Type 2 Diabetes Mellitus (T2DM), Atherosclerosis, Cardiovascular Diseases
Conditions
Keywords
Colchicine, Inflammation, Neutrophils, Carotid Intima-Media Thickness, Primary Prevention
Brief summary
This study will test whether a low-cost anti-inflammatory medicine called colchicine can help protect the blood vessels of people with type 2 diabetes. Diabetes speeds up hardening of the arteries (atherosclerosis), partly because of ongoing low-grade inflammation. Colchicine has already been shown to help prevent heart attacks and strokes in people who already have heart disease; this study looks at whether it can also help prevent early blood vessel damage before heart disease develops. Around 300 adults with type 2 diabetes will be randomly assigned to take colchicine or a placebo (dummy pill) once daily for 24 weeks, in addition to their usual diabetes and heart-risk medications. Neither participants nor the study team will know who is taking colchicine or placebo. The main measurement will be the change in the thickness of the wall of the neck (carotid) artery, measured by ultrasound, which is an early sign of blood vessel disease. The study will also look at markers of inflammation in the blood, blood vessel stiffness and function, and changes in the gut bacteria.
Detailed description
Cardiovascular disease remains the leading cause of death in T2DM, occurring earlier and at substantially higher rates than in the general population. Despite optimisation of conventional risk factors, residual cardiovascular risk remains high, with chronic low-grade inflammation driven by dysregulated neutrophil activity recognised as a key contributor. Patients with T2DM exhibit a distinct pro-inflammatory neutrophil phenotype characterised by increased neutrophil extracellular trap (NET) formation, heightened endothelial adherence, and altered rolling kinetics, which correlates with impaired vascular function and subclinical atherosclerosis. Colchicine inhibits neutrophil activation, migration, and NET formation, and has demonstrated efficacy in secondary cardiovascular prevention in large randomised trials. Evidence in primary prevention, particularly in T2DM, remains limited. Col-DM takes a precision medicine approach, hypothesising that colchicine's benefit will be concentrated among T2DM patients with a high-risk inflamed neutrophil signature rather than being uniform across the broader population. Col-DM is a 24-week, parallel-group, Phase 2 randomised controlled trial. Adults with T2DM and no prior atherosclerotic cardiovascular disease are randomised 1:1 to colchicine 0.5 mg daily or matched placebo, stratified by neutrophil inflammatory phenotype classified using a microfluidic organ-on-chip platform. The primary outcome is progression of carotid intima-media thickness (CIMT), estimated overall and separately within each neutrophil-signature stratum. Secondary outcomes cover vascular function, inflammatory and oxidative stress biomarkers, and thrombotic potential. Gut microbiome composition is examined as an exploratory outcome. All outcome measures are estimated overall and separately within each neutrophil-signature stratum. Safety is monitored by an independent Data and Safety Monitoring Committee.
Interventions
For 24 weeks
DRUGPlacebo
Matched placebo tablets (identical in size, shape, taste, and packaging to colchicine), once daily, for 24 weeks
Sponsors
Tan Tock Seng Hospital
Nanyang Technological University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* T2DM on stable diabetes medications (no change in last 3 months) * At least one other comorbidity of hypertension, dyslipidaemia and/or obesity (BMI ≥27), with no previous history of ASCVD * Able to provide informed consent
Exclusion criteria
1. Recent hospitalization or acute infections within last 2 weeks. 2. Current Treatment with corticosteroids or immunosuppressive agents 3. Pre-existing malignancies or other terminal conditions with limited prognosis 4. Pregnancy 5. Breastfeeding 6. Inability to provide written consent 7. Renal impairment (eGFR\< 60ml/min) 8. Liver cirrhosis or ALT/AST \>3x ULN 9. Pharmacogenomics indicative of adverse effects 10. Hypersensitivity to the active substance or to the following excipients: Lactose, Maize starch, Sodium laurilsulfate, Magnesium stearate 11. Known blood dyscrasia 12. Women of childbearing age who are keen to conceive in the next 1 year 13. Taking a strong P-glycoprotein inhibitor (e.g. cyclosporine, ranolazine) or a strong CYP3A4 inhibitor 14. Known myositis with raised creatine kinase with statins (statin myopathy). 15. Gout attack within the last 1 year 16. Currently taking Aspirin 17. Taking any oral contraceptives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in Mean-Maximum Carotid Intima-Media Thickness (Mean-Maximum CIMT) | Baseline and 24 weeks | Mean-maximum CIMT is defined as the average of the maximum CIMT values obtained from the far wall of the left and right common carotid arteries, each derived from six measurements taken across three projections (lateral, anterior, and posterior) at 1 cm proximal to the carotid bifurcation, measured by high-resolution B-mode carotid ultrasonography. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in Mean Carotid Intima-Media Thickness (avgCIMT) | Baseline and 24 weeks | Mean CIMT (avgCIMT) is defined as the average of all twelve individual IMT measurements obtained from the far wall of the left and right common carotid arteries (six measurements per side), measured by high-resolution B-mode carotid ultrasonography. |
