Clinical Randomisation of an Antifibrinolytic in Significant Head injury (CRASH-3)

ISRCTN	ISRCTN15088122
DOI	https://doi.org/10.1186/ISRCTN15088122
ClinicalTrials.gov (NCT)	NCT01402882
Clinical Trials Information System (CTIS)	2011-003669-14
Protocol serial number	PACTR20121000441277
Sponsor	London School of Hygiene and Tropical Medicine (UK)
Funders	London School of Hygiene and Tropical Medicine, J P Moulton Charitable Foundation (UK)

Submission date: 28/06/2011
Registration date: 19/07/2011
Last edited: 06/11/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Injury, Occupational Diseases, Poisoning

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Worldwide, about 10 million people die or are hospitalised following a sudden head injury. Bleeding into the brain at the time of injury, which can continue many hours afterwards, is associated with increased rates of death and disability. It is important to find better ways of treating patients who bleed into the brain after a head injury. A drug called tranexamic acid has been shown to reduce death from bleeding after other types of traumatic injury. In addition, it is often used to reduce bleeding after major surgery such as heart operations. The CRASH-3 study is being done to see if tranexamic acid can improve outcomes for people after traumatic brain injury. The main outcome we will assess is the effect on the number of people who die from this injury. Other important outcomes will also be assessed such as its effect on disability and complications.

Who can participate?
Adults within three hours of a head injury can take part in the CRASH-3 trial. Patients with significant bleeding outside of the head cannot take part. We plan to study 13,000 patients worldwide.

What does the study involve?
Patients with this problem will be admitted to hospital. Because this bleeding is an emergency situation, doctors will need to decide very quickly whether a patient is suitable for the trial or not (usually as soon as possible after the problem is identified). Brief information will be collected on an entry form to see if a patient is suitable. In this emergency situation it is difficult for patients to give written informed consent to take part. We will therefore ask the ethics committee for permission to put patients into the trial without written consent but where possible will get agreement from patients and relatives first, and we will explain to patients later what happened to them and how the information from the trial will be used. We have asked the opinions of members of the public about this and they agree that this is the only way we can do good research on life-threatening emergency problems. Everyone will get all the treatments that doctors usually give for this condition. In addition, they will get the trial treatment by an intravenous infusion (drip) for about 8 hours. Half of the patients will receive tranexamic acid and the other half a dummy medicine called a placebo. To make sure that the two groups are the same apart from tranexamic acid, we will decide who gets tranexamic acid and who gets placebo using a computer programme, a modern equivalent of the toss of a coin (this is called randomisation). We will collect some information on the progress of patients and whether they have any side effects for up to 28 days after they receive treatment. Brain scan (CT Scan) are usually done routinely on admission to hospital in patients who are part of this trial to check for bleeding or any other damage. Scans are repeated whenever the doctors want to check the progress of a patient. We will collect information about bleeding and clotting from these routine scans in about 1000 patients who are part of the trial. This will provide information on how the drug tranexamic acid works.

What are the possible benefits and risks of participating?
We hope that tranexamic acid will help reduce the number of patients who die from this condition without increasing disability. The knowledge that we gain from this study will help other people with head injury in the future. Tranexamic acid is not a new drug. It has been used for years to reduce bleeding after operations and heavy menstruation and more recently to treat other types of serious injury. It works by stopping the breakdown of the blood clots which are needed to control bleeding. Studies have shown that it does not cause unwanted clotting and there are no serious side effects with short term use. However, patients will be monitored closely and doctors will report to the study organisers if there are any unexpected problems.

Where is the study run from?
The CRASH-3 trial is organised by the London School of Hygiene and Tropical Medicine (UK) and will involve hundreds of doctors and nurses worldwide.

When is the study starting and how long is it expected to run for?
September 2011 to January 2020

Who is funding the study?
The JP Moulton Charitable Trust, United Kingdom is funding the initial costs for this trial and the recruitment of up to 500 participants. Full funding for the main trial is provided by the Joint Global Health Trials scheme which is coordinated by provided by the United Kingdom’s National Institute for Health research -Health Technology Assessment (HTA) Programme and the Medical research Council.

Who is the main contact?
Ms Haleema Shakur
crash@lshtm.ac.uk

Contact information

Prof Ian Roberts
Scientific

Clinical Trials Unit
London School of Hygiene and Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom

Email	crash@lshtm.ac.uk

Study information

Primary study design	Interventional
Study design	Large pragmatic randomised double-blind placebo-controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Tranexamic acid for the treatment of significant traumatic brain injury: an international randomised, double blind placebo controlled trial
Study acronym	CRASH-3
Study objectives	The CRASH-3 trial will provide reliable evidence about the effect of tranexamic acid on mortality and disability in patients with traumatic brain injury. The effect of tranexamic acid on the risk of vascular occlusive events and seizures will also be assessed. Protocol can be found at: http://crash3.lshtm.ac.uk/index.php/about/protocol/ Added 20/12/2016: CRASH-3 Intracranial Bleeding Sub-study (CRASH-3 IBS) The CRASH-3 IBS is nested in a cohort of CRASH-3 trial participants and aims to examine the effect of tranexamic acid on intracranial haemorrhage and cerebral ischaemia in a sample of CRASH-3 trial participants. Approximately 1,000 patients in the CRASH-3 trial, across several centres, will have their pre- and post-randomisation computed tomography scans examined for evidence of intracranial haemorrhage, cerebral ischaemia and other computed tomography endpoints. The hypothesis is that the administration of tranexamic acid will reduce intracranial haemorrhage volume in patients with traumatic brain injury.
Ethics approval(s)	LSHTM has approved the trial as the lead institution on 17/11/2011 (ref: 6060). All sites taking part will have the relevant approvals before recruitment starts.
Health condition(s) or problem(s) studied	Traumatic Brain Injury
Intervention	1. Tranexamic acid versus placebo 2. Patients will be randomised to either tranexamic acid (loading dose 1 gram over 10 minutes then infusion of 1 gram over 8 hours) or matching placebo Added 20/12/2016: CRASH-3 Intracranial Bleeding Sub-study (CRASH-3 IBS) Information about bleeding and clotting from routine CT scans is collected in about 1000 patients who are part of the trial. This will provide information on how the drug tranexamic acid works.
Intervention type	Drug
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Tranexamic acid
Primary outcome measure(s)	Death in hospital within 28 days of injury (Added 22/01/2018: among patients randomised within 3 hours of injury) (cause of death will be described) Added 20/12/2016: CRASH-3 IBS primary outcome: The primary outcome is the total volume of intracranial haemorrhage after randomisation, adjusting for the baseline volume of haemorrhage.
Key secondary outcome measure(s)	1. Vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, clinical evidence of deep vein thrombosis) 2. Disability assessed using the Disability Rating Scale and Patient Orientated Outcomes 3. Seizures 4. Neurosurgical intervention 5. Days in intensive care 6. Other adverse events will be described Added 20/12/2016: CRASH-3 IBS secondary outcome: Secondary outcomes will include: frequency of progressive haemorrhage (number of patients with a post-randomisation CT scan with total haemorrhage volume of more than 25% of the volume of the pre-randomisation scan); frequency of delayed haemorrhage (number of patients with haemorrhage on the post-randomisation CT scan when there was not one on the pre-randomisation scan); new focal ischaemic lesions (ischaemic lesions which appear on the post-randomisation CT scan but not on the pre-randomisation scan); total volume of intracranial bleeding after randomisation in patients who undergo surgical evacuation of haemorrhage, adjusting for volume of baseline bleeding.
Completion date	31/08/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	13000
Total final enrolment	12737
Key inclusion criteria	1. Adult 2. Traumatic brain injury 3. Within 8 hours of injury (Added 22/01/18: limited to within 3 hours from September 2016) 4. Any intracranial bleeding on CT scan OR a GCS of 12 or less 5. No significant extra-cranial haemorrhage 6. Where the responsible clinician is substantially uncertain as to the appropriateness of antifibrinolytic agents in the patient
Key exclusion criteria	The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular patient with traumatic brain injury
Date of first enrolment	01/12/2011
Date of final enrolment	31/01/2019

Locations

Countries of recruitment

United Kingdom
England
Afghanistan
Albania
Cambodia
Cameroon
Canada
Colombia
Egypt
El Salvador
Georgia
Indonesia
Iraq
Ireland
Italy
Jamaica
Kenya
Malaysia
Mexico
Myanmar
Nepal
Nigeria
Pakistan
Papua New Guinea
Romania
Spain
United Arab Emirates
Zambia

Study participating centre

London School of Hygiene and Tropical Medicine

London
WC1E 7HT
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in repository
IPD sharing plan	The datasets generated during and/or analysed during the current study are stored in a publically available repository: https://ctu-app.lshtm.ac.uk/freebird/

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	09/11/2019	21/10/2019	Yes	No
Results article	sub-study results	01/12/2020	07/12/2020	Yes	No
Results article		01/04/2021	05/05/2021	Yes	No
Results article		03/09/2024	06/11/2024	Yes	No
Protocol article	protocol	21/06/2012		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

06/11/2024: Publication reference added.
05/05/2021: Publication reference added.
07/12/2020: Publication reference added.
21/10/2019: The following changes were made:
1. Publication reference added.
2. The final enrolment number was added from the reference.
3. The EudraCT number has been added.
4. The PACTR number has been added to the protocol/serial number field.
08/02/2019: The overall trial end date was changed from 31/01/2020 to 31/08/2019; the intention to publish date was changed from 31/08/2019 to 31/08/2020.
13/07/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2018 to 31/01/2019.
2. The overall trial end date was changed from 31/01/2020 to 31/01/2020.
3. The intention to publish date was added.

22/01/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/12/2017 to 30/06/2018.
2. The overall trial end date was changed from 30/12/2018 to 31/01/2020
3. Argentina was removed as a country of recruitment.
4. Participant inclusion criteria and primary outcome measures were updated with added statements.
5. Links to protocol and PIS were updated.
6. Plain English Summary was updated accordingly.

20/12/2016: The trial record has been updated to include the CRASH-3 Intracranial Bleeding Sub-study (CRASH-3 IBS). This involves:
1. Updates to the hypothesis and outcome measures
2. The target number of participants have been changed from 10,000 to 13,000
3. The recruitment end date has been updated from 31/12/2016 to 31/12/2017 and the overall trial end date has been updated from 30/12/2016 to 30/12/2018
4. Ethics approval information added