Mannitol for stopping or preventing brain swelling (cerebral oedema) after stroke from bleeding in the brain (intracerebral haemorrhage): a feasibility study

ISRCTN	ISRCTN15383301
DOI	https://doi.org/10.1186/ISRCTN15383301
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	2022-000283-22
Integrated Research Application System (IRAS)	1004870
Protocol serial number	22SR001, IRAS 1004870
Sponsor	Nottingham University Hospitals NHS Trust
Funder	Research for Patient Benefit Programme

Submission date: 05/10/2022
Registration date: 18/05/2023
Last edited: 18/09/2025

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Stroke from bleeding into the brain, known as intracerebral haemorrhage(ICH) affects about 15,000 adults in the UK each year and to-date there is no effective treatment. Brain swelling after ICH is common and can worsen damage resulting in disability or death. Large haemorrhages (~10-15%) cause brain swelling very quickly and the only option that is possible in some young patients is to do a major operation 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 ICH 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 ICH, but no definite study has been performed.
We want to test if it is possible to do a small study of mannitol in ICH to find out how acceptable and manageable it is to inform a larger study.

Who can participate?
Forty-five adult patients with ICH with or at risk of brain swelling from ten UK hospitals will be recruited within 72 hours after stroke.

What does the study involve?
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.
Participants will be monitored for side effects, urine output, 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 postal structured questionnaires. If a participant is unable to provide information, we will contact their relative/carer or GP.

What are the possible benefits and risks of participating?
Participation in this study may reduce the symptoms of intracerebral haemorrhage, reduce mortality, and may improve long-term recovery. We hope that the information we get will provide benefit to other people who have a stroke in the future.
Common side effects of mannitol are increased urination, nausea, vomiting, fever, chills, headache, runny nose, chest pain, rash, dizziness, or blurred vision. The drug can cause burning, pain or swelling around the needle when it is given as an injection and the treating team will closely monitor you for this.
Mannitol can affect the salt levels in the blood, cause damage to the kidneys, worsen bleeding in the brain, or lung congestion.
Because mannitol is already routinely used to reduce brain swelling from liver damage or severe head injury, we expect the potential benefits of the drug (stopping or preventing brain swelling in intracerebral haemorrhage) to outweigh the risk of side effects.

Where is the study run from?
Nottingham University Hospitals NHS Trust (UK)

When is the study starting and how long is it expected to run for?
October 2022 to November 2024

Who is funding the study?
NIHR Research for Patient Benefit Programme (UK)

Who is the main contact?
The email address for the CI requires updating to kailash.krishnan@nhs.net

Contact information

Dr Kailash Krishnan
Principal investigator

Nottingham University Hospitals NHS Trust
Derby Road
Nottingham
NG7 2UH
United Kingdom

Phone	+44 115 9249924
Email	kailash.krishnan@nhs.net

Dr MACE-ICH trial team
Public

Nottingham University Hospitals NHS Trust
Derby Road
Nottingham
NG7 2UH
United Kingdom

