Study of Heart and Renal Protection (SHARP) Post-trial Follow-Up (PTFU)

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

Objective for processing

This The Data Sharing Agreement is an extension of previous iterations of this Agreement, permitting access to NHS England data will be used for the purpose of the a research project: SHARP post-trial follow-up (PTFU) project. [7 paragraphs unchanged] Efforts were previously made to minimise the data requested which resulted in [68 words unchanged] is no alternative, less intrusive way of achieving the purposes outlined above. In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS England. To ensure comprehensive information on all potentially relevant outcomes, the data previously requested included individual patient level data concerning both the occurrence and timing of any deaths and cancers, as well as data regarding in-patient hospitalisations (i.e., hospital episode statistics [HES] data) including: major cardiac events (such as heart attacks), strokes, procedures to open up blocked arteries (known as 'revascularisation') and end-stage renal disease (such as the need for long-term dialysis or a kidney transplant). In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS England. To ensure comprehensive information on all potentially relevant outcomes, the data previously requested included individual patient level data concerning both the occurrence and timing of any deaths and cancers, as well as data regarding in-patient hospitalisations (i.e., hospital episode statistics [HES] data) including: major cardiac events (such as heart attacks), strokes, procedures to open up blocked arteries (known as 'revascularisation') and end-stage renal disease (such as the need for long-term dialysis or a kidney transplant). [5 paragraphs unchanged]

Expected output

[12 paragraphs unchanged] Due to the COVID pandemic, some staff had to be re-deployed to work on research related to this issue and so this impacted upon staff resource has been limited to work on this project over the last 12-24 months. at that time. In addition, significant staff sickness and bereavement has delayed this work. Therefore, the estimated timeline for preliminary results of analyses is now 2024. 2026-7.

Expected measurable benefits

[3 paragraphs unchanged] CVD is the most common cause of death in patients with CKD. [21 words unchanged] with only 32.4% among those without CKD. Mortality rates also increase with each progressive stage of CKD, as CKD worsens, and dramatically increase when kidney function, measured by glomerular filtration rate (GFR) [36 words unchanged] patients over age 65 years to above 75 (US 2018 data) https://www.sciencedirect.com/science/article/pii/S0735109721001960#bib4. [6 paragraphs unchanged]

Benefits reported

The SHARP post-trial follow-up project is ongoing due to staffing being affected by the Covid pandemic as well as staff sickness and bereavement, hence no ongoing. No results have been published yet. yet and hence there are no yielded benefits to date. However analyses have been performed and write up of these is planned.

Unchanged: Processing activities.

