J Neurol Neurosurg Psychiatry 76:1366-1372 doi:10.1136/jnnp.2004.054882
  • Paper

A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients

  1. H C A Emsley1,
  2. C J Smith2,
  3. R F Georgiou2,
  4. A Vail3,
  5. S J Hopkins4,
  6. N J Rothwell5,
  7. P J Tyrrell2,
  8. for the IL-1ra in Acute Stroke Investigators
  1. 1Division of Neuroscience, The University of Liverpool, The Walton Centre for Neurology & Neurosurgery, Lower Lane, Liverpool L9 7LJ, UK
  2. 2Division of Medicine and Neurosciences – Hope, University of Manchester, Hope Hospital, Salford, UK
  3. 3Biostatistics Group, University of Manchester, Hope Hospital, Salford, UK
  4. 4Injury Research, Hope Hospital, Salford, UK
  5. 5Faculty of Life Sciences, University of Manchester, UK
  1. 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.


  • 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.

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