PHOSPHATE - Pragmatic randomised trial of High Or Standard PHosphAte Targets in End-stage kidney disease

University of Cambridge and Cambridge University Hospitals NHS Foundation Trust require access to NHS England data for the purpose of the following research project: Pragmatic randomised trial of High Or Standard PHosphAte Targets in End-stage kidney disease (PHOSPHATE) study.

The following is a summary of the aims of the research project provided on behalf of the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust:

“The PHOSPHATE research study aims to assess whether phosphate levels within dialysis patients, and the current treatment guidelines suggesting a target reduction in phosphate levels result in improved health outcomes for patients. The primary objective of the PHOSPHATE Study is to test the hypothesis that phosphate-lowering treatment to reduce serum phosphate level towards the normal level (≤1.5 mmol/L [millimoles per litre]) reduces fatal and non-fatal major cardiovascular events in patients receiving dialysis compared to a strategy of liberalised phosphate control with phosphate-lowering treatment for serum phosphate levels ≤2.5 mmol/L.

“Patients receiving dialysis often have higher levels of phosphate compared with people with healthy kidneys. Research suggests that higher phosphate levels may increase the risk of heart disease and death. Current treatment guidelines suggest that high phosphate levels should be reduced towards the normal level and standard care is to reduce these levels below a threshold. However, existing supporting evidence for clinical guidelines are based solely on low quality evidence from observational and pre-clinical studies. Currently, there is a lack of existing evidence from adequately powered randomised trials that phosphate lowering with any binder improves clinical or patient reported outcomes or is cost-effective.

“The study will examine whether reducing phosphate levels in dialysis patients will improve the following areas:

· Life expectancy

· Heart health

· How patients feel or function.”

Primary and secondary outcomes (listed below) will be ascertained by data linkage with NHS England data sets for participants from England, and equivalent data sets from Wales and Scotland.

Primary outcomes:

Time to a composite endpoint of cardiovascular death, non-fatal myocardial infarction, coronary revascularization, stroke, or peripheral arterial event.

Secondary outcomes

• Time to individual components of the primary composite endpoint

• Time to all-cause death

• All cause hospitalisation

• Utility-based quality of life EQ-5D-5L

Primary endpoint data for participants recruited in other countries will be collected in case report forms in the conventional manner. Data for subjects recruited from the rest of the world will be transferred to the UK for analysis alongside the UK data.

The following NHS England data will be accessed:

· Hospital Episode Statistics - Admitted Patient Care – necessary to provide information on secondary care records to assess non-fatal cardiovascular events in participants to classify study endpoints. This data will also include the assessment of all-cause hospitalisations to measure secondary outcomes in participant health outcomes.

· Civil Registration Mortality – necessary to assess primary endpoints of participants, providing information on participant cause of death to identify events as non-cardiovascular or cardiovascular (CV) related events, providing further information on CV related causes of death. This data will also be used to manage communications with participants involved in the study. Cause of Death variables have been requested under this agreement as they are necessary in order to identify the factors contributing to instances of mortality within cohort members, as this information is key to categorising primary endpoints and variations of these within the study groups participants are assigned to.

The level of the data will be identifiable. All analysis for the purpose of the study will be performed with the pseudonymised data. NHS England data will be held separately within the University of Cambridge secure environment however there may be a justifiable reason for reidentifying a cohort member (for example, to enable direct care).

The data will be minimised as follows:

· Limited to a study cohort of patients who consented to participate. Recruitment to the study cohort is ongoing. Recruitment began in August 2022 and is planned to continue until December 2025. The target number of participants recruited to the study within the timeframe above is 2000. Recruitment may be extended if the deadline is reached and the target participant number is not reached.

· Limited to data from August 2022 onwards. For each individual patient, HES data will only be provided from the date participant consented to join the study. The Controllers will conduct updates to the cohort on a quarterly basis, accounting for any withdrawals.

The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are the study sponsors and the joint data controllers as the organisations 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)(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 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 the scope of patients within England that could benefit from improved treatment and intelligence within this area of healthcare. There are currently approximately 29,000 patients across the UK currently receiving dialysis treatment. The leading cause of death in patients receiving dialysis is cardiovascular disease. A wide range of interventions currently employed in this population in the NHS are aimed at improving survival and quality of life but have either failed to show any benefit (erythropoiesis stimulating agents, lipid lowering, calcimimetics) or have not been adequately evaluated in randomised trials. This processing aims to improve the understanding of the effectiveness of interventions to allow more informed decision making on patient treatments.

The funding is provided by National Institute for Health Research (NIHR). The funding is specifically for the PHOSPHATE study described. Funding is in place until December 2027.

The following organisations are members of the Trial Steering Committee (TSC), a group of representatives who provide advisory support to the study for the purposes of recruitment practises, study endpoints, interpretation of outputs and the length of the study.

- University of Glasgow

- London School of Hygiene and Tropical Medicine

- University Hospitals Dorset NHS Foundation Trust

This study is linked to a wider global study of the same name. The PHOSPHATE Global study aims to address similar aims to that of the study performed within the UK. The global study involves multiple organisations conducting similar studies within their own territories. Additional international organisations include:

- St Michael’s Hospital, Canada

- McMaster University, Canada

- University of Toronto, Canada

- University of Otago Christchurch, New Zealand

- University New South Wales, Australia

- St George Hospital, Australia

The global study also includes the following UK based organisations:

- Dorset County Hospital NHS Foundation Trust

- University of Manchester

The organisations above involved in the PHOSPHATE Global study are not involved in the management of the UK based PHOSPHATE study. This includes the decision-making on study processes and processing of study and NHS England data.

