ASPIRING - Antiplatelet Secondary Prevention International Randomised Study After Intracerebral Haemorrhage - Recruitment Agreement

The University of Edinburgh and NHS Lothian requires access to NHS England data for the purpose of the ASPIRING study.

The aims of the research project are to test the hypothesis that starting oral antiplatelet drug monotherapy is superior to avoiding antiplatelet drugs, in addition to standard care at the participating hospital, for increasing the time to first Major Adverse Cardiovascular Events (MACE) for survivors of stroke due to Intracerebral Haemorrhage (ICH).

ASPIRING also seeks to answer these research questions:

(1) What is the efficacy of antiplatelet drug monotherapy, determined by its effect on ischaemic MACE after ICH?

(2) What is the safety of antiplatelet drug monotherapy, determined by its effect on haemorrhagic MACE after ICH?

(3) What are the effects of antiplatelet drug monotherapy on individual components of MACE after ICH

(4) What are the effects of antiplatelet drug monotherapy after ICH on all MACE, ischaemic MACE, and haemorrhagic MACE in clinically important sub-groups?

(5) What are the effects of antiplatelet drug monotherapy after ICH on non-cardiovascular death?

(6) Are the effects of antiplatelet drug monotherapy on the primary outcome generalisable between countries (or is there heterogeneity of treatment effect by country of randomisation)?

Stroke due to intracerebral haemorrhage (ICH) is a devastating cardiovascular disease that causes 48% of disability-adjusted life years due to stroke. ICH survivors are at high risk of further major adverse cardiovascular or cerebrovascular events (MACE, i.e. hospitalisation due to stroke [ischaemic or ICH], hospitalisation due to myocardial infarction, or cardiovascular death [by ischaemia, bleeding or other vascular causes]). In the REstart or STop Antithrombotics Randomised Trial

(RESTART) of 537 people with cardiovascular diseases who survived ICH in the UK, starting antiplatelet drugs after ICH seemed safe and might have reduced MACE risk (Lancet 2019). ASPIRING aims to provide definitive evidence of the superiority of starting antiplatelet drug monotherapy compared with avoiding antiplatelet drugs in addition to standard care to prevent MACE for all ICH survivors

For the ASPIRING Study to achieve its objectives 4,148 people will need to be recruited, including 2,828 in England, Scotland and Wales.

NHS England will identify potential participants meeting the eligibility criteria specified by the controllers and facilitate contact via letter to provide information about the study and provide details of how they can give consent to participate if they wish.

The number of individuals who will be sent communications will be proportionately limited based on the estimated response rate. If the target number of participants is not achieved, the number of individuals who are sent communications will be increased in increments.

To identify individuals meeting the eligibility criteria, NHS England will utilise the following datasets:

• Hospital Episode Statistics - Admitted Patient Care

• Demographics

• Medicines Dispensed in Primary Care (NHSBSA)

The level of the Data will be as follows:

Identifiable – necessary because the third-party mailing provider require enough information to be able to contact potential participants.

The Data will be minimised as follows:

• Limited to the minimum demographic details required to enable the third-party mailing provider to send a communication to each individual selected for contact.

The University of Edinburgh and Lothian Health Board are the research sponsors and the controllers as the organisations responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The Health Regulatory Authority (HRA) Confidentiality Advisory Group (CAG) provided support to temporarily lift the Common Law Duty of Confidentiality under section 251 of the National Health Service Act 2006 and its current Regulations, the Health Service (Control of Patient Information) Regulations 2002, for the purpose of contacting potentially eligible participant.

In addition to the National Data Opt-out, members of the public will be able to specifically request not to be contacted for involvement in the ASPIRING. University of Edinburgh and NHS Lothian will promote this information via their trial webpage and NHS England will also promote this information via a dedicated opt-out webpage for the study on its website. This will replicate the format used for other NHS DigiTrials Recruitment Pilots, and will be published shortly after this Agreement is approved. NHS England will record these requests not to take part and ensure that anyone who has registered for this will be excluded from the cohort selection. As a result, their details will not be on the list passed to the third-party mailing provider (PSL Print Management Ltd and Datagraphic Ltd – see more information below) for invitations to be sent.

ASPIRING is funded by the British Heart Foundation (BHF), UK, Canadian Institutes of Health Research (CIHR), Canada, Dutch Heart Foundation / Hartstichting (DHF) The Netherlands, Flanders / Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO), and The Australian NHMRC Medical Research Future Fund. Funding is in place until 31 July 2030.

NHS England are a processor on behalf of the University of Edinburgh and NHS Lothian and are responsible for:

1. Identifying individuals to be contacted applying the agreed inclusion and exclusion criteria and applying the National Data Opt-Out

2. Sending the list of invitees on to the third-party provider (Datagraphic Ltd) for generating the invitation letters.

3. Reporting on progress, performance against the agreed service levels, issues and response rates to the University of Edinburgh and NHS Lothian

4. Maintaining a record of people invited and ensuring they are excluded from second rounds of invitations, as may be applicable.

