Background: Worldwide,
traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial
bleeding is common after TBI, increasing the risk of death and disability.
Tranexamic acid reduces blood loss in surgery and death due to
bleeding in
trauma patients with extra-cranial injury. Early administration of
tranexamic acid in TBI patients might limit intracranial
bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of
tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an
intravenous infusion of
tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is
head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that
tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives,
seizures, neurosurgical intervention, neurosurgical blood loss, days in
intensive care and adverse events. Sub-group analyses will examine the effect of
tranexamic acid on
head injury death stratified by
time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of
tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011.