The data other organisations outside of the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust receive is a different format to that of the NHS England data under this Data Sharing Agreement and requires processing differently. These data are periodic updates including information on recruitment, baseline demographics, phosphate separation between the two treatment groups and occurrence of end points (major cardiovascular events). This data is provided in aggregated tables, with small number suppression rules applied, and no patient level data is shared. The Chief Investigator of the UK study solely determines the processing of NHS England data under this Data Sharing Agreement in order to determine the primary and secondary outcomes above.

The Global management committee has set out the objectives and the primary and secondary end points for the study. The Chief Investigator for the UK Study, employed by the University of Cambridge and Cambridge University Hospitals NHS Foundation trust, has acted independently to the global collaborators to identify the personal data and processing activities needed to determine those end points and the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust will be responsible for all decisions relating to the processing of that data. Other organisations involved in the global study may act in an advisory capacity as part of the Trial Steering Committee but will not be able to determine how the data under this Data Sharing Agreement will be processed.

A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above. The proposed purpose was presented to Cambridge University Hospitals Patient and Public Involvement (PPI) panel prior to the start of the study. The study’s Trial Steering Committee (TSC) also includes public and patient representatives to insight into the public views of study practises, including the processing of data over the course of the study. These groups were consulted on data collection and will be provided with updates to the study on a regular basis.

University of Cambridge will transfer data to NHS England. The data will consist of identifying details (NHS Number, Name, Date of Birth, Postcode, Gender and a unique study ID) for the cohort to be linked with NHS England data.

NHS England data will provide the relevant records from the Hospital Episode Statistics – APC and Civil Registrations of Death datasets to University of Cambridge. The data will be returned containing the Study ID only. This data will be linked together with the data collected by the University of Cambridge from the UK Renal Registry including phosphate levels, and Case Report Forms from the participants. Identifying items will remain in a secure environment within University of Cambridge servers. Once received by University of Cambridge, the data will be pseudonymised using a unique study ID. Participant identifiers will be kept separate within a secure area on University of Cambridge servers. A pseudonymised subset of the data will be used by researchers and analysts at University of Cambridge and Cambridge University Hospitals NHS Foundation Trust to address the study questions outlined in this Data Sharing Agreement. A further pseudonymised subset of data will be transferred to Cambridge University Hospitals NHS Foundation Trust servers for the purpose of categorising Serious Adverse Events (SAEs) and producing line listings of these events to support the study purpose indicated above. There will be no requirement and no attempt to reidentify individuals when using the data for the purposes of this study.

The data will not be transferred to any other location. The data will be stored on servers at University of Cambridge and Cambridge University Hospitals NHS Foundation Trust.

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 at any time.

Access is restricted to employees of University of Cambridge and Cambridge University Hospitals NHS Foundation Trust who have authorisation from the Chief Investigator. All personnel accessing the data have been appropriately trained in data protection and confidentiality. Researchers from the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust will process the data for the purposes described above.

The expected outputs of the processing will be:

• A report of findings to NIHR annually throughout the conduct of the study

• A report of findings to National Institute for Health and Care Excellence (NICE) once the results have been clarified, expected within 2027.

• Submissions to peer reviewed journals following the results of the study being clarified, expected to be completed within early 2027.

• Presentations to national and international conferences such as the British Renal Society at the annual UK Kidney Week, the European Renal Association, and the American Society of Nephrology annual meeting. These outputs will take place annually over the course of the study.

• Publication of study outputs within participant newsletters upon clarification of results. Newsletters are planned to be submitted quarterly to participants during the data processing.

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.

These outputs are also shared with international collaborators of the PHOSPHATE Global study who will conduct statistical analysis of outputs from the studies. For the avoidance of doubt, all outputs remain aggregated with small number suppression rules upheld.

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

• Journals

• Public reports

• Co-hosted events directed at healthcare professionals within associated fields of care or research.

• Participant newsletters

• Reports aimed at patients.

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.

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, or health and care system design to improve health and care outcomes or experience.

• advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions such as kidney disease.

• inform planning health services and programmes, for example to improve equity of access, experience and outcomes.

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

Phosphate-lowering medications, the mainstay of phosphate-lowering treatment, are associated with substantially increased pill burden, non-adherence, adverse gastrointestinal symptoms, poor quality of life, and are costly to individual patients and health systems.

It is hoped outcomes from an adequately powered clinical trial will evaluate the impact implementation of phosphate-lowering treatments have on reducing the risk of cardiovascular death or non-fatal major cardiovascular events; improvements to physical health, fatigue, and patient satisfaction in End-stage kidney disease (ESKD) patients receiving dialysis. It is hoped that outcomes from this study will inform policy and clinical guidelines, providing further intelligence to support improvements in the effectiveness of care provided to patients suffering from ESKD. Through identifying areas where improvements can be made in altering the current clinical standard for this area of treatment, these outcomes hope to contribute to actively addressing the shortfalls of the current treatment indicated above.

The findings of the study will be provided to National Institute for Health and Care Excellence (NICE). Study findings will have the potential to influence the NICE guidelines and other guidelines regarding clinical practice in these areas.

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

Yielded Benefits is not a requirement for new applications.