Aspirin in Preventing Disease Recurrence in Patients With Barrett Esophagus After Successful Elimination by Radiofrequency Ablation

Study Overview
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Brief Summary
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This randomized phase II trial studies the safety of and how well aspirin works in preventing Barrett's esophagus from returning after it has been successfully eliminated by radiofrequency ablation. Studying samples of tissue from patients with Barrett's esophagus for the levels of a specific protein that is linked to developing Barrett's esophagus may help doctors learn whether aspirin can prevent it from returning after it has been successfully treated.

Detailed Description
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PRIMARY OBJECTIVES: I. 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 messenger ribonucleic acid (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). SECONDARY OBJECTIVES: I. To assess safety at 12 months. II. To assess differences in the expression of CDX2 at 18 months, activation status of NF-kB by assessing levels of total and phosphorylated (phospho)-p65 and cytoplasmic to nuclear translocation of phospho-p65 which is likely to be affected by aspirin. III. To assess 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. IV. To assess differences in the expression of proinflammatory cytokines known to induce activation of NFkB, i.e., TNFalpha, IL-1beta, IL-6, IL-10, IL-17A, IL-23 will be measured. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive aspirin orally (PO) once daily (QD) for 12 months. ARM B: Patients receive placebo PO QD for 12 months. After completion of study treatment, patients are followed up at 1, 3, 6, 9, 12, and 18 months.

Official Title
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Effect of Aspirin on Biomarkers of Barrett's Esophagus After Successful Eradication of Barrett's Esophagus With Radiofrequency Ablation

Conditions
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Barrett Esophagus

