ATEMPT: Antihypertensive Treatment in Elderly Multimorbid Patients (Pilot Study)

GLOSSARY

> Multimorbidity - means more than two illnesses or diseases occurring in the same person at the same time.

> Antihypertensive drugs - A type of drug used to treat high blood pressure. There are many different types of antihypertensive agents, and they work in different ways to lower blood pressure. Some remove extra fluid and salt from the body. Others relax and widen the blood vessels or slow the heartbeat.

> Polypharmacy - refers to the use of multiple medications in a patient, commonly an older adult. While the most commonly used definition of polypharmacy is being on five or more medicines, definitions are variable.

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It is currently unclear how to best manage blood pressure (BP) in older patients or in the presence of many underlying health problems, in particular when BP is not very high. The Antihypertensive Treatment in Elderly Multimorbid Patients (ATEMPT) Clinical Trial (Pilot), run by the University of Oxford, aims to improve the understanding of BP management in older, multimorbid people by comparing the effectiveness and safety of changing the number of prescribed antihypertensive drugs in two similar groups of such individuals. The study additionally aims to assess the acceptability and tolerability of the intervention (using patient-reported outcomes) and to rule out any major excess harms (risk of serious adverse events).

It is hoped that the results from the ATEMPT trial will be relevant for the management of hypertension in older people with multimorbidity or polypharmacy, a patient group for whom currently the treatment effects of pharmacological blood pressure (BP) reduction remains uncertain. These patients have been underrepresented or excluded in previous research, thus, leaving an important gap in our understanding of treatment effects. One key reason for the existing gap in evidence is the challenge of recruiting sufficiently large numbers of older and multimorbid patients into clinical trials. This pilot study aims to address this challenge by recruiting approximately 200 participants aged 65 or over who have at least three long-term health conditions or are taking at least five medications in addition to any being taken to manage blood pressure.

The study also aims to test the feasibility and reliability of the remote recruitment, monitoring and follow up procedures without any scheduled clinic visits, and to obtain information about resource requirements for the larger trial. The experience gained from utilising IT-enabled systems to remotely recruit and monitor participants will be evaluated with a view to expanding the use of the software to manage other research trials within the department and wider University.

The intervention for this study refers to the participants being randomised (1:1 ratio) to up to 2 more or 2 fewer blood pressure-lowering medications, taking account of any pre-existing treatment and other indications or contra-indications for blood pressure-lowering treatment.

If the Pilot shows that an intervention can lead to important changes in BP, this information will help to assess whether a larger trial is feasible and beneficial to investigate the effect of the intervention on clinical outcomes. An additional aim is to test the feasibility of the main components of the trial, namely participant recruitment, randomisation, delivery of treatment, and remote assessment of trial outcomes and to obtain information about resource requirements for the main trial.

ATEMPT is a two-armed, parallel-group, partially blinded randomised controlled trial, comparing more versus fewer antihypertensive medications in older patients; ≥65 years) with multi-morbidity (or polypharmacy) who are willing to have their BP-lowering treatment changed. Participants eligible for the trial will be randomised to one of the two treatment arms A or B:

Arm A (more antihypertensive drugs): up to two more classes of antihypertensive drugs, vs

Arm B (fewer antihypertensive drugs): up to two fewer classes of antihypertensive drugs.

As a pragmatic trial, ATEMPT will include participants with different background antihypertensive treatments and a wide range of baseline BP. ATEMPT is not a trial of specific types of medications or a particular BP target, but rather a trial of more versus fewer antihypertensive treatments.

For the ATEMPT Clinical Trial (Pilot), the University of Oxford has previously submitted a separate data application for Demographic data (restricted to the Thames Valley Region) to facilitate recruitment which was approved by NHS Digital (DARS-NIC-311182-F5W4X-v0.5). As enrolment is complete the demographic data under this application has been destroyed.

This agreement forms the second phase of the study request, with participant consent, and is for the hospital health outcomes data and Mortality data of participants enrolled on the ATEMPT study to provide safety data for the trial. The majority of the participants are from the Thames Valley region but some are just outside on the fringes of the Thames Valley region as they were recruited from another source.

Now that enrolment to the study is complete (December 2021) the last five years and 3 months (2017 up to end June 2022) of Hospital Episode Statistics (HES) Admitted Patient Care (APC) data along with the latest Civil Registrations (Deaths) Summary Care Cut is now requested from NHS Digital linked to a cohort of approximately 200 study participants. This amount of data is requested to make a thorough evaluation of multi-morbidity in this cohort.

The study team will provide NHS Digital with the cohort participant unique Study ID and identifiers according to when the participant was consented. Cohort participant consented between 19 December 2020 to 24 May 2021 will provide the NHS Number only (approx 67 records), along with Study ID, date of consent and withdrawal date (if applicable). Cohort participant consented between 02 July 2021 to present will provide name, address, postcode, and date of birth (approx 154 records), along with Study ID, date of consent and withdrawal date (if applicable).

The data requested in this agreement have been minimised to only that which the study requires. NHS Digital will provide the University of Oxford with record-level pseudonymised data extracts.

