
 
 
These findings suggest that acidic bile salt media-induced nuclear translocation of p65 is necessary for the 
induction of CDX2 expression through the binding of p50 to the CDX2 promoter in esophageal squamous 
cells. Therefore, reflux-induced induction of CDX2 might be prevented by agents that reduce 
phosphorylation and nuclear translocation of p65 and may be useful chemopreventive agents to 
prevent recurrent Barrett’s metaplasia after RFA. 
 
Assessment of Differences in prostaglandin E2 are based on data from investigators involved in this 
study which demonstrate that a combination of esomeprazole and aspirin reduces tissue concentrations of 
prostaglandin E2 in patients with BE (14), and the methodology involved in that study. 
Assessment of differences in the expression of proinflammatory cytokines known to induce 
activation of NFkB, i.e., TNFα, IL-1β, IL-6, IL-10, IL-17A, IL-23 will be measured according to 
standard methodology (27). 
 
9.2 
Comparable Methods 
 
The methodology described above are those previously used (see details above), and the resulting data 
will be able to be compared to existing data. 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
The laboratory of Dr. Rhonda Souza MD at the Center for Esophageal Research, Baylor Scott & 
White Research Institute, Dallas, TX will serve as the biomarker laboratory for assessment of the 
primary biomarker (differences in the change of CDX2 mRNA levels from baseline to 12 months  post-
randomization in esophageal squamous tissue between participants taking aspirin supplementation versus 
those taking placebo) and two important secondary biomarkers (differences in the change of CDX2 
mRNA levels from baseline to 18 months  post-randomization in esophageal squamous tissue between 
participants taking aspirin supplementation versus those taking placebo and  differences in the activation 
status of NF-kB by assessing levels of total and phospho-p65 and cytoplasmic to nuclear translocation of 
phospho-p65.  Dr. Souza’s research has focused on the pathogenesis of reflux esophagitis, BE and 
esophageal adenocarcinoma.  For the past 19 years, she has worked closely with Dr. Stuart Spechler to 
establish a translational research program at the Dallas VA that incorporates cell culture models, animal 
models, and in vivo patient studies to answer research questions related to GERD, BE, and esophageal 
Figure 5.  Acidic bile salts cause a 
significant increase in CDX2 promoter 
activity in NES-B10T cells containing 
control siRNA but this same exposure 
does not increase CDX2 promoter 
activity in NES-B10T cells containing 
p65 siRNA.  ***, p<0.001 

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adenocarcinoma. Dr. Souza and Dr. Huo in her laboratory will provide expertise in molecular and cell 
biology as well as our technical experience in investigating the role of phospho-p65 and CDX2 as 
biomarkers in esophageal squamous in predicting the recurrence of Barrett’s metaplasia after 
radiofrequency ablation.   
 
Differences in the the prostanoid marker, prostaglandin E2, and prostaglandin synthases and 
Differences in the expression of proinflammatory cytokines known to induce activation of NFkB, 
i.e., TNFα, IL-1β, IL-6, IL-10, IL-17A, IL-23 will be measured in the laboratory of Dr. PeiyingYang 
Ph.D. at the University of Texas MD Anderson Cancer Center.  Dr. Yang’s lab have developed highly 
sensitive and specific methods for the analysis of both endogenous and exogenous bioactive lipids, such 
as prostaglandins, leukotrienes and HETEs, derived from cyclooxygenase and lipoxygenase enzymes. 
These methods have been applied to in vitro and in vivo studies in support of cancer research already used 
extensively by numerous investigators nationally. Dr Yang served as a leader of Analytical Core for the 
P01 project, led by Dr. Raymond Dubois to understand the role of bioactive lipid in inflammation and 
cancer and her lab helped analyze eicosaniods levels in over 2000 samples in various biological matrices. 
The methodology for these analyses is based primarily on an LC/MS/MS method using stable isotope 
dilution techniques employing deuterated internal standards (IS). The eicosanoid analyses are routinely 
carried out by Dr. Yang’s laboratory. Additionally, the availability of the methods to simultaneously 
quantify COX and LOX metabolites has allowed a number of studies to illustrate the interrelationship of 
COX and LOX metabolites in certain malignancies.  
 
 
10.2 
Collection and Handling Procedures 
 
 
Research Mucosal Biopsy Specimens 
 
Esophageal mucosa biopsy techniques have been described in Section 7.  Types of assay conducted for 
each biopsy specimen are described in Section 8.  Research biopsies will be obtained at baseline (after 
consent but prior to randomization), at 12 months and at 18 months as described in Section 7. 
Endoscopic research biopsies will be obtained with the Boston Scientific Radial Jaw  
RJ4 large capacity biopsy forceps (provided by coordinating center at no additional cost to participating 
sites) from 1 cm above the level of the lower esophageal sphincter, just above the proximal margin of the 
gastric folds, in a zone corresponding to the middle of the former Barrett’s segment, and a zone 2 cm 
above the upper extent of the former Barrett’s segment. 
 
Tissue kits will be provided by the coordinating Center at the University of Texas MD Anderson Cancer 
Center.  Tissue collection, handling, and shipping instructions will be included with each kit. Participating 
Sites may obtain tissue kits by faxing the Supply Order Form to the number provided (found in the Forms 
Packet).  At least two weeks should be allowed to receive the shipping kits. Kits will be sent via FedEx ® 
at no additional cost to the participating institutions.  They will not be forwarded by FedEx ® rush 
delivery service unless the participating institution provides their own FedEx ® account number or 
alternate billing number for express service.  Because charges are incurred for all outgoing kits, a small, 
but sufficient, supply of the specimen collection kits should be ordered prior to participant entry. 
 

