HPS 3 / TIMI 55: REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification)

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Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics; + Emergency Care Data Set (ECDS); + Hospital Episode Statistics Admitted Patient Care (HES APC); + Medicines dispensed in Primary Care (NHSBSA data); + National Diabetes Audit · − MRIS - Personal Demographics Service; − MRIS - Scottish NHS / Registration

Objective for processing

This Agreement is for the REVEAL Legacy Study. REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification) is led by the Nuffield Department of Population Health (NDPH) at the University of Oxford. The University of Oxford is the sole data controller. University of Oxford requires access to NHS England data for the purpose of the following research project: The REVEAL trial was a randomized, double-blind, placebo-controlled trial of the CETP (Cholesterol ester transfer protein) inhibitor anacetrapib (a drug that raises HDL (High-Density Lipoprotein, or, 'good' cholesterol). 30,449 men and women older than 50 years of age were recruited between August 2011 and October 2013 in Europe (UK, Germany, Italy, Denmark, Finland, Norway, Sweden), North America (USA and Canada), and China. Individuals were eligible if they had a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral artery disease, or diabetes mellitus with symptomatic coronary heart disease. Individuals with an acute coronary event or stroke less than 3 months before randomization or with a planned coronary revascularization were excluded. After an 8 to 12-week pre-randomization run-in phase with study atorvastatin alone, eligible patients were randomized to receive the addition of anacetrapib 100 mg once daily or matching placebo. Atorvastatin was given to all study participants to make sure that LDL cholesterol (Low-Density Lipoprotein, or, 'bad' cholesterol) was well controlled. Atorvastatin is a type of statin used for lowering LDL (bad) cholesterol (this was provided free of charge by Merck Sharp & Dohme Corp). This enabled reliable assessment of the efficacy & safety of anacetrapib. The trial was approved by all relevant institutional review boards and regulatory authorities, and participants provided written informed consent. REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification) The main trial (i.e. the period when participants were receiving study treatment and having regular study visits at clinic sites) started in August 2011 ended in January 2017. The results from this showed for the first time that adding anacetrapib to intensive statin therapy reduces the incidence of cardiovascular events for high-risk patients. The treatment was very well tolerated and there were no major safety concerns. The following is a summary of the aims of the research project provided by University of Oxford: Post-trial follow-up of all eligible randomized participants continued for 2-years (from May 2017 to April 2019) beyond the final main trial visit. During this time, participants did not receive any study medication. Post-trial follow-up was conducted primarily by telephone with information sometimes collected from GPs, hospital records and also via central registry data linkage. Post-trial follow-up results were published in December 2021. They showed that the beneficial effects of anacetrapib on major coronary events increased with longer follow-up, with no adverse effects emerging for non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomised trials of lipid-modifying agents to assess their full benefits and harms. REVEAL was a randomized, double-blind, placebo-controlled trial of a cholesteryl ester transfer protein (CETP) inhibitor called anacetrapib, which has the effect of raising HDL-cholesterol and lowering LDL-cholesterol. The trial was designed, conducted, analysed, and interpreted by independent investigators from the Nuffield Department of Population Health (NDPH) at the University of Oxford. This was in collaboration with the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital and Harvard Medical School in Boston, USA, along with other members of the Steering Committee and Merck & Co, Inc, New Jersey, USA (Merck). Between August 2011 and October 2013, 30,499 men and women aged 50 years or older with pre-existing atherosclerotic vascular disease were randomly allocated to receive anacetrapib 100 mg daily or a matching placebo after having been given an open-label atorvastatin regimen intended to lower their pre-randomization LDL-cholesterol to below 2.0 mmol per litre (77 mg per decilitre), during an 8-12 weeks run-in phase prior to randomisation. Participants were recruited from the UK, Germany, Italy, Denmark, Finland, Norway, Sweden, USA, Canada and China. Both study medications and funding for the main trial were provided by Merck, who were also the manufacturers of anacetrapib. Information about the results, including publications, have been posted on the REVEAL website: https://www.ctsu.ox.ac.uk/research/hps3-timi55-reveal. After stopping the randomly-allocated treatment, 26,129 surviving participants (worldwide) entered a 2-year post-trial follow-up (PTFU) period, blind to their original treatment allocation, from May 2017 to April 2019. During this time, participants did not receive any study medication. The PTFU was conducted primarily by telephone with information sometimes collected from GPs, hospital records and also via NHS England and the National Health Service Central Register (NHSCR; for Scotland) data linkage. DATA LINKAGE Demographics, mortality and cancer registration data was previously used to confirm outcomes for the analyses in REVEAL, during its on-treatment and PTFU phases. The study team now wish to extend the follow-up of participants further. Extended follow-up of UK participants is planned for at least a further 15-years (from 2019). The research objective is to investigate the long-term effects of allocation to anacetrapib versus placebo on cardiovascular events, deaths, cancers and other serious adverse events during extended follow-up. The main outcomes of interest are mortality, cancer, cardiovascular events, and other serious adverse events. In addition, exploratory assessments will be made of other possible effects of anacetrapib among particular subgroups of participants based on data recorded at the randomization visit. Following post-trial follow-up, subsequent extended long-term follow-up of UK participants only is planned for at least a further 15-years (from 2019) in order to provide valuable information on the longer-term effects of anacetrapib. There will be no direct contact with participants. There will be a particular focus on clinical safety, including cause-specific mortality, cancers, and vascular events. Information on these and other reasons for hospitalization and other serious adverse events will be collected from central registries such as NHS Digital, Public Health Scotland, the NHS Central Register (NHSCR) and Digital Health & Care Wales (DHCW). In the absence of equivalent national repositories of healthcare data elsewhere in the world, the longer-term follow-up (LTFU) shall involve participants randomised in the UK only. The study team have previously received data from NHS Digital. This Agreement will permit the ongoing retention of data previously disseminated. The following NHS England data will be accessed: 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, under future proposed amendments to this Agreement. > Hospital Episode Statistics, specifically: 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. - Admitted Patient Care (APC) – necessary to determine the diagnosis of cardiovascular events and other serious adverse events. This dataset may also be used for identification of cardiovascular outcomes, in comparison with adjudicated events, which may be relevant to the design of future trials. The research objective is to investigate the long-term effects of allocation to anacetrapib versus placebo on vascular events, deaths, and other serious adverse events during extended follow-up. > Emergency Care Data Set (ECDS) – necessary to detect additional coronary events and strokes that may not be present in the HES APC data. This dataset may also be used for identification of cardiovascular outcomes, in comparison with adjudicated events, which may be relevant to the design of future trials. The main outcomes of interest are: > Civil Registration Mortality – necessary to identify participants who have died, plus cause and date of death. This dataset may also be used for identification of cardiovascular outcomes, in comparison with adjudicated events, which may be relevant to the design of future trials. Cause of deaths data is also required to feed into the efficacy and safety outcomes. i. Mortality > Cancer Registration – necessary to identify participants who have had a cancer diagnosis, plus information about the type of cancer, and related dates. This dataset may also be used for identification of cardiovascular outcomes, in comparison with adjudicated events, which may be relevant to the design of future trials. ii. Cancer > Demographics – necessary to identify individuals during follow-up who no longer have a registered GP. This is because if a study