Colchicine for Primary Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes (Col-DM)

Colchicine 0.5 mg orally once daily for 24 weeks, in addition to usual risk-factor-based therapy

For 24 weeks

Matched placebo orally once daily for 24 weeks, in addition to usual risk-factor-based therapy

Matched placebo tablets (identical in size, shape, taste, and packaging to colchicine), once daily, for 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.

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.

Carotid plaque volume is measured using 3D plaque volume software following standard acquisition protocol in participants with identified carotid plaque on ultrasonography.

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.

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.

Arterial stiffness is assessed by carotid-femoral pulse wave velocity (PWV) measured using SphygmoCor XCEL, a validated applanation tonometry-based device.

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.

Tissue advanced glycation end product (AGE) accumulation is measured non-invasively using the AGE Reader, which quantifies skin autofluorescence using ultraviolet light excitation.

Retinal layer thickness is measured by optical coherence tomography (OCT) as a surrogate of retinal and systemic microvascular health.

Retinal microvascular density is measured by optical coherence tomography angiography (OCTA) as a surrogate of systemic microvascular health.

Serum high-sensitivity C-reactive protein (hsCRP) is measured as a marker of systemic inflammation.

Plasma interleukin-6 (IL-6) is measured as a marker of systemic inflammation and cytokine activity.

Plasma plasminogen activator inhibitor-1 (PAI-1) is measured as a marker of impaired fibrinolysis and endothelial dysfunction.

Plasma cell-free DNA is measured as a marker of neutrophil extracellular trap (NET) formation and neutrophil-mediated inflammatory activity.

Plasma citrullinated histone H3 is measured as a specific marker of neutrophil extracellular trap (NET) formation and NETosis.

Plasma E-selectin is measured as a marker of endothelial activation and inflammation.

Plasma ICAM-1 is measured as a marker of endothelial activation and leucocyte adhesion.

Plasma VCAM-1 is measured as a marker of endothelial activation and vascular inflammation.

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.

Clot waveform analysis is performed to characterise the kinetics of clot formation and fibrinolysis in plasma as a measure of overall thrombotic potential.

Plasma von Willebrand factor antigen (VWF:Ag) is measured as a marker of endothelial activation and thrombotic risk.

Plasma von Willebrand factor activity (VWF:Act) is measured as a functional marker of thrombotic risk and platelet adhesion capacity.

Plasma factor VIII levels are measured as a marker of coagulation activation and thrombotic potential.

Thrombin generation is measured using a calibrated automated thrombogram to assess overall coagulation potential and thrombotic risk.

Plasma oxidised LDL (Ox-LDL) is measured by nuclear magnetic resonance (NMR) spectroscopy as a marker of lipid oxidation and atherogenic risk.

Atherogenic lipid subfractions are characterised by nuclear magnetic resonance (NMR) spectroscopy, providing detailed lipoprotein particle profiling beyond standard lipid panels.

Gut microbiome composition is characterised from stool samples by metagenomic sequencing, to examine whether colchicine-associated shifts in microbial composition relate to treatment response.

As an exploratory analysis, plasma metabolomic profiling will be performed on stored blood samples to characterise changes in the metabolite profile over 24 weeks.

Safety is assessed by the incidence of adverse events (AEs) and serious adverse events (SAEs), defined per standard regulatory criteria, ascertained at each study visit and telephone contact, and adjudicated by an independent Data and Safety Monitoring Committee.