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

February 14, 2020 updated by: London School of Hygiene and Tropical Medicine

Tranexamic Acid for the Treatment of Significant Traumatic Brain Injury: an International Randomised, Double Blind Placebo Controlled Trial

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

12737

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Georgia
      • Tbilisi, Georgia
        • High Technology Medical Center, University Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
within 28 days of injury

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Time Frame
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)
1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation)
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)
1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation)
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)
1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation)
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)
1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation)
• 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)
1) CT scan done before receipt of trial treatment; (2) CT scan done after receipt of trial treatment (up to 28 days after randomisation)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

London School of Hygiene and Tropical Medicine

Investigators

  • Study Director: Haleema Shakur, LSHTM

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2012

Primary Completion (Actual)

October 1, 2019

Study Completion (Actual)

October 1, 2019

Study Registration Dates

First Submitted

July 25, 2011

First Submitted That Met QC Criteria

July 25, 2011

First Posted (Estimate)

July 26, 2011

Study Record Updates

Last Update Posted (Actual)

February 17, 2020

Last Update Submitted That Met QC Criteria

February 14, 2020

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ISRCTN15088122

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

After all relevant publications are completed, totally anonymised data will be available at https://ctu-app.lshtm.ac.uk/freebird/

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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