Esomeprazole Magnesium With or Without Aspirin in Preventing Esophageal Cancer in Patients With Barrett Esophagus

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00474903
First received: May 16, 2007
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

This randomized phase II trial is studying esomeprazole magnesium and aspirin to see how well they work compared with esomeprazole and placebo in preventing esophageal cancer in patients with Barrett esophagus. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of esomeprazole magnesium with or without aspirin may prevent esophageal cancer in patients with Barrett esophagus.


Condition Intervention Phase
Barrett Esophagus
Esophageal Cancer
Drug: acetylsalicylic acid
Drug: esomeprazole magnesium
Other: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Randomized, Double-Blinded Phase II Trial of Esomeprazole Versus Esomeprazole + Two Doses of Aspirin in Barrett's Esophagus Patients

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Change in mean tissue PGE2 concentration as determined from Barrett's research mucosal biopsy samples [ Time Frame: Baseline to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Compared between arms.


Secondary Outcome Measures:
  • Change in mean PGE2 concentration in the aspirin, placebo, and esomeprazole magnesium arm [ Time Frame: From baseline up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Determined using a two-sided one-sample t-test.

  • Comparison of the change in mean and individual tissue PGE2 concentration between the two active intervention arms [ Time Frame: From baseline up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
  • Effects of treatment on proliferation (Ki-67), apoptosis (caspase-3 expression), cyclooxygenase-2 expression, and p16 methylation [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Assessed using Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests. Differences within each arm are assessed using McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests.

  • Toxicities, defined as adverse events that are classified as either possibly, probably, or definitely related to the interventional agent, graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    The number and severity of adverse events (overall and by intervention group) will be tabulated and summarized.


Estimated Enrollment: 168
Study Start Date: April 2007
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (placebo, esomeprazole magnesium)
Patients receive two oral placebos once daily and oral esomeprazole magnesium twice daily.
Drug: esomeprazole magnesium
Given orally
Other: placebo
Given orally
Experimental: Arm II (aspirin, esomeprazole magnesium, placebo)
Patients receive oral acetylsalicylic acid (aspirin) and oral placebo once daily and oral esomeprazole magnesium twice daily.
Drug: acetylsalicylic acid
Given orally
Drug: esomeprazole magnesium
Given orally
Other: placebo
Given orally
Experimental: Arm III (aspirin, esomeprazole magnesium, placebo)
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.
Drug: acetylsalicylic acid
Given orally
Drug: esomeprazole magnesium
Given orally
Other: placebo
Given orally

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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 interest.

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 (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
  • 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 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00474903

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Investigators
Principal Investigator: Paul Limburg Mayo Clinic
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00474903     History of Changes
Other Study ID Numbers: NCI-2009-00838, NCI-2009-00838, MAY04-4-01, CDR0000544180, MAYO-MAY04-4-01, MAY04-4-01, N01CN35000
Study First Received: May 16, 2007
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Additional relevant MeSH terms:
Barrett Esophagus
Esophageal Neoplasms
Digestive System Abnormalities
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Aspirin
Omeprazole
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Hematologic Agents
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors

ClinicalTrials.gov processed this record on April 15, 2014