A Phase III, Randomized, Study of Aspirin and Esomeprazole Chemoprevention in Barrett's Metaplasia
Phase: PHASE3
Conditions: Esophageal Cancer, Precancerous Condition
Sponsor: University of Oxford

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AspECT 
 
Full title: AspECT: A PHASE III, RANDOMISED STUDY OF ASPIRIN AND 
ESOMEPRAZOLE CHEMOPREVENTION IN BARRETT’S METAPLASIA 
Short title: AspECT 
 
 
Protocol Version & date: 
AspECTProtocol_V12.0_26Jan2016 
Ethics Number: 
P1/04/Q0603/1 
EudraCT Number: 
2004-003836-77 
NIHR Portfolio Number: 
1339 
Clintrials.gov. No. 
NCT00357682 
ISRCTN: 
85156844 
 
 
 
 
 
 
 
 
 
          
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Sponsored by the University of Oxford 
 
 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the 
Trial Office, the Investigator Team, host NHS Trust(s), regulatory authorities, and members of the Research Ethics 
Committee.   

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General contact information 
 
Chief Investigator 
Professor Janusz Jankowski 
 
Consultant Physician and Honorary Professor 
 
University Hospitals Coventry & Warwickshire NHS Trust 
 
Warwick Medical School 
University of Warwick 
Warwick CV2 2DX 
Tel +44 (0)24 7696 8609 
Fax +44 (0)24 7696 8653 
 
Email: Janusz.Jankowski@uhcw.nhs.uk 
 
 
Trial Office (OCTO) 
AspECT Trial Office 
 
Oncology Clinical Trials Office (OCTO) 
 
Department of Oncology, The University of Oxford 
 
Old Road Campus Research Building 
 
Oxford OX3 7DQ 
 
Tel: 01865 617011 
 
Email: aspect@octo-oxford.org.uk 
 
Website:http://www.octo-oxford.org.uk 
 
 
Clinical Trial Coordinator 
Adelyn Wise 
 
Tel.: 01865 617011     
 
Fax:   01865 617010 
 
Email: octo-aspect@oncology.ox.ac.uk 
 
 
Sponsor 
The University of Oxford 
Ms Heather House 
 
 
Clinical Trials and Research Governance 
 
Joint Research Office, Block 60 
 
Churchill Hospital 
 
Oxford OX3 7LE 
 
Tel: +44 (0)1865 572224 
 
Fax: +44 (0)1865 572228 
 
E-mail: ctrg@admin.ox.ac.uk 
 
 
Statistician 
Ms Sharon Love 
 
Senior Medical Statistician 
 
Oxford Clinical Trials Research Unit (OCTRU) 
 
Centre for Statistics in Medicine, The University of Oxford 
 
Botnar Research Centre 
Windmill Road  
Oxford, OX3 7LD 
 
Tel : 01865 223441 
 
Email: sharon.love@csm.ox.ac.uk  
 
 
Trial Laboratory  
Mr Sean James 
 
ChOPIN/AspECT Office 
3rd Floor PRI suite- opposite ward 32 
University Hospitals Coventry & Warwickshire NHS Trust 
Coventry 
CV2 2DX 
Office Tel: 02476 967587  
Tissue Bank Tel: 02456 967033  
 
Email: AspECTLab@uhcw.nhs.uk 
 
 

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Other key contacts 
 
AspECT Trial Management 
Group  
 
Professor Janusz Jankowski 
 
Dr John De Caestecker (Chair) 
 
Professor Hugh Barr (Deputy Chair) 
Professor Paul Moayyedi 
 
Dr Rebecca Harrison 
 
Professor Stephen Attwood 
 
Dr Peter Watson 
 
Dr Pradeep Bhandari 
 
Dr Yeng Ang 
 
Ms Sharon Love 
 
Dr Scott Sanders 
 
Mrs Adelyn Wise 
TMG Advisory non-executive 
members 
 
Dr Mark Anderson, City Hospital, Birmingham 
 
Dr Cathryn Edwards, Torbay Hospital, Torbay 
 
Dr Danielle Morris, QEII Welwyn Garden City 
 
Dr Colin Rodgers, Antrim, NI 
 
Dr Michael Gibbons, Craigavon, NI 
 
Dr Krish Ragunath, Nottingham 
 
Other observers at the invitation of the CI 
 
 
Data and Safety Monitoring 
Committee 
 
Dr Barrie Rathbone, Leicester Royal Infirmary, Leicester (Chair) 
 
Prof Julia Brown, Clinical Trial Research Unit, Leeds (Statistical Advisor)  
 
 
Non-Independent Members 
Prof David Ferry, New Cross Hospital, Wolverhampton 
 
Prof Janusz Jankowski (CI) 
Sharon Love (Trial Statistician) 
Adelyn Wise(Trial Coordinator) 
 
Trial Steering Committee  
Independent Members 
 
Prof John Primrose, Southampton University Hospital, Southampton (Chair) 
 
Ms Sally Stenning, MRC Clinical Trials Unit, London (Statistical Advisor) 
 
Prof Nick Talley, Newcastle, Australia  
 
Mrs Gwen Harlow  (Patient Representative) 
 
 
Trial Steering Committee  
Non-Independent Members 
 
Prof Janusz Jankowski (CI) 
 
Dr John de Caestecker (TMG Chair) 
 
Sharon Love (Trial Statistician) 
 
Adelyn Wise(Trial Coordinator) 
 
Trial Steering Committee  
Observers 
Representative from Cancer Research UK 
 
Peter Nagy, AstraZeneca 
 
Heather House, University of Oxford (Sponsor) 
 
 
Independent Pharmaceutical 
Advisor 
Dr Emma Roffe 
 
 
 

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Clinical queries and emergency contact details  
 
During office hours: Clinical Queries should be directed to the AspECT Trial Office and contact the Clinical Trial 
Coordinator.  The call will be passed on to the Chief Investigator or to the Clinical Coordinator (medically qualified) or 
an appropriate member of the Trial Management Group. 
 
Out of office hours: call the John Radcliffe Hospital switchboard on Tel: 01865 741166 and ask to call the AspECT 
Clinical Coordinator. 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................................................. 8 
SUMMARY SCHEDULE OF EVENTS ............................................................................................................................ 11 
ABBREVIATIONS ....................................................................................................................................................... 12 
1 
INTRODUCTION ..................................................................................................................................... 13 
1.1 
BACKGROUND .................................................................................................................................................... 13 
1.2 
INVESTIGATIONAL MEDICINAL PRODUCT(S) USED IN THE STUDY .................................................................................... 13 
1.3 
PHARMACOKINETICS OF ASPIRIN ............................................................................................................................ 14 
1.4 
PHARMACOKINETICS OF ESOMEPRAZOLE ................................................................................................................. 15 
1.5 
RATIONALE FOR THE STUDY ................................................................................................................................... 16 
2 
TRIAL DESIGN ......................................................................................................................................... 16 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 17 
4 
PATIENT SELECTION ............................................................................................................................... 18 
4.1 
ELIGIBILITY CRITERIA FOR ENTRY INTO THE STUDY ....................................................................................................... 18 
4.2 
EXCLUSION CRITERIA: .......................................................................................................................................... 18 
4.3 
PROTOCOL DEVIATIONS ........................................................................................................................................ 19 
5 
TRIAL ASSESSMENTS AND PROCEDURES ................................................................................................ 19 
5.1 
EVALUATIONS DURING THE STUDY .......................................................................................................................... 19 
5.2 
DURATION OF PATIENT PARTICIPATION .................................................................................................................... 20 
5.3 
POST-TRIAL CARE AND FOLLOW-UP......................................................................................................................... 20 
6 
EARLY PATIENT WITHDRAWAL .............................................................................................................. 20 
6.1 
WITHDRAWAL FROM TREATMENT .......................................................................................................................... 20 
6.2 
WITHDRAWAL FROM ENDOSCOPY .......................................................................................................................... 20 
6.3 
CONSENT WITHDRAWAL ....................................................................................................................................... 20 
6.4 
REACHING A TRIAL ENDPOINT ................................................................................................................................ 21 
6.5 
DEATH .............................................................................................................................................................. 21 
7 
SAMPLES FOR LABORATORY ANALYSIS .................................................................................................. 21 
7.1 
SAMPLES TO BE ANALYSED IN LOCAL TRUST’S LABORATORIES ....................................................................................... 21 
7.2 
SAMPLES TO BE SENT TO AND ANALYSED IN A TRIAL LABORATORY ................................................................................. 21 
7.2.1 
RESEARCH BIOPSIES IN FORMALIN .......................................................................................................................... 22 
7.2.2 
FORMALIN FIXED PARAFFIN EMBEDDED TISSUE BLOCKS ............................................................................................... 22 
7.2.3 
FRESH SPECIMENS IN RNA LATER SOLUTION ............................................................................................................. 22 
7.2.4 
BLOOD SAMPLES ................................................................................................................................................. 22 
7.3 
HELICOBACTER TESTING ....................................................................................................................................... 22 
7.4 
CLINICAL REPORTING OF EXPLORATORY RESEARCH ASSAY RESULTS................................................................................. 22 
7.5 
TRIAL SAMPLE RETENTION AT END OF STUDY ............................................................................................................. 23 
7.6 
WITHDRAWAL OF CONSENT FOR SAMPLE COLLECTION AND/OR RETENTION .................................................................... 23 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) ................................................................................. 23 
8.1 
NAME OF IMPS ................................................................................................................................................. 23 
8.2 
TREATMENT DOSE ............................................................................................................................................... 23 
8.3 
DURATION OF TREATMENT ................................................................................................................................... 23 
8.4 
SPECIAL PRECAUTIONS ......................................................................................................................................... 23 
8.5 
DOSE MODIFICATION ........................................................................................................................................... 24 
8.6 
COMPLIANCE ..................................................................................................................................................... 25 
8.7 
MANAGEMENT OF OVERDOSE ............................................................................................................................... 25 
8.8 
CONCOMITANT MEDICATION AND NON-DRUG THERAPIES ........................................................................................... 25 
8.9 
(POTENTIAL) DRUG INTERACTIONS ......................................................................................................................... 25 
9 
DRUG MANAGEMENT ............................................................................................................................ 26 

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9.1 
DRUG SUPPLIES .................................................................................................................................................. 26 
9.2 
DRUG ORDERING ................................................................................................................................................ 26 
9.3 
IMP RECEIPT ..................................................................................................................................................... 26 
9.4 
HANDLING AND STORAGE ..................................................................................................................................... 27 
9.5 
LABELLING ......................................................................................................................................................... 27 
9.6 
DOSING DISPENSING ............................................................................................................................................ 27 
9.7 
DRUG ACCOUNTABILITY........................................................................................................................................ 27 
9.8 
DRUG RETURNS FROM PATIENTS ............................................................................................................................ 27 
9.9 
DRUG DESTRUCTION ............................................................................................................................................ 27 
10 
ASSESSMENT OF SAFETY ........................................................................................................................ 27 
10.1 
ADVERSE EVENT DEFINITIONS ................................................................................................................................ 28 
10.2 
DETERMINING ADVERSE EVENT CAUSALITY ............................................................................................................... 28 
10.3 
EXPECTED ADVERSE EVENTS .................................................................................................................................. 29 
10.4 
REPORTING OF SAES ........................................................................................................................................... 33 
10.5 
SUSPECTED UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (SUSARS) .................................................................... 33 
10.6 
FOLLOW-UP OF SERIOUS ADVERSE EVENTS .............................................................................................................. 33 
10.7 
REPORTING ADVERSE EVENTS ON THE CRF .............................................................................................................. 34 
10.8 
EVENTS EXEMPT FROM BEING REPORTED AS AE/ SAES............................................................................................... 34 
10.9 
INFORMING INVESTIGATORS OF NEW SAFETY INFORMATION ........................................................................................ 34 
11 
PREGNANCY ........................................................................................................................................... 34 
12 
DEFINING THE END OF TRIAL ................................................................................................................. 34 
13 
STATISTICAL CONSIDERATIONS .............................................................................................................. 34 
13.1 
PRIMARY AND SECONDARY ENDPOINTS ................................................................................................................... 34 
13.2 
SAMPLE SIZE AND POWER ..................................................................................................................................... 35 
13.3 
RANDOMISATION – STRATIFICATION AND STANDARDISATION ...................................................................................... 36 
14 
STATISTICAL ANALYSIS PLAN.................................................................................................................. 36 
14.1 
FINAL ANALYSIS .................................................................................................................................................. 37 
15 
TRIAL COMMITTEES ............................................................................................................................... 37 
15.1 
TRIAL MANAGEMENT GROUP (TMG) .................................................................................................................... 37 
15.2 
DATA AND SAFETY MONITORING (DSMC) .............................................................................................................. 37 
15.3 
TRIAL STEERING COMMITTEE (TSC) ....................................................................................................................... 37 
16 
DATA MANAGEMENT ............................................................................................................................ 37 
16.1 
DATABASE CONSIDERATIONS ................................................................................................................................. 37 
16.2 
CASE REPORTS FORMS (CRFS) ............................................................................................................................... 37 
16.3 
ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA. .......................................................................................... 37 
17 
CLINICAL STUDY REPORT ....................................................................................................................... 38 
18 
STUDY SITE MANAGEMENT ................................................................................................................... 38 
18.1 
STUDY SITE RESPONSIBILITIES ................................................................................................................................ 38 
18.2 
STUDY DOCUMENTATION ..................................................................................................................................... 38 
19 
REGULATORY AND ETHICAL CONSIDERATIONS ...................................................................................... 38 
19.1 
ETHICAL CONDUCT OF THE TRIAL AND ETHICS APPROVAL ............................................................................................. 38 
19.2 
REGULATORY AUTHORITY APPROVAL ...................................................................................................................... 38 
19.3 
NHS RESEARCH GOVERNANCE .............................................................................................................................. 38 
19.4 
PROTOCOL AMENDMENTS .................................................................................................................................... 38 
19.5 
URGENT SAFETY MEASURES .................................................................................................................................. 39 
19.6 
TEMPORARY HALT ............................................................................................................................................... 39 
19.7 
SERIOUS BREACHES ............................................................................................................................................. 39 
19.8 
REPORTS: PROGRESS, SAFETY AND END OF STUDY REPORTS ..................................................................................... 40 
20 
EXPENSES AND BENEFITS ....................................................................................................................... 40 

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21 
QUALITY ASSURANCE ............................................................................................................................ 40 
21.1 
RISK ASSESSMENT ............................................................................................................................................... 40 
21.2 
CENTRAL MONITORING ........................................................................................................................................ 40 
21.3 
QUALITY MONITORING COMMITTEES ..................................................................................................................... 40 
21.4 
AUDIT AND REGULATORY INSPECTION ..................................................................................................................... 41 
22 
RECORDS RETENTION & ARCHIVING ...................................................................................................... 41 
23 
PATIENT CONFIDENTIALITY .................................................................................................................... 41 
24 
STUDY FUNDING .................................................................................................................................... 41 
25 
SPONSORSHIP AND INDEMNITY ............................................................................................................ 42 
25.1 
SPONSORSHIP .................................................................................................................................................... 42 
25.2 
INDEMNITY ........................................................................................................................................................ 42 
25.3 
CONTRACTS/AGREEMENTS ................................................................................................................................... 42 
26 
PUBLICATION POLICY ............................................................................................................................. 42 
27 
REFERENCES ........................................................................................................................................... 43 
 
 
 

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PROTOCOL SYNOPSIS 
Full Title of study: 
AspECT: A Phase III, Randomised Study of Aspirin and Esomeprazole Chemoprevention in 
Barrett’s Metaplasia 
Short Title: 
AspECT 
Trial Acronym: 
AspECT 
Objectives: 
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 
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 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 assess the genomics of 
aspirin sensitivity (efficacy and side 
effects) 
 
To assess how quality of life is 
affected by the different treatments 
 
To assess what the biological risk factors 
are for cardiac disease and aspirin 
resistance 
 
To assess gender differences in 
outcomes 
 
Exploratory 
Objectives: 
 
To assess aspirin’s role on the development of colorectal adenomas and cancer 
 
To collect and bank samples for use in future ethically approved studies 
Scientific rationale: 
The role of aspirin in the prevention of not only colorectal cancer but also oesophageal 
adenocarcinoma is already accepted in epidemiological studies (19 - 22). Although aspirin 
is already being used prophylactically in premalignant colorectal lesions, a study of its 
application to BM is urgently needed. PPIs are used widely but their efficacy in 
chemoprevention is unclear and if there is an effect the most cost-effective dose is not 
known. Esomeprazole is arguably the leading agent in its class. 
Clinical rationale: 
Conventional clinical risk factors for BA have not been proven in randomised controlled 
studies, although males have an excess risk of oesophageal adenocarcinoma compared 
with females at a ratio of 3 to 1 (6 - 16). In the absence of proven stratification, 
surveillance of all cases of BM is required; this is neither feasible nor cost effective (17). 
Primary prevention strategies should be aimed at reducing the initiation and malignant 
degeneration of BM by pharmaceutical manipulation of the oesophageal environment.  

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Potent acid suppressing drugs and aspirin for chemoprotection have the greatest 
applicability.  
Primary Endpoint: 
A composite primary endpoint of all-cause mortality and conversion to adenocarcinoma 
and conversion to high grade dysplasia. 
Secondary Endpoints: 
 
All-cause mortality 
 
Conversion to oesophageal adenocarcinoma 
 
Conversion to high grade dysplasia 
 
Death from oesophageal cancer 
 
Cost/oesophageal adenocarcinoma prevented  
 
Cost/life year saved 
 
Molecular markers to be identified at the end of the trial and used during analyses of 
collected blood and/or tissue samples 
 
Cost/quality adjusted life saved 
 
Formation of new tumours 
 
Composite endpoint of all-cause mortality and conversion to adenocarcinoma and 
conversion to high grade dysplasia according to gender  
Study Design: 
This is a pragmatic, national, multicentre, phase III, randomised 2x2 factorial controlled 
trial of low or high dose esomeprazole with or without low dose aspirin for 8-10 years 
Patient Numbers: 
2513  
Target Population: 
Patients with 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) 
Inclusion and 
exclusion criteria 
Inclusion Criteria 
A patient is eligible for inclusion in this 
study if all of the following criteria apply.  
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 
A patient is not be eligible for the trial if 
any of the following apply: 
 
1. High grade dysplasia or carcinoma at 
enrolment. 
2. Medical conditions which would make 
completing endoscopies or 
completing the trial difficult, 
including: 
a) Frequent transient ischaemic 
attacks (3 or more) or severe 
cerebral vascular accident in the 
previous 6 months*. 
b) Severe respiratory disease with 
arterial oxygen saturation of less 
than 90% at rest 
c) Severe ischaemic heart disease 
(exercise tolerance less than 100 
yards or life expectancy < 4 years) 
or myocardial infarction in the 
previous 3 months. 
d) 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 criteria (a) 
were eligible for the PPI-only (non-
aspirin) arms of the trial.  
3. Patients with absolute 
contraindications to PPIs, aspirin or 
their excipients i.e. allergies, ulcers, 

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renal impairment or use of oral 
anticoagulants.  
4. 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. 
Trial dose and 
administration: 
Patients receive either continuous PPI 20mg/day or continuous PPI 80mg/day (40mg BD) 
with or without aspirin 300mg/day.  
Duration on study: 
Participants will be in the study for approximately 8 years or 10 years (if they re-
consented to extend) from randomisation to last protocol visit. Follow up will end when 
the participant either reaches their 8th (or 10th if they re-consented) anniversary on trial, 
choose to withdraw consent, end treatment or on 28th February 2017 (+3 months for 
appointment slippage); whichever is soonest. 
Study Procedures and 
frequency: 
 
(Procedures For 
Remainder of Study) 
Follow Up 
Patients will be asked questions and their medical notes checked to determine disease, 
survival and osteoporosis status. Any unreported SAEs, concomitant medications taken 
and use of other medications/interventions to treat Barrett’s will also be determined and 
noted. 
Frequency: Annually whilst on study. 
 
Endoscopy & Biopsy 
Endoscopy will be performed on patients to assess their Barrett’s status. Biopsy samples 
will also be taken for local pathology assessment and the Trial Laboratory. 
Frequency: Year 6, 8 and 10 (if patients re-consented) 
 
Blood Samples 
Blood samples will be taken for the Trial Laboratory to assess for cancer and 
cardiovascular risk factors. 
Frequency: Between year 4 and 6 (once), 8 and 10 (if patients re-consented). 
Patient care post-trial: 
Following the end of study visit patients will receive standard care. 
Pharmacokinetic 
assays: 
N/A 
Pharmacodynamic 
assays: 
N/A 
No. of Study Site(s) 
85 Centres in the UK 
End of study 
Last Patient Last Visit Date is 28th February 2017 (we will allow +3 months for 
appointment slippage). Patients should be on the study for a maximum of 123 months. 
Publication policy 
The results of this study will be published in a peer-reviewed scientific journal and other 
academic research purposes as agreed by the Investigators. 

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SUMMARY SCHEDULE OF EVENTS 
Date Due at OCTO 
(time after randomisation) 
CRFs Due 
Samples Due 
5 years 
5 year Follow-up 
 
Between 4 and 6 years 
 
Blood sample 
6 years  (+/- 3 months) 
6 year Follow-up 
Endoscopy and Pathology 
Biopsy Sampling 
Endoscopy 
Biopsy samples 
7 years 
7 year Follow-up 
 
8 years  (+/- 3 months) 
8 year Follow-up 
Endoscopy and Pathology 
Biopsy Sampling 
End of Treatment (if not re-consented to 10 years follow up) 
Endoscopy 
Biopsy samples  
Blood sample 
9 years 
(only if patient consented for 
10 years follow up) 
9 year Follow-up 
 
10 years  (+/- 3 months) 
(only if patient consented for 
10 years follow up) 
10 year Follow-up 
Endoscopy and Pathology 
Biopsy Sampling 
End of Treatment  
Endoscopy 
Biopsy samples  
Blood sample 
Unscheduled 
Serious Adverse Event 
Death (when no causal relationship with trial medication is suspected) 
End of Treatment (for patients who withdraw from treatment early) 
Consent Withdrawal Notification (for patients who withdraw from all parts of the 
study) 
Change of Treatment 
Additional Data (for any other information you feel necessary to report or if you need 
more space to continue on from another CRF) 
Endpoint Sampling (for patients with low or high grade dysplasia or oesophageal 
adenocarcinoma) 
Pregnancy Notification 
Bowel Screening 
Clopidogrel 
 
 

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ABBREVIATIONS 
ALT 
Alanine Aminotransferase (blood test to detect liver injury) 
AST 
Aspartate Aminotransferase (blood test to detect liver injury) 
AE 
Adverse Event 
AUC 
Area Under Curve 
BA 
Barrett’s Adenocarcinoma 
BM 
Barrett’s Metaplasia 
BUN 
Blood Urea Nitrogen (measurement of renal function) 
CI 
Chief Investigator 
COX 
Cyclo-oxygenase 
CRF 
Case Report Form 
CVA 
Cerebral Vascular Accident (stroke) 
DNA 
Deoxyribonucleic Acid 
DSMC 
Data and Safety Monitoring Committee 
DSUR 
Development Safety Update Report 
EA 
Esophageal Adenocarcinoma (see also OA) 
ER 
Endoscopic Resection 
GAL 
Grant Award Letter 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase (blood test to detect liver injury) 
GI 
Gastrointestinal 
GORD 
Gastro-Oesophageal Reflux Disease 
HGD 
High Grade Dysplasia 
HSCIC 
Health and Social Care Information Centre 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IHD 
Ischaemic Heart Disease 
IM  
Intestinal Metaplasia 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio (measure of blood clotting time) 
LGD 
Low Grade Dysplasia 
LPLV 
Last Patient Last Visit 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MREC 
Main Research Ethics Committee 
MRC 
Medical Research Council 
MRIS 
Medical Research Information Service 
NSAID 
Non-Steroidal Anti Inflammatory Drug 
OA 
Oesophageal Adenocarcinoma (see also EA) 
PBMC 
Peripheral Blood Mononuclear Cell 
PGE2 
Prostaglandin E2 
PI 
Principal Investigator 
PPI  
Proton Pump Inhibitor 
PUB 
Peptic Ulcer Bleeding 
RNA  
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SNP 
Single Nucleotide Polymorphism 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
WHO 
World Health Organisation 
 

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1 
INTRODUCTION 
1.1 
Background  
Erosive oesophagitis secondary to gastro-oesophageal reflux disease (GORD) is arguably the most common medical 
condition in Western countries affecting 10% of adults (1, 2). 10% of patients with erosive oesophagitis will progress 
to Barrett’s metaplasia (BM), which is pre-malignant columnar epithelium that lines the distal oesophagus (1, 2). 
While dysplasia in BM is still the gold standard for assessing the premalignant potential, many individuals develop 
their adenocarcinoma without having dysplasia detected.   
 
Barrett’s adenocarcinoma (BA) is characterised by a poor prognosis, with a median survival time, following diagnosis, 
of less than one year and fewer than 10% surviving for more than five years. Detection is needed at an earlier stage 
where intervention can dramatically improve survival.  
1.2 
Investigational medicinal product(s) used in the study  
Acid and bile are the predominant injurious agents in gastro-oesophageal reflux disease. Proton pump inhibitors (PPIs) 
are widely used in the treatment. They are highly effective and safe in minimising symptoms and healing of 
oesophagitis, but there is no clear evidence that they inhibit the evolution of cancer. There are no clinical studies that 
address this issue adequately. Proof of concept for the notion that PPIs can reduce cancer risk comes from 
observations that partial regression of metaplastic mucosa may be induced by suppression of acid (and bile) reflux 
with PPIs (23, 24). Whether this translates into a subsequent decrease in neoplastic change is unclear. Intermediate 
markers from patients with BM in whom intraoesophageal pH had been normalised on PPI therapy showed decreased 
cell proliferation and improved differentiation. Conversely, incomplete acid suppression that allows short pulses of 
acid led to epithelial changes, selecting poorly differentiated cells with increased proliferative potential (23). These 
data indicate that gastro-oesophageal reflux is implicated in the pathogenesis of BM and there is preliminary evidence 
to show that its attenuation reverses the surrogate markers in the short term and perhaps the cancer risk in the 
longer term.  
 
The counter argument is that PPIs may not be protective against oesophageal cancer. Epidemiological studies suggest 
that since the widespread introduction of acid suppressing drugs (H2 antagonists and PPIs) BA has increased 
dramatically (1). In animal models of duodenogastric reflux there is an enhanced cancer risk when gastric acid 
blockade by omeprazole is employed (25). Bile acids may be more cytotoxic at a neutral pH, and it is therefore 
possible that PPI therapy could promote oesophageal cancer. It is likely that any cytotoxic effects of PPIs either 
directly or indirectly, are determined by the extent and/or pattern of acid suppression i.e. total acid suppression by 
high dose PPI or incomplete/partial acid suppression by low dose PPI.  
 
Because BM is relatively insensitive to acid (24, 25, 26), symptom control is easier to achieve than complete 
normalisation of intra-oesophageal pH (26, 27, 28). Therefore, symptoms are an unreliable indicator of the adequacy 
of treatment. Most patients’ reflux symptoms are controlled with a once daily standard dose of PPI (esomeprazole 
20mg) and normalisation of intra-oesophageal pH is achieved in about 65% (29). Patients with Barrett’s oesophagus 
may have substantially greater degrees of reflux and may require higher doses of PPI to achieve normalisation of the 
oesophageal pH. Evidence indicates that the latest PPI esomeprazole is more effective than other PPIs at both 
suppressing acid (43) and at treating more severe reflux disease including Barrett’s (29, 30). Although 20mg/day will 
be sufficient for symptomatic relief in the majority of reflux patients, the level of acid suppression achieved is not 
optimal (only 53% of 24hour period has gastric acid at pH > 4) and normalisation of oesophageal pH is even worse 
(acid reflux in the oesophagus reduced to ‘current accepted physiological levels’). However, a recent study has 
demonstrated that twice daily dosing with esomeprazole 40mg produces a profound level of acid suppression that is 
superior to that demonstrated by any other PPIs. In this regard, 40mg esomeprazole twice daily usually achieves a 
96% of 24 hour period with pH > 4 (44) compared with < 50% on 20mg/day esomeprazole or equivalent (31).  
 
BM does not regress once the external stimulus for its initiation is removed. In epidemiological studies aspirin has 
been shown to be associated with a dramatically decreased incidence of both oesophageal and gastric 
adenocarcinoma. Its anticancer effects are thought to be mediated in part by its ability to inhibit the enzyme cyclo-
oxygenase (COX). Aspirin inhibits PGE2 thereby inhibiting prostaglandin formation by COX-1 and the inducible COX-2 
enzymes, as well as the inhibitor of apoptosis protein (c-IAP)-2. Aspirin also dampens down -catenin signalling and 
NF transcription (33, 34).  This makes aspirin a potentially more effective cancer chemopreventative agent than 
Non-Steroidal Anti Inflammatory Drugs (NSAIDs). 
 

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A meta-analysis of aspirin in eight upper GI cancer prevention cohorts has estimated cancer reduction by about 50% 
when compared with NSAIDs (35). In addition, combined aspirin and PPI therapy was shown in a recent model to be 
more effective and cheaper than any other intervention including surveillance. Early pilot data also indicates that low 
dose aspirin is also more effective in decreasing PGE2 levels in Barrett’s patients than 25mg of rofecoxib, a selective 
COX-2 inhibitor (personal communication Prof George Triadofilopoulos, USA). In a model of cancer prevention a 
selective COX-2 inhibitor was not as effective as a non-selective NSAID (36).  
 
There is some controversy surrounding the potential for cardiovascular side effects of some of the COX-2 selective 
inhibitors in susceptible patients. Aspirin is unique in its drug group because it irreversibly inhibits platelet activity at 
low doses. This property explains the well-established cardioprotective properties of aspirin in at-risk individuals. 
Patients with BM have an increased risk of cardiovascular events. Therefore use of aspirin may be useful for secondary 
prevention and perhaps even primary prevention in certain at-risk groups (37). The peak incidence of Ischaemic Heart 
Disease (IHD) is about 10 years before the development of adenocarcinoma in Barrett’s and therefore in order to both 
chemoprevent and cardioprotect, aspirin should be commenced in the early 50s for maximum benefit. Any NSAID 
drug (including the COX-2 selectives) other than aspirin would carry risks of cardiovascular complication. For this 
reason, together with the fact that aspirin is the best-studied anti-cancer COX inhibitor, aspirin is the drug of choice 
for this trial.  
 
