Biomarkers for RAtional Investigation for Neurological decision Support in TBI: BRaINS-TBI

In the UK ~1 million people attend emergency departments (ED) annually with mild traumatic brain injury (mTBI). The focus in an ED is to evaluate the requirement for a CT brain scan to determine which patients require hospital admission or neurosurgical intervention. However only ~7% of scans have a traumatic lesion, and most patients are sent home with simple written advice and no planned follow-up despite ~40% of mTBI patients having persistent problems >6 months after injury.

Our failure to prognosticate in this group means those with persisting problems are often lost to the ongoing care they need. This issue is a particular concern for those from deprived areas exacerbating health inequalities and an unmet need affecting millions worldwide each year.

Certain proteins (fluid biomarkers) are released after mTBI. This proposal will evaluate the most promising protein biomarkers to address two key questions: - Can they be used to predict which patients with mTBI are at risk of long-term problems? - Can they be used to safely reduce the number of CT scans performed in EDs for mTBI?

The 2023 NICE Head Injury Guideline update conducted systematic reviews of evidence relating to both these questions and could not recommend the use of biomarkers on the basis of current evidence. Biomarker use in head injury management has been identified as a top research priority by NICE and emergency medicine JLA.

Work Packages (WP) 1 and 2 will focus on predicting outcome in adults (n=2082, 10 representative sites) and children (up to 750). Biomarkers will be collected in the ED for all, and at 2 weeks using at home testing for adults. Follow-up will be online, or by phone or letter at 3 and 6 months. Models evaluating how the predictive biomarker levels relate to outcome will be developed.

WP3 will be a nested randomised control trial in WP1 with 954 adult patients (477 each group) enrolling in both studies. An internal pilot phase will be performed first. Usual clinical practice to decide if someone at intermediate (medium) risk requires a CT will be compared to point of care biomarker informed CT decisions to see if scans are reduced.

WP4: Biomarkers may revolutionize the way that severity of TBI is characterised. If they can predict long-term outcomes understanding how best to present this information to patients and clinicians will be important. A mixed methods approach will be used to understand how best to introduce biomarkers into routine clinical assessment.

WP5: Health economic analyses will be performed to understand if biomarkers use is cost effective.

Patient Public Involvement & Engagement: Key concerns expressed included worry about time in ED, current lack of routine follow-up and long-term consequences. These have been integrated into this proposal. Patient perspectives will be integrated in all aspects of design, implementation and results. Expected outcomes:

- Understanding whether biomarkers can predict long-term outcomes after mTBI. This would enable improved identification for follow-up facilitating earlier interventions and aid clinical trial design. - Understanding whether biomarkers can be used to safely and cost effectively reduce CTs.

Dissemination: via publications and presentations at academic meetings. We will work together with groups including Headway and UKABIF to provide regular updates to the patients and public during the study and disseminate findings. This study will utilise the UKRI Platform for TBI research (TBI-REPORTER).