Title: Understanding the therapeutic potential of interleukin-1 inhibition in intracerebral haemorrhage
Funder: Department of Health and Social Care

Abstract: Background: Intracerebral haemorrhage (ICH) causes at least 10% of strokes, has a high mortality and morbidity, and few evidence-based treatments. Inflammation may increase death and/or disability after ICH through perihaematomal secondary brain injury, worsening of cerebral oedema, and by increasing the risk of haematoma expansion. The prototypical, pro-inflammatory cytokine, interleukin-1 (IL-1), plays a key role in coordinating the early, damaging inflammatory response both within the brain and systemically. The naturally occurring IL-1 blocker, IL-1 receptor antagonist (IL-1Ra) is already in clinical use, has an excellent safety record, lowers plasma inflammatory markers in other vascular diseases, and thus represents a promising anti-inflammatory intervention. This application aims to address the key outstanding questions to take IL-1Ra forward to a definitive clinical trial in ICH. Key research questions: What is the nature and time course of inflammation in the perihaematomal brain in acute clinical ICH and thus what is the time window for treatment with IL-1Ra? To what extent does blood-brain barrier breakdown during acute ICH co-localise with activated microglia (the major source of IL-1 in the brain) and thus does IL-1Ra need to cross an intact blood-brain barrier to inhibit brain inflammation? Does blocking the systemic and central actions of IL-1 with IL-1Ra reduce subacute perihaematomal oedema after ICH? Plan of investigation: Work package 1: To investigate the brain inflammatory response in acute clinical ICH, an observational study nested within MISTIE III (an international, multicentre trial of minimally invasive surgery and clot lysis in ICH) will recruit 50 patients randomised to surgical intervention (haematoma drain in situ for 4 days) and 50 to standard medical care. Samples will be collected every 24 h from the haematoma drain (surgical patients only) and from peripheral blood (all patients) for measurement of key pro- and anti-inflammatory mediators. The time profiles of key mediators within the haematoma will inform the time window for treatment with IL-1Ra. Work package 2: To determine the extent and distribution of blood-brain barrier breakdown after ICH and how it co-localises with microglial activation, 40 patients with spontaneous, supratentorial ICH will be recruited to undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at Salford Royal Hospital, up to 48 h after symptom onset. Our pilot study suggests that 20 of these patients will be suitable for a positron emission tomography scan at 2-5 days to determine the extent and distribution of microglial activation using [11C]-(R)-PK11195. Maps of blood-brain barrier transfer constant and binding potential of [11C]-(R)-PK11195 will be co-localised for analysis. Work package 3: An open-label, blinded assessment, randomised, controlled, multi-centre, phase 2 trial will compare the effect of IL-1Ra (vs. standard care alone) on perihaematomal oedema at 72 h in a total of 80 acute, spontaneous, supratentorial, ICH patients. As we do not know the relative importance of blocking the central and systemic actions of IL-1 in ICH, an IL-1Ra regimen designed to block both has been chosen (200 mg bolus and 2 mg/kg/h infusion for 24 h then 100mg every 12 h from 24-72 h) which may be further refined on completion of work packages 1&2. High intravenous (IV) doses of IL-1Ra have been previously shown to be safe. Secondary outcomes will be early blood-brain barrier breakdown (DCE-MRI), haematoma growth, acute inflammatory markers (over 72 h) and clinical outcomes at 3 months. Potential benefits: IL-1Ra may improve outcomes across the range of ICH severity, both as monotherapy for smaller bleeds and as an adjunct to surgery for larger bleeds. This proposal aims to inform the optimal delivery of IL-1Ra and test for evidence of biological effect in clinical ICH, paving the way for a definitive clinical trial.

Lay abstract: Inflammation is the body's response to injury, but after a stroke caused by bleeding into the brain it worsens damage and causes brain swelling. To better understand inflammation after bleeding in the brain, we will test fluid drained from brain blood clots in patients taking part in a trial of surgery. To know how best to give drugs to block inflammation after bleeding in the brain, we will see how leaky brain blood vessels are using brain scans. We will then test whether an inflammation blocking drug reduces brain swelling in patients who have had a stroke caused by bleeding.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE