A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients
- H C A Emsley1,
- C J Smith2,
- R F Georgiou2,
- A Vail3,
- S J Hopkins4,
- N J Rothwell5,
- P J Tyrrell2,
- for the IL-1ra in Acute Stroke Investigators
- 1Division of Neuroscience, The University of Liverpool, The Walton Centre for Neurology & Neurosurgery, Lower Lane, Liverpool L9 7LJ, UK
- 2Division of Medicine and Neurosciences – Hope, University of Manchester, Hope Hospital, Salford, UK
- 3Biostatistics Group, University of Manchester, Hope Hospital, Salford, UK
- 4Injury Research, Hope Hospital, Salford, UK
- 5Faculty of Life Sciences, University of Manchester, UK
- Correspondence to: Professor N J Rothwell Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK;
- Received 30 September 2004
- Accepted 9 February 2005
- Revised 1 February 2005
Objectives: The cytokine interleukin (IL)-1 mediates ischaemic brain damage in rodents. The endogenous, highly selective, IL-1 receptor antagonist (IL-1ra) protects against ischaemic cerebral injury in a range of experimental settings, and IL-1ra causes a marked reduction of cell death when administered peripherally or at a delay in transient cerebral ischaemia. We report here the first randomised, double blind, placebo controlled trial of recombinant human IL-1ra (rhIL-1ra) in patients with acute stroke.
Methods: Patients within 6 hours of the onset of symptoms of acute stroke were randomised to rhIL-1ra or matching placebo. Test treatment was administered intravenously by a 100 mg loading dose over 60 seconds, followed by a 2 mg/kg/h infusion over 72 h. Adverse events and serious adverse events were recorded for up to 3 months, serial blood samples were collected for biological markers up to 3 months, and 5–7 day brain infarct volume was measured by computed tomography.
Results: No adverse events were attributed to study treatment among 34 patients randomised. Markers of biological activity, including neutrophil and total white cell counts, C reactive protein, and IL-6 concentrations, were lower in rhIL-1ra treated patients. Among patients with cortical infarcts, clinical outcomes at 3 months in the rhIL-1ra treated group were better than in placebo treated.
Conclusions: These data suggest that rhIL-1ra is safe and well tolerated in acute stroke. In addition, rhIL-1ra exhibited biological activity that is relevant to the pathophysiology and clinical outcome of ischaemic stroke. Our findings identify rhIL-1ra as a potential new therapeutic agent for acute stroke.
- BI, Barthel Index
- ESR, erythrocyte sedimentation rate
- CRP, C reactive protein
- CT, computed tomography
- IL, interleukin
- NIHSS, National Institutes of Health Stroke Scale
- OCSP, Oxfordshire Community Stroke Project
- PICH, primary intracerebral haemorrhage
- rhIL-1ra, recombinant human interleukin-1 receptor antagonist
- SAE, serious adverse event
- TACS, total anterior circulation syndromes
The IL-1RA in Acute Stroke Investigators are as follows. Steering committee: P J Tyrrell (UK), NJ Rothwell (UK), S J Hopkins (UK), A Vail (UK), G J del Zoppo (USA), J M Hallenbeck (USA); Data Monitoring committee: G Ford (UK), A Sharma (UK), S Hollis (UK); study investigators (UK) P J Tyrrell, N J Rothwell, S J Hopkins, A Vail, H C A Emsley, C J Smith, R F Georgiou, C M Gavin, E M Barberan, A Parry-Jones, J Selvarajah, J Staniland, C Sherrington, D G Hughes, IW Turnbull, G Morris, S Scarth, K Illingworth.
Competing interests: N J Rothwell holds a patent for interleukin-1 receptor antagonist in acute neurodegeneration.