Table 2 BEST3 Trial objectives and endpoints

1. To compare histologically confirmed BE diagnosis between intervention and control

BE diagnosis within 12 months of joining the study (excluding BE found on random 12 month research endoscopy that will occur following 12 month snapshot).

Anonymised data aggregated by sex and age group from:

- GP databases

- Confirmed by upper GI endoscopy (biopsy result) as recorded in the GP record within 12 months

Anonymised data aggregated by sex and age group from:

- GP databases

- Confirmed by upper GI endoscopy (biopsy result) as recorded in the GP record within 12 months

In addition, for patients with Cytosponge™ -TFF3 test:

- Endoscopy record and pathology results

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

Objective

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

(i) Mean cost per patient receiving the Cytosponge™-TFF3 test versus usual care. Costs to include costs of diagnosis using the Cytosponge™-TFF3 test, endoscopies and biopsies, endotherapy, oesophagectomy, medications, and follow-up in primary and secondary care.

(ii) Incremental cost per QALY gained of the Cytosponge™-TFF3 test versus usual care

(i) Volume of resource use (endoscopies and biopsies, endotherapy, oesophagectomy, medications, and follow-up in primary and secondary care) from patient records.

Unit costs (of each item of resource use) from published sources.

(ii) Calculation of incremental cost per QALY gained to be based on a pre-existing model, supplemented with new data from the Trial.

(i) Volume of resource use (Cytosponges™, endoscopies and biopsies, endotherapy, oesophagectomy, medications, and follow-up in primary and secondary care) from patient records.

Unit costs (of each item of resource use) from published sources.

(ii) Calculation of incremental cost per QALY gained to be based on a pre-existing model, supplemented with new data from the trial.

To assess the diagnostic accuracy of the Cytosponge™ in primary care

Positive Predictive Value (PPV), Negative Predictive Value (NPV) in relation to the length of BE

N/A

- PPV: proportion of TFF3 positive results confirmed to have BE by endoscopy

- NPV: proportion of TFF3 negative cases confirmed to not have BE by endoscopy (10% endoscopy)

To assess diagnostic performance of Cytosponge™ in detecting severity for BE

Score of BE severity based on BE biopsy results

N/A

Endoscopy reports for participants

To report on the sampling adequacy

Inadequacy rate (same as BEST1 and BEST2)

N/A

CRF to capture:

- Sample sufficient to generate result

- Proportion of Cytosponge™ samples with < 5 and < 1 columnar cells (minimal standard)

To confirm the endoscopy referral rate in the intervention arm

Proportion positive out of all adequate TFF3 tests and out of all patients swallowing a Cytosponge™ at least once

N/A

Cytosponge™-TFF3 test results

To report on patient acceptability for Cytosponge™

(i) Willingness: proportion of patients offered Cytosponge™ test who accept

(ii) Cytosponge™ swallowing failures

(iii) Increased and decreased cancer worry due to procedure and results

(iv) Long term emotional or physical harm caused by procedure

(v) Test experience

(vi) Willingness to have repeat procedure

N/A

(i) Number of patients invited vs those consenting to Cytosponge™-TFF3 test

(ii) Number of patients who fail to swallow and number of attempts

Acceptability measures at baseline:

(iii) STAI-6

(iv) Perceived risk of oesophageal cancer

Acceptability measures at day 7–14:

(iii) Perceived risk of oesophageal cancer

(iv) STAI-6

(v) A visual analogue scale to rate experience

(v-vi) the Inventory to Assess Patient Satisfaction,

(iii – v) up to 30 qualitative patient interviews

To assess physician/nurse acceptability of the Cytosponge™

Experience and acceptability of Cytosponge™: administration, skills, reliability, side effects, user information

N/A

Qualitative interviews of clinical staff

To report on the safety of the Cytosponge™ in primary care

Any ADE/ARs reported by patients up to 7 days post swallowing

N/A

Contact card given in case of ADE/SADE and 7-day telephone call

(i) To understand how much BE is missed in current management of patients

(ii) To compare undiagnosed BE in general population vs those who have been tested with Cytosponge™-TFF3

- BE at 12 months

- PPV for endoscopy referral, i.e. Cytosponge™ vs current GP criteria for referring for an endoscopy to look for BE

12 month endoscopy for 10% of patients not requiring a clinically indicated endoscopy in time period of the study

Confirmatory endoscopy for patients with positive result and endoscopy findings from patients with negative result who accept research endoscopy at 12 months.