participant no longer has a GP, then no further follow-up data can be obtained, so the date of removal of the study participant is needed to calculate the follow-up time for each participant. This dataset will also contribute information about fact and date of death. iii. Cardiovascular events; and > Medicines dispensed in Primary Care (NHSBSA data) – This dataset will be used as a source of information about REVEAL’s main cardiovascular efficacy outcomes, in combination with other datasets. The information will provide intelligence about the safety and effectiveness of medications tested in the trial, and is directly relevant to the large number of patients in the UK and globally who require lipid modification for the secondary prevention of major atherosclerotic cardiovascular events. The CETP inhibitor class of drugs might also have a role in the management of diabetes and neurodegenerative diseases such as Alzheimer’s disease. The NHSBSA dataset will also contribute information about prescriptions for these outcomes. Finally, the dataset may be used for identification of cardiovascular outcomes, in comparison with adjudicated events, which may be relevant to the design of future trials. iv. Other serious adverse events > National Diabetes Audit (NDA) – necessary to provide data on lipid, albuminuria, creatinine, HbA1c, BMI, blood pressure measurement and prescribing, which will allow specific safety and efficacy analyses in approximately 2,445 REVEAL participants of the cohort who have diabetes. The lipid data will provide a mechanistic insight into any ongoing effects of anacetrapib, specifically whether these are conveyed by the drug’s LDL-cholesterol lowering or HDL-cholesterol raising actions. The data will also help to interpret whether the persistent benefits of anacetrapib seen during the PTFU, were a legacy effect of previous intensive lipid modification, or an effect of ongoing lipid modification as a result of the drug’s accumulation and slow release from adipose tissue. These outstanding questions may have implications for the duration of treatment and follow-up in trials of other lipid-modifying therapies. The study team would also like to compare the effects of anacetrapib on renal parameters, new-onset diabetes and blood pressure because there were between-group differences in these items during the main trial. The prescribing data held by the audit will also help verify new-onset diabetes diagnoses. This dataset may also be used for identification of cardiovascular outcomes, in comparison with adjudicated events, which may be relevant to the design of future trials. In addition, exploratory assessments will be made of other possible effects of anacetrapib among particular subgroups of participants based on data recorded at the randomization visit (as specified in the protocol), and on other serious adverse events during the extended follow-up period. The level of the data will be: The data subjects are all UK participants of the original randomized controlled trial. Identifiable – necessary to verify the cohort linkage, and to enable linkage of the data with data collected from other sources, specifically, the existing long-term follow-up study database. Cause of deaths data is also required to feed into the efficacy and safety outcomes. Participants were resident in and recruited from across the UK. The data will be minimised as follows: 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 outside of the UK. > Limited to the REVEAL study cohort of 8,381 UK participants identified by University of Oxford, minus any withdrawals. The cohort were recruited between August 2011 and October 2013, and included men and women aged 50 years or older with pre-existing atherosclerotic vascular disease and excludes any individuals who did not consent to post-trial follow-up. Linking participants to their data held by NHS Digital is the least intrusive way of achieving the study's purpose. Participants have provided informed consent to be followed-up long-term via central registry data linkage. > Limited to data between August 2011 (the month the first patient was added to the study cohort) – latest available. 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 randomized treatments and baseline factors. Blood and urine samples were collected from participants during the main trial. Participants gave consent separately to allow samples of plasma, serum & urine to be retained for unspecified analysis in the future. Similarly supplementary consent was sought to permit genetic material in the blood samples to be analysed. Where genomic analyses have been done in specialist laboratories outside of the NDPH, all samples are sent with only the study identifier and no personal data. All data is returned to Oxford for statistical analyses. DNA analysis carried out on blood samples provided by participants previously may be linked with NHS Digital data. > Participants were resident in and recruited from across the UK (excluding Northern Ireland) and may have moved between nations since recruitment. The study team therefore need to link all participants (including potentially those in Scotland & Wales) to data held across England and Wales. The study team intend to link data from participant DNA analyses to NHS Digital data under a future Agreement. Linkage to longer-term outcomes (including those identified from NHS Digital data) is of considerable importance in fully understanding response to statins/anacetrapib and cardiovascular risk and its consequences as a whole. Genetic data may be able to add insights into the determinants and mechanisms of risk factors and disease outcomes, that can contribute to the development of better patient treatments and precision medicine approaches. University of Oxford is the research sponsor and the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. LEGAL BASIS FOR PROCESSING, COMMON LAW DUTY OF CONFIDENTIALITY, AND ETHICS The lawful basis for processing personal data under the UK GDPR is: The legal basis Article 6(1)(e) - processing is necessary for processing and storing data under this Agreement is Article 6(1)e (GDPR), i.e. it is the performance of 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 anacetrapib (and HDL cholesterol raising) interest or in the UK population and is therefore exercise of official authority vested in the public interest. controller. 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 anacetrapib (and HDL cholesterol raising) on important health outcomes. The lawful basis for processing special category data under the UK GDPR is: The common law duty of confidentiality is addressed by having patient consent. Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The research team have taken the opinion of the South Central – Oxford B 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 (by requesting only the data fields that are relevant to the research for the REVEAL cohort only), and technical and organisational safeguards. Analysis will occur in a safe, NHS DSP Toolkit compliant environment and identifiers will not be included in the analysis. The study team have asked for the opinion of participants in similar studies, and they have agreed that the use of the data in the way that the study team have proposed is reasonable. The scientific research aim of the study is to provide reliable evidence about the very long-term effects of anacetrapib on important health outcomes. As well as being directly relevant to REVEAL participants, these findings are also of interest more widely. Although Merck decided not to pursue regulatory approval or commercialization of anacetrapib, other CETP inhibitors are still in development. There are also implications for the treatment and follow-up duration of other trials of lipid modifying drugs. CONTROLLERSHIP AND FUNDING The funding comes from multiple sources. Some funding funds the REVEAL study specifically, while others fund the NDPH more broadly. Current funders include: The University of Oxford are the sole data controller who also process the data for the purposes described within this Agreement. > Health Data Research UK – Funding is in place until March 2028. Funding for the extended follow-up study will be provided internally from the University of Oxford. Previously, Merck (who manufactured anacetrapib) had provided funding for the main trial and the 2-year post-trial follow-up (up to 2019). The grant from Merck ends in December 2022 (Merck are not able to determine how the University of Oxford spend the remainder of this grant, all decisions are made by the REVEAL study team alone). Funding from the remainder of this grant is adequate to cover the NHS Digital DSA costs. > Medical Research Council – Funding is in place until March 2025. > British Heart Foundation – Funding is in place until March 2024. Funding to continue the work described will be sought on an ongoing basis. The funders will have no ability to suppress or otherwise limit the publication of findings. Members of the REVEAL Steering Committee have an advisory and oversight role. They will review and approve analyses and study publications. However, they are not involved in the detailed conduct of the study and are not involved with data linkage activities or decisions on how NHS England data is used.