There is undoubted risk with aspirin (and without PPI) of gastrointestinal haemorrhagic complications (1-2%). But this 
is decreased 10 fold with PPI therapy as the damage is acid related (38, 39, 40), and still further with helicobacter 
pylori (HP) eradication. Indeed, aspirin may sensitise the organism to eradication therapy (41). Also, to a lesser extent, 
haemorrhagic stroke has also been reported. However, several reports have indicated that aspirin’s advantages far 
outweigh any adverse effects, with major complications occurring in 0.002% and death from major complications in 
0.00005% (35). While the optimal dose of aspirin for cardiac protection is probably 75mg/day, the ideal dose for 
chemoprevention is currently unknown and lies between 75-300mg/day. 
 
Anti-reflux surgery has been advocated for patients with BM but it is not first line therapy due to issues of fitness for 
surgery and peri-operative mortality rate for surgery. It is also clear that anti-reflux surgery has at most a modest 
effect on cancer prevention (2). Other forms of surgical intervention including endoscopic mucosal resection and laser 
therapy are at present carried out in too few centres and by too few people to be able to be exploited reproducibly in 
a national study in the near future.  
 
The majority of adenocarcinomas in the oesophagus in the community are not diagnosed in surveillance programs. 
The average life expectancy in the UK for males is 73 years and for females 77 years. At these ages the commonest 
cause of death is ischaemic heart disease and cerebrovascular or peripheral vascular disease (42). The average age of 
presentation of patients with BA is 69 years. Therefore chemoprevention aims to prolong survival or delay onset of 
the cancer by 4 years in males and 8 years in females to allow other ‘morbid diseases’ to intervene naturally. 
 
AspECT is a chemoprevention trial of acid suppression and aspirin in patients with Barrett’s oesophagus. This study 
will allow the validation of several surrogates including biomarkers and clinical parameters. Aspirin is an effective 
chemoprotective agent in a number of cancers of the gastrointestinal tract. Continuous acid suppression therapy is 
well tolerated, has extremely low morbidity and mortality, and is available readily in every centre in the UK. These two 
treatments are unlikely to ‘neutralise’ the real benefits of each other in the majority of patients as the drugs act 
independently and their effects will be additive and possibly complementary. In addition, the use of these two drugs 
together may help decrease the side effects of aspirin intervention alone, especially in men. PPIs will be required for 
symptom control of reflux and aspirin may have additional benefits in reducing colorectal cancer and cardiovascular 
events. While the main study concentrates on males we will assess a smaller cohort of females in the integrated 
women’s AspECT study (WASP). By doing so we will be able to address genetic and environmental reasons why males 
develop more oesophageal adenocarcinoma than females. 
1.3 
Pharmacokinetics of aspirin 
Absorption 
Absorption of non-ionised aspirin occurs in the stomach and intestine. 
 
Metabolism 
Some aspirin is hydrolysed to salicylate in the gut wall. After absorption, aspirin is rapidly converted to salicylate but 
during the first 20 minutes following oral administration, aspirin is the predominant form of the drug in the plasma. 

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Aspirin is bound to plasma proteins and is widely distributed. Plasma aspirin concentrations decline rapidly (half life 
15-20 minutes) as plasma salicylate concentrations increase. 
 
Hepatic Insufficiency 
Salicylate is mainly eliminated by hepatic metabolism – the metabolites including salicylic acid, salicyl phenolic 
glucuronide, salicylic acyl glucuronide, gentisic acid and gentisuric acid. As a result of zero order kinetics, plasma 
steady state salicylate concentrations increase disproportionately with dose.  Aspirin should be avoided in patients 
with severe hepatic impairment (ALT > 150 or bilirubin over 100). 
 
Renal Insufficiency 
Salicylate is also excreted unchanged in the urine to an extent which depends on the dosage and urinary pH. Renal 
excretion involves glomerular filtration, active renal tubular secretion and passive tubular reabsorption. Aspirin may 
cause salt and water retention and renal failure, especially in patients with pre-existing renal impairment. Aspirin 
should be avoided in patients with severe renal impairment (Urea > 30 and/or Creatinine > 300). 
 
Indications relevant to Barrett’s Metaplasia 
None 
1.4 
Pharmacokinetics of esomeprazole 
Absorption 
Esomeprazole is acid labile and is administered orally as enteric coated granules. In vivo conversion to the R-isomer is 
negligible. Absorption of esomeprazole is rapid with peak plasma levels occurring approximately 1-2 hours after dose. 
The absolute bioavailability is 64% after a single dose of 40mg and increases to 89% after repeated once-daily 
administration. For 20mg esomeprazole, the corresponding values are 50% and 68% respectively. Food intake both 
delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of 
esomeprazole on intragastric acidity. 
 
Metabolism 
Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of 
esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and 
desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, 
responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. 
 
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive 
metabolisers. 
 
Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma 
elimination half-life is about 1.3 hours after repeated once-daily dosing. The area under the plasma concentration-
time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a 
non-linear dose-AUC relationship after repeated administration. This time- and dose- dependency is due to a decrease 
of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by 
esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses 
with no tendency for accumulation during once-daily administration. 
 
The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of 
esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is 
found in urine. 
 
Hepatic insufficiency 
The metabolism of esomeprazole in patients with mild to moderate liver dysfunction is similar to that in patients with 
symptomatic Gastro Oesophageal Reflux Disease (GORD) with normal liver function. The metabolic rate is decreased 
in patients with severe liver dysfunction resulting in a doubling of the area under the plasma concentration-time curve 
of esomeprazole. Therefore, a maximum dose of 20mg should not be exceeded in patients with severe dysfunction. 
Esomeprazole or its major metabolites do not show any tendency to accumulate with once daily dosing. 
 
 
 

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Renal insufficiency 
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the 
excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of 
esomeprazole is not expected to be changed in patients with impaired renal function.  
 
Indications relevant to Barrett’s Metaplasia 
Esomeprazole tablets are indicated for: 
 
• 
Gastro-oesophageal Reflux Disease (GORD) 
• 
Treatment of erosive reflux oesophagitis 
• 
Long-term management of patients with healed oesophagitis to prevent relapse 
• 
Symptomatic treatment of gastro-oesophageal reflux disease 
1.5 
Rationale for the study 
The rationale for medical intervention before the development of dysplasia or indeed neoplasia currently lacks an 
evidence base. The UK has one of the highest worldwide prevalence of BM (0.5-2% of adults) (3).  The resulting 
incidence of Barrett’s adenocarcinoma (BA) is 3-4 times that seen in either Europe or North America (4). In addition 
the conversion rate to BA of individuals with BM in surveillance programmes is twice as common in the UK compared 
with the USA (5).  
 
Oesophageal adenocarcinoma causes over 7,500 deaths in the UK each year and the incidence is increasing at a rate 
greater than that of any other cancer in the western world. The study of aspirin is timely in relation to popular 
expectation and now is the time to do this trial.  Prevention by using simple, cheap and commonly used medications is 
much more likely to be an effective way to reduce these deaths than the current attempts of treating established 
disease. In this regard, the role of aspirin in the prevention of not only colorectal cancer but also oesophageal 
adenocarcinoma is already accepted in epidemiological studies (19 - 22). Although aspirin is already being used 
prophylactically in premalignant colorectal lesions, a study of its application to BM is urgently needed. PPIs are used 
widely but their efficacy in chemoprevention is unclear and if there is an effect the most cost-effective dose is not 
known. Esomeprazole has been introduced into the clinical arena and is arguably the leading agent in its class. 
 
Conventional clinical risk factors for BA have not been proven in randomised controlled studies, although males have 
an excess risk of oesophageal adenocarcinoma compared with females at a ratio of 3 to 1 (6 - 16). In the absence of 
proven stratification, surveillance of all cases of BM is required; this is neither feasible nor cost effective (17). Primary 
prevention strategies should be aimed at reducing the initiation and malignant degeneration of BM by pharmaceutical 
manipulation of the oesophageal environment.  Potent acid suppressing drugs and aspirin for chemoprotection have 
the greatest applicability.  Detecting additional risk factors (including aneuploidy, p16, p53 mutations, altered catenin 
biology and cyclinD1 expression), which more accurately predict the subgroups that will progress to malignancy, may 
help to prove the hypothesis that cancer can be prevented (18).  
 
2 
TRIAL DESIGN 
This is a pragmatic, national, multicentre, phase III, randomised 2x2 factorial controlled trial of low or high dose 
esomeprazole with or without aspirin for at least 8 years. Recruitment closed at the end of February 2009. 2012 male 
patients and 501 female patients were recruited. A subset of patients re-consented to extend their trial participation 
to 10 years or until the 28th February 2017 (whichever will be sooner). 
 
ARM A: 20mg PPI 
= symptomatic treatment only 
standard therapy control arm 
Arm B: 80mg PPI 
strong acid suppression arm 
No Aspirin 
(A&B) 
Arm C: 20mg PPI 
symptomatic treatment and aspirin arm 
ARM D: 80mg PPI 
strong acid suppression and aspirin 
arm 
Aspirin (C&D) 
Low dose PPI (A&C) 
High dose PPI (B&D) 
 
 
Patients are followed up annually by a trial nurse via phone call or clinic visit and by endoscopy at approximately 2 
yearly intervals from the date of randomisation (+/- 3 months either side). Once patients come out of the trial 
endoscopy schedule due to clinical need/patient choice, the endoscopy for trial can be performed every 2 years from 

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that date (+/- 3months) and not have to revert back to trial schedule. In 2010 BSG guidance recommended a 2 year 
surveillance interval. Thereafter patients should be endoscoped at 2 yearly intervals unless they develop dysplasia, in 
which case they should be managed according to local procedure. 
 
Although current guidelines, including the recent British Society of Gastroenterology guidelines (Fitzgerald et al, GUT 
2014), suggest 3 year instead of 2 year surveillance intervals, these are purely empirical. The BoB CAT (Benign 
Barrett’s and CAncer Taskforce) group provides a more comprehensive systematic review, has a larger consensus 
group and is badged by over 10 international organisations including NICE (Bennett et al, Am J Gastro 2015). The 
group has indicated the need for more evidence in this area. 
 
AspECT patients should remain on the 2 year surveillance interval. At the end of the trial this will help AspECT to 
contribute to the discussion on different surveillance intervals. 
3 
OBJECTIVES AND ENDPOINTS 
 
Primary Objectives 
Endpoints/ Outcome measures 
Timepoint(s) of 
evaluation of this 
end point  
 
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 
therapy results in a decreased rate of 
all causes of mortality or conversion 
rate from Barrett’s metaplasia to 
adenocarcinoma or high grade 
dysplasia 
 
A composite primary endpoint of all-
cause mortality and conversion to 
adenocarcinoma and conversion to 
high grade dysplasia 
2 yearly 
Secondary Objectives 
Endpoints/ Outcome measures 
 
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 
 All-cause mortality 
 Conversion to oesophageal 
adenocarcinoma 
 Conversion to high grade dysplasia 
 Death from oesophageal cancer 
2 yearly 
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 
 All-cause mortality 
 Conversion to oesophageal 
adenocarcinoma 
 Conversion to high grade dysplasia 
 Death from oesophageal cancer 
2 yearly 
To assess whether there are clinical and 
molecular risk factors which can be 
identified in BM for the development of BA 
 Conversion to oesophageal 
adenocarcinoma 
 
2 yearly 
To assess the cost effectiveness of aspirin 
and/or PPI treatment in the prevention of 
BA 
 
Cost/oesophageal adenocarcinoma 
prevented  
 
Cost/life year saved 
End of trial 
To assess whether intervention with PPI 
and/or aspirin induces changes in the 
expression of molecular markers for BA. To 
assess the genomics of aspirin sensitivity 
(efficacy and side effects) 
 
Molecular markers to be identified at 
the end of the trial and used during 
analyses of collected blood and/or 
tissue samples  
End of trial 

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To assess how quality of life is affected by 
the different treatments 
 
Cost/quality adjusted life saved  
End of trial 
To assess what the biological risk factors 
are for cardiac disease and aspirin 
resistance 
 
Molecular markers to be identified at 
the end of the trial and used during 
analyses of collected blood and/or 
tissue samples 
End of trial 
To assess gender differences in outcomes 
 
A composite endpoint of all-cause 
mortality and conversion to 
adenocarcinoma and conversion to 
high grade dysplasia 
 All-cause mortality 
 Conversion to oesophageal 
adenocarcinoma 
 Conversion to high grade dysplasia 
 Death from oesophageal cancer 
End of trial 
Tertiary/Exploratory Objectives 
Endpoints 
 
To assess aspirin’s role on the 
development of colorectal adenomas and 
cancer 
New tumour 
End of trial 
To collect and bank samples for use in 
future ethically approved studies 
Not applicable  
Not applicable 
4 
PATIENT SELECTION 
Written informed consent must be obtained before any study specific procedures are performed. The Investigator will 
determine patient eligibility based on the following criteria:  
4.1 
Eligibility criteria for entry into the study 
Inclusion criteria:  
A patient is eligible for inclusion in this study if all of the following criteria apply.  
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. 
4.2 
Exclusion criteria: 
A patient is not be eligible for the trial if any of the following apply: 
1. High grade dysplasia or carcinoma at enrolment. 
2. Medical conditions which would make completing endoscopies or completing the trial difficult, including: 
a. 
Frequent transient ischaemic attacks (3 or more) or severe cerebral vascular accident in the 
previous 6 months* 
b. 
Severe respiratory disease with arterial oxygen saturation of less than 90% at rest 
c. 
Severe ischaemic heart disease (exercise tolerance less than 100 yards or life expectancy < 4 
years) or myocardial infarction in the previous 3 months 
d. 
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. Patients with absolute contraindications to PPIs, aspirin or their excipients i.e. allergies, ulcers, renal 
impairment or use of oral anticoagulants.  
4. 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. complete 

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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. 
4.3 
Protocol deviations 
Protocol adherence is a fundamental part of the conduct of a clinical study.  Changes to the approved protocol need 
prior approval unless for urgent safety reasons.  
 
Investigators should not deviate from the protocol for the management of enrolled subjects deliberately unless 
essential to protect the rights or safety of the individual. Examples might include the addition or deletion of tests, 
dosing, duration of treatment, etc. It may be necessary to withdraw the patient from further study.  All waivers and 
deviations should be fully documented/ justified and reported to the Trial Office without delay. 
5 
TRIAL ASSESSMENTS AND PROCEDURES 
Please refer to the Schedule of Investigations given at the front of this protocol. Details of all protocol evaluations and 
investigations must be recorded in the patient’s medical record for extraction onto the CRF.  
5.1 
Evaluations during the study 
All patients will be followed-up annually after study entry, and an annual Follow-Up Form completed. The patients 
should be asked about their disease and osteoporosis status and this should be recorded on the form. The Follow-Up 
Site staff are reminded to: 
 
a) Ask patients at each follow-up visit/call about any hospital admissions or event. 
  
AND  
 
b) Check patient medical records for any hospital admissions or events which should be reported as a Serious 
Adverse Event.  
 
Treatment or intervention for Barrett’s since the previous follow-up should also be determined and recorded along 
with any concomitant medication that the patient may have taken.  
 
The Patients may be followed up by telephone or in person at year 1, 3, 5, 7 and 9 (if patients re-consented) post 
randomisation. A Follow-Up Form must be completed on all occasions. 
 
At year 2, 4, 6, 8 and 10 (if patients re-consented) post randomisation (+/- 3 months either side) patients will have an 
endoscopy to assess their Barrett’s. The following forms must be completed at these time points: 
Biopsy Sampling Form 
Endoscopy and Pathology Form 
Follow-up Form 
 
If the final endoscopic procedure is performed later than 8 years + 3 months (for those patients that did not re-
consent to additional follow up) or later than 10 years + 3 months (for those patients who did re-consent to additional 
follow up), or later than 28th February 2017 (the date of LPLV) + 3 months, then provided that the patient has agreed, 
trial biopsy samples and trial endoscopy & pathology data will be collected.  
Patients whose trial medication dose changes or is temporarily suspended (see section 8.5) should be reported using 
the Change of Treatment Form. 
 
