Aspirin To Target Arterial Events in Chronic Kidney Disease (ATTACK)

Chronic kidney disease (CKD) is a term used by doctors when the kidneys are not working as well as they should. It is very common and affects as many as one in eight adults in the UK. CKD is important because it is linked to a much higher chance of cardiovascular disease (CVD). CVD is usually caused by small blood clots. Aspirin reduces the risk of blood clot formation but also increases the chances of bleeding. Studies in people with previous CVD show that aspirin reduces the risk of further heart attacks and strokes, and that these benefits are much greater than the risks of bleeding. As a result, aspirin is recommended for people (both with CKD and without CKD) who already have CVD.

The Aspirin To Target Arterial Events in Chronic Kidney Disease (ATTACK) trial is a large open-label randomised multi-centre study set in UK Primary Care, currently just in England. ATTACK aims to demonstrate whether the addition of low-dose (75mg non-enteric coated) aspirin to usual care reduces the risk of major vascular events (excluding confirmed intracranial haemorrhage) in people with CKD who do not have pre-existing CVD, and whether and to what extent the benefits outweigh any harms due to an increased risk of bleeding.

The University of Southampton are sponsors for the ATTACK trial and are the sole Controller for this data sharing agreement. The University of Southampton delegated the task of applying for NHS England data to the Trial Coordinating Centre hosted by the University of Nottingham. As the trial managers, the University of Nottingham will be Processors of NHS England data. Nottinghamshire Health Informatics Service own the servers upon which the ATTACK database is stored and are therefore listed as Processors. TCR (Nottingham) Ltd own the data management software for the trial, storing and handling the data on the ATTACK database in their capacity as Processors. There are other universities and Trusts involved with recruiting patients and advising on the study design and recruitment strategies as detailed in the study’s protocol, but they will not be involved in data processing or handling record level data received from NHS England.

ATTACK is funded by the National Institute for Health Research and the British Heart Foundation. The funders assess the scientific value of the trial, and require periodic trial updates, but have no involvement in the trial’s analysis or any data processing. The trial start date was 1st January 2018 and is due to finish in July 2025. The trial will continue and NHS England data will be requested until 1,827 major vascular events have occurred, providing enough statistical power to address the study aim.

In order to answer the trial’s primary question of whether aspirin should be prescribed to patients with CKD, the ATTACK trial requires Hospital Episode Statistics (HES) Admitted Patient Care (APC), Civil Registrations of Death data, and Cancer Registration data from NHS England. These data, along with relevant SNOMED-coded data from GP practice records which are directly collected by the trial management team (not from NHS England), will serve as the primary source of potential outcome events for the trial. These are events which are monitored as part of the study to determine if there is a true difference between the two arms of the trial. The Emergency Care Data Set (ECDS) is additionally required in order to complete the necessary health economic analysis for the trial. Processing of these routinely collected electronic healthcare data allows large scale trials addressing key clinical topics to be delivered cost-effectively and without the need for commercial sector funding.

The primary outcome measure is the time to first major vascular event from the date of randomisation. A major vascular event is defined as a primary composite outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (excluding confirmed intracranial haemorrhage). Major bleeding events will be captured as a key safety (secondary) outcome measure. Following the findings of another recently published aspirin trial (ASPREE, New England Journal of Medicine 2018), the Data Monitoring and Ethics Committee (DMEC) for ATTACK has specifically requested regular cancer data as a part of their ongoing safety assessment. Incident cancer is one of the secondary outcomes. There is some evidence that certain types of cancer (e.g. colorectal) are reduced by regular aspirin, and the study seeks to add to this evidence. Mortality, cancer incidence, unplanned hospitalisation and health-related quality of life are additional trial outcomes.

Record-level NHS England data is required to track which patient was randomised to which arm of the trial, and compare the outcomes in the two arms of the study. There are no alternative, less intrusive ways of achieving the purpose. Data minimisation has been considered and, as part of that process, a Health Economist has reviewed the list of fields available from HES APC and ECDS and confirmed those that are essential for their analysis.

