Conditions: Esophageal Cancer Precancerous Condition
Keywords: esophageal cancer Barrett's esophagus
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 2557
Healthy volunteers: no

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

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

Detailed description:
PRIMARY OBJECTIVES

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

SECONDARY OBJECTIVES

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

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

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

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

Arms:
arm 1: 20mg Esomeprazole arm 2: 80mg Esomeprazole arm 3: 20mg Esomeprazole + 300mg Aspirin arm 4: 80mg Esomeprazole + 300mg Aspirin

Interventions: intervention 1: Esomeprazole intervention 2: Esomeprazole intervention 3: Aspirin
Intervention descriptions: intervention 1: 20mg per day intervention 2: 80mg per day intervention 3: 300mg per day

Protocol document:
Prot_000.pdf: 

 
AspECTProtocol_V12.0_26Jan2016 
 
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Page 1 of 45 
 
 
 
 
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 
Screening Form. 


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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 
machinery. 


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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 
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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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Vlahcevic ZR, Young R, Williford W.  Long term outcome of medical and surgical therapies for 
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Jankowski J, Perry I, Harrison RF.  Gastro-oesophageal cancer: death at the junction. Brit Med J 2000;321:463-
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Gastroenterology 1992;103:1241-1245 
7. 
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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 
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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 


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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 


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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  

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AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 2 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Contents 
1. INTRODUCTION .............................................................................. 4 
1.1 TRIAL STATISTICIAN: SHARON LOVE ........................................................ 4 
1.2 CHIEF INVESTIGATOR:   PROFESSOR JANUSZ JANKOWSKI .............................. 5 
1.3 TRIAL MANAGER:    
CLAIRE BROOKS ....................................................... 5 
2. BACKGROUND INFORMATION ........................................................ 6 
2.1 OBJECTIVES ......................................................................................... 6 
2.2 STUDY DESIGN AND TREATMENT INTERVENTIONS .......................................... 7 
2.3 TIMINGS ............................................................................................. 9 
2.4 PATIENT ELIGIBILITY .............................................................................. 9 
2.5 SAMPLE SIZE ...................................................................................... 10 
2.6 RANDOMISATION ................................................................................ 12 
2.7 DEFINITION OF PRIMARY AND SECONDARY OUTCOMES .................................. 14 
2.8 OUTCOMES ASSESSMENT SCHEDULE ......................................................... 16 
3. QC DURING TRIAL ........................................................................ 17 
4. DATA MONITORING COMMITTEE AND INTERIM ANALYSES ....... 17 
5. DATA VALIDATION ........................................................................ 17 
6. DESCRIPTIVE ANALYSES .............................................................. 18 
6.1 REPRESENTATIVENESS OF STUDY SAMPLE AND PATIENT THROUGHPUT ............... 18 
6.2 BASELINE COMPARABILITY OF RANDOMISED GROUPS .................................... 19 
6.3 COMPARISON OF LOSSES TO FOLLOW-UP ................................................... 21 
6.4 DESCRIPTION OF COMPLIANCE WITH THERAPY ............................................ 21 
6.5 RELIABILITY OF DATA ........................................................................... 22 
6.6 DESCRIPTION OF AVAILABLE DATA ........................................................... 22 
7. PATIENT GROUPS FOR ANALYSIS ................................................ 23 
8. PRIMARY AIM COMPARATIVE ANALYSES .................................... 24 
8.1 EVALUATION/DEFINITION OF PRIMARY OUTCOME ......................................... 24 
8.2 STATISTICAL METHODS USED FOR ANALYSIS OF PRIMARY OUTCOME................. 24 
8.3 ADJUSTMENT OF P VALUES FOR MULTIPLE TESTING ...................................... 25 
8.4 MISSING DATA ................................................................................... 25 
8.5 PRE-SPECIFIED SUBGROUP ANALYSIS ........................................................ 26 
8.6 SENSITIVITY ANALYSIS.......................................................................... 26 
8.7 TREATMENT BY CENTRE INTERACTION ...................................................... 27 
8.8 SUPPORTING INFORMATION ................................................................... 27 
9. ANALYSIS TO ADDRESS SECONDARY AIMS ................................. 27 
9.1 RESOURCE USE AND COST DATA ............................................................. 30 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 3 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
10. EXPLORATORY ANALYSES NOT SPECIFIED PRIOR TO RECEIVING 
DATA.................................................................................................. 30 
11. SERIOUS ADVERSE EVENTS ........................................................ 31 
12. DATA FROM CANADA………………………..……………………………31 
APPENDIX 1: INTERPRETATION OF THERAPEUTIC DOSE ............... 32 
APPENDIX 2: VARIABLES TO BE USED IN ANALYSIS ....................... 33 
DOCUMENT HISTORY ........................................................................ 34 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 4 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
1. Introduction 
This document details the proposed presentation and analysis for the main 
paper(s) reporting results from the CTAAC funded multicentre randomised 
controlled trial of aspirin and esomeprazole in the prevention of 
adenocarcinoma or high grade dysplasia in Barrett’s metaplasia (AspECT). The 
results reported in these papers should follow the strategy set out here. 
Subsequent analyses of a more exploratory nature will not be bound by this 
strategy, though they are expected to follow the broad principles laid down 
here. The principles are intended to establish the rules that will be followed, 
as closely as possible, when analysing and reporting the trial.  
 
This analysis strategy should be available on request when the principal 
papers are submitted for publication in a journal. Suggestions for subsequent 
analyses by journal editors or referees will be considered carefully, and 
carried out as far as possible in line with the principles of this analysis 
strategy; if reported, the source of the suggestion will be acknowledged. 
 
Any deviations from the statistical analysis plan will be described and justified 
in the final report of the trial. The analysis should be carried out by an 
identified, appropriately qualified and experienced statistician, who should 
ensure the integrity of the data during their processing. Examples of such 
procedures include quality control and evaluation procedures. 
 
Version 0.4 of this analysis plan was released for the first DSMC. Since the 
trial is of a longer duration, it is expected that some of the analysis may be 
updated with the agreement of the TSC and DSMC. Version 1.0 of the 
analysis plan was released before the 4 year interim analysis. Version 2.0 is 
due to be the final version used to analyse the primary aim. Any additional 
analysis carried out will be mentioned in the published paper of the trial 
results. 
 