Patients who are prescribed clopidogrel should be reported using the clopidogrel CRF.  
 
Patients who become pregnant should be reported using the Pregnancy Notification Form. 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. During the first trimester only Gaviscon should be taken, after this it is advised that 
Omeprazole is prescribed if required. Patients may re-start esomeprazole after a break of 1 year. 
 
Patients who undergo colonoscopy or flexible sigmoidoscopy during the trial should be reported using the Bowel 
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Patients will also be flagged with the NHS Health and Social Care Information Centre (HSCIC, previously called MRIS) in 
the UK if the patient agreed during the consent process. This should be done so that endpoint data can be 
subsequently gathered from those lost to follow-up. 
 
Patients who are not already members of the patient support group called FORT (Fight Oesophageal Reflux Together) 
may be invited to join. 
 
5.2 
Duration of patient participation 
Participants will be in the study for approximately 8 years or 10 years (if they re-consented to extend) from 
randomisation to last protocol visit. Follow up will end when the participant either reaches their 8th (or 10th if they re-
consented) anniversary on trial, choose to withdraw consent completely, end treatment or on 28th February 2017 (+ 3 
months); whichever is soonest. 
 
5.3 
Post-trial care and follow-up 
Following the end of study visit, patients will receive standard care. Patients they should discuss this with their GP. 
Regular endoscopic follow up should continue as per local standard of care. This may not be every 2 years as it was on 
the study. The endoscopist should advise the patient’s GP as to the recommended treatment for normal clinical 
practice. 
 
6 
EARLY PATIENT WITHDRAWAL 
6.1 
Withdrawal from treatment 
At any time during the course of the trial, a patient may withdraw early from treatment.  The Investigator also has the 
right to withdraw patients from the study or study treatments if he/she feels that it is in the best interests of the 
patient. This may happen for a number of reasons, including: 
- 
Unacceptable toxicity 
- 
AE/SAEs requiring discontinuation 
- 
Clinical decision 
- 
Patient decision 
When the patient stops treatment early, an ‘End of Treatment’ Form must be completed along with any other 
relevant forms, e.g. SAE Form or Consent Withdrawal Notification Form if the patient has withdrawn consent from the 
whole study. In this case a Consent Withdrawal Form should be offered to the patient to sign (see section 6.3. below).  
The reason for withdrawing from treatment early should be clearly documented on the End of Treatment form. The 
patient should continue to be followed-up as per protocol. 
 
At the end of trial participation, all patients must have an End of Treatment Form completed, recording whether they 
complete treatment as per protocol or withdrew from treatment early.  
6.2 
Withdrawal from endoscopy 
If a patient absolutely cannot tolerate endoscopy every 2 years, or is removed by clinical decision from routine 
endoscopic screening, the patient may remain on trial medication (if clinically indicated) and remain on trial follow up 
as “withdrawn from endoscopic follow up”. The Trial Office should be notified when a patient withdraws from 
endoscopic follow up and a File Note be created. The patient should still be seen by the local PI every 2 years even if 
not endoscoped.  
6.3 
Consent withdrawal 
Consent withdrawal means that a patient has expressed a wish to withdraw from the study in its entirety.  Under 
these circumstances, the site needs to document all relevant discussions in the patient notes and offer the patient the 
current Consent Withdrawal Form to sign. It is not compulsory for a patient to sign the Consent Withdrawal Form in 
order to withdraw from the trial, but in this case the patient’s intentions must be clearly documented in their notes.  
 
Sites must notify the Trial Office of the patient’s wishes using the Consent Withdrawal Notification form.  
 

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If the patient withdraws from any or all parts of the study, investigators are still responsible for following up any SAEs 
until resolution. 
6.4 
Reaching a trial endpoint 
Low Grade dysplasia  
Low grade dysplasia is NOT a strict AspECT trial endpoint however the AspECT laboratory need to receive a tissue 
sample in formalin (and if possible fresh tissue in RNA later) from the diseased area in order to address endpoints 
related to translational studies. Please complete an Endpoint Sampling form and send to the Trial Office. Patients 
must stay on trial medication and be followed up according to protocol. BSG guidelines suggest 6-12 monthly 
endoscopy – this is at the discretion of the local investigator. Once patients come out of the trial endoscopy schedule 
due to clinical need/patient choice, the endoscopy can be continued to be repeated for trial every 2 years from that 
date (+/- 3months) and not have to revert back to trial schedule.  
 
High Grade dysplasia 
When a patient is diagnosed with high grade disease, they should be withdrawn from trial medication and transferred 
to standard care as per local procedure. An End of Treatment form should be completed. Both formalin and fresh 
tissue (RNA later) from the diseased area should be collected for the trial and sent to the AspECT laboratory. An 
Endpoint Sampling form should be completed and sent to the Trial Office. Patients should be treated and followed up 
as per BSG and MDT guidance but for the purpose of the trial they should additionally continue to be followed up (off 
trial medication) as per trial protocol (annual follow-up, 2 yearly endoscopies and biopsy collection). The subsequent 
management of the HGD should be notified to the Trial Office on the annual Follow-up Form (e.g. continued 
surveillance, endoscopic mucosal resection, radio frequency ablation, argon plasma coagulation, laser therapy, 
minimal access surgery, oesophagectomy or other and any combinations). 
 
Oesophageal adenocarcinoma 
When a patient is diagnosed with OA, they should be withdrawn from trial medication and transferred to standard 
care as per local procedure. An End of Treatment form should be completed. Both formalin and fresh tissue (RNA 
later) from the diseased area should be collected for the trial and sent in formalin to the AspECT laboratory. An 
Endpoint Sampling form should be completed and sent to the Trial Office. Patients should be treated and followed up 
as per BSG and MDT guidance but for the purpose of the trial they should additionally continue to be followed up (off 
trial medication) as per trial protocol (annual follow-up, 2 yearly endoscopies and biopsy collection). The subsequent 
management of the OA should be notified to the Trial Office on the annual Follow-up Form (e.g. continued 
surveillance, endoscopic mucosal resection, radio frequency ablation, argon plasma coagulation, laser therapy, 
minimal access surgery, oesophagectomy or other and any combinations). 
6.5 
Death 
If a patient dies, an End of Treatment Form and a Death Form should be completed and sent to the Trial Office 
immediately. Deaths resulting from SAEs must be reported on the trial SAE report form instead of the Death Form. 
 
7 
SAMPLES FOR LABORATORY ANALYSIS 
7.1 
Samples to be analysed in local Trust’s laboratories 
Pathology 
Biopsy samples are collected from patients participating in the trial. Patients were endoscoped at baseline (the 
endoscopy prior to randomisation is defined as the baseline visit for patients recruited retrospectively) and thereafter, 
will be endoscoped at approximately 2 yearly intervals from the date of randomisation (+/- 3 months either side). At 
each endoscopy any macroscopic abnormality of the Barrett’s metaplasia will be biopsied for formalin fixation and 
histological assessment for dysplasia.  
The routine diagnostic pathology samples taken at endoscopy will be labelled, processed and reported according to 
local hospital protocols.   
7.2 
Samples to be sent to and analysed in a Trial Laboratory 
All samples sent to the Trial Laboratory should be labelled with the trial code, trial patient number, and date taken.  
Should the laboratory receive any samples carrying unique patient identifiers, the recipient must immediately 
obliterate this information and re-label. The study site will be informed of the error. In order to create a unique tissue 

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bank, extra samples must be collected for submission to the tissue bank in addition to the usual diagnostic samples 
collected during the endoscopy. The new tissue bank will be the Arden Biobank based at the University Hospitals of 
Coventry and Warwick. 
7.2.1 
Research biopsies in formalin 
Oesophageal biopsies for the AspECT trial must be performed in the following manner every 2 years or when a patient 
is diagnosed with low grade dysplasia, high grade dysplasia or oesophageal adenocarcinoma:  
 
Research biopsies (1 each for formalin, 3 in total) must be taken from:  
a. The unaffected squamous oesophagus.  
b. Just below the squamo-columnar junction. 
c. 
Below the gastro-oesophageal junction.  
The research biopsies should be submitted to the Trial Laboratory in formalin solution as per the SOPs provided by the 
laboratory. In addition for longer segments of Barrett’s oesophagus, extra discretionary biopsies for metaplastic 
segments are encouraged to achieve adequate sampling. 
7.2.2 
Formalin fixed paraffin embedded tissue blocks 
Formalin fixed paraffin embedded (FFPE) tissue blocks were requested from the local pathology lab for patients who 
were recruited retrospectively and therefore did not have trial biopsy samples collected at baseline, or for patients for 
whom biopsy samples for the Trial Laboratory were not collected during a follow-up endoscopy. These should be sent 
to the Trial Laboratory. FFPE blocks will be returned at the end of the trial unless they are required sooner in which 
case they will be returned on request. These tissues will be anonymised. 
7.2.3 
Fresh specimens in RNA later solution  
All sites which have recruited 25 or more patients should additionally provide fresh tissue specimens from the normal 
oesophagus, Barrett’s oesophagus, and fundus (3 in total), using RNA Later solution which will be supplied by the Trial 
Laboratory and should be submitted to the laboratory as per the SOPs provided. This is compulsory for sites which 
have recruited 25 or more patients as these tissues are required for secondary endpoints and these larger sites 
contribute 80% of the patients. DNA and RNA will be extracted from additional samples in RNA later (although in 
occasional circumstances paraffin embedded material may be used when the former isn’t available) for SNP analysis 
and micro array analysis. 
7.2.4 
Blood samples 
Blood samples are collected from all patients at baseline, between 4 and 6 years post randomisation, plus at 8 and 10 
(if patients re-consented) years post randomisation to assess cancer and cardiovascular risk factors. The remainder 
will be stored for analysis of circulating genetic mutations as and when reliable assays become available. Patients who 
did not provide a blood sample at any of these visits or whose sample was collected but found to be clinically 
unsuitable will be asked to provide a blood sample at the next follow-up visit. The blood tubes and packaging to post 
samples to the Trial Laboratory are provided by the laboratory. The procedure for taking blood is provided with the 
supplies. Samples should not be taken from patients who are known to be HIV, HBV or HCV positive.  Samples which 
may contain any other infectious material should not be submitted. 
7.3 
Helicobacter testing 
Helicobacter testing can be completed in two ways; either a blood or biopsy sample (preferred) maybe taken for 
diagnosis at local pathology lab or a Clo test may be taken on a biopsy sample during the endoscopy. In the case of the 
latter, the result this should be recorded in the relevant section of the Endoscopy and Pathology CRF.   If the initial 
biopsy test is positive then patients should be tested post treatment with a breath test.  If the Clo test is the initial test 
and it is negative it is preferable that serum testing is done in these individuals at some point during the study. This 
may be done from the donated serum. All patients should have their Helicobacter Pylori status checked at least once 
during the study. At the end of the trial all patients should have Helicobacter Pylori status noted even if eradicated (as 
eradication can be unsuccessful in 10% of cases). 
7.4 
Clinical reporting of exploratory research assay results 
The results of the AspECT trial research assays are exploratory and are not intended to influence the individual 
patient’s medical care. Findings will not be reported routinely to the responsible clinician except in the unlikely event 
that the result might be beneficial to the patient’s clinical management. 

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7.5 
Trial sample retention at end of study 
Trial samples collected from AspECT patients will fall under the custodianship of the ChOPIN trial which runs under its 
own separate approval, REC Ref: 06/Q1603/07 (East London Research Ethics Committee 1). The CI for ChOPIN is also 
Prof Jankowski. Laboratories are instructed to retain any surplus samples pending instruction from the Chief 
Investigator on use, storage or destruction.  It is possible that new or alternative assays may be of future scientific 
interest. At the end of the research study, any surplus samples may be retained for use in other projects that have 
received ethical approval.  Hence, any surplus study samples may be transferred to a licensed tissue bank where they 
will be managed in accordance with applicable host institution policies and the Human Tissue Act (HTA) requirements.  
7.6 
Withdrawal of consent for sample collection and/or retention 
A patient may withdraw consent to provide samples for research at any time without giving a reason. The Investigator 
must ensure that their wishes are recorded in their medical record and will inform the Trial Office accordingly. The 
investigator should discuss with patients the valuable use of samples that have already been provided and under 
circumstances where these samples have already been processed and anonymised, it would not be possible to 
destroy such samples. 
 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS)  
8.1 
Name of IMPs 
Esomeprazole (Nexium) 
Aspirin  
8.2 
Treatment dose 
Patients receive either continuous PPI 20mg/day or continuous PPI 80mg/day with or without aspirin 300mg/day. No 
washout period was required for individuals already on aspirin or PPI to allow baseline blood tests and biopsy to be 
assessed easily.   
If patients are on low dose aspirin for medical reasons (i.e. previous IHD or CVA rather than self-prescribed) they were 
randomised to either continuous PPI 20mg/day or continuous PPI 80mg/day arms. They are allowed to continue to 
take their aspirin therapy. 
Patients are allowed to default from the prescribed drugs or doses for up to six months at one time or for a total of 12 
months during the length of the trial. A drug holiday longer than this time period will be deemed a protocol violation 
but the patient should still be kept on follow-up. 
8.3 
Duration of treatment 
Patients should remain on trial medication for the duration of follow-up period of 8 years or 10 years (if the patients 
re-consented) unless they withdraw or are withdrawn from treatment or withdraw consent.  
8.4 
Special precautions 
Aspirin 
Aspirin - Gastro-intestinal 
The risk of significant gastro-intestinal complications associated with NSAIDs is not completely eliminated by low dose 
aspirin.  Ulcers and upper GI perforations, ulcers or bleeds (PUBs) did occur in osteoarthritis patients treated with 
aspirin.   
 
Aspirin - Hepatic 
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has 
occurred, should be evaluated and treatment should be discontinued if persistently abnormal tests are detected 
(bilirubin > 100, ALT > 150 and caution used when any enzymes are 3x upper limit of normal). 
 
Aspirin - Effects on ability to drive and operate machinery 
Patients who experience dizziness or somnolence whilst taking aspirin should refrain from driving or operating 
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Esomeprazole 
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase 
insufficiency should not take this medicine. 
 
Esomeprazole - Hepatic insufficiency 
The metabolism of esomeprazole in patients with mild to moderate liver dysfunction is similar to that in patients with 
symptomatic Gastro Oesophageal Reflux Disease (GORD) with normal liver function. The metabolic rate is decreased 
in patients with severe liver dysfunction resulting in a doubling of the area under the plasma concentration-time curve 
of esomeprazole. Therefore, a maximum dose of 20mg should not be exceeded in patients with severe dysfunction i.e. 
advanced liver failure with a combination of ascites, encephalopathy and varices and other biochemical or 
haematological features.  Esomeprazole or its major metabolites do not show any tendency to accumulate with once 
daily dosing. 
 
Esomeprazole - Renal Insufficiency 
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the 
excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of 
esomeprazole is not expected to be changed in patients with impaired renal function.  
 
Other special precautions 
Asthma: Patients with asthma or other respiratory disease were entered into the trial provided that there was no 
history of side effects or complications when taking aspirin.  If a patient with asthma was randomised to one of the 
aspirin arms of the trial, then monitoring of their condition may have been indicated.  If the patient’s asthma worsens 
due to the aspirin, then the aspirin should be ceased. 
 
