Barretts Esophagus Clinical Trial
Official title:
BRIDE (Barrett&Apos;s Randomised Intervention for Dysplasia by Endoscopy) - a Feasibility Study
LAY SUMMARY
A type of gullet cancer (oesophageal adenocarcinoma) has become the 5th commonest UK cause
of cancer death. Unfortunately, by the time patients have symptoms, the cancer is often
incurable. People with Barrett's oesophagus (change of gullet lining occurring in some with
acid reflux) at risk of this cancer can have regular check-ups, involving examination
through an endoscope (an instrument inserted by mouth, under mild sedation if required). A
small proportion of people with Barrett's develop further changes (which might become
cancer) in the gullet lining; if they do, it is important to remove the affected tissue
before cancer develops, or when it is at an early stage.
There are several ways of removing this tissue but the investigators do not know which is
best. The standard treatment is surgery, but there is a small risk of dying from the
operation, and patients often suffer complications affecting them for a year or more
afterwards. Two endoscopic treatments do not involve surgery. Both involve removing visible
abnormalities by a technique called endoscopic resection, followed by cauterising the
remaining Barrett's gullet lining by 1 of 2 techniques. One is recommended by the National
Institute for Health and Clinical Excellence, but it is expensive and less widely available
than the second. No-one has compared these treatments with each other, nor with surgery, in
randomised trials (the most reliable way of deciding which is best). Patient groups say they
would prefer to avoid surgery if the alternative works, and have encouraged us to do trials.
This feasibility study is a vital step towards two trials: (a) a trial to compare the two
non-surgical techniques and (b) a trial comparing surgery with endoscopic treatment. It will
help us find out whether it will be possible to enroll and retain enough patients by using
several centres, and to identify/resolve any other potential barriers to recruitment and
retention, including exploring viewpoints of patients and surgeons.
The study will comprise 2 parts:
Firstly, randomising up to 100 suitable patients over a 1 year period, identified at the
upper gastrointestinal cancer specialist multidisciplinary team meeting in 6 expert English
centres. Patients will have either high grade dysplasia (HGD) or early cancer in Barrett's
oesophagus (BE) and will be randomised to two curative endoscopic non-surgical therapies
(endoscopic resection [ER] and argon plasma photocoagulation [APC] versus ER and
radiofrequency ablation [RFA]). All techniques are used in current clinical practice, but
have never been directly compared.
Secondly, 2 qualitative studies in which we will examine clinicians' and surgeon's attitudes
towards a trial of oesophageal surgery compared to endoscopic treatment (ER and ablation) by
questionnaire. Qualitative interviews with a purposive sample of patients will explore their
views of randomisation, recruitment and participation to help identify and pre-empt problems
in subsequent planned trials of endoscopic treatments compared to each other and to surgical
removal of all or part of the gullet.
Participants will be randomised to the ER plus RFA or ER plus APC group at enrollment. The
randomisation schedule will be managed by the University of Leicester Clinical Trials Unit,
using a computer generated random assignment.
Randomisation will be stratified for length of Barrett's epithelium (< 5; 5-10; > 10 cm).
DETAILS OF SAMPLE SIZE
Currently available estimates of eradication rates have poor precision, being derived from
small case series. Consequently the sample size has been chosen to allow estimation of the
quantities of interest whilst not exposing too many patients to trial procedures.
10- -15 new cases per million population per year are treated. Each participating centre is
based on an upper gastrointestinal cancer treatment centre serving 1.5- - 2 million people.
Since each centre would expect to see 15- - 20 new patients a year, we aim recruit up to 100
patients over 1 year from 6 UK centres.
ENDOSCOPIC INTERVENTIONS
ER, RFA and APC are all techniques used in current practice, with which all investigators
are familiar. We will ensure that all investigators are using the same techniques and that
histological assessment is scrutinised by an an external expert pathology panel (see quality
control below).
Best practice is to perform ER of all visible lesions. We will therefore aim for complete
resection of all visible lesions initially and ablate residual flat Barrett's mucosa at
subsequent treatment sessions (at 2 monthly intervals up to 8 months after the initial
treatment by ER).
The treatment phase of the trial terminates at 8 months. At T= 12 months, diagnostic high
resolution endoscopy is performed with targeted biopsies of any abnormal areas as well as 4
quadrant biopsies at 2 cm intervals of the area containing or previously containing the BE.
The biopsies are in order to identify 'buried' Barrett's glands under the new squamous
epithelium. The clinical endpoint is at 1 year when recurrent or persistent HGD or cancer
will be assessed. Any residual BE (not containing HGD or cancer) will be assessed and
recorded.
QUALITATIVE STUDIES
A purposive sub-sample of patients (sampling strategy designed to include a wide range of
views and experiences, including patients from each centre) will be interviewed by telephone
after being invited to take part in the feasibility trial, using a topic guide (developed
collaboratively with lay representatives, with an emphasis on encouraging patients to
describe their own perspectives freely - a preliminary topic guide has been developed and is
included with this application), exploring views on being invited to participate in research
in which they are randomised to different treatment options. The interview would also invite
views on conducting a trial of endotherapy versus surgery. Interviews will be audio-recorded
with separate consent and transcribed verbatim by transcribers working to professional
standards of confidentiality.
Analysis of Qualitative Data
Analysis of the interview transcripts will be based on the constant comparative approach and
managed by NVivo software. The findings will thus include a set of issues that are important
from a patient perspective, that can help/hinder recruitment and retention, to inform
subsequent trials.
Surgeon/clinician Questionnaires
A purposive sample of surgeons and clinicians at expert centres will receive questionnaires
to explore views to endotherapy and surgery for the treatment of Barrett's oesophagus with
HGD or early cancer and on the proposed trials (including 'free text' options inviting views
on randomization to a trial comparing surgery to endoscopic treatment). Questionnaires will
be distributed to up to 100 oesophagogastric surgeons and clinicians (lead MDT
gastroenterologists or expert endoscopists) from the participating centres and other centres
in the UK as advised by our surgical lead. The questionnaires will be administered by e
mail. A second e mail will follow after a month in the case of non-response, but those who
chose not to respond thereafter will not be further contacted.
Quality of life assessments and healthcare cost assessment
Quality of Life will be assessed at baseline and at the 6 and 12 months visits, using the
EORTC Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) and module QLQ-OES18 to
assess specific relevant aspects of quality of life related to oesophageal disease. General
quality of life will also be assessed using EQ-5D. Additional data on healthcare utilisation
will be collected at baseline, 6 and 12 months using a questionnaire we have developed which
patients will be asked to complete at these scheduled visits for endoscopy.
The perspective of the economic analysis will be that of the NHS and personal social
service. Costs to be obtained will include the costs of endoscopic treatment and continued
endoscopic surveillance in both groups, as well as any additional intervention after the
initial 8- month therapeutic phase of the trial. The costs of any salvage treatment at any
stage will be included. We will test the validity and feasibility of administering the
economic evaluation questionnaire (patient healthcare utilisation questionnaire and EQ-5D),
examining the response rate achieved and levels of missing data. EORTC QLQ- C30 will also be
tested to directly estimate QALYs using EORTC- 8D. Both EQ-5D and EORTC will be used to
obtain the appropriate information for cost per QALY analysis in future economic evaluation.
The economic analysis will inform sample size calculation and other necessary information to
calculate the cost savings for future economic evaluation.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Health Services Research
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