The information provided by NHS England will contain identifiable information to allow study team members to associate it with the correct trial participant. When data analysis is performed, this will be pseudonymised, and patient screening numbers (i.e. study IDs) will be used instead of identifiable data. As the trial is open label (i.e. there is no placebo), the participants and their treating practitioners will know whether they are in the aspirin or usual care arm of the trial. GP records, annual questionnaires to patients, and hospital attendance alerts which are also collected and scrutinised as part of the trial may therefore be subject to bias, or be incomplete sources of information. Record-level NHS England data is therefore required to build upon and validate these other sources of information.

Where these sources indicate a potential cardiovascular or major bleeding event, the study team will collect relevant supporting information (from hospital discharge summaries and medical records) and present this to an Endpoint Adjudication Committee who will evaluate this information (blinded to treatment allocation) in order to determine whether patients have reached a trial endpoint. Other trial endpoints will be recorded in the trial database for subsequent statistical analysis and monitoring by the DMEC but are not formally adjudicated.

The ATTACK trial methodology is summarised as follows:

• Potentially eligible adult (aged 18 and over) patients, both male and female, from across England, with historical blood/urine tests suggestive of stage 1-4 CKD (and who meet all other eligibility criteria) identified from GP records are invited to participate. They receive an invitation letter from their GP practice, and if they would like to take part, are asked to return a reply slip in a pre-paid return envelope to the study team. Those who respond are invited to attend a screening visit (this is several weeks after their initial invitation, so they have plenty of time to consider their study participation). Following consent, and signing of the ethically-approved consent form, they undergo a brief baseline health assessment. Patients who are eligible are randomised in an open-label fashion to either 75mg aspirin daily, or to usual care. This means there is no placebo involved in the trial, but both the patient, their GP and the research team are aware of which arm of the trial the patient has been allocated to. GPs are then asked to prescribe aspirin to patients in this arm of the trial via normal NHS systems.

• The scale of the ATTACK trial is large (approximately 25,000 randomised patients are expected overall). Patients make no follow up visits but can notify the trial office of any relevant events, as can their treating healthcare professionals. Patients also receive an annual questionnaire asking them about their health status and aspirin consumption.

• Follow up data is obtained by interrogation of GP electronic records on roughly a 4-weekly basis, and by linkage by TCR (Nottingham) Ltd to data from NHS England approximately annually. University of Southampton cannot reasonably achieve the above in a different way other than accessing HES APC/ ECDS, Civil Registrations of Death, and Cancer Registration data from NHS England.

Consented study patients give explicit permission for subsequent scrutiny of their medical records by the research team. This includes relevant sections of medical notes and NHS England data. They also explicitly consent for their NHS number and date of birth to be used for linkage purposes, and to be sent to NHS England. Patients’ GP data are regularly uploaded to a bespoke ATTACK database/management system via electronic searches looking for any new relevant information in the patients' medical record, or any changes since the last upload. This database/management system has also been prepared to detect and store disease and procedure codes from HES and ECDS.

Data is only requested and collected on patients who have consented for this to happen, via a signed consent form. The University of Southampton only collect relevant data from the patients’ medical record, as agreed with the trial statistician and health economist, to answer the questions the trial is designed to answer.

The legal bases for processing personal data for the ATTACK trial are Articles 6(1)(e) and 9(2)(j) of the General Data Protection Regulation (2018).

GDPR Article 6(1)(e) is justified because processing is necessary for the performance of a task carried out in the public interest. The University of Southampton is a public authority conducting clinical research with the intention of publication of trial outcomes in clinical journals.

GDPR Article 9(2)(j) is justified because processing of special category data is necessary for scientific research purposes. Processing 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 subjects. Civil Registrations of Death data, Cancer Registration data, and HES APC / ECDS data are required in order to test the hypothesis of the ATTACK trial; assess the safety of the trial drug in this patient population; and determine cost-effectiveness.

The trial will continue until 1,827 major vascular events have occurred: this is anticipated 6 years after the planned recruitment start date of October 2018, so in approximately October 2024 – March 2025.

