Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke

Inflammation is a key pathophysiological contributor to unstable atherosclerotic plaque and thrombo-embolic events, stroke, myocardial infarction, and vascular death. Internationally, clinical trials are targeting atherosclerotic inflammation in patients with coronary disease using methotrexate, colchicine, and canukinumab.

Aims:

The primary aim is to compare low-dose colchicine (0.5mg/day) plus usual care, to usual care alone, to prevent non-fatal recurrent ischaemic stroke and coronary events and vascular death after non-severe, noncardioembolic TIA/stroke. Secondary objectives will investigate safety of low-dose colchicine, and efficacy for each component of the primary outcome, fatal and non-fatal events, disabling and non-disabling stroke, effect modification by prespecified subgroups, and impact on direct health care costs, adjusted for quality-adjusted life years.

Inclusion criteria

• Written informed consent consistent with ICH-GCP guidelines and local laws signed prior to all trial-related procedures.
• Age 40 years or greater
• Either,

• ischaemic stroke without major disability (modified Rankin score 3 or less)
• or high-risk TIA
• Qualifying stroke/TIA probably caused by large artery stenosis, small artery occlusion (lacunar stroke), or cryptogenic embolism, with cardiac embolism or other defined stroke mechanism deemed unlikely in the opinion of the treating physician.
• GFRgreater than or equal to 50 ml/min.
• In the opinion of the treating physician, patient is medically-stable, capable of participating in a randomised trial, and willing to attend follow-up.

Exclusion criteria

• Cardio-embolic stroke/TIA, probably caused by identified atrial fibrillation (permanent or paroxysmal), in the opinion of the treating physician.
• Cardio-embolic stroke/TIA probably caused by other identified cardiac source (intra-cardiac thrombus, endocarditis, metallic heart valve, low ejection fraction <30%), in the opinion of the treating physician.
• Stroke/TIA caused by dissection, endocarditis, paradoxical embolism, drug use, venous thrombosis, within 48 hours aftercarotid or cardiac surgery, hypercoagulability states, migraine, or inherited cerebrovascular disorders (eg. Fabry's disease, CADASIL), in the opinion of the treating physician.
• History of myopathy or myalgias with raised creatine kinase (CK) on statin therapy.
• Blood dyscrasia defined as anaemia (haemoglobin <10g/dL), thrombocytopenia (platelet count <150 x109/L) or leucopenia (white cell count <4 x109/L) at randomisation.
• Impaired hepatic function (transaminases greater than twice upper limit of normal) at randomisation.
• Concurrent treatment with moderate or strong CYP3A4 inhibitors (clarithromycin, erythromycin, telithromycin, other macrolide antibiotics, ketoconazole, itraconazole, voriconazole, ritonavir, atazanavir, indinavir, other HIV protease inhibitors, verapamil, diltiazem, quinidine, digoxin, disulfiram) or P-gp inhibitors (cyclosporine) at randomisation.
• Symptomatic peripheral neuropathy and pre-existing progressive neuromuscular disease
• Inflammatory bowel disease (Crohn's or ulcerative colitis) or chronic diarrhoea.

• Dementia, sufficient to impair independence in basic activities of daily living.

• Active malignancy, known hepatitis B or C, or HIV infection prior to qualifying stroke/TIA.

• Impaired swallow preventing oral administration of study medication. 12. History of poor medication compliance. 13. Unlikely to comply with study procedures and follow-up visits due to severe or fatal comorbid illness or other factor (eg. inability to travel for follow up visits), in opinion of randomising physician.

• Pregnancy, breast-feeding, or pre-menopausal women 15. Patient concurrently participating in another clinical trial with an investigational drug or device, or use of investigational drug within 30 days or 5 half-lives before the Screening visit (whichever is longer) 16. Known allergy or sensitivity to colchicine.