DAPA MI - A Registry-based, Randomised, Double-blind, Placebo-Controlled Cardiovascular Outcomes Trial

GLOSSARY:

- Clinical trial randomisation is the process of assigning patients by chance to groups that receive different treatments.

- Myocardial Infarction (MI) is the clinical term for a heart attack.

- Standard of Care (SoC) therapies - this is treatment that is accepted by medical experts as the most appropriate for a certain type of disease in a particular setting and is widely used by healthcare professionals. Also called best practice.

- Ecode - this refers to the study's pseudonymised Study ID used to track patients without identifying them.

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AstraZeneca requires access to NHS England data for the purpose of the following clinical trial:

DAPA MI - A Registry-based, Randomised, Double-blind, Placebo-Controlled Cardiovascular Outcomes Trial

The following is a summary of the aims of the research project provided by AstraZeneca:

Approximately 7 million individuals suffer a heart attack (also called a myocardial infarction (MI)) annually, and survivors of MI remain at high risk for new major adverse cardiovascular (CV) events, including CV death and heart failure (HF). The development of heart failure following an MI is strongly associated with incapacitating symptoms, poor functional status, reduced health-related quality of life and unfavourable long-term prognosis. HF is also one of the leading causes of all hospital admissions, generating substantial costs for health care systems. Therefore, MI therapies that could prevent the development of heart failure as well as re-occurrence of major CV events represent a large and unmet medical need.

This study will evaluate the effect of the drug called dapagliflozin (10 mg) versus a placebo, given once daily, in addition to Standard of Care (SoC) therapies for patients with MI, for the prevention of hospitalisation for heart failure or CV death. The study seeks to determine dapagliflozin’s potential in the early prevention of serious complications, hospitalisations for heart failure or CV death, immediately following an MI.

This multi-centre clinical trial has been designed as a registry-based randomised controlled trial (R-RCT) which combines traditional study design elements within a pragmatic trial framework to provide high quality evidence on the potential benefit of dapagliflozin when administered in the early phase after MI. Traditional design elements such as randomisation and double blinding will minimise potential bias while the pragmatic and streamlined trial elements are expected to capture a broad MI population that will increase external validity and generalisability of study results and at the same time limit study burden on patients and investigators by usage of existing healthcare infrastructure and enabled by continuous clinical quality registries/clinical audits used in routine health care.

Ethics committee approval and patient consent:

The trial has been approved by the relevant Ethics Committees in the UK and Sweden. The subjects participating in this study will have provided informed consent for their data to be linked to the different National data bases. The patients have also consented to their data being transferred to Uppsala Clinical Research Center, Sweden, and for identifiers to be sent to NHS England for the purpose of linkage to routine health data to be analysed in this clinical trial. However, only pseudonymised NHS England data will be transferred to the trial database after the initial linkage necessary via the randomisation module.

Registry-based randomised controlled trial design:

The R-RCT contains a framework, which allows for randomisation and blinding and enables a pragmatic data collection using existing clinical registry data with readily available trial infrastructure facilitating data and endpoint collection. The study design is intended to ensure a robust yet streamlined trial capable of producing high-quality evidence of clinical effectiveness and safety.

This is a parallel group treatment study with 2 arms that is participant and investigator blinded. The original protocol required patients admitted with MI to be consecutively screened for participation with the aim of achieving a target of at least 6,400 randomly assigned patients to study intervention (3,200 from UK, 3,200 from Sweden). After the event rate was observed to be lower than expected, the end-points were changed and patient number requirement was refined to at least 4,000. The trial was stopped when 4,098 patients were enrolled (2,839 from the UK and 1,259 from Sweden). During the course of the trial, it was observed that the number of collected primary endpoint events of cardiovascular death and hospitalisation for HF was substantially lower than anticipated. In February 2023, after a blinded event count for the primary outcome events, the trial was modified from an event-driven time-to-event approach to a hierarchical composite outcome approach to be analysed with the win ratio method. The new hierarchical composite outcome included non-cardiovascular death, investigator-reported HF event, nonfatal MI, atrial fibrillation/flutter, type 2 diabetes mellitus, New York Heart Association (NYHA) Functional Classification at the last visit, and body weight decrease of 5% or greater at the last visit, in addition to cardiovascular death and adjudicated hospitalization for HF. A new power calculation estimated the need for 4000 patients. Enrolment was ended in March 2023 with 4017 randomised patients (2839 from the UK).

Randomisation and evaluation of subsequent CV events:

All participating patients have consented to their inclusion and the use of their data for the purposes of the trial. Following randomisation, NHS England have previously received the NHS Number, Ecode (pseudo Study ID) and Inclusion Date for each consented patient on a twice-weekly basis from Uppsala Clinical Research Center (UCR). NHS England then extracted the relevant MINAP registry data for each consented patient and passed this securely to UCR where the complete electronic case record was created for the trial. From this, the final data was passed to the trial database (EntimeICE) held by AstraZeneca AB. No patient identifiable data is used in EntimeICE.

The study has utilised 2 high-quality national, population-based clinical registries:

(1) the Swedish-based Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).

(2) the UK-based Myocardial Ischaemia National Audit Project (MINAP*).

*MINAP data was shared with NHS England under the COPI Directions for dissemination for Covid purposes only. HQIP have granted permission for MINAP data to be used for this research study rather than re-sharing the same data. HQIP have advised NHS England that they are able to use the data already held. NHS England have updated the Data Provision notice to cover these circumstances.

The study was conducted in Sweden (39 hospitals) and in the United Kingdom (UK) (64 hospitals). Trial conduct at each site was monitored by AstraZeneca AB. The UK centres were connected to the MINAP clinical audit and Swedish centres to the SWEDEHEART Registry.

Patients were recruited into the study at hospital level. Once the patients had been randomised the study number/ Ecode (Pseudo Study ID) was generated and entered into the study database, known as ‘EDC/MACRO’. Participating hospitals followed patients up in accordance with Good Clinical Practice and identified and collected endpoints and reported adverse and serious adverse events.

With consent, patient identifiers (e.g. the NHS Number) were used in the randomisation/blinding process and subsequently for linkage purposes via NHS England with Civil Registrations of Death data to provide evidence of key CV end-points. In addition to MINAP, other National Cardiac Audit Programme domains, the National Audit of Percutaneous Coronary Intervention (NAPCI) and the National Adult Cardiac Surgery Audit (NACSA) will be interrogated to identify whether there is evidence that randomised patients have undergone subsequent percutaneous coronary intervention (PCI) and cardiac surgery during the designated follow-up period of the trial.

The following NHS England Data will be accessed:

· Hospital Episode Statistics

o Admitted Patient Care – necessary to seek evidence of hospitalisations for key end-points such as heart failure or acute myocardial infarction, to identify patients who have suffered these end-points but which were not identified by the enrolling research teams.

· Civil Registration Mortality – necessary to provide evidence of key CV end-points.

. Myocardial Ischaemia National Audit Project (MINAP)

The level of the Data will be pseudonymised.

The Data will be minimised as follows:

· Limited to members of the DAPA-MI consented cohort.

· Limited to HES data for each patient from date of that patient’s entry to trial to their last follow-up visit.

AstraZeneca AB is the research sponsor and the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

AstraZeneca AB relies upon two Article 6 sub-sections for the processing of Personal Data:

> Article 6(1)(c) - "processing of data in this clinical trial (for the protection of health) is that it is necessary for compliance with a legal obligation (Clinical Trial Regulations)". Processing is necessary for fulfilling the legal obligations around on-going safety evaluation and safety reporting on medicinal products, for example, adverse events and reactions, in accordance with the following clinical trials regulations:

- EU Clinical Trials Regulation (EU 536/2014)

- EU Pharmacovigilance Regulation (EC 726/2004)

- Medicines for Human Use (Clinical Trials) Regulations 2004 and any other applicable law including UK laws and statutory instruments relating to clinical trials.

> Article 6(1)(f) - "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child". AstraZeneca AB has completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS England or after a defined period on completion of the project. The data to which access is requested are proportionate and necessary to achieve those interests.

The lawful basis for processing special category data under the UK GDPR is:

Article 9 (2) (i) "processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy".

Schedule 1, Part 1 of the Data Protection Act 2018 contains specific conditions for the various employment, health and research purposes under Articles 9(2) (b), (h), (i) or (j). As, through the DARS application process (detailed below) NHS England have identified, the dissemination and processing of this data is necessary for health care purposes specifically for AstraZeneca AB to:

- drive improvements in the quality and safety of patient care.

- to improve treatment outcomes for patients.

Additionally, under GDPR Article 9 (2) (i), the Data Protection Act 2018, in Schedule 1 condition 3 stipulates a further condition. The applicant has confirmed that that in order to rely on this condition the processing will be carried out under the responsibility of a health professional.

Furthermore, the data required by AstraZeneca AB to conduct this purpose is no less intrusive to the data subject. The data required by AstraZeneca AB is pseudonymised by NHS England to minimise the risk of identification and the data required by AstraZeneca AB is being collected by NHS England from NICOR.

This potential is also supported by Healthcare Quality Improvement Partnership (HQIP), NHS England and the National Institute for Cardiovascular Outcomes Research (NICOR).

The funding is provided by AstraZeneca AB. The funding is specifically for the trial described.

Uppsala Clinical Research Center (UCR) is a processor acting under the instructions of AstraZeneca AB. UCR's role is limited to flowing cohort data for the DAPA-MI trial, and storing NHS England data on the EDC/MACRO database, before passing the final data to the trial database (EntimeICE) held by AstraZeneca AB. Analysis of the pseudonymised HES data will be undertaken by UCR on behalf of AstraZeneca AB.

UCR is a non-profit academic research organization within Uppsala University and Uppsala University Hospital. UCR is also a National Clinical Quality Registry Center assigned by SALAR (Swedish Association of Local Authorities and Regions). In all its assignments UCR follows GDPR, the national supplement laws, The Data Protection Act and The Patient Data Act, and other regulations and guidelines in relation to Clinical Quality Registries and Research. The County Council of Uppsala (the public authority responsible for health care in the Uppsala Region, including Uppsala University Hospital) is the principal for all operations within UCR, including all aspects of Personal Data Protection and GDPR compliance, ensuring that all appropriate security arrangements are in place.

Under the EU's General Data Protection Regulation (EU/2016/679), each member state must designate an agency to be responsible for supervising the application of the regulation. This supervisory authority is to be fully independent in the performance of its duties and exercise of its authority. A corresponding authority is also to be designated in accordance with the EU's directive concerning data protection for law enforcement agencies (EU/2016/680). The Swedish government has designated the Swedish Data Protection Authority (DPA) to be the supervisory authority under the General Data Protection Regulation and the data protection directive. The Swedish DPA is also the supervisory authority under the Swedish law that is to supplement the General Data Protection Regulation, the Data Protection Act (2018:218). The Swedish DPA is also to monitor and describe developments in IT regarding issues concerning privacy and technology.

More information about the Swedish Data Protection Authority and its supervision can be found here https://www.imy.se/en/about-us/contact-us/. The Swedish Data Protection Authority´s national registration number is 202100-0050.

SCORE is a UK management company contracted by AstraZeneca AB to act as a proxy for the payment of invoices relating to the work on the trial in the UK. SCORE will not have any access to any of the data within the trial, the data from NHS England, or be a part of any decision-making in relation to the running of the trial. As such, they are not listed as a Data Processor or Data Controller in this agreement. Any access to the data held under this agreement would be considered a breach of the agreement.

Uppsala Clinical Research Center (UCR) employ Rackspace UK to host the physical server upon which the trail database is stored called EDC/MACRO (Electronic Data Capture (EDC); MACRO is the name of the database – not an acronym). Rackspace UK do not access data held under this agreement as they only supply the building. 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.

The UK’s Principal Investigator is based at the University of Sheffield and is responsible for the provision of clinical leadership and ensuring that the UK centres are conducting the research in compliance with the protocol. However, University of Sheffield will not be receiving any NHS England patient data nor processing any study related data.

No other organisations are involved in the trial, either in the running of it, the processing of the data, or in any other capacity.

The Executive Committee (EC) will be responsible for the overall design, including the development of the protocol and any protocol amendments, supervision, interpretation and reporting (presentations at international congresses and publications in peer reviewed journals) of the study. The EC will make recommendations to AZ regarding early stopping or modifications of the study based on the information received from the Data Monitoring Committee (DMC). Members of this committee are all contracted to the Sponsor. These contracts are service agreements (not contracts of employment). The EC provides recommendations to the Sponsor (AstraZeneca), however AstraZeneca have confirmed the EC is not a data controller in its own right. Members of the EC have no access to record-level NHS England data.

A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above. The group had involvement in the design of the consent forms and participation information sheets used to recruit participants to the DAPA-MI trial.

In the future AstraZeneca AB - as manufacturer of Dapagliflozin - may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. Should the results of the trial favour the clinical use of Dapagliflozin as a core secondary preventive medication for patients with impaired left ventricular function following a heart attack, and regulatory approval is provided for this indication, then AstraZeneca AB will achieve a financial advantage from the trial. Results indicate a high likelihood of success.

Manuscripts of the key primary and secondary results will be submitted for peer review in high level journals as is standard for medical research. Submissions to major scientific conferences will be made, with their associated press and media releases.

Only study-level aggregate data will be reported with small number suppression as per the HES analysis guide where necessary.

PPIE involvement has been specified in the applications, mainly around the design of the patient information sheet and consent form. However, AstraZeneca AB are aware from multiple other studies of the need to communicate back to the participating patients and hospitals and this is part of their strategy. Trial Result Summaries are a short and easy to understand summary of the results of this study. These will be added to www.trialsummaries.com within 1 year of the last study participant’s last site visit. Study participating patients can visit www.trialsummaries.com website anytime to sign up to be notified via email when the trial results summary from the study is available. These can also be shared upon the participating patient’s request from their local study doctor as a printed copy of the document. Study participating patients will also receive information on the treatment they received in this study. This will be shared with them around the same time as the Trial Results Summary. Technical Information about this research study will be posted on http://astrazenecaclinicaltrials.com and http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/. These websites do not contain any information about each patient.

A description of this clinical study will be available on http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the summary of the study results when they are available. The clinical study and/or summary of study results may also be available on other websites according to the regulations of each participating country.

Should enrolment and the expected clinical events occur as per the power calculation, the internal report would be expected by September 2024 and the main publication of the trial be expected by September 2025.

Should the trial results demonstrate a clinically important result in favour of the use of Dapagliflozin, the trial sponsor will submit appropriate applications to regulatory authorities to apply for a change in the indication for the clinical use of this drug. The results could also influence national and international guidelines on the optimal secondary preventive therapy to be offered to patients with a heart attack who have impaired left ventricular function. Trial results will be disseminated via publication in peer-reviewed journals regardless of if study treatment shows benefit or not.

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The main trial results were presented at the American Heart Association meeting in November 2023 and published in the journal NEJM Evidence - James S et al, Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure; NEJM Evid. 2024;3(2) - https://evidence.nejm.org/doi/full/10.1056/EVIDoa2300286

4017 patients presenting with an acute heart attack, who were identified to have a degree of impairment to the left side heart pump function, were randomised to receive 10mg of

dapagliflozin or placebo, given once daily, in addition to standard care.

Overall, the researchers found that the participants who took dapagliflozin with standard care had improved health outcomes compared to the participants who took the placebo with standard care. To test this, the researchers kept track of different health outcomes that the participants experienced. The outcomes the researchers kept track of were:

- Death

- Hospitalization due to heart failure

- Heart attacks

- An irregular and abnormally fast heart rate (Atrial fibrillation)

- Development of type 2 diabetes

- Symptoms of heart failure

- Reduced body weight by 5% or more

All of these features are associated with worse long-term outcomes for patients with cardiovascular disease. The outcomes were ranked based on how serious they were. Then, the

researchers compared the outcomes experienced by the participants who took dapagliflozin with standard care to the outcomes experienced by the participants who took the placebo with standard care.

The researchers used this information as part of a calculation that showed whether there were any differences in the health outcomes between the 2 groups. This is called the “win ratio”. If the win ratio is more than 1, this means that dapagliflozin improved health outcomes compared to the placebo.

In this trial, the researchers found that the win ratio was 1.34. This meant that the participants who took dapagliflozin with standard care had improved health outcomes compared

to the participants who took the placebo with standard care. There were no new safety concerns identified regarding the trial medication.

Further analyses are planned to determine groups of patients that have the highest chances of benefit from this medication.

GLOSSARY:

- Clinical trial randomisation is the process of assigning patients by chance to groups that receive different treatments.

- myocardial infarction (MI) is the clinical term for a heart attack.

- Standard of Care (SoC) therapies - this is treatment that is accepted by medical experts as the most appropriate for a certain type of disease in a particular setting and is widely used by healthcare professionals. Also called best practice.

- Ecode - this refers the the study's pseudonymised Study ID used to track patients without identifying them.

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Approximately 7 million individuals suffer a heart attack (also called a myocardial infarction (MI)) annually, and survivors of MI remain at high risk for new major adverse cardiovascular (CV) events, including CV death and heart failure (HF). The development of heart failure following an MI is strongly associated with incapacitating symptoms, poor functional status, reduced health-related quality of life and unfavourable long-term prognosis. HF is also one of the leading causes of all hospital admissions, generating substantial costs for health care systems. Therefore, MI therapies that could prevent the development of heart failure as well as re-occurrence of major CV events represent a large and unmet medical need.

