Acute Coronary Syndromes Clinical Trial
— IVORYOfficial title:
Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes
Acute coronary syndromes (ACS) result from coronary plaque(s) disruption, which initiates a thrombotic process leading to partial or complete obstruction of the vessel lumen with subsequent myocardial ischaemia and necrosis. The mainstay of treatment is currently focused on the re-establishment and maintenance of coronary artery patency using anti-platelets and anticoagulants with or without mechanical dilatation and stenting of the culprit artery. Despite important advances in management, ACS still carries a risk of substantial morbidity and mortality. The improved efficacy of novel anti-platelet and anticoagulant agents have been limited by increased risk of haemorrhagic events. Future breakthroughs in management are most likely to arise from targeting other relevant pathophysiological pathways. Particularly, the immune response which is an important process that has been neglected in the management of patients with ACS. In this trial the investigators investigate the efficacy of low dose IL-2 compared with placebo in patients with ACS.
Status | Recruiting |
Enrollment | 60 |
Est. completion date | January 1, 2024 |
Est. primary completion date | January 1, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 85 Years |
Eligibility | Inclusion Criteria: - Able to provide written informed consent to participate. - Current admission (on the screening visit) with an acute coronary syndrome - ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), or unstable angina (UA) with symptoms suggestive of myocardial ischaemia lasting 10 minutes or longer with the patient at rest or with minimal effort AND EITHER i. elevated levels of TnI on admission OR ii. dynamic changes in ECG (new ST-T changes or T-wave inversion). - Where applicable, to be included in the trial women must be: i) Postmenopausal (for the purposes of this trial, postmenopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms) OR ii) Have had a documented hysterectomy and/or bilateral oophorectomy or sterilised OR iii) Peri-menopausal with a negative pregnancy test at screening (for the purposes of inclusion in this trial. Peri-menopausal is defined as women with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms, irregular periods). They will also have to comply with the use of contraception for the duration of the trial and undergo additional pregnancy tests during and after treatment. - High sensitivity C-reactive protein of >2 mg/L at any point from index admission for acute event to screening (inclusive). - Willingness and possibility to start dosing within 14 days from initial date of admission to the primary hospital for ACS. - Able to comply with all trial mandated visits. Exclusion Criteria: - Current presentation (at screening) with cardiogenic shock (systolic blood pressure <80 mm Hg, unresponsive to fluids, or necessitating catecholamines). - Current presentation with cardiac arrest. - Signs or symptoms of active infection requiring intravenous antibiotic treatment at screening. - History of malignancies requiring active treatment (However, patients with a history of treated localised basal or squamous cell skin cancer are not excluded from participation in this trial). - History of solid organ transplantation or other bone marrow transplantation. - History of recurrent epileptic seizures in the previous 4 years; repetitive or difficult to control seizures, coma or toxic psychosis lasting >48 hours. - Uncontrolled hypotension (Systolic BP (SBP)<80mmHg or DBP<50mmHg) OR uncontrolled hypertension (SBP>180 or DBP>120 mmHg) at screening. - Average corrected QT interval (QTc) > 450 msecs using Bazett's formula from average of triplicate ECGs (or > 480 msecs if bundle branch block). - Renal impairment defined as Creatinine clearance [Cockcroft-Gault] <45ml/min at screening. - Liver dysfunction (defined as ALT > 2xULN) at screening. - Evidence of cholestasis defined as elevated Total Bilirubin Levels, (TBL > 1.5 x ULN) and Alkaline Phosphatase, ALP (ALP > 1.5 x ULN), at screening. - Known hypothyroidism or hyperthyroidism. - Known autoimmune disease requiring active immunosuppressive treatment. - Any oral or intravenous immunosuppressive treatment including regular prednisolone, hydrocortisone or disease modifying drugs. [Inhaled or topical steroids are permissible]. - Patients on cytotoxic drugs and interferon-alpha. - Diabetics on oral hypglycaemics/diet control with HbA1c (DCCT) >8% (OR HbA1c (IFCC) >64mmol/mol) at screening. Diabetics on insulin are excluded from the study. - Contraindication to IL-2 treatment or hypersensitivity to IL-2 or to any of its excipients. - Participation in a previous research trial in the last 3 years which involved exposure to significant ionising radiation (i.e. cumulative research radiation dose >5 mSv) - Participation in a clinical trial where the patient has received a drug or new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of the drug (whichever is longer) prior to the first dose of trial medication, Visit 3 (Day 1). - Any medical history or clinically relevant abnormality that is deemed by the principal investigator/delegate to make the patient ineligible for inclusion because of a safety concern. - Pregnant women or breast feeding women. - Patients who are COVID-19 PCR positive at the time of screening. - Known severe allergy to the CT-contrast agents. |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Addenbrooke's Hospital | Cambridge | Cambridgeshire |
Lead Sponsor | Collaborator |
---|---|
Cambridge University Hospitals NHS Foundation Trust |
United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Change in serum cardiac biomarkers: hsCRP | High-sensitivity C-reactive protein (hsCRP), in mg/L | Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 12, day 40; Visit 14, day 54; Visit 15, day 61. | |
Other | Change in serum cardiac biomarkers: IL-6 | Interleukin 6 (IL-6), in pg/ml | Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 12, day 40; Visit 14, day 54; Visit 15, day 61. | |
Other | Change in serum cardiac biomarkers: Troponin I | Troponin I, in ng/L | Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 12, day 40; Visit 14, day 54; Visit 15, day 61. | |
Other | Change in ejection fraction | Change in ejection fraction. Measures on transthoracic echocardiograms | Visit1 day -14 to day 0; visit 14 (can be done between visit 14 and 16) | |
