IVORY

Low-dose interleukin-2 for the reduction of vascular inflammation in Acute Coronary Syndromes

Research 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 focussed 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. Thus, future breakthroughs in management are most likely to arise from targeting other relevant pathophysiological pathways. Particularly, we believe that the immune response is an important process that has been neglected in the management of patients with ACS.

The experimental and clinical background in low-dose IL-2 therapy suggests a potential clinical utility of Treg cell expansion in patients with ACS. Administration of low doses of IL-2 in various clinical settings appears to be safe and remarkably efficacious at promoting selective expansion of Treg cells with preserved suppressive function. Circulating Tregs are reduced at admission for ACS and during the first 8 weeks after the index event, but recover to normal levels thereafter. Quick re-establishment and maintenance of ‘normal’ Treg levels during that phase is paramount. Indeed we speculate that increasing Treg levels to above normal may have beneficial effects on myocardial repair and decrease atherosclerotic progression.

IVORY is a randomised, double-blind, placebo controlled, parallel group experimental medicine trial. The aim of the trial is to test the superiority of low dose IL-2 compared to placebo in reducing vascular inflammation in ACS patients with hs-CRP>2mg/l. There will be 2 hospital sites in Cambridge taking part. Addenbrooke’s Hospital, Cambridge, will be the main trial site and Royal Papworth Hospital (which is now situated on the Cambridge Biomedical Campus) will be a shared care site where patients may be recruited and/or have study visits.

Main inclusion criteria

To be included in the trial the patient must meet the following criteria:

  1. Able to provide written informed consent to participate

  2. Aged between 18 and 85

  3. 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

    • 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

    • Have had a documented hysterectomy and/or bilateral oophorectomy or sterilised

      • OR

    • 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 screening

  • Willingness and possibility to start dosing within 8 days from initial date of admission to the primary hospital for ACS

  • Able to comply with all trial mandated visits.

Main exclusion criteria

The presence of any of the following will preclude patient inclusion:

  • 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

  • Known Type 1 or Type 2 diabetes mellitus

  • 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

Chief investigator

Dr Joseph Cheriyan

Contact details

Senior Clinical Trials Coordinator: Heike Templin

Telephone: 01223 250874 | Email:[email protected]