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

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling the University of Oxford to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). This Data Sharing Agreement is an extension of previous iterations of this Agreement, permitting access to NHS England data for the purpose of the SHARP post-trial follow-up (PTFU) project. This Data Sharing Agreement permits access to NHS Digital data for the purpose of the SHARP post-trial follow-up (PTFU) project. The Clinical Trial Service Unit (CTSU, part of the Nuffield Department of Population Health (NDPH) at the University of Oxford) has extensive experience in developing and running large-scale streamlined randomised clinical trials (RCTs), many of which have significantly changed clinical practice and majorly influenced national and international clinical guidelines. One of these trials was the Study of Heart and Renal Protection (SHARP), one of the largest RCTs to date in patients with chronic kidney disease (CKD). The Clinical Trial Service Unit (CTSU, part of the Nuffield Department of Population Health (NDPH) at the University of Oxford) has extensive experience in developing and running large-scale streamlined randomised trials, many of which have significantly changed clinical practice and majorly influenced national and international guidelines. One of these trials was the Study of Heart and Renal Protection (SHARP). It is the largest trial to date worldwide in patients with chronic kidney disease (CKD) and involved >9000 participants with CKD but no known history of myocardial infarction or coronary revascularisation. The SHARP trial involved >9000 participants worldwide and was carried out in 18 countries, with 1,987 people in the United Kingdom selected at random. It assessed the effect of lowering low-density lipoprotein (LDL) or 'bad' cholesterol with a combination tablet (known as simvastatin 20mg plus ezetimibe 10mg) versus a matching 'dummy' or placebo tablet on events including major vascular disease (e.g. heart attacks, strokes) and renal disease (e.g. the need to start dialysis or have a kidney transplant). People who took part in the trial were followed regularly in study clinics with all serious outcomes (such as being admitted to hospital or death, known as 'serious adverse events') being recorded. The SHARP trial was carried out in 18 countries, with 1,987 people in the United Kingdom selected at random. It assessed the effect of lowering low-density lipoprotein (LDL) cholesterol with a combination of simvastatin 20mg plus ezetimibe 10mg versus a matching placebo on major vascular disease (e.g. heart attacks, strokes) and renal disease (e.g. starting dialysis) events. Participants were followed regularly in study clinics with all serious adverse events (SAEs) being recorded. The SHARP trial started in 2003 and finished in 2010 (with an average follow-up of 4.9 years) and concluded that around a quarter of all heart attacks, strokes and operations to open blocked arteries could be avoided in people with CKD by using the combination tablet to lower blood cholesterol levels. The results were published in The Lancet (2011; 377: 2181–92). The SHARP trial started in 2003 and finished in 2010 (median follow-up of 4.9 years) and concluded that around a quarter of all heart attacks, strokes and operations to open blocked arteries could be avoided in people with CKD by using the combination tablet to lower blood cholesterol levels (Lancet 2011; 377: 2181–92). Whilst the SHARP study resolved much of the uncertainty regarding whether LDL-lowering therapy should be used in patients with CKD, the longer-term effects of such therapy remain to be answered, and so the aim of the SHARP post-trial follow-up (PTFU) project is to assess such longer term effects of the combination tablet among surviving SHARP trial participants. Whilst the SHARP study resolved much of the uncertainty regarding whether LDL-lowering therapy should be used in patients with CKD, several key questions about longer-term effects of such therapy remain to be answered and this is the aim of the SHARP post-trial follow-up (PTFU) project. This will be done by analysing data routinely reported into UK clinical databases (known as registries, notably NHS England) from when the SHARP trial ended in 2010. The use of registry data was clearly stipulated in the SHARP protocol and consent form but extended post trial follow up was not explicitly stated. The University of Oxford sought section 251 support to authorise access to participants’ NHS England HES Admitted Patient Care data, as well as additional demographics, mortality and cancer registration data for extended follow up. The key aim of the SHARP post trial follow-up (PTFU) is to assess the longer term effects among surviving SHARP patients on the time to first major atherosclerotic events (MAEs) and major vascular events (MVEs), defined as non-fatal myocardial infarction or cardiac death, non-fatal or fatal stroke, or any arterial revascularisation procedure (excluding vascular access surgery for dialysis). This will be done by analysing data routinely reported into UK clinical databases (known as registries) from when the SHARP trial ended in 2010. The use of registry data was clearly stipulated in the SHARP protocol and consent form but extended post trial follow up was not explicitly stated. The University of Oxford sought section 251 support to authorise access to participants’ HES Admitted Patient Care data, as well as additional demographics, mortality, cancer registration data for extended follow up. The findings of SHARP post-trial follow-up (PTFU) are therefore anticipated to be relevant to patients with kidney disease, kidney specialists and clinical guideline groups. Secondary aims are to assess the longer term effects among surviving SHARP patients on: (i) progression to end stage renal disease (ii) any hazardous effects (such as site specific cancers, other than non-melanoma skin cancer) and mortality by cause. The UK SHARP PTFU study is a highly streamlined cohort study with no study interventions and will not involve any direct input from the original SHARP trial UK participants; specifically, it will not require them to take any study medication or attend study visits, and will not impact upon their routine clinical care. The UK SHARP PTFU cohort will consist of SHARP participants in the UK identified as being alive at the end of the SHARP study (i.e. surviving participants) who are not documented as having withdrawn consent. No additional inclusion or exclusion criteria will apply, and no further screening of potential new participants is required. The SHARP post trial follow-up (PTFU) aims to answer the following key questions: 1. Does the benefit for major atherosclerotic events (MAE) and major vascular events (MVE) seen in the main SHARP study persist in the longer term? Although there have been several previous long-term follow-up studies of statin trials, many of these did not include patients with moderate to severe CKD as were included in SHARP. Extended follow-up of the SHARP study should allow assessment of whether the benefit for MAEs and MVEs resulting from around 5 years of LDL-lowering with simvastatin plus ezetimibe in such patients persists in the longer term. 2. Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? While the SHARP trial was in progress some investigators had postulated, on the basis of analyses of the SEAS trial of simvastatin plus ezetimibe versus placebo in patients with aortic stenosis, that ezetimibe might increase the risk of cancer. This hypothesis-generating observation was not supported at the time by a hypothesis-testing meta-analysis of interim data for unadjudicated cancers that had occurred by July 2008, in SHARP and the IMPROVE-IT trial of simvastatin plus ezetimibe versus simvastatin among patients with acute coronary syndromes. The results from the SHARP trial involved substantially larger numbers of cancers than were available for that previous meta-analysis and, again, provided no credible evidence of any excess risk of cancer or of death from cancer, either overall or at any particular site, and no evidence of any trend towards an increased risk with longer exposure to study treatment. This finding is consistent with the results of the updated meta-analyses reported by the Cholesterol Treatment Trialists’ (CTT) Collaboration, which concluded that there was no evidence of any excess risk of cancer, or of cancer mortality, associated with statin therapy. Despite this robust evidence of lack of hazard, it is theoretically possible that the 4.9 year median follow-up in the SHARP trial was too short to detect any latent carcinogenic potential of LDL-lowering with simvastatin plus ezetimibe. Extended follow-up of the SHARP study should allow a longer term benefit-risk assessment of exposure to LDL-lowering with simvastatin plus ezetimibe in patients with moderate to severe CKD. 3. Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? Although the chief aim of SHARP was to determine any vascular benefits of LDL-lowering among patients with advanced CKD, the trial also provided an opportunity to test the hypothesis that lowering LDL cholesterol might reduce the rate of loss of renal function. Among people without known CKD, meta-analyses of randomized trials had suggested that statin therapy might reduce the rate of loss of eGFR by about one third; so a similar proportional effect among patients with advanced CKD, in whom there is rapid loss of renal function, might have yielded a worthwhile delay in the need for renal replacement therapy (i.e. dialysis or transplantation). However, in SHARP, among the 6247 patients not on dialysis at randomisation, allocation to simvastatin plus ezetimibe did not produce significant reductions in any of the pre-specified measures of renal disease progression: end-stage renal disease defined as commencement of maintenance dialysis or transplantation (1057 [33.9%] vs 1084 [34.6%]; RR 0.97, 95% CI 0.89–1.05, p=0.41); end-stage renal disease or death (1477 [47.4%] vs 1513 [48.3%]; RR 0.97, 0.90–1.04, p=0.34); and end-stage renal disease or doubling of baseline creatinine (1190 [38.2%] vs 1257 [40.2%]; RR 0.93, 0.86–1.01; p=0.09). Extended follow-up of the SHARP study will clarify whether approximately 5 years of exposure to LDL-lowering with simvastatin plus ezetimibe in patients with moderate to severe CKD has any reno-protective effect over a longer period. The findings of SHARP post-trial follow-up (PTFU) are therefore anticipated to be highly relevant to patients with kidney disease, kidney specialists and clinical guideline groups. The UK SHARP PTFU study will be a highly streamlined cohort study with no study interventions and will not involve any direct input from the original SHARP trial UK participants; specifically, it will not require them to take any study medication or attend study visits, and will not impact upon their routine clinical care. The UK SHARP PTFU cohort will consist of SHARP participants in the UK identified as being alive at the end of the SHARP study (i.e. surviving participants) who are not documented as having withdrawn consent. No additional inclusion or exclusion criteria will apply, and no further screening of potential new participants is required. [1 paragraph unchanged] In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS Digital. England. To ensure comprehensive information on all the outcomes specified above, potentially relevant outcomes, the data previously requested will include included individual patient level data concerning both the occurrence and timing of any deaths and cancers, as well as data regarding in-patient hospitalisations (i.e., hospital episode statistics (HES) [HES] data) including: major cardiac events (such as myocardial infarcts), heart attacks), strokes, arterial revascularisation procedures, procedures to open up blocked arteries (known as 'revascularisation') and end-stage renal disease (such as the need for long-term dialysis or renal transplantation). a kidney transplant). The Nuffield Department of Population Health Participant Panel (now known as the [88 words unchanged] public health. The perceived risks are therefore minimal, and the anticipated benefits greatly outweigh any foreseen harms. The study has support under section 251 of the NHS Act 2006 [18 words unchanged] be transferred to the applicant without the discloser (in this case NHS Digital) England) being in breach of the common law duty of confidentiality. Section 251 of the NHS Act 2006 also supports the study to obtain all relevant registry associated outcomes from healthcare data sources, such as NHS Digital England and similar organisations, plus other disease specific registries (e.g., the UK Renal Registry), for all UK-based SHARP trial participants from the time of randomisation. randomisation, if thought to be relevant/applicable. The lawful basis for processing the data meets the criteria for article [15 words unchanged] under the public interest or in the exercise of official authority vested I in the controller’, and article 9(2)(j) of the GDPR, that is, ‘processing is necessary for archiving achieving purposes in the public interest, scientific or historical research purposes or statistical purposes ’. [1 paragraph unchanged]

