CRASH-4 Trial - Intramuscular tranexamic acid for the treatment of symptomatic mild traumatic brain injury in older adults: a randomised, double-blind, placebo-controlled trial

London School of Hygiene and Tropical Medicine (LSHTM) requires access to NHS England Data for the purpose of the following research project:

CRASH-4 Trial - Intramuscular tranexamic acid for the treatment of symptomatic mild traumatic brain injury in older adults.

The CRASH-4 Trial is a randomised, double-blind, placebo-controlled clinical trial (ClinicalTrials.gov Identifier: NCT04521881, EudraCT Number: 2020-003391-40) which aims to assess the effects of early intramuscular tranexamic acid (TXA) on intracranial haemorrhage, disability, death, and dementia in older adults with symptomatic mild traumatic brain injury (TBI). To assess safety and effectiveness, CRASH-4 need to monitor deaths due to intracranial bleeding and other causes, and the risk of key outcomes associated with having at TBI at 1 year. Key outcomes include dementia, mood disorders, blood clots and other bleeds around the brain, epilepsy and convulsions.

The following NHS England Data will be accessed:

- Civil Registrations of Death – necessary to understand which participants have died within 1 year of randomisation into the trial, and of what cause

- Hospital Episode Statistics (HES) Admitted Patient Care (APC) - necessary as the most suitable and complete dataset for capturing the dementia diagnoses, which are commonly given clinically during hospital admission. Other key outcomes listed above may also be captured during inpatient hospital admissions.

The level of the Data will be identifiable because LSHTM retains the identifying details of the study participants beyond the time at which NHS England Data is disseminated to LSHTM. However, the data that will be disseminated under this Agreement will contain no identifying details.

The Data will be minimised as follows:

• Limited to a study cohort of ~5000 participants identified by NHS research site staff, Ambulance Services and Acute Care Trusts located in the United Kingdom as meeting the CRASH-4 Trial inclusion criteria, and not fitting any of the exclusion criteria. All participants are consented directly or via a legal representative. As of 22/10/2023, 6% of all participants recruited to date had been via a legal representative.

• Limited to Data between April 2021 and February 2026. For each individual patient, NHS England Data will only be provided for a period of 12 months from their date of randomisation into the trial.

• Limited to HES APC Data relating to diagnoses of all cause dementia, mood disorders, blood clots and other bleeds around the brain, epilepsy and convulsions, identified by specific ICD-10 codes

LSHTM is the research sponsor and the Controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

LSHTM's lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e): - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the Controller

The lawful basis for processing special category personal data under the UK GDPR is:

Article 9(2)(j): processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because aims to produce reliable evidence to inform future decisions over the care of thousands of patients with mild traumatic brain injury each year.

The funding comes from multiple sources. Funders include:

• The JP Moulton Charitable Foundation – This funding is for the pilot phase of the trial and ended on 31/08/2023

• The National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme – Funding is in place until 31/01/2027

The funder(s) will have no ability to suppress or otherwise limit the publication of findings.

Rackspace Technology is a Processor acting under the instructions of LSHTM. Rackspace Technology’s role is limited to storing CRASH-4 trial Data only.

A Patient and Public Involvement (PPI) advisory group has been established for the trial and contributed significantly to the design of the trial, outcomes of importance to patients and their families, the consent process and the data to be collected. This group includes a representative from RoadPeace, a national charity who represent road crash victims; a representative who is highly experienced in advising on the public perspective on emergency ambulance care; and a representative who has suffered a traumatic brain injury (TBI) and experienced being included in a TBI trial.

The PPI advisory group aided the development and finalisation of the content of the informed consent documents. They also agreed the need for 1-year follow-up and the personal data to be collected. They considered these as essential for the trial. The CRASH-4 trial has also received written recommendation from the Caldicott Guardian at LSHTM for this Data Sharing Agreement.

LSHTM will transfer data to NHS England. The data will consist of identifying details (specifically Surname, Forename, Date of Birth, Postcode, NHS Number, and a unique person ID) for the cohort to be linked with NHS England Data. LSHTM will also supply dates of randomisation into the trial and 12 months post-randomisation, for each individual participant in the trial.

NHS England will provide the relevant records from the HES APC and Civil Registrations (Deaths) datasets to LSHTM.

The Data will contain no direct identifying data items but will contain a unique person ID which can be used to link the Data with other record level data already held by the recipient.

The Data will be stored on servers at RackSpace Technology.

The Data will be accessed onsite at the premises of LSHTM only.

The Data will not leave England at any time.

Access is restricted to employees of LSHTM who have authorisation from the Chief Investigator.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will be linked at person record level with de-identified health outcomes data collected through Case Report Forms as part of the CRASH-4 Trial.

There will be no requirement and no attempt to reidentify individuals when using the Data. The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

Researchers from the LSHTM CTU will analyse the Data for the purposes described in Objective for Processing.

The expected outputs of the processing will be:

• Submissions to peer reviewed journals

• Presentations at appropriate conferences

• Creation of, for example, videos, cartoons, comic strips and/ or films

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Journals

• Trials websites

• Social Media

• Direct bilateral engagement with trial participants, governments, patient organisations, donors, stakeholder organisations, manufacturers, NGOs, hospital directors and clinicians

• Press/ media engagement

• Links to publications in applicable trial registries

The estimated production of outputs: ~6 months post study completion, anticipated August 2026.

The findings of the CRASH-4 research study are expected to provide reliable evidence about the effects of early treatment with intramuscular tranexamic acid in older adults with symptomatic mild head injury.

Traumatic brain injury (TBI) accounts for half of trauma admissions (UK) in older adults and is the leading cause of trauma, death and disability. TBI is a strong risk factor for dementia, particularly in older adults. Bleeding into the brain is a common and serious complication of TBI and older adults are at highest risk. Furthermore, according to NHS figures, one in three Britons over 65 and half of those over 80 have at least one fall every year, which can commonly result in a TBI.

If an early injection of tranexamic acid is shown to reduce hospital admissions, morbidity, and mortality in older adults with mild TBI, this would be a major medical advance that would have the potential to improve the care, outcomes, and quality of life of many millions of patients world-wide and in the future with similar injuries. It has huge potential to be implemented into clinical policies and practices globally as a standard treatment for mild TBI in older adults.

Furthermore, a safe and effective treatment for mild TBI that can be easily administered at home and reduces hospital admissions and poor outcomes should reduce the strain on inpatient and outpatient NHS/health setting resources and thus have economic benefits.

Dementia is a growing and significant health care challenge; according to NHS England, there are approximately 850,000 people suffering from dementia in the UK currently and 540,000 carers of people with dementia. There is a considerable economic cost associated with the disease too, estimated at £23 billion a year, which is predicted to triple by 2040. This highlights the importance of this outcome, not only for the economic significance for health care settings and policy makers, but for the emotional and practical implications for patients of a TBI and their families/carers. TBI is also associated with a number of other outcomes negatively affecting patient morbidity and wellbeing, such as epilepsy and other convulsions, blood clots and mood disorders.

The knowledge gained from the results of the CRASH-4 Trial is likely to inform clinical guidelines and policies on the treatment of a mild traumatic brain injury in older adults, and impact the clinical care of mild TBI patients.

The use of the Data could:

• help the system to better understand the health and care needs of populations

• lead to the identification or improvement of treatments or interventions to improve health and care outcomes or experience

• inform planning health services and programmes

• inform decisions on how to effectively allocate and evaluate funding according to health needs

• support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work).

Once results are published, the CRASH-4 trial will follow a comprehensive dissemination strategy to share the trial results widely, to key organisations and policy makers as well as to the public and patients.

The Trial Management Group will be responsible for the publication of trial results and the dissemination strategy. LSHTM Clinical Trials Unit aims to set up a Dissemination advisory group during the last year of the trial which will include Patient and Public Involvement (PPI) groups, media experts, patient support organisations, and clinical groups including those from the ambulance service, trauma and neurosurgery.

The PPI group will input into:

• drafting of the dissemination strategy as the trial is ongoing

• interpreting of the trial results when available

• reporting of the trial results

Yielded Benefits is not a requirement for new applications.