1.1 Trial statisticians: 
Sharon Love 
 
 
 
 
Senior Statistician and Deputy Director CSM 
 
 
 
 
Centre for Statistics in Medicine 
 
 
 
 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LD 
 
 
 
 
 
 
 
 
 
 
Email: sharon.love@csm.ox.ac.uk  
 
 
 
 
Phone: 01865 223441 
 
 
 
 
Urgent contact: 07960 230994 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 5 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Gavin Reilly 
Statistician 
 
Email: gavin.reilly@csm.ox.ac.uk 
 
1.2 Chief Investigator:   
Professor Janusz Jankowski  
 
 
 
 
 
 
Adelphi Building 
Preston 
Lancs 
England   
PR1 2HE. 
 
 
 
 
 
Email: jjankowski@uclan.ac.uk 
 
 
 
 
Phone: 01772 896 340  
 
 
 
 
Urgent contact: 07968 479 355 
 
1.3 Trial Manager:   Adelyn Wise 
 
 
 
 
AspECT Trial Coordinator 
Oncology Clinical Trials Office 
Department of Oncology 
Old Road Campus Research Building 
University of Oxford 
Old Road Campus 
Headington 
Oxford OX3 7DQ 
 
Email: octo-aspect@oncology.ox.ac.uk 
Phone: 01865 617011  
Fax: 01865 617010 
 
 
 
 
Urgent contact: 07708249215 
 
 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 6 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
2. Background Information 
 
2.1 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 (BM) 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 Barrett’s Adenocarcinoma 
(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 aims 
1. To assess aspirin’s role on the development of colorectal adenomas and 
cancer. 
2. To collect and bank samples for use in future ethically approved studies 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 7 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
 
Exploratory uses of the data 
1. Describe Barrett’s length over repeat biopsies and investigate a change in 
length from baseline to 2 years between treatment groups. 
2. Can intervention with aspirin result in a lower stage of adenocarcinoma ? 
Can intervention with PPI result in a lower stage of adenocarcinoma ?  
3. Does adjustment for Oesophagectomy, Ablation therapy, Endoscopic 
mucosal resection change the treatment effect ? 
4. Is the event rate different for those previous users of aspirin who were not 
randomised to it compared to previous users who continued with aspirin 
as their randomised treatment?  
5. Investigation of the hypothesis that aspirin will have a chemopreventive 
effect on all epithelial cancers using the same mechanism it does to 
reduce oesophageal cancer, however, high dose PPI therapy may arguably 
increase colon cancer incidence as gastrin levels increase and this 
hormone is a known stimulant for colon cancer in mice. 
6. Look for a dose/time response effect for aspirin and for esomeprazole. 
 
 
2.2 Study Design and Treatment Interventions 
 
This is a national, multi-centre, phase III, randomised controlled trial of low 
or high dose PPI (drug name: Esomeprazole) with or without low dose aspirin 
for 8 years with expected accrual of 5000 patients. The trial sample size was 
recalculated to 2500 and some patients re-consented to 10 years follow-up or 
28Feb2017 (whichever was the sooner). 
 
The trial is a pragmatic, multi-centre, phase III, randomised, open, 2x2 
factorial trial. 
 
ARM A: 20mg PPI 
Symptomatic treatment only 
= standard therapy control 
ARM B: 80mg PPI 
Strong acid suppression 
 
No Aspirin 
(A+B) 
 
ARM C: 20mg PPI 
Symptomatic treatment 
and aspirin 
 
ARM D: 80mg PPI 
Strong acid suppression 
and aspirin 
 
 
Aspirin  (C+D) 
 
 
Low dose PPI (A +C) 
 
High dose PPI (B + D) 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 8 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
Patients will receive either continuous PPI 20mg/day or continuous PPI 
80mg/day with or without aspirin 300mg/day.  
 
If patients are on low dose aspirin for medical reasons (i.e. previous IHD or 
CVA’s rather than self prescribed) they will be randomised to either 
continuous PPI 20mg/day or continuous PPI 80mg/day arms. They will be 
allowed to continue to take their aspirin therapy. 
 
Questionnaires dealing with demographics, family history, drug history, 
smoking, cardiac disease, alcohol, diet and quality of life measures will be 
completed at baseline. Quality of Life data collection was not possible in all 
patients and not at all timepoints. 
 
The majority of patients will have an endoscopy at baseline and thereafter at 
2 yearly intervals. A number of patients whose baseline endoscopy was more 
than 12 months before randomisation should have another endoscopy within 
6 months of randomisation. A number of patients will have had an endoscopy 
within the 12 months prior to randomisation. These patients will not have a 
baseline endoscopy but may have an endoscopy at 2 years from their last 
endoscopy or 2 years from randomisation at the PI’s discretion. These two 
groups of patients are called retrospective patients. 
NOTE on retrospective patients. It is acceptable for primary outcome 
investigation not to be linked to date of randomisation since we will be using 
the actual time of an event. Events linked to endoscopy may occur at 
screenings or during an endoscopy for change of symptoms. Follow-up forms 
will be completed at yearly intervals from randomisation and QOL forms 
posted out at 2 yearly intervals from randomisation (for relevant patients).  
 
At each endoscopy any macroscopic abnormality of the Barrett’s metaplasia 
will be biopsied as per local practice and samples taken for formalin fixation 
and local histological assessment for dysplasia. DNA and RNA will be 
extracted from the paraffin embedded material for SNP analysis and micro 
array analysis. In addition an extra biopsy will be taken at each level and snap 
frozen for genetic studies. In addition to the endoscopy, blood samples will be 
taken at baseline, between 4 and 6 years, 8 years and at 10 years if the 
patient consented to extended follow-up, to assess cardiovascular risk factors 
and the remainder stored for analysis of circulating genetic mutations as and 
when reliable assays become available.  
 