Other | Change in phenotype and function of peripheral blood mononuclear cell subsets | Change in phenotype and function of peripheral blood mononuclear cell (PBMC) subsets (such as B lymphocytes and Natural Killer cells). Assessed by flow cytometry, gene expression, in vitro activation and suppression assays | Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 12, day 40; Visit 14, day 54; Visit 15, day 61. | |
Other | Differences in gut microbiota composition between low-dose IL-2 vs placebo | Differences in gut microbiota composition between low-dose IL-2 vs placebo will be identified using 16S- RNAseq. Assessed by stool sample. | Visit 3, day 1 and Visit 15, day 61 | |
Other | The effect of low-dose IL-2 on coronary artery inflammation | The effect of low-dose IL-2 on coronary artery inflammation, measured by perivascular fat attenuation using computed tomography coronary angiography. | Visit 15, day 61 | |
Other | The effect of low-dose IL-2 on 18F-FDG uptake in cervical/thoracic vertebrae | The effect of low-dose IL-2 on 18F-FDG uptake in cervical/thoracic vertebrae. Assessed by FDG PET/CT scan. | Visit 2, day -6-0 and Visit 15, day 61 | |
Primary | Change in vascular inflammation | Vascular inflammation (as measured by mean TBR max in the index vessel) is measured by mean TBR max in the index vessel by 18F-FDG PET/CT | Baseline: Visit 2, day -6-0, and Follow Up: Visit 15, day 61 | |
Secondary | Change in mean TBR max in each arterial region | Change in mean max TBR in each arterial region individually restricted to those slices with TBR>1.6 | Baseline: Visit 2, day -6-0, and Follow Up: Visit 15, day 61 | |
Secondary | Change in lymphocyte subsets | Lymphocyte subsets:T effector [Teffs] cells defined as central memory and effector memory T cells in the non-Treg gated T cells. Evaluated by flow cytometry | Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 12, day 40; Visit 14, day 54, Visit 15, day 61 | |
Secondary | Change in percentage of Treg cells between low dose IL-2 and placebo | Treg cells are defined as CD3+CD4+CD25highCD127low cells within the CD3+CD4+ T cell gate. Evaluated by flow cytometry | Throughout treatment period: Visit 3, day 1; Visit 7, day 5; Visit 8, day 12; Visit 10, day 26; Visit 12, day 40; Visit 14, day 54, Visit 15, day 61. | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of Adverse Events | Number of incidences of adverse events is assessed via adverse change in routine test results and patient consultation. Events will be catalogued using MedDRA coding. | Visit 1 (day -14-0) through to Visit 16 (day 82) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of injection site reaction | Location of injection site will be recorded as will incidences of induration, redness and swelling at the injection site | All dosing visit: Visit 3 (day 1) through to Visit 14 (day 54) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: total white cell count | Haematology tests - full blood count: Total white cell count (WBC), in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Red cell count | Haematology tests - full blood count: Red cell count (RBC), in 10^12/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Haemoglobin | Haematology tests - full blood count: Haemoglobin (Hb), in g/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Platelets | Haematology tests - full blood count: Platelet Count, in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Neutrophils | Haematology tests - differential blood count: Neutrophils, in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Lymphocytes | Haematology tests - differential blood count: Lymphocytes, in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Monocytes | Haematology tests - differential blood count: Monocytes, in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Eosinophils | Haematology tests - differential blood count: Eosinophils, in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Basophils | Haematology tests - differential blood count: Basophils, in 10^9/L | Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry - Urea | Clinical biochemistry test: level of urea, in mmol/L | Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry - Creatinine | Clinical biochemistry test: level of creatinine, in µmol/L | Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - ALT | Clinical biochemistry blood test for liver function: Alanine Aminotransferase (ALT), in µ/L | Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - ALP | Clinical biochemistry blood test for liver function: Alkaline Phosphatase (ALP), in µ/L | Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - Albumin | Clinical biochemistry blood test for liver function: Albumin, in g/L | Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - Bilirubin | Clinical biochemistry blood test for liver function: Bilirubin, in µmol/L | Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Thyroid function | A thyroid function blood test of level of TSH (thyroid-stimulating hormone) in the blood will be performed. T4 (Thyroxine) will be performed if TSH is abnormal. | Visit 1 (day -14-0) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Electrical activity of the heart recorded using a 12-lead electrocardiogram | 12-lead ECG recording - QTcB (Corrected QT using Bazett's formula) intervals, in ms | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Blood pressure assessment | Blood pressure will be assessed using systolic and diastolic pressure measured in mmHg. | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Heart rate assessment | Heart rate assessed using bpm | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Respiratory rate assessment | Measured using breaths per minute | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Oxygen saturation assessment | Assessment of oxygen saturation and measured in percentage | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Physical examination evaluation - Gastrointestinal | Incidences of a abdominal distention, palpations and/or patient self-report of physical discomfort or pain | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Physical examination evaluation - Skin | Incidences of ISR lesions, nodules and/or bruising | Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital) | |
Secondary | Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of cardiovascular events | Occurrence of another important cardiovascular event(s) such a myocardial infarction. These will be captured through AEs and SAEs | Visit 2 (day -6-0) and Visit 15 (day 61) |
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