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

RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming. The use of esomeprazole with or without aspirin may prevent esophageal cancer in patients with Barrett esophagus.

PURPOSE: This randomized phase II trial is studying esomeprazole and aspirin to see how well they work compared with esomeprazole and placebo in preventing esophageal cancer in patients with Barrett esophagus.

Study Type: Interventional

Study Design: Prevention, Randomized, Double-Blind, Placebo Control

Study Primary Completion Date: April 2009

OBJECTIVES:

Primary - Compare the effects of esomeprazole magnesium with vs without acetylsalicylic acid on the absolute change in tissue PGE_2 concentration in mucosal biopsy samples from patients with Barrett esophagus.

Secondary - Determine if the change in the tissue PGE_2 concentration decreases significantly in patients treated with esomeprazole magnesium. - Compare the change in mean tissue PGE_2 concentration in patients treated with these regimens. - Determine the effects of these regimens on proliferation (Ki-67), apoptosis (caspase-3 expression), cyclooxygenase-2 expression, and p16 methylation in these patients. - Determine the effects of these regimens on serum salicylate levels in these patients. - Determine adverse events in patients treated with these regimens. - Provide descriptive summaries of the esophagogastroduodenoscopy results, the rate of dysplasia, and adverse events. - Provide exploratory summaries of PGE_2 concentration values by patient subgroups of interest.

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 daily. - 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.

PROJECTED ACCRUAL: A total of 168 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: acetylsalicylic acid
  • Given orally
• Drug: esomeprazole magnesium
  • Given orally
• Drug: placebo
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Arm I
  • Patients receive two oral placebos once daily and oral esomeprazole magnesium twice daily.
• Experimental: Arm II
  • Patients receive oral acetylsalicylic acid (aspirin) and oral placebo once daily and oral esomeprazole magnesium twice daily.
• Experimental: 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.

Primary Measures

• Change in mean tissue PGE2 concentration from the pre-intervention to the post-intervention evaluation
  • Safety Issue?: No

Secondary Measures

• Change in PGE2 concentration from the pre-intervention to the post-intervention evaluation (arm I)
  • Safety Issue?: No
• Comparison of the change in PGE2 concentration (arms II and III)
  • Safety Issue?: No
• Effects of treatment on proliferation (Ki-67), apoptosis (caspase-3 expression), cyclooxygenase-2 expression, p16 methylation, and salicylate levels
  • Safety Issue?: No
• Adverse events
  • Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• 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 (EGD)
• 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

PATIENT CHARACTERISTICS:

• 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

PRIOR CONCURRENT THERAPY:

• 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 surgery
• 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 following:
• Warfarin
• Heparin
• Low-molecular weight heparin
• Clopidogrel bisulfate
• Extended-release dipyridamole

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Mayo Clinic

Overall Clinical Trial Officials and Contacts

Paul J. Limburg, MD, MPH Principal Investigator Mayo Clinic  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00474903

Study ID Number: CDR0000544180

ClinicalTrials.gov Identifier: NCT00474903

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database