Survival Improvement with Colecalciferol in Patients on Dialysis – The SIMPLIFIED Registry Trial

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Objective for processing

The ​​The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust (CUH) require access to NHS England data for the purpose of the following research project: Survival ​Survival Improvement with Colecalciferol in Patients on Dialysis – The SIMPLIFIED Registry Trial The ​The following is a summary of the aims of the research project provided by the University of Cambridge and CUH: Vitamin ​Vitamin D deficiency is highly prevalent in patients with kidney failure and is [140 words unchanged] implemented given the lack of evidence of its effectiveness from randomised trials. The ​The randomised controlled trial (SIMPLIFIED) aims to assess the effect of colecalciferol (vitamin [41 words unchanged] Life, cardiovascular events requiring admission, infections requiring admission, and fractures requiring admission. The following NHS England data will be accessed: ​The Data will also be used collectively to check the main outcomes against routine data sources, extend the follow-up of patients in the trial and collect the long-term outcome and health resource usage data, without needing further contact with study participants. This is important as it will link a trial of treatments that may become a clinical standard of care to long-term outcomes that are routinely collected in clinical data but will not be manually collected during the follow-up period of the trial. > Hospital Episode Statistics ​Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out​ - Admitted Patient Care (APC) – necessary to obtain data on cardiovascular, fracture, and infection events to measure the secondary outcomes. Regulatory requirements from the Medicines and Healthcare products Regulatory Agency (MHRA) demand strict safety monitoring of serious adverse events (SAEs), defined as any untoward medical occurrence(s) that at any dose results in death, hospitalisation or prolongation of existing hospitalisation, persistent or significant disability/incapacity or a congenital anomaly or birth defect, which will also be extracted from the HES APC dataset. - Critical Care (CC) - necessary to obtain cardiovascular, infection and infection events. > Emergency Care Data Set (ECDS) and HES Accident and Emergency (A&E) - necessary to obtain cardiovascular, infection and infection events. > Civil Registration Mortality – necessary to measure the primary outcome of the trial, all-cause mortality. > Cancer Registration Dataset and Cancer Consolidated Dataset- necessary to determine the incidence of cancer (a secondary trial outcome measure). This is required due to the limitation of Cancer registration data reconciliation period and its impact on trial integrity, which in turn could significantly impact participant care. The Data will also be used collectively to check the main outcomes against routine data sources, extend the follow-up of patients in the trial and collect the long-term outcome and health resource usage data, without needing further contact with study participants. This is important as it will link a trial of treatments that may become a clinical standard of care to long-term outcomes that are routinely collected in clinical data but will not be manually collected during the follow-up period of the trial. The level of the Data will be: > Identifiable – necessary for the purposes of identifying the relevant patients. The retention of this identifiable Data in the files received from NHS England enables researchers to check that the subject ID has remained paired to the correct individual and their Data, prior to the pseudonymisation of the files and statistical analysis. As the Data provided by NHS England contains the primary endpoints and the majority of secondary endpoints for the trial, it is crucial to ensure that misalignment of participants from their subject IDs has not occurred, as this could affect statistical outputs and the overall trial findings. The Data will be minimised as follows: > Limited to the SIMPLIFIED trial cohort of approximately 3,358 patients who consented to participate (recruitment ongoing; expected final cohort size: 4,200) – all participants have end stage renal disease. > Limited to Data from 2016/17. For each individual patient, HES Data will only be provided from the participant’s consent start date, i.e., the date they consented to join the trial, and until 7–8-years after their start date. For the deaths Data, which will not be filtered by start date by NHS England, files extracted from this dataset will instead be filtered by the University of Cambridge and CUH upon receipt, and the destruction of any Data on events prior to the consent date will be undertaken quarterly. The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are the research sponsors and the joint controllers as the organisations jointly 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 it adheres to the UK Policy Framework for Health and Social Care Research 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). The funding is specifically for the trial described. Funding is in place until April 2024, with the expectation of extension until October 2025. The funder will have no ability to suppress or otherwise limit the publication of findings. Telefonica provide IT support to CUH and provide IT back up services to CUH and will store copies of the data as contracted by CUH. UK Renal Registry, University College London, Imperial College London, Manchester Royal Infirmary and St James University Teaching Hospital are involved as contributors toward the study protocol. These organisations act within an advisory capacity and do not access the Data, nor control how the Data is processed. Data will be accessed by: > Substantive employees of the University of Cambridge and CUH > Individuals with a Letter of Access with CUH; currently, this is just one individual, a health economist, from the University of East Anglia (UEA). This individual has a signed Letter of Access with CUH, and their employing organisation, UEA, also signs a Service Level Agreement (SLA) with CUH. This same process will be followed by any other individuals requiring access to the Data who are not substantive employees of the University of Cambridge and CUH. There are expected to be a more individuals requiring access to the Data via a Letter of Access with CUH as the project progresses. Various Public and Patient Information and Engagement groups were consulted regarding the collection of the Data for the purposes described above. These include groups at the British Renal Society and UK Kidney Association. These groups were consulted on data collection and will be provided with updates to the trial on a regular basis. Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out