This study will evaluate the effect of the drug called dapagliflozin (10 mg) versus a placebo, given once daily, in addition to Standard of Care (SoC) therapies for patients with MI, for the prevention of hospitalisation for heart failure or CV death. The study seeks to determine dapagliflozin’s potential in the early prevention of serious complications, hospitalisations for heart failure or CV death, immediately following an MI.

This multi-centre clinical trial has been designed as a registry-based randomised controlled trial (R-RCT) which combines traditional study design elements within a pragmatic trial framework to provide high quality evidence on the potential benefit of dapagliflozin when administered in the early phase after MI. Traditional design elements such as randomisation and double blinding will minimise potential bias while the pragmatic and streamlined trial elements are expected to capture a broad MI population that will increase external validity and generalisability of study results and at the same time limit study burden on patients and investigators by usage of existing healthcare infrastructure and enabled by continuous clinical quality registries/clinical audits used in routine health care.

Ethics committee approval and patient consent:

The trial has been approved by the relevant Ethics Committees in the UK and Sweden. The subjects participating in this study will have provided informed consent for their data to be linked to the different National data bases. The patients have also consented to their data being transferred to Uppsala Clinical Research Center, Sweden, and for identifiers to be sent to NHS England for the purpose of linkage to routine health data to be analysed in this clinical trial. However, only pseudonymised NHS England data will be transferred to the trial database after the initial linkage necessary via the randomisation module.

Registry-based randomised controlled trial design:

The R-RCT contains a framework, which allows for randomisation and blinding and enables a pragmatic data collection using existing clinical registry data with readily available trial infrastructure facilitating data and endpoint collection. The study design is intended to ensure a robust yet streamlined trial capable of producing high-quality evidence of clinical effectiveness and safety.

This is a parallel group treatment study with 2 arms that is participant and investigator blinded. The patients admitted with MI will be consecutively screened for participation to achieve at least 6,400 randomly assigned to study intervention (3,200 from UK, 3,200 from Sweden).

As of February 2022, 934 patients had been enrolled in the UK. The rates have ranged between 25-50 a week over the last few months of 2021 (about 35-40 a week on average) but more sites have just been started up so the study team are hopeful that the weekly numbers will be 40-50 on average going forward with a hope that they recruit the remaining participants in 2022.

The anticipated duration of the study is approximately 30 months with an estimated median treatment period for a patient of 21 months. The study closure procedures will be initiated when the predetermined number of primary endpoints are predicted to have occurred (n = 722) i.e., the primary analysis censoring date. The study duration may be changed if the event rate or randomisation rate is different than anticipated. The study may be terminated early if either a clear beneficial or harmful effect of the study treatment is detected during the Data Monitoring Committee (DMC) review.

Randomisation and evaluation of subsequent CV events:

All participating patients will consent to their inclusion and the use of their data for the purposes of the trial. Following randomisation, NHS England will receive the NHS Number, Ecode (pseudo Study ID) and Inclusion Date for each consented patient on a twice-weekly basis from Uppsala Clinical Research Center (UCR). NHS England will then extract the relevant MINAP registry data for each consented patient and pass this securely to UCR where the complete electronic case record will be created for the trial. From this, the final data will be passed to the trial database (EntimeICE) held by AstraZeneca AB. No patient identifiable data is used in EntimeICE.

The study will utilise 2 high-quality national, population-based clinical registries:

(1) the Swedish-based Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).

(2) the UK-based Myocardial Ischaemia National Audit Project (MINAP*).

*MINAP data was shared with NHS England under the COPI Directions for dissemination for Covid purposes only. HQIP have granted permission for MINAP data to be used for this research study rather than re-sharing the same data. HQIP have advised NHS England that they are able to use the data already held. NHS England have updated the Data Provision notice to cover these circumstances.

Patients will be recruited into the study at hospital level. For the purposes of the original application (v0), recruitment will take place in around 50 hospitals based in England. Once the patients have been randomised the study number/ Ecode (Pseudo Study ID) will be generated and this will be entered into the study database, known as ‘EDC/MACRO’. Participating hospitals will follow patients up in accordance with Good Clinical Practice and identify and collect end-points and report adverse and serious adverse events.

With consent, patient identifiers (e.g. the NHS Number) will be required for the randomisation/blinding process and subsequently for linkage purposes via NHS England with Civil Registrations of Death data to provide evidence of key CV end-points. In addition to MINAP, other National Cardiac Audit Programme domains, the National Audit of Percutaneous Coronary Intervention (NAPCI) and the National Adult Cardiac Surgery Audit (NACSA) will be interrogated to identify whether there is evidence that randomised patients have undergone subsequent percutaneous coronary intervention (PCI) and cardiac surgery during the designated follow-up period of the trial.

This agreement renews the request for MINAP and Civil Registration (Deaths) datasets for another year, which includes Welsh patient data in the twice-weekly data disseminations to Uppsala Clinical Research Center (UCR).

The anonymised trial data generated from the MINAP registries is prepared in blinded form for the trial's Data Monitoring Committee (DMC). The study team feel it is essential that data flows to the EDC/MACRO database on all patients, including patients enrolled in Wales, to support the work of the DMC, failure of which would threaten the successful completion of the trial.

GDPR Lawful Basis for Processing of data

AstraZeneca AB relies upon two Article 6 sub-sections for the processing of Personal Data:

> Article 6(1)(c) - "processing of data in this clinical trial (for the protection of health) is that it is necessary for compliance with a legal obligation (Clinical Trial Regulations)". Processing is necessary for fulfilling the legal obligations around on-going safety evaluation and safety reporting on medicinal products, for example, adverse events and reactions, in accordance with the following clinical trials regulations:

- EU Clinical Trials Regulation (EU 536/2014)

- EU Pharmacovigilance Regulation (EC 726/2004)

- Medicines for Human Use (Clinical Trials) Regulations 2004 and any other applicable law including UK laws and statutory instruments relating to clinical trials.

> Article 6(1)(f) - "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child". AstraZeneca AB has completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS England or after a defined period on completion of the project. The data to which access is requested are proportionate and necessary to achieve those interests. NHS England have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally, as health data is a special category of personal data, AstraZeneca additionally relies upon Article 9 (2) (i) "processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy".

Schedule 1, Part 1 of the Data Protection Act 2018 contains specific conditions for the various employment, health and research purposes under Articles 9(2) (b), (h), (i) or (j). As, through the DARS application process (detailed below) NHS England have identified, the dissemination and processing of this data is necessary for health care purposes specifically for AstraZeneca AB to:

- drive improvements in the quality and safety of patient care.

- to improve treatment outcomes for patients.

Additionally, under GDPR Article 9 (2) (i), the Data Protection Act 2018, in Schedule 1 condition 3 stipulates a further condition. The applicant has confirmed that that in order to rely on this condition the processing will be carried out under the responsibility of a health professional.

Furthermore, the data required by AstraZeneca AB to conduct this purpose is no less intrusive to the data subject. The data required by AstraZeneca AB is pseudonymised by NHS England to minimise the risk of identification and the data required by AstraZeneca AB is being collected by NHS England from NICOR.

This potential is also supported by Healthcare Quality Improvement Partnership (HQIP) and National Institute for Cardiovascular Outcomes Research (NICOR)

Trial coordination:

The study is funded by AstraZeneca AB, who are also the sole Controller for this agreement. The study will be conducted in Sweden and in the United Kingdom (UK) - with 50 sites in each country. Trial conduct at each site will be monitored by AstraZeneca AB. The UK centres will be connected to the MINAP clinical audit and Swedish centres to the SWEDEHEART Registry. The recruitment period is planned for 18 months during which 6,400 patients will be randomised. The total trial period is planned for 30 months. AstraZeneca AB are also a Processor for this agreement.

The Executive Committee (EC) will be responsible for the overall design, including the development of the protocol and any protocol amendments, supervision, interpretation and reporting (presentations at international congresses and publications in peer reviewed journals) of the study. The EC will make recommendations to AZ regarding early stopping or modifications of the study based on the information received from the Data Monitoring Committee (DMC). Members of this committee are all contracted to the Sponsor. These contracts are service agreements (not contracts of employment). The EC provides recommendations to the Sponsor (AstraZeneca), however AstraZeneca have confirmed the EC is not a data controller in its own right. Members of the EC have no access to record-level NHS England data.

The UK’s Principal Investigator is based at the University of Sheffield and is responsible for the provision of clinical leadership and ensuring that the UK centres are conducting the research in compliance with the protocol. However, University of Sheffield will not be receiving any NHS England patient data nor processing any study related data.