PSL Print Management Ltd are a sub-processor on behalf of NHS England and are responsible for maintaining a service contract with NHS England and managing the mailout performed by Datagraphic Ltd. PSL Print Management Ltd will not receive, store or have access to NHS England record level Data under this DSA. *

Datagraphic Ltd are a sub-processor on behalf of NHS England and PSL Print Management Ltd and are responsible for receiving the list of updated cohort participants from NHS England and mailing out to them accordingly.

* PSL Print Management Ltd and Datagraphic Ltd work in partnership to provide robust, secure and time critical communication solutions. PSL Print Management Ltd provide project management, training and implementation skill and knowledge. Datagraphic Ltd develop, maintain and host the systems that enable secure and resilient communication to occur. Datagraphic Ltd also provide secure data processing, document composition, sortation, mail item production, enclosing, despatch and inbound mail services from their UK Midlands based development and production hub. NHS England maintains a service contract with PSL Print Management Ltd, and Datagraphic Ltd, in turn, are contracted to PSL, therefore both organisations are considered sub-processors in this DSA.

The following oversight committees are in place for the ASPIRING study:

The Data Monitoring Committee (DMC):

The DMC is an independent expert advisory group, which has been commissioned and charged with the responsibility of evaluating cumulative safety and efficacy data, as well as clinical trial conduct, at regular intervals. The DMC must comply with the Sponsor’s requirements and the guidelines of the British Heart Foundation, (the charity that funds the trial coordinating centre).

The Trial Steering Committee (TSC):

The TSC will provide oversight for the trial on behalf of the Sponsor/funder. The specific roles of the TSC include; monitoring recruitment rates and encouraging the Trial Management Group (TMG) to develop strategies to deal with recruitment issues, review regular reports of the trial, review adverse events and serious adverse events blind to treatment allocation and assess the impact and relevance of any accumulating external evidence. It should also provide advice through its independent Chair to the TMG on all aspects of the trial.

The TSC will be responsible for promptly reviewing the DMC recommendations, to decide whether to continue or terminate the trial, and to determine whether amendments to the protocol or changes in study conduct are required.

Throughout the lifecycle of ASPIRING, the PPIE advisory group lead will be supported by Edinburgh Clinical Trials Unit (ECTU) to organise input from a diverse Patient, Carer and Public Involvement (PCPI) Advisory Group, which meet on alternate months. The Patient Advisory Group (PAG) will continue to advise the Trial Management Group (TMG) about ASPIRING, monitor inclusion, and review progress with existing recommendations such as separate short and supplementary patient information sheets (PIS), plain language video abstracts to inform patients and to standardise presentation of information about the trial, and interviews with participants and carers.

The ASPIRING PCPI Lead is a brain haemorrhage survivor who has used antithrombotic medicine. The PCPI Lead assisted in co-designing ASPIRING from the very beginning as a grant applicant and co-writer of the ASPIRING PCPI summaries. They advised on feasibility, acceptability, practicality & patient-facing materials study materials. The PAG has advised on the content of the short and supplementary patient information leaflets, aphasia-friendly easy-read versions, and videos to inform patients and standardise presentation of information about the study. The PAG will be available to support participants/carers with questions about recruitment/withdrawal. The public, patients, and carers will be kept informed about progress via the study website and social media channels.

The PAG will eventually interpret the study results to help to identify relevant themes, check the validity of conclusions from a public perspective and highlight findings that are most relevant to participants and the public. They'll be included in the clinical study report.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA).

NHS England will identify a cohort meeting the following criteria:

INCLUSION CRITERIA:

• Admitted to Hospital with Intracerebral Haemorrhage

• Male or Female

• Age 18 or over at time of invite

• Resides in England

EXCLUSION CRITERIA:

• Not a current user of any antiplatelet or anticoagulant medication at the time of invitation

• Cause of Intracerebral Haemorrhage cannot be due to certain diagnosis and procedure codes, as detailed in the study protocol.

NHS England will provide the relevant records from the Demographics dataset to Datagraphic Ltd. The Data will contain directly identifying data items including: Names, Address and Postcode which are required for the purpose of contacting potential participants.

The Data will be stored on servers at Datagraphic Ltd.

The Data will be accessed on servers at Datagraphic Ltd.

The Data will not leave the UK at any time.

Access is restricted to employees of NHS England and Datagraphic Ltd only.

NHS England will also provide an aggregate data quality report containing information about gender, age and geographic demographics of the mailing to University of Edinburgh and NHS Lothian for the purposes of confirming that inclusion and exclusion criteria have been met for each mailing. This report will also contain the total number of people who received the letter from Datagraphic Ltd, and the number of people removed from the cohort prior to mailing based on trial-specific opt out, national data opt out, and special categories of people for whom the data should not be disseminated.

