학술논문
SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.
Document Type
Academic Journal
Author
Smith CJ; From the Greater Manchester Comprehensive Stroke Centre, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, United Kingdom (C.J.S., A.R.P.-J., P.J.T.) craig.smith-2@manchester.ac.uk.; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Hulme S; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Vail A; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Centre for Biostatistics, University of Manchester, Manchester Academic Health Science Centre, United Kingdom (A.V., C.H.).; Heal C; Centre for Biostatistics, University of Manchester, Manchester Academic Health Science Centre, United Kingdom (A.V., C.H.).; Parry-Jones AR; From the Greater Manchester Comprehensive Stroke Centre, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, United Kingdom (C.J.S., A.R.P.-J., P.J.T.).; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Scarth S; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Hopkins K; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Hoadley M; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Allan SM; Division of Neuroscience and Experimental Psychology, University of Manchester, United Kingdom (S.M.A., N.J.R.).; Rothwell NJ; Division of Neuroscience and Experimental Psychology, University of Manchester, United Kingdom (S.M.A., N.J.R.).; Hopkins SJ; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).; Tyrrell PJ; From the Greater Manchester Comprehensive Stroke Centre, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, United Kingdom (C.J.S., A.R.P.-J., P.J.T.).; Division of Cardiovascular Sciences, University of Manchester, United Kingdom (C.J.S., S.H., A.R.P.-J., S.S., K.H., M.H., S.J.H., P.J.T.).
Source
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0235266 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4628 (Electronic) Linking ISSN: 00392499 NLM ISO Abbreviation: Stroke Subsets: MEDLINE
Subject
Language
English
Abstract
Background and Purpose: The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke.
Methods: SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale.
Results: We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 ( P <0.001) and plasma C-reactive protein ( P <0.001). IL-1Ra was well tolerated with no safety concerns. Allocation to IL-1Ra was not associated with a favorable outcome on modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29-1.52), P =0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit.
Conclusions: IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229.
(© 2018 American Heart Association, Inc.)
Methods: SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale.
Results: We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 ( P <0.001) and plasma C-reactive protein ( P <0.001). IL-1Ra was well tolerated with no safety concerns. Allocation to IL-1Ra was not associated with a favorable outcome on modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29-1.52), P =0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit.
Conclusions: IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229.
(© 2018 American Heart Association, Inc.)