Intervention / Treatment
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* Drug: Aspirin
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 involvement 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 biopsies) as determined by the pathologist at each site; completion of ablation should have occurred no greater than 36 months prior to randomization 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 Willingness to provide tissue samples for research purposes No chronic use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) or selective cyclooxygenase-2 (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 Hemoglobin >= 10 g/dL or hematocrit >= 30% (obtained =< 45 days prior to randomization) Leukocyte count >= 3,000/microliter (obtained =< 45 days prior to randomization) Platelet count >= 100,000/microliter (obtained =< 45 days prior to randomization) Absolute neutrophil count >= 1,500/microliter (obtained =< 45 days prior to randomization) Creatinine =< 2.5 x institutional upper limit of normal (ULN) (obtained =< 45 days prior to randomization) OR glomerular filtration rate (GFR) > 30 ml/min/1.73 m^2 (obtained =< 45 days prior to randomization) Total bilirubin =< 2 x institutional ULN (obtained =< 45 days prior to randomization) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional ULN (obtained =< 45 days prior to randomization) Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 45 days prior to randomization) A negative serum pregnancy test at baseline, but within 21 days of randomization, for persons of childbearing potential only Eastern Cooperative Oncology Group (ECOG) performance status =< 2 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 Exclusion Criteria: 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 Current or planned use of anticoagulant drugs such as: warfarin, heparin, low molecular weight heparin, Plavix, or Aggrenox throughout the course of the study 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 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 pro re nata [prn (when necessary)] 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 Individuals with uncontrolled renal insufficiency or renal failure Participants with fundoplication within the past year, bariatric surgery or any other major upper gastrointestinal (GI) surgery; fundoplication more than one year ago will not be grounds for exclusion; cholecystectomy will not be grounds for exclusion History of invasive cancer diagnosis =< 12 months prior to randomization, excepting nonmelanoma skin cancer; patients with T1a adenocarcinoma of the esophagus arising in the setting of Barrett's esophagus are eligible for enrollment in the trial 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) 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 History of allergic reactions attributed to aspirin or compounds of similar chemical or biologic composition to the study agent 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 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 compliance with study requirements Pregnant women Breast feeding women Surveillance biopsies demonstrating residual BE at qualifying exam 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 Patients with human immunodeficiency virus (HIV) infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (aspirin)<br>Patients receive aspirin PO QD for 12 months. | Drug: Aspirin<br>* Given PO<br>* Other names: Measurin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Arm B (placebo)<br>Patients receive placebo PO QD for 12 months. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the Change of CDX2 mRNA Levels in Esophageal Mucosa Between Participants Taking Aspirin and Placebo at 12 Months (Location A) | Measured the absolute and relative values in percentage of biomarker levels CDX2 mRNA levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location A (1 cm above GE Junction.) The difference in the change were measured by the total RNAs were isolated from squamous and neosquamous mucosal biopsy specimens using Trizol and quantitated by spectrophotometry. | Baseline and 12 months | 
| Differences in the Change of CDX2 Messenger Ribonucleic Acid (mRNA) Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo (Location B) | Measured the absolute and relative values change in the biomarker levels CDX2 mRNA levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the total RNAs were isolated from squamous and neosquamous mucosal biopsy specimens using Trizol and quantitated by spectrophotometry. | Baseline and 12 months | 
| Differences in the Change of CDX2 Messenger Ribonucleic Acid (mRNA) Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo ( Location C) | Measured the absolute and relative values change in the biomarker levels CDX2 mRNA levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the total RNAs were isolated from squamous and neosquamous mucosal biopsy specimens using Trizol and quantitated by spectrophotometry. | Baseline and 12 months | 
| Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 12 Months (Location A) | Measured the absolute and relative values change in the biomarker levels p-p65/total p65 in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location A, 1 cm above GE Junction. The difference in the change were measured by using esophageal squamous and neosquamous mucosal biopsies taken before and after treatment with aspirin, levels of phospho-p65 and total p65 were determined by Western blot and quantitated by densitometry. | Baseline and 12 months | 
| Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 12 Months (Location B) | Measured the absolute and relative values change in the biomarker levels p-p65/total p65 in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment)The difference in the change were measured by using esophageal squamous and neosquamous mucosal biopsies taken before and after treatment with aspirin, levels of phospho-p65 and total p65 were determined by Western blot and quantitated by densitometry. | Baseline and 12 months | 
| Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 12 Months (Location C) | Measured the absolute and relative values change in the biomarker levels p-p65/total p65 in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by using esophageal squamous and neosquamous mucosal biopsies taken before and after treatment with aspirin, levels of phospho-p65 and total p65 were determined by Western blot and quantitated by densitometry. | Baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) | Number of Participants experiencing adverse events by maximum grade (grades 1-3). Safety 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. All adverse events are listed in the Adverse Events Overview. | Up to 18 months | 
| Differences in the Change of CDX2 mRNA Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo at 18 Months (Location A) | Measured the change in the biomarker levels CDX2 mRNA levels in esophageal mucosa at baseline and 18 months for each participant taking aspirin versus placebo at Location A, 1 cm above GE Junction. The difference in the change were measured by the total RNAs will be isolated from squamous and neosquamous mucosal biopsy specimens using Trizol and quantitated by spectrophotometry. | Baseline to 18 months | 
| Differences in the Change of CDX2 mRNA Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo at 18 Months (Location B) | Measured change in the biomarker levels CDX2 mRNA levels in esophageal mucosa at baseline and 18 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the total RNAs will be isolated from squamous and neosquamous mucosal biopsy specimens using Trizol and quantitated by spectrophotometry. | Up to 18 months | 
| Differences in the Change of CDX2 mRNA Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo at 18 Months (Location C) | Measured the change in the biomarker levels CDX2 mRNA levels in esophageal mucosa at baseline and 18 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the total RNAs will be isolated from squamous and neosquamous mucosal biopsy specimens using Trizol and quantitated by spectrophotometry. | Baseline to 18 months | 
| Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 18 Months (Location A) | Measured the change in the biomarker levels p-p65/total p65 in the esophageal mucosa at baseline and 18 months for each participant taking aspirin versus placebo at Location A, 1 cm above GE Junction. The difference in the change were measured by using esophageal squamous and neosquamous mucosal biopsies taken before and after treatment with aspirin, levels of phospho-p65 and total p65 were determined by Western blot and quantitated by densitometry. | Baseline up to 18 months | 
| Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 18 Months (Location B) | Measured the change in the biomarker levels of p-p65/total p65 in the esophageal mucosa at baseline and 18 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by using esophageal squamous and neosquamous mucosal biopsies taken before and after treatment with aspirin, levels of phospho-p65 and total p65 were determined by Western blot and quantitated by densitometry. | Baseline up to 18 months | 
| Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 18 Months (Location C) | Measured the change in the biomarker levels p-p65/total p65 in esophageal mucosa at baseline and 18 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by using esophageal squamous and neosquamous mucosal biopsies taken before and after treatment with aspirin, levels of phospho-p65 and total p65 were determined by Western blot and quantitated by densitometry. | Baseline up to 18 months | 
| Differences in the Change of txb2 at 12 Months (Location A) | Measured the absolute and relative values change in the biomarker levels txb2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location A, 1 cm above GE Junction. The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of tbx2 at 12 Months (Location B) | Measured the absolute and relative values change in the biomarker levels txb2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of tbx2 at 12 Months (Location C) | Measured the absolute and relative values change in the biomarker levels txb2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of pge1 at 12 Months ( Location A) | Measured the absolute and relative values change in the biomarker levels pge1 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at A (1 cm above GE Junction). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of pge1 at 12 Months (Location B) | Measured the absolute and relative values change in the biomarker levels pge1 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of pge1 at 12 Months (Location C) | Measured the absolute and relative values change in the biomarker levels pge1 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of pge2 at 12 Months (Location A) | Measured the absolute and relative values change in the biomarker levels pge2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at A (1 cm above GE Junction). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of pge2 at 12 Months (Location B) | Measured the absolute and relative values change in the biomarker levels pge2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change in pge2 at 12 Months (Location C) | Measured the absolute and relative values change in the biomarker levels pge2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of a13pge1 at 12 Months (Location A) | Measured the absolute and relative values change in the biomarker levels a13pge1 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location A (1 cm above GE Junction). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of a13pge1 at 12 Months ( Location B) | Measured the absolute and relative values change in the biomarker levels a13pge1 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change in a13pge1 at 12 Months (Location C) | Measured the absolute and relative values change in the biomarker levels a13pge1 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of a13pge2 at 12 Months (Location A) | Measured the absolute and relative values change in the biomarker levels a13pge2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location A (1 cm above GE Junction). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of a13pge2 at 12month (Location B) | Measured the absolute and relative values change in the biomarker levels a13pge2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location B (middle of former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months | 
| Differences in the Change of a13pge2 at 12 Months (Location C) | Measured the absolute and relative values change in the biomarker levels a13pge2 levels in the esophageal mucosa at baseline and 12 months for each participant taking aspirin versus placebo at Location C (2 cm above former Barrett's segment). The difference in the change were measured by the Liquid chromatography-mass spectrometry (LC/MS/MS) analyses. | Baseline and 12 months |