Dose-finding Study of Colchicine in Type 2 Diabetic Patients With Coronary Artery Disease

Mortality rate in Japanese coronary artery disease (CAD) patients has been deemed the lowest among developed countries for the long time. However, cohort study of the investigators based on the registry of 8000 patients with CAD and type 2 diabetes has shown that cardiovascular mortality of such patients even under the optimized standard therapy and relatively intensive control of risk factors was higher than the investigators thought. Given substantial experimental evidence suggesting roles of inflammation as a key player in the development of atherosclerosis and significant association of enhanced inflammatory reaction and cardiovascular events in registry-based cohort of the investigators, the investigators are planning of phase 3 trial of colchicine, which is an ancient anti-inflammatory drug, for the regulatory approval as a drug preventing of cardiovascular events in diabetic CAD patients with enhanced inflammatory reaction. To develop appropriate study protocol of phase 3 trial, a dose-finding study is apparently warranted since our pharmacokinetics study and pharmacokinetics /pharmacodynamics study showed that colchicine stays in leukocytes with a long half life being more than 40 hours and showed consistent inhibition of leukocyte activation for more than 48 hours. In terms of safety issue, 0.5mg of colchicine, which has been frequently used in several cardiovascular trials, is associated with high incidence of diarrhea. As dose-dependency is assumed regarding diarrhea, a dose finding study for safety issue is also needed. The investigators, thus, conduct a double-blind randomized controlled trial to investigate dose-dependent effects on inflammatory responses using highly sensitive-CRP as an indicator, endothelial function using FMD, and incidence of diarrhea comparing once daily oral administration of 0.5 mg, 0.25 mg of colchicine and placebo for 12 weeks in CAD patients with type 2 diabetes mellitus and leukocyte activation. The investigators focus on patients with type 2 diabetes and leukocyte activation among CAD patients for regulatory approval because it is likely that such patients are at highest risk and respond well to colchicine.

Inclusion criteria

• The subjects in this trial must have all of the following criteria.

• Patients with type 2 diabetes mellitus with coronary artery disease(*1) with increased inflammatory response(*2).

• 1:"Type 2 diabetes" mellitus is diagnosed by criteria according to The Japan Diabetes Society. "Coronary artery disease" is defined as having equal to or greater than 75% stenosis in coronary angiography, history of acute coronary syndrome, and history of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
• 2:"Increased inflammatory response" is defined as follow; White blood cell levels at confirmation tests of eligibility is equal to or greater than 7000 /μL.
• Patients aged 20 years and older
• In female subjects who had possibility of pregnancy and male subjects who had female partner who had possibility of pregnancy and not undergone a contraceptive surgery(*3), patients with consent of performing optimal contraception from starting study drug to 90 days from final taking.

• 3: Male subjects who had undergone a contraceptive surgery are defined as elapsing for at least one year after vasectomy and having a certification of no sperm at ejaculation.
• After receiving sufficient explanation for the participation of this study, patients who wrote document of informed consent by the patient's free will with sufficient understanding.

Exclusion criteria

• The subjects who conflict with at least one of the following criteria are exclude from this trial.

• Patients with prior hypersensitivity to Colchicine.
• Patients with taking Colhicine presently or to 30 days before confirmation tests of eligibility.
• Patients with liver cirrhosis
• Patients with clinical cholestasis.
• Patients with decreasing renal function (eGFR < 30 mL/min/1.73m2) at confirmation tests of eligibility.
• Patients with active malignancy.
• Patients taking drugs that are indicated as "combined caution" in the package insert of Colchicine as a drug which may interact with Colchicine. 1. Drugs inhibiting cytochrome P450 drug-metabolizing enzyme

• Strong Inhibitor Atazanavir, Clarithromycin, Indinavir, Itraconazole, Nelfinavir, Ritonavir, Saquinavir, Darunavir, Telithromycin, Telaprevir, Preparation including Cobicistat
• Moderate Inhibitor Amprenavir, Aprepitant, Diltiazem, Erythromycin, Fluconazole, Fosamprenavir, Verapamil 2. P-glycoprotein inhibitor Ciclosporin
• Patients taking Amiodarone or Quinidine.
• Patients with infectious or inflammatory disease at confirmation tests of eligibility.
• Current smoker
• Patients with pregnancy, possible pregnancy, on breast-feeding or who wish to become pregnant during trial. (The female subjects who had possibility of pregnancy receive a pregnancy test.)
• Patients registered in other clinical trials presently or within 30 days before acquisition consent of this trial.
• Patients whom physician in charge considered inappropriate for the study.