Phone	None available
Email	mace-ich@nottingham.ac.uk

Study information

Primary study design	Interventional
Study design	Interventional randomized parallel group controlled trial
Secondary study design	Randomised controlled trial
Scientific title	MAnnitol for Cerebral oEdema after IntraCerebral Haemorrhage (MACE-ICH): a feasibility trial
Study objectives	Primary objective: To assess the feasibility of screening, randomising, administering mannitol to acute intracerebral haemorrhage patients with cerebral oedema or at risk and completing follow-up to inform the design and conduct of an adequately powered, pragmatic, prospective, definitive trial. Secondary objective: To provide preliminary data on the effect of mannitol on secondary outcomes including clinical, radiological, laboratory, safety and health-economics.
Ethics approval(s)	Approved 10/05/2023, East Midlands - Leicester Central Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, UK; +44 207 104 8066; Leicestercentral.rec@hra.nhs.uk), ref: 22/EM/0242
Health condition(s) or problem(s) studied	Acute intracerebral haemorrhage (ICH)
Intervention	There are three arms in the MACE-ICH study, and patients are randomised into one of the arms via a 1:1:1 online, bespoke, randomisation system, built specifically for the purpose of the trial. The randomisation system will only be accessible for members of the research team who have been trained and delegated by their local Principal Investigator. The arms are as follows: 1. One dose of manntiol: Manntiol (1g/kg of 10% IV infusion at 10ml/min) + Standard care on Day 0; blood tests performed on day 1; CT head scan on day 5 (±2); day 28 follow-up by research team; day 180 follow-up by central trial office (MACE-ICH team based in Nottingham). 2. Two doses of mannitol: Manntiol (1g/kg of 10% IV infusion at 10ml/min) + Standard care on Day 0; blood tests performed on day 1; if blood tests, specifically serum osmolality, are stable then participants receive a second dose of mannitol (1g/kg of 10% IV infusion at 10ml/min); blood tests done again on day 2; day 28 follow-up by research team; day 180 follow-up by central trial office (MACE-ICH team based in Nottingham). 3. Standard care (e.g., at the clinician's discretion: IV fluids, nasogastric tube, other medications); blood tests performed on day 1; CT head scan on day 5 (±2); day 28 follow-up by research team; day 180 follow-up by central trial office (MACE-ICH team based in Nottingham).
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Mannitol
Primary outcome measure(s)	1. Number of patients: screened and eligible: collected on screening logs that are requested from sites on a monthly basis. 2. Number of eligible patients recruited and reasons for not recruiting: collected on screening logs that are requested from sites on a monthly basis. 3. Proportion of eligible patients who received allocated treatment and reasons for non-allocation: This can be retrieved from the bespoke MACE-ICH database, whenever it is needed. 4. Recruitment rate derived from the sample size: This can be retrieved from the bespoke MACE-ICH database, and this data can also be collected on screening logs that are requested from sites on a monthly basis. 5. Treatment adherence: This can be continuously monitored, throughout the duration of the trial, within the bespoke MACE-ICH database. 6. Retention rate (number of participants with complete follow-up data at 180 days as a proportion of those randomised): This can be continuously monitored, throughout the duration of the trial, within the bespoke MACE-ICH database. All completed follow-ups will be visible in the MACE-ICH bespoke database. 7. Number of patients with outcome data and reasons for non-availability: This data will be continuously monitored within the MACE-ICH bespoke database. Any reasons for missing data will be collected by the monitor. 8. Effectiveness of blinded follow-up: Day-180 follow-up data will be checked by the trial monitor. 9. Incidence and type of adverse events, protocol violations and trial withdrawal. This data will be continuously monitored within the MACE-ICH bespoke database, in conjunction with any adverse event/protocol violation logs that are available to monitor.
Key secondary outcome measure(s)	1. Laboratory tests (U&E’s; e-GFR; serum osmolality): measured on days 1 and 2 (day 2 only for patients randomised to receive two doses of mannitol) 2. Participants' levels of consciousness are measured using the Glasgow Coma Scale (GCS) on day 5+/-2, 3. Participants' stroke severity is measured using the National Institutes Health Stroke Scale (NIHSS) on day 5+/-2, 4. Number of patients who had urinary tract infection collected from medical records on day 5±2 and day 28, 5. Number of patients who had sepsis collected from medical records on day 5±2 and day 28, 6. Mortality collected from medical records on day 5±2 and day 28 7. Participants' disability is measured using the Barthel Index on day 180, 8. Participants' mood is measured using the Zung depression scale [ZDS] on day 180, 9. Participants' cognition is measured using the TICS-M assessment on day 180, 10. Participants' quality of life is measured using the Euro-[EQ] QOL and EQ-VAS, on day 180, 11. Health economic assessment is measured using the EQ-5D questionnaire on day 180, 12. Participants' death or dependency is measured using the modified Rankin scale (mRS) on day 180, 13. Participants' length of stay in hospital is collected from the participant on the day-180 telephone questionnaire, 14. Participants' discharge destination is collected from the participant on the day-180 telephone questionnaire, 15. Long-term outcomes post Covid-19 and ICH is collected from the participant on the day-180 telephone questionnaire, 16. Number of patients who were transferred to high dependency unit - this can be continuously monitored, throughout the duration of the trial, within the bespoke MACE-ICH database. 17. Number of patients needing high dependency or intensive care unit - this can be continuously monitored, throughout the duration of the trial, within the bespoke MACE-ICH database. 18. Number of patients undergoing neurosurgical intervention - this can be continuously monitored, throughout the duration of the trial, within the bespoke MACE-ICH database. 19. Participants' recurrent strokes (if applicable) data will be collected throughout the trial by sites completing SAE reporting forms. 20. Number of patients intubated and ventilated - his can be continuously monitored, throughout the duration of the trial, within the bespoke MACE-ICH database. 21. The Follow-up CT scan on day 5±2 days will assess changes in oedema volume, oedema extension distance, haematoma volume, midline shift and hydrocephalus. 22. Safety Outcomes: All safety outcomes (e.g. death; thrombophlebitis; hyper/hyponatremia; pulmonary oedema; hypotension; renal impairment and serious adverse events) will be continuously reported and recorded until day 180.
Completion date	30/11/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	45
Total final enrolment	46
Key inclusion criteria	1. Adults (>18 years); spontaneous ICH confirmed by CT scan with estimated largest diameter > 2 cm; 2. </= 72 hour of ictus (or from last seen healthy); 3. Cerebral oedema with or without evidence of mass effect; 4. At risk of developing oedema (limited GCS <9 (eye opening and motor only) and NIHSS>/=8); 5. Signed consent (patient, personal or professional representative or independent physician)
Key exclusion criteria	1. GCS<5; premorbid mRS >3; 2. Isolated subarachnoid haemorrhage; 3. 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; 4. Known hypersensitivity to mannitol; 5. Severe renal failure (e-GFR<30ml/min or dialysis); 6. Cardiac failure; 7. Hypotension at baseline (SBP <90 mm Hg); 8. Anuria; 9. Patient unwilling to participate; 10. Geographical or other factors which prohibit follow-up; 11. Pre-existing comorbidity with pre-ictal life expectancy <6 months; 12. Severe dementia; 13. Planned for palliative care; 14. Severe hypernatremia (sodium >160 mmol); 15. Severe hyponatremia (sodium <125 mmol); 16. Women of child-bearing age with a positive pregnancy test at the time of admission or lactating; 17. Patients in whom peripheral intravenous cannula cannot be placed; 18. Planned neurosurgery
Date of first enrolment	14/02/2024
Date of final enrolment	15/04/2025

