A Randomized, 2x2 Factorial Design Biomarker Prevention Trial of Low-dose ASA and Metformin in Stage I-III Crc Patients

Inclusion Criteria: * Patients aged \> 18 and ≤ 80 years. * Patients with completely resected stage I, II, or III primary colorectal cancer within 24 months prior to randomization, regardless of (neo-)adjuvant chemotherapy. Patients with pT1 CRC treated with endoscopic polypectomy. * Adjuvant chemotherapy and (neo-)adjuvant radiotherapy terminated at least 3 months before randomization. * ECOG performance status ≤ 1. * Satisfactory hematological and biochemical functions: * Platelets ≥ 100 x 10\^9/L * Creatinine clearance estimated with the Cockcroft - Gault formula ≥ 60 mL/min. Patients with Gault formula ≥ 45-59 ≤ ml/min are eligible but they will receive a single (evening) tablet of MET, 850 mg. * AST and ALT ≤ 2.5 times ULN. * Females of childbearing potential/males with partners of childbearing potential participating in the study are to use effective methods of birth control during study participation. Female participants must provide a pregnancy test, according to local/national guidelines. * Able to understand and sign an informed consent (or have a legal representative who is able and willing to do so). Exclusion Criteria: * Patients who are not able to undergo colonoscopy. * Patients who are allergic or intolerant to ibuprofen or naproxen,or who have MET-, or ASA-, or salicylate intolerance or more generalized drug intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with study procedures. * Chronic treatment with ASA or other NSAIDs or MET or patients who are on current long term treatment (≥ 4 consecutive weeks) with ASA, NSAID or COX -2 inhibitors or MET. * Diabetic patients on drug treatment are excluded. * Anticoagulant therapy (dicumarol, heparin, fondaparinux, apixaban, dabigatran etexilate, rivaroxaban) or active current treatment with antiplatelet agents (e.g. off-study ASA, clopidogrel, prasugrel, ticagrelor, or ticlopidine). * Any other invasive malignancies (with the exclusion of basal cell carcinoma or cutaneous squamous cell carcinoma) diagnosed during the last 5 years before randomization. Past history of any other invasive CRC than the one the patient is currently being treated for * Alcohol or drug abuse. * Prior history of gastro-intestinal bleeding or hemorrhagic diathesis (e.g. hemophilia). * Erosive-ulcerative lesions in the gastrointestinal tract. * History of erosive GERD or active erosive GERD on gastroscopy. * Concomitant corticosteroid treatment. * Known deficiency of glucose-6-phosphate dehydrogenase (G6PD). * Treatment with another investigational drug \< 28 days prior to study entry. * Concurrent participation in a clinical trial with the same endpoints. * History of hemorrhagic stroke. * Lynch Syndrome (HNPCC). * Crohn's disease (CD) and Ulcerative Colitis (UC). * Pregnant or lactating females. * History of lactic acidosis. * Liver dysfunction including chronic active hepatitis and cirrhosis not compensated. * History of vitamin B12 deficiency or megaloblastic anemia. * Uncontrolled coronary syndrome or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association's Functional Classification). * Inability or unwillingness to swallow tablets.