| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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. |
|
| E.1.1.1 | Medical condition in easily understood language |
Further stroke or cardiac events after stroke or TIA (like stroke but symptoms resolve quickly) not caused by a clot in the heart or other
identifiable causes unrelated to fat deposition in arteries. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10044376 |
| E.1.2 | Term | Transient cerebrovascular events |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023027 |
| E.1.2 | Term | Ischaemic stroke NOS |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051615 |
| E.1.2 | Term | Atherosclerotic cardiovascular disease |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10007962 |
| E.1.2 | Term | Central nervous system vascular disorders NEC |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10007963 |
| E.1.2 | Term | Central nervous system vascular disorders |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10008205 |
| E.1.2 | Term | Cerebrovascular embolism and thrombosis |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 |
|
| E.4 | Principal 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) |
|
| E.5 End points |
| E.5.1 | 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: 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) Hospitalisation for Unstable Angina: TIMI definition
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. |
|
| E.5.1.1 | 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).
In order to standardise the number of weeks between visits for all patients in the study: "weeks" rather than "calendar months" are being used. Therefore for this study the definition of a month is 4 weeks, a year is 52 weeks and a half a year is 26 weeks. All visits for each patient are scheduled out for the entire study based on the randomisation date of each patient.
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. |
|
| E.5.2 | 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.
|
|
| E.5.2.1 | 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).
In order to standardise the number of weeks between visits for all patients in the study: "weeks" rather than "calendar months" are being used. Therefore for this study the definition of a month is 4 weeks, a year is 52 weeks and a half a year is 26 weeks. All visits for each patient are scheduled out for the entire study based on the randomisation date of each patient.
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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Prospective Randomised Open-Label Blinded-Endpoint Assessment |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 150 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| North Macedonia |
| Belgium |
| Denmark |
| Estonia |
| Germany |
| Ireland |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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