Hepatic and renal function: If hepatic and renal function tests are indicated, and the result is above normal limits for 
any test, then the patient should not have been entered into the trial if the local investigator feels it is appropriate.  
Please note, hepatic and renal function tests are not mandatory.  If done, we consider ALT, GGT and bilirubin should 
not be over x3 the upper end of the normal range. In that case we would recommend cessation of aspirin especially if 
the platelets are less than 60 and the INR is prolonged greater than 1.6. If further advice is required, please contact 
the Trial Office on 01865 617011. 
 
Osteoporosis: The potential risk of osteoporosis/osteoporotic fracture including hip fracture, in relation to PPI 
(including esomeprazole) exposure has been discussed in the published literature but no causal link has been 
established. However, patients with suspected osteoporosis will be investigated by bone scan. If the results of the 
bone scan indicate a requirement for therapy according to local guidelines, they may be prescribed calcium and 
vitamin D or indeed biphosphonates according to local practice and this must be noted in the CRFs. 
 
Cardiac Disease: There is caution required for those on clopidogrel as esomeprazole may decrease bioavailability. 
Patients should be advised by their local investigator. In the management of these patients the SmPC of clopidogrel 
should be considered: http://www.medicines.org.uk/emc/medicine/24206. Trial staff are asked to document patients 
who are prescribed clopidogrel using the clopidogrel CRF. 
 
Witholding drugs prior to endoscopy 
There is no need to withhold esomeprazole therapy prior to endoscopy.  Aspirin, as with all antiplatelet drugs, can 
aggravate bleeding in an unpredictable way. BSG guidelines regarding suspension of aspirin prior to endoscopy should 
be followed. The decision lies with the local PI.  
 
Investigators should ask specifically about these special precautions on each return visit and record this on the Follow-
Up CRFs. 
8.5 
Dose modification  
Aspirin dose reduction: 
Dyspepsia is a risk factor for NSAID GI bleeding (Aalycke, 1999). If the patient has dyspepsia and it is thought this 
might be due to aspirin therapy the patient may decrease from 300mg/day to 150mg/day at the decision of the local 
PI. If symptoms still persist after 3-7 days the patient can be decreased to 75mg/day. If the symptoms have not 
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e.g. Thursday and Sunday). Further symptoms or a frank GI bleed (malaena or vomiting of blood) should be clinically 
reviewed and may lead to immediate cessation of aspirin. 
Esomeprazole dose changes:  
If the patient is receiving 80mg/day of esomeprazole and expresses a wish to take a lower dose, the dose can be 
changed to 40mg/day indefinitely at the decision of the local PI. This should be prescribed as 20mg BD. 
 
Alternatively if the patient is on 20mg/day of esomeprazole and still has reflux symptoms, the dose can be increased 
to 40mg/day indefinitely. This should be prescribed as 20mg BD. 
 
Patients are allowed 6 months of another treatment option or a break from treatment for any 6 month period or 12 
months in total over the entire trial length of up to 10 years.  
 
All dose changes or breaks in treatment must be documented on a Change of Treatment Form. 
8.6 
Compliance 
Compliance should be checked by asking patients to bring all their unused/remaining trial medicines (empty, opened 
or unopened) with them when they visit the hospital pharmacy to pick up their new drug supply. 
8.7 
Management of overdose 
Aspirin 
Symptoms of overdose include dizziness, tinnitus, sweating, nausea, vomiting, hyperventilation, fever and 
restlessness. Treatment includes gastric lavage or emesis, rehydration and forced alkaline diuresis. Serum electrolytes, 
particularly potassium and acid base balance should be treated accordingly. Haemo or peritoneal dialysis may be 
necessary in the case of severe overdose. 
Esomeprazole 
There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280mg 
were gastrointestinal symptoms and weakness. Single doses of 80mg esomeprazole were uneventful. No specific 
antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any 
case of overdose, treatment should be symptomatic and general supportive measures should be utilised. 
8.8 
Concomitant medication and non-drug therapies 
Concomitant medication may be given as medically indicated.  At every annual follow-up, all patients are asked to 
provide a complete list of prescription and over-the-counter medications that have been taken for more than 2 weeks 
during the last 12 months. Details (including indication, doses, frequency and start / stop dates) of concomitant 
medication taken during the trial until the completion of the off-study visit must be recorded in the medical record 
and the appropriate CRF. 
8.9 
 (Potential) Drug Interactions 
Aspirin 
Alcohol and corticosteroids may enhance the effects of aspirin on the gastrointestinal tract. Aspirin may enhance the 
effects of coumarin anticoagulants and oral hypoglycaemics of the sulphonylurea type. The toxicity of methotrexate 
may be enhanced by concomitant use of aspirin. Aspirin diminishes the action of uricosurics. Post marketing reports 
have suggested that the plasma concentration of lithium could be increased whilst taking aspirin [25]. Stop aspirin if 
there is a chance of bleeding, such as INR > 1.6 or platelets < 60. If INR is between 1.3 and 1.6 the local clinician can 
judge the collective risk/benefit of aspirin use or if in doubt ask the Trial Office. If the patient is also on other 
anticoagulants such as warfarin, aspirin should only be used if necessary for other conditions such as CVA prophylaxis 
or post-coronary stent insertion as prescribed by the physician caring for this problem.  
Esomeprazole 
The decreased intragastric acidity during treatment with esomeprazole might increase or decrease the absorption of 
drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of the other inhibitors of 
acid secretion or antacids, the absorption of ketoconazole, itraconazole and erlotinib can decrease and the absorption 
of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) 
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Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is 
combined with drugs metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin 
etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should 
be considered especially when prescribing esomeprazole for on-demand therapy. Concomitant administration of 
30mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. 
 
Concomitant administration of 40mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in 
epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with 
esomeprazole is introduced or withdrawn. Concomitant administration of 40mg esomeprazole to warfarin-treated 
patients in a clinical trial showed that coagulation times were within the accepted range. However a few isolated 
cases of elevated INR of clinical significance have been reported post marketing, during concomitant treatment. 
Monitoring is recommended when initiating and ending concomitant treatment. 
 
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxycillin or 
quinidine. 
 
There is no firm evidence suggesting a required change to the way esomeprazole or clopidogrel are prescribed but the 
MHRA suggests the concomitant use of clopidogrel and omeprazole or esomeprazole is to be discouraged unless 
considered essential.  
See Nexium IB and Summary of Product Characteristics as well as 
http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON076501 for further information. Any 
important updates may be provided by newsletters. 
 
Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 
inhibitor, clarithromycin (500 mg bid) resulted in a doubling of the exposure (AUC) to esomeprazole. Dose adjustment 
of esomeprazole is not required. 
 
For further information please refer to the Investigator Brochure (IB) and Summary of Product Characteristics (SmPC) 
provided.  Copies are available from the Trial Office. 
9 
DRUG MANAGEMENT 
9.1 
Drug supplies 
Commercial esomeprazole (Nexium) tablets are supplied by AstraZeneca free of charge for a period of 8 or 10 
years (if the patients re-consented) from the date of each patient’s randomisation or until 28th February 2017 
(we will allow +3 months for appointment slippage). The last delivery of study drug will be on or around 31st 
August 2016. Esomeprazole is supplied in blister packs of 2 x 28 tablets.  
Aspirin should be supplied by the local hospital pharmacy. There is no specification on the brand of aspirin, 
although soluble aspirin should be supplied wherever possible. 
Patients are requested to come to the hospital pharmacy every 6 months to return unused medication and pick 
up a new 6-month supply. In some cases where this is not possible, special dispensation by the local research 
team may allow the medication to be posted as per local procedures. However, there is no central funding 
available to cover postage costs.  
9.2 
Drug ordering 
The Trial Office will calculate the quantity of 20mg and 40mg esomeprazole required for the year based on the 
number of patients taking each dose (20mg/40mg/80mg). The Trial Office will order the IMP and Astra Zeneca 
will deliver the IMP to the hospital on a 6-monthly basis until 31st August 2016. Ad hoc drug orders are not 
possible.   
9.3 
IMP Receipt 
Upon receipt of trial medication, a fax-back confirmation form (included in the delivery) included in the 
delivery, must be signed and faxed from the hospital pharmacy to the Trial Office Fax: 01865 617010 

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If supplies are damaged on arrival, contact the Trial Office. Damaged supplies should be destroyed on site and a 
Drug Destruction Form completed and a copy forwarded to the Trial Office by Fax or email. 
9.4 
Handling and storage 
Esomeprazole should not be stored above 30C. There is no minimum storage temperature specified, although 
Astra Zeneca have confirmed that the drug remains stable at sub-zero temperatures. Store in the original 
package (blister). Esomeprazole has a shelf life of 3 years. Aspirin should be stored in a dry place below 25C. 
Aspirin has a shelf life of 3 years.  
9.5 
Labelling  
The responsible Pharmacy will ensure that IMP supplies dispensed for trial use are appropriately labelled in 
accordance with all applicable regulatory requirements.  
Labelling of trial esomeprazole is to be carried out by the site pharmacies. MHRA approved labels for 
esomeprazole for clinical trial use will be supplied by the Trial Office. 
MHRA approved labels for aspirin for clinical trial use are not required and labels for aspirin will not be supplied 
by the Trial Office. Aspirin must be labelled as per normal dispensing requirements. 
9.6 
Dosing dispensing 
Both esomeprazole and aspirin should be dispensed from the participating hospital’s pharmacy every six 
months (from date of first trial prescription). 
9.7 
Drug accountability 
Participating pharmacies must maintain a Dispensing and Returns Log to document all aspirin and 
esomeprazole dispensed to trial participants.  This Log must be available for inspection by AspECT staff and the 
MHRA if required.  Each Dispensing and Returns Log must be copied and the original returned to the Trial 
Office once the patient has completed their treatment. The photocopy must be retained in the Pharmacy File.  
9.8 
Drug returns from patients 
Patients must return unused tablets to their local trial pharmacy for accountability and compliance checks.  
9.9 
Drug destruction 
Unused drugs must be destroyed on site as per local practice and a Drug Destruction Form completed. The 
Drug Destruction Form must be faxed to the Trial Office Fax: 01865 617010 
 
10 ASSESSMENT OF SAFETY 
The Investigator must monitor each patient for clinical and laboratory evidence of adverse events at each contact with 
the participant throughout the study. During the course of the annual Follow Up, all patients should be asked directly 
if they have had any hospital admissions or events which should be reported as a SAE (see definition in Section 10.1). 
Their patient notes should also be checked for such occurrences. All SAEs should be reported to the Trial Office as 
described in Section 10.4. 
 
Adverse event monitoring starts from the time the patient commences study medication until they complete the trial. 
An SAE which occurs more than 30 days after a patient has stopped taking trial medication is not required to be 
reported, unless the event is related to a trial procedure (e.g. biopsy or blood collection). All SAEs will be followed to a 
satisfactory conclusion. Any SAEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated. 
 
All SAEs reported to the Trial Office will be processed according to internal SOPs. The Trial Office may request 
additional information for any SAE as judged necessary. 
 

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10.1 Adverse event definitions  
An Adverse Event or experience (AE) is any untoward medical occurrence in a study subject temporally associated 
with the administration of an investigational medicinal product (IMP) or a comparator product, whether or not 
considered related to the IMP or a comparator product. An AE can therefore be any unfavourable and unintended 
sign, symptom, disease (new or exacerbated) and /or significant abnormal laboratory or physiological observation 
temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure 
to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
 
A Serious Adverse Event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
 
Results in death 
 
 
Is life-threatening  
This refers to an event in which the subject was at risk of death at the 
time of the event.  It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
 
Requires in-patient hospitalisation  
or prolongs existing inpatient 
hospitalisation  
 
In general, hospitalisation signifies that the subject has been admitted 
(usually involving at least an overnight stay) at the hospital or 
emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or out-patient setting.  
Hospitalisation for a pre-existing condition, including elective 
procedures, which has not worsened, does not constitute a serious 
adverse event. Complications that occur during hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfils any other 
serious criteria, the event is serious.  When in doubt as to whether 
hospitalisation occurred or was necessary, the AE should be 
considered serious. 
Results in persistent or significant 
incapacity or disability 
This means a substantial disruption of a person’s ability to conduct 
normal life functions.  It does not include experiences of relatively 
minor medical significance or accidental trauma (e.g. sprained ankle), 
which do not constitute a substantial disruption. 
Is a congenital anomaly or birth 
defect 
 
Is any other medically other 
medically important event 
Defined as an event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above. 
 
 
 
An Adverse Drug Reaction (ADR) is an AE which is considered to be causally related to any dose of the IMP.  This 
means that a causal relationship between the IMP and the AE is at least a reasonable possibility, i.e. the relationship 
cannot be ruled out. 
 
An Unexpected Drug Reaction is an adverse drug reaction, the nature or severity of which, is not consistent with 
applicable product information (referring to information in the SmPC or IB). 
 
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse drug reaction, the nature or 
severity of which is not consistent with the applicable product information (e.g. Investigator’s Brochure for an 
unapproved investigational product or SmPC for an approved product). 
 
10.2 Determining adverse event causality 
The Investigator will assess and classify the relationship of an AE to the trial IMP as follows: 
 
Classification 
Relationship 
Definition 

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Drug-related 
(reasonable 
possibility) 
Definitely Related 
 
 Starts within a time related to the study drug administration 
and 
 No obvious alternative medical explanation. 
 
Probably Related 
 
 Starts within a time related to the study drug administration 
and 
 Cannot be reasonably explained by known characteristics of 
the patient’s clinical state. 
 
Possibly Related 
 
 Starts within a time related to the study drug administration 
and 
 A causal relationship between the study drug and the 
adverse event is at least a reasonable possibility. 
 
No reasonable 
possibility of being 
drug related 
Probably Not 
Related 
 
 The time association or the patient’s clinical state is such that 
the study drug is not likely to have had an association with 
the observed effect. 
 
Definitely Not 
Related 
 
 The AE is definitely not associated with the study drug 
administered. 
 
 
 
The Investigator must endeavour to obtain sufficient information to confirm the causality of the adverse event (i.e. 
relation to study drug, other illness, progressive malignancy etc.) and give their opinion of the causal relationship 
between each AE and study drug.  This may require instituting supplementary investigations of significant AEs based 
on their clinical judgement of the likely causative factors and/or include seeking a further specialist opinion. 
10.3 Expected adverse events 
Section 4.8 of the SmPC for aspirin lists all the expected side effects associated with the use of aspirin. A copy of this 
document must be held in the Site File for reference.   
 
Section 4.8 of the SmPC for 20mg and 40mg esomeprazole lists all the expected side effects associated with the use of 
20mg and 40mg esomeprazole. A copy of this document must be held in the Site File for reference. 
 
For patients receiving the 80mg esomeprazole dose, Section 4.8 of the IB lists all the expected side effects associated 
with the use of esomeprazole. A copy of this document must be held in the Site File for reference.  
 
A list of the most noteworthy expected side effects known at the time of writing is given below for ease of reference. 
 
Aspirin 
Side effects are grouped on the basis of System Organ Class. Within each system organ class the frequencies are 
defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). 
 