DCP Protocol Number: MDA2013-02-02 
Protocol Version, dated 5/3/2019 
 
DCP Protocol Template Version 8.3 
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  Biopsy # 
Planned Use 
Level 1 (1 cm above GE junction) 
 
Biopsy A1 (Formalin fixed) 
Histological evaluation and immunohistochemistry 
2 Biopsy A2 (RNAlater®) 
CDX2 mRNA  
2 Biopsies A3 (Flash Frozen) 
CDX2 mRNA 
Biopsy A4 (Flash Frozen) 
total and phospho-p65 and cytoplasmic to nuclear 
translocation of phospho-p65 
Biopsy A5 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
Biopsy A6 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
Biopsy A7 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
Level 2 (middle of former Barrett’s 
segment) 
 
Biopsy B1 (Formalin fixed) 
Histological evaluation and immunohistochemistry 
2 Biopsies B2 (RNAlater®)) 
CDX2 mRNA 
2 Biopsies B3 (Flash Frozen) 
CDX2 mRNA 
Biopsy B4 (Flash frozen) 
total and phospho-p65 and cytoplasmic to nuclear 
translocation of phospho-p65 
Biopsy B5 (Flash frozen) 
PGE2 and proinflammatory cytokines 
Biopsy B6 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
Biopsy B7 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
Level 3 (2 cm above former Barrett’s 
segment) 
 
Biopsy C1 (Formalin fixed) 
Histological Evaluation 
2 Biopsies C2 (RNAlater®) 
CDX2 mRNA 
2 Biopsies  C3 (Flash Frozen) 
CDX2 mRNA 
Biopsy C4 (Flash Frozen) 
total and phospho-p65 and cytoplasmic to nuclear 
translocation of phospho-p65 
Biopsy C5 (Flash Frozen) 
PGE2 and proinflammatory cytokines 

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Biopsy C6 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
Biopsy C7 (Flash Frozen) 
PGE2 and proinflammatory cytokines 
 
Biopsies A1, B1 and C1 will be placed in neutral buffered formalin at room temperature. Biopsies A2, B2 
and C2 will be placed in RNAlater® at 2°-8°C.  The remainder of the biopsies will be washed in 
phosphate buffered saline, each biopsy placed in a cryovial then placed in liquid nitrogen.  Vials will be 
stored at a temperature of -80°C. Specimens must not be thawed before analysis.  
 
Random, blinded, unique ID numbers will be assigned to specimens at each time point (baseline and post-
treatment: 12 months and 18 months) and will be distributed with the PID number.  All specimens will be 
labeled with the unique specimen number (XXXX), date (DD-MM-YY) and product code (N) using a 
permanent, waterproof marker.  Laboratories will be blinded from distinguishing participant information 
and visit point but this information will be kept available in a password protected electronic  log at each 
site to indicate which specimen number belongs to which participant and at what visit and at the 
Coordinating Center.   
 
 
10.3 
Shipping Instructions 
 
Biopsies taken for research specimens (A1, B1, C1) will be placed in formalin and shipped overnight to 
the MD Anderson (MDACC) Coordinating Center for further processing.  MDACC Research Histology 
Core will process and paraffin-embed the samples, and then cut one H & E and 20 unstained slides.  Dr. 
Dipen Maru or his designee will provide a diagnosis for these samples (confirmed absence of Barrett’s 
metaplasia or dysplasia, or presence of Barrett’s metaplasia or dysplasia). 
Biopsies A2, B2 and C2 will be shipped the 3rd week of each month. 
 
Biopsies taken for formalin fixation and paraffin embedding will be placed in prefilled 10% neutral 
buffered formalin (Azer Scientific 10 ml prefilled in 20 ml containers supplied by the coordinating 
center).  Containers will be wrapped in parafilm, placed in plastic bags, bags sealed and shipped overnight 
to the coordinating center at the address listed below. 
 
Frozen specimens will be batch shipped on dry ice monthly to the Coordinating Center at MDACC.  
 
• 
All tissue samples must be kept frozen (-80oC or below) after preparation and until 
shipment is initiated. 
• 
Wrap the frozen samples in bundles using an elastic band or place samples in appropriate 
sample storage box and place in a plastic freezer bag. 
• 
Use newspaper or other similar material to insulate the bagged sample bundles from 
direct contact with the dry ice. 
• 
Shipping containers (e.g., outer foam/cardboard shipping boxes) should be insulated, 
filled with dry ice and sealed with tape at the time the shipment is made. The shipping 
labels supplied should be affixed firmly to the outside of each container. 
• 
All samples must be shipped in accordance with local biohazard requirements. Please 
refer to your institutional policy for biohazard labeling and packaging for shipment of 
hazardous and infectious human samples.  If sealed biohazard containers are used, DO 
NOT place dry ice inside these containers.  Place dry ice outside the containers only.  
Include a minimum of 10 kg dry ice when shipping by overnight express. Record the 
estimated weight of the dry ice used per box. 
• 
Shipments should not be made on Friday or the day prior to a public holiday. 

DCP Protocol Number: MDA2013-02-02 
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• 
An inventory listing of all the samples must be included in the shipment. The inventory 
listing should contain the following information from each sample label: protocol 
number, patient number, patient initials and date and time of collection, along with any 
other pertinent information. Before placing in the shipping container, put the inventory 
list in a plastic bag for protection. 
 
Samples will be shipped in containers provided and according to instructions provided by the 
Coordinating from collaborating Institutions to the following location: 
 
 
Tamara Tipps 
UT MD Anderson Cancer Center 
Department of Gastroenterology, Hepatology and Nutrition 
1400 Pressler Street, FCT13.6013 
Houston, Texas 77030-4900 
Telephone 713-794-1439 
Back-up Telephone: 713-745-4340 
Fax:     713-745-9295 
Email: tltipps@mdanderson.org  
 
The Coordinating Center will be notified via e-mail when samples are shipped, so if samples are delayed 
or lost, tracking may be initiated by the sending site.  Sample shipment forms are included with 
shipments.  These data forms describe the date of sample receipt, and availability of sample, along with 
tracking information.  The Coordinating Center will evaluate the sample condition on arrival, enter the 
sample numbers in the database, verify samples shipped match samples sent, and store at appropriate 
conditions until shipment to analytical labs. 
 
