The prevention of recurrent stroke and coronary events (fatal and non- fatal) after ischaemic stroke and transient ischaemic attack (TIA) not caused by cardiac embolism or other causes unrelated to atherosclerosis. MedDRA version: 20.0 Level: HLT Classification code 10044376 Term: Transient cerebrovascular events System Organ Class: 10029205 - Nervous system disorders MedDRA version: 20.0 Level: HLT Classification code 10008205 Term: Cerebrovascular embolism and thrombosis System Organ Class:
Conditions
Interventions
Trade Name: Colchicine 500microgram tablets
Product Name: Colchicine
Pharmaceutical Form: Tablet
Trade Name: Colchicine Tiofarma 500 microgram Tablets
Product Name: Colchicine
Pharmaceutical Form: Ta
Sponsors
University College Dublin
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: To be eligible for inclusion, each subject must meet each of the following criteria at the screening assessment and baseline visit. 1. Written informed consent consistent with ICH-GCP guidelines and local laws signed prior to all trial-related procedures. 2. Age 40 years or greater. 3. Patient has had either;- An ischaemic stroke without major disability (modified Rankin score 3 or less)(Clarification - retinal infarction due to retinal artery occlusion is allowed ) or A high risk TIA* AND A brain CT or MRI has excluded primary intracranial haemorrhage AND The stroke/TIA has occurred more than 72 hours before randomisation AND no more than 28 days prior to randomisation * High-risk TIA is defined as transient focal neurological symptoms of presumed vascular cause with, in addition, one or more of the following criteria: (a) ABCD2 score 4 or more, with motor or speech symptoms (dysarthria or dysphasia) (b) DWI hyperintensity on acute MRI (c) Stenosis (lumen narrowing of 50% or greater on ultrasound, MRA, CTA, or invasive angiography) of the internal cartoid, vertebral, middle cerebral, anterior cerebral, or basilar artery in the arterial territory consistent with symptoms. 4. 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. 5. eGFR greater than or equal to 50 ml/min. 6. In the opinion of the treating physician, patient is medically-stable, capable of participating in a randomised trial, and willing to attend follow-up. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 1125 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2029
Exclusion criteria
Exclusion criteria: 1. Stroke/TIA, probably caused by identified atrial fibrillation (permanent or paroxysmal), in the opinion of the treating physician. 2. Stroke/TIA probably caused by other identified cardiac source (intracardiac thrombus, endocarditis, metallic heart valve, low ejection fraction <30%), 3. Stroke/TIA caused by dissection, endocarditis, paradoxical embolism, drug use, venous thrombosis, carotid or cardiac surgery, hypercoagulability states, migraine, or inherited cerebrovascular disorders. 4. History of myopathy or myalgias with raised creatine kinase (CK) on statin therapy. 5. Blood dyscrasia (haemoglobin<10g/dL,platelet count <150 x109/L, white cell count <4 x109/L) 6. Impaired hepatic function (transaminases ALT and/or AST greater than twice upper limit of normal) 7. Concurrent treatment with colchicine contraindicated drugs:- CYP3A4 inhibitors (clarithromycin, erythromycin, telithromycin, other macrolide antibiotics, ketoconazole, itraconazole, voriconazole,tolbutamide, ritonavir, atazanavir, indinavir, other HIV protease inhibitors, verapamil, diltiazem, quinidine, digoxin, disulfiram) or P-gp inhibitors (cyclosporine) at randomisation. 8. Symptomatic peripheral neuropathy and pre-existing progressive neuromuscular disease 9. Inflammatory bowel disease (Crohn's or ulcerative colitis) or chronic diarrhoea. 10. Dementia, sufficient to impair independence in basic activities of daily living. 11. Active malignancy, known hepatitis B or C, or HIV infection. 12. Impaired swallow preventing oral administration of Colchicine 13. History of poor medication compliance. 14. Unlikely to comply with study procedures due to severe or fatalcomorbid illness or other factor (eg. inability to travel for follow up visits), in opinion of randomising physician. 15. Women of childbearing potential (WCBP), or pregnant or are breastfeeding, are not eligible to participate in this study. (Clarification: A woman of childbearing potential is a woman who: - has not had surgery to remove the uterus and ovaries - has had menstrual periods at any time in the preceding 24 consecutive months - Menstrual periods interrupted due to cancer chemotherapy treatment are considered WCBP as this may still allow conception.) Pregnancy is considered highly unlikely during the trial because women of childbearing potential are excluded. However, in the unlikely event that a woman in the trial becomes pregnant, pregnancy information will be collected. 