Processing activities

The CTSU at the University of Oxford (part of the NDPH) previously sent a cohort of participants in the SHARP study to NHS Digital England prior to the end of the main SHARP study for flagging and [7 words unchanged] data. 1,759 participants in England and Wales were flagged in this way. [1 paragraph unchanged] Access to the database is secure and restricted to NDPH study investigators [24 words unchanged] Information Governance (including data protection and confidentiality). The main comparisons will involve logrank survival analyses of the first post-randomisation occurrence of the progression of end-stage renal disease and site-specific cancers major clinical events (such as death) during the post-trial period among surviving SHARP participants originally allocated the simvastatin plus ezetimibe daily combination tablet versus all those allocated matching 'dummy' placebo tablets. The work in relation to the NHS Digital England data will be carried out by trained staff in the Nuffield Department [21 words unchanged] UK. The SHARP PTFU data outputs from the data derived from NHS Digital England data will be combined with data outputs from other countries participating in [35 words unchanged] identification would be negligible. No data processing or analysis of the NHS Digital England dataset will be undertaken outside of the NDPH SHARP PTFU database or [17 words unchanged] be shared with anyone not substantively employed by the University of Oxford. [3 paragraphs unchanged]

Expected output

The outputs expected are papers published in peer reviewed journals and/or presentations at relevant scientific meetings communicating the findings of the following key questions: The main output will be the results of the analyses. The publicly available outputs will be of aggregate data. 1. Does the benefit for major atherosclerotic events (MAE) and major vascular events (MVE) seen in the main SHARP study persist in the longer term? Specifically, it is planned for an article to be published in a peer reviewed journal and/or presented at relevant scientific meetings. 2. Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? 3. Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? [2 paragraphs unchanged] - European Renal Association – European Dialysis and Transplant Association (ERA EDTA); associated publications Nephrology Dialysis Transplantation (NDT) and Clinical Kidney Journal (CKJ); American Society of Nephrology (ASN); associated publications Journal of American Society of Nephrology (JASN) and Clinical Journal of the American Society of Nephrology (CJASN) (CKJ) - American Society of Nephrology (ASN); associated publications Journal of American Society of Nephrology (JASN) and Clinical Journal of the American Society of Nephrology (CJASN) [3 paragraphs unchanged] The results of these analyses will also be posted on the SHARP website (http://www.sharpinfo.org/) in a similar manner to multiple previous SHARP-related publications. In addition, the intention is to post them on the Nuffield Department of Population Health (NDPH) news website (https://www.ndph.ox.ac.uk/news). - The UK Medical Research Council In communicating the results, the CTSU will liaise with the NDPH Public Advisory Panel (https://www.ndph.ox.ac.uk/research/participant-panel) and the NDPH public engagement team to ensure that communication of the results are informed by patient and public perspectives. The results of these analyses will also be posted on the SHARP website (http://www.sharpinfo.org/) in a similar manner to multiple previous SHARP-related publications. Due to the COVID pandemic, some staff had to be re-deployed to work on research related to this issue and so staff resource has been limited to work on this project over the last 12 months. In addition, staff sickness has delayed this work. Therefore, the estimated timeline for preliminary results of analyses is now 2023. In communicating the results, the CTSU will liaise with the NDPH public engagement team to ensure that communication of the results are informed by patient and public perspectives. The level of data contained in the outputs will be aggregate data with small numbers suppressed in line with the relevant disclosure rules for the datasets including the HES Analysis Guide. Due to the COVID pandemic, some staff had to be re-deployed to work on research related to this issue and so staff resource has been limited to work on this project over the last 12-24 months. In addition, significant staff sickness and bereavement has delayed this work. Therefore, the estimated timeline for preliminary results of analyses is now 2024.

Expected measurable benefits

Chronic Kidney Disease (CKD) and the cardiovascular disease (CVD) associated with CKD is a major public health issue. In 2011, results from the Study of Heart and Renal Protection (SHARP) randomized controlled trial (RCT) were published (Lancet 2011; 377: 2181–92). SHARP was one of the largest RCTs to be conducted in people with chronic kidney disease (CKD). Volunteers were randomly allocated to take either daily cholesterol-lowering therapy with a combination tablet containing simvastatin 20mg plus ezetimibe 10mg, or matching 'dummy' or placebo tablets for an average of 5 years. The SHARP study finished in 2010 and concluded that around a quarter of all heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of simvastatin and ezetimibe to lower blood cholesterol levels. Further SHARP clinical trial results can be found at: http://www.ctsu.ox.ac.uk/~sharp/ and http://www.sharpinfo.org/. In 2017, the prevalence of CKD was estimated as 9.1% of the world's population. 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded. In the United Kingdom, the prevalence of CKD approaches 15% of the adult population (UK 2016 data) : http://healthsurvey.hscic.gov.uk/media/63736/HSE2016-Adult-kid-liv.pdf. This project is an extended follow-up to the original SHARP trial, and its outputs are hoped to achieve the stated purposes (and thus the benefits of processing) since dissemination of its results are anticipated to clarify the longer term effects (i.e. beyond 5 years) of allocation to such cholesterol-lowering medication (simvastatin plus ezetimibe) in those with CKD. CVD is the most common cause of death in patients with CKD. The prevalence of CVD among patients older than age 65 years who have CKD in the United States is 64.5%, compared with only 32.4% among those without CKD. Mortality rates also increase with each progressive stage of CKD, and dramatically increase when glomerular filtration rate (GFR) drops below 45 ml/min. As the leading cause of death in ESRD, the prevalence of CVD among ESRD patients age 22 to 44 years is approximately 50% and increases substantially among ESRD patients over age 65 years to above 75 (US 2018 data) https://www.sciencedirect.com/science/article/pii/S0735109721001960#bib4. This is important because CKD and the cardiovascular disease (CVD) associated with CKD is a major public health issue. In 2017, the prevalence of CKD was estimated as 9.1% of the world's population. 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded. In the United Kingdom, the prevalence of CKD approaches 15% of the adult population (UK 2016 data) : http://healthsurvey.NHS England.gov.uk/media/63736/HSE2016-Adult-kid-liv.pdf. The questions the SHARP PTFU study aims to address (i.e. outputs) are as follows: CVD is the most common cause of death in patients with CKD. The prevalence of CVD among patients older than age 65 years who have CKD in the United States is 64.5%, compared with only 32.4% among those without CKD. Mortality rates also increase with each progressive stage of CKD, and dramatically increase when kidney function, measured by glomerular filtration rate (GFR) drops below 45 ml/min. As the leading cause of death in End Stage Renal Disease (ESRD), the prevalence of CVD among ESRD patients age 22 to 44 years is approximately 50% and increases substantially among ESRD patients over age 65 years to above 75 (US 2018 data) https://www.sciencedirect.com/science/article/pii/S0735109721001960#bib4. 1. Does the benefit for major atherosclerotic events (MAE) and major vascular events (MVE) seen in the main SHARP study persist in the longer term? This project's outputs are therefore important because any treatments shown to be effective in the longer term in those with CKD would be potentially expected to influence national and international kidney clinical treatment guidelines, and in turn affect clinical care. This could lead to reduced CKD-related morbidity and mortality (which may consequently be detectable through national registry data). 2. Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? 3. Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? These outputs are therefore important because any treatments shown to safely reduce the incidence of CVD in those with CKD or slow the progression of CKD would be expected to influence national and international kidney clinical treatment guidelines, and in turn affect clinical care. This could lead to reduced CKD-related morbidity and mortality (which may consequently be detectable through national registry data). [1 paragraph unchanged] - Significant health Health economic savings due to the reduced CKD-related morbidity and mortality adverse health outcomes [3 paragraphs unchanged]

Benefits reported

Results from the main SHARP study (as published in 2011; Lancet 2011; 377: 2181–92) showed that In SHARP, allocation to the combination of simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) safely reduced major atherosclerotic events (MAEs), defined as non-fatal MI or coronary death, non-haemorrhagic stroke, or any arterial revascularization procedure, by 17% (95% confidence interval [CI] 6–26%; p = 0.0021) in a wide range of patients with chronic kidney disease (CKD). The SHARP post-trial follow-up project is ongoing due to staffing being affected by the Covid pandemic as well as staff sickness and bereavement, hence no results have been published yet. The SHARP post-trial follow-up project is ongoing, and no results have been published yet.