Uppsala Clinical Research Center (UCR) is a Processor for this agreement. UCR is a non-profit academic research organization within Uppsala University and Uppsala University Hospital. UCR is also a National Clinical Quality Registry Center assigned by SALAR (Swedish Association of Local Authorities and Regions). In all its assignments UCR follows GDPR, the national supplement laws, The Data Protection Act and The Patient Data Act, and other regulations and guidelines in relation to Clinical Quality Registries and Research. The County Council of Uppsala (the public authority responsible for health care in the Uppsala Region, including Uppsala University Hospital) is the principal for all operations within UCR, including all aspects of Personal Data Protection and GDPR compliance, ensuring that all appropriate security arrangements are in place.

Under the EU's General Data Protection Regulation (EU/2016/679), each member state must designate an agency to be responsible for supervising the application of the regulation. This supervisory authority is to be fully independent in the performance of its duties and exercise of its authority. A corresponding authority is also to be designated in accordance with the EU's directive concerning data protection for law enforcement agencies (EU/2016/680). The Swedish government has designated the Swedish Data Protection Authority (DPA) to be the supervisory authority under the General Data Protection Regulation and the data protection directive. The Swedish DPA is also the supervisory authority under the Swedish law that is to supplement the General Data Protection Regulation, the Data Protection Act (2018:218). The Swedish DPA is also to monitor and describe developments in IT regarding issues concerning privacy and technology.

More information about the Swedish Data Protection Authority and its supervision can be found here https://www.imy.se/en/about-us/contact-us/. The Swedish Data Protection Authority´s national registration number is 202100-0050.

SCORE is a UK management company contracted by AstraZeneca AB to act as a proxy for the payment of invoices relating to the work on the trial in the UK. SCORE will not have any access to any of the data within the trial, the data from NHS England, or be a part of any decision-making in relation to the running of the trial. As such, they are not listed as a Data Processor or Data Controller in this agreement. Any access to the data held under this agreement would be considered a breach of the agreement.

Uppsala Clinical Research Center (UCR) employ Rackspace UK to host the physical server upon which the trail database is stored called EDC/MACRO (Electronic Data Capture (EDC); MACRO is the name of the database – not an acronym). Rackspace UK do not access data held under this agreement as they only supply the building. 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.

No other organisations are involved in the trial, either in the running of it, the processing of the data, or in any other capacity.

In the future AstraZeneca AB - as manufacturer of Dapagliflozin - may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. Should the results of the trial favour the clinical use of Dapagliflozin as a core secondary preventive medication for patients with impaired left ventricular function following a heart attack, and regulatory approval is provided for this indication, then AstraZeneca AB will achieve a financial advantage from the trial.

Manuscripts of the key primary and secondary results will be submitted for peer review in high level journals as is standard for medical research. Submissions to major scientific conferences will be made, with their associated press and media releases.

Only study-level aggregate data will be reported with small number suppression as per the HES analysis guide where necessary.

PPIE involvement has been specified in the applications, mainly around the design of the patient information sheet and consent form. However, AstraZeneca AB are aware from multiple other studies of the need to communicate back to the participating patients and hospitals and this is part of their strategy. Trial Result Summaries are a short and easy to understand summary of the results of this study. These will be added to www.trialsummaries.com within 1 year of the last study participant’s last site visit. Study participating patients can visit www.trialsummaries.com website anytime to sign up to be notified via email when the trial results summary from the study is available. These can also be shared upon the participating patient’s request from their local study doctor as a printed copy of the document. Study participating patients will also receive information on the treatment they received in this study. This will be shared with them around the same time as the Trial Results Summary. Technical Information about this research study will be posted on http://astrazenecaclinicaltrials.com and http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/. These websites do not contain any information about each patient.

A description of this clinical study will be available on http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the summary of the study results when they are available. The clinical study and/or summary of study results may also be available on other websites according to the regulations of each participating country.

Should enrolment and the expected clinical events occur as per the power calculation, the internal report would be expected by September 2024 and the main publication of the trial be expected by September 2025.

Should the trial results demonstrate a clinically important result in favour of the use of Dapagliflozin, the trial sponsor will submit appropriate applications to regulatory authorities to apply for a change in the indication for the clinical use of this drug. The results could also influence national and international guidelines on the optimal secondary preventive therapy to be offered to patients with a heart attack who have impaired left ventricular function. Trial results will be disseminated via publication in peer-reviewed journals regardless of if study treatment shows benefit or not.

-----------------

The main trial results were presented at the American Heart Association meeting in November 2023 and published in the journal NEJM Evidence - James S et al, Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure; NEJM Evid. 2024;3(2) - https://evidence.nejm.org/doi/full/10.1056/EVIDoa2300286

4017 patients presenting with an acute heart attack, who were identified to have a degree of impairment to the left side heart pump function, were randomised to receive 10mg of

dapagliflozin or placebo, given once daily, in addition to standard care.

Overall, the researchers found that the participants who took dapagliflozin with standard care had improved health outcomes compared to the participants who took the placebo with standard care. To test this, the researchers kept track of different health outcomes that the participants experienced. The outcomes the researchers kept track of were:

- Death

- Hospitalization due to heart failure

- Heart attacks

- An irregular and abnormally fast heart rate (Atrial fibrillation)

- Development of type 2 diabetes

- Symptoms of heart failure

- Reduced body weight by 5% or more

All of these features are associated with worse long-term outcomes for patients with cardiovascular disease. The outcomes were ranked based on how serious they were. Then, the

researchers compared the outcomes experienced by the participants who took dapagliflozin with standard care to the outcomes experienced by the participants who took the placebo with standard care.

The researchers used this information as part of a calculation that showed whether there were any differences in the health outcomes between the 2 groups. This is called the “win ratio”. If the win ratio is more than 1, this means that dapagliflozin improved health outcomes compared to the placebo.

In this trial, the researchers found that the win ratio was 1.34. This meant that the participants who took dapagliflozin with standard care had improved health outcomes compared

to the participants who took the placebo with standard care. There were no new safety concerns identified regarding the trial medication.

Further analyses are planned to determine groups of patients that have the highest chances of benefit from this medication.

GLOSSARY:

- Clinical trial randomisation is the process of assigning patients by chance to groups that receive different treatments.

- myocardial infarction (MI) is the clinical term for a heart attack.

- Standard of Care (SoC) therapies - this is treatment that is accepted by medical experts as the most appropriate for a certain type of disease in a particular setting and is widely used by healthcare professionals. Also called best practice.

- Ecode - this refers the the study's pseudonymised Study ID used to track patients without identifying them.

**************************

Approximately 7 million individuals suffer a heart attack (also called a myocardial infarction (MI)) annually, and survivors of MI remain at high risk for new major adverse cardiovascular (CV) events, including CV death and heart failure (HF). The development of heart failure following an MI is strongly associated with incapacitating symptoms, poor functional status, reduced health-related quality of life and unfavourable long-term prognosis. HF is also one of the leading causes of all hospital admissions, generating substantial costs for health care systems. Therefore, MI therapies that could prevent the development of heart failure as well as re-occurrence of major CV events represent a large and unmet medical need.

This study will evaluate the effect of the drug called dapagliflozin (10 mg) versus a placebo, given once daily, in addition to Standard of Care (SoC) therapies for patients with MI, for the prevention of hospitalisation for heart failure or CV death. The study seeks to determine dapagliflozin’s potential in the early prevention of serious complications, hospitalisations for heart failure or CV death, immediately following an MI.

This multi-centre clinical trial has been designed as a registry-based randomised controlled trial (R-RCT) which combines traditional study design elements within a pragmatic trial framework to provide high quality evidence on the potential benefit of dapagliflozin when administered in the early phase after MI. Traditional design elements such as randomisation and double blinding will minimise potential bias while the pragmatic and streamlined trial elements are expected to capture a broad MI population that will increase external validity and generalisability of study results and at the same time limit study burden on patients and investigators by usage of existing healthcare infrastructure and enabled by continuous clinical quality registries/clinical audits used in routine health care.

Ethics committee approval and patient consent:

The trial has been approved by the relevant Ethics Committees in the UK and Sweden. The subjects participating in this study will have provided informed consent for their data to be linked to the different National data bases. The patients have also consented to their data being transferred to Uppsala Clinical Research Center, Sweden, and for identifiers to be sent to NHS England for the purpose of linkage to routine health data to be analysed in this clinical trial. However, only pseudonymised NHS England data will be transferred to the trial database after the initial linkage necessary via the randomisation module.

Registry-based randomised controlled trial design:

The R-RCT contains a framework, which allows for randomisation and blinding and enables a pragmatic data collection using existing clinical registry data with readily available trial infrastructure facilitating data and endpoint collection. The study design is intended to ensure a robust yet streamlined trial capable of producing high-quality evidence of clinical effectiveness and safety.

This is a parallel group treatment study with 2 arms that is participant and investigator blinded. The patients admitted with MI will be consecutively screened for participation to achieve at least 6,400 randomly assigned to study intervention (3,200 from UK, 3,200 from Sweden).

