MR1055 - HPS2-THRIVE Treatment of HDL to Reduce the Incidence of Vascular Events

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

Objective for processing

[2 paragraphs unchanged] Participants were recruited into the main trial using informed patient consent as a legal basis to process data. However, after advice from NHS Digital England and the Confidentiality Advisory Board (CAG), the data controller now has section [25 words unchanged] least 20 years, with continued data linkage to allow for future analyses The data under this Agreement is identifiable because the data controller continues to retain the patient identifiers which will be provided to NHS Digital. England. [9 paragraphs unchanged] The study team has previously received data from NHS Digital. England. Under this Agreement further data are requested and the data controller wish [111 words unchanged] can be found in admitted patient care, death and mental health records. [10 paragraphs unchanged] The study team request linkage of individual participants by their identifying information (name, NHS number, date of birth, gender) by NHS Digital. England. NHS Digital England will return data to the Nuffield Department of Population Health at the [6 words unchanged] trial identity number with data from the linkage, i.e. pseudonymised record-level data. [3 paragraphs unchanged] The study team will also link to equivalent datasets received from Digital [21 words unchanged] any way to data from any other organisations. None of the NHS Digital England data will be shared with any of the organisations involved in the wider study including the centres in China, Denmark, Norway, Finland and Sweden. Linking participants to their data held by NHS Digital England is the least intrusive way of achieving the study's purpose. The data [62 words unchanged] is applied at the point of disclosure and does not apply retrospectively. [4 paragraphs unchanged] The study team have three similar studies with common aims but for which three separate data sharing agreements are held with NHS Digital. England. Due to the similarities between the studies and the cohorts used, where [57 words unchanged] variables on major health events such as stroke, myocardial infarction and dementia. [1 paragraph unchanged] Participants who consented to have their medical records followed up also consented [69 words unchanged] on blood samples provided by participants previously will be linked with NHS Digital England data. The study team intend to link data from participant DNA analyses to NHS Digital England data. Linkage to longer-term outcomes (including those identified from NHS Digital England data) is of considerable importance in fully understanding response to statins and [35 words unchanged] contribute to the development of better patient treatments and precision medicine approaches. [6 paragraphs unchanged] All processing of NHS Digital England data will take place within the University of Oxford, therefore Oxford are listed as sole data processor under this Agreement. [3 paragraphs unchanged]

Processing activities

[6 paragraphs unchanged] NHS Digital England will link the identifiers with the following data-sets: [7 paragraphs unchanged] NHS Digital England will not return any identifiers to the data controller. Only the Study ID and data from the data-sets listed above will be returned. The data controller will retain the data for at least 25 years [12 words unchanged] will be required to maintain a valid Data Sharing Agreement with NHS Digital . England. The applicant will only hold and analyse data-sets with trial numbers, the [16 words unchanged] Controller’s NDPH NHS DSP Toolkit compliant environment via an encrypted transfer method. Participants who have applied the National Opt-Out will be excluded from the flow of data from NHS Digital. England. Opt-outs will be upheld for each new flow of data from NHS Digital England at the time of release. In addition, participants who have read the [67 words unchanged] remove any participant from future analysis who has requested to be withdrawn. Once data from NHS Digital England is held by the University of Oxford, NHS Digital England data will be linked to data collected from participants during the trial, [29 words unchanged] NDPH is used for large meta-analysis of trial data. No pseudonymised NHS Digital England or identifiable data will be shared other than with substantive employees of the data controller. [1 paragraph unchanged] Other than the linkages already described within this Agreement, researchers will not link NHS Digital England data to other datasets. No attempt will be made to re-identify participants. [4 paragraphs unchanged]

Expected output

[2 paragraphs unchanged] The NDPH contributes widely to health policy, particularly in the area of [10 words unchanged] conference participation, lectures to the public and advice to government (including NHS Digital). Enlgand). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 [10 paragraphs unchanged]

Unchanged: Expected measurable benefits, Benefits reported.

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

Datasets: + Bridge file: Hospital Episode Statistics to Mental Health Minimum Data Set; + Cancer Registration Data; + Civil Registrations of Death; + Demographics; + Hospital Episode Statistics Admitted Patient Care (HES APC); + Mental Health Minimum Data Set (MHMDS); + Mental Health Services Data Set (MHSDS); + Mental Health and Learning Disabilities Data Set (MHLDDS)

