Chronic inflammation
Conditions
Interventions
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
Sponsors
King's College Hospital NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion 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: 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 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)
Exclusion criteria
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 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, United Kingdom
Contacts
Public ContactMichael McGarvey
Outcome results
None listed