All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 
 
10.4 
Tissue Banking 
 
All research specimens are shipped to the study repository at the UTMDACC for storage which will be 
housed in the laboratory of the Principal Investigator, Robert S. Bresalier, M.D. The laboratory is 
equipped with five -80 degree freezers which serve as repositories for research samples.    
 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course 
of the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense.   
 
 
11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign), 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 

DCP Protocol Number: MDA2013-02-02 
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Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported 
as AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up 
further for a final determination, if possible. 
 
A list of AEs that have occurred or might occur  can be found in §6.2 Reported Adverse Events and 
Potential Risks, as well as the Investigator Brochure or package insert.  
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are completed 
(including run-in) must be recorded on the AE CRF whether or not related to study agent. 
 
11.1.2 AE Data Elements: 
 
The following data elements are required for adverse event reporting. 
• 
AE verbatim term 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a serious adverse event (SAE) 
• 
Whether or not the participant dropped due to the event 
• 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
 
 
11.1.3.1 
Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive 
terminology (MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE 
can be found at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0. as stated below.  
 
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 

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Grade 
Severity 
Description  
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the adverse event is related to study agent will be classified as one of the following: 
not related, unlikely, possible, probable, definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will 
be followed according to good medical practices and documented as such. 
 
11.2 
Serious Adverse Events  
 
11.2.1 Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any untoward medical 
occurrence that at any dose has one or more of the following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
perform normal life functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in 
death or hospitalization should also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
The organization that experiences the serious adverse event (SAE) should report the SAE to the 
following 3 entities: 1) NCI DCP, 2) DCP’s regulatory contractor CCSA, and 3) MDACC, the 
CLO.  Detailed reporting instructions are provided below.  In addition, all participating 
organizations will follow their IRB requirements for SAE reporting. 
 
11.2.2.1 
The Lead Organization and all Participating Organizations will report SAEs on the DCP 
SAE form found at http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia. 
 

DCP Protocol Number: MDA2013-02-02 
Protocol Version, dated 5/3/2019 
 
DCP Protocol Template Version 8.3 
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11.2.2.2 Reporting within 24 hours of knowledge of the event.  
11.2.2.2(A) Report to the NCI DCP Medical Monitor within 24 hours: 
Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.   
Gary Della'Zanna, DO, MSc  
National Cancer Institute  
Division of Cancer Prevention 
Gastrointestinal and Other Cancers Research Group 
9609 Medical Center Drive, MSC-9782 
Rockville, MD 20850 
Phone: 240-276-7042 
Fax (with cover sheet, Attn: Dr. G. Della'Zanna): 240-276-7848 
Email: gary.dellazanna@nih.gov 
DellaZannagj@mail.nih.gov 
 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug and expectedness 
 
 
11.2.2.2(B) Report to the Consortium Lead Organization (CLO) PI (Dr. Powel 
Brown) within 24 hours of knowledge of the event: 
Report all SAEs to the Consortium Lead Organization PI (Dr. Powel Brown) within 24 
hours of knowledge of the event.  The same information reported to the DCP Medical 
Monitor should be provided to the CLO Coordinator via email, phone or fax within 24 
hours of knowledge of the event.  
 
11.2.2.3 Reporting within 48 hours of knowledge of the event: 
11.2.2.3 (A) Email the written SAE reports to the DCP Medical Monitor within 48 hours 
of learning of the event using the paper SAE form. The SAE forms should be obtained at 
http://prevention.cancer.gov/files/clinical-trials/SAE_form.doc. 
 
11.2.2.3 (B) The written SAE reports will also be  emailed to DCP’s Regulatory 
Contractor, CCS Associates at safety@ccsainc.com  
 
11.2.2.3 (C) The written SAE report will also be emailed to the Consortium Lead 
Organization PI (Dr. Powel Brown), at PHBrown@mdanderson.org.  
 
It is the responsibility of the CLO to inform the Lead Protocol PI upon receipt of the 
report from the organization experiencing the event.  
 
11.2.2.4 The DCP Medical Monitor and CCSA regulatory and safety staff will determine which SAEs 
require FDA submission. 
 

DCP Protocol Number: MDA2013-02-02 
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11.2.2.5 The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.2.6 Follow-up of SAE 
Site staff should send follow-up reports as requested when additional information is available.  
Additional information should be entered on the DCP SAE form in the appropriate format.  
Follow-up information should be sent to DCP as soon as available. SAEs related to the study 
agent will be followed until resolved. 
 
 
12. 
STUDY MONITORING  
 
12.1 
Data Management 
 
This study will report clinical data using the Data Management Initiative (DMI) web-based application 
managed by the Consortium Biostatistics and Data Management Core.  Data Management Initiative 
(DMI) infrastructure has been developed in the Division of Quantitative Sciences (DQS), MD Anderson 
Cancer Center.  This infrastructure supplies integrated database and software services for web-based data 
collection, randomized treatment assignment, reporting, query, data download, and data quality 
management.  The DMI will be the database of record for the protocol and participant to NCI and FDA 
audit.  All DMI users will be trained to use the DMI system and will comply with the instructions in the 
protocol-specific “DMI User Manual” as well as applicable regulatory requirements such as 21 CFR; Part 
11.  Data management procedures for this protocol will adhere to the Data Management Plan (DMP) on 
file at the DCP for contract HHSN261201200034I.  
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRF) developed from the 
standard set of DCP Chemoprevention CRF Templates and utilizing NCI-approved Common Data 
Elements (CDEs). The approved CRFs will be used to create the electronic CRF (e-CRF) screens in the 
DMI application. Site staff will enter data into the e-CRF. Amended CRFs will be submitted to the DCP 
Protocol Information Office for review and approval.  Approved changes will be programmed into the 
DMI database by the Consortium Biostatistics and Data Management Core. 
 
