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.