The Use of Colchicine (an anti-inflammatory drug) in Prevention of Recurrent Stroke or heart attack after first Stroke; a randomised controlled trial

• Register: EUCTR
• Last refreshed on: 8 August 2016
• Main ID: EUCTR2015-004505-16-ES
• Date of registration: 15/07/2016
• Prospective Registration: Yes
• Primary sponsor: University College Dublin
• Public title: The Use of Colchicine (an anti-inflammatory drug) in Prevention of Recurrent Stroke or heart attack after first Stroke; a randomised controlled trial
• Scientific 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
• Date of first enrolment: 20/07/2016
• Target sample size: 2623
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004505-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: yes Other trial design description: Prospective Randomised Open-Label Blinded-Endpoint Assessment If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Standard Usual Care Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Canada, Spain, United States

Contacts

• Name: Prof Peter Kelly
• Affiliation: The Irish Stroke Clinical Trials Network

• Name: Prof Peter Kelly
• Affiliation: The Irish Stroke Clinical Trials Network

Key inclusion & exclusion criteria

Inclusion criteria:
To be eligible for inclusion, each subject must meet each of the following criteria at Screening Assessment and must continue to fulfil these criteria at enrolment into the trial (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. Either,
• ischaemic stroke without major disability (modified Rankin score 3 or less)
• or high-risk TIA
within 72 hours-28 days of randomisation

and

Primary intracranial haemorrhage excluded by brain CT or MRI.

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) Diffusion-Weighted Imaging (DWI) hyperintensity on acute MRI
(c) Stenosis (lumen narrowing of 50% or greater on ultrasound, magnetic resonance angiography (MRA), computed tomographic angiography (CTA), or invasive angiography) of the internal carotid, 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 Investigator.

5. Creatinine clearance >50 ml/min, by MDRD or CKD-EPI formula.

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 875
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1748

Exclusion criteria:
Subjects are excluded from the study if any of the following criteria are met:

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 after carotid 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 <4 109/L) within 14 days of randomisation.

6. Impaired renal function (creatinine clearance =50mL/min or dialysis) or hepatic function (aspartate Aminotransferase (AST) or alanine aminotransferase (ALT) greater than twice upper limit of normal).

7. Use of a moderate or strong CYP3A4 inhibitor or a P-gp inhibitor at randomisation (clarithromycin, erythromycin, telithromycin, other macrolide antibiotics, ketoconazole, voriconazole, itraconizole, HIV protease inhibitors [ritonavir, indinavir, atazanavir], verapamil, diltiazem, quinidine, disulfiram, cyclosporine, regular grapefruit juice, cimetidine, tolbutamide).

8. Symptomatic peripheral neuropathy.

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 considered significant in opinion of randomising physician.

13. Unlikely to comply with study procedures and follow-up visits due to severe or fatal comorbid illness or other factor (e.g. inability to travel for follow up visits), in opinion of randomising physician.

14. Pregnancy, breast-feeding, or pre-menopausal women, defined as one or more menstrual periods within the last 12 months

15. Patient concurrently participating in another clinical trial with an investigational drug or device.

16. Known allergy or sensitivity to colchicine.

17. Requirement for colchicine therapy for treatment of gout or other rheumatological disorder.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

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: 19.0 Level: HLT Classification code 10044376 Term: Transient cerebrovascular events System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 19.0 Level: HLT Classification code 10008205 Term: Cerebrovascular embolism and thrombosis System Organ Class: 100000004866
MedDRA version: 19.0 Level: LLT Classification code 10051615 Term: Atherosclerotic cardiovascular disease System Organ Class: 100000004866
MedDRA version: 19.0 Level: LLT Classification code 10023027 Term: Ischaemic stroke NOS System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 19.0 Level: HLT Classification code 10007962 Term: Central nervous system vascular disorders NEC System Organ Class: 10029205 - Nervous system disorders
MedDRA version: 19.0 Level: HLGT Classification code 10007963 Term: Central nervous system vascular disorders System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Trade Name: Colchicine 500microgram tablets
Product Name: Colchicine
Pharmaceutical Form: Tablet
INN or Proposed INN: colchicine
CAS Number: 64-86-8
Other descriptive name: COLCHICINE
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 500-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Clinic visits will be performed at 4 weeks, 6 months, and every 6 months thereafter until an outcome event occurs or end of trial (maximum duration approximately 60 months in patients entered in the Vanguard Stage, Year 1).

