Condition category
Injury, Occupational Diseases, Poisoning
Date applied
09/04/2019
Date assigned
16/04/2019
Last edited
06/08/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Over one million people a year suffer injuries to their heads which require them to go to hospital. The most severe injuries often result in significant brain swelling. If left untreated, this swelling causes the pressure inside the head to increase, compressing the brain and causing further brain damage. The main treatments used for severe brain swelling involve placing the patient into an artificial coma (to rest the brain), giving drugs (to reduce brain swelling) or brain surgery (to release the pressure). Even with current treatments delivered in intensive care, over half of people with severe brain injury die or are left with severe brain damage. To improve outcomes for patients, doctors need to know the best treatments for severe brain swelling after head injuries. The two main drugs that are currently used to treat brain swelling are hypertonic saline (a strong salt solution) and mannitol (a sugary solution). Both of these drugs work by reducing brain swelling which helps to reduce pressure on the brain. Currently, it is not known which drug is the most effective treatment. Both drugs have undesirable side effects (hypertonic saline causes an imbalance of salts in the blood and mannitol can cause kidney failure). To deliver the best treatment doctors need to know which is most the safest and most effective. The aim of this study is to work out which is the safest and most effective drug to treat the swelling of the brain that occurs after severe trauma to the head.

Who can participate?
Patients aged 16 or over admitted to an intensive care unit with a traumatic brain injury (an injury to the brain which occurs after trauma to the head)

What does the study involve?
Participants are randomly allocated to receive either the salty solution (hypertonic saline) or the sugary solution (mannitol). The study compares how effective the different drugs are at reducing the pressure on the brain. It also assesses which was better at helping the patient to recovery and what the side effects of treatment were. The study team keeps in contact with patients for 12 months after the study to check on how well they have recovered over time. Researchers also calculate how much each treatment costs and compare this to how beneficial they were.

What are the possible benefits and risks of participating?
Doctors do not know which of the two treatments is best, and that is why we are conducting this research. The researchers therefore cannot promise any direct benefits as a result of taking part in this study. However, it is hoped that the research will provide benefit to future patients who have a severe brain injury, as it will help doctors to know which is the best treatment to give. The risk of physical harm from taking part in the study is not considered to be any higher than the risks of standard clinical care, because the study is testing two existing treatments rather than a new treatment. Because the study involves completing questionnaires, there is a risk that participants may find it upsetting to answer some questions about their recovery. Trained research staff are available to talk to participants about any such feelings and can offer to put them in contact with professional services if this would be helpful.

Where is the study being run from?
Queen Elizabeth Hospital - University Hospitals Birmingham NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
June 2019 to December 2023

Who is funding the study?
National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (UK)

Who is the main contact?
University of Warwick study team
sostrial@warwick.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Gavin Perkins

ORCID ID

Contact details

Warwick Clinical Trials Unit
University of Warwick
Gibbet Hill Road
Coventry
CV4 7AL
United Kingdom
+44 (0)2476150479
sostrial@warwick.ac.uk

Type

Public

Additional contact

Ms Louisa Hamilton

ORCID ID

Contact details

Warwick Clinical Trials Unit
University of Warwick
Gibbet Hill Road
Coventry
CV4 7AL
United Kingdom
+44 (0)2476151738
sostrial@warwick.ac.uk

Additional identifiers

EudraCT number

2019-001688-66

ClinicalTrials.gov number

Nil known

Protocol/serial number

17/120/01

Study information

Scientific title

Sugar or Salt (SOS) Trial: hyperosmolar therapy in traumatic brain injury

Acronym

SOS

Study hypothesis

The primary hypothesis is that hypertonic saline is more effective than mannitol in the management of raised ICP after severe TBI through improving clinical outcomes and cost-effectiveness.

Ethics approval

Ethics approval information added 23/09/2019:
Approved 09/09/2019, East of England – Essex Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; +44 (0)207 104 8115), ref: 19/EE/0228

Study design

Multicentre open-label randomized controlled clinical and cost-effectiveness trial with an internal pilot

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Traumatic brain injury

Intervention

Current interventions as of 10/06/2019:
A simple and secure, web-based and allocation concealed randomisation system will be used. Randomisation will be stratified by site and predicted probability of 6-month unfavourable outcome. This predicted probability will be calculated using age, pupillary response and documented Glasgow Coma Scale (GCS) motor score at intubation using the IMPACT calculator (Steyerberg et al, 2008).

