ESCALATion of Medical Therapy Following Multimodality Plaque Evaluation in High-risk Chronic Coronary Syndromes (ESCALATE)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Colchicine 0.5 MG

Detailed Description

1. 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.

2. Who can participate?

   Patients aged 18 to 90 years old with coronary artery disease and high clinical risk

3. 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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anne-Marie Murtagh; Phone Number: 31285 +44 02032999000; Email: qm.khpcto@kcl.ac.uk
• Study Contact Backup: Name: Michael McGarvey, MA MBBS MRCP; Phone Number: 31285 +44 02032999000; Email: michael.mcgarvey@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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:

   • Previous spontaneous acute myocardial infarction (diagnosed according to the universal MI criteria) with or without persistent ST-segment elevation
   • Previous stroke or intervention for peripheral arterial disease (i.e., evidence of atherosclerotic disease affecting >1 vascular bed)
   • Established diagnosis of diabetes mellitus
   • 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%)

   - At least one non-flow limiting (FFR >0.80) moderate lesion with TCFA (minimum fibrous cap thickness of less than or equal to120µm and lipid arc >90°)

6. History of prescribed statin therapy, at a stable dose, for >4 weeks
7. Evidence of residual inflammation at baseline (i.e., high-sensitivity CRP ≥2)

Exclusion Criteria:

1. Women who are pregnant, breast feeding, 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:

    1. those with evidence of Human Immunodeficiency Virus (HIV) infection; Patients on anti-retroviral therapy are excluded
    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-gpi) (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose colchicine 0.5mg OD; Low dose colchicine 0.5mg OD for 6 months	Drug: Colchicine 0.5 MG; Low dose daily colchicine
No Intervention: Guideline directed therapy; Guideline directed therapy; participants will be maintained on maximal tolerated dose of established statin therapy (>4 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute change in minimal fibrous cap thickness	The absolute change (µm) in minimal fibrous cap thickness, in a defined arterial region of interest, as assessed by OCT	6months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major adverse clinical events	Major adverse cardiovascular event (MACE): Composite of cardiovascular death, non-fatal MI, unplanned revascularisation and ischaemic stroke	6 months
Acute kidney injury	AKI secondary to contrast induced nephropathy	6 months
Major bleeding events (BARC 3-5)	Periprocedural major bleeding events (BARC 3-5)	6 months
Hospitalisation with serious infection	Hospitalisation requiring intravenous antibiotics	6 months
% change in minimal fibrous cap thickness	Percentage change in minimal fibrous cap thickness, as determined by OCT, in a defined arterial region of interest	6 months
% change in maximal lipid arc	Percentage change in lipid arc, as determined by OCT, in a defined arterial region of interest	6 months
Percentage change in lipid index	Percentage change in lipid index, as determined by OCT, in a defined arterial region of interest	6 months
Absolute change in maximum lipid core burden index in a 4-mm segment (maxLCBI4mm)	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	6 months
Relative change (%) in maximum lipid core burden index in a 4-mm segment (maxLCBI4mm)	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	6 months
Change in total atheroma volume	Change in percent atheroma volume, as determined by IVUS, in a defined arterial region of interest	6 months
Absolute and percentage change in coronary flow reserve (CFR)	Absolute and percentage change in coronary flow reserve (CFR), measured in artery of interest	6 months
Absolute and percentage change in index of microvascular resistance (IMR)	Absolute and percentage change in index of microvascular resistance (IMR), measured in artery of interest	6 months
Absolute and percentage change in vessel fractional flow reserve (FFR)	Absolute and percentage change in vessel fractional flow reserve (FFR), measured in artery of interest	6 months
Percentage change in high-sensitivity c-reactive protein (hs-CRP)	Percentage change in high-sensitivity c-reactive protein (hs-CRP)	6 months

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Collaborators: King's College London
• Investigators: Principal Investigator: Nilesh Pareek, MA MBBS PhD, King's College Hospital NHS Trust

Study record dates

Study Major Dates

• Study Start (Estimated): June 24, 2024
• Primary Completion (Estimated): October 5, 2025
• Study Completion (Estimated): October 5, 2026

Study Registration Dates

• First Submitted: June 10, 2024
• First Submitted That Met QC Criteria: June 17, 2024
• First Posted (Actual): June 21, 2024

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: June 17, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Chronic coronary syndromes
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: KCH23-187

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No