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

• ClinicalTrials.gov Identifier: NCT01402882
• Recruitment Status: Completed
• First Posted: July 26, 2011
• Last Update Posted: February 17, 2020
• Sponsor: London School of Hygiene and Tropical Medicine
• Information provided by (Responsible Party): London School of Hygiene and Tropical Medicine

Study Description

Brief Summary:

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. Additionally, a nested study will be conducted in a subset of CRASH-3 trial participants. This nested study (CRASH-3 Intracranial Bleeding Sub-Study [CRASH-3 IBS]) will examine the effect of tranexamic acid on intracranial haemorrhage and cerebral ischaemia using CT Scans in approximately 1,000 patients randomised into the CRASH-3 trial.

Condition or disease	Intervention/treatment	Phase
Traumatic Brain Injury	Drug: Tranexamic Acid	Phase 3

Detailed Description:

BACKGROUND: Worldwide, over 10 million people are killed or hospitalised because of traumatic brain injury (TBI) each year. About 90% of deaths from TBI occur in low and middle income countries. TBI mostly affects young adults and many experiencing long lasting or permanent disability. The social and economic burden of TBI is considerable. Tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. TXA has been shown to reduce the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding in elective surgical patients. More recently, the CRASH-2 trial showed that the administration of TXA within 8 hours of injury significantly reduces deaths due to bleeding (RR=0.85, 95% CI 0.76-0.96; p=0.008), and all-cause mortality (RR=0.91, 95% CI 0.85-0.97; p=0.0035), with no apparent increase in vascular occlusive events. A meta-analysis of randomised controlled trials of TXA in TBI showed a significant reduction in haemorrhage growth (OR=0.61, 95%CI 0.41 to 0.91) and mortality (OR=0.59, 95%CI 0.35 to 0.99) with TXA. Although the results from these trials are promising, the estimates are imprecise and there are no data on the effect of TXA on disability. Additionally, a nested study will be conducted in a subset of CRASH-3 trial participants. This nested study (CRASH-3 Intracranial Bleeding Sub-Study [CRASH-3 IBS]) will examine the effect of tranexamic acid on intracranial haemorrhage and cerebral ischaemia using CT Scans in approximately 1,000 patients randomised into the CRASH-3 trial.

AIM: The CRASH-3 trial will provide reliable evidence about the effect of tranexamic acid on mortality and disability in patients with TBI. The effect of TXA on the risk of vascular occlusive events and seizures will also be assessed.

PRIMARY OUTCOME: The primary outcome is death in hospital (within 28 days of injury) of patients randomised within 3 hours of injury (cause of death will be described).

SECONDARY OUTCOMES:

1. Vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, clinical evidence of deep vein thrombosis)
2. In hospital disability assessed using the Disability Rating Scale and Patient Orientated Outcome
3. Seizures
4. Neurosurgical intervention
5. Days in intensive care Other adverse events will be described

Other Outcome Measures: CRASH-3 IBS Primary outcome - the total volume of intracranial haemorrhage after randomisation, adjusting for baseline haemorrhage volume.

Secondary outcome -

• Frequency of progressive haemorrhage: number of patients with a post-randomisation CT scan with total haemorrhage volume of more than 25% of the volume on 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 in patients who undergo surgical evacuation of haemorrhage after randomisation, adjusting for volume of baseline bleeding.

TRIAL DESIGN: A large, pragmatic, randomised, double blind, placebo controlled trial among 13,000 traumatic brain injury patients

DIAGNOSIS AND INCLUSION/EXCLUSION CRITERIA:

Adults with traumatic brain injury who

• are within eight hours of injury
• with any intracranial bleeding on CT scan or who have a GCS of 12 or less, and
• have no significant extra-cranial haemorrhage The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use tranexamic acid in a particular patient with traumatic brain injury.

TEST PRODUCT, REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION: A loading dose of tranexamic acid

(1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation. A maintenance dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given after the loading dose is finished.

SETTING: This trial will be coordinated from the London School of Hygiene & Tropical Medicine (University of London) and conducted worldwide in hospitals in low, middle and high income countries.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12737 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Tranexamic Acid for the Treatment of Significant Traumatic Brain Injury: an International Randomised, Double Blind Placebo Controlled Trial
• Actual Study Start Date: July 2012
• Actual Primary Completion Date: October 2019
• Actual Study Completion Date: October 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tranexamic acid	Drug: Tranexamic Acid; 2 grams (1 gram over 10 minutes and 1 gram over 8 hours)
Placebo Comparator: Placebo; (Sodium Chloride 0.9%)	Drug: Tranexamic Acid; 2 grams (1 gram over 10 minutes and 1 gram over 8 hours)

Outcome Measures

Primary Outcome Measures :

