CRASH-4 trial (Clinical Randomisation of an Anti-fibrinolytic in Symptomatic mild Head injury in older adults) Intramuscular tranexamic acid for the treatment of symptomatic mild traumatic brain injury in older adults: a randomised, double-blind, placebo-controlled trial

Study question: What are the effects of early intramuscular tranexamic acid on intracranial bleeding, hospital admission, death, disability and dementia in older adults with mild TBI. Background: Mild traumatic brain injury (TBI) can cause death, disability and dementia in older adults. Timely tranexamic acid (TXA) treatment, by preventing or limiting intracranial bleeding, could reduce these risks. The CRASH-4 trial will assess the effects of early intramuscular TXA in about 5,000 older adults with mild TBI. Methods: We are recruiting patients aged 50 years or older if they have a history or signs (laceration, bruise, swelling or pain in head or face) of a head injury; a GCS = 13; any impairment of consciousness and are within 3 hours of injury. We enrol patients at the scene of the injury or in the ambulance. We also enrol patients who present directly to NHS emergency departments. We randomly allocate patients to receive an intramuscular (IM) injection of 500 mg tranexamic acid or matching placebo. We give one 5mL injection (100mg/ml TXA or placebo) or two 2.5mL injections depending on muscle mass. The primary outcome is discharge home from the emergency department within 24 hours. Secondary outcomes include: intracranial bleeding on CT scan, death, disability, vascular occlusive events, seizures, pneumonia, other adverse events, re-admission to hospital within 28 days and any dementia diagnosis at 1 year follow up. Dementia is identified through linkage to routinely collected health-care data. To test the trial procedures and the acceptability of the intervention, we conducted a pilot phase in 500 patients. The pilot confirmed that the study procedures work and that the IM injection is tolerated. The main phase will run for 44 months. There will be a 30-month recruitment period with six months for data analysis, reporting and closeout. Impact and dissemination: Hundreds of thousands of patients attend emergency departments after mild TBI. The main threat is intracranial bleeding. Timely TXA treatment could prevent this bleeding, but most older patients are seen too late to benefit. In general, mild TBI patients attend emergency departments where they are admitted, observed and discharged but not treated. This worsens hospital crowding with marginal patient benefit. The information from this trial could improve treatment strategies. Rather than being admitted but not treated, mild TBI patients could be treated and (on many occasions) not admitted. An early IM TXA injection at the scene could reduce intracranial bleeding and the need for hospital admission. We will disseminate the trial results via conferences, publications, social media and films. We work with victim organisations and head injury charities who will help ensure timely implementation. Our results will inform NICE head injury guidelines and Joint Royal Colleges Ambulance Liaison Committee (JRCALC) guidelines for pre-hospital care. We have discussed the trial with the JRCALC guidelines’ authors and with the National Ambulance Services Medical Directors' Group and they are strongly supportive. NHS England recognises the urgent need to reduce emergency admissions and improve outcomes. Timely out of hospital TXA treatment could help to achieve this.