Table 1 Inclusion and exclusion criteria

•Patients aged > 18 and ≤ 80 years.

•Patients with completely resected stage I, II, or III primary CRC 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.

•Platelets ≥100 × 10^9/L;

•Creatinine clearance estimated with the Cockcroft - Gault formula ≥60 mL/min. Patients with Gault formula ≥30–59 ≤ ml/min are eligible but they will receive a single (evening) tablet of metformin, 850 mg.

•AST and ALT ≤2.5 times upper limit of normal (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).

•Patients who are not able to undergo colonoscopy.

•Patients who are allergic or intolerant to ibuprofen or naproxen, or who have metformin, or aspirin, or salicylate intolerance or more generalized drug intolerance to 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 aspirin or other NSAIDs or metformin or patients who are on current long-term treatment (≥ 4 consecutive weeks) with aspirin, NSAID, COX − 2 inhibitors, or metformin.

•Diabetic patients on drug treatment.

•Anticoagulant therapy (e.g. dicumarol, heparin, fondaparinux, apixaban, dabigatran etexilate, rivaroxaban) or active current treatment with antiplatelet agents (e.g. off-study aspirin, 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 gastro-esophageal reflux disease (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.

•Crohn’s disease or ulcerative colitis.

•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.