Clinical trial NCT02898610: Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke
Official title: CONVINCE - (COlchicine for preventioN of Vascular Inflammation in Non- CardioEmbolic Stroke) - a Randomised Clinical Trial of Low-dose Colchicine for Secondary Prevention After Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ischemic Attack, Transient
Stroke
Lead sponsor: University College Dublin
Sponsor class: OTHER
Collaborators: name: Health Research Board, Ireland
name: Irish Heart Foundation
name: University of Limerick
name: University of Edinburgh
name: National University of Ireland, Galway, Ireland
name: Universitat de Lleida
name: Universitaire Ziekenhuizen KU Leuven
First posted: 2016-09-13
Enrollment: 3154
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This study evaluates the use of Colchicine in adults over 40 years of age who have suffered an ischaemic stroke or transient ischaemic attack NOT caused by cardiac embolism or other defined causes. Patients will be randomised to 0.5 mg/day of Colchicine plus usual care, or to usual care alone.

To investigate the efficacy of low dose colchicine (0.5mg/day) plus usual care (defined as 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, hospitalization 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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. Either,

   * ischaemic stroke without major disability (modified Rankin score 3 or less)
   * or high-risk TIA
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. GFRgreater 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.

Exclusion Criteria:

1. Cardio-embolic stroke/TIA, probably caused by identified atrial fibrillation (permanent or paroxysmal), in the opinion of the treating physician.
2. 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.
3. 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.
4. History of myopathy or myalgias with raised creatine kinase (CK) on statin therapy.
5. Blood dyscrasia defined as anaemia (haemoglobin \<10g/dL), thrombocytopenia (platelet count \<150 x109/L) or leucopenia (white cell count \<4 x109/L) at randomisation.
6. Impaired hepatic function (transaminases greater than twice upper limit of normal) at randomisation.
7. 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.
8. Symptomatic peripheral neuropathy and pre-existing progressive neuromuscular disease
9. Inflammatory bowel disease (Crohn's or ulcerative colitis) or chronic diarrhoea.

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

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

11. 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.

14. 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.

