Intensive Care Unit Randomised Trial Comparing Two Approaches to OXygen Therapy (UK-ROX) - Consent

Intensive Care National Audit & Research Centre (ICNARC) requires access to NHS England data for the purpose of the following research project: Intensive Care Unit Randomised Trial Comparing Two Approaches to OXygen Therapy (UK-ROX)

The following is a summary of the aims of the research project provided by ICNARC:

UK-ROX is a large-scale, multi-centre, data-enabled, registry-embedded, randomised clinical trial (RCT) aiming to evaluate the clinical and cost-effectiveness of conservative oxygen therapy versus usual oxygen therapy, in adults receiving invasive mechanical ventilation (MV) with supplemental oxygen following an unplanned ICU admission. Oxygen is one of the most common treatments given to patients in the ICU. However, there is currently insufficient evidence to guide clinicians in the use of oxygen to minimise the potential harm caused by giving too little or too much oxygen. The long-standing fear of harm due to hypoxia from giving too little oxygen has led to a tendency to give too much oxygen in order to counter-balance this. However, giving too much oxygen risks damaging the lungs and other vital organs.

The importance of this research is demonstrated by the large number of critically ill patients requiring MV treated in NHS ICUs each year. Of the 337,312 admissions to ICUs participating in the Case Mix Programme (CMP - national clinical audit of adult critical care) between 1 April 2017 and 31 March 2019, 96,028 (29%) received MV during their stay. Of these, 34% died before hospital discharge, extending to an anticipated 37% by 90 days. Prior to starting the UK-ROX trial, the UK-ROX trial team conducted a meta-analysis (a method of combining the results of previous clinical trials carried out answering a similar research question). With the risk ratio from the meta-analysis of 0.91 (0.75 to 1.09) in favour of more conservative oxygen therapy, if a similar effect size is observed in UK-ROX, this would equate to >3,000 lives saved annually in the UK if the intervention was implemented. Optimising oxygen therapy may also reduce the financial burden of critical illness on society by reducing morbidity and improving quality of life after discharge. The proportion of admissions to adult ICUs in the UK receiving MV has remained >30% over the past 10 years and is expected to rise with increasing admissions of elderly patients. The recent COVID-19 pandemic, in which 72% of ICU patients with COVID-19 received MV demonstrates the need for a comprehensive evidence base for patients requiring MV as part of their ICU care. As a specialised high-cost service, it is imperative to optimise treatments that are delivered to large proportions of ICU patients.

ICNARC aim to conduct an ambitious, cost-efficient, data-enabled trial to address a fundamental knowledge gap in intensive care medicine. ICNARC will evaluate the clinical effectiveness of conservative oxygen therapy (versus usual oxygen therapy) on 90-day all-cause mortality and its cost-effectiveness for incremental costs, quality-adjusted life years (QALYs) and net monetary benefit at 90 days. ICNARC propose an RCT that will recruit 16,500 MV ICU patients into either conservative or usual oxygen therapy. ICNARC wish to provide a definitive answer as to whether reducing the amount of oxygen given to ICU patients receiving MV improves their survival and from this develop national guidance that can be easily and immediately implemented throughout the NHS.

The primary objective for processing NHS England Data in this agreement is to provide important outcome data for UK-ROX. The outcomes for the trial are:

1. Primary outcome:

• 90-day all-cause mortality

2. Secondary outcomes:

• In-hospital mortality (censored at 90 days)

• Mortality at ICU discharge, 60-days and one-year

• Duration of ICU and acute hospital stay (censored at 90 days)

• Health-related Quality of Life (HrQoL), assessed using the EuroQol EQ-5D-5L questionnaire (descriptive system; patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement), at 90 days

3. Primary economic evaluation outcome:

• Incremental costs, quality-adjusted life years (QALYs) and net monetary benefit at 90 days

4. Secondary economic evaluation outcomes:

• HrQoL, assessed using the EuroQol EQ-5D-5L questionnaire, at 90-days

• Resource use and costs at 90 days

• Estimated lifetime incremental cost-effectiveness.

Data from NHS England is requested to contribute to the analysis of the study outcomes, alongside separate trial data collected from hospital records at participating sites and reported outcomes from the participants themselves.

Common Law Duty of Confidentiality and Patient Objections:

The decision to initiate invasive mechanical ventilation is most often made during a time-sensitive emergency, where any delay in commencing treatment could be detrimental to the patient and the scientific validity of the trial. Attempts to obtain fully informed prospective consent would not be appropriate during such an emergency – patients will lack capacity to consent during this time, and approaching their Personal Consultee (relative/friend) could cause additional stress to family/ friends who are already very distressed by the patient’s critical illness. In addition, the oxygen target range used in the conservative oxygen group is relatively safe and is not outside the range which can be used in current clinical practice, as determined by treating clinicians.