Locations

Countries of recruitment

United Kingdom

Study participating centres

Queen's Medical Centre

Nottingham University Hospitals NHS Trust
Derby Road
Nottingham
NG7 2UH
United Kingdom

Royal Derby Hospital

University Hospitals of Derby and Burton NHS Foundation Trust
Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Yeovil District Hospital

Yeovil District Hospital NHS Foundation Trust
Higher Kingston
Yeovil
BA21 4AT
United Kingdom

Addenbrooke's Hospital

Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Royal London Hospital

Whitechapel
London
E1 1BB
United Kingdom

Royal Devon and Exeter Hospital

Royal Devon and Exeter NHS Hospital Foundation Trust
Barrack Road
Exeter
EX2 5DW
United Kingdom

Royal Stoke University Hospital

Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom

Queen Elizabeth University Hospital

1345 Govan Road
Glasgow
G51 4TF
United Kingdom

Aberdeen Royal Infirmary

Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

University Hospital of North Tees

Hardwick Road
Stockton-on-tees
TS19 8PE
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. We use bespoke, secure, encrypted systems, that are only accessible by members/coordinators in the central research team. All individuals who have access will be approved and delegated by local PI/CI. One system will store patients' data, including contact details, addresses and next-of-kin contact details (required for the day 180 follow-up). To access this system, users must be using the University of Nottingham network, or be connected to the University of Nottingham VPN. The other bespoke database will store all of the data collected for the day 0, day 1-2, day 5 +/-2, day 28 and day 180 assessments. There is currently no weblink for these sites as they are still in development, however we have used almost-identical systems for our other stroke clinical trials in Nottingham. Data will be available until the trial is complete; all data will be stored and archived after trial completion, in compliance with the University of Nottingham’s archiving procedures. Patients that fit the eligibility criteria will provide informed consent, however consent may also be sought from a legal representative if the patient lacks capacity to consent themselves. All un-anonymised consent forms will be uploaded to the secure bespoke system, and will only be accessible by a select few members of the central trial team in Nottingham (for monitoring purpose only). Any other documents uploaded for the purposes of monitoring will have all patient identifiers removed, in accordance with GCP. A unique ID number will be provided for each patient that is randomised into the trial.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article		28/07/2025	29/07/2025	Yes	No
HRA research summary			20/09/2023	No	No
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

18/09/2025: Sponsor email updated.
29/07/2025: Publication reference added.
11/06/2025: The following changes were made to the trial record:
1. Sponsor details updated.
2. Contact details updated.
3. The plain English summary was updated to reflect these changes.
08/05/2025: The following changes were made to the trial record:
1. The recruitment end date was changed from 27/05/2025 to 15/04/2025.
2. The total final enrolment was added.
04/04/2025: The recruitment end date was changed from 15/04/2025 to 27/05/2025. The overall study end date was changed from 30/08/2024 to 30/11/2025.
27/08/2024: The recruitment end date was changed from 04/03/2024 to 15/04/2025.
15/05/2024: The recruitment start date was changed from 01/12/2022 to 14/02/2024.
20/09/2023: A link to the HRA research summary was added.
19/06/2023: The following changes have been made to the study record:
1. The study email address was changed and the plain English summary was updated accordingly.
2. The study website was added.
05/10/2022: Trial's existence confirmed by NHS HRA.