Add-Aspirin Trial: A phase III double-blind placebo-controlled randomized trial assessing the addition of aspirin after standard primary therapy in early stage common solid tumours

Design: Add-Aspirin aims to assess whether regular aspirin use after standard therapy, including surgery and neo-adjuvant/adjuvant chemotherapy and/or radiotherapy, can prevent recurrence and prolong survival in participants with common solid tumours. The question will be addressed in four common cancers (breast, colorectal, gastro-oesophageal, and prostate) by means of a phase III, multi-centre, double-blind, placebo-controlled, randomised trial with four parallel, individually powered tumour-site specific cohorts. A secondary aim is to collect data on other potential healthcare benefits of aspirin, such as cardiovascular system diseases (including those associated with diabetes) and cognitive function. Setting: Participants will potentially be recruited from all NHS oncology centres and units in the UK. To date, expressions of interest to participate have been received from investigators at 130 hospitals, encompassing all of the NIHR Cancer Research Networks. For the breast and gastro-oesophageal cohorts, a collaboration with the Tata Memorial Centre (a leading Asian cancer research centre) and other hospitals in India has been established. Target population: Eligible participants will have had a diagnosis of non-metastatic cancer and undergone primary treatment with curative intent. This can include surgery and any standard neoadjuvant/adjuvant therapy, radical chemoradiation (oesophageal cancer) or radical radiotherapy (prostate cancer). Colorectal cancer patients who have undergone resection of liver metastases with clear margins and no residual metastatic disease are also eligible. With the exception of the gastro-oesophageal cohort, where prognosis is poor, eligibility criteria will identify groups at high risk of disease recurrence. Those already participating in primary therapy trials will be eligible subject to agreement from the relevant trial team. Health technologies: Within each tumour-specific cohort participants will be randomised to 100mg aspirin, 300mg aspirin, or a matching placebo, to be taken daily for at least 5 years. A single, enteric-coated tablet will be self-administered, orally. Neither clinician nor participant will be aware of treatment allocation. The intervention will be given after standard primary therapy, rather than replacing any element of it. For elderly participants (=75 years), where side-effects may be a greater concern, randomisation between only the placebo and 100mg aspirin arms will be permitted. Measurement of outcomes: The primary aims of the trial are to assess whether aspirin can prevent recurrence and prolong survival in individuals who have had radical treatment for cancer. This will be achieved by means of a combined cohort analysis on overall survival including all four cohorts. Allied to this, cohort-specific analyses will allow investigation of the specific effects of aspirin on each tumour type. The co-primary outcome measures for the cohort-specific analyses are designed to ensure that they are appropriate, feasible, and convincing to the clinical communities. Invasive disease-free survival will be used for the breast cohort, disease-free survival for the colorectal cohort, overall survival for the gastro-oesophageal cohort and biochemical recurrence–free survival for the prostate cohort. Other secondary outcomes include adherence, toxicity and cognitive function. Planned associated translational research will investigate potential mechanisms of action for an anti-cancer effect of aspirin. Outcome assessments will be based on standardised, widely–accepted definitions, such as those established by the COMET (Core Outcome Measurements in Effectiveness Trials) initiative, to ensure that results are comparable with other datasets, particularly for secondary outcomes such as cardiovascular disease. Assessment of tumour recurrence and side-effects will be based on standard, validated criteria (e.g. CTCAE). Strategies for improving adherence which have proven effective in other aspirin trials will be used. In a subset of UK participants, adherence will be assessed by measuring serum thromboxane B2 (an indicator of platelet inhibition) and this will be compared with patient-reported adherence. In the UK, outcome data will also be collected through registries and national databases provided by the National Cancer Intelligence Network. Use of long-term routinely-collected healthcare data will ensure that the full benefits of the intervention are recognised. An embedded sub-study will aim to verify the quality of these data by comparison with data collected from participating centres during early follow-up, with potential resource savings for future trials. Sample size: Tumour site-specific cohorts will be individually powered at 90%, with the exception of the gastro-oesophageal cohort which will have 80% power. Target effect sizes are of a similar magnitude across the four cohorts, corresponding to hazard ratios between 0.78 and 0.84, and absolute improvements in 5-year outcomes of 4%-8%. The modest effect sizes are similar to benefits seen with a range of adjuvant therapies across tumour sites and would be sufficient to change practice. Sample size calculations take into account expected recruitment rates and some loss to follow-up, resulting in target sample sizes of 3100, 2600, 2100 and 2120 for the breast, colorectal, gastro-oesophageal and prostate cohorts respectively (total n=9,920). Project timetable: Recruitment is expected to take 3-6 years, depending on cohort, based on previous trials in the UK and India and recruitment estimates provided by investigators in feasibility surveys. The cohort-specific primary analyses will occur 5-6 years after the last randomisation for that cohort. Thus, cohort-specific primary outcome results will be reported in approximately 2025. The combined cohort analysis of overall survival will look at the longer-term effects of aspirin and is planned for 15 years after the randomisation of the first Add-Aspirin participant. Expertise: The research team includes oncologists, surgeons and trialists specialising in each of the tumour sites in the UK and India, as well as participant representatives and experts in translational research, pharmacology, cardiovascular disease, methodology, statistics, trial management, and healthcare databases. The MRC CTU at UCL will have overall responsibility for coordinating the trial with a team at the Tata Memorial Centre co-ordinating Indian participation with the aid of a contract research organisation. Both centres have the appropriate infrastructure and experience in conducting large oncology trials to run the project successfully. Additional countries may join the trial subject to resource and organisational considerations, and assessment of individual centres.