Data linkage request for (TIME) Treatment in Morning versus Evening Study

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

Objective for processing

[7 paragraphs unchanged] Under GDPR, the lawful basis on which processing of data from NHS Digital England concerning participants in the TIME study is laid out by Articles 6(1)(e) [76 words unchanged] the outcomes of this research are for the benefit of public interest. [1 paragraph unchanged]

Processing activities

[3 paragraphs unchanged] Data processing of the data from NHS Digital England is only carried out by substantive employees of the University of Dundee [33 words unchanged] governance and data management controls (as per Data Security and Protection Toolkit). The TIME study will supply participant identifiers (e.g. NHS number name, date of birth, address, TIME Study ID number) to NHS Digital England to allow the identification of TIME participants in their datasets of hospitalisation and mortality. NHS Digital England will return any such records to the TIME study identified only by TIME study ID. These NHS Digital England data, including health data, will be used within the TIME study to [47 words unchanged] already been reported to the study team by a participant directly, NHS Digital England data will be used to confirm dates and places of admission. Once [73 words unchanged] status of the participant and gather information required for study endpoint verification. This additional clinical information will be used to create de-identified packages for [15 words unchanged] clinicians via a secure web portal. These packages will not contain NHS Digital England data. For information, a statistician based at the University of Glasgow will [14 words unchanged] data (final report, Independent Data Monitoring Committee reports). To confirm, no NHS Digital England data is shared with this individual or others at the University of Glasgow, or any other organisation. As this work is drawing to a close, the University of Dundee requires one final provision of the data from NHS Digital, England, including the additional fields 'location of hospitalisation' and 'GP Practice Code', to [11 words unchanged] would be from the most relevant source before the study is closed. [1 paragraph unchanged] There will be no data linkage undertaken with NHS Digital England data provided under this agreement that is not already noted in the agreement.

Expected output

The study results will be reported in peer-reviewed journals (e.g BMJ) and at major scientific meetings/conferences (e.g. European Society of Cardiologists). All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. No individual level or identifiable data will be disclosed. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. Participant involvement concluded on 31st March 2021. The main TIME study results were reported in a peer-reviewed journal (Mackenzie IS, Rogers A, Poulter NR, et al. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. Published online October 11, 2022. doi:10.1016/S0140-6736(22)01786-X) and at a major scientific conference (53rd Annual European Society of Cardiology Congress, Barcelona, Spain). These results, including a non-technical summary written with patient involvement, were also disseminated to participants, recruiting centres, and other stakeholders, alongside a press release. Results will also be disseminated to participants, recruiting centres, health media outlets (e.g. BBC), guidelines groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network), and other stakeholders. The results of prespecified sub-studies included in the trial protocol will be reported in peer-reviewed journals and presented at scientific conferences within the next two years. Non-technical summaries will be produced and posted on the study website. The research team will produce a non-technical summary of the results which the research team will send to patients who participated in the trial and cardiovascular charities. The research team and funder will work to generate media coverage of the study results and communicate these to the wider public. NB outputs may be shared with funders, but ownership and control of the outputs rests with the University of Dundee. All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. No individual level or identifiable data will be disclosed. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. Ownership and control of all outputs rests with the University of Dundee. Participant involvement concluded on 31st March 2021. Final record linkage is expected by Summer 2021. Data analysis will take place after database lock (the point in time at which data collection halts and no more data will be added to the database) with publication of results expected in 2022. NHS Digital data will be essential to determine the date of database lock.

Expected measurable benefits

Ischaemic heart disease (including heart attacks and strokes) is the commonest cause [43 words unchanged] around 30% of adults. Although effective treatments are available for hypertension, it is was not known when the best time of day that these should be taken for greatest effect on heart attack and stroke prevention. If the TIME study demonstrates demonstrated a clinically significant difference between evening dosing and morning dosing in terms of heart attacks and strokes, this would offer have offered a simple way to achieve even better health outcomes for people with [11 words unchanged] have a huge impact on reducing NHS costs if changing dosing times is was shown to reduce major cardiovascular events. It could lead have led to a reduction in morbidity and mortality and huge cost savings for the NHS in terms of admissions with major cardiovascular events. The magnitude of such potential benefits will be was unclear until study completion, however, if a significant difference between doing time groups is had been found, the study intervention type is such that similar benefits could be seen in the general hypertensive population within a few years. After the publication of study results (in 2022), any recommendation by guidelines to change usual hypertension medication dosing time advice could be implemented quickly and at minimal expense. This would allow patients taking antihypertensive medications to benefit quickly from this research. Equally, should no difference be found between doing times, this would allow reassurance for patients and doctors who may be concerned as to the ideal dosing time. The prespecified sub-studies of TIME are designed to explore potential relationships between dosing time, cardiovascular events, blood pressure control, and sleep quality, mood, chronotype, and cognitive function. The results of these studies will advance scientific understanding of the interplay between cardiovascular health, brain health, and circadian rhythm. They may also suggest opportunities for future research and potential precision medicine dosing time interventions to improve cardiovascular outcomes in specific patient groups. Dissemination of study findings is in the public interest as it will help give clarity to clinicians and patients with regard to whether there is a benefit (reduction in the number of cardiovascular events) in patients taking their antihypertensive medication in the evening rather than the morning.

