COLO-PREVENT – do simple drugs (aspirin or aspirin plus metformin) or food supplements (resveratrol) reduce the occurrence of bowel polyps (small growths on the bowel lining), which in turn reduce bowel cancer risk?

INTERVENTION: For the Main trial, participants are randomised in a 1:1 ratio and have an equal chance of receiving one of the following therapies: Therapy1 – aspirin tablet Therapy 2 – aspirin tablet and metformin tablets Aspirin 75mg tablets once daily OR Aspirin 75mg tablets once daily AND Metformin hydrochloride 500mg tablets twice daily will be taken orally for the duration of the surveillance period within the BCSP, up until the exit colonoscopy at 3 years. For participants randomised to Therapy 2 in the main trial, metformin 500mg will be started once daily for 4 weeks. This 4 week run‐in period is for the purposes of maximising gastrointestinal tolerability. If the participant is tolerating the 500mg dose of metformin, they will be advised to increase their dose to twice daily, with one tablet to be taken with breakfast and one tablet to be taken with their evening meal. If tolerated, the maximum daily dose of metformin will be 1g for the remainder of the trial. The main trial is not blinded (open‐label) and participants and the research team will be aware of the treatment assignment. For the resveratrol sub‐trial, participants will be randomised in a 1:1:1 ratio and have an equal chance of receiving one of the following three treatment arms: Therapy 1 ‐ 5mg resveratrol capsules Therapy 2 ‐ 1g resveratrol capsules Therapy 3 ‐ placebo (dummy) capsules Resveratrol 5mg or resveratrol 250mg (X4 to give a total daily dose of 1g) or placebo capsules will be taken orally once daily for a period of 1 year, until the day of the participant’s research colonoscopy. The sub‐trial will be double‐blinded, so the research team and participants wi CONDITION: Patients with high risk findings undergoing surveillance in the national Bowel Cancer Screening Programme ; Digestive System ; ‘high risk’ findings after completion of a BCSP screening episode, large non‐pedunculated colorectal polyp PRIMARY OUTCOME: ; Polyp number measured by MPP (Mean number of Polyps per Participant) at exit surveillance colonoscopy; 154 weeks for main trial; 52 weeks for sub‐trial; SECONDARY OUTCOME: ; Measured at exit surveillance Colonoscopy (154 weeks for main trial; 52 weeks for sub‐trial).; 1. Polyp Detection Rate (PDR, proportion of individuals with one or more qualifying* pre‐malignant polyp(s) at surveillance); 2. Advanced polyps (measured as MPP and PDR); these are defined as serrated polyp =10mm, serrated polyp with any dysplasia, adenoma =10mm, adenoma with high‐grade dysplasia; 3. Polyp subtype based on histopathology (adenoma/serrated); also reported as MPP and PDR; 4. Location of polyps (right colon ‐ any part of the colon proximal to the splenic flexure; left colon – the rectum and the colon distal to and including the splenic flexure); 5. Polyp size (maximum dimension in mm as described in the histopathology report or endoscopic size if no histopathological size available); ; Safety measured from first administration of IMP until the final visit at 156 weeks for the main trial and 54 weeks for the sub‐trial:; 6. Adverse events, including clinically significant bleeding episodes and GI tolerability.; ; Compliance measured in the main trial at: weeks 25, 52, 78, 104, 130 and 154; resveratrol sub‐trial at: weeks 25 and 52; 7. Assessment of compliance by counting residual numbers of tablets/capsules returned by each patient.; ; Exploratory endpoints; 8. Measurement of molecular (glucose, insulin (HOMA), HbA1c, triglycerides, cholesterol, IGFBP‐3, free IGF‐1) and physical (BMI, waist circumference) markers of metabolic status.; 9. Assessment of dietary patterns and fat intake using the EPIC FFQ.; 10. Plasma drug concentrations and metabolite profile for resveratrol and metformin.; 11. Urinary resveratrol/metabolite levels in 20% of participants in the sub‐trial from randomly selected sites that are willing and able to collect urine samples.; 12. In the main trial: Measurement of pharmacodynamic biomarkers common to both aspirin and metformin, including p65, pS6/S6 and cleaved PARP in tissue samples.; 13. In the resveratrol sub‐trial: Analysis of tissue and plasma pharmacodynamic biomarkers, including NQO1, protein carbonyls, Ki67 proliferation index, ML Xand CIDEB.; 14. Characterisation of the gut microbiome.; INCLUSION CRITERIA: General inclusion criteria for both trials: 1. Patients with high risk findings (=2 premalignant polyps including =1 advanced colorectal polyp; or =5 premalignant polyps) at a completed screening episode according to BCSP criteria 2. Patients with a large (=20mm) non‐pedunculated colorectal polyp that is resected with histological R0 en bloc excision at a completed screening episode 3. Patients with a large (=20mm) non‐pedunculated colorectal polyp after piecemeal excision. These will only be eligible if the 2nd site check is a full clearance colonoscopy 4. Adequate renal function, defined as GFR =45ml/min/1.73m2, at any time in the preceding 4 weeks 5. Willing and able to consent to participate in trial Inclusion criteria for the main trial but not the resveratrol Signal‐Seeking trial: 6. Aged 50‐71 years Additional inclusion criteria for the resveratrol Signal‐Seeking trial only: 7. Age