Aspirin: Undesirable Effects 
Blood and lymphatic system 
disorders 
Common: 
Increased bleeding tendencies. 
Rare: 
Thrombocytopenia, agranulocytosis, aplastic anaemia. 
Not known: 

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Cases of bleeding with prolonged bleeding time such as epistaxis, gingival bleeding. Symptoms 
may persist for a period of 4–8 days after acetylsalicylic acid discontinuation. As a result there 
may be an increased risk of bleeding during surgical procedures. 
Existing (haematemesis, melaena) or occult gastrointestinal bleeding, which may lead to iron 
deficiency anaemia (more common at higher doses). 
anaemia, haemolytic anaemia, hypoprothrombinaemia, pancytopenia, occult blood loss, 
elevated transaminase levels 
Immune system disorders 
Rare: 
Hypersensitivity reactions, angio-oedema, allergic oedema, anaphylactic reactions including 
shock. 
Metabolism and digestive 
system disorders 
Not known: 
Hyperuricemia. 
Nervous system disorders 
Rare: 
Intracranial haemorrhage 
Not known: 
Headache, vertigo. 
Ear and labyrinth disorders 
Not known: 
Reduced hearing ability; tinnitus. 
Vascular disorders 
Rare: 
Haemorrhagic vasculitis. 
Respiratory, thoracic and 
mediastinal disorders 
Uncommon: 
Rhinitis, dyspnoea. 
Rare: 
Bronchospasm, asthma attacks. 
Reproductive system and 
mammary disorders 
Rare: Menorrhagia 
Gastrointestinal disorders 
Common: 
Dyspepsia. 
Rare: 
Severe gastrointestinal haemorrhage, nausea, vomiting. 
Not known: 
Gastric or duodenal ulcers and perforation which can occasionally be major (may develop 
bloody or black tarry stools, severe stomach pain and vomiting blood), gastrointestinal irritation 
(mild stomach pain), erosions, heartburn, Fatalities have occurred. 
Hepatobiliary disorders 
Not known: 
Hepatic insufficiency, hepatitis (particularly in patients with SLE or connective tissue disease) 
Skin and subcutaneous 
tissue disorders 
Uncommon: 
Urticaria. 
Rare: 
Steven-Johnsons syndrome, Lyells syndrome, purpura, erythema nodosum, erythema 
multiforme. 
Renal and urinary tract 
disorders 
Not known: Impaired renal function 
Body as a whole – general 
disorders 
Not known: 
Salicylism – (mild chronic salicylate intoxication may occur after repeated administration of large 
doses, symptoms include dizziness, tinnitus, deafness, sweating, nausea, vomiting, headache 
and mental confusion, and may be controlled by reducing the dose) 
 
 
Children 
Aspirin may be associated with the development of Reye's Syndrome (encephalopathy and hepatic failure) in children 
presenting with an acute febrile illness. 
 

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 Esomeprazole: Undesirable Effects 
 
 
Common  
(1/100) 
Uncommon 
(1/1000 and <1/100) 
Rare 
(1/10000 and <1/1000) 
Very rare 
<1/10000 
Blood and lymphatic 
system disorders 
 
 
Leukopenia, 
thrombocytopenia 
Agranulocytosis, 
pancytopenia 
Immune system disorders 
 
 
Hypersensitivity reactions 
e.g. angioedema and 
anaphylactic reaction/shock 
 
Metabolism and nutrition 
disorders 
 
Peripheral oedema  
Hyponatraemia 
Hypomagnesaemia; severe 
hypomagnesaemia may also 
result in hypocalcaemia. 
Hypomagnesaemia may also 
result in hypokalaemia. 
Psychiatric disorders 
 
Insomnia  
Agitation, confusion, 
depression 
Aggression, hallucination 
Nervous system disorders 
Headache 
Dizziness*, paraesthesia, 
somnolence  
Taste disturbance 
 
Eye disorders 
 
 
Blurred vision* 
 
Ear and labyrinth disorders 
 
Vertigo 
 
 
Respiratory, thoracic and 
mediastinal disorders 
 
 
Bronchospasm 
 
Gastrointestinal disorders 
Abdominal pain, 
diarrhoea, flatulence, 
nausea/vomiting, 
constipation 
Dry mouth 
Stomatitis, gastrointestinal 
candidiasis 
Microscopic colitis 
Hepatobiliary disorders 
 
Increased liver enzymes 
Hepatitis with or without 
jaundice  
Hepatic failure, hepatic 
encephalopathy 
Skin and subcutaneous 
tissue disorders 
 
Dermatitis, pruritus, 
urticaria, rash 
Alopecia, photosensitivity  
 
Erythema multiforme, 
Stevens-Johnson syndrome, 
toxic epidermal necrolysis 
(TEN) 
Muscoloskeletal, 
connective tissue and 
bone disorders 
 
 
Arthralgia, myalgia 
Muscular weakness 

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Common  
(1/100) 
Uncommon 
(1/1000 and <1/100) 
Rare 
(1/10000 and <1/1000) 
Very rare 
<1/10000 
Renal and urinary 
disorders 
 
 
 
Interstitial nephritis 
Reproductive system and 
breast disorders 
 
 
 
Gynaecomastia 
General disorders and 
administration site 
conditions 
 
 
Malaise, hyperhidrosis 
 
 
*The SmPC for esomeprazole has been updated with the following: “Esomeprazole has minor influence on the ability to drive or use machines. Adverse reactions such as dizziness 
(uncommon) and blurred vision (rare) has been reported. If affected patients should not drive or use machines.”

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10.4 Reporting of SAEs 
In the case of a Serious Adverse Event, an SAE Form must be completed as soon as possible and faxed to 01865 
227038. This should be done within 24 hours of becoming aware of the event. If the SAE has not been reported within 
the specified timeframe, a reason for lateness must be provided when sending the SAE Form.  
 
Each separate SAE episode must be recorded.  For example, if an SAE resolves completely or resolves to baseline and 
then recurs or worsens again, this must be recorded as a separate SAE. For SAEs to be considered intermittent, the 
events must be of similar nature and severity. 
 
SAEs for which there is no reasonable possibility of being drug related to one or both of the IMPs should be reported 
by completing sections 1-5 and the Reporting Information in section 10 of the SAE Form. Sites must provide data that 
is minimal for the assessment of the SAE, including: reason for seriousness, causality, event term and a narrative of 
the event. 
 
All other SAEs (where there is at least reasonable possibility of it being related to trial medication) i.e. SARs - should be 
reported by completing all sections of the SAE Form. 
 
On receipt of the SAE Form, the Trial Office staff will check the SAE Form for minimal criteria, then log the SAE and 
allocate it an identifying number. The Trial Office will confirm receipt of the SAE by sending a copy of the SAE log to 
the site within 24 hours of receipt. If the site have not received notification of receipt within 24 hours, it is the 
responsibility of site staff to confirm that the Trial Office have received the SAE form. For SARs the Trial Office will 
send the SAE Form to a clinical review panel who will give their opinion on the Site Investigator’s classification of the 
SAR with respect to seriousness, causality and expectedness. 
10.5 Suspected Unexpected Serious Adverse Drug Reactions (SUSARs) 
A Suspected Unexpected Serious Adverse Drug Reaction (SUSAR) is a serious adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s Brochure for an unapproved 
investigational product or SmPC for an approved product). SUSARS therefore are suspected to be at least possibly 
related to the study agent, fulfil the definition of a SAE, but the nature and severity of which are not consistent with 
the applicable product information. 
 
All SUSARS must be reported to the responsible Authority and main REC by the Trial Office within the required 
timelines: 
 
 
Fatal or life threatening SUSARs will be reported within 7 days of the Trial Office receiving the initial report. 
Any additional information will be reported within eight days of sending the first report. 
 
All other SUSARs will be reported within 15 days of the Trial Office receiving the initial report. 
 
The Trial Office will report SUSARs according to their SOPs. In addition, other safety issues may qualify for expedited 
reporting where they might materially alter the current risk assessment of an IMP or be sufficient to change IMP 
administration or the overall conduct of the trial.  
10.6 Follow-up of Serious Adverse Events  
If new or amended information on a reported SAE becomes available, the Investigator should update the existing 
form, without obscuring any initial information.  All new data must be initialled and dated so that all changes are 
clearly identified.  
 
Follow-up will continue until all the necessary safety data for the event has been gathered. Any SAE that is ongoing 
when a subject completes his/her participation in the trial must be followed until any of the following occurs: 
 
The event resolves or stabilizes; 
 
The event returns to baseline condition or value (if a baseline value is available); 
 
The event is attributed to other agent(s) or to factors unrelated to study conduct. 

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10.7 Reporting Adverse Events on the CRF 
Adverse events (non-serious) need only be recorded if the event leads to the patient withdrawing from study 
medication. Details must be recorded on the End of Treatment Form. 
 
Terms and Grading of Events 
The NCI CTCAE Version 4.0 (currently up to Version 4.03) must be used to report AEs and where possible use the 
Lowest Level Terms provided.  Where indicated on the form, provide the severity grade for each AE/SAE. 
10.8 Events exempt from being reported as AE/ SAEs 
Progression of underlying disease 
Trial endpoints will be reported on Follow-Up CRFs and are not be required to be reported as an SAE. 
Death on study 
Provided it is not as a result of an SAE, then a death during the course of the study should be recorded on the Death 
CRF. Deaths arising from SAEs should be reported using the SAE Form. 
10.9 Informing Investigators of new safety information 
The Trial Office or the Chief Investigator will ensure that all investigators are kept informed in a timely manner as new 
safety profile information becomes available. Investigators are responsible for briefing their study team and onward 
transmission to R&D office as appropriate. 
11 PREGNANCY  
Pregnancies (in a participant or partner) occurring within 30 days of the last IMP dose require expedited reporting.  A 
Pregnancy Notification Form should be completed and faxed to the Trial Office within the same timelines as an SAE. 
Women who become pregnant should be withdrawn from the interventions at the earliest opportunity.  All reported 
pregnancies should be followed and the outcome reported using the same form. If the outcome of the pregnancy 
meets any of the criteria for seriousness, it must also be reported as an SAE.  Examples of pregnancy outcomes that 
are SAEs: 
 
Reports of congenital anomalies or developmental delay, in the foetus or the child. 
 
Reports of foetal death and spontaneous abortion.           
 
Reports of suspected adverse reactions in the neonate that are classified as serious. 
12 DEFINING THE END OF TRIAL  
For this study the end of the trial is defined as “The last visit of the last patient after a minimum of 8 years follow-up in 
the trial (LPLV)”.  
 
The Sponsor and the Chief Investigator reserve the right to terminate the study earlier at any time. In terminating the 
study, they must ensure that adequate consideration is given to the protection of the participants’ best interests. 
13 STATISTICAL CONSIDERATIONS  
13.1 Primary and Secondary Endpoints 
 
PRIMARY: Time from randomisation to the first of the following: 
 
conversion from Barrett’s oesophagus to adenocarcinoma of the oesophagus (event) 
 
high grade dysplasia (event) 
 
death by all causes (event) 
 
last known follow-up (no event) 
 
SECONDARY: Time from randomisation to: 
 
adenocarcinoma of the oesophagus  
 
high grade dysplasia 
 
all-cause mortality 
 
cause-specific mortality 
Also safety, quality of life, health economics, new tumours and molecular markers. 

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13.2 Sample size and power   
Original sample size statement 
The event rate in the UK is 0.98% (95% CI = 0.67 to 1.39%) (This is higher in the UK than the USA) however to be 
cautious we have agreed on 0.76%/year (approximately half way between the UK and USA). 
 
Aspirin has a hazard ratio of 1.5 (33.3% effective) in preventing the colorectal cancer rate. Evidence from 
epidemiological studies suggests that aspirin may decrease BA rates with a hazard ratio of 1.6 to 10 (40-90%) (35-37). 
While we believe that current evidence indicates that aspirin is at least equally effective in the prevention of 
oesophageal adenocarcinoma as colorectal cancer, the role of PPI is more difficult to estimate for the reasons given 
previously. Therefore we have chosen a hazard ratio of 1.4 (28% effective) to assess weaker therapeutic effects.  
 
Compliance to repeated endoscopy is excellent with over 90% of patients coping well with repeated examinations. 
Compliance to the therapy indicates that 90% manage well with no serious side effects to PPIs or low dose aspirin 
according to drug data sheet based on over 1 million patients for PPI and millions of people with over 50 years’ 
experience for aspirin therapy. In addition evidence from other chemoprevention trials using 300mg of aspirin 
suggests that it is well tolerated over several years (< 5% side effects) UKcap study. Therefore a 20% non-compliance 
rate will be included in our calculations over and above losses calculated for loss to follow-up. Patients will be 
returning unused drugs to their local pharmacy every 6 months. The annual follow-up will be used to remind patients 
about the importance of compliance.  
 
A total of 5000 patients (1250 in each intervention group) will allow us to detect a difference in conversion rates of 
0.22% per year between the PPI and aspirin intervention. The sample size required was calculated using nQuery 
Advisor Release 4.0 based on the following: 
 
• 
Patients will be recruited over 2 years and followed up for a further 8 years. 
• 
Exponential time to conversion with a constant event rate of at least 0.76% per year 
• 
Conversion hazard ratio (drug response) of control to treatment is 1.4  
• 
Power = 80% (2-sided test at 5% level of significance).  
• 
No interaction between the effects of aspirin and PPI interventions.  
• 
A 10% loss to follow-up from NHS HSCIC flagging 
• 
A 20% non-compliance with medication 
• 
Calculations adjusted for competing causes of mortality.  A further proportion may take their medication but be 
lost to follow-up as they do not return their questionnaire and/or attend for surveillance endoscopy.  This will not 
affect the primary outcome as all-cause mortality and conversion to BA will be assessed by the Office of National 
Statistics, which has almost complete follow-up of registered subjects (we have conservatively assumed a 90% 
follow-up rate). 
Exploratory sample size statement October 2008 
Due to protocol amendments and an expected restriction on the number of patients to be recruited, an exploratory 
sample size is presented at the request of the Funders. Since the trial recruited until the end of February 2009 in the 
UK rather than to the number calculated in the original sample size, this calculation should be considered as a guide to 
the power and treatment effect size the trial should achieve. 
 
 This exploratory sample size is calculated as per the original sample size, but with  
• 
Annual rate of conversion of 1% (allowing for the composite primary endpoint of all-cause mortality and 
conversion to adenocarcinoma and conversion to high grade dysplasia.)  
Justification: Using the National Statistics figures for 2005 based on the age and gender structure of the first 2046 
patients recruited to AspECT gives a mortality rate in a year of 1.16%.  
Using the UK Barrett’s conversion rate to adenocarcinoma of at least 0.98% per year without treatment for 60% of the 
sample and 40% with a lower conversion rate of 0.66% (due to being female, have tongues of Barrett’s metaplasia or 
only 1cm of Barrett’s, or being <45 years old). Differing rates are not published for these patients so a rate of two 
thirds the UK conversion rate has been used) i.e. 0.85% conversion rate without treatment over the whole sample. 
No good estimates of rates for conversion to high grade dysplasia for the UK could be found. 
In this population, it is unlikely that the event rate for the composite primary endpoint in the control arm will be less 
than 1%. 
• 
Hazard ratio as in colorectal cancer 
• 
No adjustment for compliance 
• 
the follow-up increased to 10 years (subject to available funding) 

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Apart from limited recruitment and checking the event rate using the age/sex structure, no information or estimates 
from the current trial are used.  
 