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

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling the University of Oxford to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). [20 paragraphs unchanged] In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS Digital, potentially augmented by data routinely reported into the UK Renal Registry (UKRR). Digital. To ensure comprehensive information on all the outcomes specified above, the UK registry data requested will include individual patient level data concerning both the occurrence [34 words unchanged] renal disease (such as the need for long-term dialysis or renal transplantation). [5 paragraphs unchanged]

Processing activities

[3 paragraphs unchanged] The CTSU also plans to separately share the participants' identifying details with the UKRR so that UKRR can return to the CTSU linked data which it routinely collects from 71 adult and 13 paediatric renal centres. CTSU will separately receive data from NHS Digital and UKRR. Each dataset will be added to CTSU SHARP PTFU database and linked with the existing data in that database. Through this process, the data from UKRR and the data from NHS Digital will be linked by virtue of a common SHARP unique participant identifier. No linkage of the two datasets will be undertaken outside of the CTSU SHARP PTFU database (i.e. the datasets will not be linked externally and then imported as combined data). [4 paragraphs unchanged]

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

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

Objective for processing

The original Study of Heart and Renal Protection (SHARP) resolved much of the uncertainty regarding whether low density lipoprotein (LDL) cholesterol lowering therapy should be used in patients with chronic kidney disease (CKD), but several key questions remain to be answered, in particular: This Data Sharing Agreement permits access to NHS Digital data for the purpose of the SHARP post-trial follow-up (PTFU) project. The Clinical Trial Service Unit (CTSU, part of the Nuffield Department of Population Health (NDPH) at the University of Oxford) has extensive experience in developing and running large-scale streamlined randomised trials, many of which have significantly changed clinical practice and majorly influenced national and international guidelines. One of these trials was the Study of Heart and Renal Protection (SHARP). It is the largest trial to date worldwide in patients with chronic kidney disease (CKD) and involved >9000 participants with CKD but no known history of myocardial infarction or coronary revascularisation. The SHARP trial was carried out in 18 countries, with 1,987 people in the United Kingdom selected at random. It assessed the effect of lowering low-density lipoprotein (LDL) cholesterol with a combination of simvastatin 20mg plus ezetimibe 10mg versus a matching placebo on major vascular disease (e.g. heart attacks, strokes) and renal disease (e.g. starting dialysis) events. Participants were followed regularly in study clinics with all serious adverse events (SAEs) being recorded. The SHARP trial started in 2003 and finished in 2010 (median follow-up of 4.9 years) and concluded that around a quarter of all heart attacks, strokes and operations to open blocked arteries could be avoided in people with CKD by using the combination tablet to lower blood cholesterol levels (Lancet 2011; 377: 2181–92). Whilst the SHARP study resolved much of the uncertainty regarding whether LDL-lowering therapy should be used in patients with CKD, several key questions about longer-term effects of such therapy remain to be answered and this is the aim of the SHARP post-trial follow-up (PTFU) project. The key aim of the SHARP post trial follow-up (PTFU) is to assess the longer term effects among surviving SHARP patients on the time to first major atherosclerotic events (MAEs) and major vascular events (MVEs), defined as non-fatal myocardial infarction or cardiac death, non-fatal or fatal stroke, or any arterial revascularisation procedure (excluding vascular access surgery for dialysis). This will be done by analysing data routinely reported into UK clinical databases (known as registries) from when the SHARP trial ended in 2010. The use of registry data was clearly stipulated in the SHARP protocol and consent form but extended post trial follow up was not explicitly stated. The University of Oxford sought section 251 support to authorise access to participants’ HES Admitted Patient Care data, as well as additional demographics, mortality, cancer registration data for extended follow up. Secondary aims are to assess the longer term effects among surviving SHARP patients on: (i) progression to end stage renal disease (ii) any hazardous effects (such as site specific cancers, other than non-melanoma skin cancer) and mortality by cause. The SHARP post trial follow-up (PTFU) aims to answer the following key questions: [9 paragraphs unchanged] The findings of SHARP PTFU post-trial follow-up (PTFU) are therefore anticipated to be highly relevant to patients with kidney disease, kidney specialists and clinical guideline groups. The UK SHARP PTFU study will be a highly streamlined cohort study [54 words unchanged] UK identified as being alive at the end of the SHARP study (ie, (i.e. surviving participants) who are not documented as having withdrawn consent. No additional inclusion or exclusion criteria will apply, and no further screening of potential new participants is required. Efforts were previously made to minimise the data requested which resulted in NHS number, Latest Identifiers and Supplied Identifiers no longer being disseminated. The University of Oxford have extensively reviewed the Product List and only selected fields believed to be essential to this project, only the years needed for successful follow-up, and has been limited to a cohort of 1,759 participants from England and Wales. The University of Oxford has taken careful consideration regarding data minimisation efforts and confirm there is no alternative, less intrusive way of achieving the purposes outlined above. In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS Digital, potentially augmented by data routinely reported into the UK Renal Registry (UKRR). To ensure comprehensive information on all the outcomes specified above, the UK registry data requested will include individual patient level data concerning both the occurrence and timing of any deaths and cancers, as well as data regarding in-patient hospitalisations (i.e., hospital episode statistics (HES) data) including: major cardiac events (such as myocardial infarcts), strokes, arterial revascularisation procedures, and end-stage renal disease (such as the need for long-term dialysis or renal transplantation). [1 paragraph unchanged] The Clinical Trial Service Unit (CTSU, part of the Nuffield Department of Population Health [NDPH] at the University of Oxford) has extensive experience in developing and running large-scale streamlined randomised trials, many of which have significantly changed clinical practice and majorly influenced national and international guidelines. One of these trials was the Study of Heart and Renal Protection (SHARP). It is the largest trial to date worldwide in patients with chronic kidney disease (CKD) and involved >9000 participants with CKD but no known history of myocardial infarction or coronary revascularisation. The SHARP trial was carried out in 18 countries, with 1,987 people in the United Kingdom selected at random. It assessed the effect of lowering low-density lipoprotein (LDL) cholesterol with a combination of simvastatin 20mg plus ezetimibe 10mg versus a matching placebo on major vascular disease (e.g. heart attacks, strokes) and renal disease (e.g. starting dialysis) events. Participants were followed regularly in study clinics, with all serious adverse events (SAEs) being recorded. The SHARP trial started in 2003 and finished in 2010 (median follow-up of 4.9 years) and concluded that around a quarter of all heart attacks, strokes and operations to open blocked arteries could be avoided in people with CKD by using the combination tablet to lower blood cholesterol levels (Lancet 2011; 377: 2181–92). Whilst the SHARP study resolved much of the uncertainty regarding whether LDL-lowering therapy should be used in patients with CKD, several key questions about longer-term effects of such therapy remain to be answered, and this is the aim of the SHARP post-trial follow-up (PTFU) project. The key aim of the SHARP post trial follow-up (PTFU) is to assess the longer term effects among surviving SHARP patients on the time to first major atherosclerotic events (MAEs) and major vascular events (MVEs), defined as non fatal myocardial infarction or cardiac death, non fatal or fatal stroke, or any arterial revascularisation procedure (excluding vascular access surgery for dialysis). This will be done by analysing data routinely reported into UK clinical databases (known as registries) from when the SHARP trial ended in 2010. The use of registry data was clearly stipulated in the SHARP protocol and consent form but extended post trial follow up was not explicitly stated. The University of Oxford sought Section 251 support approval to request HES Admitted Patient Care data, as well as additional MRIS data for extended follow up. Secondary aims are to assess the longer term effects among surviving SHARP patients on: (i) progression to end stage renal disease (ii) any hazardous effects (such as site specific cancers, other than non-melanoma skin cancer) and mortality by cause. In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS Digital, potentially augmented by data routinely reported into the UK Renal Registry (UKRR). To ensure comprehensive information on all the outcomes specified above, the UK registry data requested will include individual patient level data concerning both the occurrence and timing of any deaths and cancers (i.e., MRIS data), as well as data regarding in-patient hospitalisations (i.e., hospital episode statistics [HES] data) including: major cardiac events (such as myocardial infarcts), strokes, arterial revascularisation procedures, and end-stage renal disease (such as the need for long-term dialysis or renal transplantation). Efforts were previously made to minimise the data requested which involved phone calls with NHS Digital and resulted in NHS number, Latest Identifiers and Supplied Identifiers no longer being disseminated. The University of Oxford have extensively reviewed the Product List and only selected fields believed to be essential to this project, only the years needed for successful follow-up, and has been limited to a cohort of 1,759 participants from England and Wales. The University of Oxford has taken careful consideration regarding data minimisation efforts and confirm there is no alternative, less intrusive way of achieving the purposes outlined in this application. [3 paragraphs unchanged] The University of Oxford is the sole Data Controller who also and will process the data for the purpose described in this Agreement.

Processing activities

The CTSU at the University of Oxford (part of the NDPH) previously [12 words unchanged] prior to the end of the main SHARP study for flagging and MRIS reporting of demographics, mortality and cancer registration data. 1759 1,759 participants in England and Wales were flagged in this way. Subsequent to this, the CTSU received MRIS registry demographics, mortality and cancer registration data corresponding to deaths and cancers in relation to these 1759 1,759 participants. This data was held on secure servers within the University's Nuffield [71 words unchanged] was received in 2019 and is now held securely on NDPH servers. [1 paragraph unchanged] The CTSU also plans to separately share the participants' identifying details with [96 words unchanged] datasets will not be linked externally and then imported as combined data). This has not been done yet and it is currently being reassessed whether this will be feasible due to Covid-19. [2 paragraphs unchanged] No data will be shared with 3rd third parties. [1 paragraph unchanged]

Expected output

Results of the analyses will be presented at relevant scientific meetings, and in peer reviewed journals. Specific conferences or journals can not be named as it is not possible to predict where the material may be accepted. However, these will be targeted to ensure that the results are disseminated widely among the clinical trials community. The outputs expected are papers published in peer reviewed journals and/or presentations at relevant scientific meetings communicating the findings of the following key questions: The results of these analyses will also be posted on the SHARP website (http://www.sharpinfo.org/) in a similar manner to multiple previous SHARP-related publications. 1. Does the benefit for major atherosclerotic events (MAE) and major vascular events (MVE) seen in the main SHARP study persist in the longer term? Due to the Covid pandemic, some staff had to be re-deployed to work on research related to this issue, and so staff resource has been limited to work on this project over the last 12 months. Therefore the estimated timeline for publication of the results of analyses is now 2023. 2. Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? 3. Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? These findings are expected to be of potential interest to the following types of scientific bodies and their associated publications/ conferences: - UK Kidney Association (UKKA); associated publication: Journal of Kidney Care - European Renal Association – European Dialysis and Transplant Association (ERA EDTA); associated publications Nephrology Dialysis Transplantation (NDT) and Clinical Kidney Journal (CKJ); American Society of Nephrology (ASN); associated publications Journal of American Society of Nephrology (JASN) and Clinical Journal of the American Society of Nephrology (CJASN) Other bodies or charities which are likely to have an interest in this study, and which have strong patient and public advocacy include: - The British Heart Foundation (BHF) - Kidney Care UK The results of these analyses will also be posted on the SHARP website (http://www.sharpinfo.org/) in a similar manner to multiple previous SHARP-related publications. In addition, the intention is to post them on the Nuffield Department of Population Health (NDPH) news website (https://www.ndph.ox.ac.uk/news). In communicating the results, the CTSU will liaise with the NDPH Public Advisory Panel (https://www.ndph.ox.ac.uk/research/participant-panel) and the NDPH public engagement team to ensure that communication of the results are informed by patient and public perspectives. Due to the COVID pandemic, some staff had to be re-deployed to work on research related to this issue and so staff resource has been limited to work on this project over the last 12 months. In addition, staff sickness has delayed this work. Therefore, the estimated timeline for preliminary results of analyses is now 2023. The level of data contained in the outputs will be aggregate data with small numbers suppressed in line with the relevant disclosure rules for the datasets including the HES Analysis Guide.

Expected measurable benefits

The aim of the SHARP PTFU project is to carry out extended follow-up of SHARP participants to determine whether, in the longer-term: Chronic Kidney Disease (CKD) and the cardiovascular disease (CVD) associated with CKD is a major public health issue. (i) the beneficial effects in reducing the risk of heart attacks, strokes and operations to open blocked arteries seen in SHARP persist; (ii) there is any protective effect on the kidneys; (iii) any hazardous effects (such as cancer) emerge. CKD and the CVD associated with CKD is a major public health issue. [2 paragraphs unchanged] Any treatments shown to safely reduce the incidence of CVD in those with CKD or slow the progression of CKD would therefore be expected to reduce CKD-related morbidity and mortality and hence have both significant health economic and quality of life benefits. The questions the SHARP PTFU study aims to address (i.e. outputs) are as follows: Expected benefits: 1. Does the benefit for major atherosclerotic events (MAE) and major vascular events (MVE) seen in the main SHARP study persist in the longer term? Researchers/health and social care; 2. Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? - Generation of knowledge about safe prevention of CVD in those with CKD, and prevention of progression of CKD which is highly relevant to clinical guidelines and practice and improved quality of care. 3. Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? - Increased awareness of the potential for routinely collected data to augment existing understanding and knowledge of a therapeutic area. These outputs are therefore important because any treatments shown to safely reduce the incidence of CVD in those with CKD or slow the progression of CKD would be expected to influence national and international kidney clinical treatment guidelines, and in turn affect clinical care. This could lead to reduced CKD-related morbidity and mortality (which may consequently be detectable through national registry data). Patients with CKD: Other expected benefits could include: - Increased knowledge which will be used to inform their healthcare decisions; if treatment shown to be safe and effective, potentially decreased hospitalisation and improved quality of life. - Significant health economic savings due to the reduced CKD-related morbidity and mortality - Improved quality of life for kidney patients - Increased patient and public knowledge of treatments for CKD which could be used to inform their healthcare decisions - Increased researcher and public awareness of the potential for routinely collected data to augment existing understanding and knowledge of a therapeutic area

Unchanged: Benefits reported.

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

Objective for processing

The Clinical Trial Service Unit (CTSU, part of the Nuffield Department of Population Health [NDPH] at the University of Oxford) has extensive experience in developing and running large-scale streamlined randomised trials, many of which have significantly changed clinical practice and majorly influenced national and international guidelines. One of these trials was the Study of Heart and Renal Protection (SHARP). It is the largest trial to date worldwide in patients with chronic kidney disease (CKD) and involved >9000 participants with CKD but no known history of myocardial infarction or coronary revascularisation . The original Study of Heart and Renal Protection (SHARP) resolved much of the uncertainty regarding whether low density lipoprotein (LDL) cholesterol lowering therapy should be used in patients with chronic kidney disease (CKD), but several key questions remain to be answered, in particular: The SHARP trial was carried out in 18 countries, with 1,987 people in the United Kingdom being randomised. It assessed the effect of lowering LDL cholesterol with a combination of simvastatin 20mg plus ezetimibe 10mg versus a matching placebo on major vascular disease (e.g. heart attacks, strokes) and renal disease (e.g. starting dialysis) events. Participants were followed regularly in study clinics, with all serious adverse events (SAEs) being recorded. 1. Does the benefit for major atherosclerotic events (MAE) and major vascular events (MVE) seen in the main SHARP study persist in the longer term? Although there have been several previous long-term follow-up studies of statin trials, many of these did not include patients with moderate to severe CKD as were included in SHARP. Extended follow-up of the SHARP study should allow assessment of whether the benefit for MAEs and MVEs resulting from around 5 years of LDL-lowering with simvastatin plus ezetimibe in such patients persists in the longer term. 2. Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? While the SHARP trial was in progress some investigators had postulated, on the basis of analyses of the SEAS trial of simvastatin plus ezetimibe versus placebo in patients with aortic stenosis, that ezetimibe might increase the risk of cancer. This hypothesis-generating observation was not supported at the time by a hypothesis-testing meta-analysis of interim data for unadjudicated cancers that had occurred by July 2008, in SHARP and the IMPROVE-IT trial of simvastatin plus ezetimibe versus simvastatin among patients with acute coronary syndromes. The results from the SHARP trial involved substantially larger numbers of cancers than were available for that previous meta-analysis and, again, provided no credible evidence of any excess risk of cancer or of death from cancer, either overall or at any particular site, and no evidence of any trend towards an increased risk with longer exposure to study treatment. This finding is consistent with the results of the updated meta-analyses reported by the Cholesterol Treatment Trialists’ (CTT) Collaboration, which concluded that there was no evidence of any excess risk of cancer, or of cancer mortality, associated with statin therapy. Despite this robust evidence of lack of hazard, it is theoretically possible that the 4.9 year median follow-up in the SHARP trial was too short to detect any latent carcinogenic potential of LDL-lowering with simvastatin plus ezetimibe. Extended follow-up of the SHARP study should allow a longer term benefit-risk assessment of exposure to LDL-lowering with simvastatin plus ezetimibe in patients with moderate to severe CKD. 3. Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? Although the chief aim of SHARP was to determine any vascular benefits of LDL-lowering among patients with advanced CKD, the trial also provided an opportunity to test the hypothesis that lowering LDL cholesterol might reduce the rate of loss of renal function. Among people without known CKD, meta-analyses of randomized trials had suggested that statin therapy might reduce the rate of loss of eGFR by about one third; so a similar proportional effect among patients with advanced CKD, in whom there is rapid loss of renal function, might have yielded a worthwhile delay in the need for renal replacement therapy (i.e. dialysis or transplantation). However, in SHARP, among the 6247 patients not on dialysis at randomisation, allocation to simvastatin plus ezetimibe did not produce significant reductions in any of the pre-specified measures of renal disease progression: end-stage renal disease defined as commencement of maintenance dialysis or transplantation (1057 [33.9%] vs 1084 [34.6%]; RR 0.97, 95% CI 0.89–1.05, p=0.41); end-stage renal disease or death (1477 [47.4%] vs 1513 [48.3%]; RR 0.97, 0.90–1.04, p=0.34); and end-stage renal disease or doubling of baseline creatinine (1190 [38.2%] vs 1257 [40.2%]; RR 0.93, 0.86–1.01; p=0.09). Extended follow-up of the SHARP study will clarify whether approximately 5 years of exposure to LDL-lowering with simvastatin plus ezetimibe in patients with moderate to severe CKD has any reno-protective effect over a longer period. The findings of SHARP PTFU are therefore anticipated to be highly relevant to patients with kidney disease, kidney specialists and clinical guideline groups. The UK SHARP PTFU study will be a highly streamlined cohort study with no study interventions and will not involve any direct input from the original SHARP trial UK participants; specifically, it will not require them to take any study medication or attend study visits, and will not impact upon their routine clinical care. The UK SHARP PTFU cohort will consist of SHARP participants in the UK identified as being alive at the end of the SHARP study (ie, surviving participants) who are not documented as having withdrawn consent. No additional inclusion or exclusion criteria will apply, and no further screening of potential new participants is required. The Nuffield Department of Population Health Participant Panel (now known as the NDPH Public Advisory Panel) is a focus group that routinely meets to discuss research projects. The opinion of the Panel was sought regarding SHARP PTFU, as although the use of registry data was clearly stipulated in both the SHARP protocol and consent form, extended post-trial follow-up was not explicitly stated in either document. The consensus of the panel was that the consent obtained for the main SHARP trial adequately covered extended follow-up and that as patients, they would want use of their data to be maximized to benefit public health. The perceived risks are therefore minimal, and the anticipated benefits greatly outweigh any foreseen harms. The Clinical Trial Service Unit (CTSU, part of the Nuffield Department of Population Health [NDPH] at the University of Oxford) has extensive experience in developing and running large-scale streamlined randomised trials, many of which have significantly changed clinical practice and majorly influenced national and international guidelines. One of these trials was the Study of Heart and Renal Protection (SHARP). It is the largest trial to date worldwide in patients with chronic kidney disease (CKD) and involved >9000 participants with CKD but no known history of myocardial infarction or coronary revascularisation. The SHARP trial was carried out in 18 countries, with 1,987 people in the United Kingdom selected at random. It assessed the effect of lowering low-density lipoprotein (LDL) cholesterol with a combination of simvastatin 20mg plus ezetimibe 10mg versus a matching placebo on major vascular disease (e.g. heart attacks, strokes) and renal disease (e.g. starting dialysis) events. Participants were followed regularly in study clinics, with all serious adverse events (SAEs) being recorded. The SHARP trial started in 2003 and finished in 2010 (median follow-up of 4.9 years) and concluded that around a quarter of all heart attacks, strokes and operations to open blocked arteries could be avoided in people with CKD by using the combination tablet to lower blood cholesterol levels (Lancet 2011; 377: 2181–92). [1 paragraph unchanged] The key aim of the SHARP post trial follow-up (PTFU) is to assess the longer term effects among surviving SHARP patients on the time to first MAEs major atherosclerotic events (MAEs) and major vascular events (MVEs), defined as non fatal myocardial infarction or cardiac death, non fatal or fatal stroke, or any arterial revascularisation procedure [excluding (excluding vascular access surgery for dialysis]). dialysis). This will be done by analysing data routinely reported into UK clinical databases (known as registries) from when the SHARP trial ended in 2010. The use of registry data was clearly stipulated in the SHARP protocol and consent form but extended post trial follow up was not explicitly stated. The University of Oxford sought Section 251 support approval to request HES Admitted Patient Care data, as well as additional MRIS data for extended follow up. Secondary aims are to assess the longer term effects among surviving SHARP patients on:(i) on: (i) progression to end stage renal disease (ii) any hazardous effects (such as site specific cancers, other than non-melanoma skin cancer) and mortality by cause. To expand on the rationale for each of the points above: In the UK, the SHARP PTFU project will be done by analysing data routinely reported into NHS Digital, potentially augmented by data routinely reported into the UK Renal Registry (UKRR). To ensure comprehensive information on all the outcomes specified above, the UK registry data requested will include individual patient level data concerning both the occurrence and timing of any deaths and cancers (i.e., MRIS data), as well as data regarding in-patient hospitalisations (i.e., hospital episode statistics [HES] data) including: major cardiac events (such as myocardial infarcts), strokes, arterial revascularisation procedures, and end-stage renal disease (such as the need for long-term dialysis or renal transplantation). (1) Does the benefit for MAEs and MVEs seen in the main SHARP study persist in the longer term? Efforts were previously made to minimise the data requested which involved phone calls with NHS Digital and resulted in NHS number, Latest Identifiers and Supplied Identifiers no longer being disseminated. The University of Oxford have extensively reviewed the Product List and only selected fields believed to be essential to this project, only the years needed for successful follow-up, and has been limited to a cohort of 1,759 participants from England and Wales. The University of Oxford has taken careful consideration regarding data minimisation efforts and confirm there is no alternative, less intrusive way of achieving the purposes outlined in this application. There have been several previous long-term follow-up studies of statin trials; however, many of these did not include patients with moderate to severe CKD. Extended follow-up of the SHARP study should allow assessment of whether the benefit for MAEs and MVEs resulting from around 5 years of LDL-lowering with simvastatin plus ezetimibe in such patients persists in the longer term. The study has support under section 251 of the NHS Act 2006 to enable the common law duty of confidentiality to be temporarily lifted so that confidential patient information can be transferred to the applicant without the discloser (in this case NHS Digital) being in breach of the common law duty of confidentiality. (2) Does treatment with simvastatin 20 mg plus ezetimibe 10 mg significantly delay renal disease progression? Section 251 of the NHS Act 2006 also supports the study to obtain all relevant registry associated outcomes from healthcare data sources, such as NHS Digital and similar organisations, plus other disease specific registries (e.g., the UK Renal Registry), for all UK-based SHARP trial participants from the time of randomisation. Although the chief aim of SHARP was to determine any vascular benefits of LDL-lowering among patients with advanced CKD, the trial also provided an opportunity to test the hypothesis that lowering LDL cholesterol might reduce the rate of loss of renal function. Among people without known CKD, meta-analyses of randomised trials had suggested that statin therapy might reduce the rate of loss of estimated glomerular filtration rate (eGFR) by about one third; so a similar proportional effect among patients with advanced CKD, in whom there is rapid loss of renal function, might have yielded a worthwhile delay in the need for renal replacement therapy (i.e. dialysis or transplantation). However, in SHARP, among the 6247 patients not on dialysis at randomisation, allocation to simvastatin plus ezetimibe did not produce significant reductions in any of the pre-specified measures of renal disease progression. Extended follow-up of the SHARP study will clarify whether approximately 5 years of exposure to LDL-lowering with simvastatin plus ezetimibe in patients with moderate to severe CKD has any renoprotective effect over a longer period. The lawful basis for processing the data meets the criteria for article 6(1)(e) of the GDPR, that is, ‘processing is necessary for the performance of a task under the public interest or in the exercise of official authority vested I the controller’, and article 9(2)(j) of the GDPR, that is, ‘processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes ’. (3) Is treatment with simvastatin 20 mg plus ezetimibe 10 mg safe? The University of Oxford is the sole Data Controller who also process the data for the purpose described in this Agreement. While the SHARP trial was in progress, some investigators had postulated, on the basis of analyses of other studies, that ezetimibe might increase the risk of cancer. This hypothesis was not supported at the time by a subsequent meta-analysis. The results from the SHARP trial involved substantially larger numbers of cancers than were available for that previous meta-analysis and, again, provided no credible evidence of any excess risk of cancer or of death from cancer, either overall or at any particular site, and no evidence of any trend towards an increased risk with longer exposure to study treatment. Despite this robust evidence of lack of hazard, it is theoretically possible that the 4.9 year median follow-up in the SHARP trial was too short to detect any latent carcinogenic potential of LDL-lowering with simvastatin plus ezetimibe. Extended follow-up of the SHARP study through the SHARP PTFU study should allow a longer term benefit-risk assessment of exposure to LDL-lowering with simvastatin plus ezetimibe in patients with moderate to severe CKD. The SHARP PTFU project will be done by analysing data routinely reported into NHS Digital and the UK Renal Registry (UKRR). The SHARP PTFU cohort will consist of SHARP UK participants, who are already flagged with NHS Digital and UKRR, and who have not been documented as having withdrawn consent. To ensure comprehensive information on all the outcomes specified above, the UK registry data requested will include individual patient level data concerning both the occurrence and timing of any deaths and cancers (ie, MRIS data), as well as data regarding in-patient hospitalisations (ie, hospital episode statistics [HES] data) including: major cardiac events (such as myocardial infarcts), strokes, revascularisation procedures, advanced kidney disease, admissions to hospital with acute kidney damage and infections. The SHARP PTFU study will not involve any input from the original UK trial participants, i.e. the extended follow-up will not involve taking any further study medication or participants attending any study visits.

Processing activities

The CTSU at the University of Oxford (part of the NDPH) previously sent a cohort of participants in the SHARP study to NHS [14 words unchanged] data. 1759 participants in England and Wales were flagged in this way. Subsequent to this, the CTSU received MRIS registry data corresponding to deaths and cancers in relation to these 1759 participants. This data is currently was held on secure servers within the University's Nuffield Department of Population Health (of which CTSU is a part). However, this data is does did not include any HES outcomes. The SHARP 'within trial' registry data is was required so as to make biological sense of the 'post-trial' data. For [12 words unchanged] data capture commencing from 2002/3) comprising HES data, mortality and cancer outcomes is was therefore required for the SHARP PTFU project. This was received in 2019 and is now held securely on NDPH servers. NHS Digital still holds the cohort data consisting of 1759 participants and will link this in a one-off extract with MRIS mortality, cancer and HES Admitted Patient Care data. It is believed that the data which was previously disseminated by MRIS is incomplete for the post-trial period as some deaths and other events have been identified as occurring but not reported. At the request of the University of Oxford, NHS Digital will provide all available MRIS mortality and cancer data for the cohort for the purpose of the SHARP PTFU project. On receipt of the new data, the University of Oxford will link it to the existing SHARP database and any duplicates with records already held will be destroyed in a secure manner and the remaining records used to fill any gaps in data coverage. The University of Oxford will confirm destruction of the duplicate data by returning a completed Certificate of Data Destruction. Access to the database is secure and restricted to NDPH study investigators and authorised personnel. Analysis will be performed by substantive employees at the NDPH at the University of Oxford who have been appropriately trained in Information Governance (including data protection and confidentiality). The main comparisons will involve logrank analyses of the first post-randomisation occurrence of the progression of end-stage renal disease and site-specific cancers during the post-trial period among surviving SHARP participants originally allocated simvastatin plus ezetimibe daily versus all those allocated matching placebo tablets. The data is stored securely on a database within the CTSU. Access to the database will be restricted to study investigators and authorised personnel. Analysis will be performed by appropriately qualified clinicians and statisticians. The CTSU also plans to separately share the participants' identifying details with the UKRR so that UKRR can return to the CTSU linked data which it routinely collects from 71 adult and 13 paediatric renal centres. CTSU will separately receive data from NHS Digital and UKRR. Each dataset will be added to CTSU SHARP PTFU database and linked with the existing data in that database. Through this process, the data from UKRR and the data from NHS Digital will be linked by virtue of a common SHARP unique participant identifier. No linkage of the two datasets will be undertaken outside of the CTSU SHARP PTFU database (i.e. the datasets will not be linked externally and then imported as combined data). This has not been done yet and it is currently being reassessed whether this will be feasible due to Covid-19. The CTSU also separately shares the participants' identifying details with the UKRR so that UKRR can return to the CTSU linked data which it routinely collects from 71 adult and 13 paediatric renal centres. CTSU separately receives data from NHS Digital and UKRR. Each dataset is added to CTSU SHARP PTFU database and linked with the existing data in that database. Through this process, the data from UKRR and the data from NHS Digital are linked by virtue of a common SHARP unique participant identifier. No linkage of the two datasets is undertaken outside of the CTSU SHAPR PTFU database (i.e. the datasets will not be linked externally and then imported as combined data). The work in relation to the NHS Digital data will be carried out by trained staff in the Nuffield Department of Population Health (NDPH) within the University of Oxford. The SHARP trial originally involved 18 countries, one of which was the UK. The SHARP PTFU data outputs from the data derived from NHS Digital data will be combined with data outputs from other countries participating in the SHARP PTFU project (including a combined dataset from Australia, New Zealand, Malaysia). This data analysis will likely involve combining the record level linkages, but all such data would be pseudonymised so any risk of identification would be negligible. No data processing or analysis of the NHS Digital dataset will be undertaken outside of the NDPH SHARP PTFU database or by anyone who is not substantively employed by the University of Oxford. This combined data will not be shared with anyone not substantively employed by the University of Oxford. The data from NHS Digital will not be linked in any other way or with any other datasets beyond those described above. [3 paragraphs unchanged]

Expected output

[2 paragraphs unchanged] The target time frame for publication of the results of analyses is 2020-2021. Due to the Covid pandemic, some staff had to be re-deployed to work on research related to this issue, and so staff resource has been limited to work on this project over the last 12 months. Therefore the estimated timeline for publication of the results of analyses is now 2023.

Expected measurable benefits

[4 paragraphs unchanged] CKD and the CVD associated with CKD is a major public health issue. In 2017, the prevalence of CKD was estimated as 9.1% of the world's population. 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded. In the United Kingdom, the prevalence of CKD approaches 15% of the adult population (UK 2016 data) : http://healthsurvey.hscic.gov.uk/media/63736/HSE2016-Adult-kid-liv.pdf. CVD is the most common cause of death in patients with CKD. The prevalence of CVD among patients older than age 65 years who have CKD in the United States is 64.5%, compared with only 32.4% among those without CKD. Mortality rates also increase with each progressive stage of CKD, and dramatically increase when glomerular filtration rate (GFR) drops below 45 ml/min. As the leading cause of death in ESRD, the prevalence of CVD among ESRD patients age 22 to 44 years is approximately 50% and increases substantially among ESRD patients over age 65 years to above 75 (US 2018 data) https://www.sciencedirect.com/science/article/pii/S0735109721001960#bib4. Any treatments shown to safely reduce the incidence of CVD in those with CKD or slow the progression of CKD would therefore be expected to reduce CKD-related morbidity and mortality and hence have both significant health economic and quality of life benefits. [2 paragraphs unchanged] - Generation of knowledge about safe prevention of CVD in those with CKD, and prevention of progression of CKD which is highly relevant to clinical guidelines and practice and improved quality of care. - Increased awareness of the potential for routinely collected data to augment existing understanding and knowledge of a therapeutic area area. Patients: Patients with CKD: - Increased knowledge which will be used to inform their healthcare decisions leading decisions; if treatment shown to be safe and effective, potentially decreased hospitalisation and improved safety and quality of patient care life.

Benefits reported

[1 paragraph unchanged] The SHARP post-trial follow-up project is ongoing, and no results have been published yet. Staff redeployment to work relating the COVID pandemic has resulted in work on this project being delayed and the expected date of data analyses publication in journals being pushed back to 2023. As such, no yielded benefits can be obtained until the results have been published. The SHARP post-trial follow-up project is ongoing, and no results have been published yet.

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

Benefits reported

[1 paragraph unchanged] The SHARP post-trial follow-up project is ongoing; the data have not been extensively analysed to date pending receipt of an updated dataset which will contain HES data, which will make the results much more informative. The SHARP post-trial follow-up project is ongoing, and no results have been published yet. Staff redeployment to work relating the COVID pandemic has resulted in work on this project being delayed and the expected date of data analyses publication in journals being pushed back to 2023. As such, no yielded benefits can be obtained until the results have been published.

Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits.