A Phase III, Randomized, Study of Aspirin and Esomeprazole Chemoprevention in Barrett's Metaplasia

RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of esomeprazole and aspirin may prevent esophageal cancer in patients with Barrett's metaplasia. It is not yet known whether esomeprazole is more effective with or without aspirin in preventing esophageal cancer in patients with Barrett's metaplasia.

PURPOSE: This randomized phase III trial is studying esomeprazole with or without aspirin to compare how well they work in preventing esophageal cancer in patients with Barrett's metaplasia.

PRIMARY OBJECTIVES

* To assess whether intervention with aspirin results in a decreased rate of all causes of mortality or conversion rate from Barrett's metaplasia to adenocarcinoma or high grade dysplasia.
* To assess whether high dose PPI (protein pump inhibitor) therapy results in a decreased rate of all causes of mortality or conversion rate from Barrett's metaplasia to adenocarcinoma or high grade dysplasia.

SECONDARY OBJECTIVES

* To assess whether intervention with aspirin results in decreased high-grade dysplasia, in decreased all cause mortality, in decreased oesophageal cancer incidence and in decreased cause-specific mortality when each is considered separately
* To assess whether intervention with high dose PPI results in decreased high-grade dysplasia, in decreased all cause mortality, in decreased oesophageal cancer incidence and in decreased cause-specific mortality when each is considered separately
* To assess whether there are clinical and molecular risk factors which can be identified in BM (Barrett's Metaplasia) for the development of BA.
* To assess the cost effectiveness of aspirin and/or PPI treatment in the prevention of BA.
* To assess whether intervention with PPI and/or aspirin induces changes in the expression of molecular markers for BA.
* To investigate new genes important in the progression of BA, as a unique tissue bank will be available with a complete endoscopic, histological, physiology and pharmaceutical history.
* To assess inherited genetic factors for predisposition to oesophagitis above BM, BM, LGD HGD and BA.
* To assess what the biological risk factors are for cardiac disease and aspirin resistance.
* To assess gender differences in outcomes.

Cancer Research UK approved the study in 2003 for a 10 year period to run from 1st January 2005 to 31st December 2014. Funding is renewable annually and is dependent on a satisfactory review by an independent committee.

An application for a funding extension was made to CRUK 18 months before the end of the grant and the funding was extended to 31Aug2018.

A total of 2557 patients have been accrued for this study in the UK.

Eligibility Criteria:
INCLUSION CRITERIA

1. Aged ≥18 years.
2. Circumferential Barrett's metaplasia of at least 1cm in length (≥C1M1) or a tongue of Barrett's metaplasia of at least 2cm in length (≥C0M2) (irrespective of the presence now or historically of histologically proven intestinal metaplasia).
3. Able to give written informed consent.
4. WHO performance status of 0 or 1 i.e. fully active and self-caring.

EXCLUSION CRITERIA

1. High grade dysplasia or carcinoma at enrolment.
2. Medical conditions which would make completing endoscopies or completing the trial difficult including:

   1. Frequent transient ischaemic attacks (3 or more) or severe cerebral vascular accident in the previous 6 months\*
   2. Severe respiratory disease with arterial oxygen saturation less 90% at rest
   3. Severe ischaemic heart disease (exercise tolerance less than 100 yards or life expectancy \< 4 years) or myocardial infarction in the previous 3 months
   4. Severe inflammatory bowel disease requiring at least one hospital admission of 5 days in the last year or bowels open \> 6 times/day \* Patients answering yes to criterion a. were eligible for the PPI-only (non-aspirin) arms of the trial
3. Continuous/frequent non-steroidal anti-inflammatory drug use or COX-2 inhibitors (more than 60 days per year in total).
4. Patients with absolute contraindications to PPIs, aspirin or their excipients i.e. allergies, ulcers, renal impairment or use of oral anticoagulants.
5. Pregnant or lactating women will not undergo endoscopy and may be given dispensation to stop drug therapy for a year. This should be discussed with the Trial Office.

If a patient was suitable for inclusion but later becomes unsuitable this should be discussed with the Trial Office before they are withdrawn. Only in exceptional circumstances should patients not be followed up i.e. withdrawal of consent or current life threatening disease with poor outcome and therefore unable to tolerate endoscopy. In these circumstances patients should be followed up in outpatient clinics.