A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients

Abstract

Objectives: The cytokine interleukin (IL)-1 mediates ischaemic brain damage in rodents. The endogenous, highly selective, IL-1 receptor antagonist (IL-1ra) protects against ischaemic cerebral injury in a range of experimental settings, and IL-1ra causes a marked reduction of cell death when administered peripherally or at a delay in transient cerebral ischaemia. We report here the first randomised, double blind, placebo controlled trial of recombinant human IL-1ra (rhIL-1ra) in patients with acute stroke. Methods: Patients within 6 hours of the onset of symptoms of acute stroke were randomised to rhIL-1ra or matching placebo. Test treatment was administered intravenously by a 100 mg loading dose over 60 seconds, followed by a 2 mg/kg/h infusion over 72 h. Adverse events and serious adverse events were recorded for up to 3 months, serial blood samples were collected for biological markers up to 3 months, and 5-7 day brain infarct volume was measured by computed tomography. Results: No adverse events were attributed to study treatment among 34 patients randomised. Markers of biological activity, including neutrophil and total white cell counts, C reactive protein, and IL-6 concentrations, were lower in rhIL-1ra treated patients. Among patients with cortical infarcts, clinical outcomes at 3 months in the rhIL-1ra treated group were better than in placebo treated. Conclusions: These data suggest that rhIL-1ra is safe and well tolerated in acute stroke. In addition, rhIL1ra exhibited biological activity that is relevant to the pathophysiology and clinical outcome of ischaemic stroke. Our findings identify rhIL-1ra as a potential new therapeutic agent for acute stroke.

Clinical Trials of Immunomodulation in Ischemic Stroke

“…No adverse events were attributed to treatment and the recombinant human IL-1Ra was deemed safe. Ready transfer across the blood-brain barrier was shown [46]. Furthermore, systemic markers of biological activity (including neutrophil and total white cell counts, Creactive protein, and IL-6 concentrations) were lower in the treatment arm.…”

“…Clinical outcomes after at least 3 months were better in the treatment group. Median NIHSS score was reduced to 4 versus 1 in the placebo arm, and more patients receiving anakinra had mRS 0-1 at 3 months (30 % vs 7 %) [46].…”

Targeting Astrocytes for Stroke Therapy

“…74 Animal studies demonstrated that a naturally occurring selective antagonist of the IL-1 receptor (IL-1ra) reduced stroke volume and disability when administered for up to 3 hours after onset of MCAO in rats. 72 Similarly, treatment with IL-1ra was initiated within 6 hours of stroke onset in stroke patients and was continued for 72 hours.…”

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

“…The IL-1 receptor antagonist (IL-1Ra) is a naturally occurring, competitive inhibitor of IL-1 action, which is highly selective. There is considerable preclinical and clinical evidence showing that IL-1Ra is a promising candidate for the treatment of stroke and related disorders (Banwell et al, 2009;Emsley et al, 2005;Hannum et al, 1990;Rothwell, 2003). In experimental stroke, endogenous IL-1Ra is upregulated and protects the brain (Denes et al, 2008;Pinteaux et al, 2006), while administration of exogenous IL-1Ra reduces ischemic injury, even when administered 3 hours after the insult (Garcia et al, 1995;Loddick and Rothwell, 1996;Mulcahy et al, 2003;Relton et al, 1996;Stroemer and Rothwell, 1997).…”

“…In experimental stroke, endogenous IL-1Ra is upregulated and protects the brain (Denes et al, 2008;Pinteaux et al, 2006), while administration of exogenous IL-1Ra reduces ischemic injury, even when administered 3 hours after the insult (Garcia et al, 1995;Loddick and Rothwell, 1996;Mulcahy et al, 2003;Relton et al, 1996;Stroemer and Rothwell, 1997). Subcutaneous IL-1Ra, administered at the time of occlusion, is neuroprotective in the rat and localizes to salvageable brain tissue (Greenhalgh et al, 2010), and IL-1Ra showed some beneficial effects in a small phase II clinical study in acute stroke (Emsley et al, 2005).…”