A multi-centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol (MHP) activation. CRYOSTAT2- Application to access 1 year mortality data for recruited patients

On 1 February 2023, NHS Digital merged with NHS England. NHS England has assumed responsibility for all activities previously undertaken by NHS Digital. The merger was completed by a statute change. Any reference made to NHS Digital within this Data Sharing Agreement is in reference to the merged organisation known as NHS England.

No new data will flow under this version of the agreement.

Queen Mary University of London (QMUL) together with NHS Blood and Transplant (NHSBT) is currently undertaking a large multi-centre trial in major trauma funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA ref: 15/57/02). The study is led by QMULs Chief Investigator and NHSBTs Consultant Haematologist and started recruitment in May 2017, which is ongoing.

QMUL are the Sponsor for the study. NHSBT (UKCRC registered Clinical Trials Unit) are the Host Institution managing the day to day activities for the trial, including data collection and analysis. For the purposes of this study, NHSBT (Host Institution) and QMUL (Sponsor) are joint data controllers. NHSBT are the sole data processors. The funder for the study (NIHR HTA) is not a data controller or processor.

Bleeding is a major cause of death in severely injured patients. Many of these patients rapidly develop an abnormality of the clotting system, known as ‘acute traumatic coagulopathy’ (ATC). The two most important abnormalities in ATC are low fibrinogen and increased clot breakdown. It has been hypothesised (and there are some non-randomised studies that show this) that in treatment of major trauma patients who are massively bleeding, fibrinogen therapy stops bleeding more effectively than standard care, reduces transfusion needs and may reduce death rates.

Patients who have severe bleeding after injury develop a problem with their clotting system which means that they tend to bleed more. One of the main problems is due to low levels of fibrinogen, a clotting protein normally circulating in the bloodstream. Fibrinogen acts as the ‘glue’ which holds a blood clot together and at low levels, blood clots don’t form properly and bleeding can continue. Cryoprecipitate is a frozen blood component prepared from plasma and rich in fibrinogen. By transfusing a high dose of Cryoprecipitate (e.g. 3 pools of cryoprecipitate equivalent to 15 single units cryoprecipitate or 6g fibrinogen supplementation) early to replace fibrinogen levels in bleeding trauma patients the study believe blood clots will be more stable and reduce bleeding.

The primary aim of the multi-centre, randomised controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol (MHP) activation study, CRYOSTAT 2 study (for short), is to evaluate the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage, particularly to understand if it reduces mortality. The primary outcome is all-cause mortality at 28 days post-injury and secondary outcomes include all-cause mortality (including death from bleeding) at 6 hrs, 24 hours, 6 months and 12 months from arrival at hospital. This is an unblinded parallel group randomised control trial with two cohorts – the intervention group will receive 3 pools of cryoprecipitate within 90 minutes of arrival at hospital plus the standard major haemorrhage protocol; the control group will be treated with the standard major haemorrhage protocol only. The study is only recruiting these specific patients and the applicants are requesting data for those patients only.

CRYOSTAT 2 is a follow-on trial from a previous pilot study, CRYOSTAT 1, which showed early replacement of fibrinogen with Cryoprecipitate can rapidly restore fibrinogen levels and may halve mortality for patients with major trauma haemorrhage. No NHS Digital data was collected/analysed as part of the CRYOSTAT 1 pilot study.

As part of the CRYOSTAT 2 informed consent process, patients can confirm or refuse consent for their identifiable data to be recorded and used for the purpose of the trial. Consented participants can withdraw from the study at any time. CRYOSTAT 2 research teams will always respect the wishes of participants in accordance with NHS guidance on good clinical practice. Another Agreement NIC-365492-H6D6V provides the detail on the cohort that relies on Section 251.

This study has the potential to change national and international clinical guidelines in the treatment of this patient group.

The objective of the previous DARS agreement was the collection of NHS Digital mortality data (date of death, cause of death) in patients recruited to CRYOSTAT 2 to calculate survival rates. Identifiable data was required to enable matching of NHS Digital data with CRYOSTAT-2 participants. As participants may not survive post-discharge, it is only by capturing the centralised NHS Digital mortality data that post-discharge survival rates can be calculated. By using NHS Digital data, NHS BT avoid burdening participants and research teams with additional follow up data capture. Identifiable data will be kept for two years after the trial is completed to enable analysis to take place, after which it will be destroyed.

The lawful basis for processing of data in this study are GDPR Article 6(1) e, and Article 9(2) j; Article 6(1)e: processing is necessary for the performance of the trial, which is carried out in the public interest.

Public Authority: The Data Protection Act 2018 s 7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”. Schedule 1 of the FOI Act 2000 lists “maintained schools and further and higher education institutions” as public authorities and the ICO confirms “Within the education sector, it is the governing body of a school, further education institution or university that is the public authority.” NHS Blood and Transplant is an NHS special health authority and is therefore considered a public authority

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).

All participants will be enrolled in the study without informed participant consent due to the emergency nature of the trial (i.e. a “waiver of consent” will be applied). The participant will then be randomised, and the allocated intervention will be delivered within ninety minutes. This may be before the participant regains capacity or there is any opportunity to identify and approach a personal consultee. As a result, consent can only be sought for the participant to remain in the study through the ongoing collection of follow-up data, and “retrospective consent” for the administration of cryoprecipitate is not possible.

As soon as appropriate, after the administration of the intervention, a personal consultee for the participant will be identified and approached, given an information sheet and asked to provide their advice for the participant to remain in the trial. If the participant remains incapacitated and a personal consultee is not available, or if approaching the personal consultee is likely to induce a delay or it is deemed by the research team to be inappropriate to approach the personal consultee, advice from a professional consultee will be sought.

For the purpose of this study, a professional consultee is defined as a clinician (qualified doctor or registered nurse) with appropriate training (according to local Trust policies) to take on the role of professional consultee. Professional consultees must not be directly

involved in the patient’s care and cannot be a member of the core research team at site. Professional consultees should be aware of the aims of the study and know what the intervention is.

Sites should obtain the advice of a professional consultee as soon as possible after randomisation to enable continued collection of data should the patient be discharged/self-discharge/transferred to another NHS Trust before the research team can approach the patient and/or personal consultees for consent/advice.

The research team will monitor the ongoing status of the participant and their ability to provide informed consent. If the participant does not regain capacity, a personal and/or professional consultee’s advice is sufficient for the participant to remain in the study for the ongoing collection of follow-up data at site up to day 28, discharge or death.

No new data will flow under this version of the agreement.

The primary aim of the CRYOSTAT 2 study is to evaluate the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage, particularly to understand if it reduces mortality. The primary outcome is all-cause mortality at 28 days post-injury and secondary outcomes include all-cause mortality (including death from bleeding) at 6 hrs, 24 hours, 6 months and 12 months from arrival at hospital.

The objective of the previous agreement was the collection of NHS Digital mortality data (date of death, cause of death) in patients recruited to CRYOSTAT 2 to calculate survival rates. By capturing the centralised NHS Digital mortality data, it will avoid burdening participants and research teams with additional follow up data capture post-discharge.

Twenty-three Major Trauma Centres (hospitals) across England and Wales are participating in the study. Up to five sites in the United States will also be taking part. This agreement does not apply to the US centres, as mortality data will be collected from these sites separately. The data will not be shared/used with any other institutions/agencies or US centres."

The data is only to be used for research analysis purposes and will not be shared/used with any other institutions/agencies or US centres. The study statisticians from NHSBT will have access to the NHS Digital data for analysis purposes. However, if required, aggregated data with grouped mortality and small numbers suppressed will be viewed by the Chief Investigator (Queen Mary University of London) or Co-Chief Investigator (NHSBT). Data will be viewed in a secure office with a study statistician and not electronically transferred outside NHSBT.

Permission to share patient identifiable data is achieved by signed informed consent.

Under the previous version of the agreement, participating hospitals securely submitted the minimum participant identifiable data set required for linkage to NHS Digital data to NHSBT data managers. This consisted of a unique study identifier, NHS number, forename, last name, date of birth, gender and postcode.

NHSBT data managers securely received the data and stored it on secure servers. The NHSBT data managers and statisticians have been appropriately trained in data protection and confidentiality as part of NHSBT’s annual mandatory training process. Access to areas where processing will take place requires a secure cardkey and secure logins are used on computers. Access is restricted to only NHSBT data management and statisticians involved in the study who are all substantive employees of NHSBT who have been appropriately trained in data protection and confidentiality.

The data will be verified by the statisticians to ensure consistency of data and that current data protection legislation is followed.

NHSBT have sent the data set required for linkage to NHS Digital.

NHS Digital securely received, processed and returned the data (unique identifier, cause of death, date of death, sex, postcode) to the NHSBT study statisticians who stored it on secure servers with restricted access.

The NHSBT study statistician will only use the data for mortality analysis for CRYOSTAT 2 participants. There will be no further linkage to other data sets.

The non-derived data set will be kept for the duration of the CRYOSTAT 2 trial. All patient identifiable data will be deleted two years after the end of the study by the study statisticians and data managers. This will be evidenced with quality assurance processes in place. There will be no requirement or attempts to re-identify individuals.

NHS BT will compare NHS Digital data with information held for CRYOSTAT 2 participants on when the patient was admitted to hospital and create (derive) a flag that indicates whether or not the trial participant was alive or dead 28 days after hospital admission. This new variable would have been derived from the NHS Digital data received.

Patient identifiable data for trials are kept accordingly to the NHSBT Clinical Trials Unit policy which states that data is kept for two years after study completion to allow for analysis to take place.

