MACE-ICH

Title	MAnnitol for Cerebral oEdema after IntraCerebral Haemorrhage (MACE-ICH)
Acronym	MACE-ICH
Chief investigator	Dr Kailash Krishnan
Objectives	To determine the feasibility of screening, assessing eligibility, approaching potential participants, randomisation, administering mannitol and completing follow-up for acute haemorrhagic stroke patients with cerebral oedema, or at risk of cerebral oedema, to inform a definitive trial. To determine the feasibility and inform the design and conduct of an adequately powered, pragmatic, prospective multi-centre RCT testing mannitol as a treatment for cerebral oedema in spontaneous ICH.
Trial configuration	A multicentre, prospective, randomised, open-label, blinded-endpoint trial.
Setting	Ten UK, NHS hospitals providing acute stroke services.
Sample size estimate	This is a feasibility trial so there is no formal sample size calculation. It is likely that a planned target of 45 participants with high rates of adherence to treatment and follow-up data would inform a definite trial. Lower recruitment would not preclude progression if there is evidence that barriers to recruitment could be overcome.
Number of participants	45
Eligibility criteria	Inclusions Adults aged 18 and above Spontaneous ICH confirmed by CT scan with estimated largest diameter over 2 cm Within 72 hours of ictus (or from last seen healthy) Cerebral oedema with or without evidence of mass effect at baseline or subsequent scanning At risk of developing cerebral oedema limited GCS score less than 9 (eye opening and motor only) and NIHSS total of 8 or above Signed consent – patient, personal or professional legal representative Exclusions GCS less than 5 Premorbid mRS of 4 or 5 Isolated subarachnoid haemorrhage Haemorrhage known to be from: trauma or venous thrombosis or arteriovenous malformation or brain tumour or transformation of cerebral infarct or cerebral aneurysm or thrombolytic drug Known hypersensitivity to mannitol Severe renal failure (e-GFR under 30ml/min or dialysis) Cardiac failure Hypotension at baseline (systolic BP under 90 mm/Hg) Anuria Patient unwilling to participate Geographical or other factors which prohibit follow-up Pre-existing comorbidity with pre-ictal life expectancy under 6 months Severe dementia Planned for palliative care Severe hypernatraemia (sodium over 160 mmol) Severe hyponatraemia (sodium under 125 mmol) Women of child-bearing potential with a positive pregnancy test at the time of admission or lactating Patients in whom peripheral intravenous cannula cannot be placed Planned neurosurgery
Description of interventions	1 g/kg 10% single dose mannitol infusion at 10 ml/min, in addition to standard care. 1 g/kg 10% mannitol at 10 ml/min followed by a second dose 1 g/kg repeated at 24 hours, if the serum osmolality is under 320 mOsm/kg and sodium under 160 mEq/L after the first dose, in addition to standard care. Standard care only.
Duration of study	Follow-up duration: 6 months from enrolment. Planned trial period: 24 months.
Randomisation and blinding	Randomisation will be to one dose of mannitol vs two doses of mannitol vs standard care in a 1:1:1 ratio. Randomisation will be performed by the stroke trials unit (STU), University of Nottingham, with computerised minimisation on key prognostic factors: age, limited GCS, time from stroke onset and largest haemorrhage diameter. Outcome assessors will be masked to treatment allocation.
Outcome measures	Feasibility outcomes (primary outcomes) Number of patients: screened and eligible Number of eligible patients recruited and reasons for not recruiting Proportion of eligible participants who received allocated treatment and reasons for non-allocation Recruitment rate Treatment adherence Retention rate Number of participants with outcome data and reasons for non-availability Effectiveness of blinded follow-up Incidence and type of adverse events, protocol violations and trial withdrawal Secondary outcomes Laboratory (day 1-2) U+Es e-GFR Serum osmolality to correlate response to mannitol Glasgow Coma Scale (GCS) (day 5±2 days) NIH Stroke Scale (NIHSS) (day 5±2 days) Number of participants who had urinary tract infection (day 5±2 days, day 28) Number of participants who had sepsis (day 5±2 days, day 28) Mortality (day 5±2 days, day 28) Disability (Barthel Index, day 180) Mood (Zung depression scale [ZDS], day 180) Cognition (TICS-M day 180) Quality of life (EQ-5D; EQ-VAS, day 180) Health economic assessment (EQ-5D, day 180) Death or dependency (modified Rankin scale, day 180) Length of stay (day 180) Discharge destination (day 180) Long-term outcomes post COVID-19 and ICH (day 180) Number of participants who were transferred to high dependency unit Number of participants needing high dependency or intensive care unit Number of participants undergoing neurosurgical intervention Recurrent stroke Number of participants intubated and ventilated Mechanistic Follow-up CT scan to assess changes in oedema volume, oedema extension distance, haematoma volume, midline shift, hydrocephalus (day 5±2 days) Safety outcomes Death Thrombophlebitis Hypernatremia/hyponatremia Pulmonary oedema Hypotension Renal impairment Serious Adverse Events until day 180
Statistical methods	Analysis will primarily be descriptive to address the feasibility objectives of the trial. A full statistical analysis plan (SAP) will be finalised prior to database lock.

Contact details
Address:	Room S/D2105 Stroke Trials Unit School of Medicine University of Nottingham Queen's Medical Centre Derby Road Nottingham NG7 2UH United Kingdom Tel: 0115 823 1782
Email:

MACE-ICH trial

MAnnitol for Cerebral oEdema after IntraCerebral Haemorrhage