| Change from Baseline in Carotid Plaque Volume | Baseline and 24 weeks | Carotid plaque volume is measured using 3D plaque volume software following standard acquisition protocol in participants with identified carotid plaque on ultrasonography. |
| Change from Baseline in Endothelial Function (Flow-Mediated Dilation) | Baseline and 24 weeks | Endothelial function is assessed by flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound, expressed as the percentage change in brachial artery diameter following reactive hyperaemia. |
| Change from Baseline in Microvascular Reactivity (Reactive Hyperaemia Index) | Baseline and 24 weeks | Microvascular reactivity is assessed by the reactive hyperaemia index (RHI) measured using EndoPAT, a non-invasive device that quantifies peripheral arterial tone response to forearm occlusion. |
| Change from Baseline in Arterial Stiffness (Pulse Wave Velocity) | Baseline and 24 weeks | Arterial stiffness is assessed by carotid-femoral pulse wave velocity (PWV) measured using SphygmoCor XCEL, a validated applanation tonometry-based device. |
| Change from Baseline in Arterial Stiffness (Cardio-Ankle Vascular Index) | Baseline and 24 weeks | Arterial stiffness is additionally assessed by the cardio-ankle vascular index (CAVI), a measure of arterial stiffness from the origin of the aorta to the ankle that is less dependent on blood pressure at the time of measurement. |
| Change from Baseline in Skin Advanced Glycation End Products (Skin Autofluorescence) | Baseline and 24 weeks | Tissue advanced glycation end product (AGE) accumulation is measured non-invasively using the AGE Reader, which quantifies skin autofluorescence using ultraviolet light excitation. |
| Change from Baseline in Retinal Layer Thickness (Optical Coherence Tomography) | Baseline and 24 weeks | Retinal layer thickness is measured by optical coherence tomography (OCT) as a surrogate of retinal and systemic microvascular health. |
| Change from Baseline in Retinal Microvascular Density (Optical Coherence Tomography Angiography) | Baseline and 24 weeks | Retinal microvascular density is measured by optical coherence tomography angiography (OCTA) as a surrogate of systemic microvascular health. |
| Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | Baseline and 24 weeks | Serum high-sensitivity C-reactive protein (hsCRP) is measured as a marker of systemic inflammation. |
| Change from Baseline in Interleukin-6 (IL-6) | Baseline and 24 weeks | Plasma interleukin-6 (IL-6) is measured as a marker of systemic inflammation and cytokine activity. |
| Change from Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) | Baseline and 24 weeks | Plasma plasminogen activator inhibitor-1 (PAI-1) is measured as a marker of impaired fibrinolysis and endothelial dysfunction. |
| Change from Baseline in Cell-Free DNA (NETosis Marker) | Baseline and 24 weeks | Plasma cell-free DNA is measured as a marker of neutrophil extracellular trap (NET) formation and neutrophil-mediated inflammatory activity. |
| Change from Baseline in Citrullinated Histone H3 (NETosis Marker) | Baseline and 24 weeks | Plasma citrullinated histone H3 is measured as a specific marker of neutrophil extracellular trap (NET) formation and NETosis. |
| Change from Baseline in E-selectin | Baseline and 24 weeks | Plasma E-selectin is measured as a marker of endothelial activation and inflammation. |
| Change from Baseline in Intercellular Adhesion Molecule-1 (ICAM-1) | Baseline and 24 weeks | Plasma ICAM-1 is measured as a marker of endothelial activation and leucocyte adhesion. |
| Change from Baseline in Vascular Cell Adhesion Molecule-1 (VCAM-1) | Baseline and 24 weeks | Plasma VCAM-1 is measured as a marker of endothelial activation and vascular inflammation. |
| Change from Baseline in Oxidative Stress Index | Baseline and 24 weeks | An integrated oxidative stress index is derived from nuclear magnetic resonance (NMR)-based redox profiling of plasma and erythrocytes, providing a composite measure of systemic oxidative stress. |
| Change from Baseline in Thrombotic Potential (Clot Waveform Analysis) | Baseline and 24 weeks | Clot waveform analysis is performed to characterise the kinetics of clot formation and fibrinolysis in plasma as a measure of overall thrombotic potential. |
| Change from Baseline in Von Willebrand Factor Antigen (VWF:Ag) | Baseline and 24 weeks | Plasma von Willebrand factor antigen (VWF:Ag) is measured as a marker of endothelial activation and thrombotic risk. |
| Change from Baseline in Von Willebrand Factor Activity (VWF:Act) | Baseline and 24 weeks | Plasma von Willebrand factor activity (VWF:Act) is measured as a functional marker of thrombotic risk and platelet adhesion capacity. |
| Change from Baseline in Factor VIII | Baseline and 24 weeks | Plasma factor VIII levels are measured as a marker of coagulation activation and thrombotic potential. |
| Change from Baseline in Thrombin Generation | Baseline and 24 weeks | Thrombin generation is measured using a calibrated automated thrombogram to assess overall coagulation potential and thrombotic risk. |
| Change from Baseline in Oxidised LDL (Ox-LDL) | Baseline and 24 weeks | Plasma oxidised LDL (Ox-LDL) is measured by nuclear magnetic resonance (NMR) spectroscopy as a marker of lipid oxidation and atherogenic risk. |
| Change from Baseline in Atherogenic Lipid Subfractions | Baseline and 24 weeks | Atherogenic lipid subfractions are characterised by nuclear magnetic resonance (NMR) spectroscopy, providing detailed lipoprotein particle profiling beyond standard lipid panels. |
Countries
Singapore
Contacts
CONTACTSanchalika Acharyya, PhD, MPH
CONTACTShirley Lin Shangmei
PRINCIPAL_INVESTIGATORRinkoo Dalan, MD, PhD
Tan Tock Seng Hospital
Outcome results
None listed