A total of 2224 patients (approximately 556 in each intervention group) will allow us to detect a difference in 
conversion rates of 0.34% per year between low dose and high dose PPI and aspirin or no aspirin. This sample size was 
calculated using ARTMENU in STATA release 10.0 based on the following: 
• 
Patients will be recruited over 3 years and followed up for a further 10 years (subject to available funding) 
• 
Exponential time to conversion with a constant event rate of at least 1% per year without treatment  
• 
Conversion hazard ratio (drug response) of control to treatment is 1.5 (1 year conversion rate 1% no or 
 
standard treatment vs 0.66% in the treated patients) 
• 
Power = 80% (2-sided test at 5% level of significance) 
• 
No interaction between the effects of aspirin and PPI interventions 
• 
A 10% loss to follow-up from NHS HSCIC flagging 
 
13.3 Randomisation – Stratification and Standardisation 
Randomisation was by minimization with a random element. The variables were: 
 
Length of Barrett’s – tongue, <2cm, ≥2cm and ≤3cm, >3cm and ≤8cm, >8cm 
Age - 18-49, 50-59, 60-69, ≥70 
Intestinal metaplasia – yes, no 
 
These may be risk factors for the development of dysplasia and adenocarcinoma. Through using minimization with the 
same variables, women and men are randomised separately, as are those only taking part in the PPI randomisation. 
14 STATISTICAL ANALYSIS PLAN 
All analyses will be on an intention-to-treat basis. This means that patients will be analysed as they are randomised 
irrespective of the treatment actually received. The intention-to-treat population will include all patients who have 
given their informed consent and for whom there is confirmation of successful allocation of a randomisation number. 
All participants who receive one dose of IMP will be evaluable for the safety analysis.     
 
It is therefore important that every effort is made to encourage patients, including those patients who do not 
receive/complete their allocated treatment, to attend for follow-up clinic visits and complete the questionnaires to 
avoid bias in the analysis of the results. 
 
Analyses will be carried out at the 5% level of significance. The main analysis will be a comparison of A+B v C+D 
(aspirin v no aspirin) and A+C v B+D (high v low dose PPI) assuming no treatment interaction. Logrank analysis will be 
used to compare the time from randomisation to primary outcome (high grade dysplasia, adenocarcinoma of the 
oesophagus or death from all causes) for the different treatment comparisons. An Accelerated Failure Time (AFT) 
model will be constructed to adjust the treatment comparisons for length of Barrett’s metaplasia, age and occurrence 
of intestinal metaplasia (as used in the minimisation procedure). This will be repeated with Cox regression model for 
comparison with other research. Interim analyses of the primary aim were planned at 2 and 4 years after the end of 
recruitment.  
A number of patients will be randomised to the PPI comparison only; hence they will only be included in the analysis 
of the effect of high vs low dose PPI. 
Sensitivity analysis will use the per protocol sample and the possibility of interaction between the two treatments will 
be investigated. 
 
Health economics: An economic analysis will be undertaken, which compares the mean per patient cost of the 
alternative trial arms using resource use data collected in the trial and appropriate UK unit costs. Differential costs 
could then be related to conversion to BA. To increase the value to decision makers, the economic data collected in 
the trial could be synthesised with other evidence by relating long-term (lifetime) health service costs to long-term 
quality-adjusted life expectancy. The analysis would be based on a state transition model, which would characterise 
how patients progress from BM to dysplasia and to BA competing risk of death. The annual cost and health-related 
quality of life associated with each stage of the disease will be estimated using trial data collected and literature. In 
addition, some limited data collection in appropriate non-trial patients would be undertaken. Assessments will be 
completed at baseline and every two years at the time of endoscopy. 

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14.1 Final analysis 
This trial completed recruitment within 4 years of opening to recruitment. The DSMC will decide the time point for the 
final analysis. Final analysis is planned 8 years after the end of patient recruitment and will be guided by the fulfilment 
of the sample size calculation to be when there are at least 200 events and a median of at least 5 years follow up. 
 
15 TRIAL COMMITTEES 
15.1 Trial Management Group (TMG) 
The Chief Investigator will chair a TMG responsible for overseeing the successful conduct and publication of the trial. 
The TMG will provide regular progress reports to the Trial Steering Committee.  
15.2 Data and Safety Monitoring (DSMC) 
An independent Data and Safety Monitoring Committee (DSMC) is established for this trial.  This committee meet to 
assess the trial data; frequency will depend on event rates, and may be increased upon request by the committee.  
The DSMC will monitor protocol compliance as well as toxicity and serious adverse events taking into account relevant 
worldwide information.  The main outcomes will be analysed as stated above and in the analysis plan. The DSMC will 
run in accordance with its charter. 
15.3 Trial Steering Committee (TSC) 
The TSC (at least 3 members including an independent chair) provide overall supervision of the safe and effective 
conduct of the trial according to its terms of reference. It reviews trial progress against agreed milestones, adherence 
to protocol, patient safety and consider new information. The TSC has the authority to recommend study closure 
where appropriate. The TSC will run in accordance with its charter. 
16 DATA MANAGEMENT 
16.1 Database considerations 
Data management will be performed by the Trial Office via a bespoke trial database. 
16.2 Case reports forms (CRFs) 
AspECT collects data on paper CRFs. The Investigator and study site staff (as noted on the Site Contact and 
Responsibility Sheet) should ensure that data collected on each subject is recorded in the CRF as accurately and 
completely as possible. Please ensure that: 
 
The relevant CRFs are completed legibly, accurately and as thoroughly as possible. 
 
All CRF data are verifiable in the source documentation or the discrepancies must be explained.  
 
CRF sections are completed in a timely fashion, as close to the visit or event being recorded as possible. 
 
Data queries are resolved and documented by authorised study staff, giving a reason for the change or 
correction where appropriate. 
Any errors must be crossed out with a single stroke, the correction inserted and the change initialled and dated.  If it is 
not clear why the change has been made, an explanation should be written next to the change. 
The above considerations also apply to patients who are withdrawn early from treatment. If a patient withdraws from 
the study, the reason must be noted on the appropriate form and the patient must be followed-up as per protocol.  
 
CRFs must be photocopied and a copy kept on site. The original (wet-ink) is to be sent to the Trial Office using the 
address on page 2 (OCTO). 
16.3 Accounting for missing, unused, or spurious data. 
Missing data will be chased up and supplemented where possible after consultation with the Investigator. The control 
of the correctness of the data is performed with ranking tests, validity tests and consistency checks. Unused data will 
be retained as for used data. 

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17 CLINICAL STUDY REPORT  
All clinical data will be presented at the end of the study as data listings. These will be checked to confirm the lists 
accurately represent the data collected during the course of the study.  The trial data will then be locked and a final 
data listing produced. The clinical study report will be based on the final data listings. The locked trial data may then 
be used for analysis and publication.  
18 STUDY SITE MANAGEMENT 
18.1 Study site responsibilities 
The Principal Investigator (the PI or lead clinician for the study site) has overall responsibility for conduct of the study, 
but may delegate responsibility where appropriate to suitably experienced and trained members of the study site 
team.  All members of the study site team must complete the Staff Contact Responsibility Sheet provided, prior to 
undertaking any study duties.  The PI must counter sign and date each entry in a timely manner, authorising staff to 
take on the delegated responsibilities.  
18.2 Study documentation 
The Trial Office has provided an Investigator File and Pharmacy File to each investigational site containing the 
documents needed to conduct the study.  The Trial Office must review and approve any local changes made to any 
study documentation including patient information and consent forms prior to use. Additional documentation 
generated during the course of the trial, including relevant communications must be retained in the site files as 
necessary to reconstruct the conduct of the trial. 
19 REGULATORY AND ETHICAL CONSIDERATIONS 
The Sponsor and Investigators should ensure that this protocol will be conducted in compliance with the UK Clinical 
Trials Regulations1, the Principles of Good Clinical Practice (GCP)2 and the applicable policies of the Sponsoring 
organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory 
requirements for clinical trials of an investigational medicinal product under the European Union Clinical Trials 
Directive. 
19.1 Ethical conduct of the trial and ethics approval 
The protocol, patient information sheet, consent form and any other information that will be presented to potential 
trial patients (e.g. advertisements or information that supports or supplements the informed consent) will be 
reviewed and approved by an appropriately constituted, independent Research Ethics Committee (REC). Principal 
Investigators will be approved by the REC. 
19.2 Regulatory Authority approval 
This study is conducted under a UK Medicines and Healthcare Products Regulatory Agency (MHRA) Clinical Trials 
Authorisation (CTA). Approval to conduct the study has been obtained from the Responsible Authority prior to 
initiating the study.  
19.3 NHS Research Governance 
Investigators are responsible for ensuring they obtain local Trust management agreement to conduct the trial in 
accordance with local arrangements and policies. 
19.4 Protocol amendments 
Amendments are changes made to the research following initial approval. A ‘substantial amendment’ is an 
amendment to the terms of the Responsible Authority application, the REC application, or to the protocol or any other 
supporting documentation, that is likely to affect to a significant degree: 
 
the safety or physical or mental integrity of the subjects of the trial; 
 
the scientific value of the trial; 
                                                                
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 GCP Directive 2005/28/EC . 

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 
the conduct or management of the trial; or 
 
the quality or safety of the investigational medicinal product(s) used in the trial.  
 
Non-substantial amendments are those where the change(s) involve only minor logistical or administrative aspects of 
the study. 
 
All amendments will be generated and managed according to the Trial Office standard operating procedures to ensure 
compliance with applicable regulation and other requirements. Written confirmation of all applicable REC, regulatory 
and local approvals must be in place prior to implementation by Investigators. The only exceptions are for changes 
necessary to eliminate an immediate hazard to study patients. 
 
It is the Investigator’s responsibility to update patients (or their authorised representatives, if applicable) whenever 
new information (in nature or severity) becomes available that might affect the patient’s willingness to continue in the 
trial.  The Investigator must ensure this is documented in the patient’s medical notes and the patient is re-consented if 
appropriate. 
19.5 Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures to protect trial participants from any 
immediate hazard to their health or safety. Urgent safety measures may be taken without prior authorisation. The 
trial may continue with the urgent safety measures in place. The Investigator must inform the Trial Office 
IMMEDIATELY if the study site initiates an urgent safety measure. 
The notification must include: 
 
Date of the urgent safety measure; 
 
Who took the decision; and 
 
Why the action was taken. 
 
The Investigator will provide any other information that may be required to enable the Trial Office to report and 
manage the urgent safety measure in accordance with the current regulatory and ethical requirements for expedited 
reporting and close out. 
The Trial Office will follow written procedures to implement the changes accordingly.    
19.6 Temporary halt 
The Sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short periods for 
administrative reasons or to declare a temporary halt. A temporary halt is defined a formal decision to: 
 
 
interrupt the treatment of subjects already in the trial for safety reasons; 
 
stop recruitment on safety grounds; or 
 
stop recruitment for any other reason(s) considered to meet the substantial amendment criteria, including 
possible impact on the feasibility of completing the trial in a timely manner. 
 
The Trial Office will report the temporary halt via an expedited substantial amendment procedure. The trial may not 
restart after a temporary halt until a further substantial amendment to re-open is in place.  If it is decided not to 
restart the trial this will be reported as an early termination. 
19.7 Serious breaches 
The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "serious breaches" to the 
MHRA within 7 days of the Sponsor becoming aware of the breach. A serious breach is defined as “A breach of GCP or 
the trial protocol which is likely to effect to a significant degree:  
 
the safety or physical or mental integrity of the subjects of the trial; or 
 
the scientific value of the trial” 
 
Investigators must notify the Trial Office at once if any serious breach of GCP is suspected. The Trial Office will review 
the event and, if appropriate a report will be submitted to the REC, Regulatory Authority and the NHS (host) 
organisation within 7 days of the Trial Office becoming aware of the breach as per Trials Office SOPs. 

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19.8 REPORTS: Progress, Safety and End of Study Reports 
This protocol will comply with all current applicable Regulatory Authority, Research Ethics Committee and Sponsor 
requirements for the provision of periodic study safety and progress reports. Any additional reports will be provided 
on request. Reporting will be managed by the Trial Office according to internal SOPs. Sites will be urged to return as 
much data as possible before each database lock point. 
 
The Trial Office will determine which reports need to be circulated Principal Investigators and other interested parties 
according to internal SOPs. Study sites are responsible for forwarding trial reports they receive to their local Trust as 
required. 
20 EXPENSES AND BENEFITS 
There are no intended payments or any other benefits to sites or participants. 
21 QUALITY ASSURANCE 
21.1 Risk assessment  
A risk assessment and a monitoring plan have been prepared. The risk assessment will be repeated if necessary in the 
light of changes while the study is ongoing or in response to monitoring reports.  Monitoring plans will be amended as 
appropriate. 
21.2 Central monitoring 
Regular central monitoring is performed according to the central monitoring plan. Data is evaluated for compliance 
with the protocol and accuracy in relation to source documents.  
Study sites are monitored centrally by checking incoming forms for compliance with the protocol, data consistency, 
missing data and timing. All changes to data that could influence the outcome will be queried with and approved by 
the study site in a timely manner. For all other data, where there is no doubt about the source of any errors, clear 
changes to data will be made internally by OCTO staff without referring back to the study site. Study staff will be in 
regular contact with site personnel (by phone/fax/email/letter) to check on progress and deal with any queries that 
they may have including those arising from queries raised by the Trial Office. In the event of site visits, reports will be 
sent to the site in a timely fashion and sites are expected to action any points highlighted in the report. 
In sites where concern has arisen, including those arising from queries raised by the Trial Office and in consultation 
with the TMG, audit teams may be sent by or on behalf of the Sponsor to inspect the site according to appropriate 
SOPs. The Trial Office will inform the relevant committees e.g. TMG, DSMC and TSC of issues arising in a timely 
manner. The DSMC will monitor data and may recommend to the Sponsor inspection of sites where concern arises. 
21.3 Quality Monitoring Committees 
There are specific central Quality Monitoring Committees (QMCs) for endoscopy (coordinator Prof H Barr), pathology 
(coordinators S Sanders/R Harrison), physiology (coordinator Dr J de Caestecker), molecular biology (coordinator Prof 
J Jankowski) and health economics (coordinator P Moayyedi).  
 
Endoscopy QMC: During the trial, visits will be undertaken by the trial and endoscopy coordinator (or their deputies) 
to sites where concerns about endoscopy rise.  
 
Pathology QMC: this group will jointly assess the suitability of the local pathology resources. A proportion of all 
normal cases (approximately 10%) will have their slides reviewed centrally. In addition, all dysplastic and neoplastic 
specimens will also be reviewed centrally by one of two panels of five expert pathologists, who will return a consensus 
score. They will ensure that all criteria for the histological diagnosis for metaplasia, dysplasia and cancer are met. Any 
normal cases found to be dysplastic or neoplastic on review will be put into the abnormal panel review process. All 
cases will have ‘research paraffin tissue blocks’ as well as fresh tissue where available. The central pathology panels 
will report compliance to the TMG. The pathology coordinator will submit the final pathology review results to the 
local site PI.  
 
Molecular biology QMC:   this group will assess the suitability of the local resources for collecting additional blocks for 
pathology as well as tissue storage. All patients had blood samples collected at baseline and 4-6 years after 
randomisation. They will have blood sample taken 8 years after randomisation. In addition, all patients will have at 

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least one histological block from each case sent to the Trial Laboratory. Furthermore, where available, fresh tissue 
samples can be stored locally and sent in batches to the AspECT Trial Laboratory. The co-ordinators will ensure that all 
assays are carried out to standard operating procedures. The conversion to cancer will be assessed from baseline to 
the end of the study. All individuals will be assessed for trial inclusion/exclusion criteria and after informed consent 
they will have a baseline blood sample for helicobacter serology, PBMC isolation, storage of blood DNA for genetic 
assessment and baseline biochemistry.  
 
Physiology QMC: this group may assess the local resources prior to activation of each site in the physiology sub study. 
A sub-group of up to 400 patients will have 24hour pH, oesophageal manometry and/or impedance and bile acid 
studies as outlined in physiology sub study protocol. 
 