As of February 2022, 934 patients had been enrolled in the UK. The rates have ranged between 25-50 a week over the last few months of 2021 (about 35-40 a week on average) but more sites have just been started up so the study team are hopeful that the weekly numbers will be 40-50 on average going forward with a hope that they recruit the remaining participants in 2022.

The anticipated duration of the study is approximately 30 months with an estimated median treatment period for a patient of 21 months. The study closure procedures will be initiated when the predetermined number of primary endpoints are predicted to have occurred (n = 722) i.e., the primary analysis censoring date. The study duration may be changed if the event rate or randomisation rate is different than anticipated. The study may be terminated early if either a clear beneficial or harmful effect of the study treatment is detected during the Data Monitoring Committee (DMC) review.

Randomisation and evaluation of subsequent CV events:

All participating patients will consent to their inclusion and the use of their data for the purposes of the trial. Following randomisation, NHS England will receive the NHS Number, Ecode (pseudo Study ID) and Inclusion Date for each consented patient on a twice-weekly basis from Uppsala Clinical Research Center (UCR). NHS England will then extract the relevant MINAP registry data for each consented patient and pass this securely to UCR where the complete electronic case record will be created for the trial. From this, the final data will be passed to the trial database (EntimeICE) held by AstraZeneca AB. No patient identifiable data is used in EntimeICE.

The study will utilise 2 high-quality national, population-based clinical registries:

(1) the Swedish-based Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).

(2) the UK-based Myocardial Ischaemia National Audit Project (MINAP*).

*MINAP data was shared with NHS England under the COPI Directions for dissemination for Covid purposes only. HQIP have granted permission for MINAP data to be used for this research study rather than re-sharing the same data. HQIP have advised NHS England that they are able to use the data already held. NHS England have updated the Data Provision notice to cover these circumstances.

Patients will be recruited into the study at hospital level. For the purposes of the original application (v0), recruitment will take place in around 50 hospitals based in England. Once the patients have been randomised the study number/ Ecode (Pseudo Study ID) will be generated and this will be entered into the study database, known as ‘EDC/MACRO’. Participating hospitals will follow patients up in accordance with Good Clinical Practice and identify and collect end-points and report adverse and serious adverse events.

With consent, patient identifiers (e.g. the NHS Number) will be required for the randomisation/blinding process and subsequently for linkage purposes via NHS England with Civil Registrations of Death data to provide evidence of key CV end-points. In addition to MINAP, other National Cardiac Audit Programme domains, the National Audit of Percutaneous Coronary Intervention (NAPCI) and the National Adult Cardiac Surgery Audit (NACSA) will be interrogated to identify whether there is evidence that randomised patients have undergone subsequent percutaneous coronary intervention (PCI) and cardiac surgery during the designated follow-up period of the trial.

This agreement renews the request for MINAP and Civil Registration (Deaths) datasets for another year, which includes Welsh patient data in the twice-weekly data disseminations to Uppsala Clinical Research Center (UCR).

The anonymised trial data generated from the MINAP registries is prepared in blinded form for the trial's Data Monitoring Committee (DMC). The study team feel it is essential that data flows to the EDC/MACRO database on all patients, including patients enrolled in Wales, to support the work of the DMC, failure of which would threaten the successful completion of the trial.

GDPR Lawful Basis for Processing of data

AstraZeneca AB relies upon two Article 6 sub-sections for the processing of Personal Data:

> Article 6(1)(c) - "processing of data in this clinical trial (for the protection of health) is that it is necessary for compliance with a legal obligation (Clinical Trial Regulations)". Processing is necessary for fulfilling the legal obligations around on-going safety evaluation and safety reporting on medicinal products, for example, adverse events and reactions, in accordance with the following clinical trials regulations:

- EU Clinical Trials Regulation (EU 536/2014)

- EU Pharmacovigilance Regulation (EC 726/2004)

- Medicines for Human Use (Clinical Trials) Regulations 2004 and any other applicable law including UK laws and statutory instruments relating to clinical trials.

> Article 6(1)(f) - "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child". AstraZeneca AB has completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS England or after a defined period on completion of the project. The data to which access is requested are proportionate and necessary to achieve those interests. NHS England have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally, as health data is a special category of personal data, AstraZeneca additionally relies upon Article 9 (2) (i) "processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy".

Schedule 1, Part 1 of the Data Protection Act 2018 contains specific conditions for the various employment, health and research purposes under Articles 9(2) (b), (h), (i) or (j). As, through the DARS application process (detailed below) NHS England have identified, the dissemination and processing of this data is necessary for health care purposes specifically for AstraZeneca AB to:

- drive improvements in the quality and safety of patient care.

- to improve treatment outcomes for patients.

Additionally, under GDPR Article 9 (2) (i), the Data Protection Act 2018, in Schedule 1 condition 3 stipulates a further condition. The applicant has confirmed that that in order to rely on this condition the processing will be carried out under the responsibility of a health professional.

Furthermore, the data required by AstraZeneca AB to conduct this purpose is no less intrusive to the data subject. The data required by AstraZeneca AB is pseudonymised by NHS England to minimise the risk of identification and the data required by AstraZeneca AB is being collected by NHS England from NICOR.

This potential is also supported by Healthcare Quality Improvement Partnership (HQIP) and National Institute for Cardiovascular Outcomes Research (NICOR)

Trial coordination:

The study is funded by AstraZeneca AB, who are also the sole Controller for this agreement. The study will be conducted in Sweden and in the United Kingdom (UK) - with 50 sites in each country. Trial conduct at each site will be monitored by AstraZeneca AB. The UK centres will be connected to the MINAP clinical audit and Swedish centres to the SWEDEHEART Registry. The recruitment period is planned for 18 months during which 6,400 patients will be randomised. The total trial period is planned for 30 months. AstraZeneca AB are also a Processor for this agreement.

The Executive Committee (EC) will be responsible for the overall design, including the development of the protocol and any protocol amendments, supervision, interpretation and reporting (presentations at international congresses and publications in peer reviewed journals) of the study. The EC will make recommendations to AZ regarding early stopping or modifications of the study based on the information received from the Data Monitoring Committee (DMC). Members of this committee are all contracted to the Sponsor. These contracts are service agreements (not contracts of employment). The EC provides recommendations to the Sponsor (AstraZeneca), however AstraZeneca have confirmed the EC is not a data controller in its own right. Members of the EC have no access to record-level NHS England data.

The UK’s Principal Investigator is based at the University of Sheffield and is responsible for the provision of clinical leadership and ensuring that the UK centres are conducting the research in compliance with the protocol. However, University of Sheffield will not be receiving any NHS England patient data nor processing any study related data.

Uppsala Clinical Research Center (UCR) is a Processor for this agreement. UCR is a non-profit academic research organization within Uppsala University and Uppsala University Hospital. UCR is also a National Clinical Quality Registry Center assigned by SALAR (Swedish Association of Local Authorities and Regions). In all its assignments UCR follows GDPR, the national supplement laws, The Data Protection Act and The Patient Data Act, and other regulations and guidelines in relation to Clinical Quality Registries and Research. The County Council of Uppsala (the public authority responsible for health care in the Uppsala Region, including Uppsala University Hospital) is the principal for all operations within UCR, including all aspects of Personal Data Protection and GDPR compliance, ensuring that all appropriate security arrangements are in place.

Under the EU's General Data Protection Regulation (EU/2016/679), each member state must designate an agency to be responsible for supervising the application of the regulation. This supervisory authority is to be fully independent in the performance of its duties and exercise of its authority. A corresponding authority is also to be designated in accordance with the EU's directive concerning data protection for law enforcement agencies (EU/2016/680). The Swedish government has designated the Swedish Data Protection Authority (DPA) to be the supervisory authority under the General Data Protection Regulation and the data protection directive. The Swedish DPA is also the supervisory authority under the Swedish law that is to supplement the General Data Protection Regulation, the Data Protection Act (2018:218). The Swedish DPA is also to monitor and describe developments in IT regarding issues concerning privacy and technology.

More information about the Swedish Data Protection Authority and its supervision can be found here https://www.imy.se/en/about-us/contact-us/. The Swedish Data Protection Authority´s national registration number is 202100-0050.

SCORE is a UK management company contracted by AstraZeneca AB to act as a proxy for the payment of invoices relating to the work on the trial in the UK. SCORE will not have any access to any of the data within the trial, the data from NHS England, or be a part of any decision-making in relation to the running of the trial. As such, they are not listed as a Data Processor or Data Controller in this agreement. Any access to the data held under this agreement would be considered a breach of the agreement.

Uppsala Clinical Research Center (UCR) employ Rackspace UK to host the physical server upon which the trail database is stored called EDC/MACRO (Electronic Data Capture (EDC); MACRO is the name of the database – not an acronym). Rackspace UK do not access data held under this agreement as they only supply the building. 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.