Benefits reported

As the study is ongoing, there have not yet been any study outputs using NHS Digital data and it has not yet been possible to demonstrate benefits. However, data accrued in the previous linkages has allowed the identification of 2,085 potential endpoint events. The main TIME study did not demonstrate a clinically significant difference between evening dosing and morning dosing in terms of heart attacks and strokes. This finding was of great importance as it provided clarity to clinicians and patients over whether a particular time of day was preferable for antihypertensive administration. The findings of the main TIME study have already been incorporated into international guidelines on the management of hypertension (Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41(12):1874-2071.) which now advise “In the general hypertensive population morning dosing or bedtime dosing results in similar outcome (CoR I, LoE B)”. Additionally, the results of the trial were widely reported in the clinical literature with consensus statements, clinical reviews, and decision support citing the study results internationally. For example: - Park S, Ihm SH, Cho IJ, et al. Statement on chronotherapy for the treatment of hypertension: consensus document from the Korean society of hypertension. Clin Hypertens. 2023;29(1):25. - Liu J, Li Y, Zhang X, et al. Management of nocturnal hypertension: An expert consensus document from Chinese Hypertension League. J Clin Hypertens . Published online December 21, 2023. doi:10.1111/jch.14757 - Bassil E, Thomas G, Dhingra J, Mehdi A. Should my patients take their blood pressure medications in the evening to enhance cardiovascular benefit? Cleve Clin J Med. 2023;90(12):725-727. - Choice of drug therapy in primary (essential) hypertension. UpToDate. Published June 22, 2023. https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension - Patel H, Berglund F, Laffin L, Ruthmann N. Should Antihypertensive Medications Be Routinely Administered in the Nighttime Instead of Daytime? Am J Med. 2023;136(10):975-978. - Perry D, Moe SS, Thomas B, et al. Top studies of 2022 relevant to primary care: From the PEER team. Can Fam Physician. 2023;69(5):325-329.

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

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Datasets: + Demographics

Objective for processing

The University of Dundee (the "University") aims to determine if morning or evening administration of blood pressure-lowering pressure lowering (antihypertensive) medications is more effective in the prevention of heart attacks and [18 words unchanged] medications reduces the risk of cardiovascular events compared with conventional morning dosing. Note: the study is called the TIME study, but originally was named as the DIVINE or DIVINE-MOVE study. [3 paragraphs unchanged] The University of Dundee is the sole data controller and data processor [10 words unchanged] of Dundee and funded by an academic grant from the British Heart Foundation. Foundation (the BHF have no control over how the data are used). The study has been adopted by the British and Irish Hypertension Society (BIHS) Collaborative Research Working Party (see https://bihsoc.org/about-us/working-parties-network-groups/collaborative-research-working-party/). https://bihsoc.org/aboutus/working-parties-network-groups/collaborative-research-working-party/). This means that they have endorsed the study and assisted with recruitment [18 words unchanged] been approved by Research Ethics Committee and the relevant local NHS R+D (Research and Development) Offices. [2 paragraphs unchanged] (A note for historical clarity: the study is called the TIME study, but originally was named as the DIVINE or DIVINE-MOVE study.) GP Practice Code has been requested by the data controller in order to help trace patients that have been lost to follow-up. Any event reported in the record linkage that represents a potential study endpoint requires validation from primary source documents (such as discharge letters and investigation results). These are obtained by contacting the patient’s General Practitioner. The addition of the General Practitioner data allows the study team to follow these events up when the participant has not updated their GP practice details on the TIME study portal. Participants have explicitly consented to the study team contacting their GP; the consent and patient information materials state that the study will contact the GP to “inform them of the patient's participation in the study and capture consent to use information held by the NHS... to contact [participants] and follow up [their] health status where relevant to this study", It further states that “we will need your agreement to be able to contact your family doctor to find out about your health if required” . Researchers will contact the GP of participant's who have not replied to recent correspondence from the research team to check on the health status of the participant – specifically, the patient’s mortality status, whether they have suffered a heart attack, stroke, Transient Ischaemic Attack (TIA), or been admitted to a hospital due to a heart failure. As in the case of an admissions record of a cardiac event that the patient has not reported, there is the possibility of a mortality event and additional care must be taken to not cause further trauma to the patient/those close to the patient by attempting to contact them when the information is available from another source that the patient has consented to being contacted on the matter. The addition of this field is compatible with the consent. Based on the information provided to participants, the request for GP Practice code in order to contact participants is deemed compatible with the consent.

Processing activities

[1 paragraph unchanged] - Data management (including e-CRF electronic Case Report Form design, database setup and management, data validation, record-linkage) - clinical endpoint adjudication - clinical endpoint adjudication [1 paragraph unchanged] Data processing of the data from NHS Digital is only carried out [36 words unchanged] access subject to departmental information governance and data management controls (as per NHS Digital Data Security and Protection Toolkit). [1 paragraph unchanged] These individual level NHS Digital data, including health data, will be used within the TIME [7 words unchanged] or deaths occurring in individuals who are taking part in the TIME study. study (by matching with TIME study ID). This information will be used by study personnel to identify potential study [66 words unchanged] Coroner (for deaths). Study participants have given written consent for this processing. This additional clinical information The GP practice data will be used by researchers to create de-identified packages for independent clinical adjudication contact the GP of potential study endpoints. These packages will participants who have not contain NHS digital data and will be identified only by a unique study ID and package number and contain only replied to recent correspondence from the necessary details research team to check on the health status of the event to allow a clinical assessment of whether a participant and gather information required for study endpoint has occurred. All potentially identifiable information will be redacted by study personnel. Packages are shared with the independent adjudicating NHS clinicians via a secure web portal. verification. This additional clinical information will be used to create de-identified packages for independent clinical adjudication of potential study endpoints. Packages are shared with the independent adjudicating NHS clinicians via a secure web portal. These packages will not contain NHS Digital data. For information, a statistician based at the University of Glasgow will also receive such a package and will perform analysis and reporting on pseudonymised study data (final report, Independent Data Monitoring Committee reports). To confirm, no NHS Digital data is shared with this individual or others at the University of Glasgow, or any other organisation. As this work is drawing to a close, the University of Dundee requires one final provision of the data from NHS Digital, including the additional fields 'location of hospitalisation' and 'GP Practice Code', to ensure that the information regarding the currently unresolved Cohort Endpoint events would be from the most relevant source before the study is closed. [2 paragraphs unchanged]

Expected output

[3 paragraphs unchanged] The timescale for outputs is expected to be between 2020 and 2021 dependent on events accrued within the study. NHS Digital data will be essential to determine the study end date. Participant involvement concluded on 31st March 2021. Final record linkage is expected by Summer 2021. Data analysis will take place after database lock (the point in time at which data collection halts and no more data will be added to the database) with publication of results expected in 2022. NHS Digital data will be essential to determine the date of database lock.

Expected measurable benefits

[2 paragraphs unchanged] After the publication of study results (in late 2020/ 2021), 2022), any recommendation by guidelines to change usual hypertension medication dosing time advice [36 words unchanged] and doctors who may be concerned as to the ideal dosing time. Dissemination of study findings is in the public interest as it will help give clarity to clinicians and patients with regard to whether there is a benefit (reduction in the number of cardiovascular events) in patients taking their antihypertensive medication in the evening rather than the morning.

Benefits reported

As the study is ongoing, there have not yet been any study outputs using NHS Digital data. data and it has not yet been possible to demonstrate benefits. However, data accrued in the previous linkage linkages has allowed the identification of 1,286 2,085 potential endpoint events.

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

Objective for processing

The University of Dundee (the "University") aims to determine if morning or evening administration of blood pressure lowering pressure-lowering (antihypertensive) medications is more effective in the prevention of heart attacks and [18 words unchanged] medications reduces the risk of cardiovascular events compared with conventional morning dosing. The reason that such a study is required is that recent research [61 words unchanged] medication at a single morning dosing time. Since the publication of the study study, there have been several calls for a large scale randomised trial to determine if evening dosing is better at preventing heart attacks and strokes. If there is a significant difference in effectiveness between dosing times for these medications, this will represent an opportunity to reduce the risk of major cardiovascular events in people with high blood pressure without increased cost or exposure to additional medications. The study is sponsored by the University of Dundee, funded by an academic grant from the British Heart Foundation. The study has been adopted by the British and Irish Hypertension Society (BIHS) Collaborative Research Working Party (see https://bihsoc.org/about-us/working-parties-network-groups/collaborative-research-working-party/). This means that they have endorsed the study and assisted with recruitment via their network of clinicians. They will also assist with dissemination of study results. The study has been approved by Research Ethics Committee and the relevant local NHS R+D Offices. The TIME study is a prospective randomised open-label blinded endpoint (PROBE) trial. Study participants are adults (aged 18+) with diagnosed high blood pressure who have voluntarily consented to take their usual anti-hypertensive medications in the morning or evening, according to their randomised dosing time assignment. The primary method of identifying study endpoints (hospitalisations for heart attack, stroke and deaths) that have occurred in these randomised study participants is record linkage of the study cohort with nationally held datasets of hospital admissions and mortality. This data will be used to compare rates of cardiovascular events between the two randomised dosing time groups, morning and evening. The primary method of identifying study endpoints (hospitalisations for heart attack, stroke and deaths) is record linkage of the study cohort with nationally held datasets of hospital admissions and mortality. Approximately bi-annual drops of study cohort-linked pseudonymised data from HES products (hospitalisations and linked mortality data) are required to identify potential study endpoint events. It is important that this data is available throughout the study to allow the study independent data monitoring committee to assess study safety and to enable the study team to plan for the end of this event-driven study. Although the study does collect participant reports of cardiovascular events, we recognise that participants who are unwell or have died cannot inform us of these important study events. For this reason, linked data will be essential to ensure that all potential study endpoint events are identified. The data requested are the minimum necessary to allow the identification of potential study endpoint events (by trained clinicians) and subsequent retrieval of supporting information from treating GPs and hospitals. The University of Dundee is the sole data controller and data processor for this application. The study is sponsored by the University of Dundee and funded by an academic grant from the British Heart Foundation. The study has been adopted by the British and Irish Hypertension Society (BIHS) Collaborative Research Working Party (see https://bihsoc.org/about-us/working-parties-network-groups/collaborative-research-working-party/). This means that they have endorsed the study and assisted with recruitment via their network of clinicians. They will also assist with the dissemination of study results. The study has been approved by Research Ethics Committee and the relevant local NHS R+D Offices. [1 paragraph unchanged] A note for historical clarity: the study is called the TIME study, but originally was named as the DIVINE or DIVINE-MOVE study. Under GDPR, the lawful basis on which processing of data from NHS Digital concerning participants in the TIME study is laid out by Articles 6(1)(e) and 9(2)(j) namely that processing is necessary for the performance of a task carried out in the exercise of official authority, such authority to make provision for research being vested in the University by virtue of the Royal Charter establishing the University dated 20 July 1967, and, that in respect of special category personal data, processing is necessary for research purposes carried out in accordance with Article 89(1). University of Dundee are a public authority and the outcomes of this research are for the benefit of public interest. (A note for historical clarity: the study is called the TIME study, but originally was named as the DIVINE or DIVINE-MOVE study.)