HES APC will detail the date of admission, all relevant diagnostic and operative codes, episode start and end dates, date of discharge and ethnic category. Civil Registrations (Deaths) Secondary Care Cut will detail the Date of Death (if applicable), plus Date of Registration, the Original underlying cause of death and any Subsequent activity.

HES data (all diagnostic and operative codes) and the Civil Registrations (deaths) data are required so the analysis can include all outcomes. Ethnicity is requested to allow stratification for ethnicity during analysis.

The University of Oxford is the sole data controller who also processes the data for this study.

There are other organisations involved in the study which are not processing the NHS Digital data requested in this application and will have no access to the NHS Digital data. They are therefore not listed as data processors in this agreement, but for transparency are listed below for information.

>CFH Docmail will facilitate sending letters to inform the relevant GP that their patient has joined the trial.

>Midland Pathology will be analysing participant blood samples.

>Esendex Ltd will be facilitating SMS notifications (no personal data in the messages) and

>Pharmacy 2U will be providing contact details of potential participants from their customer base to aid recruitment, dispensing and delivering prescriptions and providing repeat prescription information as safety data. Pharmacy 2U’s customer base have consented to the sharing of their contact details to the trial for recruitment purposes.

The trial is funded by research grants from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and the Oxford Martin School (Social Sciences Division of the University of Oxford). The NIHR does not make any decisions determining the purposes and means of the processing, nor the way the Study is conducted and is therefore not considered a Data Controller.

COMMERCIAL PURPOSES

NHS Digital is content that the purpose of this study is to improve the understanding of Blood Pressure management in older people with multimorbidity or polypharmacy, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in England.

In the interests of full transparency, it is noted here that study participants are required to create an account with Pharmacy2U in order to obtain the dispensed prescriptions for the study, and any repeat prescription information as safety data. Thus, the recruitment methodology of this study may contribute towards an intangible benefit for Pharmacy2U (and her sister company Chemist Direct) in being perceived as a trusted pharmacy for a prestigious University study, and the tangible benefit of obtaining new customers who might transfer their other regular prescriptions to Pharmacy2U as offered in the initial account set-up stage. However, NHS Digital is content that the purpose of this study is to improve the understanding of Blood Pressure management in older people with multimorbidity or polypharmacy, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in England.

Pharmacy2U (and her sister company Chemist Direct) will have no access to record-level NHS Digital data, nor any involvement in the processing of NHS Digital record-level data, and are therefore not considered a Data Processor for NHS Digital data in this study.

PATIENT AND PUBLIC ENGAGEMENT (PPI)

As part of PPI, Patient Research Ambassadors were consulted on the study design and proposed trial processes including the participant portal of the bespoke clinical trial management system. Five patient ambassadors attended a meeting held at the University of Oxford. Useful feedback was received on all elements of the study. The ambassadors were able to use the online participant portal, view the videos about the study, enter information, use blood pressure cuffs and practice entering the data. Feedback on the participant portal was positive with useful suggestions for improvements for both the videos and registration process, which were adopted.

GDPR Legal Basis for Processing of data

The University of Oxford rely on Article 6(1)(e) of the General Data Protection Regulation (GDPR) to provide the legal basis for public authorities (e.g. universities and NHS organisations) to process personal data for research purposes: "processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller". The Data Protection Act 2018 s7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”. The FOI Act 2000 Part 1, section 3 (1)(a)(i) specifies that a public authority means any body which is listed in Schedule 1. Schedule 1 of the FOI Act 2000 lists “Maintained schools and further and higher education institutions” as public authorities.

Additionally, article 9(2)(j) of the GDPR provides the legal basis for processing special categories of (sensitive) personal data which includes data concerning health and ethnicity for scientific research purposes: "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 data requested are required for research purposes in the public interest - meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) - which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data.

NHS Digital data is intend to be used for scientific research purposes in the public interest. This trial could impact the treatment regime of millions of patients in the UK, by facilitate in providing evidence for a more dynamic assessment of BP and patient well-being for more tailored treatment recommendations in the future.

The processing of personal data outlined in this application occurs with the consent of the data subjects.

METHODOLOGY

1. The University of Oxford will send NHS Digital a cohort of approximately 221 consented individual records via Secure Electronic File Transfer service (SEFT). These specific identifiers will be provided according to when the study participant was consented:

> Cohort participant consented between 19 December 2020 to 24 May 2021 will provide the NHS Number only (approx 67 records), along with Study ID, date of consent and withdrawal date (if applicable).

> Cohort participant consented between 02 July 2021 to present will provide name, postcode, and date of birth (approx 154 records), along with Study ID, date of consent and withdrawal date (if applicable).

This information will be requested in one dissemination of five years and 3 months of data (2017 up to end June 2022).

2. NHS Digital will use the cohort identifiers to identify and extract relevant data from Hospital Episode Statistics (HES) Admitted Patient Care (APC) and Civil Registrations (Deaths) Secondary Care Cut. NHS Digital will then remove all identifiers, leaving the Study ID.