No other organisations are involved in the trial, either in the running of it, the processing of the data, or in any other capacity.

In the future AstraZeneca AB - as manufacturer of Dapagliflozin - may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. Should the results of the trial favour the clinical use of Dapagliflozin as a core secondary preventive medication for patients with impaired left ventricular function following a heart attack, and regulatory approval is provided for this indication, then AstraZeneca AB will achieve a financial advantage from the trial.

Manuscripts of the key primary and secondary results will be submitted for peer review in high level journals as is standard for medical research. Submissions to major scientific conferences will be made, with their associated press and media releases.

Only study-level aggregate data will be reported with small number suppression as per the HES analysis guide where necessary.

PPIE involvement has been specified in the applications, mainly around the design of the patient information sheet and consent form. However, AstraZeneca AB are aware from multiple other studies of the need to communicate back to the participating patients and hospitals and this is part of their strategy. Trial Result Summaries are a short and easy to understand summary of the results of this study. These will be added to www.trialsummaries.com within 1 year of the last study participant’s last site visit. Study participating patients can visit www.trialsummaries.com website anytime to sign up to be notified via email when the trial results summary from the study is available. These can also be shared upon the participating patient’s request from their local study doctor as a printed copy of the document. Study participating patients will also receive information on the treatment they received in this study. This will be shared with them around the same time as the Trial Results Summary. Technical Information about this research study will be posted on http://astrazenecaclinicaltrials.com and http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/. These websites do not contain any information about each patient.

A description of this clinical study will be available on http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the summary of the study results when they are available. The clinical study and/or summary of study results may also be available on other websites according to the regulations of each participating country.

Should enrolment and the expected clinical events occur as per the power calculation, the internal report would be expected by September 2024 and the main publication of the trial be expected by September 2025.

Should the trial results demonstrate a clinically important result in favour of the use of Dapagliflozin, the trial sponsor will submit appropriate applications to regulatory authorities to apply for a change in the indication for the clinical use of this drug. The results could also influence national and international guidelines on the optimal secondary preventive therapy to be offered to patients with a heart attack who have impaired left ventricular function. Trial results will be disseminated via publication in peer-reviewed journals regardless of if study treatment shows benefit or not.

The concept that data can be accumulated for the trial from the national registries in both the UK and Sweden has proved successful, and the data flows have been established as designed. There is now a need to provide the quarterly mortality data to ensure that these outcomes are tracked (not previously disseminated).

Recruitment to the study has been good despite a pandemic, and thus there is evidence to support that the principles around the R-RCT are realistic.

GLOSSARY:

- Clinical trial randomisation is the process of assigning patients by chance to groups that receive different treatments.

- myocardial infarction (MI) is the clinical term for a heart attack.

- Standard of Care (SoC) therapies - this is treatment that is accepted by medical experts as the most appropriate for a certain type of disease in a particular setting and is widely used by healthcare professionals. Also called best practice.

- Ecode - this refers the the study's pseudonymised Study ID used to track patients without identifying them.

**************************

Approximately 7 million individuals suffer a heart attack (also called a myocardial infarction (MI)) annually, and survivors of MI remain at high risk for new major adverse cardiovascular (CV) events, including CV death and heart failure (HF). The development of heart failure following an MI is strongly associated with incapacitating symptoms, poor functional status, reduced health-related quality of life and unfavourable long-term prognosis. HF is also one of the leading causes of all hospital admissions, generating substantial costs for health care systems. Therefore, MI therapies that could prevent the development of heart failure as well as re-occurrence of major CV events represent a large and unmet medical need.

This study will evaluate the effect of the drug called dapagliflozin (10 mg) versus a placebo, given once daily, in addition to Standard of Care (SoC) therapies for patients with MI, for the prevention of hospitalisation for heart failure or CV death. The study seeks to determine dapagliflozin’s potential in the early prevention of serious complications, hospitalisations for heart failure or CV death, immediately following an MI.

This multi-centre clinical trial has been designed as a registry-based randomised controlled trial (R-RCT) which combines traditional study design elements within a pragmatic trial framework to provide high quality evidence on the potential benefit of dapagliflozin when administered in the early phase after MI. Traditional design elements such as randomisation and double blinding will minimise potential bias while the pragmatic and streamlined trial elements are expected to capture a broad MI population that will increase external validity and generalisability of study results and at the same time limit study burden on patients and investigators by usage of existing healthcare infrastructure and enabled by continuous clinical quality registries/clinical audits used in routine health care.

Ethics committee approval and patient consent:

The trial has been approved by the relevant Ethics Committees in the UK and Sweden. The subjects participating in this study will have provided informed consent for their data to be linked to the different National data bases. The patients have also consented to their data being transferred to Uppsala Clinical Research Center, Sweden, and for identifiers to be sent to NHS Digital for the purpose of linkage to routine health data to be analysed in this clinical trial. However, only pseudonymised NHS Digital data will be transferred to the trial database after the initial linkage necessary via the randomisation module.

Registry-based randomised controlled trial design:

The R-RCT contains a framework, which allows for randomisation and blinding and enables a pragmatic data collection using existing clinical registry data with readily available trial infrastructure facilitating data and endpoint collection. The study design is intended to ensure a robust yet streamlined trial capable of producing high-quality evidence of clinical effectiveness and safety.

This is a parallel group treatment study with 2 arms that is participant and investigator blinded. The patients admitted with MI will be consecutively screened for participation to achieve at least 6,400 randomly assigned to study intervention (3,200 from UK, 3,200 from Sweden).

*** UPDATE FOR VERSION 1 OF AGREEMENT - FEB 2022: On 14 February 2022, 934 patients had been enrolled in the UK. The rates have ranged between 25-50 a week over the last few months of 2021 (about 35-40 a week on average) but more sites have just been started up so the study team are hopeful that the weekly numbers will be 40-50 on average going forward with a hope that they recruit the remaining participants in 2022. ****

The anticipated duration of the study is approximately 30 months with an estimated median treatment period for a patient of 21 months. The study closure procedures will be initiated when the predetermined number of primary endpoints are predicted to have occurred (n = 722) i.e., the primary analysis censoring date. The study duration may be changed if the event rate or randomisation rate is different than anticipated. The study may be terminated early if either a clear beneficial or harmful effect of the study treatment is detected during the Data Monitoring Committee (DMC) review.

Randomisation and evaluation of subsequent CV events:

All participating patients will consent to their inclusion and the use of their data for the purposes of the trial. Following randomisation, NHS Digital will receive the NHS Number, Ecode (pseudo Study ID) and Inclusion Date for each consented patient on a twice-weekly basis from Uppsala Clinical Research Center (UCR). NHS Digital will then extract the relevant MINAP registry data for each consented patient and pass this securely to UCR where the complete electronic case record will be created for the trial. From this, the final data will be passed to the trial database (EntimeICE) held by AstraZeneca AB. No patient identifiable data is used in EntimeICE.

The study will utilise 2 high-quality national, population-based clinical registries:

(1) the Swedish-based Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).

(2) the UK-based Myocardial Ischaemia National Audit Project (MINAP*).

*MINAP data was shared with NHS Digital under the COPI Directions for dissemination for Covid purposes only. HQIP have granted permission for MINAP data to be used for this research study rather than re-sharing the same data. HQIP have advised NHS Digital that they are able to use the data already held. NHS Digital have updated the Data Provision notice to cover these circumstances.

Patients will be recruited into the study at hospital level. For the purposes of the original application (v0), recruitment will take place in around 50 hospitals based in England. Once the patients have been randomised the study number/ Ecode (Pseudo Study ID) will be generated and this will be entered into the study database, known as ‘EDC/MACRO’. Participating hospitals will follow patients up in accordance with Good Clinical Practice and identify and collect end-points and report adverse and serious adverse events.

With consent, patient identifiers (e.g. the NHS Number) will be required for the randomisation/blinding process and subsequently for linkage purposes via NHS Digital with Civil Registrations of Death data to provide evidence of key CV end-points. In addition to MINAP, other National Cardiac Audit Programme domains, the National Audit of Percutaneous Coronary Intervention (NAPCI) and the National Adult Cardiac Surgery Audit (NACSA) will be interrogated to identify whether there is evidence that randomised patients have undergone subsequent percutaneous coronary intervention (PCI) and cardiac surgery during the designated follow-up period of the trial.

****** This version of the agreement (v1) renews the request for MINAP and Civil Registration (Deaths) datasets for another year, but also includes the amendment that Welsh patient data should be included in the twice-weekly data disseminations to Uppsala Clinical Research Center (UCR).

