COLchicine and Non-enteric Coated Aspirin in the Cardiovascular Outcomes Trial of Patients With Type 2 Diabetes

Inclusion Criteria:

1. Men and women aged 55 to 80 years

2. Type 2 diabetes treated as per national guidelines

3. No previous history of coronary artery disease-related clinical event

4. And at least one of the following:

5. Duration of diabetes of 5 years or more,

6. HbA1c ≥ 8.0% or more in the last 2 years

7. Active cigarette smoking,

8. High hs-CRP (> 2.0 mg/L),

9. High coronary calcium score (Agatston score >100),

10. High TG-levels (≥1.7 mmol/L) despite lipid lowering therapy administered as perguidelines,

11. High LDL-C levels (≥3.5 mmol/L) or high non-HDL-C levels (≥4.2 mmol/L) despitelipid lowering therapy administered as per guidelines

12. High Apo-B (≥1.05 g/L)

13. Reduced HDL-C (<1.05 mmol/L in men, <1.3 mmol/L in women),

14. Lp(a) >50 mg/dL,

15. Peripheral artery disease with stenosis ≥50% or prior revascularization,

16. Cerebrovascular disease with stenosis ≥50% or prior revascularization,

17. Diabetic retinopathy or diabetic neuropathy,

18. Mild or moderate proteinuria (dipstick analysis) or micro-albuminuria

19. Women of childbearing potential must have a negative urine pregnancy test atscreening/randomization visit 1 and must agree to use an effective method of birthcontrol throughout the study. Acceptable means of birth control include: oralcontraceptives, implantable contraceptives, injectable contraceptives, transdermalcontraceptives, intrauterine devices, male or female condoms with spermicide,abstinence, or a sterile sexual partner. Women are considered not of childbearing potential if they either:

20. Have had a hysterectomy or tubal ligation prior to baseline visit or

21. Are postmenopausal defined as no menses for 12 months or a FSH level (ifavailable) in the menopausal range.

22. Patients with the capacity to provide informed consent.

Exclusion Criteria:

1. Any prior history of myocardial infarction, angina, coronary revascularization,coronary stenosis >30%, stroke, transient ischemic attack, or known heart failure

2. Known chronic renal insufficiency defined as an estimated glomerular filtration rate (eGFR), using the MDRD equation, of < 35 mL/min/1.73m2

3. History of cancer or lymphoproliferative disease within the last 3 years other thana successfully treated non-metastatic cutaneous squamous cell or basal cellcarcinoma and/or localized carcinoma in situ of the cervix and/or low-grade prostatecancer

4. Inflammatory bowel disease (Crohn's disease or ulcerative colitis) or chronicdiarrhea

5. Peptic ulcer diagnosed within the last 24 months or previous gastro-intestinalbleeding, except for mild hemorrhoidal bleeding more than 5 years ago which ispermitted (patients meeting this exclusion criterion will not be randomized toreceive aspirin or placebo but can be randomized to receive colchicine or placebo)

6. Pre-existent progressive neuromuscular disease or known CPK level > 3 times theupper limit of normal as measured within the past 30 days and determined to benon-transient through repeat testing

7. Any of the following known parameters as measured within the past 90 days, anddetermined to be non-transient through repeat testing:

8. hemoglobin < 100 g/L

10. white blood cell count < 3.0 X 10⁹/L

11. platelet count <110 X 10⁹/L

12. ALT > 3 times the upper limit of normal (ULN)

13. total bilirubin > 2 times ULN (unless due to Gilbert syndrome, which isallowed)

14. History of cirrhosis, chronic active hepatitis or severe hepatic disease

15. Female patient who is pregnant, or breast-feeding or is considering becomingpregnant during the study or for 6 months after the last dose of study medication

16. History of clinically significant drug or alcohol abuse in the last year

17. Patient is currently using or plans to begin chronic systemic steroid therapy (oralor intravenous) during the study (topical or inhaled steroids are allowed, as wellas replacement corticosteroids for adrenal insufficiency)

18. Current chronic treatment with aspirin or another antiplatelet agent (patientsmeeting this exclusion criterion will not be randomized to receive aspirin orplacebo but can be randomized to receive colchicine or placebo)

19. Chronic treatment with an anticoagulant agent (patients meeting this exclusioncriterion will not be randomized to receive aspirin or placebo but can be randomizedto receive colchicine or placebo)

20. Current use of colchicine for other indications (mainly chronic indicationsconsisting of Familial Mediterranean Fever or gout); there is no wash-out periodrequired for patients who have been treated with colchicine and stopped treatmentprior to enrolment

21. History of an allergic reaction or significant sensitivity to colchicine

22. History of an allergic reaction or significant sensitivity to aspirin (patientsmeeting this exclusion criterion will not be randomized to receive aspirin orplacebo but can be randomized to receive colchicine or placebo)

23. Chronic treatment with an anti-inflammatory agent (for example, anti-TNF-alpha ornonsteroidal anti-inflammatory drug (NSAID))

24. Use of an investigational chemical agent less than 30 days or 5 half-lives prior tothe screening visit (whichever is longer)

25. Patient is considered by the investigator, for any reason, to be an unsuitablecandidate for the study.