12.3 
Source Documents 
 
Source documentation will include only those documents containing original forms of data, including 
clinic charts, shadow files, hospital charts, and physician notes.  Data recorded directly on the CRFs 
designated as source documents (i.e., no prior written or electronic record of data) will be considered 
source data.  All other data recorded on the CRFs will not be considered source documentation. 
 
 
12.4 
Data and Safety Monitoring Plan 
 
The Data and Safety Monitoring Plan for the MD Anderson Consortium is on file at the DCP.  This study 
will be monitored by the MDACC Data and Safety Monitoring Board, the data and safety monitoring 
board of record for this study.   The Data Safety and Monitoring Board (DSMB) reports to the President, 
or his designee, as the on-campus representative of The University of Texas Board of Regents. It oversees 
the data and patient safety issues for randomized clinical trials that originate at MD Anderson; that are 
coordinated or analyzed by MD Anderson and are not being monitored by any other DSMB; or have been 

DCP Protocol Number: MDA2013-02-02 
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designated as requiring DSMB monitoring at the request of the IRB, the CRC, or institution. The primary 
objectives of the DSMB are to ensure that patients' rights pertaining to participation in a research study 
are protected, and that patients' interests are prioritized over the interests of the scientific investigation. 
Responsibilities include: 
(a) Review interim analyses of outcome data (prepared by the study statistician or other 
responsible person at the time points defined in the study) approved by the IRB and 
additional time points as determined by the DSMB, and to recommend, if necessary, whether 
the study needs to be changed or terminated based on these analyses; 
(b) Determine whether, and to whom, outcome results should be released prior to the reporting of 
study results; 
(c) Review interim toxicity data and efficacy of treatment; 
(d) Review major research modifications proposed by the investigator or appropriate study 
committee prior to implementation (e.g., termination, dropping an arm based on toxicity 
results from the study or results of other studies, increasing target sample size). 
 
Refer to the Data and Safety Monitoring Plan for the MD Anderson Consortium on file at the DCP for 
further details. 
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCP requirements, unless the standard at the site is more stringent.  For NCI/DCP, records will 
be retained for at least three years after the completion of the research. NCI will be notified prior to the 
planned destruction of any materials. The records should be accessible for inspection and copying by 
authorized persons of the Food and Drug Administration. If the study is done outside of the United States, 
applicable regulatory requirements for the specific country participating in the study also apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
The agent(s) supplied by DCP, NCI, used in this protocol, is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as Collaborator(s)) and the NCI Division of Cancer Prevention. Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator@ 
contained within the terms of award, apply to the use of Agent(s) in this study: 
 
12.7.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational agents contain confidential 

DCP Protocol Number: MDA2013-02-02 
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DCP Protocol Template Version 8.3 
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information and should not be shared or distributed without the permission of the NCI. If a patient 
participating on the study or participant’s family member requests a copy of this protocol, the individual 
should sign a confidentiality agreement. A suitable model agreement can be downloaded from the DCP 
website. 
 
12.7.2 For a clinical protocol where there is an Investigational Agent used in combination with (an) 
other investigational Agent(s), each the subject of different collaborative agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-party Data”). This section is not applicable to the present protocol.  
 
12.7.3 NCI must provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NIH, the design of the proposed combination protocol, 
and the existence of any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. This section is not applicable to the present protocol. 
 
12.7.4 Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval, or commercialize its own investigational agent. 
 
12.7.5 Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational agent. 
 
12.7.6 Clinical Trial Data and Results and Raw Data developed under a collaborative agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate. All data made 
available will comply with HIPAA regulations. 
 
12.7.7 When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators of Collaborator's wish to contact them. 
 
12.7.8 Any manuscripts reporting the results of this clinical trial must be provided to DCP for immediate 
delivery to Collaborator(s) for advisory review and comment prior to submission for publication. 
Collaborator(s) will have 30 days (or as specified in the CTA) from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in 
order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to DCP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to DCP prior to release. Copies of any 
manuscript, abstract, and/or press release/ media presentation should be sent to the Protocol Information 
Office at NCI_DCP_PIO@mail.nih.gov. 
 
The Protocol Information Office will forward manuscripts to the DCP Project Officer for distribution to 
the Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/proprietary information. 
 
 
 
 
 

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13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description  
 
This a placebo-controlled phase II study to evaluate the effect of aspirin on the modulation of CDX2 
mRNA levels from baseline to 12 months post-randomization in esophageal squamous tissue in 
participants with BE after successful eradication with radiofrequency ablation. 
 
13.2 
Randomization/Stratification  
 
Randomization will be performed using the random permutated block design to ensure the balance 
between the two arms (aspirin and placebo).  The randomization list will be generated by the study 
statistician and incorporated into the data base in a double blind fashion, i.e. both the study investigators 
and the study participants are blinded to the designation of the specific treatment arm to which the 
participant is assigned. 
 
13.3 
Accrual and Feasibility 
 
1. Planned duration of accrual: Two years (including study initiation) 
2. Expected accrual rate per month: 5-7 
3. Number of expected participants registered per month per site:  approx. 1-2 
 
The investigators participating in this study have extensive experience in the treatment and study of 
patients with BE, and specifically follow large cohorts who have undergone RFA for this disease. Active 
and ongoing programs insure entry of new eligible participants who will undergo RFA for Barrett’s 
(range 50 to 120/site/year). RFA cohorts (completed and currently under active treatment; new RFA 
pts/year) at each site include MDACC (250;120), UNC (386;70), St Michael’s Hospital (370;80), Mayo 
Rochester (320;110), Northwestern U (310;100), UCLA (250;48), U Colorado (150;70), U Pennsylvania 
(130;50), U Kansas VA (70;30), BCM (115;35).    
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary endpoint of the study will be differences in the change of CDX2 mRNA levels from 
baseline to 12 months post-randomization in esophageal squamous tissue between participants 
taking aspirin supplementation versus those taking placebo. 
 
