Primary objectiveTo 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…
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Brief title
Condition
- Central nervous system vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome measures:
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, hospitalization 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) Brain imaging is strongly recommended for evaluation of recurrent stroke
events. 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. Hospitalization for Unstable Angina: TIMI definition (Appendix 6 of research
protocol)
5. 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. Ischaemic stroke will be defined as
detailed above.
Secondary outcome
Secondary Outcomes:
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. Fatal and non-fatal ischaemic stroke will be
defined as in primary outcomes section above.
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, Appendix 3] 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) (Appendix 5 of the research protocol).
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.
Background summary
Importance of stroke:
The World Health Organisation (WHO) estimates that cardiovascular diseases are
the leading cause of death globally, causing 17.3 million deaths in 2008. Of
these, stroke was the second leading cause of global death and a major cause of
healthcare costs.
Importance of atherosclerosis in cerebrovascular disease:
Population-based studies by our group and others have reported ipsilateral
carotid atherosclerosis (>=50% arterial lumen narrowing) in up to 20% of
ischaemic stroke patients, with intracranial atherosclerosis in a further
8-12%. Athero-thrombosis in the arterial tree is also likely to account for a
substantial proportion of the 30-40% of patients with stroke in whom no direct
mechanism is identified. For example, 73% of patients in the North Dublin
Population Stroke Study with TOAST-classified stroke of unidentified etiology
had evidence of aortic or cranio-cervical atherosclerosis defined by the ASCO
classification.
In addition, disease of cerebral small vessels (arteries and arterioles)
accounts for up to 20% of stroke and is a major contributor to dementia.
Although the pathophysiology of cerebral ischaemic small vessel disease is
varied and not fully understood, existing data suggest two common mechanisms:
(1) micro-atheroma of larger penetrating arterioles, causing single,
frequently-symptomatic acute lacunar infarcts, and (2) lipohyalinosis
(*arteriolosclerosis*), more frequently associated with diffuse white matter
hyperintensity on neuroimaging and neuropathological evidence of cerebral
demyelination.
After exclusion of stroke due to a defined cardio-embolic source (eg. atrial
fibrillation) or other identified mechanism (eg. carotid dissection),
atherosclerosis of the aorta, cervical, or intracranial large or small arteries
is a major pathophysiological mechanism underlying most ischemic stroke.
Randomised trials of statins and antiplatelet agents (eg. SPARCL, CHANCE) have
demonstrated benefit of targeting plaque-related lipid accumulation and
platelet activation in non-cardioembolic stroke to prevent recurrent vascular
events.
High risk of recurrent vascular events in stroke survivors:
Despite high rates of optimal medical and surgical treatment, we and others
have demonstrated high risk of recurrent stroke associated with atherosclerosis
of the internal carotid and intracranial arteries. A recent systematic review
reported a cumulative pooled recurrent stroke risk of 11.1% at one year and
26.4% at 5 years. The risk of myocardial infarction and vascular death is also
substantial in long-term stroke/TIA survivors. In a systematic review (39
studies, 65,996 patients), Touze found a 2.1%/year rate of non-stroke vascular
death and 0.9%/year risk of non-fatal Myocardial Infarction (MI) in stroke
survivors.
Importance of inflammation:
Accumulating evidence indicates that inflammation is of key importance in the
pathophysiology of atherosclerotic plaque destabilisation and thrombo-embolism.
The central inflammatory pathway is characterised by the key cytokines
interleukin-1, interleukin-6 [IL-6], and tumor-necrosis factor α [TNF-α].
Epidemiological studies have consistently described dose-dependent associations
between *downstream* markers of this pathway (eg. C- reactive protein [CRP])
and *up-stream* markers (eg. IL-6, TNF-α]) and vascular disease, including
stroke.
Mendelian randomisation studies have shown that polymorphisms in the IL-6
receptor are associated with lower CRP and reduced vascular risk. In the
JUPITER trial, rosuvastatin reduced the rate of vascular events in patients
with low LDL but high CRP at entry, with benefit proportionate to the degree of
CRP reduction.
In large-artery atherosclerosis, plaque inflammatory cells (mainly
monocyte-macrophages), are increasingly recognised as key mediators of lipid
oxidation, plaque remodelling, smooth muscle cell apoptosis, loss of
extracellular matrix integrity via release of collagenolytic matrix
metalloproteinases and other proteolytic enzymes, leading to fibrous cap
rupture and thrombo-embolism. Tawakol reported high FDG uptake on positron
emission tomography (PET) in symptomatic carotid plaque, with high (r=0.89)
correlation with plaque macrophage density. We have shown that carotid plaque
inflammation-related FDG uptake predicts stroke recurrence independently of
stenosis.