Patients will come to the hospital pharmacy every 6 months to drop off 
unused medication and pick up a new 6 month supply.  
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 9 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
The factorial design is efficient due to each patient contributing to the answer 
to 2 questions. Not only must it be possible for patients to receive both 
treatments (practically and with consideration of toxicity) but the anticipated 
treatment effects must be approximately additive. The patients taking part in 
the PPI only randomisation will be analysed for the PPI primary aim but will 
not be available for the aspirin primary aim. 
 
2.3 Timings 
 
Date of start of recruitment: 
 
 
August 2005@ 
Date of end of recruitment: 
 
 
25February2009 
First interim analysis* 
 
 
 
April 2011 
Second interim analysis*  
 
 
August 2013 
Final analysis start*  
 
 
 
September 2017 
Actual number of subjects:  
 
2513  
 
* Analyses are due 2 and 4  years after last patient recruitment and at the end of the trial..  
@ A pilot site was open from Mar2005 
 
2.4 Patient eligibility 
 
INCLUSION CRITERIA 
• Male between 40 - 75 years;  *** AGE LIMIT REMOVED March 2006 
now 18 years and over*** *** Planned 500 women entered for 
generalisability*** 
• at least 2cm from the gastro-oesophageal junction of circumferential 
BM (Histologically proven by intestinal metaplasia in at least one 
sample)  *** LATER CHANGED TO 1CM ***  *** also changed to or a 
past history of intestinal metaplasia *** **changed 4th Feb 2008 to no 
need for IM and tongues of Barrett’s are enough for inclusion** 
• able to give written informed consent.  
• WHO activity profile of 0 or 1  i.e. fully active and self-caring 
 
EXCLUSION CRITERIA  
1. those with high grade dysplasia or carcinoma at enrolment;  
2. medical conditions which would make endoscopy 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  


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 10 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
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 this criteria were eligible for the PPI-only 
(non-aspirin) randomisation. 
3. Patients with absolute contraindications to PPIs, aspirin or their 
excipients i.e. allergies, ulcers, renal impairment or use of oral 
anticoagulants. 
*** added 
4. pregnant or lactating women *** 
*** amended*** 
• Up to 100 previous aspirin users will be entered providing they agree 
to stop aspirin use if not randomised to it. 
 ***amended*** 
• Patients not wishing to stop aspirin or who have an absolute 
contraindication to it can be randomised to the low/high PPI dose arms 
only and will be analysed for that comparison only 
 
For patients on existing PPI therapy, there is no washout period. 
 
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. 
 
2.5 Sample size  
 
2.5.1 Sample size – estimates used 
The conversion 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 the 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%). 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.  


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 11 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
2.5.2 Sample Size – original statement 
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 (pre CSM 
involvement) 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 Office of National Statistics 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). 
 
 
2.5.3 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 will recruit until end Dec 2008 in the UK 
and possibly until the end of June in Canada 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 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 12 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
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) ie 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%. 
• HR as in colorectal cancer 
• No adjustment for compliance 
• the follow-up increased to 10 years 
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 (196 events) (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 
• 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 Office of National Statistics flagging 
 
2.6 Randomisation  
 
Randomisation is by minimisation using age split into four groups and length 
of Barrett’s metaplasia split into three groups. There is a random component, 
with the patient having an 80% chance of being assigned the treatment that 
reduces the imbalance. 
 
Age 
40-49 
50-59 
60-69 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 13 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
70-75 
 
Length of Barrett’s metaplasia 
≤3cm 
>3 and ≤8cm 
>8cm 
 
Initially the trial accrued only males. From Sept 2005, there are separate 
minimisation routines running for males and females. 
 
**** Change in 2007  
Limit on age to be removed and Barrett’s from 1cm to be included*** 
Then 
Age 
18-49 
50-59 
60-69 
≥70 
 
Length of Barrett’s metaplasia 
<2cm 
≥2cm and ≤3cm 
>3 and ≤8cm 
>8cm 
 
 
2.6.1 *** Change 25th Feb 2008 *** 
IM to be added as stratification factor 
Tongue of Barretts to be added as a level in length 
Individuals participating only in the PPI randomisation are randomised in a 
separate routine (same stratification) 
Gender already separate routine  
Then 
Age 
18-49 
50-59 
60-69 
≥70 
 
Length of Barrett’s metaplasia 
Tongue of Barretts 
<2cm 
≥2cm and ≤3cm 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 14 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
>3 and ≤8cm 
>8cm 
 
IM 
 
 
Yes 
 
 
No 
 
 
2.6.2 Blinding 
After randomisation, both the patient and the treating doctor knows what 
treatment the patient is receiving. There is no blinding of treatments. (The 
cost of placebo drugs was prohibitively expensive.) 
 
2.7 Definition of Primary and Secondary Outcomes 
 
Primary outcome is 
• Time from randomisation date to conversion from Barrett’s metaplasia 
to high grade dysplasia (event), or to adenocarcinoma of the 
oesophagus (event) or time to death from all causes (event) or time to 
last follow-up (no event) 
I.e. the time is noted as the time from date of randomisation to high grade 
dysplasia, adenocarcinoma of the oesophagus or death, whichever is the 
earlier, with the survival time coded as an event. For patients who do not 
have one of these events of interest, the time from randomisation to date of 
last follow-up is calculated and the survival time coded as a censored event. 
 
Secondary outcomes are   
• Time from randomisation date to conversion from Barrett’s metaplasia 
to high grade dysplasia (event) or time to last follow-up (no event) or 
event that precludes getting high grade dysplasia (for example death) 
(no event) 
• Time from randomisation date to progression from Barrett’s metaplasia 
to adenocarcinoma of the oesophagus (event) or time to last follow-up 
(no event) ) or event that precludes getting adenocarcinoma of the 
oesophagus (for example death) (no event) 
• Time from randomisation date to death from all causes (event) or time 
to last follow-up (no event) 
• Time from randomisation date to death from oesophageal 
cancer(event) or time to last follow-up (no event) or death from a 
cause other than oesophageal cancer (no event) 
• Molecular markers to be identified at the end of the trial and used 
during analyses of collected blood and/or tissue samples 
• Cost per oesophageal adenocarcinoma prevented 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 15 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
• Cost per life year saved  
• Molecular markers to be identified at the end of the trial and used with 
samples collected across time along with treatment information 
• Cost per quality adjusted life saved 
• Cardiac event from SAE (our best data on cardiac disease) and new 
tumours (a marker of aspirin resistance) 
• For gender secondary, same outcome as for primary 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 16 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
2.8 Outcomes Assessment Schedule 
 
sample collection and CRF completion 
 
Baseline 
1 month 
1 year 
2years 
3 years 
4years 
5years 
6years 
7years 
8years 
CRFs 
Randomisation form 
√ 
 