Processing activities

The TIME study will supply participant identifiers (e.g. NHS number name, date of birth, address, TIME Study ID number) to NHS Digital to allow the identification of TIME participants in their datasets of hospitalisation and mortality. NHS Digital will return any such records to the TIME study identified only by a unique TIME study ID. The University of Dundee is the Data Controller. The TIME Study Data will only be held and processed in in the Medicines Monitoring Unit (MEMO) at the University of Dundee. MEMO is solely responsible for the following: These individual level NHS Digital Data will be used within the TIME study to identify and confirm any hospitalisations or deaths occurring in individuals who are taking part in the TIME study and have consented to this data linkage. This information will be used by study personnel to identify potential study endpoint. In instances where a potential study endpoint hospitalisation event has already been reported to the study team by a participant directly, NHS Digital data will be used to confirm dates and places of admission. Once potential endpoint events have been identified, study personnel will obtain further information on these events directly from the treating GPs and/or hospitals (for hospitalisations) and from the local registrar and/or Coroner (for deaths). Study participants have given written consent for this processing. This additional clinical information will be used to create de-identified packages for independent clinical adjudication of potential study endpoints. These packages will not contain NHS digital data and will be identified only by a unique study ID and package number and contain only the necessary details of the event to allow a clinical assessment of whether a study endpoint has occurred. All potentially identifiable information will be redacted by study personnel. Packages are shared with the independent adjudicating NHS clinicians via a secure web portal. - Data management (including e-CRF design, database setup and management, data validation, record-linkage) - clinical endpoint adjudication - project management and quality assurance Data processing of the data from NHS Digital is only carried out by substantive employees of the University of Dundee who have been appropriately trained in data protection and confidentiality. Data will be stored in a secure environment and accessed by appropriately trained staff only through direct system access subject to departmental information governance and data management controls (as per NHS Digital Toolkit). The TIME study will supply participant identifiers (e.g. NHS number name, date of birth, address, TIME Study ID number) to NHS Digital to allow the identification of TIME participants in their datasets of hospitalisation and mortality. NHS Digital will return any such records to the TIME study identified only by TIME study ID. These individual level NHS Digital data, including health data, will be used within the TIME study to identify and confirm any hospitalisations or deaths occurring in individuals who are taking part in the TIME study. This information will be used by study personnel to identify potential study endpoints. In instances where a potential study endpoint hospitalisation event has already been reported to the study team by a participant directly, NHS Digital data will be used to confirm dates and places of admission. Once potential endpoint events have been identified, study personnel will obtain further information on these events directly from the treating GPs and/or hospitals (for hospitalisations) and from the local registrar and/or Coroner (for deaths). Study participants have given written consent for this processing. This additional clinical information will be used to create de-identified packages for independent clinical adjudication of potential study endpoints. These packages will not contain NHS digital data and will be identified only by a unique study ID and package number and contain only the necessary details of the event to allow a clinical assessment of whether a study endpoint has occurred. All potentially identifiable information will be redacted by study personnel. Packages are shared with the independent adjudicating NHS clinicians via a secure web portal. For information, a statistician based at the University of Glasgow will also receive such a package and will perform analysis and reporting on pseudonymised data (final report, Independent Data Monitoring Committee reports). To confirm, no NHS Digital data is shared with the University of Glasgow, or any other organisation. [2 paragraphs unchanged]

Expected output

The study results will be reported in peer reviewed journals and at major scientific meetings. Results will also be disseminated to participants, recruiting centres, guidelines committees and other stakeholders. The study results will be reported in peer-reviewed journals (e.g BMJ) and at major scientific meetings/conferences (e.g. European Society of Cardiologists). All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. No individual level or identifiable data will be disclosed. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. No individual level or identifiable data will be disclosed and small numbers will be suppressed, where necessary, in line with HES guidance. Results will also be disseminated to participants, recruiting centres, health media outlets (e.g. BBC), guidelines groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network), and other stakeholders. It is expected that the study will complete at the end of 2019. The exact date will be determined by the observed endpoint event rate. The study results will be reported in peer reviewed journals (e.g. BMJ) and at major scientific meetings (e.g. European Society of Cardiologists). Results will also be disseminated to participants, recruiting centres, guidelines committees and other stakeholders. The research team will produce a non-technical summary of the results which the research team will send to patients who participated in the trial and cardiovascular charities. The research team and funder will work to generate media coverage of the study results and communicate these to the wider public. NB outputs may be shared with funders, but ownership and control of the outputs rests with the University of Dundee. The output of the first NHS Digital linkage will allow researchers to more accurately predict the likely end date of the study. The target is to reach 631 participants having had an adjudicated first primary endpoint event. The timescale for outputs is expected to be between 2020 and 2021 dependent on events accrued within the study. NHS Digital data will be essential to determine the study end date. All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. Record level information will not be released to any third party.

Expected measurable benefits

[1 paragraph unchanged] If the TIME study demonstrates a clinically significant difference between evening dosing [22 words unchanged] for people with high blood pressure without exposing them to additional medications. The resulting reductions This could have a huge impact on reducing NHS costs if changing dosing times is shown to reduce major cardiovascular events. It could lead to a reduction in heart attacks, strokes morbidity and additional drug prescribing would also translate into significant mortality and huge cost savings for the NHS. NHS in terms of admissions with major cardiovascular events. The magnitude of such potential benefits will be unclear until study completion, however, if a significant difference between doing time groups is found, the study intervention type is such that similar benefits could be seen in the general hypertensive population within a few years. After the publication of study results (in late 2019/early 2020), 2020/ 2021), any recommended changes recommendation by guidelines to change usual hypertension medication dosing time advice could be implemented quickly and at minimal expense. This would allow patients taking antihypertensive medications to benefit quickly from this research. Equally, should no difference be found between doing times, this would allow reassurance for patients and doctors who may be concerned as to the ideal dosing time.

Benefits reported

Not stated in the previous version; added here.

As the study is ongoing, there have not yet been any study outputs using NHS Digital data. However, data accrued in the previous linkage has allowed the identification of 1,286 potential endpoint events.

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

Benefits reported

Stated in the previous version and removed here.

Yielded Benefits is not a requirement for new applications.

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