Developmental Clinical Studies - Does subcutaneous IL-1RA reduce inflammation following subarachnoid haemorrhage?

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

SAH occurs when a blood vessel within the brain bursts; affecting up to 6,000 people every year in the UK. It is often due to a weakening in the blood vessel wall (aneurysm) and can occur without warning. Up to half of all patients who have a SAH do not survive long enough to receive hospital treatment. Of those who survive, blood flow to the brain may be reduced due to blood from the haemorrhage irritating the outer surface of brain arteries causing them to spasm and become narrower. Reduction in blood flow prevents oxygen reaching brain cells causing them to die. This is known as cerebral ischaemia (CI) and causes patients to experience symptoms similar to a stroke. However, these symptoms may not be immediately apparent as they commonly occur between 3-15 days after the initial haemorrhage. This is known as Delayed Cerebral Ischaemia (DCI).

A protein called interleukin-1 (IL-1) is an important trigger for damage happening after CI. After SAH, IL-1 causes the release of other proteins which cause inflammation in the circulation and the brain. IL-1 can be blocked, limited or even reversed by another protein present naturally in our body; interleukin-1 receptor antagonist (IL-1RA). A company has duplicated IL-1RA; marketing it as an anti-inflammatory treatment for rheumatoid arthritis (Kineret?). Our group has successfully tested Kineret? and found that when given in high doses at the onset of CI; it reduces inflammation and ischaemia. As ischaemia in SAH is delayed, it may be possible to give Kineret? as a preventative measure rather than a treatment; allowing smaller doses to be used.

We want to establish whether injections of Kineret?, given in small amounts, reduces inflammation in brain blood vessels and the subsequent incidence of DCI. To do this, we will recruit up to 140 SAH patients from our neurosurgical centre (Salford Royal NHS Foundation Trust) over 2? years. Patients will be randomised by an independent third party to receive either Kineret? or placebo in twice daily injections for up to 21 days after the bleed. We will perform a number of assessments and blood tests at pre-determined time points. Patients will continue to receive the standard care for SAH and participation in this study will not affect or delay this care.

Throughout the study we will consult with Patient-Public Involvement groups, building on previous work and strengthening our relationship with the lay community.

Technical Summary

Cerebral ischaemia (CI) is a major cause of death and disability in subarachnoid haemorrhage (SAH), stroke and intracerebral haemorrhage. SAH has a very poor prognosis; a third of initial survivors develop delayed cerebral ischaemia (DCI). Despite contemporary treatments, DCI is still a common cause of poor outcome. Attempts to treat established DCI may be too late to effect significant improvement. There is an urgent need to develop prophylactic treatment to prevent DCI in high risk patients. Interleukin-1 (IL-1) is a proinflammatory cytokine that mediates experimental ischaemic brain injury. Inhibition of IL-1, using its naturally occurring antagonist IL-1 receptor antagonist (IL-1RA), markedly reduces diverse forms of experimental brain injury and could be a practical and widely applicable treatment for CI in man. IL-1 potentially contributes to development of DCI through several inflammatory mechanisms, including vasopasm, blood-brain barrier (BBB) dysfunction and cortical spreading ischaemia. It also drives systemic inflammatory response, enhances endothelial reactivity and procoagulant activity, and is involved in intramural cerebrovascular inflammation, all of which may influence outcome from SAH. When ischaemia is delayed after symptom onset, as in DCI, prophylactic treatment may limit subsequent injury. Inflammation in the peripherally-accessible vascular endothelium plays a pivotal role in regulating the inflammatory response in SAH. Subcutaneous (SC) IL-1RA limits peripheral inflammation in rheumatoid arthritis, type II diabetes, juvenile arthritis and Schnitzler?s syndrome and has a good safety and tolerability profile. Our hypothesis is that SC IL-1RA will reduce inflammation in patients with acute cerebrovascular disease and hence will subsequently improve outcome.
We propose a placebo-controlled, double-blind randomised phase II study of SC anakinra (r-met-HuIL-1RA) vs placebo (70 per group), administered SC, twice daily for up to 21 days in patients with SAH admitted at the Greater Manchester Neurosciences Centre. Blood samples will be taken at baseline, daily from day three to day eight and on days 14 and 21 if participants are still in-patients. Primary outcome will be an integrated measure of the peripheral inflammatory response. We will also measure clinical outcome scores including Glasgow Outcome Score, modified Rankin Score, mortality, incidence of DCI (including intensity of treatment) and length of ICU and in-hospital stay. Safety data will be analysed descriptively and pharmacokinetics of SC IL-1RA will be confirmed in these patients. Confirmation that SC IL-1RA reduces peripheral inflammation in these high risk patients would support the case for a phase III efficacy study of SC IL-1RA in SAH.

Publications

10 25 50
 
Description Manchester Stroke and Neurosurgery Research Collaboration 
Organisation Salford Royal NHS Foundation Trust
Department Department of Neurosurgery
Country United Kingdom 
Sector Hospitals 
PI Contribution We have provided opportunities for vascular neurosurgical research projects in subarachnoid haemorrhage, intracerebral haemorrhage and brain injury, with 4 PhDs and 2 MDs in the last 6 years. We have supported research activity at all levels including student, MRes, and consultant led projects.
Collaborator Contribution Direct provision of research costs to cover a study of IL-6 as a biomarker in CSF infection, a study of PET imaging in intracerebral haemorrhage and the funding of clinical research registrars to support our research efforts.
Impact There have been a number of papers from this collaboration which are detailed under publications.
 
Description NW Stroke LRN 
Organisation National Institute for Health Research
Department Stroke Research Network
Country United Kingdom 
Sector Academic/University 
PI Contribution We have obtained funding for local investigator led studies in both stroke and neurosurgical studies which are on the NIHR portfolio. Specifically, we have helped develop the neurosurgical portfolio and helped to obtain HSRC status in Salford Royal Foundation Trust.
Collaborator Contribution Assistance with 24/7 patient recruitment and assessment allowing recruitment into complex studies; research expertise and advice; PPI panels which support researchers in submitting applications and other documentation (eg Ethics submissions). Training and development support.
Impact World Stroke Day Event is a joint collaboration between our group and the NW Stroke LRN where researchers, patients and the public meet to hear about research findings in stroke; this unique event is a major PPI platform for us and other researchers. Our partnership has led to a greatly increased understanding of the role of research on the stroke and neurosurgical units where research has become "core business". LRN nurses have been trained in arterial blood sampling, sample preparation, laboratory processing and CSF sampling as a result of their collaboration with us, which is beyond the remit of most stroke research nurses. We have been able to attract exemplar studies into the LRN as a result of our intensive care and neurosurgical research expertise.
Start Year 2006
 
Description SOBI 
Organisation SOBI Swedish Orphan Biovitrum AB
Country Sweden 
Sector Private 
PI Contribution We have undertaken extensive preclinical and clinical studies in IL-1Ra in stroke and subarachnoid haemorrhage. SOBI is the only manufacturer of IL-1Ra.
Collaborator Contribution They are providing drug and placebo free of charge for our next clinical study.
Impact Successful application for funding to Stroke association and involved as Industrial partner on a MRC application (2013) which is pending.
Start Year 2011
 
Description SRN Writing Group on long term outcomes after SAH 
Organisation Newcastle University
Department Institute of Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Hiren Patel, Hon SL in neurosurgery in our group, has convened a writing group funded by SRN to write an application for funding on long term outcomes following SAH.
Collaborator Contribution provided imaging expertise for application
Impact Application to be submitted to Stroke Association Jan 2014
Start Year 2013