UK-REBOA study

Trauma is the leading cause of death in the first four decades of life, accounting for more than 1.3 million deaths per year globally. Each year around 5400 people in England and Wales die after being severely injured – for example, in a road traffic collision, or as a result of a major fall. The leading cause of preventable death following injury is uncontrolled bleeding (hemorrhage), which usually requires immediate surgery. If bleeding can be controlled quickly, patients often recover. However, some patients die before they can reach an operating theatre.

REBOA (which stands for Resuscitative Endovascular Balloon Occlusion of the Aorta) is a new and novel technique which could help with this. REBOA involves passing a small inflatable balloon into the aorta (the main artery) to stop the bleeding until a patient can be taken to an operating theatre. REBOA has shown some early promise, but it is not yet known if it is better than standard care given to trauma patients. The UK-REBOA study aims to compare a control arm of the study against REBOA intervention. The control arm comprises standard treatment of patients with life-threatening torso haemorrhage, in the setting of a major trauma centre, which includes a rapid, consultant-led assessment. Life-saving interventions such as intubation of the airway, respiratory support, blood product transfusion, and imaging, are directed by protocols and guidelines, and aimed at minimising the time to control of haemorrhage, by surgical or endovascular means. The control arm of this study is designed to mirror standard care for this cohort of patients. The intervention arm of the RCT is REBOA in addition to control / standard care. The UK-REBOA study aims to compare standard major trauma centre care with REBOA versus standard major trauma care alone, in a fair and balanced way.

The UK-REBOA study is coordinated by the University of Aberdeen’s Centre for Health And Randomised Trials (CHaRT) in collaboration with 11 major trauma centres in England. These centres are all recruiting patients into the UK-REBOA study to help determine whether REBOA is effective and offers value for money to the NHS.

Recruitment commenced on 21st January 2018 and concluded in April 2022. 90 patients were expected to the study from across 11 major trauma centres in England. Recruitment of participants is the responsibility of trauma team leaders, who assess injured patients against the trial eligibility criteria. Adult trauma patients (aged, or believed to be aged, 16 years or older) with confirmed or suspected life-threatening torso haemorrhage, which is thought to be amenable to adjunctive treatment with REBOA can be included. Women known or thought to be pregnant at presentation, children (aged, or believed to be aged 15 or younger) and patients with injuries which are deemed unsurvivable on clinical grounds will be excluded*. Recruitment takes place via a secure website, accessible from a hand held device. The enrolment process takes less than 30 seconds and is unlikely to interfere with patient care.

*Pregnant women are excluded on the basis that the aortic occlusion involved in the process would stop blood flow to the uterus and could therefore seriously harm or kill the foetus, and under 15s are excluded because their blood vessels are too small for currently available REBOA equipment and it use could result in serious iatrogenic injuries.

As acknowledged in the Declaration of Helsinki, patients who are incapable of giving consent in emergency situations are an established exception to the general rule of informed consent in clinical trials. In the context of life-threatening haemorrhage caused by trauma, treatment must start immediately in an attempt to save the person’s life. It is therefore not practicable to ask a consultee for their opinion without placing the potential participant at risk of harm from delaying emergency treatment. The clinical condition of patients in the UK-REBOA study means that seeking advice from a consultee is not reasonably practicable without placing the potential participant at risk of harm from delaying emergency treatment. Randomisation will therefore take place without consent. The legal basis for conducting medical device research in these circumstances is provided by the Mental Capacity Act (2005).

Patients will be informed about what has happened at the earliest appropriate opportunity, which is likely to be after the initial emergency situation has passed, the patient is discharged from a High Dependency Unit / Intensive Care Unit (HDU/ICU), is more likely to have regained consciousness, and is on a hospital ward. At this point, consent will relate to continuation in the trial, and the use of data, including linked data and future follow-up, as the intervention phase of the trial will have been completed long before patients or their consultees have been approached. Once discharged to a ward, research nurses and treating clinicians will assess whether the patients have the capacity to consent. For patients who have capacity, consent will be taken from the patient. For patients who do not have capacity, opinion from a consultee will be sought. Defined as a person who cares for the adult lacking capacity, or is interested in that person's welfare, but is not doing so for remuneration, or acting in a professional capacity. If a personal consultee is not available or unwilling to give advice then a nominated consultee, defined as a professional who is independent of the study can do so. Consultees are not asked to give consent on behalf of the adult, but rather to provide an opinion on the views and feelings of the potential participant. The provision of information to consultees will be conducted in line with the General Medical Council’s (GMC) guidance on handling patient information in patients who lack capacity. The consultee may decide that the patient would not want to take part in which case their feelings will be respected and their decision about taking part will be recorded, and any data collected to date will not be used. If participants regain capacity during their stay on a normal ward, consent will be sought in the usual way. Patients will also be permitted to know (if they so wish) whether REBOA formed part of their treatment. Patients who are ‘unblinded’ in this way will be noted on the trial database.

The study originally hoped to recruit approximately 120 individuals into the trial but the cohort is now approximately 90. As at end January 2022 of the 90 study participants in the cohort, 51% were recruited under consultee advice, 45% under direct participant consent and 4% under both participant and consultee advice.

To achieve this aim, the University of Aberdeen requires Hospital Episode Statistics (HES) and mortality data for use in the UK-REBOA study activity. These data will also be linked via the UK-REBOA trial study number to data held by the Trauma Audit and Research Network (TARN). TARN will provide important data on clinical outcomes and resource use data (e.g. procedure time) to enable a detailed costing of the different trial interventions. TARN and HES will never have access to each other's datasets.

The research team will be fully trained on informed consent and assessing capacity, good clinical practice (GCP) guidelines, relevant legislation and the trial-related procedures around consent. In keeping with recent GMC recommendations, the initial approach may, however, be made by clinical teams, who will have established a rapport with patients and their families/friends. The process – regardless of whether consent is sought from patients, or an opinion from consultee – will emphasise that follow-up is through routinely collected data, including a postal questionnaire relating to patient reported outcome measures (PROMS), and ask for explicitly permission to:

(i) Allow TARN to supply all details of hospital treatment for their injury, as well as outcome (including patient-reported) over the trial follow up period to the investigating team.

(ii) Allow the investigating team to have access to identifiable data (name, address, NHS number, date of admission to hospital and hospital name), via TARN, and NHS Digital to enable data linkage and follow up.

(iii) Allow survival to 90 days and 6 months on mortality to be supplied to the investigating team (via TARN or linkage to NHS Digital).

Around one third of trauma patients who suffer from exsanguinating haemorrhage won't survive. By the time the patient’s death has occurred the trial intervention will have been implemented and no further follow up will occur. Thus there is no requirement to or utility in seeking consent to follow-up this patient.

The study will collect information on the health outcomes, survival, quality of life, use of NHS services and costs with the aim of determining whether the UK-REBOA is an effective approach that offers good value for money to the NHS.

The study was developed by clinical experts and researchers at the University of Aberdeen’s Health Services Research Unit (HSRU) to improve patient care for major trauma patients and to test whether the new REBOA intervention can improve patient’s chance of survival following major trauma. University of Aberdeen is the sole data controller for this study who also processes the data.

The trial will be overseen by a Project Management Group (PMG). The only members of the PMG who will have access to the data, and who will make decisions about the data are processed those who are substantive employees of the University of Aberdeen. The University of Aberdeen and NHS Grampian are joint sponsors of the UK-REBOA study. NHS Grampian will have no role in the processing of the NHS Digital data under this agreement nor make any decisions determining the purposes and means of the processing; their involvement in the study is to oversee the progress and conduct of the clinical study to ensure the integrity of the data being collected and the safety of the participants.

A Data Monitoring Committee (DMC) will have access to summary, aggregated data from the trial dataset, provided by the trial statistician. They will not have access to any record level NHS Digital data and do not make decisions about how the data are used, nor the purposes of the study or its methodology. A Trial Steering Committee will not have any access to data from the trial, and will only be provided with summary results at the end of the study. They will not have access to any record level NHS Digital data and do not make decisions about how the data are used, nor the purposes of the study or its methodology.

None of the grant holders, other than those employed by the University of Aberdeen (the data controller) will have access to, nor make decisions regarding, the NHS Digital data under this agreement.

NHS Digital data on hospital care and mortality are needed for patients enrolled in the study to achieve the study’s aim. NHS Digital data will only be available to and accessed by researchers at the University of Aberdeen (data controller) and will not be available to the participating centres. All data will be held securely, following University of Aberdeen data security policies and all data will be pseudonymised, reducing the potential risk of participants being identified from their data. No attempt will be made by any researchers to re-identify a participant from this pseudonymised data.

The UK-REBOA study is being undertaken because researchers and clinicians want to improve patient care and test new and novel methods of improving the chances of survival and hopefully improve health outcomes following major trauma. The Centre for Health and Randomised Trials (CHaRT) at the University of Aberdeen applied for and secured research funding for the UK-REBOA study from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme to undertake this research.

The UK-REBOA trial commenced recruitment on January 21st, 2018 and recruitment closed in April 2022. Specialist trauma centres across England recruited participants to the study and the results will be available in 2023. The aims and objectives of the study have not changed since the trial commenced and data have not been provided from NHS digital for this study before.

Data are required from NHS Digital now to analyse information on the cohort of patients to pass through the trial. Data are required to determine whether patients have survived at six-months following entry into the study. For those who have survived, data are required to determine if patients needed to return to hospital for any subsequent care (e.g. at an accident and emergency department, as an outpatient, or if they were re-admitted as an inpatient to hospital). This information is required to understand any problems patients have incurred after their initial hospital discharge and to understand the costs to the NHS of treatment for major trauma survivors. The combination of costs and outcomes (i.e. survival) data will be used to inform an economic evaluation of the REBOA intervention to determine the most clinically and cost-effective use of NHS resources.

Data are required from NHS Digital for patients enrolled in the UK-REBOA study from their date of admission (also date of randomisation) for major trauma to six-months following this date. The data are required for this time frame in order to ensure that the economic evaluation for the study captures all important resource use implications that may be related to the study intervention or control treatments. In order to evaluate the costs and outcomes associated with the trial, it is necessary to obtain data from patients recruited to the UK-REBOA study, at all trial participating centres. This is the minimal possible geographical spread of data required to evaluate cost-effectiveness. The required data are not available from any other source and there is no alternative way of obtaining the data to fulfil the purpose of the study. In order to minimise the data required, data will only be sought for participants recruited into the UK-REBOA study.

Information is required on all contacts with secondary care services (e.g. A&E, outpatients, inpatients), what services were used, how often they were used, where patients were treated (e.g on a ward or critical care), and why the contact was necessary (e.g. what was the reason for admission) and what care or tests they received. This information will all be used to inform the economic evaluation study, which forms an important part of the study.

GDPR LEGAL BASIS FOR PROCESSING

The University of Aberdeen relies upon Article 6(1)(e) of the General Data Protection Regulation (GDPR) to process personal data where processing is necessary for a task carried out in the public interest. In this instance the public interest task is research. The data are required for research purposes in the public interest- meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) - which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. The ways in which the processing of data will be of benefit to the public – thereby demonstrating that the processing is in the public interest – are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’.

- In accordance with GDPR Article 89(1) processing is subject to appropriate safeguards. These include:

i. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS Digital’s acceptance criteria (see sections 2 and 5b of this application for further details);

ii. The requested data has been assessed as proportionate to the aim pursued (see section 5a of this application for further details);

iii. Controls, data retention and processing activities have been assessed to ensure respect to the essence of the right to data protection;

iv. Measures to protect the rights and freedoms of data subjects have been assessed including transparency (fair processing) publishing subject’s rights.

The University of Aberdeen also relies upon Article 9(2)(j) of the GDPR to process special category data (in this case health data) where processing is necessary for scientific research purposes. The research being carried out, as part of this UK wide trial is in the public interest because it seeks to improve the care of major trauma patients who are at high risk of mortality. The work hopes to provide essential information for trauma clinicians and emergency medicine doctors regarding how best to prevent major, life threatening bleeding following trauma. The work aims also to provide NHS decision makers and commissioners of care with the best possible evidence to make informed decisions to help standardise care for major trauma patients.

COMMERCIAL TRANSPARENCY

NHS Digital is content that the purpose of this study is to assess whether the UK-REBOA is an effective approach that offers good value for money to the NHS, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in England.

However, in the interests of full transparency, it is noted here that the trials unit deal directly with one manufacturer (Prytime Medical Devices, Inc) with whom they have a direct agreement and who provide a discount on the unit price for UK-REBOA trial participants. There are other manufacturers of the REBOA device and individual trial sites are not excluded from using their preferred manufacturer.

Thus, results of this study may contribute towards commercial work that results in tangible or intangible benefit for Prytime Medical Devices, Inc.

Prytime Medical Devices, Inc will have no access to record-level NHS Digital data, nor any involvement in the processing of NHS Digital record-level data, and are therefore not considered a Data Controller for this study. Prytime have no ability to suppress the outcomes of this study, nor any say in the management of the outputs and their dissemination to the public and health professionals.

METHODOLOGY

>The clinical trials unit at the University of Aberdeen (CHaRT) will generate two cohort files (containing a total of approximately 90 patients across the two files) randomised to the UK-REBOA study.

- One cohort is for Consented individuals (Opt outs do not apply).

- One cohort is for individuals under Consultee advice (Opt-outs do apply).

>Each file will contain unique study identification numbers (Study IDs), NHS Number, Date of Birth, Gender assigned at Birth and Post Code will be securely transferred from the University of Aberdeen to NHS Digital to enable linkage to mortality and HES records. Additional to this, the University of Aberdeen will also provide to NHS Digital with the date of consent for each participant and a withdrawal date (if applicable).

>NHS Digital will then use the participant identifiers and extract Hospital Episode Statistics (HES)/ Emergency Care Data Set (ECDS) and Civil Registrations Deaths Secondary Care Records (mortality) data for each trial participant in each cohort, linking the files via the unique UK-REBOA study number.

>NHS Digital will apply National Data Opt Out to the files of those who have participated in the study under Consultee Advice/Direction to ensure their Rights as an Individual have been maintained.

> NHS Digital will securely return the pseudonymised HES/ECDS and mortality data, including the linked UK-REBOA study number and no other identifiers to the University of Aberdeen.

>The University of Aberdeen will then link the NHS Digital HES/ECDS and mortality data to the main trial dataset, using only the UK-REBOA study number. Linkage through the study number means that it is highly unlikely that an analyst can personally identifiable data such as postcode or NHS number. Moreover, no attempt will be made to re-identify a participant by any personnel working on the UK-REBOA study.

The University of Aberdeen will securely store all data on a database within the clinical trials unit (CHaRT) in line with CHaRT standard operating procedures (SOPs). Access to the database will be restricted to study investigators and authorised personnel for the purposes described, all of whom are substantive employees of the University of Aberdeen. Analysis will be performed by appropriately qualified statisticians and health economists. The trial data are stored separately from the participant identifiers, and the data analysts will not be able to link patient identifiers to the trial or NHS Digital data. The datasets will not be re-linked and the data will remain pseudonymised.

The data controller also separately shares the participants' identifying details with the Trauma Audit and Research Network (TARN) so that TARN can provide the clinical trials unit with linked data routinely collected for patients following major trauma. The TARN data serves to capture detailed clinical outcomes over the initial phase of hospitalization. Therefore, the University of Aberdeen will separately receive data from NHS Digital and TARN. Each dataset will be added to the UK-REBOA dataset in the manner described. To this extent, the data provided by NHS Digital and TARN will be separately linked through the patient’s unique UK-REBOA study number. No linkage of the two datasets is undertaken outside of the UK-REBOA database. For example, the datasets will not be linked externally and then imported as combined data.

The University of Aberdeen will analyse the dataset to:

1) estimate six-month mortality following randomization to the UK-REBOA study;

2) estimate the costs to the NHS provided secondary care associated with REBOA + standard care compared to standard care alone;

3) determine the cost-effectiveness of REBOA + standard care compared to standard care alone over a six-month time horizon;

4) use the cost and mortality data to model longer term outcomes (e.g. survival analysis) associated with the trial interventions.

To enable these analyses and to robustly deliver the aims and objectives of the UK-REBOA study protocol, NHS Digital data (HES and mortality) are required. Data will only be requested from the date of randomisation of a patient to the UK-REBOA study until six-month post-randomisation. HES data will include all available contact with secondary care (admitted patient care, Accident and Emergency (Emergency Care Data Set), outpatients) to accurately ascertain costs to the NHS. Mortality data will include date and reason for death. Data will be restricted to include only patients participating in the UK-REBOA study.

Data analysis will be carried out via University of Aberdeen owned devices connected to the University of Aberdeen network either directly in person or remotely, using an appropriate statistical package. To remotely access the devices requires a secure 2-factor authenticator (VPN) and users are then able to securely access the secure server on the University’s IT framework run by the Directorate of Digital & Information Services (DDIS). All data analysis will be conducted within the confines of the University’s secure server, and will not be downloaded to remote devices for storage or processing.

The DDIS at the University of Aberdeen stores data in geographically remote data centres. Whilst in the dedicated folder at rest, the NHS Digital Data is held in an encrypted state. The Riverside Building (until October 2022 called the Aberdeen Business School) data centre will be a primary network storage location. The data replicates constantly between the data centres and a file saved in the Edward Wright Building would replicate to the Riverside Building seconds later. Although the Riverside Building data centre is located within a Robert Gordon University building, the data centre itself is operated and maintained by a University of Aberdeen, Robert Gordon University and North East Scotland College partnership. No staff employed by Robert Gordon University and North East Scotland College will have access to the NHS Digital data. Any attempt to gain access to the NHS Digital data stated in this agreement by employees of Robert Gordon University and North East Scotland College will constitute a breach of the agreement.

