Targeted use of low-dose colchicine in patients with coronary artery disease and high clinical risk
| ISRCTN | ISRCTN46375134 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN46375134 |
| IRAS number | 1007183 |
| Secondary identifying numbers | 3642 ESCALATE, IRAS 1007183 |
- Submission date
- 21/03/2024
- Registration date
- 10/05/2024
- Last edited
- 17/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Circulatory System
Plain English summary of protocol
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 your 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 and markers of immune cell function. This study will provide a detailed assessment of colchicine and its mechanism of action in CAD.
What are the possible benefits and risks of participating?
All patients recruited to the study will undergo an additional invasive cardiac catheterisation procedure, with an assessment with multimodality intracoronary imaging. There are known risks associated with this procedure including vascular and bleeding complications. In a recent study with a similar trial design (PACMAN-AMI), about 1% of patients experienced a complication associated with the invasive procedure (i.e., two cases of cardiac arrhythmia, two cases of coronary artery spasm and two cases of air emboli), none of which resulted in significant morbidity. Patients will be actively monitored for these complications and treated as needed.
The invasive cardiac catheterisation procedure will involve an additional radiation dose to ensure adequate visualisation of the coronary arteries and safe placement of equipment.
Blood samples (50 ml) will be taken at baseline and at a 6-month follow-up for the planned leukocyte function sub-study. The baseline blood test (20 ml or 4 teaspoons) is carried out as part of routine care - a further 30 ml or 6 teaspoons of blood will be sampled for the additional research blood tests. Blood will be drawn (20 ml or 4 teaspoons) at 90 days to monitor blood cell counts, kidney function and liver function - this will be additional to standard of care. At 6 months, prior to the repeat angiogram, 50 ml of blood (or 10 teaspoons) will be drawn in order to assess blood counts, kidney function, liver function and immune cell function. This will be additional to usual standard care. Theoretically, this carries a potential risk for bleeding, infection and thrombophlebitis but these events are rare.
For participants in the intervention arm, there is a small potential harm associated with chronic colchicine use, namely gastrointestinal upset (1-10:100), increased risk of infection (<1:1000) and blood dyscrasia (<1:1000). Contemporary data from two large clinical trials (COLCOT, LoDoCo2) confirm that complications related to low-dose Colchicine (i.e., 0.5 mg once daily) in patients with chronic coronary syndromes are rare. Participants will be monitored for adverse effects and will have clear guidance on how to contact the research team should concerns arise.
Where is the study run from?
King's College Hospital NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
March 2024 to October 2025
Who is funding the study?
King's College Hospital NHS Foundation Trust - Cardiac Research Charity (UK)
Who is the main contact?
1. Dr Nilesh Pareek, NileshPareek@nhs.net
2. Dr Michael McGarvey, Michael.McGarvey@nhs.net
Contact information
Scientific
Department of Cardiology
King's College Hospital
London
SE5 9RS
United Kingdom
| Phone | +44 (0)20 32999000 |
|---|---|
| NileshPareek@nhs.net |
Public
Cardiovascular Research Office
Department of Cardiology
King’s College Hospital
Denmark Hill
London
SE5 9RS
United Kingdom
| Phone | +44 (0)7708 396530 |
|---|---|
| Michael.McGarvey@nhs.net |
Scientific
KHP-CTO, F16 Tower Wing, Guy’s Hospital, Great Maze Pond
London
SE1 9RT
United Kingdom
| Phone | +44 020 71885732 |
|---|---|
| QM.KHPCTO@kcl.ac.uk |
Study information
| Study design | Open randomized controlled parallel-group trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Efficacy |
| Participant information sheet | See study outputs table |
| Scientific title | ESCALATion of medical therapy following multimodality plaque Evaluation in high-risk Chronic Coronary Syndromes |
| Study acronym | ESCALATE |
| Study objectives | Primary objectives: To characterise the impact of systemic anti-inflammatory therapy with colchicine on features of non-flow limiting coronary plaque using multi-modality intracoronary imaging. Secondary objectives: 1. To assess the impact colchicine on microvascular function in patients with chronic coronary syndrome and high clinical risk 2. To assess the impact of colchicine therapy on circulating leukocyte function and protein expression and correlate to changes in coronary plaque morphological characteristics |
| Ethics approval(s) |
Approved 18/04/2024, East Midlands - Leicester Central Research Ethics Committee (2 Redman Place, London, E20 1JQ, United Kingdom; +44 (0)207 104 8066, +44 (0)207 104 8227, +44 (0)207 104 8284; leicestercentral.rec@hra.nhs.uk), ref: 24/EM/0082 |
