To assess changes in inflammatory cytokine release of monocytes and neutrophils stimulated with MSU crystals, isolated from patients with chronic coronary artery disease after colchicine 0.5mg daily during one month, compared to no colchicine…
ID
Source
Brief title
Condition
- Coronary artery disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The change in inflammatory cytokine release of monocytes and neutrophils,
stimulated with MSU crystals, isolated before versus after treatment with
colchicine 0.5mg during one month compared to placebo
Secondary outcome
- To assess whether hsCRP change in serum correlates with change in cytokine
release by monocytes and neutrophils stimulated with MSU crystals, isolated
from patients with chronic coronary artery disease after colchicine 0.5mg daily
during one month compared to placebo
- To assess changes of RNA expression in CD14+ monocytes, isolated from
patients with chronic coronary artery disease after colchicine 0.5mg daily
during one month, compared to placebo
Background summary
The progression of atherosclerosis consists of a cholesterol crystal-induced
chronic inflammatory, with novel microscopic techniques revealing cholesterol
crystals in early stages of atherosclerotic lesions. These cholesterol crystals
destabilise lysosomes after phagocytosis by macrophages, which initiates
inflammation via the nucleotide-binding, leucine-rich repeat, and
pyrin-domain-containing 3 (NLRP3) inflammasome. Colchicine is an ancient drug
which blocks assembly and polymerization of microtubules. This results in
inhibition of NLRP3 inflammasome activation, possibly by its effect on
mitochondria transport, which blocks NLRP3 inflammasome assembly. However,
since colchicine affects many additional cellular processes, establishing which
affected process is most relevant in atherosclerosis remains challenging.
In vitro a number of studies have established the inhibitory effect of
colchicine on the NLRP3 inflammasome pathways, measuring pro inflammatory
cytokine secretion, e.g. interleukin (IL)-1*, of monocytes stimulated with
monosodium urate crystals (MSU). In vivo studies in patients with
cardiovascular disease provide varying results, but seem to suggest colchicine
inhibits inflammatory cytokine release during acute myocardial infarction, and
reduces circulating neutrophilic cytokines in patients with chronic coronary
artery disease.
Studies on the effect of colchicine in patients with chronic coronary disease
are even scarcer, but report a significant reduction of the downstream
C-reactive protein, while reducing cardiovascular events and reduce low
attenuation plaque volume on coronary computed tomography angiography.
In this study we hypothesis that this reduction is caused by an inhibited
response of monocytes and neutrophils on crystals present in atherosclerotic
lesions, by colchicine-induced inhibition of NLRP3 inflammasome activation.
Study objective
To assess changes in inflammatory cytokine release of monocytes and neutrophils
stimulated with MSU crystals, isolated from patients with chronic coronary
artery disease after colchicine 0.5mg daily during one month, compared to no
colchicine treatment
Study design
This is a mono-centre intervention study with a randomized double-blind
placebo-controlled crossover design, adding colchicine to usual medical therapy
for one month with a control group receiving placebo
Intervention
Colchicine 0.5mg once daily during one month.
Study burden and risks
The burden and risk of participating in this study are estimated to be low. The
study requires
a maximum of 5 study visits. Maximal blood withdrawal including clinical
laboratory assessment will be 167ml in total, spread over 2,5-3 months.
Colchicine is a registered drug for another indication, gout, and has been
described for decades in the same dosages as in this study to prevent gout. In
addition, to further avoid colchicine toxicity we exclude patients with
impaired kidney functions or use of CYP3A4 or P-glycoprotein inhibitors. As
such, we assess no risk apart from the usual mild gastro-intestinal
side-effects.
No structured risk analysis including mechanism of action, pharmacokinetic
considerations and management of effect is described in this protocol as
colchicine is a registered product.
Geert Grooteplein Zuid 10
Nijmegen 6525GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
* Have suffered from type 1 myocardial infarction
* Have been clinically stable for at least three months
* Provided written informed consent
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
* Age below 18 years or above 80 years
* Use of CYP3A4 or P-glycoprotein inhibitors such as macrolids (claritromycin
and erytromycin), ciclosporin, ketoconazol, itraconazol, voriconazol, HIV
protease inhibitors, calciumchannel antagonists such as verapamil and diltiazem
* Women who are pregnant, breast feeding or may be considering pregnancy during
the study period or six month after the end of study participation
* Male patients who may be considering conceiving during the study period or
before six months after the end of study participation
* Have renal impairment as evidenced by a serum creatinine >150 *mol/l or eGFR
<50mL/min/1.73m2)
* Have an elevated inflammatory profile as evidenced by a hsCRP >10mg/l in
order to exclude patients with intercurrent (subclinical) infections
* Have a moderate to severe hepatic disease
* Suffer from pre-existing chronic gastro-intestinal complaints which might
obscure signs of colchicine toxicity
* Malignant disease in past five years or any medical condition that could
interfere with the conduct of the study in the opinion of the investigator.
* Chronic or recent (<1 month) infections and/or clinical signs of acute
infection
* Suffering from auto-immune / inflammatory diseases
* Chronic use of immunosuppressants or anti-inflammatory drugs, including
colchicine
* A history of haematological malignant disease
* Recent hospital admission or surgery with general anaesthesia (<3 months)
* Previous vaccination within 1 month prior to study entry
* Inability or unwillingness to comply with the protocol requirements, or
deemed by investigator to be unfit for the study.
* Are currently enrolled in a competing 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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000656-35-NL |
| CCMO | NL73042.091.20 |
| Other | NL8582 |
| OMON | NL-OMON25814 |