 
 
 
 
 
 
 
 
Patient history 
 
√ 
 
 
 
 
 
 
 
 
√ 
Food diary 
 
√ 
 
 
 
 
 
 
 
 
√ 
Quality of Life 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
Family history 
 
√ 
 
 
 
 
 
 
 
 
 
Endoscopy form 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
Biopsy sampling 
form 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
Pathology form 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
1 month fu form 
 
 
√ 
 
 
 
 
 
 
 
 
Follow-up form 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
End of treatment 
form 
 
 
 
 
 
 
 
 
 
√ 
Sample 
collection
1 
Endoscopy 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
Biopsy samples 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
Blood samples 
 
√ 
 
 
 
 
 
 
 
 
√ 
Notes: Food Diary, quality of life and family history only collected for first 1000 patients 
In later versions endoscopy and pathology form combined
                                                 
1 Endoscopy, biopsy and blood samples collected 2 years from previous endoscopy for retrospective patients 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 17 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
3. QC during trial 
 
The quality and completeness of the data will be the responsibility of the data 
team during the trial. The statistician will feed back any concerns of a specific 
or general nature to the data team. 
 
1 year into the trial (September 2006), the integrity of the randomization was 
assessed. The completeness of the data is assessed at each data lock, 
discussed between the data team and statistician and any necessary action 
taken.  
 
 
4. Data Monitoring Committee and Interim Analyses 
 
The DMC met annually to monitor recruitment to the trial and protocol 
compliance as well as toxicity and serious adverse events. See Charter for full 
details. 
 
The primary aim was analysed and presented confidentially to the DSMC after 
2 years and 4 years of follow-up (interim analyses) and was reported 
considering a p value of 0.001 as significant.  The DSMC were happy for the 
trial to continue and neither interim analysis was disseminated further. 
 
 
5. Data Validation 
 
It is expected that much of the data cleaning will be done by the data team. 
However, before analysis, all fields will be summarised and any possible fields 
cross referenced. This will improve understanding of the data and allow for 
feedback of unexpected data to the data team for clarification/correction. 
 
Oesophagectomy, ablation therapy and endoscopic mucosal resection are 
commonly carried out when high grade dysplasia or oesophageal 
adenocarcinoma is found. All cases where this treatment is carried out 
without logging a disease progression will be checked. 
 
The primary analysis and first 2 secondaries will be independently analysed by 
a second statistician. 
 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 18 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
6. Descriptive Analyses  
 
A descriptive analysis will be carried out first examining the study sample. 
 
6.1 Representativeness of Study Sample and Patient 
Throughput 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm C 
Allocated to low PPI 
and aspirin (n= 
Arm B 
Allocated to high PPI 
no aspirin (n=) 
Arm A 
Allocated to low PPI 
no aspirin (n=) 
Arm D 
Allocated to high PPI 
and aspirin (n=) 
Assessed for 
eligibility and 
consent 
N≥  
Randomised 
n= 
Known Exclusions1 
Not meeting inclusion criteria      
n≥ 
Refused to participate 
n≥ 
Other reason 
n≥ 
Arm A 
low PPI no aspirin 
Analysed as ITT 
(n=) 
Arm B 
high PPI no aspirin 
Analysed as ITT 
(n=) 
Arm C 
low PPI and aspirin 
Analysed as ITT 
(n=) 
Arm D 
high PPI and aspirin 
Analysed as ITT 
(n=) 
Withdrawn 
consent from 
all data use 
n= 
Withdrawn 
consent from 
all data use 
n= 
Withdrawn 
consent from 
all data use 
n= 
Withdrawn 
consent from 
all data use 
n= 
Arm A 
low PPI no aspirin 
PP 
(n=) 
Arm B 
high PPI no aspirin 
PP 
(n=) 
Arm C 
low PPI and aspirin 
PP 
(n=) 
Arm D 
high PPI and aspirin 
PP 
(n=) 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 19 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
The above diagram was completed for each interim analysis (2 years and 4 
years after final recruitment) and will also be completed at the final analyses.  
Any randomised but ineligible patients will be described. These patients are 
included in the ITT analysis  
 
The sensitivity analysis will use a per protocol sample of patients given a 
‘therapeutic’ amount of treatment. See section 7 and appendix 1 for a 
definition of the therapeutic dose. 
 
 
6.2 Baseline Comparability of Randomised Groups 
 
A table of baseline data for all patients, each of the four intervention groups 
and the groups for the main comparisons will be given. This will include  
 
Variable at baseline 
Low 
PPI no 
aspirin 
Low 
PPI and 
aspirin 
High 
PPI no 
aspirin 
High 
PPI and 
aspirin 
TOTAL 
Length of Barrett’s 
metaplasia at rand 
(strata for minimisation 
and median(range), cm) 
 
 
 
 
 
Age  
(strata for minimisation, 
median(range),years) 
 
 
 
 
 
Gender 
       Male 
       Female 
 
 
 
 
 
Intestinal metaplasia 
       Yes 
       No 
 
 
 
 
 
Retrospective 
patient 
       Yes 
       No 
 
 
 
 
 
Duration of Barrett’s 
pre randomisation 
    Median (range), 
years 
 
 
 
 
 
Alcohol use 
      None 
      some 
 
 
 
 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 20 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Variable at baseline 
Low 
PPI no 
aspirin 
Low 
PPI and 
aspirin 
High 
PPI no 
aspirin 
High 
PPI and 
aspirin 
TOTAL 
( For some group, 
median(iq range),units 
per week) 
 
Smoker 
      No never 
      Ex 
      Yes current 
 
 
 
 
 
 
 
Myocardial Infarction  
      Yes 
      No 
 
 
 
 
 