In cerebral small artery disease, available data indicate that inflammation may
be an important mediator of lacunar stroke and arteriolar pathology. In
patients with small artery disease, increased inflammatory cells (macrophages,
activated microglia) expressing matrix metalloproteinases (MMPs) are present
around affected arterioles and ischemic demyelination, and MMP-9 is increased
in cerebrospinal fluid. In SPARCL, patients with lacunar stroke randomised to
atorvastatin lipid-lowering therapy had similar reduction in stroke and
coronary events as those with large-artery atherosclerosis. In lacunar stroke
patients enrolled in the SPS3 trial, baseline CRP independently predicted
recurrent stroke and vascular events.
Recent laboratory and clinical-pathological studies have shown that cholesterol
crystals form in atherosclerotic plaques, and may activate the
nucleotide-binding leucine-rich repeat-containing pyrin receptor (NLRP)
inflammasome, an intracellular protein complex which promotes IL-1β expression
in response to crystal stimulation, leading to elevated IL-6 and CRP These
important observations provide direct evidence linking plaque lipid metabolism
and inflammation.
Why is this trial needed now?
Few completed trials have directly tested the benefit of anti-inflammatory
agents for vascular risk reduction. Small studies have demonstrated reduction
in inflammatory blood and imaging surrogate-markers such as plaque FDG uptake
in a dose-dependent manner by statins, possibly mediated by an
anti-inflammatory effect. The LoDoCo1 trial demonstrated a 66% relative risk
reduction in cardiovascular events in patients with stable coronary disease
treated with low-dose colchicine, plus anti-platelet agents and statins,
compared with usual care.
However, several trials are currently under way. In CANTOS, canukinumab (an
interleukin-1β antagonist) is under evaluation in 10,000 patients with stable
coronary disease. The National Institutes of Health (NIH) funded Cardiovascular
Inflammation Reduction Trial (CIRT) is comparing low-dose weekly methotrexate
with placebo plus recommended care in 7,000 patients with coronary disease and
diabetes or metabolic syndrome. In Australia, the LoDoCo2 trial is testing
low-dose colchicine for prevention of vascular events in 3,000 patients with
stable coronary syndromes. Other trials have recently targeted inflammatory
pathways (eg. LpPLA2) unrelated to the IL1-IL6-TNFα pathway (STABILITY, VISTA,
SOLID-TIMI52).
Description of Colchicine and Rationale for the study
Overview:
The investigational product to be studied is low-dose colchicine, 0.5mg daily,
taken by mouth for a median duration of approximately 36 months (range 12-60
months). In Europe, colchicine is registered and marketed in a number of
countries by several pharmaceutical companies in generic forms (usually 0.5mg
and 1mg tablets, 0.6mg tablets in some countries). The US FDA also approved
single ingredient oral colchicine (0.6mg tablet) in 2009.
Pharmacokinetics - absorption, distribution, metabolism, excretion:
Colchicine has been used for many years for the treatment of acute gout and
other inflammatory and arthritic conditions. Derived originally from the Autumn
Crocus (Colchicium autumnale), colchicine is readily-absorbed after oral
administration in the jejunum and ileum, by a P-glycoprotein
(ABCB1-transporter) dependent process. It undergoes significant 1st-pass
hepatic metabolism, resulting in oral bioavailability averaging 45% (range
24-88%) in healthy volunteers. It is excreted primarily (80-90%) via biliary
secretion (via the cytochrome P450 CYPA34 system), and also partly by the renal
route (10-20%), and via intestinal epithelium.
Mechanism:
Its primary cellular action is binding to α- and β-tubulin proteins, which are
highly-expressed in neutrophils and monocyte-macrophage inflammatory cells. It
has multiple anti-inflammatory properties including inhibition of microtubule
polymerization, with inhibition of E-selectin mediated leucocyte rolling and
endothelial adhesion, and leucocyte motility, phagocytosis, and cytokine
secretion. In vitro, colchicine inhibits crystal-induced activation of the NLRP
inflammasome, possibly via inhibition of microtubule polymerisation, which is a
pre-requisite for inflammasome assembly. This leads to inhibition of
proteolytic cleavage of pro-IL1β by caspase-1, leading to reduced secretion of
active interleukin-1β from monocytes and macrophages.
Rationale for use in atherosclerotic vascular disease:
As described above, accumulating evidence indicates that inflammation is a key
process in the pathophysiology of atherosclerosis, coronary disease, and
stroke. Non-randomised data report lower rates of coronary disease in gout and
Familial Mediterranean Fever (FMF) patients treated with long-term low-dose
colchicine therapy compared to colchicine-untreated patients.
In stable coronary patients treated with statins and antiplatelet agents with
elevated CRP, a 4-week treatment with low-dose colchicine was associated with
significant reduction in CRP compared with controls, providing proof-of-concept
that colchicine could impair inflammation in patients with atherosclerotic
vascular disease.
