Barrett’s oESophagus Trial 3 (BEST3): oesophagus: A Randomized Controlled Trial Comparing the Cytosponge:TFF3 test with usual care to facilitate the diagnosis of Oesophageal pre cancer in primary care.

Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge requires access to NHS England data for the purpose of the following research project:

BEST 3 (Barrett’s oESophagus Trial 3)- A Randomized Controlled Trial Comparing the Cytosponge:TFF3 test with usual care to facilitate the diagnosis of Oesophageal pre cancer in primary care.

The following is a summary of the aims of the research project provided by Cambridge University Hospitals NHS Foundation Trust and University of Cambridge (UoC):

The Trial is a pragmatic multi-site cluster randomised controlled trial to evaluate whether an invitation to the CytospongeTM-TFF3 test will increase the number of BE diagnoses among patients on long-term treatment with acid suppressants, compared to the usual clinical pathway in primary care

BEST3 (Barrett’s oESophagus (BE) Trial 3) study was set up as a randomised controlled trial to demonstrate that the invitation to the Capsule sponge-TFF3 test leads to an increase in the number of patients diagnosed with BE compared to the usual clinical care pathway in primary care. An increase in diagnosis will not only depend on accuracy but also acceptability and therefore uptake of the test. It was also to gain an in-depth understanding of the health economics of the Capsule sponge-TFF3 test in patient on long-term treatment with acid suppressants as well as the economics for the projected reduction of EAC-related mortality.

In this trial, undertaken from April 2017-February 2020, General Practices and NHS Trust recruited participants and patients in the intervention (capsule sponge arm) were only offered an endoscopy if they tested positive. It is therefore important to ascertain any patients who tested negative who subsequently developed dysplasia or oesophageal cancer and to compare these progression and survival rates with the sponge positive group. It will also be informative to compare oesophageal and other cancer incidence and mortality statistics in those who did not accept the offer of screening to understand the opportunities and challenges amongst the harder to reach groups.

The Primary aim is:

To compare histologically confirmed BE diagnosis between intervention and the control, i.e. usual care, arms in all patients entered the study.

Secondary aims are:

(i) to evaluate the cost of the Cytosponge-TFF3 test versus usual care

(ii) to evaluate the cost effectiveness of the Cytosponge- TFF3 test versus usual care

(iii) to assess the diagnostic accuracy of the Cytosponge in primary care

The following NHS England Data will be accessed

• Civil Registration Mortality and Cancer Registration – necessary to help understand cancer treatment and cause of death whether there are differences between cases and controls in longer term outcomes

The level of the Data will be identifiable.

The Data will be minimised as follows:

• Limited to a study cohort of 2,025 participants identified by NHS sites and GP Practices who have consented to the linkage of their health data. The recruitment criteria involves participants aged 50 and over with records of least six months of prescription for acid suppressant medication in the last year at the point of providing consent.

The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are joint research sponsors and the controllers as the organisations responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The funding is provided by The Medical Research Council which is part of the Fitzgerald Lab Core Grant.

The funder will have no ability to suppress or otherwise limit the publication of findings.

The University of Cambridge will process and store the Data. Cambridge University Hospitals NHS Foundation Trust will not process or store the Data. The NHS recruitment sites will not have access to the Data.

The Data will only be accessed by employees of University of Cambridge.

The identifying details will be stored separately from the pseudonymised asset used for analysis. There will be no requirement or attempt to re-identify individuals when using pseudonymised data.

Data Monitoring Committees (DMC):

An independent Data Monitoring Committee (DMC) reviewed trial data and advised the sponsors (directly or indirectly) on the management of the Trial. Its membership included two independent clinicians and an independent statistician.

Trial Steering Committee (TSC):

The Trial Steering Committee provided overall supervision for the Trial on behalf of the trial sponsors and trial funders and ensured that the Trial complied with relevant regulatory, legal and best practice standards.

Trial Management Group (TMG):

The Trial Management Group was responsible for the day-to-day running and management of the Trial. The TMG oversaw the progress of the Trial for the day-to-day implementation and acted on the advice of the TSC. Amongst its members were the lead investigators (clinical and non-clinical), trial co-ordinators, and staff from the Centre for Cancer Prevention at QMUL.

The above committees and TMG group have since been disbanded.

There has been extensive Patient Participation and Involvement (PPIE). This has included:

• Stands/stalls/demos at science festivals such as the annual Cambridge Science Festival, and Norwich Science Festival

⦁ Stand at the BIG weekend on Parker’s Piece in Cambridge, as well as stands elsewhere in the Cambridge area at supermarkets, garden centres, Shelford cancer centre etc. to engage with the public and raise awareness.

⦁ Stalls at local fairs such as Mill Road Winter Fair in Cambridge

⦁ Demonstration of the use of the capsule sponge at the Huntingdonshire Community Cancer Network’s patient conference

⦁ Consultations with PPI panel provides input to shape recruitment, communication plans, data handling, and patient facing documents.