Considering these reasons, a deferred consent model (‘research without prior consent’) has been utilised in the UK-ROX trial, a model that has been found to be acceptable to patients and clinicians in several previous RCTs conducted in the critical care setting. This consent model has been informed and refined by patient and public involvement (PPI). The South Central - Oxford C Research Ethics Committee have approved these consent procedures and granted an emergency waiver of consent.

This DSA (DARS-NIC-427962-M3K1W-v0) covers only patients who have provided informed deferred consent. A separate DSA, DARS-NIC-754519-V1T5M-v0, covers patients who have had consultee opinion or where the common law duty of confidentiality is addressed by section 251 support. The DSAs have been separated due to operational reasons.

The following NHS England Data will be accessed:

> Hospital Episode Statistics (HES) Admitted Patient Care (APC) and HES Outpatients (OP) – necessary to understand the economic impact of conservative oxygen therapy versus usual oxygen therapy.

> Civil Registration Mortality – necessary to investigate the primary and secondary outcomes of the study.

Patient date of death is requested from NHS England to directly contribute to the clinical evaluation primary outcome data (all-cause mortality at 90 days) and secondary outcome data (all-cause mortality at 1 year, for patients who reach this time point during the trial) (primary purposes). In addition, a subset of trial participants (15%, n = 2475) are actively followed-up and sent a questionnaire by the UK-ROX trial team at ICNARC at 90 days post-randomisation. Given the nature of critical illness, unfortunately some participants will pass away during the trial follow-up period. Where the trial team learns that a participant has passed away, no contact will be made - helping to ensure relatives are not caused unnecessary distress by inappropriate contact (secondary purpose).

The level of the Data will be:

> Identifiable - The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. Although ICNARC have the technical ability to re-identify participants, there will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

The Data will be minimised as follows:

> Limited to a study cohort identified by ICNARC – 7,300 consented patients from around 100 NHS critical care units across England, Wales, and Northern Ireland. Of those, 6,800 are from England and 500 are from Wales. Recruitment is ongoing. Participants who declined or withdrew consent for data linkage will not be included in the cohort submitted to NHS England for linkage purposes.

> Limited to data between 2021/22 - 2024/25; This is because recruitment commenced in May 2021 and will continue till November 2024, with the final participant requiring follow up in February 2025 (the final data collection timepoint for this cohort) and data is required to cover this period.

> Limited to England and Wales.

> Following data receipt, ICNARC will minimise the data by date of randomisation per patient.

ICNARC 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.

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

Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party.

ICNARC has determined the processing is necessary for its legitimate interests in being able to benefit healthcare organisations. ICNARC is an independent health research charity which aims to help improve the quality of critical care through audit, research and education with, and in the interests of, patients and those who care for them. ICNARC requires data from NHS England for the purposes of these legitimate interests. ICNARC process data for this study under the legitimate interest legal basis. This is because ICNARC is a registered charity and the data processing described here is to support scientific and statistical research.

Processing personal data is necessary for ICNARC's legitimate interests which are described in this agreement. The Data to which access is requested are proportionate and necessary to achieve those interests. ICNARC has completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override ICNARC’s legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subject’s interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; pseudonymisation to minimise any risk of identifying individuals; protection of the data in a secure environment and guaranteeing secure destruction at any stage at the request of NHS England or after a defined period on completion of the project.

The lawful basis for processing special category 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 it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The funding is provided by the National Institute for Health and Care Research (NIHR), Health Technology Assessment Programme. The funding is specifically for the UK-ROX trial described.

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

London School of Hygiene and Tropical Medicine (LSHTM) is a processor acting under the instructions of ICNARC. LSHTM’s role is limited to health economic analyses as the UK-ROX trial team’s health economist is based at LSHTM.

Babble Cloud provides IT hosting services to ICNARC and will store the Data as contracted by ICNARC.

Exponential-E provides IT back up services to ICNARC and will store copies of the Data as contracted by ICNARC.

The Trial Management Group includes members from the following organisations: University of Plymouth, University of Southampton, Maidstone and Tunbridge Wells NHS Trust, Salford Royal NHS Foundation Trust, South Tyneside and Sunderland NHS Foundation Trust, Cardiff University, Wellington Regional Hospital (New Zealand), LSHTM, and ICNARC. However, only ICNARC and LSHTM will receive and process NHS England Data.

