Full title: Tranexamic acid for the treatment of significant traumatic brain injury: an international randomised, double blind placebo controlled 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.

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 experience 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. The CRASH-2 trial showed that administration of TXA 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) in trauma patients with significant extra cranial bleeding, with no increase in vascular occlusive events. A meta-analysis of randomised controlled trials of TXA in TBI showed a significant reduction in haemorrhage growth (RR=0.72; 95% CI 0.55–0.94) and mortality (RR=0.63; 95% CI 0.40–0.99) 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.

Primary outcome: The primary outcome is death in hospital within 28 days of injury among patients randomised within 3 hours of injury (cause-specific mortality will also be recorded).
Secondary outcomes:
(a) Vascular occlusive events (myocardial infarction, pulmonary embolism, clinical evidence of deep vein thrombosis)
(b) Stroke
(c) Disability assessed using the Disability Rating Scale and Patient Orientated Outcome measures
(d) Seizures
(e) Neurosurgical intervention
(f) Days in intensive care
(g) Other adverse events