Processing activities

[6 paragraphs unchanged] The ​The Data will remain on be accessed onsite at the servers at premises of the University of Cambridge and CUH at all times, with the exception of the hard paper copy stored by CUH, and the back up storage provided by Telefonica. only. [1 paragraph unchanged] The data will not leave England/Wales at any time. Data will be accessed by individuals with a Letter of Access with CUH. These individuals will act as an agent of CUH at all times under supervision from employees of CUH. Aside from these individuals, access is restricted to employees or agents of the University of Cambridge and CUH who have authorisation from the Chief investigator or Research Governance Lead. All personnel accessing the Data have been appropriately trained in data protection and confidentiality. [2 paragraphs unchanged] There will be no requirement and no attempt to reidentify individuals when using the Data. ​​Data will be accessed by individuals with a Letter of Access with CUH. These individuals will act as an agent of CUH at all times under supervision from employees of CUH. Aside from these individuals, access is restricted to employees or agents of the University of Cambridge and CUH who have authorisation from the Chief investigator or Research Governance Lead.​ Researchers from the University of Cambridge and Cambridge University Hospital NHS Foundation Trust will process the Data for the purposes described above.

Unchanged: Expected output, Expected measurable benefits, Benefits reported.

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Datasets: + NDRS Cancer Consolidated Data Set

Objective for processing

[9 paragraphs unchanged] - > Emergency Care Data Set (ECDS) and HES Accident and Emergency (A&E) - necessary to obtain cardiovascular, infection and infection events. > Emergency Care Data Set (ECDS) - necessary to obtain cardiovascular, infection and infection events. [1 paragraph unchanged] > Cancer Registration Data - Dataset and Cancer Consolidated Dataset- necessary to determine the incidence of cancer (a secondary trial outcome measure). This is required due to the limitation of Cancer registration data reconciliation period and its impact on trial integrity, which in turn could significantly impact participant care. [5 paragraphs unchanged] > Limited to Data from 2016/17. For each individual patient, HES Data [60 words unchanged] the destruction of any Data on events prior to the consent date or after the withdrawal date will be undertaken quarterly. [14 paragraphs unchanged] Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out

Processing activities

[1 paragraph unchanged] NHS England Data will provide the relevant records from the HES HES, cancer and Deaths deaths datasets to the University of Cambridge. The data will: [13 paragraphs unchanged]

Unchanged: Expected output, Expected measurable benefits, Benefits reported.

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Changed only in punctuation, spacing or capitalisation: Expected measurable benefits, Expected output.

Unchanged: Objective for processing, Processing activities, Benefits reported.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