Objective for processing

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides background: This Agreement is to request data for the HPS2-THRIVE Trial Legacy Study. The HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) study is led by the Nuffield Department of Population Health (NDPH) at the University of Oxford. The University of Oxford is the sole data controller. The HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study is led by the Nuffield Department of Population Health (NDPH) at the University of Oxford. The University of Oxford are sole data controller who also process the data for the purpose described in this Agreement. HPS2-THRIVE was a randomised, international multi-centre trial of 2g of extended-release niacin (a B vitamin that is made and used by the body to turn food into energy) and 40 mg of laropiprant (a drug used in combination with niacin to reduce blood cholesterol) or a matching placebo daily in 25,673 participants (8,035 in the UK, 10,932 in China and 6,706 in Scandinavia (Denmark, Norway, Finland & Sweden)) with a history of vascular disease that ran in 245 sites in six countries (including 89 UK clinical centres). Participants in HPS2-THRIVE were recruited to the trial between 2007 and 2010 and were followed up for a median of four years in the study clinics while they continued on their randomised treatment and background LDL-lowering treatment. Results were presented at the American College of Cardiology meeting in 2013 and published in the New England Journal of Medicine in 2014. HPS2-THRIVE was a randomised, international multi-centre trial of 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily in 25,673 participants (8,035 in the UK) with a history of vascular disease that ran in 245 sites in six countries (including 89 UK clinical centres). Participants in HPS2-THRIVE were recruited to the trial between 2007 and 2010, using informed patient consent as a legal basis to process data. Participants were recruited into the main trial using informed patient consent as a legal basis to process data. However, after advice from NHS Digital and the Confidentiality Advisory Board (CAG), the data controller now has section 251 support in place to carry-out long-term research on this cohort. The data controller has approval from REC to follow up the cohort for at least 20 years, with continued data linkage to allow for future analyses The initial trial results were published in 2014. The study showed that participants allocated to niacin/laropiprant did not have a lower risk of major vascular events than those allocated to placebo, but the niacin/laropiprant did increase the risk of serious adverse events, particularly diabetes diagnosis and control, bleeding, and infection. NDPH has a strong research interest in the more reliable assessment of the effects of LDL cholesterol lowering. This long term follow up will add important data about the effects of low-density lipoproteins (LDL) cholesterol lowering on important chronic health outcomes. In addition to the effects of randomly allocated treatment, the study team will look at the effect of clinical, genetic, and biomarker data on future health. The data under this Agreement is identifiable because the data controller continues to retain the patient identifiers which will be provided to NHS Digital. Cholesterol levels are of particular interest in relation to dementia because a genetic risk factor for Alzheimer’s disease is the APOE4 variant of the APOE gene. APOE is the genetic code for a protein (apoE) that binds to receptors in low-density lipo-protein and is involved in the transport of cholesterol in the brain. People with the APOE4 variant have higher levels of total cholesterol and triglycerides than those without, and therefore higher blood LDL cholesterol is one potential mechanism for the effect of the gene. The HPS2-THRIVE study has shown that: In observational studies, there is a link between higher cholesterol and dementia. In the short-term (up to 10 years) lower cholesterol has been associated with an increased risk of dementia, which may be because of reverse causal effects of the incipient dementia leading to lower levels. However, raised mid-life levels of LDL cholesterol have been found to be associated with increased risk of dementia 15-20 years later. There is little data, however, on whether raised levels of cholesterol and other cardiovascular risk factors at older ages are associated with an increased risk of dementia 15-20 years later. Continued follow-up for dementia in studies in older people initiated many years ago is therefore extremely valuable for investigating such effects. - Allocation to extended release (ER) niacin/laropiprant reduced LDL-cholesterol by 0.25 mmol/L and increased HDL-cholesterol by 0.16 mmol/L but did not significantly reduce the risk of major vascular events (i.e. heart attacks, strokes or coronary or non-coronary revascularisation) compared to placebo. - Allocation to ER niacin/laropiprant significantly increased the risk of disturbances in diabetes control and new onset diabetes and serious adverse events associated with the gastrointestinal and musculoskeletal systems, skin and, unexpectedly, both infection and bleeding ER Niacin increased the risk of simvastatin-induced myopathy by about 4-fold. - Participants from China were at higher risk of statin-induced myopathy than those from Europe. - The results of HPS2-THRIVE led to the withdrawal of ER niacin/laropiprant from the European market and Merck ceased development of the product. NDPH has a strong research interest in the more reliable assessment of the effects of LDL (low-density lipoprotein) cholesterol lowering. This long-term follow up will add important data about the effects of LDL cholesterol lowering on important chronic health outcomes. In addition to the effects of randomly allocated treatment, the study team will look at the effect of clinical, genetic, and biomarker data on future health. Cholesterol levels are of particular interest in relation to dementia because a genetic risk factor for Alzheimer’s disease is the APOE4 variant of the APOE gene. APOE is the genetic code for a protein (APOE4) that binds to receptors in low-density lipo-protein, and is involved in the transport of cholesterol in the brain. People with the APOE4 variant have higher levels of total cholesterol and triglycerides (a type of fat found in the blood) than those without, and therefore higher blood LDL cholesterol is one potential mechanism for the effect of the gene. In observational studies, there is a link between higher cholesterol and dementia. In the short-term (up to 10 years) lower cholesterol has been associated with an increased risk of dementia, which may be because incipient dementia leads to lower levels. However, raised levels of LDL cholesterol 15-20 years before the development of dementia have been found to be associated with increased risk of dementia. There is little data, however, on whether raised levels of cholesterol and other cardiovascular risk factors at older ages are associated with an increased risk of dementia 15-20 years later. Continued follow-up for dementia in studies in older people initiated many years ago is therefore extremely valuable for investigating such effects. [1 paragraph unchanged] The study team have previously received data from NHS Digital. Under this agreement the data controller wishes to retain all data previously disseminated while extending the period of this Agreement. The study team has previously received data from NHS Digital. Under this Agreement further data are requested and the data controller wish to retain all data previously disseminated. Additionally, the data controller now has Section 251 support to request hospital episodes, cancers, demographics, and mental health datasets for the cohort. This data will enable the data controller to examine the effect of baseline clinical, genetic and biomarker variables on major health events, including major vascular events (including, but not limited to strokes of different types and heart attacks (myocardial infarction)), cancers, renal disease and dementia. The data controller will ascertain these events, chiefly through ICD-10 coding in hospital admission, death records, and mental health records. The study team have found in previous work that the majority of cases of chronic disease (including dementia) can be found in admitted patient care, death and mental health records. The data subjects are all participants of the original randomised controlled trial. The study team will obtain data from each participant from the time they began to take part in the trial (the first participant was randomised on 1st April 2007) to the date of linkage. This allows researchers to: (i) compare the occurrence of events recorded by the study during follow up with events recorded by electronic health records; (ii) compare the very long-term incidence of major disease by randomised treatments and baseline factors. Further data releases will allow the study team to continue follow up into the extremely long term. Although the University of Oxford is not asking for personal identifiers under this Agreement, the remaining supplied data will still be linked to the existing long-term follow-up study database, which does store the identifying data. There is an ongoing need to retain identifying data to enable further data linkages, such as that which will take place under this Data Sharing Agreement. To address the GDPR principle of data minimisation the University of Oxford only requested fields that are deemed necessary for the purpose of this research, and only receive data that relates to a specific cohort of 7456 individuals. Direct identifiers will need to be retained whilst linkages are made between datasets before all data are identified primarily with the study ID, in order to pseudonymise the long-term follow-up dataset. The intention is to keep a pseudonymised dataset for future analysis for as long as is necessary, and this will be reviewed on a yearly basis. The legal basis for processing and storing data under this Agreement is Article 6(1)e (GDPR), i.e. it is a task carried out in the public interest. The aim of the study is to provide reliable evidence about the very long-term effects of cholesterol-lowering treatments in the UK population and is therefore in the public interest. In addition, it is NDPH policy to retain research data for at least 25-years after the end of a the trial as per the 2014 Clinical Trials Regulation (EU) No 536/2014: https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf In addition, processing and storage of special category (sensitive) personal data is being done under Article 9(2)(j) (GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes. The scientific research aim of the study is to provide reliable evidence about the very long-term effects of cholesterol-lowering treatments on important health outcomes. The purpose of requesting the data under this Agreement is to determine factors that contribute to the health of trial participants in the longer-term. All processing of NHS Digital data will take place within the University of Oxford; therefore, Oxford are listed as sole data processor under this Agreement. The research objectives are: One of the Investigators is employed by both the University of Edinburgh and the University of Oxford. The study team have confirmed with NHS Digital that this individual will analyse the data under this Agreement solely in his role as a substantive employee of the University of Oxford, and therefore the University of Edinburgh are not listed as a data controller under this Agreement. 1. To determine whether participants randomly allocated to treatments leading to lower levels of LDL cholesterol have a lower risk of dementia. 2. To determine whether participants randomly allocated to treatments leading to lower levels of LDL cholesterol have other long-term health effects. 3. To measure the association between baseline and in-trial vascular risk measures with future dementia. 4. To determine the association between deoxyribonucleic acid (DNA) and plasma markers with dementia and other long-term health effects. In order to determine the occurrence of the diagnosis of particular illnesses, the study team, who are all substantive employees of the University of Oxford, will need to link trial participants to hospitalisation, mental health, death and cancer records. The study team will therefore request linkage to Hospital Episode Statistics (HES) for Admitted Patient Care, the Mental Health Datasets, Demographics, Civil Registration - Deaths, and Cancer data sets. The study team request linkage of individual participants by their identifying information (name, NHS number, date of birth, gender) by NHS Digital. NHS Digital will return data to the Nuffield Department of Population Health at the University of Oxford with each participant's trial identity number with data from the linkage, i.e. pseudonymised record-level data. The data subjects will all be participants of the original randomised controlled trial. The study team will obtain data from each participant from the time they began to take part in the trial (the first participant was randomised on 1st April 2007) to the date of linkage. This allows researchers to: (i) compare the occurrence of events recorded by the study during follow up with events recorded by electronic health records; (ii) compare the very long-term incidence of major disease by randomised treatments and baseline factors. Further data releases will allow the study team to continue follow-up of participants for their entire lifespan including cause of death. Participants were resident in and recruited from across the UK, and may have moved between nations since recruitment, and therefore the study team would like to link all participants (including those in Scotland) to data held across England and Wales. The study team will also link to equivalent datasets received from Digital Health & Care Wales (DHCW), the Scottish NHS Central Register (NHSCR) and Public Health Scotland. Data will not be linked in any way to data from any other organisations. None of the NHS Digital data will be shared with any of the organisations involved in the wider study including the centres in China, Denmark, Norway, Finland and Sweden. Linking participants to their data held by NHS Digital is the least intrusive way of achieving the study's purpose. The data controller believes that re-approaching participants for further consent would lead to potentially very large biases in ascertainment of major health conditions (because of non-responder biases particularly amongst those in poorest health, or those who have died) and potentially lead to distress. Therefore, the data controller has obtained Section 251 support from the HRA CAG for this linkage. The national data opt out is applied at the point of disclosure and does not apply retrospectively. The research team have taken the opinion of the West of Scotland Research Ethics Service, who have granted approval to the study in its current form. Furthermore, potential harm to the public will be limited by data pseudonymisation, data minimisation, and technical and organisational safeguards. Analysis will occur in a safe NHS Data Security and Protection (DSP) Toolkit compliant environment and identifiers will not be included in the analysis. Although the study is not in direct contact with participants, at the time the study team asked for the opinion of available participants in these and similar studies. They agreed that the use of the data in the way that the study team have proposed is reasonable. The study team request linkage only to those datasets and data fields relevant to the research that contain information on medical diagnoses, for only the participants of the study. The study team will also link to equivalent datasets received from Digital Health & Care Wales (DHCW), the Scottish NHS Central Register (NHSCR) and Public Health Scotland. The study team have three similar studies with common aims but for which three separate data sharing agreements are held with NHS Digital. Due to the similarities between the studies and the cohorts used, where any one study (this Agreement, in addition DARS-NIC-148341-TC6TD (SEARCH) and DARS-NIC-148069-ZB4GM (HPS)) does not give sufficient power for an analysis, the study team will perform meta-analyses to a common protocol from each study. Where the randomised allocations are similar, the study team will perform study level and individual participant data meta-analyses to look at the effect of variables on major health events such as stroke, myocardial infarction and dementia. The first planned analyses will be based on at least 20 years’ follow-up from trial initiation with further analyses planned at approximately 5 yearly intervals based on on-going linkage to NHS records. Participants who consented to have their medical records followed up also consented to providing blood samples for the genomic arm of this study. The genomic analyses will be undertaken at specialist laboratories. This will involve sending pure DNA samples. DNA is not a relevant material under the Human Tissue Authority (HTA) and all samples will be sent with only the participant study identifier and no personal data. All data will be returned to Oxford for statistical analyses. DNA analysis carried out on blood samples provided by participants previously will be linked with NHS Digital data. The study team intend to link data from participant DNA analyses to NHS Digital data. Linkage to longer-term outcomes (including those identified from NHS Digital data) is of considerable importance in fully understanding response to statins and cardiovascular risk and its consequences as a whole. Genetic data may be able to add insights into our understanding of the effects of statins, determinants and mechanisms of risk factors and disease outcomes, that can contribute to the development of better patient treatments and precision medicine approaches. Although the University of Oxford is not asking for personal identifiers under this Agreement, the remaining supplied data will still be linked to the existing long-term follow-up study database, which does store the identifying data. The study team is required to do this as the long-term follow-up study is still ongoing and has to comply with Good Clinical Practice Guidelines enacted in UK law via the Medicines for Human Use Act. Within the UK, the Medicines and Healthcare Products Regulatory Agency (MHRA) ensure these regulations are enforced via inspections. There is an ongoing need to retain identifying data to enable further data linkages, such as that which will take place under this Data Sharing Agreement. This is also required by NDPH Policy and clinical trials regulations. Data will be stored for at least 5 years after the end of the long-term follow-up study so that any audits requested by the University can be undertaken as per University of Oxford policy. Identifiers will need to be retained whilst linkages are made between datasets before all data are identified primarily with the study ID, in order to pseudonymise the long-term follow-up dataset. The intention is to keep a pseudonymised dataset for future analysis for as long as is necessary, and this will be reviewed on a yearly basis. In addition, it is NDPH policy to retain research data for at least 25-years after the end of a the trial as per the 2014 Clinical Trials Regulation (EU) No 536/2014: https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf To address the GDPR principle of data minimisation the University of Oxford only request fields that are deemed necessary for the purpose of this research, and only receive data that relates to a specific cohort of ~8,035 individuals (minus any withdrawals). The legal basis for processing and storing data under this Agreement is Article 6(1)e (UK GDPR), i.e. it is a task carried out in the public interest. The aim of the study is to provide reliable evidence about the very long term effects of cholesterol-lowering treatments in the UK population and is therefore in the public interest. In addition, processing and storage of special category personal data is being done under Article 9(2)(j) (UK GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes. The scientific research aim of the study is to provide reliable evidence about the very long-term effects of cholesterol-lowering treatments on important health outcomes. All processing of NHS Digital data will take place within the University of Oxford, therefore Oxford are listed as sole data processor under this Agreement. One of the Study Investigators is employed by both the University of Edinburgh and the University of Oxford. The applicant has confirmed that this investigator will analyse the data under this Agreement solely in their role as a substantive employee of the University of Oxford, and therefore the University of Edinburgh are not listed as a data controller under this Agreement. [1 paragraph unchanged]

Processing activities

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information about processing activities permitted under previous iterations of this Agreement: The THRIVE study team will resupply the following identifiers for the original randomised UK cohort (8,035) minus any participants who have withdrawn from the study: NHS Digital already previously received identifiers for this cohort and as recruitment ended in 2010, there will be no need to resupply these identifiers. The identifiers that NHS Digital currently hold are: [3 paragraphs unchanged] - Date of death - Postcode [2 paragraphs unchanged] The applicant will only hold and analyse data-sets with trial numbers, the identifiers and linkage key will be held separately. The data will be sent to the Data Controller’s NDPH DSP Toolkit compliant environment via an encrypted transfer method. All data will be transferred, handled and processed in agreement with the NHS Digital Data Sharing Framework Contract, and will be subject to Fair Processing requirements. NHS Digital will link the identifiers with the following data-sets: There are no subsequent flows of data. - HES APC Participants who have already opted out from having their data stored by NHS Digital will be excluded. In addition, participants who have read the privacy notice and have decided that they do not wish their data to be used in this study will be able to opt out. - Mental Health datasets - Demographics - Civil Registration - deaths - Cancer Registrations Historic data will be supplied for HES, cancer and mental health data-sets from 2006 (where available) to present. For the Demographics and Civil Registration - Deaths, latest available data will be provided. NHS Digital will not return any identifiers to the data controller. Only the Study ID and data from the data-sets listed above will be returned. The data controller will retain the data for at least 25 years after the end of a the trial, as per NDPH guidelines, and will be required to maintain a valid Data Sharing Agreement with NHS Digital . The applicant will only hold and analyse data-sets with trial numbers, the identifiers and linkage key will be held separately. The data will be sent to the Data Controller’s NDPH NHS DSP Toolkit compliant environment via an encrypted transfer method. Participants who have applied the National Opt-Out will be excluded from the flow of data from NHS Digital. Opt-outs will be upheld for each new flow of data from NHS Digital at the time of release. In addition, participants who have read the privacy notice (available on the study website: https://www.ctsu.ox.ac.uk/research/hps2-thrive) and have decided that they do not wish their data to be used in this study will be able withdraw their consent to participate in the study and their data will not be included in future analysis. Although the HPS2-THRIVE long-term research is being conducted with Section 251 support, the University of Oxford consider it appropriate and ethical to remove any participant from future analysis who has requested to be withdrawn. [1 paragraph unchanged] Using existing ICD-10 code lists for different clinical phenotypes, the study team [42 words unchanged] of disease events within trial. Data linkage takes place within the NDPH IG NHS DSP Toolkit compliant environment. Data are pseudonymised prior to analysis. With the exception of linking NHS Digital to trial data, no linkage is proposed to datasets containing personal identifiers. No linkage to publicly available data is proposed. There will be no attempt will be made to re-identify participants from the NHS data. Other than the linkages already described within this Agreement, researchers will not link NHS Digital data to other datasets. No attempt will be made to re-identify participants. [2 paragraphs unchanged] All information is stored securely by the University of Oxford and is [32 words unchanged] card access only. No individuals will be identified in any study reports. All those with access to the data are substantive employees of the University of Oxford. [1 paragraph unchanged]

Expected output

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides details of Outputs described under previous iterations of this Agreement: The primary outputs from this data are and will be academic, including submissions to peer reviewed journals such as New England Journal of Medicine and the Lancet, and conferences such as the American Heart Association meeting. The primary outputs from this data will be academic, and will include submissions to peer reviewed journals such as New England Journal of Medicine and the Lancet, and conferences such as the American Heart Association meeting. The study team only present data at an aggregated level with small numbers suppressed. The study team present actual and modelled data in graphical and tabular format. The study team will only present data at an aggregated level with small numbers suppressed in line with HES Analysis Guidance. The study team will present actual and modelled data in graphical and tabular format. The NDPH contributes widely to health policy, particularly in the area of vascular risk prevention. It contributes to debate with academic papers, conference participation, lectures to the public and advice to government (including NHS Digital). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 The NDPH contributes widely to health policy, particularly in the area of vascular risk prevention. The study team also share outputs via all of the listed channels: It contributes to debate with academic papers, conference participation, lectures to the public and advice to government (including NHS Digital). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 The study team will share outputs via all of the listed channels: [8 paragraphs unchanged] HPS2-THRIVE related publications: Outputs for the HPS2-THRIVE study so far include multiple publications in peer-reviewed journals and presentations at international conferences. Information about the publications can be found on the THRIVE website (https://www.ctsu.ox.ac.uk/research/hps2-thrive), and the benefits are described in Section 6iii (Yielded Benefits). • Haynes R, Valdes-Marquez E, Hopewell JC, Chen F, Li J, Parish S, Landray MJ, Armitage J; HPS2-THRIVE Collaborative Group; HPS2-THRIVE Writing Committee members; HPS2-THRIVE Steering Committee members. Serious Adverse Effects of Extended-release Niacin/Laropiprant: Results From the Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial. Clin Ther. 2019 Sep;41(9):1767-1777 Epub 2019 Aug 22 https://www.ncbi.nlm.nih.gov/pubmed/31447131 DOI: 10.1016/j.clinthera.2019.06.01 • Offer A, Arnold M, Clarke R, Bennett D, Bowman L, Bulbulia R, Haynes R, Li J, Hopewell JC, Landray M, Armitage J, Collins R, Parish S; Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Collaborative Group. Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials. JAMA Netw Open. 2019 Mar 1;2(3):e190223 https://www.ncbi.nlm.nih.gov/pubmed/30821829 DOI: 10.1001/jamanetworkopen.2019.0223 • Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract. 2017 Apr;23(Suppl 2):1-87 https://www.ncbi.nlm.nih.gov/pubmed/28437620 DOI: 10.4158/EP171764.APPGL • Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy Lancet. 2016 Nov 19;388(10059):2532-2561 Epub 2016 Sep 8 https://www.ncbi.nlm.nih.gov/pubmed/27616593 DOI: 10.1016/S0140-6736(16)31357-5 • Kent S, Haynes R, Hopewell JC, Parish S, Gray A, Landray MJ, Collins R, Armitage J, Mihaylova B; HPS2-THRIVE Collaborative Group. Effects of Vascular and Nonvascular Adverse Events and of Extended-Release Niacin With Laropiprant on Health and Healthcare Costs. Circ Cardiovasc Qual Outcomes. 2016 Jul;9(4):348-54 https://www.ncbi.nlm.nih.gov/pubmed/27407053 DOI: 10.1161/CIRCOUTCOMES.115.002592. Epub 2016 Jul 12 • HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of extended-release niacin with laropiprant in high-risk patients N Engl J Med. 2014 Jul 17;371(3):203-12 https://www.ncbi.nlm.nih.gov/pubmed/25014686 DOI: 10.1056/NEJMoa1300955 • Donald M. Lloyd-Jones. Niacin and HDL Cholesterol - Time to Face Facts N Engl J Med 2014; 371:271-273 https://www.nejm.org/doi/full/10.1056/NEJMe1406410 DOI: 10.1056/NEJMe1406410 • HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013 May;34(17):1279-91. Epub 2013 Feb 26 https://www.ncbi.nlm.nih.gov/pubmed/23444397 DOI: 10.1093/eurheartj/eht055

Expected measurable benefits

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information described in previous iterations of this Agreement: [1 paragraph unchanged] Niacin treatment has been used for many years to reduce the risk of circulatory disease (i.e. heart attacks, strokes and procedures to open blocked arteries). HPS2-THRIVE has shown that ER niacin/laropiprant in fact does not add any benefit on top of current standard treatment and in fact causes more side-effects. This confirms the results of previous smaller studies of niacin which also did not show any benefit. [1 paragraph unchanged] The data controller will intends to produce data that other organisations (for example NICE The National Institute for Health and Care Excellence (NICE) guideline committees) will be able to use to better advise on the [16 words unchanged] that patients can better judge the impact of medicines on their health. [1 paragraph unchanged] Researchers will hope to achieve these benefits first through communication of risk. If this the study leads to a change in the apparent benefits of LDL-lowering, then this will be communicated first through published literature, and then into risk scores by the study group team and other academics. If the research shows a long term benefits benefit of LDL-lowering, then researchers the study team will measure the impact of their the work in citations, in guidelines, and work by other academics. Any benefits The study team expect to show any benefit found are expected to be realised within 5-10 years after the end of study.

Benefits reported

The HPS2-THRIVE main THRIVE study showed that participants allocated to niacin-laropiprant did not have a lower [23 words unchanged] of serious adverse events, particularly diabetes diagnosis and control, bleeding and infection. The HPS2-THRIVE and other studies conducted by the University of Oxford’s Clinical Trial Service Unit (CTSU) within the Nuffield Department of Population Health (NDPH) (NDPH), have strongly influenced the labelling of statin medication internationally, treatment guidelines, and [5 words unchanged] have contributed to reductions in mortality and morbidity from heart attack and ischaemic stroke blocked arteries (‘ischaemic stroke’) in many countries. CTSU’s randomised trials and meta-analyses of trials have shown that lowering low density lipoprotein (LDL) cholesterol safely reduces the risk of heart attacks, strokes and revascularisation procedures in a wide range of people, and work conducted in collaboration with the NDPH’s Health Economic Research Centre has provided clear evidence of cost-effectiveness of statins. countries The Clinical Trial Service Unit’s (CTSU) randomised trials and meta-analyses of trials have shown that lowering low density lipoprotein (LDL) cholesterol safely reduces the risk of heart attacks, strokes and revascularisation procedures in a wide range of people, and work conducted in collaboration with the NDPH’s Health Economic Research Centre has provided clear evidence of cost-effectiveness of statins. Some of the main points realised from the outputs and publications are: A number of previously unrecognized harmful effects, namely, new-onset diabetes, bleeding, and infection, were observed in HPS2-THRIVE and appear to have been caused largely (if not wholly) by the niacin component of the study treatment. The absolute excesses of these and other adverse effects appeared to be similar in a wide variety of patients. Consequently, practitioners or patients wishing to continue using niacin should consider the potential implications of these harmful effects in determining whether using niacin is worth the risk. The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies. The Clinical Practice Guideline (CPG) is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. [HPS2-THRIVE results contributed to this work.] Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. [HPS2-THRIVE results contributed to this work.] In HPS2-THRIVE, the addition of extended-release niacin-laropiprant to statin-based therapy reduced quality of life-adjusted survival and increased hospital costs. The consistent findings of a lack of benefit of raising the HDL cholesterol level with the use of niacin when added to effective LDL cholesterol–lowering therapy with statins seriously undermine the hypothesis that HDL cholesterol is a causal risk factor. The failure (to date) of cholesteryl ester transfer protein inhibitors, such as torcetrapib and dalcetrapib, to show any reduction in cardiovascular risk despite the marked increases in the HDL cholesterol level associated with these drugs, lends further credence to the notion that HDL cholesterol is unlikely to be causal. [HPS2-THRIVE results contributed to this work.] Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. The risk of myopathy was increased by adding extended release niacin (ERN)/laropiprant (LRPT) to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ~1 month, three-quarters continued to take it for ~4 years. The analysis of data under this Agreement has strongly influenced the international recommendation that lower LDL-cholesterol is better for prevention of heart attack and stroke, which has led to more than 6 million prescriptions of lipid lowering drugs per year in England. Additionally, the THRIVE study results have contributed to the knowledge that increasing HDL-cholesterol does not substantially reduce the risk of cardiovascular disease. This has impacted pharmaceutical companies who were developing medications to increase HDL-cholesterol. The results of HPS2-THRIVE led to the withdrawal of ER niacin/laropiprant from the European market and Merck ceased development of the product.

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

Datasets: − Bridge file: Hospital Episode Statistics to Mental Health Minimum Data Set; − Hospital Episode Statistics Admitted Patient Care (HES APC); − Mental Health Minimum Data Set (MHMDS); − Mental Health Services Data Set (MHSDS); − Mental Health and Learning Disabilities Data Set (MHLDDS)

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 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 permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides background: The following provides background information on the purpose of the original study: The HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study is led by the Nuffield Department of Population Health (NDPH) at the University of Oxford. The University of Oxford are sole data controller who also process the data for the purpose described in this Agreement. The THRIVE Study recruited a total of 20,000 men and women from the UK, Scandinavia and China who had a history of circulatory problems, such as a heart attack or stroke. HPS2-THRIVE was a randomised, international multi-centre trial of 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily in 25,673 participants (8,035 in the UK) with a history of vascular disease that ran in 245 sites in six countries (including 89 UK clinical centres). Participants in HPS2-THRIVE were recruited to the trial between 2007 and 2010, using informed patient consent as a legal basis to process data. One of the causes of circulatory disease is having too much LDL (bad) cholesterol in the blood. Despite effective LDL lowering treatments, some people still suffer recurrent heart or circulatory problems and this study hope to find a way of reducing these risks further. In general, people with higher levels of good HDL cholesterol have fewer heart attacks, strokes or circulatory problems than people with lower levels. Niacin is a medication that increases the amount of good cholesterol in the blood but it is not clear if it prevents heart attacks and strokes. There are also side effects including flushing (reddening of the skin) associated with Niacin which make it difficult for people to take their tablets regularly. The initial trial results were published in 2014. The study showed that participants allocated to niacin/laropiprant did not have a lower risk of major vascular events than those allocated to placebo, but the niacin/laropiprant did increase the risk of serious adverse events, particularly diabetes diagnosis and control, bleeding, and infection. NDPH has a strong research interest in the more reliable assessment of the effects of LDL cholesterol lowering. This long term follow up will add important data about the effects of low-density lipoproteins (LDL) cholesterol lowering on important chronic health outcomes. In addition to the effects of randomly allocated treatment, the study team will look at the effect of clinical, genetic, and biomarker data on future health. A new combination treatment, MK-5024A (MK-0524 and extended release niacin), had been developed which reduces the flushing caused by niacin. Cholesterol levels are of particular interest in relation to dementia because a genetic risk factor for Alzheimer’s disease is the APOE4 variant of the APOE gene. APOE is the genetic code for a protein (apoE) that binds to receptors in low-density lipo-protein and is involved in the transport of cholesterol in the brain. People with the APOE4 variant have higher levels of total cholesterol and triglycerides than those without, and therefore higher blood LDL cholesterol is one potential mechanism for the effect of the gene. The aim of THRIVE is to find out whether long term treatment with MK-0524A in people who have survived a heart attack, stroke or other circulatory problems produces benefits by raising HDL (good) cholesterol. It is hoped that this will prevent heart attacks, strokes and the need for arterial bypass procedures. In observational studies, there is a link between higher cholesterol and dementia. In the short-term (up to 10 years) lower cholesterol has been associated with an increased risk of dementia, which may be because of reverse causal effects of the incipient dementia leading to lower levels. However, raised mid-life levels of LDL cholesterol have been found to be associated with increased risk of dementia 15-20 years later. There is little data, however, on whether raised levels of cholesterol and other cardiovascular risk factors at older ages are associated with an increased risk of dementia 15-20 years later. Continued follow-up for dementia in studies in older people initiated many years ago is therefore extremely valuable for investigating such effects. Participants were split randomly into two groups. One group received MK0524A tablets and the other group received a placebo tablet for an initial period of 2 months before follow up in clinic. Participants were then asked if they would be willing to continue taking the tables for at least four years. Dementia is a leading cause of death in the UK and it is likely that by now many of the HPS2-THRIVE participants may have developed dementia. This study now constitutes a uniquely rich resource for study of the relationships of vascular risk factors to dementia incidence many years later. This study will look at the association of vascular risk factors measured at baseline with dementia incidence at various times into the future, with longer delays between measurement of risk factors at recruitment and incidence of dementia being particularly valuable. The study team have previously received data from NHS Digital. Under this agreement the data controller wishes to retain all data previously disseminated while extending the period of this Agreement. The data subjects are all participants of the original randomised controlled trial. The study team will obtain data from each participant from the time they began to take part in the trial (the first participant was randomised on 1st April 2007) to the date of linkage. This allows researchers to: (i) compare the occurrence of events recorded by the study during follow up with events recorded by electronic health records; (ii) compare the very long-term incidence of major disease by randomised treatments and baseline factors. Further data releases will allow the study team to continue follow up into the extremely long term. To address the GDPR principle of data minimisation the University of Oxford only requested fields that are deemed necessary for the purpose of this research, and only receive data that relates to a specific cohort of 7456 individuals. The legal basis for processing and storing data under this Agreement is Article 6(1)e (GDPR), i.e. it is a task carried out in the public interest. The aim of the study is to provide reliable evidence about the very long-term effects of cholesterol-lowering treatments in the UK population and is therefore in the public interest. In addition, processing and storage of special category (sensitive) personal data is being done under Article 9(2)(j) (GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes. The scientific research aim of the study is to provide reliable evidence about the very long-term effects of cholesterol-lowering treatments on important health outcomes. All processing of NHS Digital data will take place within the University of Oxford; therefore, Oxford are listed as sole data processor under this Agreement. One of the Investigators is employed by both the University of Edinburgh and the University of Oxford. The study team have confirmed with NHS Digital that this individual will analyse the data under this Agreement solely in his role as a substantive employee of the University of Oxford, and therefore the University of Edinburgh are not listed as a data controller under this Agreement. Funding for this study is provided internally from the University of Oxford.

Processing activities

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information about processing activities permitted under previous iterations of this Agreement: The study data, including data provided by NHS Digital under previous agreements, are currently held by University of Oxford. NHS Digital already previously received identifiers for this cohort and as recruitment ended in 2010, there will be no need to resupply these identifiers. The identifiers that NHS Digital currently hold are: The following provides background on the processing activities undertaken prior to this Agreement: - Name Identifying data was shared with ONS to carry out the linkage between the study data and civil registration data. Participants records were ‘flagged’ with the Office for National Statistics (ONS). ONS notified the study team at the University of Oxford of participants’ deaths (date and cause) and cancer events when they occurred. The ‘flagging for long-term follow up’ service transferred from ONS to the HSCIC in 2008. Data was last supplied in September 2016. - NHS Number - Date of birth - Date of death - Postcode - Gender - Study ID The applicant will only hold and analyse data-sets with trial numbers, the identifiers and linkage key will be held separately. The data will be sent to the Data Controller’s NDPH DSP Toolkit compliant environment via an encrypted transfer method. All data will be transferred, handled and processed in agreement with the NHS Digital Data Sharing Framework Contract, and will be subject to Fair Processing requirements. There are no subsequent flows of data. Participants who have already opted out from having their data stored by NHS Digital will be excluded. In addition, participants who have read the privacy notice and have decided that they do not wish their data to be used in this study will be able to opt out. Once data from NHS Digital is held by the University of Oxford, NHS Digital data will be linked to data collected from participants during the trial, including baseline clinical, genetic and biomarker data. All processing of data will be performed within the Nuffield Department of Population Health at the University of Oxford. Data held within NDPH is used for large meta-analysis of trial data. No pseudonymised NHS Digital or identifiable data will be shared other than with substantive employees of the data controller. Using existing ICD-10 code lists for different clinical phenotypes, the study team will define the date and the nature of disease events for each participant. Researchers will link the list of processed disease outcomes with existing datasets of baseline clinical, genetic and biomarkers data (including those received from Scotland and Wales), and the occurrence of disease events within trial. Data linkage takes place within the NDPH IG Toolkit compliant environment. Data are pseudonymised prior to analysis. With the exception of linking NHS Digital to trial data, no linkage is proposed to datasets containing personal identifiers. No linkage to publicly available data is proposed. There will be no attempt will be made to re-identify participants from the NHS data. NDPH researchers are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. The NDPH servers are protected against unauthorised external access by an appropriate strength firewall. Access to patient identifiable information is protected by the appropriate authentication procedures (user IDs and passwords). Authentication is only given to personnel with a need to access the required data. Only personnel involved in the long-term follow-up of these studies (processing and analysing data) will have access to this data. NDPH has a Corporate Level Security Policy that has been fully adopted by management and will apply fully to the long-term follow-up study. All information is stored securely by the University of Oxford and is kept confidential. Access to the computer database is by unique combinations of usernames and passwords and only authorised study personnel can access information about participants. The building is secure with authorised swipe card access only. No individuals will be identified in any study reports. All those with access to the data are substantive employees of the University of Oxford. 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).

Expected output

This Agreement permits the secure retention of the data only and no other processing. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides details of Outputs described under previous iterations of this Agreement: No new outputs will be produced under this Data Sharing Agreement. The primary outputs from this data will be academic, and will include submissions to peer reviewed journals such as New England Journal of Medicine and the Lancet, and conferences such as the American Heart Association meeting. The study team will only present data at an aggregated level with small numbers suppressed in line with HES Analysis Guidance. The study team will present actual and modelled data in graphical and tabular format. The NDPH contributes widely to health policy, particularly in the area of vascular risk prevention. It contributes to debate with academic papers, conference participation, lectures to the public and advice to government (including NHS Digital). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 The study team will share outputs via all of the listed channels: - Study website - Open lectures and talks - Exhibition at public events - Posters - Press/media engagement and other public promotion of the research The data controller aims to issue the next publication by Spring 2023. All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. HPS2-THRIVE related publications: • Haynes R, Valdes-Marquez E, Hopewell JC, Chen F, Li J, Parish S, Landray MJ, Armitage J; HPS2-THRIVE Collaborative Group; HPS2-THRIVE Writing Committee members; HPS2-THRIVE Steering Committee members. Serious Adverse Effects of Extended-release Niacin/Laropiprant: Results From the Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial. Clin Ther. 2019 Sep;41(9):1767-1777 Epub 2019 Aug 22 https://www.ncbi.nlm.nih.gov/pubmed/31447131 DOI: 10.1016/j.clinthera.2019.06.01 • Offer A, Arnold M, Clarke R, Bennett D, Bowman L, Bulbulia R, Haynes R, Li J, Hopewell JC, Landray M, Armitage J, Collins R, Parish S; Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Collaborative Group. Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials. JAMA Netw Open. 2019 Mar 1;2(3):e190223 https://www.ncbi.nlm.nih.gov/pubmed/30821829 DOI: 10.1001/jamanetworkopen.2019.0223 • Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract. 2017 Apr;23(Suppl 2):1-87 https://www.ncbi.nlm.nih.gov/pubmed/28437620 DOI: 10.4158/EP171764.APPGL • Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy Lancet. 2016 Nov 19;388(10059):2532-2561 Epub 2016 Sep 8 https://www.ncbi.nlm.nih.gov/pubmed/27616593 DOI: 10.1016/S0140-6736(16)31357-5 • Kent S, Haynes R, Hopewell JC, Parish S, Gray A, Landray MJ, Collins R, Armitage J, Mihaylova B; HPS2-THRIVE Collaborative Group. Effects of Vascular and Nonvascular Adverse Events and of Extended-Release Niacin With Laropiprant on Health and Healthcare Costs. Circ Cardiovasc Qual Outcomes. 2016 Jul;9(4):348-54 https://www.ncbi.nlm.nih.gov/pubmed/27407053 DOI: 10.1161/CIRCOUTCOMES.115.002592. Epub 2016 Jul 12 • HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of extended-release niacin with laropiprant in high-risk patients N Engl J Med. 2014 Jul 17;371(3):203-12 https://www.ncbi.nlm.nih.gov/pubmed/25014686 DOI: 10.1056/NEJMoa1300955 • Donald M. Lloyd-Jones. Niacin and HDL Cholesterol - Time to Face Facts N Engl J Med 2014; 371:271-273 https://www.nejm.org/doi/full/10.1056/NEJMe1406410 DOI: 10.1056/NEJMe1406410 • HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013 May;34(17):1279-91. Epub 2013 Feb 26 https://www.ncbi.nlm.nih.gov/pubmed/23444397 DOI: 10.1093/eurheartj/eht055

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information described in previous iterations of this Agreement: The research may help decisions about treatments for patients with vascular disease, or who are considering treatment with lipid lowering agents such as statins. The study of data for the HPS2-THRIVE trial has the advantage of: large size; very detailed baseline data collection; and information on several genetic and blood biomarkers which will inform researchers' knowledge of the effects of LDL-cholesterol lowering. The data controller will produce data that other organisations (for example NICE guideline committees) will be able to use to better advise on the effect of LDL-cholesterol lowering on the incidence of dementia and other long term health conditions, so that patients can better judge the impact of medicines on their health. Statins which lower LDL cholesterol are some of the most commonly prescribed medications, so the results of this study are likely to affect many people. In England, there are about 6 million prescriptions a month of lipid regulating drugs (~2 million for simvastatin, ~4 million for atorvastatin) Researchers will achieve these benefits first through communication of risk. If this study leads to a change in the apparent benefits of LDL-lowering, then this will be communicated first through published literature, and then into risk scores by the study group and other academics. If research shows a long term benefits of LDL-lowering, then researchers will measure the impact of their work in citations, in guidelines, and work by other academics. Any benefits found are expected to be realised within 5-10 years after the end of study.

Benefits reported

In any future application, the applicant will be required to provide details of the actual benefits achieved as a result of the study. The main THRIVE study showed that participants allocated to niacin-laropiprant did not have a lower risk of major vascular events despite a small reduction in LDL-cholesterol than those allocated to placebo, but the niacin/laropiprant did increase the risk of serious adverse events, particularly diabetes diagnosis and control, bleeding and infection. The HPS2-THRIVE and other studies conducted by the University of Oxford’s Clinical Trial Service Unit (CTSU) within the Nuffield Department of Population Health (NDPH) have strongly influenced the labelling of statin medication internationally, treatment guidelines, and the resulting changes in prescribing have contributed to reductions in mortality and morbidity from heart attack and ischaemic stroke in many countries. CTSU’s randomised trials and meta-analyses of trials have shown that lowering low density lipoprotein (LDL) cholesterol safely reduces the risk of heart attacks, strokes and revascularisation procedures in a wide range of people, and work conducted in collaboration with the NDPH’s Health Economic Research Centre has provided clear evidence of cost-effectiveness of statins.

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

Objective for processing

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as the THRIVE Study (Treatment of HDL to Reduce the Incidence of Vascular Events). 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 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 permits the retention of the data for an interim period but no other processing of the data is permitted. The following provides background information on the purpose of the original study: Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required. The following information provides background information on the purpose of the original study: [5 paragraphs unchanged]

Processing activities

[1 paragraph unchanged] The study data, including data provided by NHS Digital under previous agreements, are currently held by the University of Oxford. Under this interim extension all devices containing data will be securely locked away in a locked cabinet at the University of Oxford storage address specified in this Agreement. The following provides background on the processing activities undertaken for the original study: prior to this Agreement: [1 paragraph unchanged]

Expected output

This Agreement permits the secure retention of the data only and no other processing. [1 paragraph unchanged] In any future application, the applicant will be required to provide details of the outputs that were produced and disseminated by the study as well as details of any future outputs planned.

Expected measurable benefits

In any future application, the applicant will be required to provide details of the expected benefits resulting from the study. This Agreement permits the secure retention of the data only and no other processing.

Unchanged: Benefits reported.