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

Repurposing Colchicine for Reduction of Residual Inflammatory Risk in Type 1 Diabetes: A Randomized, Double-blind, Placebo-controlled, Investigator-initiated Trial

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. After the treatment period, there will a 5-year follow-up on all available outcome measures via electronic patient records for those who took part in the extension.

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 26-52 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. During the 5-year follow-up, we will collect all available outcome measures via electronic patient records.

Inclusion Criteria:

• Type 1 diabetes for more than five years according to World Health Organization criteria
• Age 18-80 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