The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial

Navneet Singh, Stephen J Hopkins, Sharon Hulme, James P Galea, Margaret Hoadley, Andy Vail, Peter J Hutchinson, Samantha Grainger, Nancy J Rothwell, Andrew T King, Pippa J Tyrrell, Navneet Singh, Stephen J Hopkins, Sharon Hulme, James P Galea, Margaret Hoadley, Andy Vail, Peter J Hutchinson, Samantha Grainger, Nancy J Rothwell, Andrew T King, Pippa J Tyrrell

Abstract

Background: Interleukin-1 (IL-1) is a key mediator of ischaemic brain injury induced by stroke and subarachnoid haemorrhage (SAH). IL-1 receptor antagonist (IL-1Ra) limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome in ischaemic stroke patients. Intravenous (IV) IL-1Ra crosses the blood-brain barrier (BBB) in patients with SAH, to achieve cerebrospinal fluid (CSF) concentrations that are neuroprotective in rats.

Methods: A small phase II, double-blind, randomised controlled study was carried out across two UK neurosurgical centres with the aim of recruiting 32 patients. Adult patients with aneurysmal SAH, requiring external ventricular drainage (EVD) within 72 hours of ictus, were eligible. Patients were randomised to receive IL-1Ra (500 mg bolus, then a 10 mg/kg/hr infusion for 24 hours) or placebo. Serial samples of CSF and plasma were taken and analysed for inflammatory mediators, with change in CSF IL-6 between 6 and 24 hours as the primary outcome measure.

Results: Six patients received IL-1Ra and seven received placebo. Concentrations of IL-6 in CSF and plasma were reduced by one standard deviation in the IL-1Ra group compared to the placebo group, between 6 and 24 hours, as predicted by the power calculation. This did not reach statistical significance (P = 0.08 and P = 0.06, respectively), since recruitment did not reach the target figure of 32. No adverse or serious adverse events reported were attributable to IL-1Ra.

Conclusions: IL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra.

Figures

Figure 1
Figure 1
Flow chart showing the screening and recruitment numbers at Salford Royal Foundation Trust and Addenbrooke’s Hospital. CUH, Cambridge University Hospitals; EVD, external ventricular drain; SRFT, Salford Royal Foundation Trust.
Figure 2
Figure 2
CSF and plasma IL-6 concentrations for 12 participants over 24 hours from the start of infusion. (a) CSF IL-6 and (b) plasma IL-6 concentrations. Solid symbols and lines represent patients that received IL-1Ra. Open symbols and dashed lines represent patients that received placebo. CSF, cerebrospinal fluid; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist.
Figure 3
Figure 3
Change from baseline for CSF IL-6, plasma IL-6, and plasma CRP for 12 participants over 72 hours. (a) CSF IL-6, (b) plasma IL-6, and (c) plasma CRP. Solid symbols and lines represent patients that received IL-1Ra. Open symbols and dashed lines represent patients that received placebo. CSF, cerebrospinal fluid; CRP, C-reactive protein; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist.

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