Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) in non-ST elevation acute coronary syndromes

We will conduct a study of a new, purely anti-inflammatory drug celled interleukin-1 receptor antagonist in patients with severe unstable angina and heart attacks. It will be given by skin injection daily for 14 days. The main outcome in this pilot study will be to see if blood tests confirm that we have indeed damped down the inflammation that we think is so damaging in this condition. The drug is already used in the treatment of rheumatoid arthritis.

Pre-clinical data indicates that the inflammatory cytokine IL-1 has powerful effects on the vascular response to injury, and in animal models inhibition of IL-1 signalling has beneficial effects on a number of vascular responses. Acute coronary syndromes arise from coronary artery inflammation that usually extends to sites in the coronary arteries beyond the culprit plaque. The work outlined in this proposal aims to translate the pre-clinical observations of IL-1 inhibition to man in the context of non ST elevation acute coronary syndromes. We propose to undertake a randomised, placebo-controlled trial to investigate the effects of IL-1receptor antagonist (IL-1ra) in this condition. IL-1ra is a naturally occurring inhibitor of the IL-1 signally receptor. It is a commercially available, is licensed for use in Rheumatoid Arthritis and appears to be a very safe compound. We propose a proof of concept trial of this first, specifically anti-inflammatory therapy in ACS in man. Outcome measures have been chosen that could predict clinical benefit as well as give insights into the mechanism of any potential beneficial effect. We propose to randomise 180 patients to either IL-1ra (100mg s.c. once daily for 14 days) or placebo between three centres (Sheffield, Edinburgh and Leeds). The primary end point will be the area under the curve of CRP over the first 7 days. Secondary endpoints will be achieved CRP at day 7 and 14 and area under the curve for Troponin-T, vWF and IL-6. Two single centre sub-studies will be undertaken; ST segment Holter monitoring between day 2 and 4 (Sheffield) and cardiac MR scanning to assess LV function, infarct and myocardial oedema area (Leeds). A positive result in this study would be easy to translate to a larger clinical endpoint trial as this is a common condition in which many therapies have been have generated their evidence base through placebo controlled clinical trials.