Following this study, one of our collaborators (SM Nidorf) demonstrated 66%
reduced risk of recurrent vascular events in 532 patients with stable coronary
disease randomised to low-dose colchicine (0.5mg/day) compared with usual care.
This large benefit was observed despite high (>90%) rates of statin and
antiplatelet treatment in colchicine and control arms. At present, a large
(3,000 patients) placebo-controlled randomised trial of low-dose (0.5mg/day)
colchicine (LoDoCo2) is under way in Australia to independently validate these
findings in stable coronary patients.
Recent trials have also demonstrated benefit of colchicine at a dose of
0.5-1mg/day for prevention of recurrent pericarditis. More recently, in a trial
of patients with acute ST-elevation myocardial infarction, colchicine (loading
dose 2mg, followed by 0.5-1mg/day for 5 days) caused lower creatine kinase
(p<0.001), lower MRI infarct size (p=0.019) and lower relative infarct size
(p=0.034) compared with placebo.
While no systematic Cochrane reviews of colchicine for vascular prevention
exist, in a recent review Ridker and Luscher stated *large-scale*.trials of
colchicine in secondary prevention are warranted*.
The underlying pathophysiology of recurrent vascular events in patients with
non-cardioembolic stroke is likely to resemble that in patients with coronary
artery disease. Therefore, we have selected the same low colchicine dose
(0.5mg/day) taken by mouth, as has already shown efficacy and safety in the
LoDoCo1 trial.
Safety:
The safety profile of colchicine is highly dose-dependent. According to the UK
SPC and FDA SPC, the most commonly reported adverse reaction in clinical trials
of colchicine for gout prophylaxis and acute treatment was diarrhoea. Less
common gastrointestinal adverse events were nausea, abdominal pain, and
vomiting. These effects were far more common at high colchicine doses (up to
4.8mg daily) compared with intermediate doses (1.8mg daily). Other adverse
events reported at a frequency of 2% or greater in studies of patients taking
high and intermediate doses (1.8mg and 4.8mg) of colchicine included nervous
system disorders, headache, and pharygolaryngeal pain.
Per the FDA SPC, excessive accumulation or overdose of colchicine has been
associated with a range of other adverse events, which are *generally
reversible upon temporarily interrupting treatment or lowering the dose*. These
include: neuropathy, alopecia, rash, myelosuppression, elevated transaminases
(ALT and/or AST), myopathy, muscle pain, rhabdomyolysis, azoospermia,
oligospermia. Serious toxic reactions associated with overdosage include
myelosuppression, disseminated intravascular coagulopathy, cardiac toxicity,
central nervous system toxicity, and death.
Low-dose colchicine has been used safely for many years for prevention of
inflammatory complications of FMF and Bechet*s disease. In contrast to the
higher doses of colchicine frequently used for treatment of acute gout,
low-dose (0.5mg/day) colchicine has been used in recent cardiovascular trials
with excellent safety profiles. In 42 patients assigned to 0.5-1.0mg daily in
the CORE trial (mean follow up 20 months), no serious adverse events occurred.
Mild diarrhoea developed in 3 patients, which quickly resolved on stopping or
lowering the dose. In the LoDoCo1 trial, among 282 patients assigned 0.5mg
colchicine daily (mean age 66.5 years, mean follow up 36 months), the overall
withdrawal rate was 16%, similar to recent trials of statins and dabigatran for
stroke prevention. Diarrhoea and other GI adverse effects occurred in 13%,
myalgia/myositis in 1%, with rash, itch, alopecia, and *peripheral neuritis*
each in 1 patient.
Adverse effects are more likely in patients with moderate-to-severe renal
failure (creatinine clearance <50mL/min), hepatic failure/cirrhosis, or those
taking CYP3A4 inhibitors (macrolide antibiotics, HIV protease inhibitors,
itraconazole, ketoconazole, diltiazem, verapamil, grapefruit juice) or
P-Glycoprotein (PGP) inhibitors (macrolide antibiotics, cyclosporine). Such
patients will be excluded from the trial. If a short course of one of these
agents (eg. clarithromycin) is required, a dose interruption of colchicine will
be allowed during treatment. Five cases of myopathy have been reported in the
literature in patients co-administered statins with colchicine. Careful
monitoring will be performed for myopathic symptoms in such patients, and they
will be instructed to report significant myalgias to study personnel.
Colchicine crosses the placenta and is secreted into breast milk of nursing
mothers, with unknown effects upon the developing foetus and infant.
Pre-menopausal women will be excluded from entry into the trial.
Study objective
Primary 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, 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.
Secondary objectives
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.
Study design
CONVINCE is a randomised, open-label, blinded endpoint-assessed, parallel group
Phase 3 clinical trial, comparing low-dose colchicine plus usual care to usual
care alone for prevention of recurrent non-fatal ischaemic stroke, myocardial
infarction and cardiac arrest, hospitalization for unstable angina and vascular
death after ischaemic stroke or TIA, not caused by cardiac embolism or other
defined mechanisms unrelated to atherosclerosis.