Cardiovascular and nutritional QMC: The data may be assessed by a random check of 10-20% of the case notes. 
21.4 Audit and regulatory Inspection 
All aspects of the study conduct may be subject to internal or external quality assurance audit to ensure compliance 
with the protocol, GCP requirements and other applicable regulation or standards. It may also be subject to a 
regulatory inspection. Such audits or inspections may occur at any time during or after the completion of the study. 
Investigators and their host Institution(s) should understand that it is necessary to allow auditors/inspectors direct 
access to all relevant documents, study facilities and to allocate their time and the time of their staff to facilitate the 
audit or inspection visit. Anyone receiving notification of a Regulatory Inspection that will (or is likely to) involve this 
trial must inform the Trial Office without delay. 
22 RECORDS RETENTION & ARCHIVING 
During the clinical trial and after trial closure, the Investigator must maintain adequate and accurate records to enable 
the conduct of a clinical trial and the quality of the research data to be evaluated and verified.  All essential 
documents must be stored in such a way that ensures that they are readily available, upon request, for the minimum 
period required by national legislation, or for longer if needed.  The medical files of trial subjects shall be retained in 
accordance with national legislation and in accordance with the host institution policy. 
 
Retention and storage of laboratory records for clinical trial samples must also follow these guidelines. 
Retention and storage of Trial Laboratory records supporting PK or PD endpoints and the disposition of samples 
donated via the trial must also comply with applicable legislation and Sponsor requirements. 
 
It is the University of Oxford’s policy to store data for a minimum of 5 years. Investigators may not archive or destroy 
study essential documents or samples without written instruction from the Trial Office. 
23 PATIENT CONFIDENTIALITY 
Personal data recorded on all documents will be regarded as confidential, and to preserve each patient’s anonymity, 
only their initials and date of birth will be recorded on the CRFs. The patient’s name and NHS number (where 
available) will be collected once to allow flagging with the NHS HSCIC, only if the site will allow and the patient has 
completed the relevant section of the Consent Form.  
 
The Investigator site must maintain the patient’s anonymity in all communications and reports related to the research. 
The Investigator site team must keep a separate log of enrolled patients’ personal identification details as necessary 
to enable them to be tracked. These documents must be retained securely, in strict confidence. They form part of the 
Investigator Site File and are not to be released externally. 
24 STUDY FUNDING 
Cancer Research UK approved the study in 2003 for a 10 year period to run from 1st January 2005 to 31st December 
2014 - CRUK reference number CRUK/05/006. Funding is renewable annually and is dependent on a satisfactory 
review by an independent committee. An application submitted in March 2014 for a 44 month funding extension 
starting from 1st January 2015 has been approved by CRUK (GAL reference no. A4584). 

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25 SPONSORSHIP AND INDEMNITY 
25.1 Sponsorship 
The Sponsor has provided written confirmation of Sponsorship and authorised the trial commencement once it was 
satisfied that all arrangements and approvals for the proper conduct of the trial were in place. A separate study 
delegation agreement, setting out the responsibilities of the Chief Investigator and Sponsor were also put into place 
between the parties.  
25.2 Indemnity 
Compensation for Harm 
Arrangements for NEGLIGENT harm 
Indemnity and/or compensation for negligent harm arising specifically from accidental injury for which the University 
is legally liable (as the Research Sponsor) is covered by the University of Oxford.  The NHS will owe a duty of care to 
those undergoing clinical treatment, with Trust Indemnity available through the NHS Litigation Authority Scheme. 
 
Arrangements for NON-NEGLIGENT harm 
Indemnity and/or compensation for harm arising specifically from an accidental injury and occurring as a consequence 
of the research subjects’ participation in the trial for which the University is the research Sponsor may be covered by 
the University of Oxford. 
25.3 Contracts/Agreements 
This trial has been subject to the Sponsor’s policy requiring that written contracts/agreements are agreed formally by 
the participating bodies as appropriate. A Clinical Trial Agreement (CTA) was placed between the Sponsor and 
participating NHS Trust(s) prior to site activation.  The Sponsor has also set up written agreements with any other 
external third parties involved in the conduct of the trial as appropriate.  
26 PUBLICATION POLICY 
The Sponsor retains ownership of all data arising from the trial, however the trial team have unfettered access to the 
data for follow-up studies and cross tabulation of genomics and other data from the ChOPIN study using the same 
patient cohort. 
 
The intention is to publish this research in a specialist peer reviewed scientific journal on completion of the study. The 
results may also be presented at scientific meetings and/or used for a thesis.  The AspECT Chief Investigator and Trial 
Management Group will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any other 
publications arising from the trial and retain final editorial control. Individuals wishing to present or publish material 
arising from AspECT must not do so without the written approval of the Chief Investigator and Trial Management 
Group. 
 
The TMG are responsible for deciding which investigators and scientists are added to the paper. Local investigators 
qualified for authorship for the main paper by recruiting a minimum of 25 patients and having a data return rate of 
95% or greater or for all clinical papers including translational studies related to AspECT by recruiting 50 patients and 
having a data return rate of 95% or greater. 
 
Authors must acknowledge that the study was Sponsored by the University of Oxford and performed with the support 
of the Oncology Clinical Trial Office.  
 
 

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27 REFERENCES 
1. 
Jankowski J, Harrison RF, Perry I, Balkwill F, Tselepis C.  Seminar: Barrett’s metaplasia. Lancet 2000;356:2079-
85 
2. 
Spechler SJ, Lee E, Ahnen D, Goyal RK, Hirano I, Ramirez F. Raufman JP, Sampliner R, Schnell T, Sontag S, 
Vlahcevic ZR, Young R, Williford W.  Long term outcome of medical and surgical therapies for 
gastroesophageal reflux disease.  JAMA 2001; 285:2376-8. 
3. 
Jankowski J, Perry I, Harrison RF.  Gastro-oesophageal cancer: death at the junction. Brit Med J 2000;321:463-
4. 
4. 
Sarr MG, Hamilton SR, Marrone GC, Cameron JL.  Barrett’s esophagus: its prevalence and association with 
adenocarcinoma in patients with symptoms of gastroesophageal reflux.  Am J Surg 1985; 149:187-193. 
5. 
Jankowski J, Provenzale D, Moayyedi P.  Oesophageal adenocarcinoma arising from Barrett’s metaplasia has 
regional variations in the West.  Gastroenterology 2002;122:588-590 
6. 
Cameron AJ, Lomboy CT. Barrett’s esophagus: age, prevalence and extent of columnar epithelium.  
Gastroenterology 1992;103:1241-1245 
7. 
Menke-Pluymers MBE, Hop WCJ, Dees J, van Blankenstein M, Tilanus HW.  Risk factors for the development 
of an adenocarcinoma in Barrett’s oesophagus.  Cancer 1993;72:1155-1158 
8. 
Lagergren J, et al., Symptomatic gastroesophageal reflux as a risk factor for oesophageal adenocarcinoma. N 
Engl J Med 1999;340:825-31 
9. 
Skinner DB, Walther BC, Riddell RH, Schmidt H, Iascone ?C, DeMeester T.  Barrett’s esophagus. Ann Surg 
1983; 198:554-566 
10. 
Lagergren J, Berstrom R, Nyren O.  Association between body mass and adenocarcinoma of the esophagus.  
Ann Intern Med 1999;130:883-90 
11. 
Romero Y, Cameron AJ, Locke GR, Schaid DJ, Slezak JM, Breanch CD, Melton LJ.  Familial aggregation of 
gastroesophageal reflux in patients with Barrett’s esophagus and oesophageal adenocarcinoma.  
Gastroenterology 1997;113:1449-56 
12. 
Lagergren J, Bergstrom R, Adami HO, Nyren O.  Association between medications that relax the lower 
oesophageal sphincter and risk for oesophageal adenocarcinoma.  Ann Intern Med 2000;133:165-75 
13. 
Morgan G, Vainio H.  Barrett’s oesophagus, oesophageal cancer and colon cancer: an explanation of the 
association and cancer chemopreventative potential of non-steroidal anti-inflammatory drugs.  Eur J Cancer 
Prev 1998;7:195-9 
14. 
Weston AP, Badr AS, Topalovski M, Cherian R, Dixon A, Hassanein RS.  Prospective evaluation of the 
prevalence of gastric Helicobacter pylori infection in patients with GERD, Barrett’s esophagus, Barrett’s 
dysplasia, and Barrett’s adenocarcinoma.  Am J Gastroenterology 2000;95:387-94 
15. 
Gray MR, Donnelly RJ, Kingsnorth AN.  The role of smoking and alcohol in metaplasia and cancer risk in 
Barrett’s oesophagus.  Gut 1993;34:727-731 
16. 
Spechler SJ, Sperber H, Doos WG, Schimmel EM.  The prevalence of Barrett’s esophagus in patients with 
chronic peptic oesophageal strictures.  Dig Dis Sci 1983;28:769-774 
17. 
Morales TG, Sampliner RE.  Barrett’s esophagus: an update on screening, surveillance and treatment.  Arch 
Intern Med 1999:159:1411-6 
18. 
Jankowski J, Wright NA, Meltzer S, Triadafilopoulos G, Geboes K, Casson A, Kerr D, Young LS.  Molecular 
evolution of the metaplasia dysplasia adenocarcinoma sequence in the esophagus (MCS) Am J Pathol 
1999;154:965-974 
19. 
Thun MJ, Namboodiri MM, Catie EE.  Aspiring use and the risk of fatal cancer.  Cancer Res 1993;53:1322-1327 
20. 
Farrow DC, Vaughan TL, Hansten PD, Stanford JL, Risch HA, Gammon MD, Chow WH, Dubrow R, Ahsan H, 
Mayne ST, Schoenberg JB, West AB, Rotterdam H, Frumeni JF, Blot WJ.  Use of aspirin and other non steroidal 
anti inflammatory drugs and risk of oesophageal and gastric cancer.  Cancer Epidemiol Biomarkers Prev 
1998;7:97-102 

AspECT 
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Protocol Template V3.0_18Feb2013 
Page 44 of 45 
21. 
Morgan G, Vainio H.  Barrett’s oesophagus, oesophageal cancer and colon cancer: an explanation of the 
association and cancer chemopreventive potential of non-steroidal anti-inflammatory drugs.  Eur J Cancer 
Prev 1998;3:195-9 
22. 
Morgan G.  Beneficial effects of NSAIDS in the gastrointestinal tract.  Eur J Gastroenterol Hepatol 1999;8:393-
400 
23. 
Van Laethem JL, Peny MO, Salmon I, Cremer M, Deviere J.  Intramucosal adenocarcinoma arising under 
squamous re-epithelialisation of Barrett’s oesophagus.  Gut 2000;46:574-7 
24. 
Murphy P et al.  Eur J Gastro Hepatol 1994;6:901-5 
25. 
Wetscher GJ, Hinder RA, Smyrk T, Perdikis G, Adrian TE, Profanter C.  Gastric acid blockade with omeprazole 
promotes gastric carcinogenesis inducted by duodenogastric reflux.  Dig Dis Sci 1999;44:1132-5 
26. 
Oritz A, Martinez de Haro LF, Parrilla P, Molina J, Bermejo J, Munitiz V.  24-h pH monitoring is necessary to 
assess acid reflux suppression in patients with Barrett’s oesophagus undergoing treatment with proton pump 
inhibitors.  Br J Surg 1999;86:1472-4 2 
27. 
Katzka DA, Castell DO.  Successful elimination of reflux symptoms does not insure adequate control of acid 
reflux in patients with Barrett’s esophagus.  Am J Gastro 1994; 98(7):989-91 
28. 
Ouatu-Lascar R, Triadafilopoulos G.  Complete elimination of reflux symptoms does not guarantee 
normalization of intraoesophageal acid reflux in patients with Barrett’s esophagus.  Am J Gastro 1998;93:711-
6 
29. 
Castell DO, Kahrilas PJ, Richter JE, Johnson DA, Vakil NB, Zuckerman S, Skammer W, Levine JG.  Esomeprazole 
provides more effective healing than Lansoprazole in GERD patients with erosive oesophagitis (EE).  American 
Journal of Gastroenterology 2001;96(9) (Suppl S):S6, Abs 17.  (Full paper Am J Gastroenterol (in press) 
30. 
Edwards SJ, Lind T, Lundell L.  Systematic review of proton pump inhibitors for the acute treatment of reflux 
oesophagitis.  Aliment Pharmacol Ther 2001;15:1729-36 
31. 
Basu KK, Bale R, West KP, de Caestecker JS.  Persistent acid reflux and symptoms in patients with Barrett’s 
oesophagus on proton pump inhibitor therapy.  Eur J Gastroenterol Hpatol 2002;14:1187-92 
32. 
Funkhouser EM, Sharp GB.  Aspirin and reduced risk of oesophageal carcinoma.  Cancer 1995;76:116-119 
33. 
Mitchell JA, Warner TD.  Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID 
therapy.  Br J Pharmacol 1999;128:1121-1132 
34. 
Warner TD, et al., Nonsteroid drug selectivity's for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are 
associated with human gastrointestinal toxicity: A full in vitro analysis. PNAS 1999;96:7563-7568 
35. 
Corley DA, Kerlikowske K, Verma R, Buffler P.  Protective association of aspirin/NSAIDs and oesophageal 
cancer: a systematic review and meta-analysis.  Gastroenterology 2003; 124: 47-56. 
36. 
Buttar NS, Wang KK, Leontovich O et al. Chemoprevention of oesophageal adenocarcinoma by COX-2 
inhibitors in an animal model of Barrett’s esophagus.  Gastroenterology 2002; 122: 1101-12. 
37. 
Derry S, Loke YK.  Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis.  BMJ 
2000; 321: 1183-7. 
38. 
Hawkey CJ, Tulassay Z, Szczepanski L et al.  Randomised controlled trial of Helicobacter pylori eradication in 
patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study.  Lancet 1998; 352: 1016-21. 
39. 
Aalykke C. Lauritsen K. Epidemiology of NSAID-related gastroduodenal mucosal injury. Best Practice & 
Research in Clinical Gastroenterology 2001; 15: 705-22. 
40. 
Lai KC, Lam SK, Chiu KM et al. Lansoprazole for the prevention of recurrences of ulcer complications from 
long-term low-dose aspirin use.  NEJM 2002; 346: 2033-8. 
41. 
Wang WH, Wong WM, Dailidiene D et al, Aspirin inhibits the growth of helicobacter pylori and enhances its 
susceptibility to antimicrobial agents. Gut 2003;52:490-5.  
42. 
MacDonald CE, Wicks AC, Playford RJ.  Final results from 10 year cohort of patients undergoing surveillance 
for Barrett’s oesophagus: observational study.  BMJ 2000;321:1252-5 

AspECT 
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Page 45 of 45 
43. 
Miner P, Katz P, Chen Y, Sostek M. Esomeprazole 40mg provides more effective intragastric acid suppression 
at steady state. Gastroenterol 2003;124:A229  
44. 
Gillen D, Wirz A, McColl K. Esomeprazole 40mg bd produces profound 24h acid suppression with minimal 
breakthrough, Gastroenterol 2003; 124:A231 
45. 
Fitzgerald RC, di Pietro M, Ragunath K, Ang Y, Kang JY et al. British Society of Gastroenterology guidelines on 
the diagnosis and management of Barrett’s oesophagus. Gut 2014;63:7-42 
46. 
Bennett C, Moayyedi P, Corley DA, DeCaestecker J et al. BOB CAT: a large-scale review and Delphi consensus 
for management of Barrett’s esophagus with no dysplasia, indefinite for, or low-grade dysplasia. Am J 
Gastroenterol 2015; 110:662-682