Clinical Randomisation of an Antifibrinolytic in Significant Head Injury

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Vascular occlusive events (myocardial infarction, stroke, pulmonary embolism, clinical evidence of deep vein thrombosis) In hospital disability assessed using the Disability Rating Scale and Patient Orientated Outcome Seizures Neurosurgical intervention 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.

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

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Tranexamic Acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranexamic acid<br> | Drug: Tranexamic Acid<br>* 2 grams (1 gram over 10 minutes and 1 gram over 8 hours)<br>|
| Placebo Comparator: Placebo<br>(Sodium Chloride 0.9%) | Drug: Tranexamic Acid<br>* 2 grams (1 gram over 10 minutes and 1 gram over 8 hours)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome is death in hospital in patients recruited within 3 hours and cause of death will be described. |  | within 28 days of injury | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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traumatic brain injury, tranexamic acid, antifibrinolytic, randomised, clinical trial