Clinical trial NCT06469528: ESCALATion of Medical Therapy Following Multimodality Plaque Evaluation in High-risk Chronic Coronary Syndromes
Official title: ESCALATion of Medical Therapy Following Multimodality Plaque Evaluation in High-risk Chronic Coronary Syndromes
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Coronary Artery Disease
Keywords: Chronic coronary syndromes
Lead sponsor: King's College Hospital NHS Trust
Sponsor class: OTHER
Collaborators: name: King's College London
First posted: 2024-06-21
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single centre, open-label prospective, randomised controlled trial; patients randomised 1:1 to low-dose colchicine 0.5mg OD vs guideline directed medical therapy
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Absolute change in minimal fibrous cap thickness
timeFrame: 6months
Secondary outcomes:
measure: Major adverse clinical events
timeFrame: 6 months
measure: Acute kidney injury
timeFrame: 6 months
measure: Major bleeding events (BARC 3-5)
timeFrame: 6 months
measure: Hospitalisation with serious infection
timeFrame: 6 months
measure: % change in minimal fibrous cap thickness
timeFrame: 6 months
measure: % change in maximal lipid arc
timeFrame: 6 months
measure: Percentage change in lipid index
timeFrame: 6 months
measure: Absolute change in maximum lipid core burden index in a 4-mm segment (maxLCBI4mm)
timeFrame: 6 months
measure: Relative change (%) in maximum lipid core burden index in a 4-mm segment (maxLCBI4mm)
timeFrame: 6 months
measure: Change in total atheroma volume
timeFrame: 6 months
measure: Absolute and percentage change in coronary flow reserve (CFR)
timeFrame: 6 months
measure: Absolute and percentage change in index of microvascular resistance (IMR)
timeFrame: 6 months
measure: Absolute and percentage change in vessel fractional flow reserve (FFR)
timeFrame: 6 months
measure: Percentage change in high-sensitivity c-reactive protein (hs-CRP)
timeFrame: 6 months
Other outcomes:
Locations:
Study officials:
affiliation: King's College Hospital NHS Trust
name: Nilesh Pareek, MA MBBS PhD
role: PRINCIPAL_INVESTIGATOR
References: