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Randomized, Double-Blinded Phase II Trial of Esomeprazole Versus Esomeprazole + Two Doses of Aspirin in Barrett's Esophagus Patients

Phase 2
18 Years
Open (Enrolling)
Barrett Esophagus, Esophageal Cancer

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Trial Information

Randomized, Double-Blinded Phase II Trial of Esomeprazole Versus Esomeprazole + Two Doses of Aspirin in Barrett's Esophagus Patients


I. To assess the effects of a 28 day intervention with aspirin 81 mg placebo orally (PO)
once daily (QD) + aspirin 325 mg placebo PO QD + esomeprazole 40 mg PO BID versus aspirin 81
mg PO QD + aspirin 325 mg placebo PO QD + esomeprazole 40 mg PO BID versus aspirin 325 mg PO
QD + aspirin 81 mg placebo PO QD + esomeprazole 40 mg PO BID on the absolute change in
tissue prostaglandin E2 (PGE2) concentration, as determined from Barrett's esophagus mucosal
biopsy samples obtained pre- and post-intervention (i.e. two pair-wise comparisons of two
different doses of active aspirin regimens versus aspirin placebo group), Specifically, the
two active aspirin + esomeprazole arms will be independently analyzed to see if they
significantly reduce the mean tissue PGE2 concentration from Pre- to Post-intervention as
compared to the aspirin placebo + esomeprazole arm.


I. To determine if the change in the tissue PGE2 concentration decreases significantly in
the aspirin placebo + esomeprazole arm.

II. To compare the change in mean tissue PGE2 concentration between the two active
intervention arms to determine which one appears the most promising for further testing.

III. To assess the effects of the three agents (arms) with respect to proliferation (Ki-67),
apoptosis (caspase-3 expression), COX-2 expression, and p16 methylation using Pre- and
Post-Intervention biopsy samples obtained from Barrett's mucosal tissue.

IV. To evaluate all adverse events associated with each of the three intervention arms.

V. To provide exploratory summaries of PGE2 concentration values by patient subgroups of

VI. To provide descriptive summaries of the esophagogastroduodenoscopy (EGD) results, the
rate of dysplasia, adverse events, and the Run-In Agent compliance on all participants that
signed a consent form and started the Run-In phase of the trial.

VII. To establish a biospecimen repository archive for future correlative studies.

OUTLINE: This is a multicenter, randomized, double-blind, placebo-controlled study. Patients
are stratified according to gender and length of Barrett segment of circumferential
involvement (5 cm vs = 5 cm). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive two oral placebos once daily and oral esomeprazole magnesium twice

ARM II: Patients receive oral acetylsalicylic acid (aspirin) and oral placebo once daily and
oral esomeprazole magnesium twice daily.

ARM III: Patients receive a higher-dose of oral aspirin (higher than in arm II) and a
lower-dose of oral placebo (lower than in arm II) once daily and oral esomeprazole magnesium
twice daily.

In all arms, treatment continues for 28 days in the absence of unacceptable toxicity. Tissue
samples are collected before and after treatment and examined for tissue-based biomarkers
(i.e., PGE_2, Ki-67, caspase-3 apoptosis, and cyclooxygenase-2) by immunohistochemistry,
enzyme immunoassay, Western blot, and polymerase chain reaction.

After completion of study therapy, patients are followed at 30 days.

Inclusion Criteria:

- Histologically confirmed Barrett esophagus, meeting all of the following criteria:

- Presence of specialized columnar epithelium anywhere in the tubular esophagus
with ≥ 2 cm of circumferential involvement

- No evidence of high-grade dysplasia or cancer by esophagogastroduodenoscopy

- No prior histologically confirmed esophageal dysplasia, including cancer

- Adequate Barrett mucosa, defined as ≥ 4 of 8 research samples with≥ 50% intestinal
metaplasia in research biopsies

- No ulcer, erosion, plaque, nodule, stricture, or other luminal irregularity within
the Barrett's segment or erosive esophagitis (Los Angeles classification > grade A)
detected at pre-intervention EGD exam

- ECOG performance status 0-2

- Hemoglobin normal

- Platelet count ≥ 100,000/mm³

- AST ≤ 2.5 times upper limit of normal (ULN)

- Alkaline phosphatase ≤ 2.5 times ULN

- Bilirubin ≤ 2.5 times ULN

- Creatinine ≤ 2.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No nasal polyps associated with asthma or induced or exacerbated by aspirin

- No malignancy within the past 5 years except for nonmelanoma skin cancer

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to the study agents or rescue medication

- No history of endoscopically or radiographically diagnosed peptic ulcer disease
(bleeding or nonbleeding)

- No other uncontrolled illness including, but not limited to, any of the following:

- 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 drinks per day)

- Psychiatric illness or social situations that would limit study compliance

- At least 3 months since prior chronic use (defined as ≥ 7 days during the 3 months
preceding the beginning of the Run-in phase) of acetylsalicylic acid (aspirin),
NSAIDs, or selective cyclooxygenase (COX-2) inhibitors

- At least 3 months since prior investigational agents except innocuous agents with no
known interaction with the study agents (e.g., standard dose multivitamins or topical
agents for limited skin conditions)

- No prior fundoplication, bariatric surgery, or any other major upper gastrointestinal

- Prior cholecystectomy allowed

- No other concurrent NSAIDs (including aspirin) or selective COX-2 inhibitor therapy

- No concurrent anticoagulant drugs including, but not limited to, any of the

- Warfarin

- Heparin

- Low-molecular weight heparin

- Clopidogrel bisulfate

- Extended-release dipyridamole

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Change in mean tissue PGE2 concentration as determined from Barrett's research mucosal biopsy samples

Outcome Description:

Compared between arms.

Outcome Time Frame:

Baseline to 30 days after completion of study treatment

Safety Issue:


Principal Investigator

Paul Limburg

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

April 2007

Completion Date:

Related Keywords:

  • Barrett Esophagus
  • Esophageal Cancer
  • Barrett Esophagus
  • Esophageal Diseases
  • Esophageal Neoplasms



Mayo Clinic Rochester, Minnesota  55905