The primary objective is to determine the effect of low dose (0.5mg once daily) colchicine on the occurrence of the composite endpoint of acute coronary syndrome, fatal or non-fatal out of hospital cardiac arrest and atherosclerotic stroke in…
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
the composite outcome of sudden cardiac death, non-fatal out of hospital
cardiac arrest, acute coronary syndromes or atherosclerotic ischemic stroke.
per protocol v2.6 20 August 2019 changed into
the composite outcome of cardiovascular death, myocardial infarction, ischemic
stroke, or ischemia-driven revascularization.
per protocol v2.7 22 January 2020 changed into
the composite of cardiovascular death, myocardial infarction, ischemic stroke,
or ischemia-driven coronary revascularization.
Secondary outcome
1. Time to the first coronary or cerebral atherosclerotic event: the composite
of sudden cardiac death, non-fatal out of hospital cardiac arrest, myocardial
infarction or unstable angina irrespective of revascularization, or
atherosclerotic ischemic stroke (the composite endpoint of the first LoDoCo
trial)
2. The composite of cardiovascular death, non-fatal myocardial infarction or
non-fatal ischemic stroke
3. All-cause mortality
4. All myocardial infarction
5. All coronary revascularizations
6. Acute coronary syndromes related to stent or graft disease, irrespective of
revascularization
per protocol v2.6 20 August 2019 changed into
The secondary objectives of this study are to evaluate clinical efficacy of
treatment with colchicine 0.5mg once daily as compared to placebo in patients
with stable coronary artery disease on the incidence of first occurrence of
1. Myocardial infarction
2. Ischemia-driven revascularization
3. Cardiovascular death or myocardial infarction
4. Cardiovascular death
5. Death from any cause
6. the composite of sudden cardiac death, non-fatal out of hospital cardiac
arrest, myocardial infarction or unstable angina irrespective of
revascularization, or atherosclerotic ischemic stroke (the composite endpoint
of the first LoDoCo trial),
7. the composite of cardiovascular death, non-fatal myocardial infarction or
non-fatal ischemic stroke,
8. Acute coronary syndromes related to stent or graft disease, irrespective of
revascularization
tertiary
1. New onset or first recurrence of atrial onset fibrillation or atrial flutter
2. New onset of diabetes mellitus and
3. Deep vein thrombosis and/or pulmonary embolism.
For the Dutch cohort: to facilitate cost-effectivenes analysis:
1. emergency department visits
2. hospitalisations
3. quality of life and productivity
per protocol v2.7 22 January 2020 changed into
The secondary objectives of this study are to evaluate clinical efficacy of
treatment with colchicine 0.5mg once daily as compared to placebo in patients
with stable coronary artery disease on the incidence of first occurrence of
1. the composite of cardiovascular death, myocardial infarction or ischemic
stroke
2. the composite of myocardial infarction or ischemia-driven coronary
revascularization
3. the composite of cardiovascular death or myocardial infarction
4. Ischemia-driven coronary revascularization
5. Myocardial infarction
6. Ischemic stroke
7. Death from any cause
8. Cardiovascular Death
Background summary
Despite major advances in treatment, the burden of cardiovascular disease
remains high. Worldwide, an estimated 17.5 million people died from
cardiovascular diseases in 2012, of which an estimated 7.4 million due to
coronary artery disease. Cardiovascular disease is the second most common cause
of mortality in the Netherlands, responsible for 40.000 deaths per year with an
estimated cost of 7 billion euro per year. There are approximately 600.000
people with coronary artery disease in the Netherlands, leading to 10.000
deaths per year.
Coronary artery disease and its complications are a disease of atherosclerosis.
Key players in the disease process are atherosclerotic plaque growth and
erosion or rupture of the fibrous cap covering the plaque. Rupture exposes the
pro-coagulant material causing thrombo-embolic occlusion of the coronary
artery, leading to myocardial infarction. Plaque instability is the result of
injury caused by a local inflammatory response from the atheroma. Critical
elements in the treatment of coronary artery disease thus are controlling lipid
burden, plaque integrity and inflammatory response. For modulation of the
latter several inflammatory pathways and therapeutic targets exist. Inhibiting
the effect of interleukin-6 (Il-6) may be essential, as this inflammatory
cytokine has proven to play a causal role in cardiovascular disease. IL-6 is
mediated by interleukin-1 (IL-1) and the so called NLRP3 inflammasome, both
upregulated by cholesterol crystals, forming the link between cholesterol
deposition and inflammation in atherosclerosis. These inflammatory cytokines
have a complex biochemical interaction. Inhibition of their action may decrease
inflammatory effects and reduce athero-thrombotic complications in patients
with coronary artery disease.