The anonymised trial data generated from the MINAP registries is prepared in blinded form for the trial's Data Monitoring Committee (DMC). The study team feel it is essential that data flows to the EDC/MACRO database on all patients, including patients enrolled in Wales, to support the work of the DMC, failure of which would threaten the successful completion of the trial. ******

GDPR Lawful Basis for Processing of data

AstraZeneca AB relies upon two Article 6 sub-sections for the processing of Personal Data:

> Article 6(1)(c) - "processing of data in this clinical trial (for the protection of health) is that it is necessary for compliance with a legal obligation (Clinical Trial Regulations)". Processing is necessary for fulfilling the legal obligations around on-going safety evaluation and safety reporting on medicinal products, for example, adverse events and reactions, in accordance with the following clinical trials regulations:

- EU Clinical Trials Regulation (EU 536/2014)

- EU Pharmacovigilance Regulation (EC 726/2004)

- Medicines for Human Use (Clinical Trials) Regulations 2004 and any other applicable law including UK laws and statutory instruments relating to clinical trials.

> Article 6(1)(f) - "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child". AstraZeneca AB has completed a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project. The data to which access is requested are proportionate and necessary to achieve those interests. NHS Digital have compared this LIA against the ICO’s checklist (https://ico.org.uk/for-organisations/guide-to-the-general-data-protection-regulation-gdpr/lawful-basis-for-processing/legitimate-interests/) and are content that all requirements are met.

Additionally, as health data is a special category of personal data, AstraZeneca additionally relies upon Article 9 (2) (i) "processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy".

Schedule 1, Part 1 of the Data Protection Act 2018 contains specific conditions for the various employment, health and research purposes under Articles 9(2) (b), (h), (i) or (j). As, through the DARS application process (detailed below) NHS Digital have identified, the dissemination and processing of this data is necessary for health care purposes specifically for AstraZeneca AB to:

- drive improvements in the quality and safety of patient care.

- to improve treatment outcomes for patients.

Additionally, under GDPR Article 9 (2) (i), the Data Protection Act 2018, in Schedule 1 condition 3 stipulates a further condition. The applicant has confirmed that that in order to rely on this condition the processing will be carried out under the responsibility of a health professional.

Furthermore, the data required by AstraZeneca AB to conduct this purpose is no less intrusive to the data subject. The data required by AstraZeneca AB is pseudonymised by NHS Digital to minimise the risk of identification and the data required by AstraZeneca AB is being collected by NHS Digital from NICOR.

This potential is also supported by Healthcare Quality Improvement Partnership (HQIP) and National Institute for Cardiovascular Outcomes Research (NICOR)

Trial coordination:

The study is funded by AstraZeneca AB, who are also the sole Data Controller for this agreement. The study will be conducted in Sweden and in the United Kingdom (UK) - with 50 sites in each country. Trial conduct at each site will be monitored by AstraZeneca AB. The UK centres will be connected to the MINAP clinical audit and Swedish centres to the SWEDEHEART Registry. The recruitment period is planned for 18 months during which 6,400 patients will be randomised. The total trial period is planned for 30 months. AstraZeneca AB are also a Data Processor for this agreement.

The Executive Committee (EC) will be responsible for the overall design, including the development of the protocol and any protocol amendments, supervision, interpretation and reporting (presentations at international congresses and publications in peer reviewed journals) of the study. The EC will make recommendations to AZ regarding early stopping or modifications of the study based on the information received from the Data Monitoring Committee (DMC). Members of this committee are all contracted to the Sponsor. These contracts are service agreements (not contracts of employment). The EC provides recommendations to the Sponsor (AstraZeneca), however AstraZeneca have confirmed the EC is not a data controller in its own right. Members of the EC have no access to record-level NHS Digital data.

The UK’s Principal Investigator is based at the University of Sheffield and is responsible for the provision of clinical leadership and ensuring that the UK centres are conducting the research in compliance with the protocol. However, University of Sheffield will not be receiving any NHS Digital patient data nor processing any study related data.

Uppsala Clinical Research Center (UCR) is a Data Processor for this agreement. UCR is a non-profit academic research organization within Uppsala University and Uppsala University Hospital. UCR is also a National Clinical Quality Registry Center assigned by SALAR (Swedish Association of Local Authorities and Regions). In all its assignments UCR follows GDPR, the national supplement laws, The Data Protection Act and The Patient Data Act, and other regulations and guidelines in relation to Clinical Quality Registries and Research. The County Council of Uppsala (the public authority responsible for health care in the Uppsala Region, including Uppsala University Hospital) is the principal for all operations within UCR, including all aspects of Personal Data Protection and GDPR compliance, ensuring that all appropriate security arrangements are in place.

Under the EU's General Data Protection Regulation (EU/2016/679), each member state must designate an agency to be responsible for supervising the application of the regulation. This supervisory authority is to be fully independent in the performance of its duties and exercise of its authority. A corresponding authority is also to be designated in accordance with the EU's directive concerning data protection for law enforcement agencies (EU/2016/680). The Swedish government has designated the Swedish Data Protection Authority (DPA) to be the supervisory authority under the General Data Protection Regulation and the data protection directive. The Swedish DPA is also the supervisory authority under the Swedish law that is to supplement the General Data Protection Regulation, the Data Protection Act (2018:218). The Swedish DPA is also to monitor and describe developments in IT regarding issues concerning privacy and technology.

More information about the Swedish Data Protection Authority and its supervision can be found here https://www.imy.se/en/about-us/contact-us/. The Swedish Data Protection Authority´s national registration number is 202100-0050.

SCORE is a UK management company contracted by AstraZeneca AB to act as a proxy for the payment of invoices relating to the work on the trial in the UK. SCORE will not have any access to any of the data within the trial, the data from NHS Digital, or be a part of any decision-making in relation to the running of the trial. As such, they are not listed as a Data Processor or Data Controller in this agreement. Any access to the data held under this agreement would be considered a breach of the agreement.

Uppsala Clinical Research Center (UCR) employ Rackspace UK to host the physical server upon which the trail database is stored called EDC/MACRO (Electronic Data Capture (EDC); MACRO is the name of the database – not an acronym). Rackspace UK do not access data held under this agreement as they only supply the building. 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.

No other organisations are involved in the trial, either in the running of it, the processing of the data, or in any other capacity.

In the future AstraZeneca AB - as manufacturer of Dapagliflozin - may receive commercial benefit (including intangible or indirect commercial benefits such as positive publicity) from the successful outcomes of the trial. Should the results of the trial favour the clinical use of Dapagliflozin as a core secondary preventive medication for patients with impaired left ventricular function following a heart attack, and regulatory approval is provided for this indication, then AstraZeneca AB will achieve a financial advantage from the trial.

Manuscripts of the key primary and secondary results will be submitted for peer review in high level journals as is standard for medical research. Submissions to major scientific conferences will be made, with their associated press and media releases.

Only study-level aggregate data will be reported with small number suppression as per the HES analysis guide where necessary.

PPIE involvement has been specified in the applications, mainly around the design of the patient information sheet and consent form. However, AstraZeneca AB are aware from multiple other studies of the need to communicate back to the participating patients and hospitals and this is part of their strategy. Trial Result Summaries are a short and easy to understand summary of the results of this study. These will be added to www.trialsummaries.com within 1 year of the last study participant’s last site visit. Study participating patients can visit www.trialsummaries.com website anytime to sign up to be notified via email when the trial results summary from the study is available. These can also be shared upon the participating patient’s request from their local study doctor as a printed copy of the document. Study participating patients will also receive information on the treatment they received in this study. This will be shared with them around the same time as the Trial Results Summary. Technical Information about this research study will be posted on http://astrazenecaclinicaltrials.com and http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/. These websites do not contain any information about each patient.

A description of this clinical study will be available on http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the summary of the study results when they are available. The clinical study and/or summary of study results may also be available on other websites according to the regulations of each participating country.

Should enrolment and the expected clinical events occur as per the power calculation, the internal report would be expected by September 2024 and the main publication of the trial be expected by September 2025.

Should the trial results demonstrate a clinically important result in favour of the use of Dapagliflozin, the trial sponsor will submit appropriate applications to regulatory authorities to apply for a change in the indication for the clinical use of this drug. The results could also influence national and international guidelines on the optimal secondary preventive therapy to be offered to patients with a heart attack who have impaired left ventricular function. Trial results will be disseminated via publication in peer-reviewed journals regardless of if study treatment shows benefit or not.

The concept that data can be accumulated for the trial from the national registries in both the UK and Sweden has proved successful, and the data flows have been established as designed. There is now a need to provide the quarterly mortality data to ensure that these outcomes are tracked (not previously disseminated).

The anonymised trial data generated from the registries is prepared in blinded form for the trial Data Monitoring Committee. It is essential that data flows to the database on all patients, including patients enrolled in Wales.

The applicant has been informed that recruitment to the study has been good despite a pandemic, and thus there is evidence to support that the principles around the R-RCT are realistic.

