title: 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.
abstract: 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 ).
authors.affiliation: 1Ninewells Hospital and Medical School, University of Dundee.|2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: James
authors.initials: J
authors.lastname: Galea
authors.affiliation: 3Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School.
authors.forename: Kayode
authors.initials: K
authors.lastname: Ogungbenro
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Sharon
authors.initials: S
authors.lastname: Hulme
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Hiren
authors.initials: H
authors.lastname: Patel
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Scarth
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Margaret
authors.initials: M
authors.lastname: Hoadley
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Karen
authors.initials: K
authors.lastname: Illingworth
authors.affiliation: 4Walton Centre for Neurology and Neurosurgery, Fazakerley, Liverpool; and.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: McMahon
authors.affiliation: 5University Hospital of North Midlands, Royal Stoke University Hospital, Stoke-on-Trent,United Kingdom.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tzerakis
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: King
authors.affiliation: 6Centre for Biostatistics, Institution of Population Health, University of Manchester.
authors.forename: Andy
authors.initials: A
authors.lastname: Vail
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hopkins
authors.affiliation: 7Faculty of Life Sciences, University of Manchester.
authors.forename: Nancy
authors.initials: N
authors.lastname: Rothwell
authors.affiliation: 2Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, Salford.
authors.forename: Pippa
authors.initials: P
authors.lastname: Tyrrell
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D023261:Glasgow Outcome Scale; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007279:Injections, Subcutaneous; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D016037:Single-Blind Method; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D005340:Fibrinogen; D002097:C-Reactive Protein
keywords: AE = adverse event; AUC = area under the curve; C-reactive protein; CRP; CRP = C-reactive protein; GOS-E = Glasgow Outcome Scale–extended; IL = interleukin; IL-1Ra = IL-1 receptor antagonist; IMP = investigational medicinal product; IV = intravenous; Phase II trial; SAE = serious AE; SC = subcutaneous; WFNS = World Federation of Neurosurgical Societies; aSAH = aneurysmal subarachnoid hemorrhage; aneurysmal subarachnoid hemorrhage; fibrinogen; inflammation; interleukin-1 receptor antagonist; interleukin-6; ln = natural log; neuroinflammation; vascular disorders