Title

Acronym

Chief investigator

Objectives

Trial configuration

Setting

Sample size estimate

Number of participants

Eligibility criteria

• 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

Randomisation and blinding

Outcome measures

• 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

• 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)

• Death
• Thrombophlebitis
• Hypernatremia/hyponatremia
• Pulmonary oedema
• Hypotension
• Renal impairment
• Serious Adverse Events until day 180

Statistical methods