Clinical trial NCT04241601: Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes - IVORY
Official title: Low-dose Interleukin-2 for the Reduction of Vascular Inflammation in Acute Coronary Syndromes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Coronary Syndromes
Keywords: Acute Coronary Syndromes
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
First posted: 2020-01-27
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: a randomised, double-blind, placebo controlled, parallel group experimental medicine trial
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Change in vascular inflammation
timeFrame: Baseline: Visit 2, day -6-0, and Follow Up: Visit 15, day 61
Secondary outcomes:
measure: Change in mean TBR max in each arterial region
timeFrame: Baseline: Visit 2, day -6-0, and Follow Up: Visit 15, day 61
measure: Change in lymphocyte subsets
timeFrame: 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
measure: Change in percentage of Treg cells between low dose IL-2 and placebo
timeFrame: 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.
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of Adverse Events
timeFrame: Visit 1 (day -14-0) through to Visit 16 (day 82)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of injection site reaction
timeFrame: All dosing visit: Visit 3 (day 1) through to Visit 14 (day 54)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: total white cell count
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Red cell count
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Haemoglobin
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Full Blood Count: Platelets
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Neutrophils
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Lymphocytes
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Monocytes
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Eosinophils
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Differential blood count - Basophils
timeFrame: Baseline, Visit 3 (day 1) thorugh Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry - Urea
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry - Creatinine
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - ALT
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - ALP
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - Albumin
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Clinical biochemistry test for liver function - Bilirubin
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54) and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Thyroid function
timeFrame: Visit 1 (day -14-0)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Electrical activity of the heart recorded using a 12-lead electrocardiogram
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Blood pressure assessment
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Heart rate assessment
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Respiratory rate assessment
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Oxygen saturation assessment
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Physical examination evaluation - Gastrointestinal
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Physical examination evaluation - Skin
timeFrame: Baseline, Visit 3 (day 1) through Visit 14 (day 54), and Visit 16 (day 82 when clinically indicated and patient attends hospital)
measure: Extended dosing of IL-2 in ACS patients safety and tolerability: Incidence of cardiovascular events
timeFrame: Visit 2 (day -6-0) and Visit 15 (day 61)
Other outcomes:
measure: Change in serum cardiac biomarkers: hsCRP
timeFrame: 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.
measure: Change in serum cardiac biomarkers: IL-6
timeFrame: 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.
measure: Change in serum cardiac biomarkers: Troponin I
timeFrame: 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.
measure: Change in ejection fraction
timeFrame: Visit1 day -14 to day 0; visit 14 (can be done between visit 14 and 16)
measure: Change in phenotype and function of peripheral blood mononuclear cell subsets
timeFrame: 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.
measure: Differences in gut microbiota composition between low-dose IL-2 vs placebo
timeFrame: Visit 3, day 1 and Visit 15, day 61
measure: The effect of low-dose IL-2 on coronary artery inflammation
timeFrame: Visit 15, day 61
measure: The effect of low-dose IL-2 on 18F-FDG uptake in cervical/thoracic vertebrae
timeFrame: Visit 2, day -6-0 and Visit 15, day 61
Locations:
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: Cambridgeshire
Study officials:
affiliation: Cambridge Unversity Hospitals NHS Foundation Trust; Unversity of Cambridge
name: Joseph Cheriyan, MBChB,FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sriranjan R, Zhao TX, Tarkin J, Hubsch A, Helmy J, Vamvaka E, Jalaludeen N, Bond S, Hoole SP, Knott P, Buckenham S, Warnes V, Bird N, Cheow H, Templin H, Cacciottolo P, Rudd JHF, Mallat Z, Cheriyan J. Low-dose interleukin 2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase II clinical trial. BMJ Open. 2022 Oct 7;12(10):e062602. doi: 10.1136/bmjopen-2022-062602.