| Health condition(s) or problem(s) studied | Chronic inflammation; atherosclerosis; coronary artery disease; chronic coronary syndromes |
| Intervention | Patients with coronary artery disease, high clinical risk and evidence of residual systemic inflammation despite established statin therapy will be eligible for recruitment. All eligible patients will undergo invasive intracoronary assessment, to identify those with non-flow limiting lesions, and high-risk features on intracoronary imaging. Using an online web-based system, patients will undergo 1:1 randomisation with alternating blocks of 2 and 4. This will be an open-label study. Those randomised to the intervention arm will receive once daily 0.5 mg oral colchicine, in addition to usual care. The control arm will involve usual care only. Patients will be followed up for 6 months. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Therapy |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Colchicine |
| Primary outcome measure | Minimal fibrous cap thickness in a defined arterial region of interest, as assessed by intracoronary optical coherence tomography (OCT) at baseline and 6 months |
| Secondary outcome measures | Secondary clinical and safety endpoints: 1. Major adverse cardiovascular event (MACE): Composite of cardiovascular death, non-fatal myocardial infarction, unplanned revascularisation and ischaemic stroke 2. All-cause mortality (i.e., number of deaths of any cause) 3. Cardiovascular death (i.e., number of deaths attributable as ‘Cardiovascular death’) 4. Non-fatal myocardial infarction 5. Unplanned revascularisation 6. Ischaemic stroke 7. Acute kidney injury 8. Major bleeding events (BARC [Bleeding Academic Research Consortium] 3-5) 9. Hospitalisation with heart failure 10. Hospitalisation with serious infection 11. Patient-reported angina, as assessed by Canadian Cardiovascular Society (CCS) Angina Grade All clinical and safety endpoints will be assessed with an in-person clinical review of the patient at hospital discharge, 3 and 6 months. Secondary intracoronary imaging endpoints: All intracoronary imaging endpoints will be assessed with intracoronary OCT or intracoronary near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) at baseline and 6 months: 12. Percentage change in minimal fibrous cap thickness, as determined by OCT, in a defined arterial region of interest 13. Absolute (°) and relative (%) change in lipid arc, as determined by OCT, in a defined arterial region of interest 14. Percentage change in lipid index, as determined by OCT, in a defined arterial region of interest 15. Absolute (°) and relative (%) change in maximal macrophage arc, as determined by OCT, in a defined arterial region of interest 16. Absolute change in maximum lipid core burden index in a 4-mm segment (maxLCBI4mm), as determined by NIRS, in a defined arterial region of interest 17. Relative change (%) in maximum lipid core burden index in a 4-mm segment (maxLCBI4mm), as determined by NIRS, in a defined arterial region of interest 18. Absolute change in lipid core burden index (LCBItotal), as determined by NIRS, in a defined arterial region of interest 19. Change in percent atheroma volume, as determined by IVUS, in a defined arterial region of interest 20. Change in maximal plaque burden, as determined by IVUS, in a defined arterial region of interest Secondary invasive haemodynamic endpoints: All invasive haemodynamic indices will be recorded at baseline and 6 months, using an intracoronary pressure/thermistor tipped wire: 21. Absolute and percentage change in coronary flow reserve (CFR), measured in artery of interest 22. Absolute and percentage change in index of microvascular resistance (IMR), measured in artery of interest 23. Absolute and percentage change in vessel fractional flow reserve (FFR), measured in artery of interest Secondary biomarker endpoints: Biomarker analysis will be performed using blood samples at baseline and 6 months: 24. High sensitivity troponin at 6 months and change from baseline 25. NT-pro BNP level at 6 months and change from baseline 26. High-sensitivity c-reactive protein (hs-CRP) at 6 months and change from baseline Leukocyte function sub-study: 27. Cytokine profile of isolated circulating neutrophils and peripheral blood mononuclear cells (PBMCs) following stimulation with oxidised-LDL, at 6 months and change from baseline 28. Surface proteomic analysis of isolated circulating neutrophils and PBMCs, at 6 months and change from baseline |
| Overall study start date | 19/03/2024 |
| Completion date | 07/10/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 90 Years |
| Sex | Both |
| Target number of participants | 50 |