The randomised controlled trial (SIMPLIFIED) aims to assess the effect of colecalciferol (vitamin D) supplementation versus standard care on health outcomes in patients with kidney failure receiving dialysis and will involve approximately 4,200 patients over a 7-8 year period. The SIMPLIFIED trail approach of capturing follow up will remove the need for additional study visits and will lessen the burden and cost of participating in research for both patients and sites. The trial is jointly sponsored by the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust (CUH) require access to NHS England data for the purpose of the following research project: Vitamin D deficiency is highly prevalent in patients with kidney failure and is associated with increased mortality. Kidney failure patients are treated with “active” vitamin D compounds (VDRAs) based on the now disproven belief that activation can only occur in the kidneys. VDRAs induce hypercalcaemia, result in tissue deficiency of calcitriol, and may promote vascular calcification. Contemporary treatment guidelines now recommend administration of “native” vitamin D (colecalciferol). This guidance is not currently implemented given the lack of evidence from randomised trials. Survival Improvement with Colecalciferol in Patients on Dialysis – The SIMPLIFIED Registry Trial Colecalciferol has been used to treat vitamin D deficiency for more than 80 years. It is cheap and safe, even at high doses. In contrast, VDRAs are expensive and despite their wide use, their efficacy and safety have never been tested in interventional trials. There is an urgent unmet need for a trial to determine which approach is preferable. In this trial, the Sponsors will test the hypothesis that population-wide supplementation with high-dose colecalciferol (inactive vitamin D) in patients receiving dialysis will reduce mortality and improve quality of life. The following is a summary of the aims of the research project provided by the University of Cambridge and CUH: The purpose is to collect the required information for the trial outcomes and safety assessments specified below for the English cohort (and Welsh deaths data). Equivalent applications have been made to the relevant organisations in the devolved nations for the Scottish and Welsh cohorts. Vitamin D deficiency is highly prevalent in patients with kidney failure and is associated with increased mortality. Kidney failure patients are treated with “active” vitamin D compounds (vitamin D receptor analogues, or VDRAs) based on the now disproven belief that activation can only occur in the kidneys. VDRAs induce hypercalcaemia (a condition in which the calcium level in your blood is above normal), result in tissue deficiency of calcitriol, and may promote vascular calcification. VDRAs are also expensive and despite their wide use, their efficacy and safety have never been tested in interventional trials. In contrast, “native” vitamin D (colecalciferol) has been used to treat vitamin D deficiency for more than 80 years, and is safe, even at high doses. It is also cheap, making it an attractive alternative to VDRAs from both a cost and a safety perspective. Contemporary treatment guidelines now recommend administration of colecalciferol, but this guidance is not currently implemented given the lack of evidence of its effectiveness from randomised trials. The primary outcome for the SIMPLIFIED Trial is all-cause mortality which will be measured via the Civil Registrations (Deaths) data extract. The randomised controlled trial (SIMPLIFIED) aims to assess the effect of colecalciferol (vitamin D) supplementation versus standard care on health outcomes in patients with kidney failure receiving dialysis, with the primary outcome being to determine whether colecalciferol is indeed beneficial for kidney failure patients through decreased mortality. Secondary outcomes include Health Related Quality of Life, cardiovascular events requiring admission, infections requiring admission, and fractures requiring admission. Secondary outcomes include Health Related Quality of Life (HRQoL / EQ5D), cardiovascular events requiring admission, infections requiring admission, cancer incidence and fractures requiring admission. The cardiovascular, infection and infection events will be collected by linkage to the Hospital Episode Statistics datasets (and also the ECDS dataset once this becomes available) for those patients participating in the trial. Similarly, cancer incidences will be obtained from the national cancer dataset. The following NHS England data will be accessed: Regulatory requirements from the MHRA demand strict safety monitoring of serious adverse events (SAEs) which will be extracted from the HES and ECDS datasets. These SAEs will be reported on a schedule to the Sponsors and the MHRA to assess the ongoing safety of the trial. > Hospital Episode Statistics 4,200 will be the maximum number of participants split across England, Scotland and Wales – therefore the number of individuals whose data are requested from NHS Digital will be lower than that number. As of October 2020, there are 2,376 participants and recruitment continues. - Admitted Patient Care (APC) – necessary to obtain data on cardiovascular, fracture, and infection events to measure the secondary outcomes. Regulatory requirements from the Medicines and Healthcare products Regulatory Agency (MHRA) demand strict safety monitoring of serious adverse events (SAEs), defined as any untoward medical occurrence(s) that at any dose results in death, hospitalisation or prolongation of existing hospitalisation, persistent or significant disability/incapacity or a congenital anomaly or birth defect, which will also be extracted from the HES APC dataset. The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are joint Data Controllers. Both organisations also process the data for this study. All data will be stored by the University of Cambridge only and all data processing will only occur within the University of Cambridge network. - Critical Care (CC) - necessary to obtain cardiovascular, infection and infection events. The lawful basis for processing data under GDPR is: - Accident and Emergency (A&E) - necessary to obtain cardiovascular, infection and infection events. Article 6(1)(e) (processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller) and > Emergency Care Data Set (ECDS) - necessary to obtain cardiovascular, infection and infection events. 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) > Civil Registration Mortality – necessary to measure the primary outcome of the trial, all-cause mortality. This trial relies on participant consent to satisfy the duty of confidentiality. > Cancer Registration Data - necessary to determine the incidence of cancer (a secondary trial outcome measure). The Data will also be used collectively to check the main outcomes against routine data sources, extend the follow-up of patients in the trial and collect the long-term outcome and health resource usage data, without needing further contact with study participants. This is important as it will link a trial of treatments that may become a clinical standard of care to long-term outcomes that are routinely collected in clinical data but will not be manually collected during the follow-up period of the trial. The level of the Data will be: > Identifiable – necessary for the purposes of identifying the relevant patients. The retention of this identifiable Data in the files received from NHS England enables researchers to check that the subject ID has remained paired to the correct individual and their Data, prior to the pseudonymisation of the files and statistical analysis. As the Data provided by NHS England contains the primary endpoints and the majority of secondary endpoints for the trial, it is crucial to ensure that misalignment of participants from their subject IDs has not occurred, as this could affect statistical outputs and the overall trial findings. The Data will be minimised as follows: > Limited to the SIMPLIFIED trial cohort of approximately 3,358 patients who consented to participate (recruitment ongoing; expected final cohort size: 4,200) – all participants have end stage renal disease. > Limited to Data from 2016/17. For each individual patient, HES Data will only be provided from the participant’s consent start date, i.e., the date they consented to join the trial, and until 7–8-years after their start date. For the deaths Data, which will not be filtered by start date by NHS England, files extracted from this dataset will instead be filtered by the University of Cambridge and CUH upon receipt, and the destruction of any Data on events prior to the consent date or after the withdrawal date will be undertaken quarterly. The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are the research sponsors and the joint controllers as the organisations jointly 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 it adheres to the UK Policy Framework for Health and Social Care Research 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). The funding is specifically for the trial described. Funding is in place until April 2024, with the expectation of extension until October 2025. The funder will have no ability to suppress or otherwise limit the publication of findings. Telefonica provide IT support to CUH and provide IT back up services to CUH and will store copies of the data as contracted by CUH. UK Renal Registry, University College London, Imperial College London, Manchester Royal Infirmary and St James University Teaching Hospital are involved as contributors toward the study protocol. These organisations act within an advisory capacity and do not access the Data, nor control how the Data is processed. Data will be accessed by: > Substantive employees of the University of Cambridge and CUH > Individuals with a Letter of Access with CUH; currently, this is just one individual, a health economist, from the University of East Anglia (UEA). This individual has a signed Letter of Access with CUH, and their employing organisation, UEA, also signs a Service Level Agreement (SLA) with CUH. This same process will be followed by any other individuals requiring access to the Data who are not substantive employees of the University of Cambridge and CUH. There are expected to be a more individuals requiring access to the Data via a Letter of Access with CUH as the project progresses. Various Public and Patient Information and Engagement groups were consulted regarding the collection of the Data for the purposes described above. These include groups at the British Renal Society and UK Kidney Association. These groups were consulted on data collection and will be provided with updates to the trial on a regular basis.