Approximately 7 million individuals suffer a heart attack (myocardial infarction (MI)) annually, and survivors of MI remain at high risk for new major adverse cardiovascular (CV) events, including CV death and heart failure (HF). The development of HF following an MI is strongly associated with incapacitating symptoms, poor functional status, reduced health-related quality of life and unfavourable long-term prognosis. HF is also one of the leading causes of all hospital admissions, generating substantial costs for health care systems. Therefore, MI therapies that could prevent the development of HF as well as re-occurrence of major CV events represent a large and unmet medical need.

This study will evaluate the effect of dapagliflozin 10 mg versus placebo, given once daily, in addition to Standard of Care (SoC) therapies for patients with MI, for the prevention of hospitalisation for HF or CV death. The study seeks to determine dapagliflozin’s potential in the early prevention of serious complications, hospitalisations for HF or CV death, immediately following an MI.

This multi-centre clinical trial has been designed as a registry-based randomised controlled trial (R-RCT) which combines traditional study design elements within a pragmatic trial framework to provide high quality evidence on the potential benefit of dapagliflozin when administered in the early phase after MI. Traditional design elements such as randomisation and double blinding will minimise potential bias while the pragmatic and streamlined trial elements are expected to capture a broad MI population that will increase external validity and generalisability of study results and at the same time limit study burden on patients and investigators by usage of existing healthcare infrastructure and enabled by continuous clinical quality registries/clinical audits used in routine health care.

Ethics committee approval and patient consent:

The trial has been approved by the relevant Ethics Committees in the UK and Sweden. The subjects participating in this study will have provided informed consent for their data to be linked to the different national data bases. The patients have also consented to their data being transferred to Uppsala Clinical Research Center, Sweden, and on to NHS Digital for the purpose of this clinical trial. However, only pseudonymised data will be transferred to the trial database after the initial linkage necessary via the randomisation module.

Registry-based randomised controlled trial design:

The R-RCT contains a framework, which allows for randomisation and blinding and enables a pragmatic data collection using existing clinical registry data with readily available trial infrastructure facilitating data and endpoint collection. The study design is intended to ensure a robust yet streamlined trial capable of producing high-quality evidence of clinical effectiveness and safety.

This is a parallel group treatment study with 2 arms that is participant and investigator blinded. The patients admitted with MI will be consecutively screened for participation to achieve at least 6,400 randomly assigned to study intervention (3,200 from UK, 3,200 from Sweden).

The anticipated duration of the study is approximately 30 months with an estimated median treatment period for a patient of 21 months. The study closure procedures will be initiated when the predetermined number of primary endpoints are predicted to have occurred (n = 722) i.e., the primary analysis censoring date. The study duration may be changed if the event rate or randomisation rate is different than anticipated. The study may be terminated early if either a clear beneficial or harmful effect of the study treatment is detected during the Data Monitoring Committee review.

Randomisation and evaluation of subsequent CV events:

All participating patients will consent to their inclusion and the use of their data for the purposes of the trial. Following randomisation, NHS Digital will receive the NHS Number, Ecode (Study ID) and Inclusion Date for each consented patient on a twice-weekly basis from Uppsala Clinical Research Center (UCR). NHS Digital will then extract the relevant MINAP registry data for each consented patient and pass this securely to UCR where the complete electronic case record will be created for the trial. From this, the final data will be passed to the trial database (EntimeICE) held by AstraZeneca AB. No patient identifiable data is used in EntimeICE.

The study will utilise 2 high-quality national, population-based clinical registries:

(1) the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).

(2) the UK-based Myocardial Ischaemia National Audit Project (MINAP).

Patients will be recruited into the study at hospital level. For the purposes of this application, recruitment will take place in around 50 hospitals based in England. Once the patients have been randomised the study number/ Ecode will be generated and this will be entered into the study database, known as ‘EDC/MACRO’. Participating hospitals will follow patients up in accordance with Good Clinical Practice and identify and collect end-points and report adverse and serious adverse events.

With consent, patient identifiers (e.g. NHS Number) will be required for the randomisation/blinding process and subsequently for linkage purposes via NHS Digital with Hospital Episode Statistics (HES) and Civil Registrations of Death data to provide evidence of key CV end-points. In addition to MINAP, other National Cardiac Audit Programme domains, the National Audit of Percutaneous Coronary Intervention (NAPCI) and the National Adult Cardiac Surgery Audit (NACSA) will be interrogated to identify whether there is evidence that randomised patients have undergone subsequent percutaneous coronary intervention (PCI) and cardiac surgery during the designated follow-up period of the trial.

GDPR:

Article 6(1)(c) - processing of data in this clinical trial (for the protection of health) is that it is necessary for compliance with a legal obligation (Clinical Trial Regulations). Processing is necessary for fulfilling the legal obligations around on-going safety evaluation and safety reporting on medicinal products, for example, adverse events and reactions, in accordance with the following clinical trials regulations:

- EU Clinical Trials Regulation (EU 536/2014)

- EU Pharmacovigilance Regulation (EC 726/2004)

- Medicines for Human Use (Clinical Trials) Regulations 2004 and any other applicable law including UK laws and statutory instruments relating to clinical trials.

Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child. Processing personal data is necessary for AstraZeneca AB’s legitimate interests which are described in this application. The data to which access is requested are proportionate and necessary to achieve those interests. AstraZeneca AB is in the process of completing a legitimate interests assessment (LIA) and are satisfied that the interests of the data subjects do not override their legitimate interests; that they would reasonably expect the processing and it would not cause unjustified harm. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields and patient records being processed; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

Article 9 (2) (i) processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy. This is justified as this clinical trial aims to drive improvements in the quality and safety of care and to improve treatment outcomes for patients.

Trial coordination:

The study is funded by AstraZeneca AB, which is the sole data controller for this agreement. It will be conducted in Sweden and in the United Kingdom (UK) - with 50 sites in each country. Trial conduct at each site will be monitored by AstraZeneca AB. The UK centres will be connected to the MINAP clinical audit and Swedish centres to the SWEDEHEART Registry. The recruitment period is planned for 18 months during which 6,400 patients will be randomised. The total trial period is planned for 30 months.

Uppsala Clinical Research Center (UCR) is the sole data processor for the trial. UCR is a non-profit academic research organization within Uppsala University and Uppsala University Hospital. UCR is also a National Clinical Quality Registry Center assigned by SALAR (Swedish Association of Local Authorities and Regions). In all its assignments UCR follows GDPR, the national supplement laws, The Data Protection Act and The Patient Data Act, and other regulations and guidelines in relation to Clinical Quality Registries and Research. The County Council of Uppsala (the public authority responsible for health care in the Uppsala Region, including Uppsala University Hospital) is the principal for all operations within UCR, including all aspects of Personal Data Protection and GDPR compliance, ensuring that all appropriate security arrangements are in place.

Under the EU's General Data Protection Regulation (EU/2016/679), each member state must designate an agency to be responsible for supervising the application of the regulation. This supervisory authority is to be fully independent in the performance of its duties and exercise of its authority. A corresponding authority is also to be designated in accordance with the EU's directive concerning data protection for law enforcement agencies (EU/2016/680). The Swedish government has designated the Swedish Data Protection Authority (DPA) to be the supervisory authority under the General Data Protection Regulation and the data protection directive. The Swedish DPA is also the supervisory authority under the Swedish law that is to supplement the General Data Protection Regulation, the Data Protection Act (2018:218). The Swedish DPA is also to monitor and describe developments in IT regarding issues concerning privacy and technology.

More information about the Swedish Data Protection Authority and it´s supervision can be found here https://www.datainspektionen.se/other-lang/. The DPA´s national registration number is 202100-0050.

SCORE is a UK management company contracted by AstraZeneca AB to act as a proxy for the payment of invoices relating to the work on the trial in the UK. SCORE will not have any access to any of the data within the trial or be a part of any decision-making in relation to the running of the trial.

No other organisations are involved in the trial, either in the running of it, the processing of the data, or in any other capacity.

An internal report will be produced for the study. Submissions will be prepared for peer-reviewed publications, as well as for presentations at cardiovascular conferences.

Only study-level aggregate data will be reported with small number suppression where necessary.

Participating hospitals and patients will be informed of the results of the study.

Should enrolment and the expected clinical events occur as per the power calculation, the internal report would be expected by September 2024 and the main publication of the trial be expected by September 2025.

Should the trial results demonstrate a clinically important result in favour of the use of Dapagliflozin, the trial sponsor will submit appropriate applications to regulatory authorities to apply for a change in the indication for the clinical use of this drug. The results could also influence national and international guidelines on the optimal secondary preventive therapy to be offered to patients with a heart attack who have impaired left ventricular function.

Yielded Benefits is not a requirement for new applications.