Repurposing Colchicine for Reduction of Residual Inflammatory Risk in Type 1 Diabetes (REC1TE)

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Type 1 Diabetes; Chronic Inflammation
• Intervention / Treatment: Drug: Colchicine 0.5 MG Oral Tablet; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David S. Mathiesen, MD; Phone Number: +4522996739; Email: david.siersbaek.mathiesen.02@regionh.dk

Study Locations

• Denmark
  • Capital Region
    • Hellerup, Capital Region, Denmark, 2900
      • Recruiting
      • Center for Clinical Metabolic Research, Gentofte Hospital
      • Contact: Filip K Knop, MD, PhD; Phone Number: 004538674266; Email: filip.krag.knop.01@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Colchicine; Colchicine tablet 0.5 mg once-daily	Drug: Colchicine 0.5 MG Oral Tablet; Colchicine 0.5 mg once-daily; Other Names: Colrefuz
Placebo Comparator: Placebo; Placebo tablet once-daily	Drug: Placebo; Placebo tablet once-daily

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fasting serum/plasma concentrations of fibrinogen (µmol/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of serum amyloid A (mg/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of haptoglobin (g/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of interleukin (IL)-1β (pg/mL)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of interleukin (IL)-2 (pg/mL)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of intercellular adhesion molecule 1 (ICAM-1) (pg/mL)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of vascular cell adhesion molecule 1 (VCAM-1) (pg/mL)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of total leukocyte count, including neutrophil, lymphocyte, basophil and eosinophil counts (10^9/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in neutrophil:lymphocyte ratio	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of very low-density lipoprotein (VLDL) cholesterol (mmol/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of high-density lipoprotein (HDL) cholesterol (mmol/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of total cholesterol (mmol/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of triglycerides (mmol/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in fasting serum/plasma concentrations of lipoprotein (a) (mg/L)	%-point	From week 0 (baseline) to week 30 (safety follow-up)
Change in thrombocyte function measured by thromboelastography	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in fasting serum/plasma concentrations of N-terminal pro-brain natriuretic peptide (pro-BNP) (pmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in consultation blood pressure (mmHg)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in heart rate (beats/minute)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of albumin (g/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in urine albumin-to-creatinine ratio (mg/g)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change left ventricular (LV) mass index evaluated by cardiovascular ultrasonography (g/m^2)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change left ventricular (LV) septal wall thickness evaluated by cardiovascular ultrasonography (mm)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change left ventricular (LV) posterior wall thickness evaluated by cardiovascular ultrasonography (mm)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change left ventricular (LV) ejection fraction (LVEF) evaluated by cardiovascular ultrasonography (%)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E) to peak velocity flow in late diastole caused by atrial contraction (A) (E/A ratio) evaluated by cardiovascular ultrasonography	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change early diastolic mitral inflow velocity (e') evaluated by cardiovascular ultrasonography (m/sec)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change ratio of early diastolic mitral inflow velocity (e') to early diastolic mitral annulus velocity (E) (E/e' ratio) evaluated by cardiovascular ultrasonography	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change ratio of early mitral inflow velocity (E) to global diastolic strain rate (e' sr) (E/e'sr ratio) evaluated by cardiovascular ultrasonography	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change left atrial volume (LAVi) evaluated by cardiovascular ultrasonography (mL)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change global longitudinal strain (GLS) evaluated by cardiovascular ultrasonography (%)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change aortic distensibility evaluated by cardiovascular ultrasonography (mmHg^-1)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change aortic strain evaluated by cardiovascular ultrasonography (%)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in mean glucose evaluated by a continous glucose monitor (mmol/L)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in standard deviation evaluated by a continous glucose monitor (mmol/L)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in coefficient of variance evaluated by a continous glucose monitor (> 0.36 defined as glycemic variability)	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in glycemic variability (continuous overall net glycemic action (CONGA)) evaluated by a continous glucose monitor	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in mean amplitude of glycemic excursion evaluated by a continous glucose monitor	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in diabetes treatment satisfactory questionnaire, status version (DTSQs) (From 0 (min) to 6 (max), higher scores indicate a better outcome )	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in diabetes treatment satisfactory questionnaire, change version (DTSQc) (From -3 (min) to 3 (max), higher scores indicate a better outcome)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in audit of diabetes-dependent quality of life questionnaire (ADDQoL) (From -9 (min) to 9 (max), higher scores indicate a better outcome )	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of ketones (mmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Adverse events	As reported by participants	From week 0 (baseline) to week 30 (end of treatment)
Change in liver fat content as per the CAP score (dB/m) measured by FibroScan®	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in liver fibrosis score (kPa) measured by FibroScan®	%-point	From week 0 (baseline) to week 26 (end of treatment)
Change in fibrosis-4 (FIB-4) score (numerical scale, higher scores indicate a higher risk of fibrosis)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fatty liver index (FLI) score (numerical scale, higher scores indicate a higher risk of fibrosis)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of hemoglobin (mmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of thrombocytes (10^9/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of glucose (mmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of potassium (mmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of sodium (mmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of creatinine (umol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of alanine aminotransferase (U/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of aspartate aminotransferase (U/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of bilirubin (umol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of amylase (units/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of creatine kinase (U/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of C-peptide (pmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of glucagon (pmol/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of C-terminal telopeptide (ng/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in fasting serum/plasma concentrations of procollagen type 1 N-terminal propeptide (ng/L)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in body composition by bioimpedance analysis	%-point (fat free mass, total fat mass, muscle mass, bone mass)	From week 0 (baseline) to week 26 (end of treatment)
Change in body mass index (kg/m^2)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in waist circumference (cm)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in hip circumference (cm)	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in waist:hip ratio	%-point	From week 0 (baseline) to week 30 (end of treatment)
Change in interleukin messenger ribonucleic acid (mRNA) expression measured by quantitative polymerase chain reaction	%-point	From week 0 (baseline) to week 26 (end of treatment)

Collaborators and Investigators

• Sponsor: Filip Krag Knop
• Collaborators: Juvenile Diabetes Research Foundation; University of Copenhagen
• Investigators: Principal Investigator: Filip K. Knop, MD, PhD, Center for Clinical Metabolic Research, Gentofte Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2023
• Primary Completion (Estimated): June 15, 2026
• Study Completion (Estimated): June 15, 2026

Study Registration Dates

• First Submitted: June 29, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 18, 2023

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Inflammation; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: 2022-502038-23-00

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No