The primary outputs of the analysis will be scientific papers/posters covering both the medical and procedural aspects of the study. The University of Southampton intends to publish the results of the ATTACK Study in a major scientific journal (such as the New England Journal of Medicine or the Lancet), and will also present details of the study at relevant scientific meetings (such as the International Conference on Trial Methodology, or the British Renal Society’s UK Kidney Week). The study research team will also share regular feedback and recruitment updates with the Clinical Research Network, to help inform and improve the design of primary care trials in the future. The University of Southampton have already been approached on numerous occasions to advise on some of the novel methodologies, include video-training of GP practice staff.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

In addition, regular summaries and reports of the number of endpoint events by trial arm will be sent to the Data Monitoring and Ethics Committee (DMEC). The role of the DMEC is to monitor these data and make recommendations on whether there are any ethical or safety reasons why the trial should not continue, ensuring that the safety, rights and well-being of the trial participants are paramount. From the trial Protocol the DMEC are required, at a minimum, to meet at the following defined time points: 18 months from the start of recruitment to review safety and assess study recruitment and feasibility; 27 months from the start of recruitment to assess safety, recruitment and the control event rate; and 36 months from the start of recruitment to assess safety, study recruitment and the control event rate.

Patient and public involvement (PPI) is crucial to the success of this project, and has helped in the following ways to date:

- 2 PPI members on the Trial Steering Committee, who attend 6 monthly meetings

- 2 PPI members on the Trial Management Group who attend regular teleconferences, and have provided advice on the protocol, participant information sheet, invitation letter, and recruitment strategies

- 4 PPI members form a "document review panel", and have provided feedback on the participant information sheet, invitation letter and annual questionnaires, both

as part of the original submission and the recent substantial amendment

- The research team are are actively consulting with their PPI colleagues regarding a trial redesign and recruitment restart in light of the COVID-19 pandemic.

The data received so far under this DSA is being analysed on an ongoing basis to identify endpoints for the trial, but the analysis has not yet been completed as this was planned to take place at the end of the study.

Chronic kidney disease (CKD) is a term used by doctors when the kidneys are not working as well as they should. It is very common and affects as many as one in eight adults in the UK. CKD is important because it is linked to a much higher chance of cardiovascular disease (CVD). CVD is usually caused by small blood clots. Aspirin reduces the risk of blood clot formation but also increases the chances of bleeding. Studies in people with previous CVD show that aspirin reduces the risk of further heart attacks and strokes, and that these benefits are much greater than the risks of bleeding. As a result, aspirin is recommended for people (both with CKD and without CKD) who already have CVD.

The Aspirin To Target Arterial Events in Chronic Kidney Disease (ATTACK) trial is a large open-label randomised multi-centre study set in UK Primary Care, currently just in England. ATTACK aims to demonstrate whether the addition of low-dose (75mg non-enteric coated) aspirin to usual care reduces the risk of major vascular events (excluding confirmed intracranial haemorrhage) in people with CKD who do not have pre-existing CVD, and whether and to what extent the benefits outweigh any harms due to an increased risk of bleeding.

The University of Southampton are sponsors for the ATTACK trial and are the sole Data Controller for this data sharing agreement. The University of Southampton delegated the task of applying for NHS Digital data to the Trial Coordinating Centre hosted by the University of Nottingham. As the trial managers, the University of Nottingham will be data processors of NHS Digital data. Nottinghamshire Health Informatics Service own the servers upon which the ATTACK database is stored and are therefore listed as data processors. TCR (Nottingham) Ltd own the data management software for the trial, storing and handling the data on the ATTACK database in their capacity as data processors. There are other universities and Trusts involved with recruiting patients and advising on the study design and recruitment strategies as detailed in the study’s protocol, but they will not be involved in data processing or handling record level data received from NHS Digital.

ATTACK is funded by the National Institute for Health Research and the British Heart Foundation. The funders assess the scientific value of the trial, and require periodic trial updates, but have no involvement in the trial’s analysis or any data processing. The trial start date was 1st January 2018 and is due to finish in July 2025. The trial will continue and NHS Digital data will be requested until 1,827 major vascular events have occurred, providing enough statistical power to address the study aim.

In order to answer the trial’s primary question of whether aspirin should be prescribed to patients with CKD, the ATTACK trial requires hospital episode statistics (HES) Admitted Patient Care (APC), Civil Registration (Deaths) data and Cancer Registration data from NHS Digital. These data, along with relevant SNOMED-coded data from GP practice records which are directly collected by the trial management team (not from NHS Digital), will serve as the primary source of potential outcome events for the trial. These are events which are monitored as part of the study to determine if there is a true difference between the two arms of the trial. The Emergency Care Data Set (ECDS) is additionally required in order to complete the necessary health economic analysis for the trial. Processing of these routinely collected electronic healthcare data allows large scale trials addressing key clinical topics to be delivered cost-effectively and without the need for commercial sector funding.

The primary outcome measure is the time to first major vascular event from the date of randomisation. A major vascular event is defined as a primary composite outcome of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage). Major bleeding events will be captured as a key safety (secondary) outcome measure. Following the findings of another recently published aspirin trial (ASPREE, New England Journal of Medicine 2018), the Data Monitoring and Ethics Committee (DMEC) for ATTACK has specifically requested regular cancer data as a part of their ongoing safety assessment. Incident cancer is one of the secondary outcomes. There is some evidence that certain types of cancer (e.g. colorectal) are reduced by regular aspirin, and the study seeks to add to this evidence. Mortality, cancer incidence, unplanned hospitalisation and health-related quality of life are additional trial outcomes.

Record-level NHS Digital data is required to track which patient was randomised to which arm of the trial, and compare the outcomes in the two arms of the study. There are no alternative, less intrusive ways of achieving the purpose. Data minimisation has been considered and, as part of that process, a Health Economist has reviewed the list of fields available from HES APC and ECDS and confirmed those that are essential for their analysis.

The information provided by NHS Digital will contain identifiable information to allow study team members to associate it with the correct trial participant. When data analysis is performed, this will be pseudonymised, and patient screening numbers (i.e. study IDs) will be used instead of identifiable data. As the trial is open label (i.e. there is no placebo), the participants and their treating practitioners will know whether they are in the aspirin or usual care arm of the trial. GP records, annual questionnaires to patients, and hospital attendance alerts which are also collected and scrutinised as part of the trial may therefore be subject to bias, or be incomplete sources of information. Record-level NHS Digital data is therefore required to build upon and validate these other sources of information.

Where these sources indicate a potential cardiovascular or major bleeding event, the study team will collect relevant supporting information (from hospital discharge summaries and medical records) and present this to an Endpoint Adjudication Committee who will evaluate this information (blinded to treatment allocation) in order to determine whether patients have reached a trial endpoint. Other trial endpoints will be recorded in the trial database for subsequent statistical analysis and monitoring by the DMEC but are not formally adjudicated.

The ATTACK trial methodology is summarised as follows:

• Potentially eligible adult (aged 18 and over) patients, both male and female, from across England, with historical blood/urine tests suggestive of stage 1-4 CKD (and who meet all other eligibility criteria) identified from GP records are invited to participate. They receive an invitation letter from their GP practice, and if they would like to take part, are asked to return a reply slip in a pre-paid return envelope to the study team. Those who respond are invited to attend a screening visit (this is several weeks after their initial invitation, so they have plenty of time to consider their study participation). Following consent, and signing of the ethically-approved consent form, they undergo a brief baseline health assessment. Patients who are eligible are randomised in an open-label fashion to either 75mg aspirin daily, or to usual care. This means there is no placebo involved in the trial, but both the patient, their GP and the research team are aware of which arm of the trial the patient has been allocated to. GPs are then asked to prescribe aspirin to patients in this arm of the trial via normal NHS systems.

• The scale of the ATTACK trial is large (approximately 25,000 randomised patients are expected overall). Patients make no follow up visits but can notify the trial office of any relevant events, as can their treating healthcare professionals. Patients also receive an annual questionnaire asking them about their health status and aspirin consumption.

• Follow up data is obtained by interrogation of GP electronic records on roughly a 4-weekly basis, and by linkage by TCR (Nottingham) Ltd to data from NHS Digital approximately annually. University of Southampton cannot reasonably achieve the above in a different way other than accessing HES APC/ ECDS, Civil Registration (Deaths) and Cancer Registration data from NHS Digital.

Consented study patients give explicit permission for subsequent scrutiny of their medical records by the research team. This includes relevant sections of medical notes and NHS Digital data. They also explicitly consent for their NHS number and date of birth to be used for linkage purposes, and to be sent to NHS Digital. Patients’ GP data are regularly uploaded to a bespoke ATTACK database/management system via electronic searches looking for any new relevant information in the patients' medical record, or any changes since the last upload. This database/management system has also been prepared to detect and store disease and procedure codes from HES and ECDS.

Data is only requested and collected on patients who have consented for this to happen, via a signed consent form. The University of Southampton only collect relevant data from the patients’ medical record, as agreed with the trial statistician and health economist, to answer the questions the trial is designed to answer.

The legal bases for processing personal data for the ATTACK trial are Articles 6(1)(e) and 9(2)(j) of the General Data Protection Regulation (2018).

GDPR Article 6 (1) (e) is justified because processing is necessary for the performance of a task carried out in the public interest. The University of Southampton is a public authority conducting clinical research with the intention of publication of trial outcomes in clinical journals.

GDPR Article 9 (2) (j) is justified because processing of special category data is necessary for scientific research purposes. Processing 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 subjects. Civil Registration (Deaths) data, Cancer Registration data and HES APC / ECDS data are required in order to test the hypothesis of the ATTACK trial; assess the safety of the trial drug in this patient population; and determine cost-effectiveness.

The trial will continue until 1,827 major vascular events have occurred: this is anticipated 6 years after the planned recruitment start date of October 2018, so in approximately October 2024 – March 2025.

The primary outputs of the analysis will be scientific papers/posters covering both the medical and procedural aspects of the study. The University of Southampton intends to publish the results of the ATTACK Study in a major scientific journal (such as the New England Journal of Medicine or the Lancet), and will also present details of the study at relevant scientific meetings (such as the International Conference on Trial Methodology, or the British Renal Society’s UK Kidney Week). The study research team will also share regular feedback and recruitment updates with the Clinical Research Network, to help inform and improve the design of primary care trials in the future. The University of Southampton have already been approached on numerous occasions to advise on some of our novel methodologies, include video-training of GP practice staff.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

In addition, regular summaries and reports of the number of endpoint events by trial arm will be sent to the Data Monitoring and Ethics Committee (DMEC). The role of the DMEC is to monitor these data and make recommendations on whether there are any ethical or safety reasons why the trial should not continue, ensuring that the safety, rights and well-being of the trial participants are paramount. From the trial Protocol the DMEC are required, at a minimum, to meet at the following defined time points: 18 months from the start of recruitment to review safety and assess study recruitment and feasibility; 27 months from the start of recruitment to assess safety, recruitment and the control event rate; and 36 months from the start of recruitment to assess safety, study recruitment and the control event rate.

Patient and public involvement (PPI) is crucial to the success of this project, and has helped in the following ways to date:

- 2 PPI members on the Trial Steering Committee, who attend 6 monthly meetings

- 2 PPI members on the Trial Management Group who attend regular teleconferences, and have provided advice on the protocol, participant information sheet, invitation letter, and recruitment strategies

- 4 PPI members form a "document review panel", and have provided feedback on the participant information sheet, invitation letter and annual questionnaires, both

as part of the original submission and the recent substantial amendment

- The research team are are actively consulting with their PPI colleagues regarding a trial redesign and recruitment restart in light of the COVID-19 pandemic.

None at time of Amendment. Amendment required to ensure 'Cause of Death' data is received.

Chronic kidney disease (CKD) is a term used by doctors when the kidneys are not working as well as they should. It is very common and affects as many as one in eight adults in the UK. CKD is important because it is linked to a much higher chance of cardiovascular disease (CVD). CVD is usually caused by small blood clots. Aspirin reduces the risk of blood clot formation but also increases the chances of bleeding. Studies in people with previous CVD show that aspirin reduces the risk of further heart attacks and strokes, and that these benefits are much greater than the risks of bleeding. As a result, aspirin is recommended for people (both with CKD and without CKD) who already have CVD.

The Aspirin To Target Arterial Events in Chronic Kidney Disease (ATTACK) trial is a large open-label randomised multi-centre study set in UK Primary Care, currently just in England. ATTACK aims to demonstrate whether the addition of low-dose (75mg non-enteric coated) aspirin to usual care reduces the risk of major vascular events (excluding confirmed intracranial haemorrhage) in people with CKD who do not have pre-existing CVD, and whether and to what extent the benefits outweigh any harms due to an increased risk of bleeding.

The University of Southampton are sponsors for the ATTACK trial and are the sole Data Controller for this data sharing agreement. The University of Southampton delegated the task of applying for NHS Digital data to the Trial Coordinating Centre hosted by the University of Nottingham. As the trial managers, the University of Nottingham will be data processors of NHS Digital data. Nottinghamshire Health Informatics Service own the servers upon which the ATTACK database is stored and are therefore listed as data processors. TCR (Nottingham) Ltd own the data management software for the trial, storing and handling the data on the ATTACK database in their capacity as data processors. There are other universities and Trusts involved with recruiting patients and advising on the study design and recruitment strategies as detailed in the study’s protocol, but they will not be involved in data processing or handling record level data received from NHS Digital.

ATTACK is funded by the National Institute for Health Research and the British Heart Foundation. The funders assess the scientific value of the trial, and require periodic trial updates, but have no involvement in the trial’s analysis or any data processing. The trial start date was 1st January 2018 and is due to finish in July 2025. The trial will continue and NHS Digital data will be requested until 1,827 major vascular events have occurred, providing enough statistical power to address the study aim.

In order to answer the trial’s primary question of whether aspirin should be prescribed to patients with CKD, the ATTACK trial requires hospital episode statistics (HES) Admitted Patient Care (APC), Civil Registration (Deaths) data and Cancer Registration data from NHS Digital. These data, along with relevant SNOMED-coded data from GP practice records which are directly collected by the trial management team (not from NHS Digital), will serve as the primary source of potential outcome events for the trial. These are events which are monitored as part of the study to determine if there is a true difference between the two arms of the trial. The Emergency Care Data Set (ECDS) is additionally required in order to complete the necessary health economic analysis for the trial. Processing of these routinely collected electronic healthcare data allows large scale trials addressing key clinical topics to be delivered cost-effectively and without the need for commercial sector funding.

The primary outcome measure is the time to first major vascular event from the date of randomisation. A major vascular event is defined as a primary composite outcome of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage). Major bleeding events will be captured as a key safety (secondary) outcome measure. Following the findings of another recently published aspirin trial (ASPREE, New England Journal of Medicine 2018), the Data Monitoring and Ethics Committee (DMEC) for ATTACK has specifically requested regular cancer data as a part of their ongoing safety assessment. Incident cancer is one of the secondary outcomes. There is some evidence that certain types of cancer (e.g. colorectal) are reduced by regular aspirin, and the study seeks to add to this evidence. Mortality, cancer incidence, unplanned hospitalisation and health-related quality of life are additional trial outcomes.

Record-level NHS Digital data is required to track which patient was randomised to which arm of the trial, and compare the outcomes in the two arms of the study. There are no alternative, less intrusive ways of achieving the purpose. Data minimisation has been considered and, as part of that process, a Health Economist has reviewed the list of fields available from HES APC and ECDS and confirmed those that are essential for their analysis.

The information provided by NHS Digital will contain identifiable information to allow study team members to associate it with the correct trial participant. When data analysis is performed, this will be pseudonymised, and patient screening numbers (i.e. study IDs) will be used instead of identifiable data. As the trial is open label (i.e. there is no placebo), the participants and their treating practitioners will know whether they are in the aspirin or usual care arm of the trial. GP records, annual questionnaires to patients, and hospital attendance alerts which are also collected and scrutinised as part of the trial may therefore be subject to bias, or be incomplete sources of information. Record-level NHS Digital data is therefore required to build upon and validate these other sources of information.

Where these sources indicate a potential cardiovascular or major bleeding event, the study team will collect relevant supporting information (from hospital discharge summaries and medical records) and present this to an Endpoint Adjudication Committee who will evaluate this information (blinded to treatment allocation) in order to determine whether patients have reached a trial endpoint. Other trial endpoints will be recorded in the trial database for subsequent statistical analysis and monitoring by the DMEC but are not formally adjudicated.

The ATTACK trial methodology is summarised as follows:

• Potentially eligible adult (aged 18 and over) patients, both male and female, from across England, with historical blood/urine tests suggestive of stage 1-4 CKD (and who meet all other eligibility criteria) identified from GP records are invited to participate. They receive an invitation letter from their GP practice, and if they would like to take part, are asked to return a reply slip in a pre-paid return envelope to the study team. Those who respond are invited to attend a screening visit (this is several weeks after their initial invitation, so they have plenty of time to consider their study participation). Following consent, and signing of the ethically-approved consent form, they undergo a brief baseline health assessment. Patients who are eligible are randomised in an open-label fashion to either 75mg aspirin daily, or to usual care. This means there is no placebo involved in the trial, but both the patient, their GP and the research team are aware of which arm of the trial the patient has been allocated to. GPs are then asked to prescribe aspirin to patients in this arm of the trial via normal NHS systems.