Additionally, DDIS will back-up all NHS Digital data held to two sets of NHS Digital specific backup tapes, ensuring the data is easily identifiable, and easily deleted on request. The DDIS will store each set of back-up tapes in a locked, restricted access room, in separate University of Aberdeen buildings, with access controlled by DDIS.

All essential data and documents (electronic, hard copy and audio recordings) shall be retained for an archiving period of at least 10 years after close of trial according to funder and ethical requirements.

The data from NHS Digital will not be linked in any other way or with any other datasets beyond those described above. All outputs from the analysis will be aggregated with small numbers suppressed in line with the HES analysis guide. No record level data falling under this agreement will be shared with any third-party. The Data will be used only for the purposes described in this agreement.

HES and ECDS DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION

In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, data processors must make sure that:

· National-level figures only may be presented unrounded, without small number suppression

· cell values from 1 to 7 (inclusive) are suppressed at a sub-national level to prevent possible identification of individuals from small counts within the table.

· Zeros (0) do not need to be suppressed.

· All other counts will be rounded to the nearest 5.

Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

Dissemination of the findings forms an integral part of the UK-REBOA study’s strategy to maximize the potential for patient benefit. The UK-REBOA trial results are expected to be available for publication in 2023 with the aim that they will inform NHS care for patients following major trauma, both in the UK and internationally. To achieve this aim, the results of the trial hope to be widely disseminated in scientific journals, at national and international conferences, and through engagement with patient and other interest groups such as charities. To ensure dissemination of the results to the widest possible range of stakeholders (i.e. clinicians, trauma researchers, patient groups, charities, policy makers, health services researchers, health economists), open-access, peer-reviewed, high impact journals hope to be targeted for publication. The study results aim to also be published in the form of a report to the study funders (NIHR), available on their website. Additional publications hope to include the main trial findings with separate publication of the cost-effectiveness findings. The choice of journal for publication and conference for presentation will depend on the subject matter and the target audience. In addition, a plain English summary that details the study findings in non-technical language aims to be developed and disseminated to trial participants, their families and other interest groups, including relevant charities.

It is expected that the final study report will be drafted and submitted for peer review in March 2023, with the final published report available at the end of 2023. It is anticipated that a number of further papers will be published and presentations delivered to national and international conferences (including clinical and cost-effectiveness findings) between late 2022 and 2023. When each paper is published, information aims to be made available on the UK-REBOA trial website and the study team will liaise with the University of Aberdeen communications office to assist in disseminating the results to the widest possible audience (e.g. through media interviews).

All dissemination outputs will include only aggregated level data, with small numbers suppressed in line with the HES analysis guide. No patient identifiable data will ever be published.

Bleeding is the most common cause of preventable death after severe injury (also known as "trauma"). Treatment for such bleeding is urgent. Research has shown that early treatment saves lives. Stopping the bleeding usually requires an operation – but some patients die before this can be done. REBOA (which stands for "Resuscitative Endovascular Balloon Occlusion of the Aorta") is a new treatment for trauma patients with severe bleeding. REBOA involves passing a small inflatable balloon into the aorta (your main artery), to stop the bleeding, until you can be taken to an operating theatre. The balloon is then removed.

It is essential to find out if REBOA is helpful to patients. The National Institute for Health Research is funding this clinical trial to answer this question. The primary clinical outcome aims to be 90-day mortality (defined as death within 90 days of injury, before or after discharge from hospital). The primary economic outcome aims to be lifetime incremental cost per Quality Adjusted Life Year (QALY) gained, from a health and personal social services perspective and, this benefit will be measured based on the NHS Digital data. The trial will provide information to clinicians on how best to treat major trauma to get the best results for patients and to determine whether REBOA offers value for money (i.e whether it is a cost-effective use of NHS resources).

The study hopes to provide the only robust evidence on the clinical and cost-effectiveness of this procedure. The results of the study aim to be shared with patients, clinicians and hospital decision makers, and outcomes will be widely disseminated to ensure they are considered for implementation as a means to improve care for major trauma patients.

It is expected that the trial will help inform the implementation of the most clinically and cost-effective intervention into NHS practice (from March 2023 onwards).

Yielded Benefits is not a requirement for new applications.