Primary outcomes:
measure: Recurrence of non-fatal ischemic stroke
timeFrame: any time within 60 month
measure: on-fatal Major Cardiac event
timeFrame: any time within 60 months
measure: Vascular death
timeFrame: 60 months
Secondary outcomes:
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: Uza, Antwerpen
city: Brugge
country: Belgium
facility: AZ Sint Jan
city: Brugge
country: Belgium
facility: AZ St. Lucas, BRUGGE
city: Brussels
country: Belgium
facility: UCL, Brussels
city: Brussels
country: Belgium
facility: UZ Brussel
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: CHC Liege
city: Oostende
country: Belgium
facility: AZ Damiaan, OOSTENDE
city: Roeselare
country: Belgium
facility: AZ Delta, ROESELARE
city: Calgary
country: Canada
facility: Foothills Medical Centre, Calgary
city: Kingston
country: Canada
facility: Kingston Hospital
city: Vancouver
country: Canada
facility: Vancouver General Hospital
city: Brno
country: Czechia
facility: St. Anne´s University Hospital
city: Jihlava
country: Czechia
facility: Hospital Jihlava
city: Bispebjerg
country: Denmark
facility: Bispebjerg Hospital
city: Glostrup
country: Denmark
facility: Rigshospitalet Glostrup
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Bad Neustadt An Der Saale
country: Germany
facility: Rhön-Klinikum Campus Bad Neustadt
city: Berlin
country: Germany
facility: Vivantes Auguste-Viktoria Klinikum
city: Berlin
country: Germany
facility: Vivantes Humboldt-Klinikum
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln, Berlin
city: Bochum
country: Germany
facility: St. Josef-Hospital Klinikum der Ruhr-Universität Bochum
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Buchholz
country: Germany
facility: Krankenhaus Buchholz
city: Dortmund
country: Germany
facility: Klinikum Dortmund gGmbH
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Frankfurt University Hospital
city: Fulda
country: Germany
facility: Klinikum Fulda gAG, Universitätsmedizin Marburg-Campus Fulda
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera GmbH
city: Halle
country: Germany
facility: Krakenhaus Martha Maria Halle Dolau
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR
city: Lohr
country: Germany
facility: Klinikum Main-Spessart, Standort Krankenhaus Lohr
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Lübeck
city: München
country: Germany
facility: Klinikum der Universität München
city: Rheine
country: Germany
facility: Mediclin-Fachklinik Rhein/Ruhr
city: Sonneberg
country: Germany
facility: Medinos Kliniken des Landkreises Sonneberg
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Cavan
country: Ireland
facility: Cavan General Hospital
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: Connolly Hospital, Blanchardstown
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: St James's Hospital
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Dublin
country: Ireland
facility: Tallaght University Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Kilkenny
country: Ireland
facility: St Lukes General Hospital
city: Limerick
country: Ireland
facility: University Hospital Limerick
city: Louth
country: Ireland
facility: Our Lady of Lourdes, Drogheda
city: Sligo
country: Ireland
facility: Sligo University Hospital
city: Tipperary
country: Ireland
facility: South Tipperary General Hospital, Clonmel
city: Waterford
country: Ireland
facility: University Hospital Waterford
city: Kaunas
country: Lithuania
facility: Lithuanian University Hospital of Health Sciences Kaunos Klinikos
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Clinics
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuis Apeldoorn
city: Delft
country: Netherlands
facility: Reinier de Graaf Hospital
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Gdańsk
country: Poland
facility: Hospital Nicholas Copernicus
city: Końskie
country: Poland
facility: Specialist Hospital of Saint Luke
city: Rokietnica
country: Poland
facility: Medical University of Silesia Hospital No7
city: Warsaw
country: Poland
facility: Institute of Psychiatry and Neurology
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria, Centro Hospitalar Lisboa Norte
city: Lisboa
country: Portugal
facility: Hospital Egas Moniz
city: Porto
country: Portugal
facility: Hospital Universitario de Sao Jao
city: Albacete
country: Spain
facility: H. de Albacete
city: Barcelona
country: Spain
facility: Hospital de Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Moises Broggi. Comprehensive Health Consortium
city: Coruna
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: Girona
country: Spain
facility: H U. Josep Trueta, Girona
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: H. U. Ramón y Cajal, Madrid
city: Oviedo
country: Spain
facility: Centro Medico de Asturias
city: Sabadell
country: Spain
facility: H Parc Taulí de Sabadell
city: Sevilla
country: Spain
facility: H U. Virgen del Rocío, Sevilla
city: Sevilla
country: Spain
facility: Hospital Virgen Macarena Sevilla
city: Tarragona
country: Spain
facility: H Joan XXIII, Tarragona
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Aberystwyth
country: United Kingdom
facility: Bronglais General Hospital
city: Aintree
country: United Kingdom
facility: Aintree University Hospital
city: Airdrie
country: United Kingdom
facility: Monklands Hospital
city: Antrim
country: United Kingdom
facility: Antrim Area Hospital
city: Ashford
country: United Kingdom
facility: William Harvey Hospital
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bury Saint Edmunds
country: United Kingdom
facility: West Suffolk Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Chichester
country: United Kingdom
facility: St Richards Hospital
city: Craigavon
country: United Kingdom
facility: Craigavon Area Hospital
city: Cramlington
country: United Kingdom
facility: Northumbria Specialist Emergency Care Hospital
city: Croydon
country: United Kingdom
facility: Croydon University Hospital
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Derry
country: United Kingdom
facility: Altnagelvin Area Hospital
city: Durham
country: United Kingdom
facility: North Durham University Hospital
city: Enniskillen
country: United Kingdom
facility: South West Acute Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital Gateshead
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
city: Glasgow
country: United Kingdom
facility: Hairmyres Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital Glasgow
city: High Wycombe
country: United Kingdom
facility: Wycombe Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Kingston
country: United Kingdom
facility: Kingston Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Lewisham
country: United Kingdom
facility: University Hospital Lewisham
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: London
country: United Kingdom
facility: St Thomas' Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Luton
country: United Kingdom
facility: Luton & Dunstable University Hospital
city: Margate
country: United Kingdom
facility: Queen Elizabeth the Queen Mother Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Peterborough
country: United Kingdom
facility: Peterborough Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Southend
country: United Kingdom
facility: Southend University Hospital
city: Stockport
country: United Kingdom
facility: Stepping Hill Hospital
city: Stoke
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton In Ashfield
country: United Kingdom
facility: King's Mill Hospital
city: Swindon
country: United Kingdom
facility: Great Western Hospital
city: Telford
country: United Kingdom
facility: Princess Royal Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Whiston
country: United Kingdom
facility: Whiston Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
Study officials:
affiliation: Mater Hospital
name: Prof Peter Kelly
role: STUDY_DIRECTOR
References:
citation: Kelly P, Lemmens R, Weimar C, Walsh C, Purroy F, Barber M, Collins R, Cronin S, Czlonkowska A, Desfontaines P, De Pauw A, Evans NR, Fischer U, Fonseca C, Forbes J, Hill MD, Jatuzis D, Korv J, Kraft P, Kruuse C, Lynch C, McCabe D, Mikulik R, Murphy S, Nederkoorn P, O'Donnell M, Sandercock P, Schroeder B, Shim G, Tobin K, Williams DJ, Price C. Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial. Lancet. 2024 Jul 13;404(10448):125-133. doi: 10.1016/S0140-6736(24)00968-1. Epub 2024 Jun 7.
citation: Bouabdallaoui N, Tardif JC. Colchicine in the Management of Acute and Chronic Coronary Artery Disease. Curr Cardiol Rep. 2021 Jul 16;23(9):120. doi: 10.1007/s11886-021-01560-w.