Proposed Sample Size: The primary endpoint is the change of CDX2 mRNA expression from baseline to 
12-months post-treatment. The sample size is determined based on the precision of measuring the CDX2 
mRNA expression at baseline as well as the change from baseline to 12-months post-treatment.   
Repeated Measures:  The effect size of aspirin on CDX2 mRNA expression in tissues is not known.  
However, we have prior data on phosphorylation of p65 in esophageal tissue after esophageal perfusion 
with bile acids which revealed an effect size (d values) that was > 1.0.  It is assumed that CDX2 will 
correlate with p65 as it is a downstream target gene.  Without treatment, it is expected that CDX2 mRNA 
levels will increase after radiofrequency ablation and that the increase in CDX2 mRNA is associated with 
the development of metaplasia. As shown in the table below, after normalization, the expected CDX2 
mRNA level at baseline is 100 in both groups.  In the placebo group, we assume that CDX2 mRNA levels 
will increase to 120 at 12 months.  On the other hand, with conservative estimates, we expect that the 
level for the aspirin treated group will remain at 100 at 12 months. Hence the difference of CDX2 mRNA 
change from baseline to 12 months is assumed to be 20 between the two groups.  Assuming a standard 
deviation of 20 for the change in CDX2 mRNA, the corresponding effect size is 1.0.  An effect size of 1.0 

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on the biomarker modulation is a conservative estimation for similar agents in chemopreventive settings.  
For example, sulindac was assumed to have an effect size of 1.06 in detecting the PGEM level in a Phase 
I trial. (32)  Naproxen was assumed to have an effect size of 1.25 in modulation of the tissue PGE2 level 
in a Phase Ib biomarker trial. (33) 
With a two-sided 5% type I error, we will have 83% power for detecting the difference of CDX2 change 
between the two groups with 18 participants per group using the two-sample t-test.  
 
In addition, the CDX2 mRNA level will be quantified in the baseline and the follow-up samples for both 
randomized and non-randomized patients. Specifically, the CDX2 mRNA level in patients with continued 
presence or recurrence of Barret’s mucosa will be analyzed to explore the value of CDX2 as a marker for 
residual disease. The analysis can be done within the same patient if CDX2 mRNA measures are 
available in both Barret’s mucosa and normal tissue.  Otherwise, the analysis will be done between 
patients.  The distribution of CDX2 mRNA level across different tissue types, different treatment groups, 
and different follow-up time will be exploratory in nature to help us in better quantify the expression level 
for understanding its value in designing future studies.  With a sample size of 18 and 36 (two treatment 
groups combined), the standard error of the mean can be reduced by 4.2 and 6.0 folds of its standard 
deviation, respectively. We plan to enroll a minimum of 20 participants per group to account for a 
potential 10% attrition rate. 
 
 
Baseline 
12-month 
Aspirin Group 
100 
100 
Placebo group 
100 
120 
 
 
Statistical Analyses: We will perform both parametric (t-test) and non-parametric (Wilcoxon) tests for 
detecting the effects of aspirin supplementation on the primary and the secondary endpoints of the study. 
Benjanimi-Hochberg FDR correction will be applied to account for multiple testing for the bioinformatics 
analyses when appropriate.  
 
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
Secondary Endpoints 
 
Safety will be assessed by comparison of adverse events using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 (Refer to Section 8.2.1).  Safety will be assessed by 
monitoring routine clinical parameters at baseline and at each visit throughout the trial (including every 3 
months by phone calls and/or mail interviews and in person at 12 and 18 months), and by monitoring 
laboratory parameters at baseline and at 12 months.  All AEs will be recorded and graded during clinical 
visits, whether or not they are considered drug-related.  All participants will be monitored for toxicity 
from the time of randomization.  Each treatment arm will be monitored separately for severe toxicities 
(grade 3 and 4 and SAEs).  We will be especially vigilant about the incidence of gastrointestinal (gastric 
and duodenal ulcers, gastritis, gastrointestinal bleeding or perforation, hematemesis) and hematological 
(anemia, thrombocytopenia) events.  Toxicity will be considered drug-related based on clinical 
assessment. In addition, at the completion of the study, the frequency of toxicities will be compared 
between the placebo and aspirin groups. 
 
The SF-36 is a multi-purpose, short-form health survey with 36 questions.  It yields an 8-scale 
profile of functional health and well-being scores as well as psychometrically-based physical and 
mental health summary measures and a preference-based health utility index. It is a generic 

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measure, as opposed to one that targets a specific age, disease, or treatment group. Since a secondary 
endpoint of our study is to determine safety in a specific clinical setting (use of aspirin following 
radiofrequecy ablation, we will compare measures of health and well-being between those receiving 
aspirin and those receiving placebo.  Bivariate analyses will be performed on study entry and completion 
of the on-drug period. Multivariate analyses will be performed between groups after controlling for 
potential confounders. 
 
Differences in the change of CDX2 mRNA levels from baseline to 18 months post-randomization in 
esophageal squamous tissue between participants taking aspirin supplementation versus those taking 
placebo.  
 
Differences in the activation status of NF-kB by assessing levels of total and phospho-p65 and 
cytoplasmic to nuclear translocation of phospho-p65 which is likely to be affected by aspirin 
(comparison between baseline, 12 and 18 months).   
 