To assess prevalence of benign oesophageal conditions

Prevalence of oesophageal conditions aside from BE in primary care population consulting with reflux symptoms

Endoscopy findings in 10% patients endoscoped

Endoscopy findings in 10% patients endoscoped and on Cytosponge™ test (via pathology assessment)

Epidemiology:

(i + ii) To confirm the prevalence (and incidence) of BE in both arms

(iii) To confirm the prevalence (and incidence) of OC diagnosis (by stage) in both arms

(iv) To confirm the prevalence (and incidence) diagnosis cancers of the gastric cardia (by stage) in both arms

(v) To produce a model to predict the reduction in EAC related mortality from this strategy

(i) Diagnosis of BE

(ii) Diagnosis BE with dysplasia

(iii) Diagnosis of oesophageal cancer (OC) + stage at diagnosis

(iv) Diagnosis of cancer of the gastric cardia + stage at diagnosis

(v) Percentage of expected reduction in EAC mortality based on prevalence of BE if Cytosponge™ test introduced

(i-iv) Aggregate data from GP databases

(i-iv) Aggregate data from GP databases

(i-iv) Endoscopy data from 10% endoscopy offered at 12 months

(i-iv) Cytosponge™ patients:

- Cytosponge™ findings

- Endoscopy findings

10% endoscopy invitation across both arms:

(i) Acceptability of endoscopy

(ii) Perceptions around Cytosponge™ use and reliability

(iii) Number of BE diagnoses 12 months after negative TFF3 tests

(i) Comparisons between acceptance of invitation to endoscopy compared to Cytosponge™ test

(ii) Proportion of patients with Cytosponge™ test who take up invitation to endoscopy

(iii) Number of BE diagnosis in TFF3 negative patients in intervention arm

(i) 10% endoscopy: uptake of invitation to endoscopy

(i) 10% endoscopy: uptake of invitation to endoscopy for all participants who have not received the CytospongeP™ P (excluding ineligible patient and non-attendees for Cytosponge™)

(i) CytospongeP™ Ptest invitation uptake

(ii) Endoscopy uptake amongst patients with previous Cytosponge™ test

(iii) BE diagnosis amongst patients with previous Cytosponge™ test

Epidemiology: For up to 10 years, to confirm the prevalence (and incidence):

(i + ii) of BE in both arms

(iii) of OC diagnosis (by stage) in both arms

(iv) of cancers of the gastric cardia (by stage) in both arms

(iv) To undertake modelling to predict the reduction in EAC related mortality from this strategy

(i) Diagnosis of BE

(ii) Diagnosis of BE with dysplasia

(iii) Diagnosis of OC + stage at diagnosis

(iv) Diagnosis of cancer of the gastric cardia + stage at diagnosis

(v) Percentage of expected reduction in EAC mortality based on prevalence of BE if Cytosponge™ test introduced

(i-iv) Anonymised data from cancer registry flagging- conducted anonymously via novel encryption method

(v) Based on BE prevalence, prevalence of BE with dysplasia, flagging with the cancer registry, ONS and HES datasets

(i-iv) Anonymised data from cancer registry flagging- conducted anonymously via novel encryption method

(v) Based on BE prevalence, prevalence of BE with dysplasia, flagging with the cancer registry, ONS and HES datasets

Research and Development (including in future studies)

Genetic and biochemical risk factors for disease progression (germline and somatic variants and other biomarkers) including targeted, exome level and whole genome sequencing.

10% patients who have endoscopy- surplus material from biopsies

- Surplus Cytosponge™ material

- Saliva samples (for TFF3 positive patients only)

- Surplus endoscopy biopsies