Processing activities

Identifiable NHS Digital datasets currently held by the REVEAL trial: University of Oxford transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, Forename, Surname, Gender and a unique person ID) for the cohort to be linked with NHS England data. - MRIS - Members and Postings Report NHS England data will provide the relevant records from the HES, ECDS, deaths, cancer, demographics, NHSBSA, and National Diabetes Audit datasets to University of Oxford. The data will - MRIS - Flagging Current Status Report > contain directly identifying data items including NHS Number and Date of Birth which are required to verify the cohort linkage and to link the Data at record level with data already held by the University of Oxford. - MRIS - Cohort Event Notification Report The Data will not be transferred to any other location. - MRIS - Cause of Death Report The Data will be stored on servers at the University of Oxford. - MRIS – Scottish NHS / Registration The Data will also be accessed by authorised personnel via remote access. The data controller will retain the pseudonymised data for at least 25 years after the end of the trial, as per NDPH guidelines, and will be required to maintain a valid Data Sharing Agreement with NHS Digital. The applicant will hold and analyse data-sets with trial numbers. The identifiers and linkage key will be held separately. The data is stored in the Data Controller’s NDPH NHS DSP Toolkit compliant environment. All data will be handled and processed in agreement with the NHS Digital Data Sharing Framework Contract, and will be subject to Fair Processing requirements. The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract. There are no subsequent flows of data. For remote access: 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. - Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA; All processing of data will be performed within the Nuffield Department of Population Health at the University of Oxford. No pseudonymised NHS Digital or identifiable data will be shared other than with substantive employees of the data controller. - Access controls granting users the minimum level of access required are in place; Data linkage takes place within the NDPH NHS DSP Toolkit compliant environment. Data are pseudonymised prior to analysis. - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect 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 from the NHS data. - Multifactor authentication (MFA) is required for remote access; NDPH researchers are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; 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 this study (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 extended follow-up study. - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy. 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. The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose). 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). The data will not leave England and Wales at any time. Access is restricted to individuals within the NDPH of the University of Oxford who have authorisation from the Principal Investigator. All such individuals are substantive employees of the University of Oxford. All personnel accessing the data have been appropriately trained in data protection and confidentiality. The data will be linked at person record level with: > equivalent data obtained from Digital Health & Care Wales (DHCW), the Welsh Secure Anonymous Information Linkage (SAIL) datasets, the Scottish NHS Central Register (NHSCR) and Public Health Scotland > data collected from participants during the trial, including their clinical, genetic and biomarker data. Genetic data may be able to add insights into the determinants and mechanisms of risk factors and disease outcomes that can contribute to the development of better patient treatments and precision medicine approaches. The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset. Researchers from the NDPH of the University of Oxford will analyse the data for the purposes described above.

Expected output

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 expected outputs of the processing will be: For the ongoing extended follow-up to be undertaken in UK participants only, an updated data analysis plan will be published on the trial website in advance of any further analyses being undertaken. Subsequent analyses will be planned when median follow-up is at least 10 years (with further analyses possible at around 20 years of median follow-up). > Submissions to peer reviewed journals such as the New England Journal of Medicine and the Lancet [annual submissions expected] The study team will only present data at an aggregated level with small numbers suppressed. The study team will present actual and modelled data in graphical and tabular format. > An updated data analysis plan will be published on the trial website in advance of any further analyses being undertaken The NDPH contributes widely to health policy, particularly in the area of vascular risk prevention. > Presentations at appropriate conferences such as the American Heart Association meeting 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 2021 is available from: https://results2021.ref.ac.uk/profiles/institutions/10007774 (Unit of assessment 2: Public Health, Health Services and Primary Care). The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. The study team outputs will share outputs via all of be communicated to relevant recipients through the listed following dissemination channels: - Study website > Journals - Open lectures and talks > Through collaborations with Health Data Research UK and the NIHR-MRC Trials Methodology Partnership - Posters > Study website updates - Press/media engagement and other public promotion of the research > Open lectures and talks The data controller aims to issue the next publication by Q4 2023. > Advice to government (including NHS England) All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. > Posters displayed at international, national, and departmental conferences. For example, the European Society of Cardiology (ESC), American Heart Association (AHA) and the Society for Clinical Trials Methodology Conference. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. > Press/media engagement Outputs for the REVEAL 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/hps3-timi55-reveal), and the benefits are described in Section 5iii (Yielded Benefits). More information about the publications can be found on the REVEAL website (https://www.ctsu.ox.ac.uk/research/hps3-timi55-reveal). The REVEAL main trial found the following results: The next publication is expected by Q4 of 2024. A diabetes sub-study paper is also expected by Q3 2025. • Adding anacetrapib to statin therapy reduced the blood level of LDL (low-density lipoprotein) cholesterol by around 20% and doubled the level of HDL (high-density lipoprotein) cholesterol. • Adding anacetrapib to intensive statin treatment produced a 9% proportional reduction in the risk of the composite outcome of heart attack, death from heart disease, or coronary revascularization (i.e. coronary artery stenting or bypass surgery). • In a subsidiary analysis, anacetrapib significantly reduced the composite outcome of coronary death or myocardial infarction. There was no significant effect on ischaemic stroke. • Anacetrapib was well tolerated and, as has been found previously, the levels of anacetrapib in body fat continued to increase while treatment continued. • Anacetrapib produced a small reduction in the risk of developing diabetes mellitus. • There were no major safety signals and no increase in death, cancer or other serious medical events, but there was a small increase in blood pressure and a small reduction in kidney function. The post-trial follow-up analysis showed that the beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no safety concerns emerged on non-vascular mortality or morbidity. The absolute reduction in major coronary events at 6 years was nearly double that seen at the end of the 4 year treatment period. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms.

Expected measurable benefits

In carrying out this long-term extended follow up researchers may be able to gain a better understanding of the long-term consequences of prescribing anacetrapib, including its effect on Major Coronary Events (MCEs), such as coronary death, myocardial infarction or coronary revascularization, and other health outcomes. Currently, a low percentage of high risk individuals achieve target LDL-cholesterol levels. Combination lipid-lowering therapy (LLT) could help improve this and CETP inhibitors are one way to do it. To date, 4 types of CETP inhibitor have been tested. The first three were unsuccessful. They showed unwanted side-effects, lack of efficacy because they were weak lipid modifiers, or the study duration was too short. REVEAL was the first trial to show a reduction in Major Coronary Events (MCE) (9%). The absolute reductions in cardiovascular events (particularly MCE) seen in-trial doubled during the Post-trial Follow-Up. However, Merck (the drug manufacturer) did not pursue licensing of the drug because of the unusually long half-life. New generation CETP inhibitors with a shorter half-life, a potent LDL-lowering effect, and good safety profile could become viable treatment options for people with established atherosclerotic cardiovascular disease. New research is also ongoing into repurposing CETP inhibitors to treat CETP-mediated cholesterol dysregulation in Alzheimers disease, diabetes and obesity. The REVEAL Long-term Follow-up is expected to help researchers gain a better understanding of the long-term effects of intensive LDL-lowering using anacetrapib and statin therapy, including effects on cardiovascular and other health outcomes. The research may also help decisions about treatments for patients with vascular disease, or who are considering treatment with lipid-modifying agents such as statins, PCSK9 inhibitors or small interfering RNA inhibitors targeting PCSK9. Findings from REVEAL could change the preferred combination of LLT used routinely. The results could also be relevant to the duration of treatment and follow-up in other lipid-lowering trials, which might underestimate treatment effects if this is not sufficiently long enough. REVEAL is also the only study of sufficient duration to investigate the effects of HDL-cholesterol raising. Given anacetrapib’s persistence in the body and the availability of high-quality electronic healthcare data in the UK, REVEAL is uniquely positioned and of sufficient duration to investigate the long-term effects of pharmacologically raising HDL-cholesterol. The use of the data could: • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience. • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). If the study leads to a change in the apparent benefits of LDL-lowering, then this will be communicated first through published literature. The study team will measure the impact of the work in citations, in guidelines, and work by other academics. To optimise the potential public benefits from the use of the data, findings will be communicated through open-access published literature, and will be made available on the NDPH and REVEAL websites. In summary, the use of NHS England data is expected to improve treatments and support knowledge creation.

Benefits reported

Health practitioners will be better informed as the The REVEAL main trial showed for the first time that anacetrapib lowers the [8 words unchanged] among patients with atherosclerotic vascular disease who are receiving intensive statin treatment. The treatment was well tolerated and there were no major safety concerns. The REVEAL post-trial follow-up results were published in December 2021. They showed that the beneficial effects of anacetrapib on major coronary events increased with longer follow-up, with no adverse effects emerging for non-vascular mortality or morbidity . The REVEAL main trial found the following results: • Adding anacetrapib to statin therapy reduced the blood level of LDL (low-density lipoprotein) cholesterol by around 20% and doubled the level of HDL (high-density lipoprotein) cholesterol. • Adding anacetrapib to intensive statin treatment produced a 9% proportional reduction in the risk of the composite outcome of heart attack, death from heart disease, or coronary revascularization (i.e. coronary artery stenting or bypass surgery). • In a subsidiary analysis, anacetrapib significantly reduced the composite outcome of coronary death or myocardial infarction. There was no significant effect on ischaemic stroke. • In a pre-specified analysis, albeit one that was not adjusted for the multiple comparisons, anacetrapib produced a small reduction in the risk of developing diabetes mellitus (510 [5.3%] in those assigned to anacetrapib vs. 571 [6.0%] in the placebo group). • There were no major safety signals and no increase in death, cancer or other serious medical events, but there was a small increase in blood pressure (mean systolic BP was 0.7 mmHg higher in the anacetrapib group vs. placebo at the final follow-up. Mean diastolic was 0.3 mmHg higher in the anacetrapib group vs placebo. There were no significant differences between hypertension-related events between treatment groups). • There was a small reduction in kidney function in the anaceptrapib group (11.5%) compared to the placebo group (10.6%). • The beneficial effects of anacetrapib on major coronary events increased with longer follow-up in the PTFU study. The PTFU findings illustrated the importance of sufficiently long treatment and follow-up duration in randomised trials of lipid-modifying agents to assess their full benefits and harms. This may be especially relevant to anacetrapib, which accumulates in adipose tissue (body fat) during continued dosing, creating a reservoir that leads to its slow elimination from the peripheral circulation. As a consequence, residual lipid-modifying effects – albeit substantially reduced – are observed for some years after stopping prolonged treatment. The following points explain why these results are important and what the wider benefits are. 1. Impact on patients Previous trials of CETP inhibitors (with different drugs and different follow-up periods) showed neutral or hazardous effects on cardiovascular outcomes. REVEAL was the first trial to show the beneficial effects of using a CETP inhibitor and no emergent safety concerns. However, a sub-study also showed that anacetrapib accumulates in adipose tissue with prolonged dosing. The long-term effects of this are currently unknown. The results of REVEAL and its extended follow-up are directly relevant to the surviving trial participants and the participants of other ongoing trials using newer CETP inhibitors. 2. Impact on healthcare providers in the UK and Worldwide REVEAL provided further reliable, randomised evidence to support the safety of reducing LDL-cholesterol to low levels, which had previously been raised as a concern. This is an important finding with implications for the treatment of many millions of people with established cardiovascular disease. 3. Impact on trial design and cost REVEAL demonstrated the importance of doing clinical trials of lipid-modifying drugs with sufficiently long treatment and follow-up durations. Methodology research conducted for other trials in the department has previously shown that routine electronic health data provided a cost-effective means of assessing the impact of vascular preventive therapies on dementia and heart failure. This experience suggests that routinely collected hospital admission and death registry data in the UK could be used as the sole method of follow-up for myocardial infarction, ischaemic stroke resulting in hospitalisation, vascular death, and arterial revascularisation in primary prevention cardiovascular trials, without the need for verification by clinical adjudication. This could have far-reaching implications for future trial design and minimising research costs.

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

Objective for processing

The Randomized EValuation of the Effects of Anacetrapib through Lipid-modification (REVEAL) trial was a randomized, double-blind, placebo-controlled trial of the CETP (Cholesterol ester transfer protein) inhibitor anacetrapib (a drug that raises HDL (good) cholesterol). 30 449 men and women older than 50 years of age were recruited between 2011 and 2013 in Europe (UK, Germany, Italy, Denmark, Finland, Norway, Sweden), North America (USA and Canada), and China. Individuals were eligible if they had a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral artery disease, or diabetes mellitus with symptomatic coronary heart disease. Individuals with an acute coronary event or stroke less than 3 months before randomization or with a planned coronary revascularization were excluded. After an 8 to 12-week pre-randomization run-in phase with study atorvastatin alone, eligible patients were randomized to receive the addition of anacetrapib 100 mg once daily or matching placebo for a median duration of about 4 years. Atorvastatin is a type of statin used for lowering LDL (bad) cholesterol (this was provided free of charge by Merck Sharp & Dohme Corp). Atorvastatin was given to all study participants to make sure that LDL cholesterol was well controlled. This enabled reliable assessment of the efficacy & safety of anacetrapib. The pre-specified primary outcome of the main trial was first major coronary event (a composite of coronary death, myocardial infarction, or coronary revascularization), with additional secondary outcomes including first major vascular event (a composite of major coronary event and presumed ischemic stroke). The trial was approved by all relevant institutional review boards and regulatory authorities, and participants provided written informed consent. The main trial (i.e. the period when participants were receiving study treatment and having regular study visits at clinic sites) ended in early 2017. This Agreement is for the REVEAL Legacy Study. REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid-modification) 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 REVEAL main trial showed for the first time that adding anacetrapib to intensive statin therapy reduces the incidence of cardiovascular events for high-risk patients. The treatment was very well tolerated and there were no major safety concerns. The REVEAL trial was a randomized, double-blind, placebo-controlled trial of the CETP (Cholesterol ester transfer protein) inhibitor anacetrapib (a drug that raises HDL (High-Density Lipoprotein, or, 'good' cholesterol). 30,449 men and women older than 50 years of age were recruited between August 2011 and October 2013 in Europe (UK, Germany, Italy, Denmark, Finland, Norway, Sweden), North America (USA and Canada), and China. Individuals were eligible if they had a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral artery disease, or diabetes mellitus with symptomatic coronary heart disease. Individuals with an acute coronary event or stroke less than 3 months before randomization or with a planned coronary revascularization were excluded. After an 8 to 12-week pre-randomization run-in phase with study atorvastatin alone, eligible patients were randomized to receive the addition of anacetrapib 100 mg once daily or matching placebo. Atorvastatin was given to all study participants to make sure that LDL cholesterol (Low-Density Lipoprotein, or, 'bad' cholesterol) was well controlled. Atorvastatin is a type of statin used for lowering LDL (bad) cholesterol (this was provided free of charge by Merck Sharp & Dohme Corp). This enabled reliable assessment of the efficacy & safety of anacetrapib. The trial was approved by all relevant institutional review boards and regulatory authorities, and participants provided written informed consent. Post-trial follow-up of all eligible randomized participants continued for 2-years (from February 2017 to April 2019) beyond the final main trial visit. During this time, participants did not receive any study medication. This was conducted primarily by telephone with additional information collected via central registry data linkage. Post-trial follow-up results are due for publication in Q4/2021. The main trial (i.e. the period when participants were receiving study treatment and having regular study visits at clinic sites) started in August 2011 ended in January 2017. The results from this showed for the first time that adding anacetrapib to intensive statin therapy reduces the incidence of cardiovascular events for high-risk patients. The treatment was very well tolerated and there were no major safety concerns. Following post-trial follow-up, subsequent extended follow-up of UK participants only is planned for at least a further 15-years in order to provide valuable information on the longer-term effects of anacetrapib. There will be no contact with participants. There will be a particular focus on clinical safety, including cause-specific mortality, cancer, and vascular events. Information on these and other reasons for hospitalization and other serious adverse events will be collected from central registries such as NHS Digital, Public Health Scotland, the NHS Central Register (NHSCR) and NHS Wales Informatics Service (NWIS). Post-trial follow-up of all eligible randomized participants continued for 2-years (from May 2017 to April 2019) beyond the final main trial visit. During this time, participants did not receive any study medication. Post-trial follow-up was conducted primarily by telephone with information sometimes collected from GPs, hospital records and also via central registry data linkage. Post-trial follow-up results were published in December 2021. They showed that the beneficial effects of anacetrapib on major coronary events increased with longer follow-up, with no adverse effects emerging for non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomised trials of lipid-modifying agents to assess their full benefits and harms. The study team have previously received data from NHS Digital, and wish to retain all data previously disseminated. Information about the results, including publications, have been posted on the REVEAL website: https://www.ctsu.ox.ac.uk/research/hps3-timi55-reveal. The research primary objective is to investigate the long-term effects of allocation to anacetrapib versus placebo on vascular events, cancer, deaths, and other serious adverse events during extended follow-up. DATA LINKAGE Following post-trial follow-up, subsequent extended long-term follow-up of UK participants only is planned for at least a further 15-years (from 2019) in order to provide valuable information on the longer-term effects of anacetrapib. There will be no direct contact with participants. There will be a particular focus on clinical safety, including cause-specific mortality, cancers, and vascular events. Information on these and other reasons for hospitalization and other serious adverse events will be collected from central registries such as NHS Digital, Public Health Scotland, the NHS Central Register (NHSCR) and Digital Health & Care Wales (DHCW). The study team have previously received data from NHS Digital. This Agreement will permit the ongoing retention of data previously disseminated. 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, under future proposed amendments to this Agreement. 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. The research objective is to investigate the long-term effects of allocation to anacetrapib versus placebo on vascular events, deaths, and other serious adverse events during extended follow-up. [1 paragraph unchanged] i. Mortality (from all causes combined and, separately, within particular categories of causes, including cardiovascular and non-vascular causes); i. Mortality ii. Cancer at all sites (fatal or non-fatal), and site-specific cancers considered separately (excluding any known to pre-date randomization and non-melanoma skin cancers); ii. Cancer [1 paragraph unchanged] iv. Other serious adverse events (overall and, separately, by type). In addition, exploratory assessments will be made of other possible effects of [6 words unchanged] based on data recorded at the randomization visit (as specified in the main protocol), and on other serious adverse events during the extended follow-up period. For the ongoing extended follow-up to be undertaken in UK participants only, the main outcomes of interest will be as listed above. An updated data analysis plan for this extended follow-up will be published on the trial website in advance of any further analyses being undertaken. Subsequent analyses will be planned when median follow-up is at least 10 years (with further analyses possible at around 20 years of median follow-up). The data subjects are all UK participants of the original randomized controlled trial. Participants have provided informed consent to be followed-up long-term via central registry data linkage. Participants were resident in and recruited from across the UK. The study team plan to link to equivalent datasets received from NHS Wales Informatics Services, 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 outside of the UK. 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 anacetrapib in the UK population and is therefore in the public interest. Linking participants to their data held by NHS Digital is the least intrusive way of achieving the study's purpose. Participants have provided informed consent to be followed-up long-term via central registry data linkage. 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 anacetrapib on important health outcomes. Blood and urine samples were collected from participants during the main trial. Participants gave consent separately to allow samples of plasma, serum & urine to be retained for unspecified analysis in the future. Similarly supplementary consent was sought to permit genetic material in the blood samples to be analysed. Where genomic analyses have been done in specialist laboratories outside of the NDPH, all samples are sent with only the study identifier and no personal data. All data is returned to Oxford for statistical analyses. DNA analysis carried out on blood samples provided by participants previously may be linked with NHS Digital data. All processing of NHS Digital data will take place within the University of Oxford who also determine the purpose and means of processing, therefore Oxford are listed as sole data controller who also processes the data for the purposes described within this Agreement. The study team intend to link data from participant DNA analyses to NHS Digital data under a future Agreement. Linkage to longer-term outcomes (including those identified from NHS Digital data) is of considerable importance in fully understanding response to statins/anacetrapib and cardiovascular risk and its consequences as a whole. Genetic data may be able to add insights into the determinants and mechanisms of risk factors and disease outcomes, that can contribute to the development of better patient treatments and precision medicine approaches. Funding for the extended follow-up study is provided internally from the University of Oxford. Previously, Merck had provided funding for the main trial and the 2-year post-trial follow-up (up to 2019). LEGAL BASIS FOR PROCESSING, COMMON LAW DUTY OF CONFIDENTIALITY, AND ETHICS 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 anacetrapib (and HDL cholesterol raising) 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 anacetrapib (and HDL cholesterol raising) on important health outcomes. The common law duty of confidentiality is addressed by having patient consent. The research team have taken the opinion of the South Central – Oxford B 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 (by requesting only the data fields that are relevant to the research for the REVEAL cohort only), and technical and organisational safeguards. Analysis will occur in a safe, NHS DSP Toolkit compliant environment and identifiers will not be included in the analysis. The study team have asked for the opinion of participants in similar studies, and they have agreed that the use of the data in the way that the study team have proposed is reasonable. CONTROLLERSHIP AND FUNDING The University of Oxford are the sole data controller who also process the data for the purposes described within this Agreement. Funding for the extended follow-up study will be provided internally from the University of Oxford. Previously, Merck (who manufactured anacetrapib) had provided funding for the main trial and the 2-year post-trial follow-up (up to 2019). The grant from Merck ends in December 2022 (Merck are not able to determine how the University of Oxford spend the remainder of this grant, all decisions are made by the REVEAL study team alone). Funding from the remainder of this grant is adequate to cover the NHS Digital DSA costs.

Processing activities

NHS Digital already hold the identifiers for this cohort and as recruitment ended in October 2013, there will be no need to resupply these identifiers. The identifiers that NHS Digital currently hold are: - Study ID - NHS Number - Date of birth - Surname - Forename - Gender [6 paragraphs unchanged] Data received from NHSD is 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. No NHS Digital data will be shared other than with substantive employees of the data controller. The data controller will retain the pseudonymised data for at least 25 years after the end of the trial, as per NDPH guidelines, and will be required to maintain a valid Data Sharing Agreement with NHS Digital. The applicant will hold and analyse data-sets with trial numbers. The identifiers and linkage key will be held separately. The data is stored in the Data Controller’s NDPH NHS DSP Toolkit compliant environment. All data will be handled and processed in agreement with the NHS Digital Data Sharing Framework Contract, and will be subject to Fair Processing requirements. Other than the linkages already described within this Agreement, researchers will not link NHS Digital data to other datasets. There are no subsequent flows of data. NDPH researchers are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. All those with access to the data are substantive employees of the University of Oxford. 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. 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 this study (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 extended follow-up study. All processing of data will be performed within the Nuffield Department of Population Health at the University of Oxford. No pseudonymised NHS Digital or identifiable data will be shared other than with substantive employees of the data controller. 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. Data linkage takes place within the NDPH NHS DSP Toolkit compliant environment. Data are pseudonymised prior to analysis. 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 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 this study (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 extended 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. [1 paragraph unchanged]

Expected output

[1 paragraph unchanged] For the ongoing extended follow-up to be undertaken in UK participants only, an updated data analysis plan will be published on the trial website in advance of any further analyses being undertaken. Subsequent analyses will be planned when median follow-up is at least 10 years (with further analyses possible at around 20 years of median follow-up). [2 paragraphs unchanged] It contributes to debate with academic papers, conference participation, lectures to the [8 words unchanged] Examples of the impact of the work performed by NDPH up to 2014 2021 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 https://results2021.ref.ac.uk/profiles/institutions/10007774 (Unit of assessment 2: Public Health, Health Services and Primary Care). [3 paragraphs unchanged] - Exhibition at public events [2 paragraphs unchanged] The data controller aims to issue the next publication by Q4 2021. 2023. [2 paragraphs unchanged] Main trial publications: Outputs for the REVEAL 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/hps3-timi55-reveal), and the benefits are described in Section 5iii (Yielded Benefits). o HPS3/TIMI55–REVEAL Collaborative Group The REVEAL main trial found the following results: Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. • Adding anacetrapib to statin therapy reduced the blood level of LDL (low-density lipoprotein) cholesterol by around 20% and doubled the level of HDL (high-density lipoprotein) cholesterol. N Engl J Med 2017;377:1217-1227 • Adding anacetrapib to intensive statin treatment produced a 9% proportional reduction in the risk of the composite outcome of heart attack, death from heart disease, or coronary revascularization (i.e. coronary artery stenting or bypass surgery). https://doi.org/10.1056/NEJMoa1706444 • In a subsidiary analysis, anacetrapib significantly reduced the composite outcome of coronary death or myocardial infarction. There was no significant effect on ischaemic stroke. Main Point: the REVEAL main trial found that among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. • Anacetrapib was well tolerated and, as has been found previously, the levels of anacetrapib in body fat continued to increase while treatment continued. o Armitage J., Holmes MV., Preiss D. • Anacetrapib produced a small reduction in the risk of developing diabetes mellitus. Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events: JACC Review Topic of the Week • There were no major safety signals and no increase in death, cancer or other serious medical events, but there was a small increase in blood pressure and a small reduction in kidney function. JACC 2019;73(4):477-487 The post-trial follow-up analysis showed that the beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no safety concerns emerged on non-vascular mortality or morbidity. The absolute reduction in major coronary events at 6 years was nearly double that seen at the end of the 4 year treatment period. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. https://doi.org/10.1016/j.jacc.2018.10.072 Main Point: Evidence from genetic studies and REVEAL - the largest clinical trial of a potent CETP inhibitor, anacetrapib - confirm that inhibition of CETP yields increases in HDL-C and reductions in LDL-C, apolipoprotein B, and non-HDL-C, and that these changes yield modest cardiovascular benefit. o Hopewell JC. et al. Impact of ADCY9 Genotype on Response to Anacetrapib. Circulation 2019;140:891-898 https://doi.org/10.1161/CIRCULATIONAHA.119.041546 Main point: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib.

Benefits reported

The Health practitioners will be better informed as the REVEAL main trial showed for the first time that anacetrapib, an inhibitor of Cholesteryl Ester Transfer Protein (CETP) activity, anacetrapib lowers the risk of heart attack and related cardiovascular complications among patients with atherosclerotic vascular disease who are receiving intensive statin treatment. The treatment was well tolerated and there were no major safety concerns. The REVEAL main trial found the following results: The REVEAL post-trial follow-up results were published in December 2021. They showed that the beneficial effects of anacetrapib on major coronary events increased with longer follow-up, with no adverse effects emerging for non-vascular mortality or morbidity . • Adding anacetrapib to statin therapy reduced the blood level of LDL (low-density lipoprotein) cholesterol by around 20% and doubled the level of HDL (high-density lipoprotein) cholesterol. • Adding anacetrapib to intensive statin treatment produced a 9% proportional reduction in the risk of the composite outcome of heart attack, death from heart disease, or coronary revascularization (i.e. coronary artery stenting or bypass surgery). • In a subsidiary analysis, anacetrapib significantly reduced the composite outcome of coronary death or myocardial infarction. There was no significant effect on ischaemic stroke. • Anacetrapib was well tolerated and, as has been found previously, the levels of anacetrapib in body fat continued to increase while treatment continued. • Anacetrapib produced a small reduction in the risk of developing diabetes mellitus. • There were no major safety signals and no increase in death, cancer or other serious medical events, but there was a small increase in blood pressure and a small reduction in kidney function.

Unchanged: Expected measurable benefits.

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

Objective for processing

The study aims to randomise at least 30,000 (6,500 in the UK) aged 50 years or older with pre-existing vascular disease, to receive either anacetrapib 100mg daily or matching placebo for a median of 4 years' follow up. The primary aim is to assess the effect of lipid-modification with anacetrapib on major coronary events (MCE - defined as coronary death, myocardial infarction or coronary revascularization). The Randomized EValuation of the Effects of Anacetrapib through Lipid-modification (REVEAL) trial was a randomized, double-blind, placebo-controlled trial of the CETP (Cholesterol ester transfer protein) inhibitor anacetrapib (a drug that raises HDL (good) cholesterol). 30 449 men and women older than 50 years of age were recruited between 2011 and 2013 in Europe (UK, Germany, Italy, Denmark, Finland, Norway, Sweden), North America (USA and Canada), and China. Individuals were eligible if they had a history of myocardial infarction, cerebrovascular atherosclerotic disease, peripheral artery disease, or diabetes mellitus with symptomatic coronary heart disease. Individuals with an acute coronary event or stroke less than 3 months before randomization or with a planned coronary revascularization were excluded. After an 8 to 12-week pre-randomization run-in phase with study atorvastatin alone, eligible patients were randomized to receive the addition of anacetrapib 100 mg once daily or matching placebo for a median duration of about 4 years. Atorvastatin is a type of statin used for lowering LDL (bad) cholesterol (this was provided free of charge by Merck Sharp & Dohme Corp). Atorvastatin was given to all study participants to make sure that LDL cholesterol was well controlled. This enabled reliable assessment of the efficacy & safety of anacetrapib. The pre-specified primary outcome of the main trial was first major coronary event (a composite of coronary death, myocardial infarction, or coronary revascularization), with additional secondary outcomes including first major vascular event (a composite of major coronary event and presumed ischemic stroke). The trial was approved by all relevant institutional review boards and regulatory authorities, and participants provided written informed consent. The main trial (i.e. the period when participants were receiving study treatment and having regular study visits at clinic sites) ended in early 2017. The REVEAL main trial showed for the first time that adding anacetrapib to intensive statin therapy reduces the incidence of cardiovascular events for high-risk patients. The treatment was very well tolerated and there were no major safety concerns. Post-trial follow-up of all eligible randomized participants continued for 2-years (from February 2017 to April 2019) beyond the final main trial visit. During this time, participants did not receive any study medication. This was conducted primarily by telephone with additional information collected via central registry data linkage. Post-trial follow-up results are due for publication in Q4/2021. Following post-trial follow-up, subsequent extended follow-up of UK participants only is planned for at least a further 15-years in order to provide valuable information on the longer-term effects of anacetrapib. There will be no contact with participants. There will be a particular focus on clinical safety, including cause-specific mortality, cancer, and vascular events. Information on these and other reasons for hospitalization and other serious adverse events will be collected from central registries such as NHS Digital, Public Health Scotland, the NHS Central Register (NHSCR) and NHS Wales Informatics Service (NWIS). The study team have previously received data from NHS Digital, and wish to retain all data previously disseminated. The research primary objective is to investigate the long-term effects of allocation to anacetrapib versus placebo on vascular events, cancer, deaths, and other serious adverse events during extended follow-up. The main outcomes of interest are: i. Mortality (from all causes combined and, separately, within particular categories of causes, including cardiovascular and non-vascular causes); ii. Cancer at all sites (fatal or non-fatal), and site-specific cancers considered separately (excluding any known to pre-date randomization and non-melanoma skin cancers); iii. Cardiovascular events; and iv. Other serious adverse events (overall and, separately, by type). In addition, exploratory assessments will be made of other possible effects of anacetrapib among particular subgroups of participants based on data recorded at the randomization visit (as specified in the main protocol), and on other serious adverse events during the extended follow-up period. For the ongoing extended follow-up to be undertaken in UK participants only, the main outcomes of interest will be as listed above. An updated data analysis plan for this extended follow-up will be published on the trial website in advance of any further analyses being undertaken. Subsequent analyses will be planned when median follow-up is at least 10 years (with further analyses possible at around 20 years of median follow-up). Participants have provided informed consent to be followed-up long-term via central registry data linkage. The study team plan to link to equivalent datasets received from NHS Wales Informatics Services, the Scottish NHS Central Register (NHSCR) and Public Health Scotland. 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 anacetrapib 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 anacetrapib on important health outcomes. All processing of NHS Digital data will take place within the University of Oxford who also determine the purpose and means of processing, therefore Oxford are listed as sole data controller who also processes the data for the purposes described within this Agreement. Funding for the extended follow-up study is provided internally from the University of Oxford. Previously, Merck had provided funding for the main trial and the 2-year post-trial follow-up (up to 2019).

Processing activities

Not stated in the previous version; added here.

NHS Digital already hold the identifiers for this cohort and as recruitment ended in October 2013, there will be no need to resupply these identifiers. The identifiers that NHS Digital currently hold are:

- Study ID

- NHS Number

- Date of birth

- Surname

- Forename

- Gender

Identifiable NHS Digital datasets currently held by the REVEAL trial:

- MRIS - Members and Postings Report

- MRIS - Flagging Current Status Report

- MRIS - Cohort Event Notification Report

- MRIS - Cause of Death Report

- MRIS – Scottish NHS / Registration

Data received from NHSD is 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. No NHS Digital data will be shared other than with substantive employees of the data controller.

Other than the linkages already described within this Agreement, researchers will not link NHS Digital data to other datasets.

NDPH researchers are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. All those with access to the data are substantive employees of the University of Oxford.

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 this study (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 extended 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.

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

Not stated in the previous version; added here.

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. 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 Q4 2021.

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.

Main trial publications:

o HPS3/TIMI55–REVEAL Collaborative Group

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease.

N Engl J Med 2017;377:1217-1227

https://doi.org/10.1056/NEJMoa1706444

Main Point: the REVEAL main trial found that among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo.

o Armitage J., Holmes MV., Preiss D.

Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events: JACC Review Topic of the Week

JACC 2019;73(4):477-487

https://doi.org/10.1016/j.jacc.2018.10.072

Main Point: Evidence from genetic studies and REVEAL - the largest clinical trial of a potent CETP inhibitor, anacetrapib - confirm that inhibition of CETP yields increases in HDL-C and reductions in LDL-C, apolipoprotein B, and non-HDL-C, and that these changes yield modest cardiovascular benefit.

o Hopewell JC. et al.

Impact of ADCY9 Genotype on Response to Anacetrapib.

Circulation 2019;140:891-898

https://doi.org/10.1161/CIRCULATIONAHA.119.041546

Main point: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib.

Expected measurable benefits

Not stated in the previous version; added here.

In carrying out this long-term extended follow up researchers may be able to gain a better understanding of the long-term consequences of prescribing anacetrapib, including its effect on Major Coronary Events (MCEs), such as coronary death, myocardial infarction or coronary revascularization, and other health outcomes.

Benefits reported

Not stated in the previous version; added here.

The REVEAL main trial showed that anacetrapib, an inhibitor of Cholesteryl Ester Transfer Protein (CETP) activity, lowers the risk of heart attack and related cardiovascular complications among patients who are receiving intensive statin treatment.

The REVEAL main trial found the following results:

• Adding anacetrapib to statin therapy reduced the blood level of LDL (low-density lipoprotein) cholesterol by around 20% and doubled the level of HDL (high-density lipoprotein) cholesterol.

• Adding anacetrapib to intensive statin treatment produced a 9% proportional reduction in the risk of the composite outcome of heart attack, death from heart disease, or coronary revascularization (i.e. coronary artery stenting or bypass surgery).

• In a subsidiary analysis, anacetrapib significantly reduced the composite outcome of coronary death or myocardial infarction. There was no significant effect on ischaemic stroke.

• Anacetrapib was well tolerated and, as has been found previously, the levels of anacetrapib in body fat continued to increase while treatment continued.

• Anacetrapib produced a small reduction in the risk of developing diabetes mellitus.

• There were no major safety signals and no increase in death, cancer or other serious medical events, but there was a small increase in blood pressure and a small reduction in kidney function.