Differences in the prostanoid marker, prostaglandin E2, and prostaglandin synthases (comparison 
between baseline, 12 and 18 months) 
 
Differences in the expression of proinflammatory cytokines known to induce activation of NFkB, 
i.e., TNFα, IL-1β, IL-6, IL-10, IL-17A, IL-23 will be measured (comparison between baseline, 12 and 
18 months).  
 
Recurrent Barrett’s Esophagus (at 12 and 18 months) will be ascertained completely and accurately.  
While we will not have sufficient power to assess differences in histological recurrence of BE during the 
short course of the study, we will examine this as an exploratory secondary endpoint. 
 
Statistical Analyses: In addition to the standard statistical hypotheses testing for the effect of aspirin on 
each individual biomarker in the proposed panel, we will use select tools from the fields of Machine 
Learning and Pattern Recognition to build multivariate classification models, e.g. Linear Discriminant 
Analyses (LDA) and k-Nearest Neighbours (kNN), based on combinations of the proposed biomarkers. 
This is an exploratory analysis to search for the joint effect of multiple biomarkers in predicting the 
outcome of potential clinical interest. The application of classification is facilitated by the presence of 
different cases with different levels of CDX2 modulation where we will be interested in the strength of 
separation between the participants who belong to one or the other class of interest.  Given that the 
biomarkers will be measured at baseline, 12 months and 18 months, we will evaluate the difference of the 
change on these biomarkers at 12 months and 18 months between two treatment arms by employing 
repeated measures analysis, including generalized mixed effect model and generalized estimating 
equations. The purpose of the exploratory analysis is for hypothesis generating and the findings will need 
to be validated in future studies. 
 
13.6 
Reporting and Exclusions 
 
Adherence to treatment will be assessed in two ways: 1) Participant-reported compliance: every 3 months, 
during the telephone and/or mail interview with the study coordinator, the participant will be asked to 
report how many pills they took per week on average since their last phone interview.  A report of 7 pills 
would represent 100 % compliance, 6 pills would represent 86 % compliance, etc...   2) Computed 
compliance based on participant-reported pill bottle start dates: participants will be asked to record and 
report to their study coordinator the date that they start each new bottle of study pills.  Given the start date 
of each pill bottle and the total number of pills in each bottle (which the participant will be instructed to 
finish prior to starting the next bottle) we will calculate a compliance rate for each bottle.  To maintain 

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blinding, these data will only be used to measure compliance at the level of treatment groups.  The Project 
Coordination Center will regularly summarize the pill-taking status of each center's participants, and list 
for each coordinator the relevant study ID numbers of those who have reported changed or inadequate 
adherence. 
 
Compliance will be defined as ingestion of ≥ 80% of the planned agent doses for the purposes of data 
analyses. 
 
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of aspirin or placebo  . 
 
13.8 
Evaluation of Response 
 
All participants included in the study will be assessed for response to intervention, even if there are major 
protocol deviations or if they are ineligible.  
 
All of the participants who met the eligibility criteria (with the possible exception of those who did not   
receive study agent) will be included in the main analysis. All conclusions regarding efficacy will be 
based on all eligible participants. 
 
Subanalyses may be performed on the subsets of participants, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
intervention, major protocol violations, etc.). However, subanalyses may not serve as the basis for 
drawing conclusions concerning efficacy, and the reasons for excluding participants from the analysis 
should be clearly reported. For all measurements of response, the 95% confidence intervals should also be 
provided. 
 
13.9 
Interim Analysis 
 
There is no formal interim analysis planned for this study. 
 
13.10 Ancillary Studies 
 
There are no plans for ancillary studies.  
 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) 
will provide a signed Form FDA 1572 stating that the study will be conducted in compliance with 
regulations for clinical investigations and listing the investigators, at each site that will participate in the 
protocol. All personnel directly involved in the performance of procedures required by the protocol and 
the collection of data should be listed on Form FDA 1572. 
 
 
 

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14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all 
Participating Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form 
FDA 1572 for the Lead Organization and all Participating Organizations 
 
Form FDA 1572 and all of the documents listed in Section 14.2 will be collected by the Consortium Lead 
Organization on behalf of the Protocol Principal Investigator, Robert S. Bresalier, M.D. 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the appropriate IRB. 
Should changes to the study become necessary, protocol amendments will be submitted to the DCP PIO 
according to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by 
the IRB prior to implementation 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. 
The investigator will explain all aspects of the study in lay language and answer all questions regarding 
the study. If the participant decides to participate in the study, he/she will be asked to sign and date the 
Informed Consent document. The study agent(s) will not be released to a participant who has not signed 
the Informed Consent document. Individuals who refuse to participate or who withdraw from the study 
will be treated without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document 

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or may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for 
Research is available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, 
the Consortium Lead Organization, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, and then submitted to each organization’s IRB for approval prior 
to initiation. 
 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for 
completeness and accuracy. Once the Consortia Lead Organization has received complete and accurate 
documents from a participating organization, the Consortium Lead Organization will forward the 
regulatory documents to DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
1923 Landings Drive 
 
Mountain View, CA 94043 
 
Phone: 650-691-4400 
 
Fax: 650-691-4410 
 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the 
Consortium Lead Organization for review, which will then be electronically forwarded to DCP’s 
Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
Participants will not be responsible for the costs of this study. Study agent will be provided at no cost to 
the participant.  If, as a result of participation in this study, an individual experiences injury from known 
or unknown risks of the research procedures as described in the informed consent, immediate medical 
care and treatment, including hospitalization, if necessary, will be available.  No monetary compensation 
is available for the costs of medical treatment for an injury, thus, the participant will be responsible for the 
costs of such medical treatment, either directly or through their medical insurance and/or other forms of 
medical coverage.   
 