Angina 
      Yes 
      No 
 
 
 
 
 
Coronary Intevention 
      Yes 
      No 
 
 
 
 
 
Stenosis 
      Yes 
      No 
 
 
 
 
 
Cardiac 
catheterisation 
      Yes 
      No 
 
 
 
 
 
Cerebrovascular 
      Yes 
      No 
 
 
 
 
 
TIA 
      Yes 
      No 
 
 
 
 
 
Peripheral Vascular 
Disease 
      Yes 
      No 
 
 
 
 
 
Diabetes 
      Yes 
      No 
 
 
 
 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 21 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Variable at baseline 
Low 
PPI no 
aspirin 
Low 
PPI and 
aspirin 
High 
PPI no 
aspirin 
High 
PPI and 
aspirin 
TOTAL 
Hypertension 
      Yes 
      No 
 
 
 
 
 
Hyperlipidaemia 
       Yes 
        No 
 
 
 
 
 
 
This table will be repeated with columns of no aspirin, aspirin, low PPI and 
high PPI. Those taking part in the PPI only randomisation will not appear in 
the noaspirin/aspirin columns since they did not take part in the aspirin 
randomisation. 
 
Numbers (with percentages) for binary and categorical variables and means 
(and standard deviations), or medians (with range) for continuous variables 
will be presented. There will be no tests of statistical significance nor 
confidence intervals for differences between randomised groups on any 
baseline variable. 
 
 
6.3 Comparison of Losses to Follow-up 
 
The numbers and distribution of losses to follow-up (defaulters and 
withdrawals) over the period of the study will be reported overall, for the four 
randomisation groups and for the primary objective comparison groups. 
Defaulters are those who attend no further trial related visits. 
 
Note that for conversion to cancer and death from any cause, the NHS digital 
flagging may still be possible for those lost to active follow-up. 
For other endpoints, the baseline characteristics of those lost to follow-up and 
between those to be analysed will be compared between the two treatment 
groups. Those randomised may be balanced, but those with data to analyse 
on the secondary objectives may not be. The consequences of this 
examination of the data will be described separately for each objective. 
 
6.4 Description of Compliance with Therapy  
 
A summary of the treatment received will be provided. This will include the 
dosage of drugs in each of the four treatment intervention groups and details 
of numbers complying with treatment. Note that compliance is assumed when 
a prescription is collected and patient attends trial visits. 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
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Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
 
 
 
6.5 Reliability of data 
 
Survival time will be calculated from date of randomisation to the first of  
 
 
date of Barrett’s adenocarcinoma 
 
date of high grade dysplasia 
 
date of death from any cause 
 
with a censor variable created coded 1 for an event. If none of the above 
exist for a patient the survival time will be calculated from date of 
randomisation to  
 
 
date of last follow-up  
 
with the censor variable coded 0 to indicate the time does not relate to an 
event. 
This may be done using difference in defined dates in STATA (or similar 
function/software available at the time of analysis).  A random 20 patient 
manual check will be done to confirm the programming of the calculation. 
 
Other derived variables will have a 20 patient check. 
 
6.6 Description of Available Data  
 
Primary endpoint – survival until adenocarcinoma, high grade dysplasia or 
death from any cause 
There will be a time for every patient. For some of the patients who do not 
reach an endpoint, the survival time will be less than the trial duration due to 
loss to follow-up. The endpoint of death and diagnosis of Barrett’s 
adenocarcinoma can be picked up in many cases from NHS digital but the 
endpoint of high grade dysplasia will be under represented due to those lost 
to follow-up.    
The median follow-up will be described using the median of those without an 
event and the median using the reverse Kaplan-Meier method.   
Kaplan-Meier curves will be drawn for all patients, then split by aspirin 
intervention and split by PPI dose (low or high). 
The analysis of the primary objective involves knowledge of the treatment 
and then knowledge of the factors used in the minimisation which will be 
available for everyone from the randomisation. 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 23 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Secondary endpoints –adenocarcinoma, high grade dysplasia, death 
As described for primary but for each event separately. 
 
Secondary endpoints – clinical and molecular risk factors 
Available for a varying number of patients 
 
Secondary endpoint - cost effectiveness 
This endpoint is not being analysed by CSM 
 
Secondary endpoints - changes in molecular markers and genomics 
This endpoint is not being analysed by CSM 
 
Secondary endpoints – quality of life 
It was not possible to collect this data across time so this analysis cannot be 
done 
 
Secondary endpoints – biological risk factors for cardiac disease and 
aspirin resistance 
Cardiac events fulfilling a seriousness criterion will be noted as SAE and this 
will be used as indicative of cardiac disease. Biological risk factors of 
hypercholestrol, family history, patient’s history, hypertension, diabetes and 
smoking will be tabled to show availability of this data. 
 
Secondary endpoints – gender effect 
Gender data should be available on all from randomisation 
 
Sensitivity analysis – presence of helicobacter will be defined as 
helicobacter seropostitivity at any point in the trial. 
 
Pathology – local pathology results will be used 
 
7. Patient Groups for Analysis 
 
To address the primary, secondary and exploratory aims, analyses will be 
conducted on an intention to treat (ITT) sample, defined in this case to mean 
all patients randomised irrespective of how much or which treatment they 
actually received.  
 
In addressing the secondary and exploratory aims the ITT sample may be 
modified (MITT) due to missing data in the variables required for the analysis, 
i.e. every randomised patient who has the data for the particular analysis will 
be included using the treatment code to which they were randomised. 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 24 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
For the PPI comparison the ITT sample will be all patients randomised. For 
the aspirin comparison, the ITT sample will exclude those only taking part in 
the PPI randomisation. 
 
A sensitivity analysis will be carried out on a per protocol (PP) basis to 
examine the robustness of the treatment effect conclusions for the primary 
aim dependent on the actual drugs the patients received. It is accepted that 
the samples used may be biased since all randomised patients will not be 
included. The PP sample will be patients who are considered to have received 
a therapeutic dose of the treatment as defined in Appendix 1. Any patients 
randomised to no aspirin who take a regular dose of aspirin will be excluded 
from this analysis. Regular use of other NSAID will not change the inclusion of 
a patient in the PP analysis  
Since this is a trial examining the policy of offering a PPI/aspirin combination, 
a formal PP analysis is not appropriate.  
 