3. NHS Digital will disseminate the record-level pseudonymised files to the University of Oxford via SEFT.

The record-level pseudonymised data from NHS Digital will be stored in the ATEMPT study database and not shared with any other organisations. The Personal Identifiable Data (PID) data the study collected from participants will be stored separately to the study data and the NHS Digital record level pseudonymised data within the study database. Whilst record-level pseudonymised data will be provided by NHS Digital, while the University of Oxford hold the identifiers for the cohort, the data is considered by NHS Digital to be potentially identifiable.

The study team makes every effort to ensure the record-level data from NHS Digital will remain pseudonymised, including using the Pseudo-Study ID to link with the ATEMPT study data. However, the Study Team point out that individuals would be re-identified if it was in the participant's interest, for example, in the case of an adverse event and for safety monitoring purposes. Re-identification would be on an individual basis and data shared only with the study participant.

Data is stored securely by the University of Oxford in a high compliance system (HCS), managed and owned by the University of Oxford, suitable for storing personal and special category data, and data can only be accessed by the ATEMPT Study Team members, who are substantive members of the University of Oxford plus one consultant under an appropriate contract with the University of Oxford, who have authorisation to access the data for the purposes described and have been appropriately trained in data protection and confidentiality.

Statistical analysis of the data will be performed using an appropriate statistical package. This will be carried out either directly in person or remotely via a University of Oxford owned remote device connected to the University's HCS, which requires a username, password and secure two-factor authenticator (Virtual Private Network or VPN). All data analysis will be conducted within the confines of the University’s secure server, and will not be downloaded to remote devices for storage or processing.

The record-level data released by NHS Digital will not be shared with any other organisation or used for any other purpose other than those stated in this agreement. NHS Digital data is not being matched or linked to publicly available data, nor being linked to other data sets held by University of Oxford which are not directly related to the ATEMPT study. The data received from NHS Digital will only be linked to data in the ATEMPT study database.

VIRTUS Holdco Ltd do not access data held under this agreement as they only supply the building for storage of back-up tapes. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. They are therefore not considered a Data Processor.

HES DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION

In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, you must make sure that:

· National-level figures only may be presented unrounded, without small number suppression

· cell values from 1 to 7 (inclusive) are suppressed at a sub-national level to prevent possible identification of individuals from small counts within the table.

· Zeros (0) do not need to be suppressed.

· All other counts will be rounded to the nearest 5.

Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

The research agenda, plan of investigation and monitoring of the execution of the ATEMPT trial is overseen by a trial steering committee. The trial steering committee is made up of professional members including a Professor of Ageing and Stroke Medicine, a Professor of Cardiology, a GP plus two PPI members, individuals who are able to contribute to the wider public perspective. The main trial results from the ATEMPT Pilot Study are expected in 2022 with a publication towards the end of that year.

The results aim to be disseminated widely, including presentation at relevant conferences such as the European Society of Cardiology annual meeting and publication in an open-access, high-impact medical journal such as the European Journal of Cardiology. Further academic papers (including a protocol paper and results of remote recruitment and management of the trial) will be published in open-access, high impact, peer-reviewed journals and on the trial website.

A non-technical summary of the main study findings will be provided to participants and other interested groups and published on the study website (https://atempt.wrh.ox.ac.uk/).

All outputs will be aggregated with small number suppression applied (as per the HES analysis Guide).

The findings from this pilot study aim to be used to inform and plan an adequately powered major, multi-national Randomised Controlled Trial to start late 2022/early 2023. Additionally, the experience gained from utilising IT-enabled systems to remotely recruit and monitor participants will be evaluated with a view to expanding the use of the software to manage other research trials within the department and wider University. The online system for the ATEMPT trial has been developed in conjunction with members of the public aged 65 years or older in order to ensure that it is as simple and easy to use as possible.

An expected benefit of the ATEMPT pilot study aims to be an improved understanding of how to best manage blood pressure (BP) in older patients, in the presence of many underlying health problems, in particular when BP is not very high, and the effectiveness and safety of changing the number of prescribed antihypertensive drugs.

An additional benefit hope to be to understand the acceptability and tolerability of the intervention (using patient-reported outcomes) and to rule out any major excess harms (risk of serious adverse events) of managing BP in this way.

The findings from this pilot study are intended to provide the feasibility required to inform the planning of a larger, multinational, home-based study to assess the effect of treatment changes on patient-important outcomes. This trial could impact the treatment regime of millions of patients in the UK. The study is designed to minimise the burden of participation to patients. There is no need for clinic attendance. Participation and follow-up will take place at home using a bespoke IT system with much of the data collected remotely.

The experience of using bespoke IT-enabled systems to remotely recruit and monitor participants will, if shown to be effective, be considered for use in the recruitment and study management of other research trials. This could provide the means for other researchers to not only streamline research processes but also include participants in trials who historically are reluctant or unable to participate in research trials due to the demands made of them to attend research visits. For instance, research suggests that the vast amount of research findings are based on studies that have included participants in close proximity to specialised centres, men and those who have fewer comorbidities. This leaves a gap in research for the majority of the population in the UK to whom research findings are being applied. This study hopes to not only encourage participation of such patients but to assess the extent to which conduct of trials can be made more efficient and hence affordable.

VERSION 1 - This study has no yielded benefits yet as they have not yet received the data.