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ESCALATE will provide a thorough investigation of how anti-inflammatory therapy, with low-dose colchicine, affects patients with stable coronary artery disease. Using traditional clinical risk factors and multimodality intracoronary imaging, the investigators will identify patients with the greatest clinical risk.
Participants will undergo repeat multimodality intracoronary imaging assessment at 6 months to measure the impact once-daily low-dose colchicine therapy on the structure and function of coronary arteries.
This study will provide valuable insights into how anti-inflammatory therapies, such as colchicine, may improve outcomes in patients with coronary artery disease.
Full description
Background and study aims
Despite recent advances, coronary artery disease (CAD) remains the main cause of death worldwide. CAD occurs when the arteries bringing blood to the heart become narrowed by a build-up of fatty material within their walls. If this occurs gradually, it can cause chest discomfort i.e., angina. In a heart attack, the artery wall becomes inflamed and splits causing blood clot formation and an abrupt blockage of flow, resulting in severe pain and damaged heart muscle.
Current treatments focus on reducing cholesterol, slowing the build-up of fatty material, and rapidly restoring blood flow during a heart attack. Chronic inflammation, acting in tandem with other risk factors, has been identified as playing a central role in CAD progression and its acute manifestations.
Colchicine is a safe, well-tolerated, anti-inflammatory therapy used in the treatment of gout and other inflammatory conditions. Daily treatment with low-dose colchicine has proven effective in reducing rates of heart attack and death in large clinical trials, but use in routine practice remains low. A contributing factor to this reticence is uncertainty regarding the mechanism through which colchicine provides benefit. This study is designed to address this knowledge gap.
Who can participate?
Patients aged 18 to 90 years old with coronary artery disease and high clinical risk
What does the study involve?
Using traditional markers of clinical risk and state-of-the-art imaging from inside the coronary artery, the researchers will identify patients with CAD and the greatest clinical risk. Eligible patients, already established on statin therapy will be allocated to a six-month course of low-dose colchicine plus usual care, or usual care only. Researchers, participants, and usual clinicians will be aware of the allocation during the study.
After 6 months, the researchers will assess the impact of colchicine on the appearance of individual coronary artery lesions, blood flow in the large and small blood vessels of the heart. This study will provide a detailed assessment of colchicine and its mechanism of action in CAD.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Ability to provide written informed consent
Age 18 to 90 years old
Male, or female of non-child-bearing potential
Elevated clinical risk, as evidenced by ≥1 of:
Documented evidence of coronary artery disease, with an angiographically moderate stenosis on invasive coronary angiography (30-80%)
History of prescribed statin therapy, at a stable dose, for >4 weeks
Evidence of residual inflammation at baseline (i.e., high-sensitivity CRP ≥2)
Exclusion criteria
Women who are pregnant, breast feeding, or of child-bearing potential
Symptoms of unstable angina, characterised as: angina at rest; new onset of severe exertional angina (CCS grade III or higher for <4 weeks); or distinct, sudden, intensification of previously stable angina
Previous spontaneous acute myocardial infarction (diagnosed according to the universal MI criteria) with or without persistent ST-segment elevation <4 weeks from recruitment
Previous coronary artery bypass grafting
Known chronic total occlusion of coronary artery
Chronic kidney disease with eGFR <50 mL/min/1.73 m2 per MDRD formula or renal replacement therapy at baseline assessment
Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B and hepatitis C, or confirmed ALT/AST levels > 3 times ULN or total bilirubin > 2 times ULN) at baseline assessment
Symptoms of severe heart failure (systolic or diastolic) with New York Heart Association (NYHA) Functional Classification 3 or 4
Moderate or severe valvular heart disease considered likely to require intervention
History of blood dyscrasia including anaemia, thrombocytopenia, neutrophilia, leukopenia or other abnormality of blood count at baseline
Peripheral neuritis, myositis or marked myo-sensitivity to statins
A history of alcohol and/or substance abuse that could interfere with the conduct of the trial
Patients with suspected or proven immunocompromised state, including:
History of hypersensitivity to the study drug or its constituents
Patients who have received an investigational drug or device within 30 days (inclusive) of baseline assessment, or who are expected to participate in any other investigational drug or device study during the conduct of this trial
Any biologic drugs targeting the immune system (for example, TNF blockers, anakinra, rituximab, abatacept, tocilizumab)
Established long-term pharmacotherapy with a strong CYP3A4 inhibitor or a P-glycoprotein inhibitor (P-gpi) (e.g., macrolide antibiotics, ciclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors, verapamil, diltiazem and disulfiram)
Contraindications to intravenous adenosine will exclude patients from adenosine induced hyperaemia
Any life-threatening condition with life expectancy <6 months that might prevent the patient from completing the study.
Primary purpose
Allocation
Interventional model
Masking
50 participants in 2 patient groups
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Central trial contact
Michael McGarvey, MA MBBS MRCP; Anne-Marie Murtagh
Data sourced from clinicaltrials.gov
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