A sensitivity analysis will be carried out using the corrected Barrett’s Length at 
randomisation – for 60 patients the length given at randomisation was found 
to be incorrect after the randomisation had occurred. Barrett’s is measured as 
columnar and maximal and reports can also give distance from teeth and 
confusion between these was not recognised prior to the trial start. 
 
The main analysis will be done on the full sample now expected to be 2500 
men and women. The entire analysis may be repeated on the male and 
female groups separately. 
 
 
8. Primary Aim Comparative Analyses 
 
8.1 Evaluation/definition of Primary Outcome  
 
See section 6 “reliability of data” for the calculation of survival time for the 
primary objective. 
 
8.2 Statistical Methods Used for Analysis of Primary Outcome  
 
In the first instance, the primary outcome will be analysed to achieve the 
primary objectives assuming there is no interaction between treatments. 
 
Kaplan-Meier curves will be produced and logrank analysis will be used to 
compare the time to primary outcome between those receiving aspirin and 
those not and also between those receiving low PPI and high dose PPI. A 
significance level of p=0.05 will be used. An accelerated failure time (AFT) 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 25 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
model will be constructed for each co-primary to adjust the treatment 
comparisons for age, length of Barrett’s metaplasia and presence of intestinal 
metaplasia (as used in the minimisation procedure). To increase precision, the 
alternative co-primary will be added into the model.  An AFT model was 
chosen so that the estimates of the effect are in terms of a time ratio (ratio of 
expected survival times in the aspirin/no aspirin comparison or low PPI/high 
PPI comparison).  
 
The logrank results will be presented in a table 
 
 
total Number of events Logrank and p value 
Aspirin 
  Aspirin 
  No aspirin 
 
 
 
 
PPI 
  Low PPI 
  High PPI 
 
 
 
 
 
The time ratios will be presented with 95% confidence intervals and will form 
the definitive analysis for the primary aim. 
 
If proportional hazards assumptions are valid, a Cox regression model with 
just aspirin treatment and then another with just PPI treatment will be 
presented. A Cox model for each coprimary considering the effect of 
treatment whilst adjusting for age, length of Barrett’s Metaplasia and 
presence of intestinal metaplasia will be also be presented. To increase 
precision, the alternative co-primary will be added into the model. These 
models will give hazard ratios with associated 95% confidence intervals. 
These are provided for comparison with other research.  
 
All centres will be analysed together. It is expected that either STATA, SAS, 
SPLUS or other similar statistical software will be used for the analysis.   
 
8.3 Adjustment of P values for Multiple Testing 
 
It is intended that no formal adjustment for multiple significance testing will 
be made.  
 
8.4 Missing Data 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 26 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
It is expected that all data will be available to make the primary objective 
analysable on all patients randomised. Nonetheless, patients will be lost to 
follow-up and this will be summarised as outlined above to allow a reader to 
adjust their interpretation of the results accordingly. 
 
The secondary endpoints will not all be complete and some analysis will be 
done on a subgroup of the patients who have the data. In these cases the 
patients in the analysis and those left out will be described. 
 
We do not expect to impute any data for the analysis in this plan.  
 
8.5 Pre-specified Subgroup Analysis  
 
The analysis applies to males and females (planned to be 500) combined but 
will be repeated on males only and on just the females. 
 
8.6 Sensitivity analysis    
 
As specified in section 7 using PP sample and variables as randomised. 
 
A Kaplan-Meier plot will be drawn with a line for each of the four treatment 
groups to look for a visual sign of interaction between the treatments. An 
interaction term will also be added to AFT and COX models containing both of 
the treatment main effect to test for significance (although this will have low 
power). If statistically significant interaction is found, the results will also be 
presented for aspirin within each PPI treatment group and for PPI within each 
aspirin group. 
 
The estimate of the treatment effect in AFT and Cox models will be adjusted 
for presence of helicobacter. 
 
AFT and Cox models will be adjusted for gender as well as the minimisation 
variables. 
 
AFT and Cox models will be adjusted for NSAID and for Cox Inhibitor use. Use 
will be defined as more than 1 month continuously and as more than 6 
months continuously. 
 
AFT and Cox models with stratifying variables will be redone using actual 
Barrett’s length at baseline. 
 
The primary analysis will be repeated using all oesophageal cancers instead of 
just adenocarcinoma of the oesophagus. 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 27 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
The primary analysis will be repeated censoring follow-up when patients start 
taking NSAID. 
 
The primary analysis for PPI will be repeated censoring patients when they 
start taking another medicine for Barrett’s (data in EOT form reasons for 
withdrawal ‘other’ and in Follow Up form in ‘treatments for Barrett’s other 
than esomeprazole’). 
 
8.7 Treatment by Centre Interaction 
 
Consistency of effect will be assessed across the centres by informal 
examination of the within centre effects. There will be limited capacity to 
investigate these formally and it is noted that such centre effects are 
expected by chance.  
 
8.8 Supporting information 
 
The withdrawal rates from aspirin and PPI will be described as well as the 
dose of drug taken at time points throughout the trial. 
 
9. Analysis to address secondary aims 
 
There are many secondary aims so these will be described under each aim 
 
• To assess whether intervention with aspirin results in decreased high-
grade dysplasia, in decreased all cause mortality, in decreased 
adenocarcinoma oesophageal cancer incidence,  and in decreased cause-
specific mortality when each is considered separately 
ANALYSIS: As for primary using the AFT model. As for primary using COX 
model for all cause mortality. For the COX model for high grade dysplasia, 
adenocarcinoma oesophageal cancer incidence and cause-specific mortality a 
competing risks approach will be used since there are expected to be many 
competing deaths for these endpoints. 
For oesophageal cancer, as a sensitivity, the analysis will be rerun including 
all oesophageal cancers rather than just adenocarcinomas. 
 
