Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study

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OBJECTIVE

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event with long-term morbidity and mortality. Patients who survive the initial bleeding are likely to suffer further early brain injury arising from a plethora of pathological processes. These may result in a worsening of outcome or death in approximately 25% of patients and may contribute to longer-term cognitive dysfunction in survivors. Inflammation, mediated by the cytokine interleukin-1 (IL-1), is an important contributor to cerebral ischemia after diverse forms of brain injury, including aSAH. Its effects are attenuated by its naturally occurring antagonist, IL-1 receptor antagonist (IL-1Ra [anakinra]). The authors hypothesized that administration of additional subcutaneous IL-1Ra would reduce inflammation and associated plasma markers associated with poor outcome following aSAH.

METHODS

This was a randomized, open-label, single-blinded study of 100 mg subcutaneous IL-1Ra, administered twice daily in patients with aSAH, starting within 3 days of ictus and continuing until 21 days postictus or discharge from the neurosurgical center, whichever was earlier. Blood samples were taken at admission (baseline) and at Days 3–8, 14, and 21 postictus for measurement of inflammatory markers. The primary outcome was difference in plasma IL-6 measured as area under the curve between Days 3 and 8, corrected for baseline value. Secondary outcome measures included similar area under the curve analyses for other inflammatory markers, plasma pharmacokinetics for IL-1Ra, and clinical outcome at 6 months.

RESULTS

Interleukin-1Ra significantly reduced levels of IL-6 and C-reactive protein (p < 0.001). Fibrinogen levels were also reduced in the active arm of the study (p < 0.002). Subcutaneous IL-1Ra was safe, well tolerated, and had a predictable plasma pharmacokinetic profile. Although the study was not powered to investigate clinical effect, scores of the Glasgow Outcome Scale–extended at 6 months were better in the active group; however, this outcome did not reach statistical significance.

CONCLUSIONS

Subcutaneous IL-1Ra is safe and well tolerated in aSAH. It is effective in reducing peripheral inflammation. These data support a Phase III study investigating the effect of IL-1Ra on outcome following aSAH.

Clinical trial registration no.: EudraCT: 2011-001855-35 (www.clinicaltrialsregister.eu)

ABBREVIATIONS AE = adverse event; aSAH = aneurysmal subarachnoid hemorrhage; AUC = area under the curve; CRP = C-reactive protein; GOS-E = Glasgow Outcome Scale–extended; IL = interleukin; IL-1Ra = IL-1 receptor antagonist; IMP = investigational medicinal product; IV = intravenous; ln = natural log; SAE = serious AE; SC = subcutaneous; WFNS = World Federation of Neurosurgical Societies.

Article Information

Correspondence James Galea, Department of Neurosurgery, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, United Kingdom. email: jgalea@dundee.ac.uk.

INCLUDE WHEN CITING Published online February 24, 2017; DOI: 10.3171/2016.9.JNS16615.

Disclosures Prof. Vail, an employee of University of Manchester, received academic credit for a successful funding application to Medical Research Council.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Screening and recruitment schema.

  • View in gallery

    Predicted (mean value in solid line, prediction intervals in dashed lines) and observed (dots) concentrations of IL-1Ra in patients receiving anakinra. Observed concentrations of IL-1Ra were within our predicted intervals, although mean values were below those predicted. conc = concentration.

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    Upper: ln(IL-6) for patients receiving anakinra and control subjects at different time points. Lower: ln(CRP) for patients receiving anakinra and control subjects at different time points.

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