repurposing colchicine for reduction of residual inflammatory risk in type 1 diabetes

Conditions: Type 1 Diabetes; Cardiovascular Diseases; Chronic Inflammation

Summary: 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 \ 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