Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes - IVORY

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
A heart attack occurs when there is reduced blood flow to heart muscle cells which results from narrowings or blockages in walls of blood vessels supplying the heart, due to fatty deposits and inflammatory cells that build up over time. This build-up leads to heart muscle damage called a heart attack. The immune system plays an important role in both the development of the narrowings and the damage to the heart muscle during a heart attack. Studies have shown that there is a lower level of protective immune cells called regulatory T-cells (Tregs) in heart attack patients. Increasing the number of circulating Tregs may have a direct effect in reducing the inflammation in arteries, preventing further narrowings in blood vessels and improving heart muscle function. Aldesleukin, also known as interleukin-2 (IL-2), is a medicine that stimulates the production of Treg cells when given at low doses and is the drug being tested in this trial. IL-2 is licensed for the treatment of kidney cancer where it is given at much higher doses than planned in this trial. It appears to be safe and well tolerated at low doses while increasing Treg cells. IVORY will be conducted in patients presenting with a heart attack (Acute Coronary Syndrome (ACS)). Approximately, 60 patients will be randomized to receive either low dose IL-2 or placebo. It is a Phase 2, randomised, double- blinded, placebo-controlled experimental trial. Total study duration for each participant will be approximately 13 weeks. Participants will undergo two PET/CT (Positron emission tomography-computed tomography) scans to observe change of inflammation in the blood vessels from baseline between the two trial groups (Primary Endpoint).

Official Title
-----------------
Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes

Conditions
-----------------
Acute Coronary Syndromes

Intervention / Treatment
-----------------
* Drug: Interleukin-2 [IL-2]
* Other: Placebo Dextrose 5% solution


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: a randomised, double-blind, placebo controlled, parallel group experimental medicine trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: low dose interleukin-2<br>Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC. Active and Placebo doses appearing identical at point of issue and administration. | Drug: Interleukin-2 [IL-2]<br>* Active Comparator: IL-2 plays a key role in Treg cell development, expansion, survival and suppressive function<br>* Other names: Aldesleukin;|
| Placebo Comparator: Placebo<br>Commercially available dextrose 5% injection with a UK marketing authorisation at equivalent dose volume will be used for the placebo formulation. Placebo and Active doses appearing identical at point of issue and administration. | Other: Placebo Dextrose 5% solution<br>* Placebo Comparator: Dextrose 5% solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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. | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Coronary Syndromes