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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
300
For 24 weeks
Matched placebo tablets (identical in size, shape, taste, and packaging to colchicine), once daily, for 24 weeks
Tan Tock Seng Hospital
Singapore, Singapore, Singapore
RECRUITINGChange from Baseline in Mean-Maximum Carotid Intima-Media Thickness (Mean-Maximum CIMT)
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.
Time frame: Baseline and 24 weeks
Change from Baseline in Mean Carotid Intima-Media Thickness (avgCIMT)
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.
Time frame: Baseline and 24 weeks
Change from Baseline in Carotid Plaque Volume
Carotid plaque volume is measured using 3D plaque volume software following standard acquisition protocol in participants with identified carotid plaque on ultrasonography.
Time frame: Baseline and 24 weeks
Change from Baseline in Endothelial Function (Flow-Mediated Dilation)
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.
Time frame: Baseline and 24 weeks
Change from Baseline in Microvascular Reactivity (Reactive Hyperaemia Index)
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.
Time frame: Baseline and 24 weeks
Change from Baseline in Arterial Stiffness (Pulse Wave Velocity)
Arterial stiffness is assessed by carotid-femoral pulse wave velocity (PWV) measured using SphygmoCor XCEL, a validated applanation tonometry-based device.
Time frame: Baseline and 24 weeks
Change from Baseline in Arterial Stiffness (Cardio-Ankle Vascular Index)
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.
Time frame: Baseline and 24 weeks
Change from Baseline in Skin Advanced Glycation End Products (Skin Autofluorescence)
Tissue advanced glycation end product (AGE) accumulation is measured non-invasively using the AGE Reader, which quantifies skin autofluorescence using ultraviolet light excitation.
Time frame: Baseline and 24 weeks
Change from Baseline in Retinal Layer Thickness (Optical Coherence Tomography)
Retinal layer thickness is measured by optical coherence tomography (OCT) as a surrogate of retinal and systemic microvascular health.
Time frame: Baseline and 24 weeks
Change from Baseline in Retinal Microvascular Density (Optical Coherence Tomography Angiography)
Retinal microvascular density is measured by optical coherence tomography angiography (OCTA) as a surrogate of systemic microvascular health.
Time frame: Baseline and 24 weeks
Change from Baseline in High-Sensitivity C-Reactive Protein (hsCRP)
Serum high-sensitivity C-reactive protein (hsCRP) is measured as a marker of systemic inflammation.
Time frame: Baseline and 24 weeks
Change from Baseline in Interleukin-6 (IL-6)
Plasma interleukin-6 (IL-6) is measured as a marker of systemic inflammation and cytokine activity.
Time frame: Baseline and 24 weeks
Change from Baseline in Plasminogen Activator Inhibitor-1 (PAI-1)
Plasma plasminogen activator inhibitor-1 (PAI-1) is measured as a marker of impaired fibrinolysis and endothelial dysfunction.
Time frame: Baseline and 24 weeks
Change from Baseline in Cell-Free DNA (NETosis Marker)
Plasma cell-free DNA is measured as a marker of neutrophil extracellular trap (NET) formation and neutrophil-mediated inflammatory activity.
Time frame: Baseline and 24 weeks
Change from Baseline in Citrullinated Histone H3 (NETosis Marker)
Plasma citrullinated histone H3 is measured as a specific marker of neutrophil extracellular trap (NET) formation and NETosis.
Time frame: Baseline and 24 weeks
Change from Baseline in E-selectin
Plasma E-selectin is measured as a marker of endothelial activation and inflammation.
Time frame: Baseline and 24 weeks
Change from Baseline in Intercellular Adhesion Molecule-1 (ICAM-1)
Plasma ICAM-1 is measured as a marker of endothelial activation and leucocyte adhesion.
Time frame: Baseline and 24 weeks
Change from Baseline in Vascular Cell Adhesion Molecule-1 (VCAM-1)
Plasma VCAM-1 is measured as a marker of endothelial activation and vascular inflammation.
Time frame: Baseline and 24 weeks
Change from Baseline in Oxidative Stress Index
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.
Time frame: Baseline and 24 weeks
Change from Baseline in Thrombotic Potential (Clot Waveform Analysis)
Clot waveform analysis is performed to characterise the kinetics of clot formation and fibrinolysis in plasma as a measure of overall thrombotic potential.
Time frame: Baseline and 24 weeks
Change from Baseline in Von Willebrand Factor Antigen (VWF:Ag)
Plasma von Willebrand factor antigen (VWF:Ag) is measured as a marker of endothelial activation and thrombotic risk.
Time frame: Baseline and 24 weeks
Change from Baseline in Von Willebrand Factor Activity (VWF:Act)
Plasma von Willebrand factor activity (VWF:Act) is measured as a functional marker of thrombotic risk and platelet adhesion capacity.
Time frame: Baseline and 24 weeks
Change from Baseline in Factor VIII
Plasma factor VIII levels are measured as a marker of coagulation activation and thrombotic potential.
Time frame: Baseline and 24 weeks
Change from Baseline in Thrombin Generation
Thrombin generation is measured using a calibrated automated thrombogram to assess overall coagulation potential and thrombotic risk.
Time frame: Baseline and 24 weeks
Change from Baseline in Oxidised LDL (Ox-LDL)
Plasma oxidised LDL (Ox-LDL) is measured by nuclear magnetic resonance (NMR) spectroscopy as a marker of lipid oxidation and atherogenic risk.
Time frame: Baseline and 24 weeks
Change from Baseline in Atherogenic Lipid Subfractions
Atherogenic lipid subfractions are characterised by nuclear magnetic resonance (NMR) spectroscopy, providing detailed lipoprotein particle profiling beyond standard lipid panels.
Time frame: Baseline and 24 weeks
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