Patients will be randomized in a 1:1 ratio to receive intravenous boluses of either 2 ml/kg 20% mannitol or 2 ml/kg hypertonic saline (or equivalent osmolar dose using concentration used locally by participating study centres).

If intracranial pressure (ICP) remains higher than 20mmHg, boluses of each treatment can be repeated until serum sodium is >155 mmol/L. If there is a second spike in ICP over 20 mmHg then the allocated IMP should continue to be used.

Trial treatment will continue until therapeutic targets have been met. The total duration of follow-up for both treatment arms will be 12 months.


Previous interventions:
A simple and secure, web-based and allocation concealed randomisation system will be used. Randomisation will be stratified by site and predicted probability of 6-month unfavourable outcome. This predicted probability will be calculated using age, pupillary response and documented Glasgow Coma Scale (GCS) motor score at intubation using the IMPACT calculator (Steyerberg et al, 2008).

Patients will be randomized in a 1:1 ratio to receive intravenous boluses of either 2 ml/kg 20% mannitol or 2 ml/kg hypertonic saline (or equivalent osmolar dose using concentration used locally by participating study centres).

If intracranial pressure (ICP) remains high, boluses of each treatment can be repeated until either ICP is less than 20 mmHg or serum sodium is >155 mmol/L or osmolarity is >320 mosmol/L. If there is a second spike in ICP over 20 mmHg then the allocated IMP should continue to be used.

Trial treatment will continue until therapeutic targets have been met. The total duration of follow-up for both treatment arms will be 12 months.

Intervention type

Drug

Phase

Phase III

Drug names

Mannitol, hypertonic saline

Primary outcome measure

Neurological outcome measured by patient/relative/clinician completion of the Extended Glasgow Outcome Scale (GOS-E) questionnaire at 6 months

Secondary outcome measures

1. Intracranial pressure (ICP) control recorded continuously or at regular intervals from ICP bolt readings during the period of monitoring on ICU
2. Progression to stage 3 therapies (i.e. any use of additional treatments e.g. barbiturate coma, decompressive craniectomy, hypothermia, CSF drainage) recorded from the patient’s medical records during their ICU stay
3. Which stage 3 therapies were required, recorded from the patient’s medical notes during their ICU stay
4. Organ support requirements during ICU recorded from the patient’s medical records, or through data linkage, according to the Critical Care Minimum Data Set definitions
5. ICU length of stay obtained from hospital records and through data linkage
6. Hospital length of stay obtained from hospital records and through data linkage
7. Discharge location obtained from hospital records and through data linkage
8. Longer term neurological outcomes measured using the modified Oxford Handicap Score (mOHS) completed by the research or clinical team at hospital discharge, and the Extended Glasgow Outcome Scale (GOS-E) completed by the patient/relative/clinician at 12 months
9. Survival measured from the patient’s medical records at hospital discharge, 3 months, 6 months and 12 months
10. Health-related quality of life measured using the EQ-5D-5L at hospital discharge, 3 months, 6 months and 12 months post-TBI, completed by the patient/relative/clinician
11. Resource use collected from hospital records and through data linkage for the patient’s duration of hospital stay and up to 12 months post-TBI
12. Serious adverse events recorded from the time that the patient is randomised through and including 28 calendar days after the last administration of IMP

Overall trial start date

01/06/2019

Overall trial end date

01/12/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Age 16 years or over
2. Admission to ICU following traumatic brain injury
3. ICP > 20mmHg for more than 5 minutes despite stage 1 procedures
4. <10 days from initial head injury
5. Abnormal CT scan consistent with traumatic brain injury

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

638

Participant exclusion criteria

Current participant exclusion criteria as of 06/08/2020:
1. Devastating brain injury with withdrawal of treatment anticipated in the next 24 hours
2. Pregnancy
3. Severe hypernatraemia (Na > 155 mmol/L)

Previous participant exclusion criteria from 10/06/2019 to 06/08/2020:
1. Devastating brain injury with withdrawal of treatment anticipated in the next 24 hours
2. Pregnancy
3. Severe hypernatraemia (Na > 160 mmol/L)

Original participant exclusion criteria:
1. Unsurvivable injuries
2. Pregnancy
3. Severe hypernatraemia (Na > 160 mmol/L)

Recruitment start date

01/12/2019

Recruitment end date

01/12/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Queen Elizabeth Hospital - University Hospitals Birmingham NHS Foundation Trust
Heritage Building Mindelsohn Way Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

John Radcliffe Hospital
Oxford University Hospitals NHS Foundation Trust Headley Way Headington
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Salford Royal Hospital
Salford Royal NHS Foundation Trust Stott Lane
Salford
M6 8HD
United Kingdom

Trial participating centre

Derriford Hospital
University Hospitals Plymouth NHS Foundation Trust Derriford Rd
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

The Walton Centre NHS Foundation Trust
Lower Lane Fazakerley
Liverpool
L9 7LJ
United Kingdom

Trial participating centre

Southampton General Hospital
University Hospital Southampton NHS Foundation Trust Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Royal Victoria Hospital
Belfast Health & Social Care Trust Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Trial participating centre

King’s College Hospital
King’s College Hospital NHS Foundation Trust Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
NHS Lothian Little France Cres
Edinburgh
EH16 4SA
United Kingdom

Sponsor information

Organisation

University Hospitals Birmingham NHS Foundation Trust

Sponsor details

Research and Development Directorate
Office 18
Education Centre
Queen Elizabeth Hospital Birmingham
Mindelsohn Way
Edgbaston
Birmingham
B15 2WB
United Kingdom
+44 (0)121 371 4185
sarah.pountain@heartofengland.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.uhb.nhs.uk/

Organisation

University of Warwick

Sponsor details

Research and Impact Services
University House
University of Warwick
Coventry
CV4 8UW
United Kingdom
+44 (0)2476 575 732
Sponsorship@warwick.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The trial protocol and statistical analysis plan will be available once finalised.

The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial co-ordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration.

The success of the trial depends on the collaboration of doctors, nurses and researchers from across the UK. Equal credit will be given to those who have wholeheartedly collaborated in the trial. The trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines (http://www.consort-statement.org).

The researchers will continue to build links with key stakeholder groups (e.g. UK Intensive Care Society, Society of British Neurological Surgeons, Neuroanaesthesia and Critical Care Society of Great Britain and Ireland, Patient/Public Involvement Groups etc). They will continue to publish editorials and review articles related to hyperosmolar therapy use in TBI. The purpose of these activities is to highlight the uncertainty of current treatment with hyperosmolar therapy and to generate and sustain interest from the clinical community so that the trial results will be eagerly anticipated. The researchers will publish the trial protocol and final trial results in high impact, open access peer-reviewed journals. The results of the trial will be reported first to trial collaborators. The main report will be drafted by the WCTU team, and the final version will be agreed by the TSC before submission for publication, on behalf of the collaboration. The trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The main publications will be the report to the funding body (HTA Monograph) and a journal publication. In addition, the results will be presented at national and international medical conferences as well as disseminated via social media (Twitter/Facebook) and blog postings. This will ensure that the results are communicated rapidly to clinicians who will then be able to put them into practice.

The researchers will aim to incorporate the results into national and international TBI guidelines via existing guideline development groups, which include several of the applicants (Hutchinson/Kolias/Andrews). They will incorporate the findings of the trial into relevant review articles and ensure the findings of the trial are available through NHS Evidence. They will work with our Marketing and Communication team to develop a strategy for communication with the media (television, radio, newspaper etc) to enhance communication of the trial results to patients and participants. They will produce a lay summary of the trial results with their public and patient involvement partners. This will be disseminated through our press officer, user groups, websites and INVOLVE database to participants of the trial who indicated they wanted to know the results.

The researchers expect the output from this trial will impact international TBI practice and they will ensure that the results of this trial are fed into the Brain Trauma Foundation and European Society of Intensive Care Medicine evidence assessment and guideline process. Finally, a policy for authorship of trial publications will be drafted and agreed by the investigators early in the trial, in accordance with the WCTU Standard Operating Procedures.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/12/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

2020 protocol in https://doi.org/10.1177/1751143720901690 (added 06/08/2020)

Publication citations

Additional files

Editorial Notes

06/08/2020: The following changes were made to the trial record: 1. Recruitment to this study is no longer paused. 2. Contact details updated. 3. The exclusion criteria were updated. 4. Publication reference added. 5. John Radcliffe Hospital, Salford Royal Hospital, Derriford Hospital, The Walton Centre NHS Foundation Trust, Southampton General Hospital, Royal Victoria Hospital, King’s College Hospital and Royal Infirmary of Edinburgh were added as trial participating centres. 21/05/2020: Due to current public health guidance, recruitment for this study has been paused. 23/09/2019: The ethics approval information has been added. 10/06/2019: The interventions and participant exclusion criteria have been updated. 16/04/2019: Trial's existence confirmed by the NIHR.