Title: MAnnitol for Cerebral oEdema after IntraCerebral Haemorrhage (MACE-ICH): a feasibility trial
Funder: Department of Health and Social Care

Abstract: Background Cerebral oedema complicates intracerebral haemorrhage (ICH) and in large strokes is associated with increased risk of death or disability through brain herniation and secondary brain injury. Although decompressive hemicraniectomy could be life-saving, there is limited evidence for surgical treatment in ICH. Mannitol, an osmotic diuretic, is readily available and easy to administer intravenously. It is licensed to treat cerebral oedema and used in traumatic brain injury and hepatic encephalopathy. Mannitol is known to reduce blood viscosity, facilitating flow and oxygen delivery to the brain. Little is known about its effects in ICH so well- designed clinical trials are needed. Aim To perform a prospective, randomised, open-label, blinded-endpoint, feasibility trial of intravenous mannitol in ICH patients with oedema or at risk to inform a definitive trial Objectives Is it feasible to: recruit, randomise and treat patients with ICH oedema or at risk 72 hours of onset? deliver the protocol and is it acceptable to participants? collect preliminary safety data of mannitol? obtain clinical and radiological data during and after treatment? follow-up participants and collect proposed outcomes? identify barriers and facilitators to participant recruitment and retention? obtain feedback on trial methodology? Methods Setting Ten UK hospitals providing acute stroke services Participants Inclusion criteria Adults (>18 years) ICH confirmed by CT scan 72 hours of onset Cerebral oedema with or without mass effect at baseline or subsequent scan or at risk (GCS >8) neurosurgery not imminent signed consent Intervention Patients will be randomised 1:1:1 to one of three groups: 1 g/kg 10% single dose mannitol infusion at 10 ml/min 1 g/kg 10% mannitol at 10 ml/min followed by a second dose 1 g/kg repeated at 24 hours standard care alone Feasibility outcomes: Number of patients: Screened and those eligible Eligible recruited and reasons for not recruiting Proportion of eligible patients who received allocated treatment and reasons for non-allocation Recruitment rate Treatment adherence Retention rate Number of patients with outcome data and reasons for non-availability Incidence and type of adverse events, protocol violations, trial withdrawal The following variables are expected to inform a definitive trial: Laboratory: U&E s; e-GFR; serum osmolarity to correlate response to mannitol Day 2-7: GCS, NIHSS; death Day 5-7: follow-up CT brain to assess changes in oedema volume, oedema extension distance, haematoma volume, midline shift Day 28 mortality Day 180 (blinded follow-up): death or dependency; disability; mood; cognition; quality of life; length of stay; discharge destination Number of patients: needing high dependency or intensive care unit; undergoing neurosurgery Recurrent stroke Safety: death; thrombophlebitis; acute kidney injury; hyper/hyponatremia; pulmonary oedema; hypotension The long-term neurological sequelae associated with Covid-19 will be collected and factored into analysis. Comparisons will be made between each group assigned to mannitol plus standard care versus standard care alone. Trial duration: 2 years The results will be disseminated via: peer-reviewed journals scientific meetings our PPI network and social media The progression criteria to a definitive trial will use a red-amber-green strategy based on recruitment and retention together with feedback from performance reviews.

Lay abstract: Stroke from bleeding into the brain, known as intracerebral haemorrhage affects about 15,000 adults in the UK each year and to-date there is no effective treatment. Brain swelling after intracerebral haemorrhage is common and can worsen damage resulting in disability or death. Large strokes (~10-15%) cause brain swelling very quickly and the only option that is possible in some young patients is to do a major operation, remove part of the skull and make more space for the brain to expand. It is unclear whether surgery is beneficial and the operation has its own risks. So, finding treatments which prevent or stop brain swelling after intracerebral haemorrhage could reduce death or disability. Mannitol is a widely available drug and as an injection through a vein can reduce brain swelling after severe head injury or liver damage. It is cheap and easy to give. Small studies suggest that mannitol may also reduce brain swelling after intracerebral haemorrhage, but no definite study has been performed. We want to test if it is possible to do a small study of mannitol in intracerebral haemorrhage to find out how acceptable, safe and manageable it is to inform a larger study. Forty-five adult patients with intracerebral haemorrhage with or at risk of brain swelling from ten UK hospitals will be recruited within 72 hours after stroke. Using a computer, participants will be allocated like the roll of a dice to one of three groups: single mannitol injection, two mannitol injections or standard medical care alone. If patients are unable to give permission to take part (consent), we will approach their relative/carer or an independent doctor to include them into the study unless there is a reason not to. Participants will be monitored for side effects, undergo blood tests and clinical assessments during and after treatment. We will do a repeat brain scan 5-7 days after treatment to see whether mannitol has reduced brain swelling. At 6 months, information on survival, participant s quality of life, mood, memory, disability and health problems in those who had Covid will be collected through telephone or postal structured questionnaires. If a participant is unable to provide information, we will contact their relative/carer or GP. We discussed this research with the Nottingham Stroke Research Partnership group, comprising stroke survivors and their carers. They fully support this study and their ideas have helped to develop this proposal. If successful, patient representatives and members of the public have agreed to help us run this study and advise on how best to improve. The results will be communicated through medical journals, presentations at stroke meetings, the internet and social media. A plain language summary of the results will be given to participants and carers.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE