Clinical Randomisation of an Anti-fibrinolytic in Symptomatic Mild Head Injury in Older Adults (CRASH-4)

Intramuscular Tranexamic Acid for the Treatment of Symptomatic Mild Traumatic Brain Injury in Older Adults: a Randomised, Double-blind, Placebo-controlled Trial

Tranexamic acid (TXA) reduces head injury deaths. The CRASH-4 trial aims to assess the effects of early intramuscular TXA on intracranial haemorrhage, disability, death, and dementia in older adults with symptomatic mild head injury

TXA reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. Results from randomised trials (CRASH-3 and NCT01990768) show that early treatment with TXA (given intravenously) reduces head injury deaths (pooled RR 0.89, 95% CI 0.80-0.99). In the CRASH-3 trial, the reduction in head injury deaths with TXA was largest in patients with mild and moderate head injuries, particularly if patients were treated soon after injury. However, the CRASH-3 trial included mild TBI patients only if they had intracranial bleeding on CT scan. It is uncertain whether the results apply to mild TBI patients more generally. CRASH-4 is a randomised, double blind, placebo-controlled trial in symptomatic mild TBI in about 10,000 older adults. The pilot phase will include about 500 patients. The trial aims to provide reliable evidence about the effects of early intramuscular TXA on intracranial haemorrhage, disability, death, and dementia in older adults with symptomatic mild head injury.

A randomised, double blind, placebo controlled trial among 10,000 older adults with mild traumatic brain injury.

Masking will be done by an independent clinical trials supply company. It will involve the removal of the original manufacturer's label and replacement with the clinical trial label bearing the randomisation number, which will be used as the pack identification. Apart from the randomisation number, all pack label texts will be identical for tranexamic acid and placebo.

The occurrence of all-cause dementia will be determined 12 months after randomisation. Dementia will be identified through linkage to routinely collected health-care data.

Inclusion Criteria: 50 years or older (actual or estimated) History or evidence of head injury (e.g. laceration, bruise, swelling or pain in head or face) GCS ≥ 13 Has one or more of the following: has or had any impaired consciousness (loss of consciousness, amnesia, or confusion) nausea or vomiting Within 3 hours of injury (do not include if interval cannot be estimated e.g. patient unable to confirm time of fall or patient found on floor after an unwitnessed fall and home alone) Not living in a nursing home, mental health institution or prison Patient will be conveyed to or is admitted to a participating hospital Exclusion Criteria: - TXA not clearly indicated (e.g. major bleeding) or contraindicated (e.g. suspected stroke)

Data will be shared publicly when all planned analyses are completed by the CRASH-4 Trial Collaborators. This will be hosted on freebird.lshtm.ac.uk

Totally anonymised data (without random allocation, patient, country and site identifiers) will be freely available.Where random allocation codes, country/site identifiers are requested, appropriate pre-specified analysis plan will need to be submitted to the Trial Management Group for review and if necessary, appropriate Ethics Committee approval will be required.