The Trial Management Group includes individuals responsible for the day-to-day management of the trial, such as the Chief Investigators, statistician, trial manager, research nurse, data manager. The role of the group is to monitor all aspects of the conduct and progress of the trial, ensure that the protocol is adhered to and take appropriate action to safeguard participants and the quality of the trial itself; members of the Trial Management Group have no control over the aims and objectives of this project, and as such, they only provide expertise and advice, and do not make data processing decisions as part of the Group.

Public and Patient Involvement (PPI) helped refine the purpose of the research and supported the collection of the data for the purposes described above. PPI has been, and is, central to the development and oversight of the UK-ROX trial. A patient representative is a co-investigator on the UK-ROX trial and has contributed significantly into the development of the trial. This has included the development and refinement of the consent procedures and consent materials (including the patient information sheets and consent forms), helping to ensure the acceptability of the trial and its procedures to patients. The patient representative contributes to the ongoing management of the trial, as a member of the Trial Management Group. The Trial Steering Committee, a majority-independent committee which oversees the trial on behalf of the Funder and Sponsor, also includes independent PPI representation.

ICNARC will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth and Postcode) and a unique person ID (UK-ROX Trial Number) for the cohort to be linked with NHS England data.

NHS England will provide the relevant records from the HES and mortality datasets to ICNARC. 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.

ICNARC will securely transfer the Data to LSHTM. Some Data may be derived before data transfer, but the majority of the NHS England Data is required by LSHTM for their economic analysis.

The Data will be stored on servers provided by Exponential-E to ICNARC and at LSHTM.

ICNARC uses offsite back-up services provided by Exponential-E.

ICNARC also stores Data on the Cloud provided by Babble Cloud.

The Data will be accessed by authorised personnel via remote access.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not leave England and Wales at any time. Remote processing will be from secure locations within England/Wales.

Access is restricted to employees of ICNARC and LSHTM who have authorisation from the UK-ROX trial team.

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

The Data will be linked at person record level with the individual UK-ROX trial participant trial data, which contains details of oxygen and ventilation treatment in ICU (obtained from participating hospitals) and quality of life questionnaires completed by patients, using the UK-ROX trial number.

The UK-ROX trial team at ICNARC will additionally create a fully pseudonymised trial dataset which will be linked to both the pseudonymised mortality data, and the pseudonymised HES data from NHS England using the unique trial number field. The pseudonymised linked record level dataset will also be made available to the health economist, who is part of the UK-ROX trial team, based at the London School of Hygiene and Tropical Medicine (LSHTM) who will conduct the health economic evaluation.

The subsequent analyses will directly answer the trial research questions and achieve the purpose of finding out whether conservative oxygen therapy is superior to usual oxygen therapy, for the benefit of future NHS patients.

The Data will not be linked with any other data.

Access to patient identifiable data is restricted according to ICNARC’s data access policies and procedures with access restricted to named individuals on a need-to-know basis, using auditable information systems.

Identifiable data will be anonymised within one year of the end of the study and the identifiers will be confidentially destroyed from all locations (ICNARC, Exponential-E). The dataset shared with LSHTM will contain no identifiers.

Analysts from ICNARC and LSHTM will analyse the Data for the purposes described above.

The expected outputs of the processing will be:

> A Study Report, detailing the project and the results along with the recommendations for future policy, practice, and research, will be submitted to the National Institute for Health Research, Health Technology Assessment (NIHR HTA) for publication. The NIHR HTA report will be submitted for publication in June 2025. HTA publishes research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS.

> Submissions to high-impact, open-access, peer reviewed scientific journals and relevant professional journals. The primary results will be submitted for publication following the completion of recruitment, follow-up, and analysis, anticipated to be April 2025.

> Presentations at appropriate conferences, such as the Critical Care Reviews (CCR) Annual Meeting; European Society of Intensive Care Medicine (ESICM) Annual Congress; Intensive Care Society (ICS) Annual Conference; British Association of Critical Care Nurses (BACCN) Annual Conference; the Case Mix Programme Annual Conference and Exhibition; and the Annual Meeting of the UK Critical Care Research Forum. It is anticipated that the findings will be presented from 2025 onwards.

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

> Conferences

> Study website

> Social media including the Study X/Twitter page and ICNARC’s X/Twitter page. ICNARC has more than 10,000 followers which can be used to actively publicise progress with the research and disseminate the findings.