The University of Edinburgh and NHS Lothian will not be given access to any individual’s data unless they are contacted directly by the individual following the mailout.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will not be linked with any other data.

Datagraphic Ltd will destroy all data files received from NHS England 2 weeks post mail-out, as instructed by NHS England.

Each time NHS England create and disseminate an extract, the records will be added to a mailing list cohort dataset. Should a fresh extract be produced, it will be checked to ensure that any records appearing in this mailing list dataset are removed in order to prevent potential participants receiving multiple invitations. This mailing list dataset will be maintained for six months after the invitation process is complete in case this is required for analysis purposes by University of Edinburgh and NHS Lothian, however it is anticipated that the data quality report will meet the trial's needs for monitoring how many individuals from different demographics were contacted in each 'mailing'. Only aggregated data would be used for such analysis.

The expected outputs of this recruitment Agreement will be University of Edinburgh and NHS Lothian reaching their recruitment target for the ASPIRING, having sent adequate numbers of invitations to potentially eligible participants.

Progress against recruitment targets will inform:

• Reporting to: The University of Edinburgh & Lothian Health Board, British Heart Foundation (BHF), UK, Canadian Institutes of Health Research (CIHR), Canada, Dutch Heart Foundation / Hartstichting (DHF) The Netherlands, and the Australian NHMRC Medical Research Future Fund and ASPIRING study partners through milestone updates linked to the funding awards.

• Reporting to the trial oversight committees (Trial Steering Committee Data Monitoring Committee) via reports to their meetings that occur at least annually.

• Lay friendly updates to the ASPIRING Patient Carer Public Involvement and Engagement Advisory Group via reports for their regular oversight meetings.

• Presentations to professional audiences

• Publications of the trial protocol and results.

Any outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset from which the information was derived. Identifiable data requested from NHS England will only be used to identify and invite potential participants.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Social Media

• Journal (in the final report of the trial and the SWAT)

• Webinars with investigators

• Public report (in any plain English summaries of the trial)

• Newsletters for investigators, usually sent on a monthly basis

University of Edinburgh and NHS Lothian hopes to reach their recruitment target for the ASPIRING study by March 2029.

The ability to utilise large message quantities will help to optimise recruitment, in order to deliver the ASPIRING study in a timely, effective and efficient manner. Using NHS England’s NHS DigiTrials Recruitment Service to generate mailing lists, in order to send invitations to members of the public about joining the ASPIRING study is expected to significantly increase the recruitment reach of the study.

If the ASPIRING study ultimately shows that antiplatelet monotherapy reduces the risk of major adverse cardiovascular events after stroke due to intracerebral haemorrhage, then this could benefit hundreds of thousands of patients each year globally in future.

Recruiting individuals into the ASPIRING study, using the NHS DigiTrials recruitment service, is ultimately expected to provide benefits to health and social care by conducting research highly relevant to the NHS (addressing digital methods of improving prevention, as recommended by the recent Darzi report) and reducing the burden of major adverse cardiovascular events in the future.

This study will enable researchers to answer key research questions around new treatments to prevent major adverse cardiovascular events (MACE) after stroke due to intracerebral haemorrhage (ICH), including:

(1) What is the efficacy of antiplatelet drug monotherapy, determined by its effect on ischaemic MACE after ICH?

(2) What is the safety of antiplatelet drug monotherapy, determined by its effect on haemorrhagic MACE after ICH?

(3) What are the effects of antiplatelet drug monotherapy on individual components of MACE after ICH

(4) What are the effects of antiplatelet drug monotherapy after ICH on all MACE, ischaemic MACE, and haemorrhagic MACE in clinically important sub-groups?

(5) What are the effects of antiplatelet drug monotherapy after ICH on non-cardiovascular death?

The trial team engage with various stakeholders and influencers to ask for their support with engaging members of the public who are eligible to join the ASPIRING study. They will be asked to raise awareness of the ASPIRING study via their own communication channels which will increase familiarity and trust to the letter invite, for example:

• ASPIRING study website

• Hospitals

• Research Delivery Networks

• Charities

• NHS DigiTrials website

The ability to utilise large message quantities will help to optimise recruitment, in order to deliver the ASPIRING study in a timely, effective and efficient manner. Using NHS England’s NHS DigiTrials Recruitment Service to generate mailing lists, in order to send invitations to members of the public about joining the ASPIRING study is expected to significantly increase the recruitment reach of the study.

If the ASPIRING study ultimately shows that antiplatelet monotherapy reduces the risk of major adverse cardiovascular events after stroke due to intracerebral haemorrhage, then this could benefit hundreds of thousands of patients each year globally in future.

Recruiting individuals into the ASPIRING study, using the NHS DigiTrials recruitment service, is ultimately expected to provide benefits to health and social care by conducting research highly relevant to the NHS (addressing digital methods of improving prevention, as recommended by the recent Darzi report) and reducing the burden of major adverse cardiovascular events in the future.

Yielded Benefits is not a requirement for new applications.