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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Type 1 Diabetes, Cardiovascular Diseases, Chronic Inflammation

Intervention / Treatment
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* Drug: Colchicine 0.5 MG Oral Tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Colchicine<br>Colchicine tablet 0.5 mg once-daily | Drug: Colchicine 0.5 MG Oral Tablet<br>* Colchicine 0.5 mg once-daily<br>* Other names: Colrefuz;|
| Placebo Comparator: Placebo<br>Placebo tablet once-daily | Drug: Placebo<br>* Placebo tablet once-daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fasting serum/plasma concentrations of C-reactive protein (CRP) measured by a high-sensitivity assay (hsCRP) (mg/L) | %-point | From week 0 (baseline) to week 26 (end of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fasting serum/plasma concentrations of C-reactive protein (CRP) measured by a high-sensitivity assay (hsCRP) (mg/L) | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Change in fasting serum/plasma concentrations of hemoglobin A1c (mmol/mol) | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Time spent in target blood glucose range (3.9 - 10 mmol/L) evaluated by a continous glucose monitor (CGM) | (% of 24 hours) | From week 0 (baseline) to week 26 (end of treatment) | 
| Time spent in hyperglycemia level 1 (10-13.9 mmol/L) evaluated by a continous glucose monitor (CGM) | (% of 24 hours) | From week 0 (baseline) to week 26 (end of treatment) | 
| Time spent in hyperglycemia level 2 (> 13.9 mmol/L) evaluated by a continous glucose monitor (CGM) | (% of 24 hours) | From week 0 (baseline) to week 26 (end of treatment) | 
| Time spent in hypoglycemia level 1 (3.0-3.8 mmol/L) evaluated by a continous glucose monitor (CGM) | (% of 24 hours) | From week 0 (baseline) to week 26 (end of treatment) | 
| Time spent in hypoglycemia level 2 (< 3.0 mmol/L)evaluated by a continous glucose monitor (CGM) | (% of 24 hours) | From week 0 (baseline) to week 26 (end of treatment) | 
| Insulin dosage | Number of units/day (both long- and short-acting insulin analogues) | From week 0 (baseline) to week 30 (safety follow-up) | 
| Change in body weight (kg) | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Change in waist:hip ratio | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Change in fasting serum/plasma concentrations of low-density lipoprotein cholesterol (LDL) (mmol/L) | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Change in fasting serum/plasma concentrations of interleukin (IL)-6 (pg/mL) | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Change in fasting serum/plasma concentrations of tumor necrosis factor alpha (pg/mL) | %-point | From week 0 (baseline) to week 30 (safety follow-up) | 
| Safety-related events | Serious adverse events (SAE), events of severe hypoglycemia, events of diabetic ketoacidosis | From week 0 (baseline) to week 30 (safety follow-up) |