 

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REFERENCES 
 
1. Bresalier RS.  Barrett’s esophagus.  Annual Review of Medicine 2009; 60:221-231. 
2. Song S, Krishnan K, Liu K, Bresaler, RS.  Polyphenon E and growth of human Barrett’s and 
aerodigestive adenocarcinoma cells bt supressiong cyclin D1 expression.   Clin Cancer Res 
2009;15:622-631. 
3. Song S, Byrd JC, Guha S, Liu K, Koul D, Bresalier RS.  Induction of MUC5AC by conjugated bile 
acids in the esophagus involves the phosphatidylinositil 2-kinase/protein kinase C/activator protein-1 
pathway.  Cancer 2011;117:2386-2397. 
4. Galipeau PC, Li X, Blount PL, et. al.  NSAIDs modulate CDKN2A, TP53, and DNA content risk for 
progression to esophageal adenocercinoma. PLoS Med 2007;4:42-54. 
5. Stairs DB, Kong J and Lynch JP.  Cdx genes, inflammation, and the pathogenesis of intestinal 
metaplasia.  Progress in Molecular Biology 2010;96:231-70. 
6. Fitzgerald RE, Abdalla S, Onuegbusi BA, Siriex P, Saeed IT, Burnham WR, Farthing MJG.  
Inflammatory gradient in Barrett's oesophagus:implications for disease complications.  Gut 
2002;51:316-22. 
7. Song S, Guha S, Liu K, Buttar NS, Bresdalier RS.   Cox-2 induction by unconjugated bile acids 
involves reactive oxygen species-mediated signaling pathways in Barrett's oesophagus and 
oesophageal carcinoma.  Gut 2007;56:1512-21. 
8. Huo X, Zhang HY, Lynch JP, Strauch ED, Wang J-Y, Melton SD, Genta RM, Wang DH, Spechler 
SJ, Souza RF.  Acid and bile salt-induced CDX2 expression differs in esophageal squamous cells 
from patients with and without Barrett's esophagus.  Gastroenterology 2010;139:194-203. 
9. Shaheen N. Overholt B, Sampliner R, et. al.  Durability of radiofrequencyablation in Barett’s 
esophagus with dysplasia.  Gastroenterology 2011;141:460-468. 
10. American Gastroenterological Association. American Gastroenterological Association technical 
review on the management of Barretts Esophagus.  Gastroenterology 2011;140:e18-e52. 
11. Orman ES, Li N, Shaheen N.  Efficacy and durability of radiofrequency ablation for Barrett's 
esophagus:sysematic review and meta-analysis.  Clinical Gastroenterology and Hepatology 
2013;epub ahead of print May 2. 
12. Orman ES, Kim HP, Bulsiewicz WJ, Cotton CC, Dellon ES, Spacek M, Chen X, Madanick RD, 
Pasricha S, Shaheen NJ.  Intestinal metaplasia recurs infrequently in pateints successfully treated for 
Barrettt's esophagus with radiofrequency ablation.  Am J Gastroenterology 2013;108:187-95. 
13. Omer ZB, Ananthakrisnan AN, Nattinger KJ, Cole EB, Lin JJ, Kong CY and Hur C.  Aspirin protects 
against Barrett's esophagus in a multivariate logistic regression analysis.  Clin Gastroenterol and 
Hepatol 2012;10:722-727.  
14. Falk G, Buttar NS, Foster NR, et. al.  A combination of esomeprazole and aspirin reduces tissue 
concentrations of prostaglandin E2 in patients with Barrett’s esophagus.  Gastroenterology 
2012;143:917-926. 
15. Rothwell PM, Wilson M, Elwin CE, et. al.  Long-term effect of aspirin on colorectal cancer incidence 
and mortality:20 year follow up of randomized trials.  The Lancet 2010;376:1741-17501.  
Oberg 
S, Johansson J, Wenner J, Walther B. Metaplastic columnar mucosa in the cervical esophagus after 
esophagectomy. Ann Surg 2002;235:338-345. 
16. Tosh D, Slack JM. How cells change their phenotype. Nat Rev Mol Cell Biol 2002;3:187-194. 
17. Vallbohmer D, DeMeester SR, Peters JH, Oh DS, Kuramochi H, Shimizu D, Hagen JA, Danenberg 
KD, Danenberg PV, DeMeester TR, Chandrasoma PT. Cdx-2 expression in squamous and 
metaplastic columnar epithelia of the esophagus. Dis Esophagus 2006;19:260-266. 
18. Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, Sugano K. Cdx1 induced 
intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. 
Gut 2004;53:1416-1423. 