| Key inclusion criteria | 1. Ability to provide written informed consent 2. Age 18 to 90 years old 3. Male, or female of non-child-bearing potential 4. Elevated clinical risk, as evidenced by ≥1 of: 4.1. Previous spontaneous acute myocardial infarction (diagnosed according to the universal MI criteria) with or without persistent ST-segment elevation 4.2. Previous stroke or intervention for peripheral arterial disease (i.e., evidence of atherosclerotic disease affecting >1 vascular bed) 4.3. Established diagnosis of diabetes mellitus 4.4. Systemic Coronary Risk Estimation 2 (SCORE2) or Systemic Coronary Risk Estimation 2 – Older Persons (SCORE2-OP) algorithm 10-year risk of fatal and non-fatal myocardial infarction or stroke >10% 5. Documented evidence of coronary artery disease, with an angiographically moderate stenosis on invasive coronary angiography (30-80%) 6. At least one non-flow limiting (FFR >0.80) moderate lesion with TCFA (minimum fibrous cap thickness of <120µm and lipid arc >90°) 7. History of prescribed statin therapy, at a stable dose, for >4 weeks 8. Evidence of residual inflammation at baseline (i.e., high-sensitivity CRP ≥2) |
| Key exclusion criteria | 1. Women who are pregnant, breastfeeding, or of child-bearing potential 2. 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 3. Previous spontaneous acute myocardial infarction (diagnosed according to the universal MI criteria) with or without persistent ST-segment elevation <4 weeks from recruitment 4. Previous coronary artery bypass grafting 5. Known chronic total occlusion of coronary artery 6. Chronic kidney disease with eGFR <50 mL/min/1.73 m2 per MDRD formula or renal replacement therapy at baseline assessment 7. 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 8. Symptoms of severe heart failure (systolic or diastolic) with New York Heart Association (NYHA) Functional Classification 3 or 4 9. Moderate or severe valvular heart disease considered likely to require intervention 10. History of blood dyscrasia including anaemia, thrombocytopenia, neutrophilia, leukopenia or other abnormality of blood count at baseline 11. Peripheral neuritis, myositis or marked myo-sensitivity to statins 12. A history of alcohol and/or substance abuse that could interfere with the conduct of the trial 13. Patients with suspected or proven immunocompromised state, including: 13.1. Those with evidence of Human Immunodeficiency Virus (HIV) infection; Patients on anti-retroviral therapy are excluded 13.2. Those with any other medical condition which in the opinion of the investigator places the patient at unacceptable risk for participation in immunomodulatory therapy 14. History of hypersensitivity to the study drug or its constituents 15. 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 16. Any biologic drugs targeting the immune system (for example, TNF blockers, anakinra, rituximab, abatacept, tocilizumab) 17. Established long-term pharmacotherapy with a strong CYP3A4 inhibitor or a P-glycoprotein inhibitor (P-gp) (e.g., macrolide antibiotics, ciclosporin, ketoconazole, itraconazole, voriconazole, HIV protease inhibitors, verapamil, diltiazem and disulfiram) 18. Contraindications to intravenous adenosine will exclude patients from adenosine induced hyperaemia 19. Any life-threatening condition with life expectancy <6 months that might prevent the patient from completing the study. |
| Date of first enrolment | 04/06/2024 |
| Date of final enrolment | 01/06/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom
Sponsor information
Hospital/treatment centre
King’s Health Partners Clinicial Trials Office
16th Floor, Tower Wing
Guy’s Hospital
Great Maze Pond
London
SE1 9RT
England
United Kingdom
| Phone | +44 (0)20 7188 5732 |
|---|---|
| amy.holton@kcl.ac.uk | |
| Website | https://www.kch.nhs.uk/ |
"ROR" |
https://ror.org/01n0k5m85 |
Funders
Funder type
Charity
No information available
Results and Publications
| Intention to publish date | 07/10/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website Access to raw data and right to publish freely by all investigators in study or by Independent Steering Committee on behalf of all investigators Data will be collected via a paper based data-capture form and from the electronic health record before being entered into an electronic case report form and stored in an online database. In accordance with GCP (Section 5.5), the electronic data entry system will be validated and ‘Working Practice Documents’ covering its use will be drafted and maintained. Trial participants will be identified by a unique trial specific number within the database. All data within the database will be de-identified, with all identifiable data removed and stored separately. The de-identified database will be available upon request to other research groups. Researchers wishing to access the database will be required to make a written request to the Chief Investigator outlining their research project and the minimum dataset that they require. Each request will be assessed for its scientific validity by the CI. The patient information sheet will highlight the potential for sharing of de-identified data with other researchers and collaborators. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Editorial Notes
17/06/2024: A scientfic contact was added.
03/05/2024: ISRCTN received notification of combined HRA/MHRA approval for this trial on 03/05/2024.
21/03/2024: Study's existence confirmed by the HRA.
