Title: Does Interleukin-1 Receptor Antagonist Improve Outcome following aneurysmal Subarachnoid Haemorrhage (aSAH)?
Funder: Department of Health and Social Care

Abstract: CONDITION: Aneurysmal subarachnoid haemorrhage (aSAH), bleeding into the space around the brain, occurs following rupture of a cerebral aneurysm. Even with optimal management and early securing of the aneurysm to prevent re-bleeding, clinical outcomes are poor: 25% of patients are dead or disabled at a year. Much of this damage is secondary to early brain injury. This term is used to describe the mechanisms underlying acute neurological deterioration following aSAH that include the cell death, cerebral oedema and neuronal dysfunction that occur following the initial bleed. Reducing the effects of early brain injury is therefore a priority. TREATMENT: Interleukin-1 (IL-1) is a pro-inflammatory cytokine readily upregulated in the brain following aSAH. Persuasive evidence of a significant contributory role in all the proposed mechanisms of early brain injury led the MRC to support our phase II study. We have now shown that blocking IL-1 with IL-1 receptor antagonist (IL-1Ra) in patients with aSAH reduces levels of plasma inflammation known to be associated with secondary ischaemia and poor outcome. HYPOTHESIS: treatment with IL-1Ra subcutaneously (SC) twice daily to patients with aSAH will improve clinical outcome. AIMS: determine efficacy by evaluating whether SC IL-1Ra from within 72 hours of ictus for up to 21 days improves outcomes at 6 months; ascertain if levels of peripheral inflammation (plasma inflammatory markers) correlate with any observed clinical effect. DESIGN: Multi-centre, parallel group, double-blind, placebo-controlled randomised phase III trial. POPULATION: Adults within 72 hours of onset of SAH. RECRUITMENT: We plan to set-up 20 sites and recruit 1-2 patients per centre per month for 42 months. INTERVENTIONS: Subcutaneous administration of 100mg IL-1Ra or placebo twice daily from randomisation until discharge from neurosurgical centre, for a maximum of 21 days. PRIMARY EFFICACY OUTCOME: Ordinal shift in modified Rankin Score (mRS) at 6months. SECONDARY OUTCOMES: Plasma IL-6 at day 3-5 post randomisation, measurement of mood, fatigue and quality of life at 6 months using HADS), Fatigue score and EQ-5D-5L score. MECHANISM: Plasma IL-6 and CRP measured at 3-5 days post randomisation SAMPLE SIZE: Target total recruitment of 1000 patients (800 participants with confirmed aSAH). Allowing for up to 10% attrition this gives 90% power at the 5% significance level to detect a common odds ratio in the primary ordinal outcome of 0.65. This is equivalent to increasing the proportion of those with ‘good’ outcome (mRS no higher than 2) from 72% to 80%. STATISTICAL ANALYSIS: We will seek outcomes for all randomised participants with confirmed aSAH regardless of protocol adherence and include them in analyses under the allocated group. Primary analysis will apply proportional odds regression to the mRS at 6 months with adjustment for the randomisation stratification criteria. Secondary outcomes will be assessed using regression methods with similar adjustment.

Lay abstract: Subarachnoid haemorrhage is a bleed onto the surface of the brain. It is usually caused when a bulge (aneurysm) on the wall of a blood vessel within the brain suddenly bursts. It affects up to 6,000 people every year in the UK. Up to half of all patients do not survive long enough to receive hospital treatment and those who do survive, often suffer long-term issues that impact on their daily life. In the hours and days after subarachnoid haemorrhage, patients are at risk of further brain damage due to inflammation. A protein called interleukin-1 (IL-1) is the main culprit and this triggers a number of other chemicals in the circulation which may lead to physical symptoms similar to stroke but can also cause problems with language, mood, anxiety and fatigue all of which impact most on recovery and in particular; return to work. The effect of IL-1 can be blocked, reduced or even reversed by another protein present naturally in our body; interleukin-1 receptor antagonist (IL-1Ra). A company has produced a man-made version of IL-1Ra, which has been used for many years as an anti-inflammatory treatment for rheumatoid arthritis. Inflammation occurs very early after the initial haemorrhage and can continue for up to 21 days, which means IL-1Ra should be given early and through the risk period to prevent or reduce these symptoms. Our group has successfully tested IL-1Ra in patients with subarachnoid haemorrhage and found it reduces inflammation in the circulation and brain and we now want to establish whether IL-1Ra improves recovery after subarachnoid haemorrhage. To do this, we will recruit 800 patients with aneurysmal subarachnoid haemorrhage from neurosurgical centres in the United Kingdom over a 3½ year period. Patients will receive either IL-1Ra or placebo (dummy-drug) as twice daily injections for up to 21 days after subarachnoid haemorrhage or until their surgeon feels they are well enough to be discharged from the neurosurgical centre. We will measure levels of inflammation in the blood before and during treatment. This will require two extra blood samples, taken where possible at the same time as clinical blood samples. All patients will continue to receive the standard care for subarachnoid haemorrhage and participation in this study will not affect or delay this care. Six months following aSAH, we will contact the participant by telephone and ask a number of questions about recover, mood, tiredness and quality of life, all of which people tell us are major problems after aSAH.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: STROKE