> The research team has strong links with the critical care community will help ensure that UK-ROX is at the forefront of the critical care community’s research agenda throughout the duration of the trial. This includes: the Faculty of Intensive Care Medicine (FICM), Intensive Care Society (ICS), British Association of Critical Care Nurses (BACCN), Royal College of Nursing Critical Care In-flight Nursing Forum (RC CCINF), NIHR Clinical Research Network Critical Care National Speciality Group and the UK Critical Care Research Group.

> One of the co-chief investigators on the trial is a member of the Academy of Medical Royal Colleges Academic Leads Committee.

> Professional societies concerned with the care of critically ill patients, including the ICS and FICM, provide them with evidence to inform future clinical guidelines arising from the research.

> Presentation slides and briefing papers will be prepared for use by the study team to disseminate the research findings.

Outputs are expected to be produced throughout 2025.

The findings of this research study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study.

In the UK, around 184,000 people are admitted to an adult intensive care unit (ICU) each year. Over 30% (55,000) of these receive advanced respiratory support in the form of mechanical ventilation (MV) with supplemental oxygen. This makes oxygen one of the commonest drugs administered to patients in ICU. Despite this, there is genuine uncertainty surrounding the best amount of oxygen to give to patients to improve survival and quality of life outcomes. It is not yet known whether conservative oxygen therapy is clinically and cost-effective compared to usual oxygen therapy, in which clinicians tend to aim for higher targets. UK-ROX will examine which treatment is best in terms of clinical and cost-effectiveness, and it is anticipated that if either treatment is found to be superior, this finding may be implemented into national and international clinical guidelines and subsequently the NHS. This may lead to improvements in the delivery of invasive mechanical ventilation with supplemental oxygen, ensuring that the amount of oxygen given to patients would be informed by robust and high-quality RCT evidence.

The use of the data could lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.

ICNARC anticipate the results to be easily adopted into clinical practice as it is a simple change in target range and does not rely upon a new drug or device becoming available. The team includes experts in guidelines and dissemination of RCTs and expect the results to influence global practice. This may reduce the burden on patients, their carers, and critical care units within the NHS and globally. It is not currently known if conservative oxygen therapy is beneficial for critically ill patients receiving mechanical ventilation in the ICU, however, if the hypothesis is true and the intervention is found to be clinically effective, participants in the intervention group and future critically ill patients within the NHS and worldwide may benefit from increased survival. The NHS and healthcare systems worldwide may also benefit in terms of net monetary benefit, if the intervention is found to be cost effective.

This research is important to patients and the NHS, because it aims to evaluate the best amount of oxygen to give to patients to increase the likelihood of survival and improve quality of life. The findings of UK-ROX may help guide clinical decision making and inform critical care clinicians and the wider NHS on the clinical and cost effectiveness of conservative oxygen therapy versus usual oxygen therapy.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies and organisations charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

Active and wide dissemination of the results of UK-ROX is an important part of the implementation strategy and will begin upon publication of the primary trial results (see ‘Specific outputs expected, including target date’ for further details). A number of approaches have been identified, including: involving stakeholders; providing evidence in an integrated and graded way; taking account of the context and identifying the elements relevant to decision making, e.g. benefits, harms and costs; making recommendations as specific as possible; and using a multifaceted approach.

Dissemination will be led by the chief investigators working closely with ICNARC CTU and supported by other members of the Trial Management Group. Dissemination of the results will commence in 2025. In line with ICNARC’s legitimate interest of processing data for research and statistical purposes - the public (e.g. future critically ill patients) and the NHS will receive the benefits of the processing. Results of UK-ROX will help to guide critical care clinicians and the wider NHS on the clinical and cost-effectiveness of conservative oxygen therapy versus usual oxygen therapy.

ICNARC will engage patients and their families to disseminate the study progress and results through the trial website, social media, and newsletters, which will be provided to participants with the follow-up questionnaires. Wider patient and public engagement will be facilitated by the co-applicants and members of the research team, who have extensive connections with critical care communities. The PPI co-applicant will be central to ensuring the outputs from UK-ROX are patient centred and disseminated through patient networks.

ICNARC has strong relationships with critical care patients, their families, and close friends, through previous collaborations on two modules for the award winning website Healthtalk and with Intensive Care Unit Support Teams for Ex-Patients (ICUsteps), a registered charity run by former intensive care patients and their relatives, which collaborated on previous Family Reported Experiences Evaluation Study funded by the Health Services and Delivery Research (HS&DR) programme (11/2003/56). The HS&DR Programme aims to produce rigorous and relevant evidence to improve the quality, accessibility and organisation of health and social care services.

Yielded Benefits is not a requirement for new applications.