• The scale of the ATTACK trial is large (approximately 25,000 randomised patients are expected overall). Patients make no follow up visits but can notify the trial office of any relevant events, as can their treating healthcare professionals. Patients also receive an annual questionnaire asking them about their health status and aspirin consumption.

• Follow up data is obtained by interrogation of GP electronic records on roughly a 4-weekly basis, and by linkage by TCR (Nottingham) Ltd to data from NHS Digital approximately annually. University of Southampton cannot reasonably achieve the above in a different way other than accessing HES APC/ ECDS, Civil Registration (Deaths) and Cancer Registration data from NHS Digital.

Consented study patients give explicit permission for subsequent scrutiny of their medical records by the research team. This includes relevant sections of medical notes and NHS Digital data. They also explicitly consent for their NHS number and date of birth to be used for linkage purposes, and to be sent to NHS Digital. Patients’ GP data are regularly uploaded to a bespoke ATTACK database/management system via electronic searches looking for any new relevant information in the patients' medical record, or any changes since the last upload. This database/management system has also been prepared to detect and store disease and procedure codes from HES and ECDS.

Data is only requested and collected on patients who have consented for this to happen, via a signed consent form. The University of Southampton only collect relevant data from the patients’ medical record, as agreed with the trial statistician and health economist, to answer the questions the trial is designed to answer.

The legal bases for processing personal data for the ATTACK trial are Articles 6(1)(e) and 9(2)(j) of the General Data Protection Regulation (2018).

GDPR Article 6 (1) (e) is justified because processing is necessary for the performance of a task carried out in the public interest. The University of Southampton is a public authority conducting clinical research with the intention of publication of trial outcomes in clinical journals.

GDPR Article 9 (2) (j) is justified because processing of special category data is necessary for scientific research purposes. Processing 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 subjects. Civil Registration (Deaths) data, Cancer Registration data and HES APC / ECDS data are required in order to test the hypothesis of the ATTACK trial; assess the safety of the trial drug in this patient population; and determine cost-effectiveness.

The trial will continue until 1,827 major vascular events have occurred: this is anticipated 6 years after the planned recruitment start date of October 2018, so in approximately October 2024 – March 2025.

The primary outputs of the analysis will be scientific papers/posters covering both the medical and procedural aspects of the study. The University of Southampton intends to publish the results of the ATTACK Study in a major scientific journal (such as the New England Journal of Medicine or the Lancet), and will also present details of the study at relevant scientific meetings (such as the International Conference on Trial Methodology, or the British Renal Society’s UK Kidney Week). The study research team will also share regular feedback and recruitment updates with the Clinical Research Network, to help inform and improve the design of primary care trials in the future. The University of Southampton have already been approached on numerous occasions to advise on some of our novel methodologies, include video-training of GP practice staff.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

In addition, regular summaries and reports of the number of endpoint events by trial arm will be sent to the Data Monitoring and Ethics Committee (DMEC). The role of the DMEC is to monitor these data and make recommendations on whether there are any ethical or safety reasons why the trial should not continue, ensuring that the safety, rights and well-being of the trial participants are paramount. From the trial Protocol the DMEC are required, at a minimum, to meet at the following defined time points: 18 months from the start of recruitment to review safety and assess study recruitment and feasibility; 27 months from the start of recruitment to assess safety, recruitment and the control event rate; and 36 months from the start of recruitment to assess safety, study recruitment and the control event rate.

Patient and public involvement (PPI) is crucial to the success of this project, and has helped in the following ways to date:

- 2 PPI members on the Trial Steering Committee, who attend 6 monthly meetings

- 2 PPI members on the Trial Management Group who attend regular teleconferences, and have provided advice on the protocol, participant information sheet, invitation letter, and recruitment strategies

- 4 PPI members form a "document review panel", and have provided feedback on the participant information sheet, invitation letter and annual questionnaires, both

as part of the original submission and the recent substantial amendment

- The research team are are actively consulting with their PPI colleagues regarding a trial redesign and recruitment restart in light of the COVID-19 pandemic.

Yielded Benefits is not a requirement for new applications.