The elucidation of possible causative inflammatory agents in atherosclerosis
and the similarities in pathophysiology in other inflammatory disorders have
led to rediscovery of conventional anti-inflammatory drugs in atherosclerosis.
Colchicine, used since decades as anti-inflammatory drug in the treatment of
gout, pericarditis and Familiar Mediterranean Fever, is an anti-mitotic drug
that inhibits multiple inflammatory pathways (IL-1, IL-6, the
NLRP3-inflammasome). There is broad clinical experience with this low cost
drug, serious adverse side effects are uncommon in those without renal
impairment and so far it is the only anti-inflammatory drug with proven effect
in patients with coronary artery disease. Using a prospective randomised open
blinded end-point (PROBE) design the original low dose colchicine for
prevention of cardiovascular disease (LoDoCo) trial demonstrated an impressive
67% reduction (hazard ratio: 0.33; 95% confidence interval [CI] 0.18 to 0.59)
in the occurrence of the composite of acute coronary syndrome, out-of-hospital
cardiac arrest, or non-cardioembolic ischemic stroke in patients with stable
coronary artery disease.
Study objective
The primary objective is to determine the effect of low dose (0.5mg once daily)
colchicine on the occurrence of the composite endpoint of acute coronary
syndrome, fatal or non-fatal out of hospital cardiac arrest and atherosclerotic
stroke in patients with stable coronary artery disease.
per protocol v2.6 20 August 2019 changed into
The primary objective of this study is to evaluate clinical efficacy of
treatment with colchicine 0.5mg once daily as compared to placebo in patients
with stable coronary artery disease on the incidence of first occurrence of the
composite of cardiovascular death, myocardial infarction, ischemic stroke, or
ischemia-driven revascularization.
Study design
Prospective, multi-centre, randomised, double blinded, placebo controlled phase
II trial that will run in Australia and the Netherlands.
Intervention
colchicine 0.5mg once daily
Study burden and risks
Burden: low, asides once daily one extra tablet no extra test (nor laboratory
nor imaging) are necessary
Risks: low, due to the low dose of colchcine and exclusion of renal impairment,
to reduce the risk of increased levels of colchicine. Furthermore, colchicine
is used since decades as anti-inflammatory drug in the treatment of gout,
pericarditis and Familiar Mediterranean Fever.
Moreelsepark 1
Utrecht 3511 EP
NL
Moreelsepark 1
Utrecht 3511 EP
NL
Listed location countries
Age
Inclusion criteria
1. Age >35 and <82 years
2. Proven coronary artery disease; as evidenced by coronary angiography, CT
coronary angiography or a Coronary Artery Calcium Score (Agatston score >400).
Individuals with a history of bypass surgery are only eligible if they have
undergone coronary artery bypass surgery more than 10 years before, or have
angiographic evidence of graft failure or have undergone percutaneous
intervention since their bypass surgery
3. Clinically stable for at least six months
Exclusion criteria
1. Women who are pregnant, breast feeding or may be considering pregnancy
during the study period
2. Renal impairment as evidenced by a serum creatinine >150 µmol/l or estimated
glomerular filtration rate (eGFR) <50mL/min/1.73m2
3. Severe heart failure * systolic or diastolic New York Heart Association
Functional classification 3 or 4
4. Moderate or severe valvular heart disease considered likely to require
intervention,
5. Dependency, frailty or a predicted life expectancy < 5 years
6. Peripheral neuritis, myositis or marked myo-sensitivity to statins
7. Requirement for long term colchicine therapy for any other reason
8. Current enrollment in another trial
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 |
|---|---|
| Other | ACTRN12614000093684 |
| EudraCT | EUCTR2015-005568-40-NL |
| CCMO | NL56036.100.16 |