⦁ Chief Investigator, and director of the Early Cancer Institute has made appearances on local and national radio such as Radio 4’s Today program.

⦁ Regular appearances in news websites, newspapers and periodicals.

⦁ Appearances at meetings, such as a talk by an active patient campaigner at the British Psychosocial Oncology Society where they talked about their experience of the capsule sponge.

⦁ Annual patient educational event (alternatively online/in person) in conjunction with HCUK, where patients are invited to come and meet the experts in BE (gastroenterologist and research nurses), Upper GI Surgeons, Scientists, Dieticians, and Pathologists to learn about current practices and advances in research and have an interactive session where they can ask questions.

In addition, from Heartburn Cancer UK (HCUK) and Action Against Heartburn.

⦁ attending events, and also have information on their websites about the capsule sponge and related studies

A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above.

The University of Cambridge will transfer data to NHS England. The data will consist of identifying details NHS Number, Date of Birth, Name, Postcode and a unique person ID for the cohort to be linked with NHS England data.

NHS England will provide the relevant records from the Cancer and mortality datasets to University of Cambridge.

The Data will

• contain directly identifying data items including Names, NHS Number, Date of Birth, Postcode, which are required to link the Data at record level with data already held by the recipient.

The Data will not be transferred to any other location.

The Data will be stored on servers at University of Cambridge Data Safe Haven.

The Data will be accessed by authorised personnel via remote access.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not leave England at any time.

Access is restricted to substantive employees of the University of Cambridge who have authorisation from the Principal Investigator.

Analysis will be carried out on pseudonymised data only.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will be linked with other information held by the BEST 3 Trial, however, only aggregated data will small numbers suppressed will be reported.

The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

Analysts from the University of Cambridge will process and analyse the Data for the purposes described above.

The expected outputs of the processing will be:

• Submissions to peer reviewed journals i.e. Nature Genetics and the British Medical Journal.

• Presentations to British Society of Gastroenterology, Digestive Disease Week

• Regular appearances in news websites, newspapers and periodicals.

• Appearances at meetings, such as a talk by an active patient campaigner at the British Psychosocial Oncology Society where they talked about their experience of the capsule sponge.

• Annual patient educational event (alternatively online/in person) in conjunction with Health Care Conferences UK (HCUK), where patients are invited to come and meet the experts in BE (gastroenterologist and research nurses), Upper GI Surgeons, Scientists, Dieticians, and Pathologists to learn about current practices and advances in research and have an interactive session where they can ask questions.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Stands/stalls/demos at science festivals such as the annual Cambridge Science Festival, and Norwich Science Festival

• Stand at the BIG weekend on Parker’s Piece in Cambridge, as well as stands elsewhere in the Cambridge area at supermarkets, garden centres, Shelford cancer centre etc. to engage with the public and raise awareness.

• Stalls at local fairs such as Mill Road Winter Fair in Cambridge

• Cancer Research Website: https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-using-the-cytosponge-test-in-gp-surgeries-for-people-with-heartburn-symptoms-best3

The expected target dates for outputs are end of 2025.

The findings of this research study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study.

It is hoped that study data collected about patient progress and survival data may continue to be used in the future to help work out who needs more careful monitoring or treatment, be able to develop ways of stopping the disease becoming oesophageal cancer. Access to NHS England survival data is key to this progress.

Continuing long-term outcome data from the BEST3 cohort is essential to inform future directions for introducing the Capsule Sponge test to patients. Analysis of NHS records will help measure long term effectiveness of the Capsule Sponge biomarkers to risk stratify patients. In addition to identifying its efficacy in an NHS setting as an alternative to endoscopies.

The potential benefits of this research include reducing the use of invasive procedures for patients and by providing evidence for policy decision makers for the use of a safe, minimally invasive, cheaper, and easily administered method to diagnose and screen for this condition. The Capsule Sponge test showed a specificity of 92% and a sensitivity of around 80% which increases with segment length and is not compromised in the presence of dysplasia. The Capsule Sponge TFF3 test could be used to diagnose patients who would otherwise be referred to endoscopy to rule out BE and therefore be a more systematic screening test for use in primary care.

Follow-up of all participants is needed to continue monitoring the presence of dysplasia and any risks of cancer progression. Currently guidelines recommend endoscopic screening for BE in individuals with multiple risk factors. However, the cost advantages associated with the Capsule Sponge TFF3 test means screenings could be offered to a larger number, thereby improving the potential to correctly identify a greater number of newly-diagnosed BE cases.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

Heartburn Cancer UK and Action Against Heartburn, are aware of the BEST 3 Study and have been involved in the proposed study purposes.

Yielded Benefits is not a requirement for new applications.