16. Patient concurrently participating in another clinical trial with an investigational drug or device, or use of investigational drug within 30 or 5 half-lives before the Screening visit (whichever is longer). 17. Known allergy or sensitivity to colchicine. 18. Requirement for colchicine therapy for treatment of acute gout, gout prevention, or other rheumatological disorder 19. Requirement for chronic daily immunosuppressants oral steroids, or non-steroidal anti-inflammatory drugs (NSAIDs)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the efficacy of low dose colchicine (0.5mg/day) plus usual care (antiplatelet, lipid-lowering, antihypertensive treatment, and appropriate lifestyle advice) compared with usual care alone to prevent non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, hospitalisation for unstable angina and vascular death after ischaemic stroke or transient ischaemic attack (TIA) not caused by cardiac embolism or other defined causes unrelated to atherosclerosis.;Secondary Objective: 1. To investigate the safety of low dose colchicine (0.5mg/day) plus usual care (antiplatelet, lipid-lowering, antihypertensive treatment, and appropriate lifestyle advice) compared with usual care alone. 2. To investigate the effect of colchicine on each component of the composite primary outcome measure. 3. To investigate the effect of colchicine on fatal and non-fatal ischaemic stroke combined. 4. To investigate the effect of colchicine on recurrent disabling and non-disabling ischaemic stroke. 5. To investigate the effect of colchicine on late disability, compared with usual care. 6. To assess whether the effect of treatment on the primary outcome is materially different among different categories of patient defined at baseline. 7. To investigate the effect of colchicine on direct health care costs, adjusted for quality-adjusted life years. ;Primary end point(s): The primary efficacy outcome measure will be time to the first occurrence of non-fatal recurrent ischaemic stroke, non-fatal myocardial infarction, non-fatal cardiac arrest, hhospitalisation for unstable angina or vascular death. Events confirmed through centralised adjudication to meet protocol-defined primary outcome criteria, will be included in the analyses of the number of occurrences of the composite primary outcome for the respective treatment group. The components of the primary composite efficacy outcome measure are defined below: 1) Non-fatal ischaemic stroke: define | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Safety The following safety outcomes will be compared between colchicine-treated and usual care groups: I. Adverse events (non-serious and serious) ii. Gastrointestinal (vomiting, nausea, diarrhoea) iii. Myalgia requiring discontinuation of study medication iv. Myopathy (defined as muscle pain or weakness associated with creatine kinase 2 or more times greater than the upper limit of normal (ULN)) v. Hepatic impairment (transaminases (AST or ALT) =2 ULN) vi. Myelosuppression (defined per NIH Common Toxicity Criteria as at least Grade 2 suppression of circulating blood counts; ie. haemoglobin less than 10 and greater than 8 g/dL in the absence of major bleeding;absolute neutrophil count <1.5 - 1.0 x 109/L;platelet count <75.0 - 50.0 x 109/L) vii. Moderate or severe renal impairment, defined as glomerular filtration rate (GFR) less than 50 ml/min/1.73m2 on two measures at least 3 months apart viii. Peripheral neuropathy, defined as new or worsened symptoms of numbness, parasthesiae, burning or weakness in the extremities, with confirmation on nerve conduction studies ix. Rash, itch, or alopecia x. Major haemorrhage, per International Society on Thrombosis and Haemostasis classification. This includes fatal and non-fatal intracranial haemorrhage. (Although colchicine has not been associated with adverse effects on platelet function or coagulation, we will record major haemorrhage rates) xi. All cause-fatality 2) Components of composite primary outcome measure The effect of colchicine on each of the components of the primary composite outcome measure will be analysed separately. 3) Recurrent fatal or non-fatal ischaemic stroke Comparison of fatal plus non-fatal ischaemic stroke between colchicine and usual care arms will be performed. 4) Recurrent disabling/non-disabling ischaemic stroke Comparison of rates of recurrent disabling ischaemic stroke (modified Rankin score 3-5) and recurrent non-disabling ischaemic stroke (modified Rankin sc | — |
Countries
Belgium, Canada, Czechia, Czech Republic, Denmark, Estonia, Germany, Ireland, Italy, Lithuania, Netherlands, North Macedonia, Poland, Portugal, Spain, Switzerland, United Kingdom
Contacts
Public ContactProf Peter Kelly
The Irish Stroke Clinical Trials Network
Outcome results
None listed