• 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  
ANALYSIS: As for primary using the AFT model. As for primary using COX 
model for all cause mortality. For the COX model for high grade dysplasia, 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 28 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
adenocarcinoma oesophageal cancer incidence and cause-specific mortality a 
competing risks approach will be used since there are expected to be many 
competing deaths for these endpoints. 
For oesophageal cancer, as a sensitivity, the analysis will be rerun including 
all oesophageal cancers rather than just adenocarcinomas. 
 
• Are there clinical and molecular risk factors than can be identified in BM 
for the development of BA? 
ANALYSIS: Variables to be specified at the end of the trial. These variables of 
interest will be added to the accelerated failure time model with the event 
oesophageal adenocarcinoma and those found to be significant will be 
reported. The variables will also be considered in the competing risk COX 
approach.; 
 
• What is the cost effectiveness of aspirin and/or PPI treatment in the 
prevention of BA? 
The analysis will not be undertaken by CSM; to be analysed by Prof Paul 
Moayyedi. Information from protocol: 
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.  
 
• 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) 
ANALYSIS: Based on analysis of the samples, this aim will be carried out after 
the end of the trial under a separate analysis plan. 
 
• To assess how quality of life is affected by the different treatments.  
It was not possible to collect quality of life across time and so this secondary 
cannot be completed. 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 29 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
• We will also assess what the biological risk factors are for cardiac disease 
and aspirin resistance. 
Cardiac disease will be ascertained from SAE. The risk factors to be tested are 
hypercholestrol, family history of cardiac disease, patient history of cardiac 
disease, hypertension, diabetes or smoking. A logistic model predicting 
cardiac disease using these factors will be built. To consider aspirin 
resistance, a logistic model predicting cardiac disease in those taking aspirin 
will be built and described. 
These 2 models will be repeated for the data from the time of the new 
tumour questions using cancer instead of cardiac disease.  
 
• To assess if gender is prognostic for conversion or survival 
ANALYSIS: Using the survival time calculated for the primary objective, a 
logrank test to assess the effect of gender with both males and females in the 
sample will be reported in a table as for the primary objective. Create an AFT 
model looking at the gender effect adjusting for age, length of Barrett’s and 
presence of intestinal metaplasia so that there is a time ratio with 95% 
confidence interval for the gender effect. Repeat with a Cox model if 
assumptions valid. Redo both of these models with treatment also included. 
 
Exploratory aim 
To assess aspirin’s role on the development of colorectal adenomas and 
cancer 
Use as outcome the time to colorectal cancer or colorectal adenoma. Using a 
logrank test, consider if aspirin use is prognostic.  
 
To collect and bank samples for use in future ethically approved studies 
To be analysed under other protocols and analysis plans. 
 
 
And the exploratory uses of the data 
 
• Describe Barrett’s length over repeat biopsies and investigate a change in 
length from baseline to 2 years between treatment groups. 
ANALYSIS: For all patients, assess if Barrett’s metaplasia length shows a trend 
with time using repeated measures anova. 
Using the baseline and 2 year length, compare the Barrett’s length difference 
between treatment groups using paired ttest. 
 
• Can intervention with aspirin result in a lower stage of adenocarcinoma ? 
Can intervention with PPI result in a lower stage of adenocarcinoma ?  
ANALYSIS: Chi square trend test on the following tables 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 30 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
No aspirin Aspirin  
 
Low PPI High PPI 
None 
 
 
 
None  
 
 
Stage I 
 
 
 
Stage I 
 
 
Stage II 
 
 
 
Stage II 
 
 
Stage III  
 
 
Stage III  
 
Stage IV  
 
      
Stage IV  
 
 
Note: this ignores the different follow-up times 
 
• Does adjustment for oesophagectomy, ablation therapy, endoscopic 
mucosal resection change the treatment effect ? 
ANALYSIS: Within the multivariate AFT and COX models, add time dependent 
variables for the above and note the new treatment effect. 
 
• Is the event rate different for those previous users of aspirin who were not 
randomised to it compared to previous users who continued with aspirin 
as their randomised treatment?  
ANALYSIS: Kaplan-Meier curve and Logrank of the previous users of aspirin 
who were not randomised to it versus those randomised to aspirin. 
 
• Investigation of the hypothesis that aspirin will have a chemopreventive 
effect on all epithelial cancers using the same mechanism it does to 
reduce oesophageal cancer, however, high dose PPI therapy may arguably 
increase colon cancer incidence as gastrin levels increase and this 
hormone is a known stimulant for colon cancer  
ANALYSIS: Define outcome as time to epithelial cancer (oesophageal, 
colorectal, other gi or skin). For those randomised to aspirin and low PPI or to 
no aspirin and low PPI, use an AFT model with stratification variables to 
assess if aspirin is predicting outcome.  
 
Where possible, all these analyses will use the ITT sample. 
 
9.1 Resource Use and Cost Data  
 
The health economics data for this trial will not be analysed by CSM; the 
analysis will be undertaken by Prof P Moayyedi. 
 
 
10. Exploratory analyses not specified prior to receiving 
data 
 
Any analyses not specified in this document will be exploratory in nature. 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
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Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
 
 
11. Serious adverse events 
 
Serious adverse events are defined as those that are fatal, life threatening, 
disabling, a congenital birth defect, another important medical event which 
require hospitalisation or prolongation of hospitalisation. Any serious adverse 
event occurring whilst a participant is continuing in the study, until trial 
medication is stopped will be recorded. All serious adverse events will be 
described in tables including causality, CTCAEgrade, 
outcome and 
seriousness. A comparison of specific serious adverse events between the 
treatment groups (aspirin vs no aspirin and low PPI vs high PPI) will be 
assessed by examination of 95% confidence intervals for the difference in 
incidence. An overall category for any serious adverse event will also be 
compared using the chi square test. The analysis will be conducted by 
intention to treat. An overall category for renal impairment (dehydration, 
renal, obstruction) will be compared using the chi square test. 
 
SAE and death major bleeds will be summed and expressed as number of 
major bleeds per 1000 person years. 2 major bleeds per 10000 person years 
is expected. 
 
 
12. Data from Canada 
One site in Canada ran a trial of 50 patients using the same protocol.  The 
entire analysis plan will be re-run including this data when it is available.


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 32 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Appendix 1: Interpretation of therapeutic dose 
 
Therapeutic dose: 1 year for esomeprazole and 6 months for aspirin. 
 