A brief telephone assessment will be performed at 90 days by the Site Investigator or Site study staff, to check for early outcome events, compliance, tolerability concerns, or adverse events.

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, 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: defined as one of the following:
(a) A new focal neurological deficit, presumed due to cerebrovascular disease, persisting beyond 24 hours, without intracerebral haemorrhage or other mimic condition (eg. abcess, tumour, subdural haematoma) on brain CT or MRI.
(b) If brain imaging is not performed, but the focal neurological deficit is acute in onset, persists beyond 24 hours, and is consistent with stroke in the opinion of the Site Investigator/Outcomes Committee, it will be classified as non-fatal ischaemic stroke
(c) If acute new focal symptoms/signs last less than 24 hours but If brain CT or MRI demonstrates acute ischaemic change, (i.e. consistent with the ‘tissue definition’ of TIA).
Note: In patients with symptom duration less than 24 hours, in whom brain CT/MRI are normal or not performed, they will be categorised as ‘TIA’ and not counted as stroke.
(d) Retinal infarction, confirmed by an ophthalmologist.
(e) Spinal cord infarction, with mimic conditions excluded by spinal MRI.

2) Non-fatal myocardial infarction: defined according to the 3rd Universal Definition of MI criteria

3) Non-fatal cardiac arrest: defined as recovery from sudden collapse, with ECG rhythm-strip verified cardiac asystole, ventricular tachycardia, or ventricular fibrillation

4) Vascular death: Defined as death caused by recurrent ischaemic stroke within the previous 30 days or sudden death due to verified cardiac causes (cardiac arrest, myocardial infarction (as defined above or on autopsy), without other identified cause.

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.

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, and vascular death after ischaemic stroke or transient ischaemic attack (TIA) not caused by cardiac embolism or other defined causes unrelated to atherosclerosis.

Secondary Outcome(s)

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 score 0-2) between colchicine and usual care arms will be performed.

5) Disability
Comparison of disability in colchicine-treated and usual care groups will be assessed by modified Rankin score (shift analysis and proportion with no, mild, or moderate disability, defined as Rankin score of 0-2).

6) Treatment effect interaction
The effect of colchicine treatment on the primary outcome stratified by categories of key baseline variables (eg. age, gender, large artery stenosis) will be assessed.

7) Health economic outcomes
The effect of colchicine treatment on direct cumulative costs of health resource utilisation related to Quality Adjusted Life Years (QALYs) during the trial will be assessed.

Exploratory outcome measures

1) Cognition
Cognition at baseline and end of study will be measured using the Montreal Cognitive Assessment, [MOCA] and compared between colchicine and usual care groups.

2) Quality of life
Health-related quality of life (self-reported) will be measured and compared using EuroQoL (EQ5D-5L).

3) CRP
Associations between colchicine treatment effect and baseline CRP will be analysed.

4) Cumulative number of ischaemic events
The relationship between colchicine therapy and the cumulative total number of component events in the primary outcome cluster detected over the duration of the trial will be investigated.

Timepoint(s) of evaluation of this end point: Clinic visits will be performed at 4 weeks, 6 months, and every 6 months thereafter until an outcome event occurs or end of trial (maximum duration approximately 60 months in patients entered in the Vanguard Stage, Year 1).

A brief telephone assessment will be performed at 90 days by the Site Investigator or Site study staff, to check for early outcome events, compliance, tolerability concerns, or adverse events.

Secondary ID(s)

CONVINCE

Source(s) of Monetary Support

Health Research Board of Ireland