Plain English Summary

Not provided at time of registration

Trial website

http://www.crash2.lshtm.ac.uk

Contact information

Type

Scientific

Primary contact

Prof Ian Roberts

ORCID ID

Contact details

London School of Hygiene and Tropical Medicine
1st Floor
Wolfson Building
Keppel Street
London
WC1E 7HT
United Kingdom
+44 (0)207 958 8128
ian.roberts@lshtm.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

NCT00375258

Protocol/serial number

HTA 06/303/20; HTA 09/102/01; SLCTR/2007/008

Study information

Scientific title

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

All trial centres will seek ethics approval before recruiting participants. As of 10/06/2008, over 275 approvals have been received.

Study design

Randomised placebo-controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Patient information can be found at: http://www.crash2.lshtm.ac.uk/prot_EngPIS.htm

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

Phase

Not Applicable

Drug names

Tranexamic acid

Primary outcome measures

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 trial start date

01/04/2007

Overall trial end date

02/03/2010

Reason abandoned

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

20,000 (Target number of participants for the sub-group analyses: up to 1,000)

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, 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

Trial participating centre

London School of Hygiene and Tropical Medicine
London
WC1E 7HT
United Kingdom

Sponsor information

Organisation

London School of Hygiene and Tropical Medicine (UK)

Sponsor details

Keppel Street
London
WC1E 7HT
United Kingdom
haleema.shakur@lshtm.ac.uk

Sponsor type

University/education

Website

http://www.lshtm.ac.uk/

Funders

Funder type

Research organisation

Funder name

NIHR Health Technology Assessment Programme - HTA (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Bupa Foundation (UK)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United Kingdom

Funder name

Moulton Charitable trust (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

London School of Hygiene and Tropical Medicine (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2006 Letter to the Editor in http://www.ncbi.nlm.nih.gov/pubmed/16790038
2. 2006 initial progress results in http://www.ncbi.nlm.nih.gov/pubmed/17072431
3. 2010 effects of tranexamic acid results in http://www.ncbi.nlm.nih.gov/pubmed/20554319
4. 2011 early treatment results in http://www.ncbi.nlm.nih.gov/pubmed/21439633
5. 2011 tranexamic acid results in http://www.ncbi.nlm.nih.gov/pubmed/21702233
6. 2011 reduced environmental impact of trials in http://www.ncbi.nlm.nih.gov/pubmed/21291517
7. 2011 cost-effectiveness analysis results in http://www.ncbi.nlm.nih.gov/pubmed/21559279
8. 2011 tranexamic acid results in http://www.ncbi.nlm.nih.gov/pubmed/21724564
9. 2012 tranexamic acid results in http://www.ncbi.nlm.nih.gov/pubmed/22417901
10. 2012 tranexamic acid mortality results in http://www.ncbi.nlm.nih.gov/pubmed/22968527
11. 2013 results in www.ncbi.nlm.nih.gov/pubmed/23477634
12. 2013 results in http://www.ncbi.nlm.nih.gov/pubmed/24346610

Publication citations

  1. Initial progress results

    Improving the evidence base for trauma care: progress in the international CRASH-2 trial., PLoS Clin Trials, 2006, 1, 6, e30, doi: 10.1371/journal.pctr.0010030.

  2. Effects of tranexamic acid results

    , Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S, Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial., Lancet, 2010, 376, 9734, 23-32, doi: 10.1016/S0140-6736(10)60835-5.

  3. Early treatment results

    , Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, Gando S, Guyatt G, Hunt BJ, Morales C, Perel P, Prieto-Merino D, Woolley T, The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial., Lancet, 2011, 377, 9771, 1096-101, 1101.e1-2, doi: 10.1016/S0140-6736(11)60278-X.

  4. Tranexamic acid results

    Williams-Johnson JA, McDonald AH, Strachan GG, Williams EW, Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) A randomised, placebo-controlled trial., West Indian Med J, 2010, 59, 6, 612-624.

  5. Reduced environmental impact of trials

    Subaiya S, Hogg E, Roberts I, Reducing the environmental impact of trials: a comparison of the carbon footprint of the CRASH-1 and CRASH-2 clinical trials., Trials, 2011, 12, 1, 31, doi: 10.1186/1745-6215-12-31.

  6. Tranexamic acid results

    Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study)., BMJ, 2011, 343, d3795.

  7. Tranexamic acid results

    Perel P, Al-Shahi Salman R, Kawahara T, Morris Z, Prieto-Merino D, Roberts I, Sandercock P, Shakur H, Wardlaw J, CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury--a nested randomised, placebo-controlled trial., Health Technol Assess, 2012, 16, 13, iii-xii, 1-54, doi: 10.3310/hta16130.

  8. Tranexamic acid mortality results

    Roberts I, Perel P, Prieto-Merino D, Shakur H, Coats T, Hunt BJ, Lecky F, Brohi K, Willett K, , Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial., BMJ, 2012, 345, e5839.

  9. Results

    Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, Cook L, Kawahara T, Perel P, Prieto-Merino D, Ramos M, Cairns J, Guerriero C, The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients., Health Technol Assess, 2013, 17, 10, 1-79, doi: 10.3310/hta17100.

  10. Results

    Edwards P, Shakur H, Barnetson L, Prieto D, Evans S, Roberts I, Central and statistical data monitoring in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial., Clin Trials, 2013, 11, 3, 336-343, doi: 10.1177/1740774513514145.

  11. Chung CH, Freiberger A, Kalkum M, Luntz SP, Shakur H, Seiler CM, CRASH2 in Germany [ISRCTN86750102]., Trials, 2006, 7, 22, doi: 10.1186/1745-6215-7-22.

  12. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I, , Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial., PLoS ONE, 2011, 6, 5, e18987, doi: 10.1371/journal.pone.0018987.

Editorial Notes