Processing activities

The Sponsors aim to harness the information routinely collected by NHS Digital (including HES and Mortality data) for use as follow-up for those patients participating in their clinical trial. The University of Cambridge will also be collecting data from the UK Renal Registry for the same purpose. Data from the UKRR will not be linked to NHS Digital data. The University of Cambridge will transfer Data to NHS England. The Data will consist of identifying details (specifically: NHS Number, Date of Birth, Gender, Forename, Surname and Study ID) for the cohort to be linked with NHS England Data. The University of Cambridge has previously submitted identifying details of cohort members to NHS Digital so that the individuals could be traced and flagged on NHS Digital’s system for reporting of deaths and cancer registrations. Under this Agreement, the University of Cambridge will submit identifying details of additional cohort members to NHS Digital for tracing and flagging. NHS England Data will provide the relevant records from the HES and Deaths datasets to the University of Cambridge. The data will: The following patient identifiers will be submitted to NHS Digital: - NHS Number, Gender, Date of Birth, Forename and Surname. A trial-specific participant identifier (Study ID) will also be provided in the format SXXX-XXXX. T > Contain directly identifying data items including Names, NHS Number, Date of Birth, Postcode and Gender, which are required to verify that the subject ID has remained paired to the correct individual and their data, prior to the pseudonymisation of the files and statistical analysis. Identifiable Cause of Death is also required to measure the primary outcome of the trial, all-cause mortality. The University of Cambridge must not supply details of any participant who has withdrawn consent for access to their data. Should any participant withdraw consent after the University of Cambridge has supplied their details to NHS Digital, the University of Cambridge must ensure the timely removal of the individual from the cohort flagged on NHS Digital’s COVE system. Pseudonymised datasets for analysis will be generated within the University of Cambridge Secure Data Hosting Server (SDHS) and transferred securely to CUH. DATA REQUESTED: The data will be stored on the SDHS server at the University of Cambridge. The data will also be stored on a server at the CUH, where a hard paper copy of the pseudo data will also be stored separately in locked offices. Request of one drop of annual refresh for 2019/20 and quarterly reports for 2020/21 (plus AR 2020/21) of record level identifiable data filtered by a cumulative cohort: CUH uses offsite back-up services provided by Telefonica. 1. ECDS Annual Refresh 2019/20 and 2020/21 Q2, Q3, and Q4 plus 2020/21 AR (5 drops) The Data will remain on the servers at the University of Cambridge and CUH at all times, with the exception of the hard paper copy stored by CUH, and the back up storage provided by Telefonica. 2. HES APC Annual Refresh 2019/20 and 2020/21 Q2, Q3, and Q4 plus 2020/21 AR (5 drops) Personnel at the University of Cambridge are not technically capable of downloading or copying data to local devices. 3. HES CC Annual Refresh 2019/20 and 2020/21 Q2, Q3, and Q4 plus 2020/21 AR (5 drops) The data will not leave England/Wales at any time. 4. Cancer CMS extract Annual Refresh 2019/20 and 2020/21 Q2, Q3, and Q4 plus 2020/21 AR (5 drops) Data will be accessed by individuals with a Letter of Access with CUH. These individuals will act as an agent of CUH at all times under supervision from employees of CUH. Aside from these individuals, access is restricted to employees or agents of the University of Cambridge and CUH who have authorisation from the Chief investigator or Research Governance Lead. 5. Civil Registration (Deaths) extract Annual Refresh 2019/20 and 2020/21 Q2, Q3, and Q4 plus 2020/21 AR (5 drops) All personnel accessing the Data have been appropriately trained in data protection and confidentiality. NHS Digital will identify and track the clinical trial patients in their cohort, providing an update of cancer registrations, cause of death (Civil Registrations - Deaths) and linked HES Admitted Patient Care (APC), Critical Care (CC) and Accident and Emergency (A&E) Data and linked Emergency Care Data Set (ECDS) which replaces the HES A&E dataset. The University of Cambridge will also be collecting data from the UK Renal Registry (UKRR) for the same purpose. Data from the UKRR will not be linked to NHS England Data. Record level identifiable data will be uploaded by NHS Digital to the Secure Electronic File Transfer service (SEFT) for download by the study team at the University of Cambridge. The Data will not be linked with any other data. The study team will download the data onto a Secure Data Hosting Server (SDHS) managed by the University of Cambridge. There will be no requirement and no attempt to reidentify individuals when using the Data. For the purpose of this study, the University of Cambridge only requires information on relevant events occurring after participants consented to be in the study. For this reason, the University of Cambridge has previously submitted, along with the cohort identifiers, a consent start date for a bespoke set of MRIS reports covering deaths and cancer registrations. However, MRIS as a service has been decommissioned and the new automated data extract CMS system cannot support additional bespoke filtering. Therefore, the University of Cambridge will submit two different cohorts when required: Researchers from the University of Cambridge and Cambridge University Hospital NHS Foundation Trust will process the Data for the purposes described above. 1) A cohort with study identifiers in the specific format requested for the CMS automated system (known as COVE). 2) A cohort with study identifiers and consent start date for HES data filtering. The study team is made up of substantive employees of both University of Cambridge and Cambridge University Hospital NHS Foundation Trust employees. Cambridge University Hospitals NHS Foundation Trust team members are required to be signed off by the data controller (University of Cambridge) in compliance with their Information Governance office. Data will be stored, processed and linked in the SDHS, which can only be accessed on a strict permission basis. Only the database programmer, coordinator and data manager have access to data in the SDHS. Access to the SDHS may be done via NHS hardware however access will only ever be permitted subject to permissions which are controlled by the University of Cambridge. These permissions are also required where a university computer is used. Access to the SDHS is only ever permitted via a secure encrypted remote desktop connection via the University network and the data will remain at all times within the SDHS. Access to the SDHS is protected by three factor authentication (username, password, PIN + Signify key fob code). All processing activities will take place within the SDHS. The data set will be kept and stored in the SDHS at patient level. The SDHS is accessed remotely and is physically located in the University of Cambridge Clinical School Computing Service main server room on the University of Cambridge campus. Aggregated data reports with small number suppression applied in line with the HES analysis guide will be generated for review by the Sponsor/MHRA as well as the Trial Steering Committee and Independent Data Monitoring Committee as required. These will not include any personally identifiable data (PID). These reports will be used for statistical analysis and incorporated into the study report. The only exception to this is safety events, which may be listed at an individual patient level as is standard practice for clinical trials study reports. In these circumstances data will be pseudonymised and un-linkable. No personal identifiable data (PID) will be included in any data exported outside of the SDHS, only the unique trial-specific participant ID will be used for patient level data. No PID is stored outside of the SDHS therefore this data cannot be linked back to a specific patient. An internal participant trial number will be used to keep the data pseudonymised at the stages of analysis, reporting and eventually publishing. The pseudonymised safety reports will only be shared to the DMEC committee members and CCTU Pharmacovigilance team.’ All other outputs and publications contain only aggregated data with small numbers suppressed in line with the HES Analysis Guide. An internal participant trial number will be used to keep the data pseudonymised at the stages of analysis, reporting and eventually publishing. The anonymised safety reports will initially be shared only by the DMEC committee members and CCTU Pharmacovigilance team. Trial results will be submitted for publishing in peer-reviewed medical journals, presented at conferences and published on EU Clinical Studies Register Website. All data collected will be stored on highly secure encrypted servers held within the University of Cambridge secure data hosting area and will be accessible only to the team of researchers directly involved with the study. All individuals with access to the data are substantive employees of the University of Cambridge or Cambridge University Hospitals NHS Foundation Trust. The secure data hosting area for this study is subject to an existing data governance agreement between the University of Cambridge and the Cambridge University Hospitals NHS Foundation Trust. The use of personal identifiers is to correctly identify clinical trial subjects only. Pseudonymised datasets for analysis will be generated within the secure data hosting environment and transferred securely to the trial statistician within the Cambridge Trials Unit. These pseudonymised datasets will be used to determine the primary and secondary endpoints of the clinical trial, namely patient survival, quality of life, and secondary clinical outcomes including cardiovascular events, infections requiring admission, cancer incidence, and fractures requiring admission. All organisations party to this Agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract - i.e. employees, agents and contractors of the Data Recipient who may have access to that data). HES AND ECDS DISCLOSURE RULES / 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: · cell values from 1 to 7 must be suppressed at a local 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.

Expected output

The University of Cambridge will test the hypothesis that supplementation with high dose colecalciferol (inactive vitamin D) in patients receiving dialysis will reduce mortality and improve quality of life. The trial results will be published in peer-reviewed journals and presented at national and international conferences. The expected outputs of the processing will be: These outputs are dependent upon the primary endpoint being achieved. With an average median survival of 5.5 years for patients on dialysis, the trial is likely to end in 2023, with the final study report being available in 2024. • Reports of trial progress to the study sponsors and funder roughly every 6 months. Prior to the final publication, the trial will have an interim analysis as described in the protocol. A feasibility assessment will be carried out between months 12 and 15 of the trial (this was actually done in September 2019). Feasibility will be predicated on recruitment rate (target 887 patients recruited after 12 months), and separation between arms by plasma vitamin D concentration after 4 months of treatment of 20nmol/l. • Submissions to high impact peer reviewed journals such as the lancet targeting multiple submissions throughout 2026 and 2027. Publications will follow in 2025 although this target date is difficult to accurately predict at this early stage. • Presentations to charities, academic groups and PPIE groups such as the UK Kidney Association, the British Renal Society and European Renal Association. The trial protocol will be submitted for publication in “Trials” (target date February 2017), and will include a section on data capture and handing. During the conduct of the trial, reports will be submitted to the NIHR as required. • Presentations at various conferences for example the UK Kidney Association annual conference. Findings from the trial will be presented at the British Renal Society annual UK Kidney Week (June 2025), the European Renal Association (May 2025) and the American Society of Nephrology annual meeting November 2025). The primary report from the trial will be submitted for publication in the New England Journal of Medicine or The Lancet during the course of 2025. 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 results will also be published on the EU Clinical Studies Register website, a central registry for all clinical trials conducted within the EU. The outputs will be communicated to relevant recipients through the following dissemination channels: All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide. • Presentations at the British Renal Society annual UK Kidney Week, the European Renal Association, and the American Society of Nephrology annual meeting. Participating patients will be informed of the results and can request a copy of published papers. • Publication of results on the EU Clinical Studies Register website, a central registry for all clinical trials conducted within the EU. The final study report will be provided to NICE. • Webinars: for example; with the UK Kidney Association (UKKA) during UK renal week (held annually), which includes presentations to academics, the charity, and other PPIE groups. • Social media: using connections with UKKA to publicise research. • Briefing documents provided to the funders and study sponsors every 6 months updating on study progress. This includes a final study report provided to the National Institute for Health and Care Excellence (NICE). • Investigatory meetings hosted by the study team, updating clinicians and healthcare professionals on the study progress with multidisciplinary teams. • Public events: participant meetings for updates on the study. • Posters displayed at dialysis units within Trusts, and study update posters to be displayed at UKKA during UK Renal week. • Participant newsletter provided throughout the lifespan of the study, every 2 months. • Public promotion of the research, various meetings during renal week to numerous renal units and PPIE groups discussing the study, outputs and promoting the research. • SAEs will be reported to the Independent Data Monitoring & Ethics Committee (IDMEC), Sponsors and the MHRA, to assess the ongoing safety of the trial.

Expected measurable benefits

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 patients with chronic kidney disease (CKD). • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience for patients with CKD. • advance understanding of the need for, or effectiveness of, preventative health and care measures for patients with CKD. • inform decisions on how to effectively allocate and evaluate funding according to health needs. • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). Patients are expected to benefit from the wider body of evidence for colecalciferol use in patients with CKD, which is expected to inform future treatments. The results of this trial may benefit the treatment of patients with CKD in the future as supplementation with colecalciferol could produce better outcomes for patients with CKD. [1 paragraph unchanged] Current treatment guidelines recommend cholecalciferol or ergocalciferol in patients on dialysis, even when they are receiving treatment with VDRAs. The Kidney Disease Improving Global Outcomes (KDIGO) guideline group identified “native” vitamin D supplementation in dialysis as a key research priority, but nevertheless argues for its use on the basis that the intervention is safe and inexpensive. Caution is necessary, however, as epidemiological data similarly supported the use of anti-oxidant vitamins including vitamins C and E, which were found to be of no benefit or even harmful in adequately powered interventional trials. Widespread supplementation with cholecalciferol should therefore be rigorously tested in an adequately powered randomised trial. 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, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients. NICE and associated policy makers within the NHS will need to act based on the information provided to them to realise the potential improvement opportunities. For example, with publication in the targeted journals, an impact is expected to be produced due to the nature of the study itself being the largest of its kind for this specific research question. This, aligned with the other engagements detailed, could produce enough impact to potentially gain the attention of the NHS treatment policy professionals looking at this area of work. Further, most clinicians continue to preferentially prescribe 1-hydroxyated compounds on the basis of epidemiological data suggesting a survival benefit compared to no vitamin D; Despite guidelines to supplement “native” vitamin D being in force since 2007, clinical practice has not changed. The study team work closely with renal week and its organisers, UKKA, with plans to produce outputs with them that are related to the research. Meetings have already taken place informing the Charity of the research. As per the aforementioned outputs, there are also plans in place to advertise the research to the wider public as well as academic groups. It is therefore imperative to generate data from an adequately powered randomised comparison of colecalciferol versus standard care. The above benefits are expected to begin to emerge within 5 years of the first output being produced. The findings of the trial will be provided to NICE. Study findings will have the potential to influence the NICE guidelines and other guidelines regarding clinical practice in these areas.

Benefits reported

As the trial is still recruiting, the final data analysis has not been performed yet. An interim analysis of the first 230 participants has clearly demonstrated a difference in circulating VitD between the two trial arms. The final benefits yielded will be reported on a later date. An interim analysis of the first 230 participants has clearly demonstrated a difference in circulating treatment and control cohort. SIMPLIFIED is a long trial, so data collection is still ongoing, and the final analysis is yet to take place. However, the data received has been used to collect the safety data for the trial; the resulting pseudonymised SAE line listing has routinely undergone clinical review. In addition, this data has been presented to the Data Monitoring Committee and Trial Steering Committee (in aggregated form) ahead of their meetings throughout the trial. As a result, this data has informed the decisions made by the committees to date and will continue to do so as we receive further data. The final benefits yielded will be reported on a later date.