This level of data flow is identifiable. There will be no subsequent flows of data.

The main academic output of this study will be a manuscript submitted for publication in 2022 in an open access international medical journal of broad readership when the trial is completed (e.g. The Lancet, New England Journal of Medicine). Whenever possible, the study team will aim to make publications free to access, depending on journal policies.

The main results will also be widely disseminated by abstracts and presentations at national and international scientific conferences and meetings in the fields of major trauma, pre-hospital medicine, emergency medicine, trauma surgery, haematology and transfusion.

Secondary outputs will be papers describing associated methodology and health economic details of the study. Study findings (including mortality data at a summary group level by treatment arm and non-identifiable) will be presented at stakeholder meetings and at forums specific for interested patient groups.

Outputs will include reporting of mortality data at a summary group level. Due to the number of patients in the trial, there will be no small numbers. It is envisaged that early phase results evaluating in-hospital outcomes will be released within 3 months of the final participant enrolment. Data on longer term outcomes and health economic evaluation will be published after the 6 month follow up period has been completed.

All participating hospital research teams and Public Advisors in Injury Research (PAIR) group involved with the study will be invited to a close out Investigator’s Meeting to discuss the findings of CRYOSTAT-2.

Members of the CRYOSTAT 2 PAIR group will be enlisted to present and contribute articles on patient forums and public and patient involvement events.

Study results (non-identifiable summary group data by treatment arm) will be made publicly available on several websites, e.g. the CRYOSTAT 2 study website, Centre for Trauma Sciences at QMUL, NHSBT, and Bart’s Charity.

It is expected that there will be wide media interest, with press releases and articles pertaining to the study from QMUL, NHSBT, NIHR and participating hospitals. Study teams will also be very active on Twitter.

Surviving study participants will receive a trial completion newsletter summarising the main results of the trial.

Further interest and outputs may be generated if the results of the trial impact on national and international guidelines for the treatment of major trauma haemorrhage.

The benefits of capturing and analysing the mortality data will be to definitively determine whether early high-dose cryoprecipitate improves survival from traumatic bleeding. This study focuses on severely injured trauma haemorrhage, where outcomes are poor, and mortality is high. As approximately 17,000 people in the UK die from traumatic injury each year, the high-quality evidence provided by the study results are clearly in the public interest.

The trial is the largest study worldwide in major trauma haemorrhage, and the results of CRYOSTAT 2 are internationally anticipated as it is considered a vital trial for trauma care. The findings will immediately influence clinical guidelines for the treatment of major trauma haemorrhage and transfusion practice. The applicants have involvement and experience of developing guidelines (NICE Trauma, British Committee Standards in Haematology) and will facilitate early rewriting of policies according to CRYOSTAT 2 results.

Findings from the study will also have an impact in other specialties where major bleeding frequently occurs (e.g. vascular surgery, post-partum haemorrhage, gastrointestinal bleeding, orthopaedics and anaesthetic haemorrhage guidelines). The study will lead to tangible benefits for patients who suffer major trauma haemorrhage, in terms of evidence-based medicine, consistency of treatment, training and equipment, as well as having the potential to prove cost effective for the NHS and society as a whole.

The health economic analysis undertaken in the study will determine whether this form of treatment is cost effective to the NHS in the following ways:

(1) Treatments for fibrinogen supplementation, including cryoprecipitate or fibrinogen concentrate (a commercially alternative) are costly. NHSBT data have shown a 22% rise in cryoprecipitate use between 2011- 2013 (at a cost of £6.4 million). There is a risk that use of these products, including more expensive fibrinogen concentrate, costs will continue to increase without assessment within a clinical trial. Cryoprecipitate is used more worldwide, forms part of the standard major haemorrhage protocol and transfusion packs and is a quarter of the cost of fibrinogen concentrate. It is important that these products are evaluated properly so they can be used in a cost-effective manner, and not waste NHS resources.

(2) The results will show if the intervention reduces the need for transfusion products, which may reduce costs to the NHS by patients needing less red blood cells, plasma and platelets.

(3) The results will inform whether patients receiving the intervention reduce costs to the NHS in terms of use of intensive care and critical care resources.

The study will demonstrate that the NIHR and HTA are world leaders in the conduct of clinical trials in trauma and transfusion medicine.

This study does not have postgraduate research student support.

CRYOSTAT 2 have been able to receive appropriate data from NHS Digital in order to analyse the short-term outcomes measures in the trial and work on 6- and 12-month outcomes and the health economic analysis is underway. The short-term results have been shared with the trial team and a manuscript summarising the results in in the late stages of preparation. When the results are made available to the wider clinical community via this manuscript, clinicians and policy makers can consider any relevant changes in care for patients with major trauma haemorrhage as described above.The final report to the NIHR HTA (which results in an HTA Monograph) has been delayed until Feb 2023.