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19. Tatsuta T, Mukaisho K, Sugihara H, Miwa K, Tani T, Hattori T. Expression of Cdx2 in early GRCL 
of Barrett's esophagus induced in rats by duodenal reflux. Dig Dis Sci 2005;50:425-431. 
20. Berenson MM, Johnson TD, Markowitz NR, Buchi KN, Samowitz WS. Restoration of squamous 
mucosa after ablation of Barrett's esophageal epithelium. Gastroenterology 1993;104:1686-1691. 
21. Brandt LJ, Blansky RL, Kauvar DR. Repeat laser therapy of recurrent Barrett's epithelium: success 
with anacidity. Gastrointest Endosc 1995;41:267. 
22. Spechler S.J., Sharma P, Souza R.F., Inadomi JM, Shaheen NJ. AGA Institute Technical Review on 
the Management of Barrett's Esophagus. Gastroenterology 2010. 
23. De Jonge PJ, Siersema PD, Van Breda SG, Van Zoest KP, Bac DJ, Leeuwenburgh I, Ouwendijk RJ, 
van Dekken H, Kusters JG, Kuipers EJ. Proton pump inhibitor therapy in gastro-oesophageal reflux 
disease decreases the oesophageal immune response but does not reduce the formation of DNA 
adducts. Aliment Pharmacol Ther 2008;28:127-136. 
24. Looby, E.  AQbdel-Latif MM, Athie-Morales V, Duggan S, Kelleher D.  Deoxycholate induces 
COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer 
cells. BMC Cancer 9:190, 2009  PMID:19534809 
25. Fan YY, Monk J , Hou T, E. Callaway, L. Vincent, B. Weeks, P. Yang and R.S. Chapkin.  
Characterization of an arachidonic acid-deficient (FADS1 knock-out) mouse model.  Journal of Lipid 
Research 53:1287-1295, 2012.  PMID: 225346. 
26. Finley, P.R., Bogert, C.L., Alberts, D.S., Einspahr, D.L. Earnest, G. Blackwell and K. Girodias.  
Measurement of prostaglandin E2 in rectal mucosal in human subjects: a methods study.  Cancer 
Epidemiol. Biomarkers Prev. 4:219-244, 1995.  PMID:7606198 
27. J.M. Monk, T.Y. Hou, H.F. Turk, B. Weeks, C. Wu, D.N. McMurray and R.S. Chapkin..  Dietary n-3 
polyunsaturated fatty acids (PUFA) decrease obesity-associated Th17 cell-mediated inflammation 
during colitis.  PLoS One 7(11)e49739, November, 2012.  PMCID:PMC3500317 
28. Dougherty, E. R., Kim, S. and Chen, Y. Coefficient of determination in nonlinear signal processing.  
Signal Processing 80:2219-2235, 2000. 
29. Sima, C. and Dougherty, E.R.  What should be expected from feature selection in small-sample 
settings.  Bioinformatics 22: 2430-2436, 2006. 
30. Dalton, L. and Dougherty, E.R.  Application of the Bayesian MMSE estimator for classification error 
to gene expression microarray data.  Bioinformatics 27:1822-1831, 2011. 
31. Chapkin, R.S., Zhao, C., Ivanov, I., Davidson, L.A., Goldsby, J.S., Lupton, J.R., Mathai, R.A., Siegel, 
M., Rai, D., Russell, M., Donovan, S.M. and Dougherty, E.R.  Non-invasive stool-based detection of 
infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells.  
Am. J. Physiol. Gastrointest Liver Physiol 298:G582-G589, 2010. 
32. Hong, M.Y., Bancroft, L.K., Turner, N.D., Davidson, L.A., Murphy, M., Carroll, R.J., Chapkin, R.S. 
and Lupton, J.R.  Fish oil decreases oxidative DNA damage by enhancing apoptosis in rat colon.  
Nutrition & Cancer 52:166-175, 2005. 
33. Thompson, P.A., Hsu, C.-H., Green, S., Stopeck, A.T., Johnson, K., Alberts, D.S., Chow, H.-H.S. 
Sulindac and sulindac metabolites in nipple aspirate fluid and effect on drug targets in a phase I Trial 
Cancer Prevention Research, 3 (1):101-107, 2010. 
34. Vilar E,You N, Lana A Vornik L1, Stoffel E, Lim RM,  Lipkin SM, Perloff M, Brown PH. A Phase Ib 
Biomarker Trial of Naproxen in Patients at Risk for DNA Mismatch Repair Deficient Colorectal 
Cancer” NCI sponsored Investigators' - Site Coordinators' Opportunity for Research Excellence (I-
SCORE) 
Workshop 
(abstract). 
 
http://prevention.cancer.gov/news-events/events/20140320-
21/posters/naproxen. 
Also: 
ClinicalTrials.gov 
Identifier:NCT02052908. 
https://www.clinicaltrials.gov/ct2/show/NCT02052908?term=A+Phase+Ib+Biomarker+Trial+of+Naproxe
n+in+Patients+at+Risk+for+DNA+Mismatch+Repair+Deficient+Colorectal+Cancer&rank=1.  
 

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APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically 
strenuous 
activity, 
but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely 
disabled, 
hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 

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Appendix B: Pill diary/calendar 
 
Patient Name: _________________________PID: ___________Visit #: ________ 
 
Number of Pills Given:____________ 
 
 
Pill Bottle(s) returned:  Circle Yes or No 
Total Daily Dose:________________ 
 
 
Number of Pills returned:_____________ 
(To be completed by RN/PI Designee)  
 
This calendar will be provided to you every three months in order to record the drug daily intake. Please do 
not forget to take 1 tablet a day, every day, in the morning with a meal.  
 
There are 100 pills in each bottle.  Please take at least 3 months of pills from each bottle prior to starting the 
next bottle. 
Please do not take an extra dose to ‘make up’ for the missed/vomited dose. Take your next dose as scheduled.   
Cross out the corresponding day of the calendar if you have taken your tablet (1 cross per day to indicate tablet 
taken). 
Do not cross out the day if you have forgotten to take your medication.  
Should you experience any symptom during the study, please write it down in the space provided and should 
you need any medical assistance, please contact [the local PI or designee name/phone #] during working hours.  
Please do not discard any empty bottles and do not forget to mail back or bring with you all the drug bottles 
(empty or full) together with the present calendar to the next clinic visit. 
 
PLEASE BRING THIS SHEET TO YOUR NEXT VISIT OR SHIP IT BACK WITH YOUR RETURNED MEDICATIONS 
 
 
 
Month: _____________________________ 
 
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Notes: 
 
 
 
 
 
 
 
 
 
Notes: 
 
 
 
 
 
 
 
 
 

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Patient Signature: _______________________________________   
Date: __________ 
Consenting Professional/Research RN /PI designee Signature: _________________ Date: __________ 
Consenting Professional/Research RN/PI designee Comments: _________________________________ 
____________________________________________________________________________________________ 
____________________________________________________________________________________________ 
____________________________________________________________________________________________ 
 
 
 
 
 
 
Notes: 
 
 
 
 
 
 
 
 
 
 
Notes: