CRASH2 Trial, a large randomised placebo-controlled trial among trauma patients with significant haemorrhage of the effects of an antifibrinolytic treatment on death and transfusion requirement

ISRCTN	ISRCTN86750102
DOI	https://doi.org/10.1186/ISRCTN86750102
ClinicalTrials.gov number	NCT00375258
Secondary identifying numbers	HTA 06/303/20; HTA 09/102/01; SLCTR/2007/008

Submission date: 13/07/2004
Registration date: 10/09/2004
Last edited: 09/07/2014

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Signs and Symptoms

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Not provided at time of registration

Study website

Contact information

Prof Ian Roberts
Scientific

London School of Hygiene and Tropical Medicine
1st Floor, Wolfson Building
Keppel Street
London
WC1E 7HT
United Kingdom

Phone	+44 (0)207 958 8128
Email	ian.roberts@lshtm.ac.uk

Study information

Study design	Randomised placebo-controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Patient information can be found at: http://www.crash2.lshtm.ac.uk/prot_EngPIS.htm
Scientific title
Study acronym	CRASH2
Study hypothesis	Because the coagulation abnormalities that occur after injury are similar to those after surgery, it is possible that antifibrinolytic agents might also reduce blood loss, the need for transfusion and mortality following trauma. However, to date there has been only one small randomised controlled trial (70 randomised patients, drug versus placebo: 0 versus 3 deaths) of the effect of antifibrinolytic agents in major trauma. As a result, there is insufficient evidence to either support or refute a clinically important treatment effect. Systemic antifibrinolytic agents have been used in the management of eye injuries where there is some evidence that they reduce the rate of secondary haemorrhage. CRASH2 aims to determine the effect of the early administration of the antifibrinolytic agent tranexamic acid (TXA) on death and transfusion requirement in adult trauma patients with ongoing significant haemorrhage, or who are considered to be at risk of significant haemorrhage. In addition, the effect on the risk of non-fatal vascular events (either haemorrhagic or occlusive) will be assessed. The initial stages of the trial was funded by the London School of Hygiene, the Bupa Foundation and the Moulton Charitable Trust. In 2007, this trial obtained main funding from the NIHR Health Technology Assessment Programme, which will fund this trial from April 2007 to September 2010. More information on the CRASH2 trial can be found at: http://www.nets.nihr.ac.uk/projects/hta/0630320 As of 16/06/2008, the CRASH2 trial will conduct sub-group analyses "CRASH-2 Intracranial Bleeding Study (IBS)" (start date: October 2009) to study the effect of TXA in participants who also have traumatic brain injury (TBI). About 40% of participants out of 9,000 enrolled so far have TBI. Details of this sub-study can be found at: http://www.nets.nihr.ac.uk/projects/hta/0910201 Hypothesis: Early administration of TXA can prevent the occurrence or increase of intracranial bleeding in patients with TBI and significant bleeding. On 21/08/2009 the anticipated start and end dates of this trial were changed from 01/05/2005 and 30/04/2010 to 01/04/2007 and 30/09/2010, respectively. This trial completed follow-up on the 02/03/2010, and the record was updated to reflect this on 09/07/2010.
Ethics approval(s)	All trial centres will seek ethics approval before recruiting participants. As of 10/06/2008, over 275 approvals have been received.
Condition	Trauma
Intervention	Tranexamic acid 2 g intravenously over 8 hours versus placebo. Please note that as of 24/03/10 this trial has completed recruitment, analysis is ongoing.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Tranexamic acid
Primary outcome measure	The primary outcome measure is death in hospital within 4 weeks of injury (causes of death will be classified). An additional outcome measure for the sub-group analyses (added as of 18/06/2008): 1. Increase in volume of intracranial bleeding. A repeat CT scan will be carried out 24-48 hours after injury and compared to a clinical baseline CT scan.
Secondary outcome measures	Secondary outcome measures will be receipt of a blood transfusion, volume of blood transfused, surgical intervention and the occurrence of vascular events (haemorrhagic stroke, occlusive stroke, myocardial infarction, pulmonary embolism, clinically diagnosed deep vein thrombosis). Data will be recorded on a single sided outcome form which can be completed entirely from the hospital notes. There will be no additional tests. Additional outcome measures for the sub-group analyses (added as of 18/06/2008): A repeat CT scan will be carried out 24 - 48 hours after injury and compared to a clinical baseline CT scan to assess the following: 1. Frequency of progressive haematomas 2. Frequency of delayed haematomas 3. New focal ischaemic lesions
Overall study start date	01/04/2007
Overall study end date	02/03/2010

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	20,000 (Target number of participants for the sub-group analyses: up to 1,000)
Participant inclusion criteria	All adult trauma patients who are considered to be at risk of significant haemorrhage and are within 8 hours of the injury, are eligible for trial entry if they appear to be at least 16 years old. There are no other pre-specified exclusion criteria, as the fundamental eligibility criterion is the responsible doctor's 'uncertainty' whether or not to use tranexamic acid (TXA) in a particular adult with traumatic haemorrhage. Patients for whom there is considered by the responsible doctor to be a clear indication for TXA should not be randomised. Likewise, any for whom there is considered to be a clear contraindication to TXA (such as, perhaps, those who have clinical evidence of a thrombotic disseminated intravascular coagulation) should not be randomised. All those for whom the responsible doctor is substantially uncertain as to whether or not to use an anti-fibrinolytic agent are eligible for randomisation, and as many such patients as possible should be considered for the trial.
Participant exclusion criteria	The fundamental eligibility criterion is the responsible doctor's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular adult with traumatic haemorrhage. Patients for whom the responsible doctor considers there is a clear indication for antifibrinolytic therapy should not be randomised. Likewise, patients for whom there is considered to be a clear contraindication to antifibrinolytic therapy (such as, perhaps, those who have clinical evidence of a thrombotic disseminated intravascular coagulation) should not be randomised. Where the responsible doctor is substantially uncertain as to whether or not to use an antifibrinolytic, all these patients are eligible for randomisation and should be considered for the trial. There are no other pre-specified exclusion criteria.
Recruitment start date	01/04/2007
Recruitment end date	02/03/2010

Locations

Countries of recruitment

Albania
Argentina
Australia
Austria
Bangladesh
Belgium
Cameroon
Canada
China
Colombia
Cuba
Czech Republic
Ecuador
Egypt
El Salvador
England
Georgia
Ghana
India
Indonesia
Iran
Iraq
Italy
Jamaica
Japan
Kenya
Malaysia
Mexico
Montenegro
Nigeria
Peru
Poland
Saudi Arabia
Serbia
Singapore
Slovakia
South Africa
Spain
Sri Lanka
Tanzania
Thailand
Tunisia
United Kingdom
Zambia

Study participating centre

London School of Hygiene and Tropical Medicine

London
WC1E 7HT
United Kingdom

Sponsor information

London School of Hygiene and Tropical Medicine (UK)
University/education

Keppel Street
London
WC1E 7HT
England
United Kingdom

Email	haleema.shakur@lshtm.ac.uk
Website	http://www.lshtm.ac.uk/
"ROR"	https://ror.org/00a0jsq62

Funders

Funder type

Research organisation

NIHR Health Technology Assessment Programme - HTA (UK)

No information available

Bupa Foundation (UK)
Private sector organisation / Trusts, charities, foundations (both public and private)

Location: United Kingdom

Moulton Charitable trust (UK)

No information available

London School of Hygiene and Tropical Medicine (UK)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Peer reviewed?	Patient-facing?
Other publications	Letter to the Editor	21/06/2006	Yes	No
Results article	initial progress results	27/10/2006	Yes	No
Results article	effects of tranexamic acid results	03/07/2010	Yes	No
Results article	tranexamic acid results	01/12/2010	Yes	No
Other publications	reduced environmental impact of trials	03/02/2011	Yes	No
Results article	early treatment results	26/03/2011	Yes	No
Results article	cost-effectiveness analysis results	03/05/2011	Yes	No
Results article	tranexamic acid results	01/07/2011	Yes	No
Results article	tranexamic acid results	01/07/2012	Yes	No
Results article	tranexamic acid mortality results	11/09/2012	Yes	No
Results article	results	01/03/2013	Yes	No
Results article	results	01/06/2014	Yes	No