SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.

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.

• Authors: Craig J Smith, Sharon Hulme, Andy Vail, Calvin Heal, Adrian R Parry-Jones, Sylvia Scarth, Karen Hopkins, Margaret Hoadley, Stuart M Allan, Nancy J Rothwell, Stephen J Hopkins, Pippa J Tyrrell
• Journal: Stroke (Stroke) Vol. 49 Issue 5 Pg. 1210-1216 (05 2018) ISSN: 1524-4628 [Electronic] United States
• PMID: 29567761 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 American Heart Association, Inc.

Chemical References

• Fibrinolytic Agents
• IL6 protein, human
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-6
• C-Reactive Protein
• Tissue Plasminogen Activator

Topics

• Aged
• Aged, 80 and over
• Area Under Curve
• Brain Ischemia (drug therapy, immunology)
• C-Reactive Protein (immunology)
• Double-Blind Method
• Female
• Fibrinolytic Agents (therapeutic use)
• Humans
• Inflammation
• Injections, Subcutaneous
• Interleukin 1 Receptor Antagonist Protein (therapeutic use)
• Interleukin-6 (immunology)
• Male
• Middle Aged
• Odds Ratio
• Stroke (drug therapy, immunology)
• Thrombolytic Therapy
• Tissue Plasminogen Activator (therapeutic use)
• Treatment Outcome