For the individual treatment groups this means  
 
Treatment  
Therapeutic dose 
Low ppi no aspirin  
High ppi no aspirin  
1 year of esomeprazole at randomised dose  
OR  
event before 1 year and esomeprazole at randomised 
dose until the event 
 
Low ppi aspirin  
High ppi aspirin  
1 year of esomeprazole at randomised dose and at 
least 6 months of aspirin at randomised dose  
OR 
event before 6 months and esomeprazole and aspirin 
at randomised dose until the event  
OR  
event between 6 and 12 months and esomeprazole at 
randomised dose until the event and aspirin at 
randomised dose for at least 6 months 
 
 
 
Since this is a trial looking at the policy of offering the drugs (whether the 
patients take them or not is part of what we need to know), looking at the 
primary objectives on the patients who received a therapeutic dose of the 
drugs is a sensitivity analysis rather than a main concern.  
 
We can only classify patients as receiving a therapeutic dose or not if they are 
a year into the trial and we have received the data through from the 
pharmacy. 
 
Any patients randomised to no aspirin (first row of the above table) who takes 
a regular dose of aspirin will be considered not to have received a therapeutic 
dose irrespective of their esomeprazole dose history. 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 33 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Appendix 2: Variables to be used in analysis 
(Not exhaustive) 
 
To check rand 
 
VARIABLE 
FORM 
Length of Barrett’s at rand or diagnosis Randomisation or IR patient history 
Age at rand 
Randomisation 
IM  
 
 
 
To describe sample 
 
VARIABLE 
FORM 
Alcohol consumption 
PR Patient history 
Smoking history 
PR Patient history 
Cardiac history 
IR Patent history 
Duration of Barrett’s pre randomisation 
IR Patient history  
Length of Barrett’s at rand or diagnosis 
Randomisation or IR patient history 
Age at rand 
Randomisation 
 
 
Primary aim  
 
VARIABLE 
FORM 
Length of Barrett’s at rand or diagnosis 
Randomisation or IR patient history 
Age at rand 
Randomisation 
 
 
Rand date 
Randomisation 
Last follow-up date 
Date of death 
Cause of death 
Follow-up form 
Date high grade dysplasia 
Endoscopy form or follow-up form 
Date adenocarcinoma 
Endoscopy form or follow-up form 
 
 
 
Secondary aims 
 
VARIABLE 
FORM 
Cardiac history 
IR Patient history  
Stage of cancer Endoscopy report 
 
 
 
 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 34 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017 
Document History 
 
Document history  AspECT statistical analysis plan 
Ver 
Date 
Comments 
0.1 
16th March 2006 
First draft by SBL 
0.2 
21st April 2006 
Draft for review by Rachel Waters 
0.3 
12th July 2006 
Draft for review by rest of MSG support and Janusz Jankowski 
0.4 
18th August 2006 
Updated to Jan 2006 version of the protocol 
Added Info from 20th July meeting with Janusz 
Added comments/clarifications from 25th July meeting with MSG support 
Passed to Louise Linsell and Rachel Waters to review and sign. 
Passed to DSMC 
0.5 
29th Sept 2006 
Added DMC comments 
Females randomised separately 
100 Previous aspirin users to be entered 
0.51 
15th August 2007 
Added gender to the tables in section 6.2 
Previous aspirin use deleted from tables in 6.2 since not collected since June 2007 on shortened forms 
Analysis of effect of high PPI by each event separately 
Analysis of effect of aspirin use by each event separately 
Randomisation to PPI arms only 
Clarification that Barretts length is at rand if available, otherwise it is at diagnosis 
Addition to appendix 2 – specifying data needed 
052 
20th Nov 2007 
Changed event list to clarify what cause-specific death means. 
0.53 
Jan 2008 
Added version 9 important changes to randomisation 
0.6 
30thJan2008 
Updated to version 9 of the protocol 
To be submitted to DSMC April 2008 
Logo added on front page 
0.7 
May 2008 
 
0.8 
19th Sep 2008 
Name of file changed to CSM policy of statistical analysis plan 
Updated to version 10 of the protocol 
Sample size section tidied, now giving only the original and the guidance for 2500 patients 
 
0.81 
3rd Oct 2008 
Contents page corrected 
Sample size exploratory calculation changed. 
Minor changes of text for clarity. 
0.82 
14th Oct2008 
Typo corrected 
0.83 
6th Jan 2009 
Put in analysis for third secondary aim and for last secondary aim 
 
1.0 
29Jul2013 
Updated to version 10 of protocol 
All contact details in section1 updated 
Secondary endpoint split into those within the study and those investigated as substudies 
Oesophagitis secondary endpoint added 
Number of events added to sample size information 
Definition of oesophageal cancer secondary endpoint added 
Interim analysis, emphasised no plans to disseminate 
Clarification that trial uses local pathology 
Describe withdrawal rates 
Added several sensitivity analyses  
Added exploratory of dose/time effect 
Added specific look at renal impairment 
Express number of major bleeds per 1000 years  
 
1.1 
20Aug2013 
Changed interim analysis p value to 0.001 as standard 
1.2 
25Jan2014 
Made notes for next version in red on page 1 
1.21 
1.22 
6Apr2017 
20Apr2017 
Updated contacts, protocol number and footer 
Updated to protocol 12 
1.31 
1.32 
1.33 
1.34 
1.35 
1.36 
1.37 
1.38 
 
2.0 
12Jun2017 
 
 
 
 
 
 
15Aug2017 
 
24Aug2017 
Updated after conversation with PI 
Minor edits – each typo corrected as it is seen 
Minor edits 
Minor edits 
Minor edits 
Minor edits 
Minor edits 
Adelyn’s comments added, explicit statement made about Canada data 
 
All changes accepted and comments deleted 


AspECT 
A phase III randomised study of Aspirin and Esomeprazole chemoprevention in Barrett’s 
metaplasia 
Funded by CR-UK, MRC, UHL and NCI 
 
ISRCTN No.85156844 
 
 
 
Page 35 of 35 
 
Version No: 2.0 
 
Author: Sharon Love 
Issue Date:  24Aug2017