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MACE-ICH trial

MAnnitol for Cerebral oEdema after IntraCerebral Haemorrhage

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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
  • 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
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