Repurposing Colchicine for Reduction of Residual Inflammatory Risk in Type 1 Diabetes

The aim of this clinical trial is to evaluate if colchicine in addition to standard of care improves markers of inflammation and cardiovascular disease in persons with type 1 diabetes. Participants will be assigned to either 0,5 mg colchicine daily or placebo in a 1:1 ratio for 26 weeks with the possibility of an additional 26 week extension of the intervention period.

The current study aims to evaluate the efficacy of 0.5 mg colchicine once-daily added to existing standard of care in persons with established type 1 diabetes, existing arteriosclerotic cardiovascular disease (CVD) or at high risk thereof and C-reactive protein (CRP) ≥ 2 mg/L. Specifically, the primary objective is to determine the effect of colchicine (0.5 mg/daily) on levels of CRP (as assessed by high-sensitivity assays) as compared with placebo following 26 weeks of treatment. Additionally, the study will investigate the short and long-term effects of colchicine treatment on other markers of CVD and inflammation, markers of metabolism and markers of glycemic control in type 1 diabetes, including glycated hemoglobin (HbA1c), time spent in hypoglycemia (level 1 glucose readings 3.0-3.8 mmol/L and level 2 glucose readings \< 3.0 mmol/L), target glycemia (glucose readings 3.9-10 mmol/L) and hyperglycemia (level 1 glucose readings 10.1-13.9 mmol/L and level 2 glucose readings \> 13.9 mmol/L) together with measures of glycemic variability evaluated by continuous glucose monitoring (CGM), insulin dosage, risk of hypoglycemia, risk of diabetic ketoacidosis and body weight.

Eligibility Criteria:
Inclusion Criteria:

* Type 1 diabetes for more than five years according to World Health Organization criteria
* Age 35-80 years
* Hemoglobin A1c \< 80 mmol/mol
* Stable insulin therapy (defined as no change in insulin brand and no newly initiated continous subcutaneus insulin infusion (CSII) or multiple-daily injection (MDI) therapy) and, if applicable, stable usage of glucose monitoring technology (e.g., continous glucose monitor (CGM) or intermittently scanned CGM) ≥ 3 months with either MDI or CSII
* CRP ≥ 2 mg/L (measured by high-sensitivity assay)
* eGFR \> 50 mL/min/L/1.73 m\^2
* Either stable arteriosclerotic cardiovascular disease (ASCVD) (as defined by ischemic heart disease including previous acute myocardial infarction, acute coronary syndrome and coronary revascularization; other arterial revascularization procedures; stroke and transient ischemic attack; aortic aneurysm; peripheral arterial disease, including carotid atherosclerosis)
* and/or risk of cardiovascular (CV) death \> 5 % within 10 years (i.e., high or very high CV risk) as defined by the European Society of Cardiology or 10-year CV risk ≥ 20 % (i.e., high CV risk) as according to 'Steno Type 1 Diabetes Risk Engine' (https://steno.shinyapps.io/T1RiskEngine/)

Exclusion Criteria:

* Hypoglycemia unawareness (inability to register low blood glucose) am modum Pedersen-Bjergaard, unless usage of CGM with alarm function
* Liver disease with elevated plasma alanine aminotransferase (ALT) \> three times the upper limit of normal (measured at screening with the possibility of one repeat analysis within seven days, and the last measured value as being conclusive)
* History of cirrhosis, chronic active hepatitis or severe hepatic disease
* Inflammatory bowel disease or chronic diarrhea
* Pre-existing progressive neuromuscular disease or persons with creatinine kinase levels \> three times the upper limit of normal (measured at screening with the possibility of one repeat analysis within a week, and the last measured value as being conclusive)
* Cancer or lymphoproliferative disease unless in complete remission for \> 5 years
* Immunosuppressive therapy or state of chronic immunodeficiency, including infection with human immunodeficiency virus (HIV)
* Blood dyscrasias (e.g., myelodysplastic syndromes or related hematological disorders)
* Leukocyte cell count \< 3.0 X 10\^9/L
* Thrombocyte count \< 110 X 10\^9/L
* Systemic (oral or intravenous), long-term steroid therapy (topical or inhaled steroids are allowed)
* Hemodialysis or peritoneal dialysis therapy (since colchicine cannot be removed by dialysis or exchange transfusion)
* Renal or hepatic impairment treated with a P-gp inhibitor or a strong CYP3A4 inhibitor
* Intake of grapefruit juice during trial participation
* Other concomitant disease or treatment that according to the investigator's assessment makes the person unsuitable for study participation
* Alcohol/drug abuse
* Fertile women not using hormonal (tablet/pill, depot injection of progesterone, subdermal gestagen implantation, hormone intrauterine devices (IUD), hormonal vaginal ring or transdermal hormonal patch), chemical (copper IUD) or mechanical (condom, femidom, sterilization) contraceptives
* Pregnant or nursing women
* On permanent treatment with colchicine that is not discontinued within 30 days of screening visit
* Known or suspected hypersensitivity to colchicine
* Receipt of any investigational drug within 30 days prior to screening visit
* Simultaneous participation in any other clinical intervention trial