Randomisation:
Randomisation will be conducted using a minimisation algorithm, to ensure
groups are balanced for key prognostic variables affecting recurrent stroke
risk. The following mandatory variables will be included in the algorithm for
randomisation:
(1) age (less than 70, 70 or greater)
(2) time since qualifying stroke/TIA (7 days or less, greater than 7 days)
(3) type of qualifying event (stroke or TIA).
Imaging of cervical and intracranial arteries is not mandatory prior to
randomisation, but is strongly encouraged. If information on large artery
stenosis (ie. verified carotid, vertebral, or intracranial artery stenosis 50%
or greater) is available at the time of randomisation, the algorithm will
include this data to achieve balance for this variable. Baseline data will be
entered at the same visit as treatment allocation, although non-mandatory data
fields may be entered later.
Randomisation will take place via an Interactive Web Response System (IWRS),.
Before randomisation occurs, informed consent and verification of trial
eligibility of key inclusion/exclusion criteria must be performed by the site
study staff.
In practice, when a patient is randomised, the patient will be allocated to
active treatment, or, usual care. If randomised to study medication, the
patient will be given one dose from the next available package of study
medication at the study site. This package (minus the first dose) and a second
package will be given to the patient to take home. The patient will be advised
to take the medication once daily and in the morning. If the dose is forgotten
in the morning it can be taken at a later time in the day. The patient will
also be instructed never to take more than one tablet per day even if a
previous day/days dosage has been missed
Blinding:
This is a Prospective Randomised Open-Label Blinded-Endpoint (PROBE) trial,
similar to other recent trials of stroke prevention (eg. RE-LY) and acute
treatment (eg. ESCAPE). Participants and treating physicians will be aware of
treatment allocation to colchicine or usual care. Therefore, to control for
bias, assessment of outcome events will be achieved by assessment of defined
*hard* endpoints with pre-specified objective evidence to support
identification (see Section 8.1, Primary Outcome Measure). The assessment will
be conducted by an Outcomes Adjudication Committee blinded to treatment
allocation. The OAC will meet or teleconference regularly during the conduct of
the trial.
SCREENING - RANDOMISATION - Investigational Arm - FOLLOW UP
Low-dose Colchicine
(0.5mg/d) plus Usual Care (antiplatelet, lipid-
lowering,
antihypertensive, lifestyle advice).
Control Arm - FOLLOW
UP
Usual Care alone
(antiplatelet, lipid-lowering, antihypertensive, lifestyle
advice).
Intervention
Low dose colchicine (0.5mg/day)
Study burden and risks
The risks of low-dose colchicine in the intended sample group for study are
judged to be low, as outlined in previous sections and the SPC. The benefits
may be as high as a 66% reduction in the risk of recurrent stroke, coronary
events, or vascular death, as reported in the LoDoCo trial. The anticipated
benefit risk to the patient population will be evaluated on an ongoing basis by
the sponsor.
UCD Clinical Research Centre 21 Nelson Street
Dublin 7
IE
UCD Clinical Research Centre 21 Nelson Street
Dublin 7
IE
Listed location countries
Age
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 greater3 A brain CT or MRI
has excluded primary intracranial haemorrhage4a. Patient diagnosed with -
An ischaemic stroke without major disability (modified Rankin score 3
or less)
Or
4b. A high-risk - defined as (one or more of the following)
TIA with DWI hyperintensity on acute MRI
TIA with ABCD2 >= 4
TIA with >= 50% Stenosis of the artery territory consistent with symptoms. 5
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.6 The
stroke/TIA has occurred more than 72 hours before randomisation AND no more
than 28
days prior to randomisation.7 eGFR greater than or equal to 50
ml/min.8. 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. 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 (intra-cardiac 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/dLplatelet count <150 x109/L,white cell count <4 x109/L) 6. Impaired
hepatic function (transaminsases 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,
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
disease9. 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 Colchicine13.
History of poor medication compliance.14. Unlikely to comply with study
procedures due to severe or fatal comorbid illness or other factor
(eg. inability to travel for follow up visits), in opinion of randomising
physician.15. Pregnancy, breast-feeding, or pre-menopausal woman 16. Patient
concurrently participating in another clinical trial with an investigational
drug or device, or
use of investigational drug within 30 days of the Screening visit 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 disorder19. Requirement for chronic
daily immunosuppressants,
oral steroids, or non-steroidal anti-inflammatory drugs (NSAIDs)
-term stroke/TIA survivors. In a systema
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004505-16-NL |
| ClinicalTrials.gov | NCT02898610 |
| CCMO | NL69808.018.19 |