1. The primary outcome is death in hospital in patients recruited within 3 hours and cause of death will be described. [ Time Frame: within 28 days of injury ]

Secondary Outcome Measures :

1. (a) Vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, clinical evidence of deep vein thrombosis) [ Time Frame: Prior death, discharge or 28 days ]
2. (b) In hospital disability assessed using the Disability Rating Scale and Patient Orientated Outcome [ Time Frame: Prior death, discharge or 28 days ]
3. (c) Seizures [ Time Frame: Prior death, discharge or day 28 ]
4. (d) Neurosurgical intervention [ Time Frame: prior death, discharge or day 28 ]
5. (e) Days in intensive care [ Time Frame: prior death, discharge or day 28 ]
6. (f) Other adverse events [ Time Frame: prior death, discharge or day 28 ]

Other Outcome Measures:

1. CRASH-3 IBS: Primary outcome - the total volume of intracranial haemorrhage [ Time Frame: 1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation) ]
2. Frequency of progressive haemorrhage: number of patients with a post-randomisation CT scan with total haemorrhage volume of more than 25% of the volume on the pre-randomisation scan [ Time Frame: 1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation) ]
3. Frequency of delayed haemorrhage: [ Time Frame: 1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation) ]
4. New focal ischaemic lesions: [ Time Frame: 1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation) ]
5. • Total volume of intracranial bleeding in patients who undergo surgical evacuation of haemorrhage after randomisation [ Time Frame: 1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation) ]

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Adults with traumatic brain injury who

• are within eight hours of injury (limited to within 3 hours from September, 2016)
• with any intracranial bleeding on CT scan or who have a GCS of 12 or less, and
• have no significant extra-cranial haemorrhage The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use tranexamic acid in a particular patient with traumatic brain injury

Exclusion Criteria:

The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use tranexamic acid in a particular patient with traumatic brain injury

Contacts and Locations

Locations

Georgia

High Technology Medical Center, University Clinic

Tbilisi, Georgia

Sponsors and Collaborators

London School of Hygiene and Tropical Medicine

Investigators

• Study Director: Haleema Shakur; LSHTM

More Information

Additional Information:

Trial website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Roberts I, Shakur-Still H, Aeron-Thomas A, Beaumont D, Belli A, Brenner A, Cargill M, Chaudhri R, Douglas N, Frimley L, Gilliam C, Geer A, Jamal Z, Jooma R, Mansukhani R, Miners A, Pott J, Prowse D, Shokunbi T, Williams J. Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT. Health Technol Assess. 2021 Apr;25(26):1-76. doi: 10.3310/hta25260.

Brenner A, Belli A, Chaudhri R, Coats T, Frimley L, Jamaluddin SF, Jooma R, Mansukhani R, Sandercock P, Shakur-Still H, Shokunbi T, Roberts I; CRASH-3 trial collaborators. Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial. Crit Care. 2020 Nov 11;24(1):560. doi: 10.1186/s13054-020-03243-4.

Mansukhani R, Frimley L, Shakur-Still H, Sharples L, Roberts I. Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results. Trials. 2020 Jul 25;21(1):681. doi: 10.1186/s13063-020-04623-5.

CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019 Nov 9;394(10210):1713-1723. doi: 10.1016/S0140-6736(19)32233-0. Epub 2019 Oct 14. Erratum In: Lancet. 2019 Nov 9;394(10210):1712.

Roberts I, Belli A, Brenner A, Chaudhri R, Fawole B, Harris T, Jooma R, Mahmood A, Shokunbi T, Shakur H; CRASH-3 trial collaborators. Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial. Wellcome Open Res. 2018 Sep 26;3:86. doi: 10.12688/wellcomeopenres.14700.2. eCollection 2018.

Mahmood A, Roberts I, Shakur H. A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS]). Trials. 2017 Jul 17;18(1):330. doi: 10.1186/s13063-017-2073-6.

Dewan Y, Komolafe EO, Mejia-Mantilla JH, Perel P, Roberts I, Shakur H; CRASH-3 Collaborators. CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials. 2012 Jun 21;13:87. doi: 10.1186/1745-6215-13-87.

• Responsible Party: London School of Hygiene and Tropical Medicine
• ClinicalTrials.gov Identifier: NCT01402882
• Other Study ID Numbers: ISRCTN15088122
• First Posted: July 26, 2011
• Last Update Posted: February 17, 2020
• Last Verified: March 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: After all relevant publications are completed, totally anonymised data will be available at https://ctu-app.lshtm.ac.uk/freebird/

Keywords provided by London School of Hygiene and Tropical Medicine:

traumatic brain injury; tranexamic acid; antifibrinolytic; randomised; clinical trial

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Tranexamic Acid; Antifibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Hemostatics; Coagulants