Outcomes Data for A Study of Cardiovascular Events iN Diabetes – PLUS (ASCEND PLUS)

The University of Oxford requires access to NHS England data to follow-up participants recruited to the following clinical trial:

Outcomes Data for A Study of Cardiovascular Events iN Diabetes – (ASCEND PLUS)

The following is a summary of the aims of the clinical trial:

The trial aims to provide evidence about both the efficacy and safety of prolonged treatment with oral semaglutide in individuals aged at least 55 years, with Type 2 Diabetes (T2DM), without a history of a heart attack or stroke, and without any upper or lower Haemoglobin A1c (HbA1c) threshold.

Oral semaglutide and other GLP-1 RAs control blood sugar, reduce weight and, in high-risk patients, reduce the risk of adverse cardiovascular health outcomes (e.g. heart attacks and strokes). There is also some evidence that oral semaglutide may protect against other complications such as dementia and kidney disease. However, these medications are not currently widely used, partly because they have not yet been shown to be beneficial in patients with T2DM without existing cardiovascular disease. The ASCEND PLUS trial is aiming to provide substantive evidence in these patients both during the 5-year treatment phase and longer term.

The trial will assess the effect of treatment on prevention of heart attacks, strokes or mini strokes, the need for heart artery ‘balloon’ and bypass procedures, and deaths, and assess the overall safety of prolonged use of oral semaglutide in treating T2DM.

The following NHS England Data will be accessed:

• The Hospital Episode Statistics (HES) Admitted Patient Care (APC), Outpatients (OP) and Critical Care (CC) subsets – necessary to determine the cause of death, cardiovascular outcomes, serious outcomes (such as major adverse limb events, the need for surgical treatment to improve poor limb blood flow, decline in kidney function), and other adverse outcomes (including dementia, cognitive impairment, chronic diseases related to excess weight)

• Emergency Care Dataset (ECDS) - necessary because for the same purposes as the HES, but also allows the study to detect A&E presentations that may have occurred as a result of low blood sugar

• Cancer Registration Data - necessary because this is necessary to detect cancer events that arise and enable the reliable assessment of the long-term safety of the treatment.

• Civil Registrations of Death - necessary to detect date and cause of deaths.

• Demographics - necessary because the trial needs to identify when to censor participants during follow-up. The censor date is needed to calculate the follow-up time for each participant.

• Diagnostic Imaging Dataset (DIDs) - necessary because the dataset may identify or confirm outcomes of heart attacks, TIAs, strokes and heart failure helping to provide the most reliable information on the outcomes being investigated for the ASCEND PLUS trial

• Medicines dispensed in Primary Care (NHS BSA data) - necessary to assess the medicines dispensed to study participants to get more comprehensive detail on their outcomes. For example, prescriptions of dementia treatments will provide crucial evidence on the diagnosis and treatment of dementia. This dataset will be used for other outcomes e.g. identifying the date when participants commence insulin therapy. The data will enable further measurement of the safety and effectiveness of oral semaglutide, including in the long-term. This information is hugely relevant to large numbers of patients in the UK and globally.

• National Diabetes Audit (NDA) - necessary to detect diabetes-specific outcomes; retinal screening results, weight, biochemistry (including HbA1c, blood lipids, serum creatinine and estimated glomerular filtration rate (eGFR), Urine Albumin-to-Creatinine Ratio (UACR).

The Data will be minimised as follows:

• Limited to a study cohort who consented to participate in the study, following being identified (as being over the age of 55 and having type 2 diabetes) and invited to join the study by the NHS DigiTrials recruitment support service. The total cohort is expected to be between 25,000 and 30,000 individuals.

• For HES CC, HES OP, ECDS, DIDS the Data will be limited to records between 1st of April 2023 and the Latest Available, with quarterly updates thereafter until the expiry of this Data Sharing Agreement.

• For HES APC, Medicines Dispensed in Primary Care and NDA the Data will be limited to records between 1st of April 2018 to the Latest Available, with quarterly updates thereafter until the expiry of this Data Sharing Agreement (with exception to NDA which will be annually thereafter).

• For Demographics and Civil Registrations of Death, the Data will be limited to reflect the current details of the participants, with quarterly updates thereafter until the expiry of this Data Sharing Agreement.

• For Cancer Registration, the Data will include all history, with annual updates thereafter until the expiry of this Data Sharing Agreement.

The University of Oxford is the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

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

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller;

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

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

The funding is provided by Novo Nordisk, who provides the drug being tested as part of this trial. The funding is specifically for the trial described. Funding is in place until 2029.

The funder will have no ability to suppress or otherwise limit the publication of findings.

Novo Nordisk has contributed to the overall purpose and high level design of the trial but has not in any way determined the purposes and means of processing, and has not commissioned the University of Oxford to carry out this work on their behalf.

The study was initiated and designed by the independent investigators at NDPH, University of Oxford.

Novo Nordisk will provide funding and study medication (oral semaglutide and matching placebo). There is a safety data exchange agreement between the sponsor (University of Oxford) and the funder (Novo Nordisk) describing potential safety reporting obligations of the funder. There are no obligations of any commercial nature with this company at this point. However, if the trial results are positive (i.e. participants in the semaglutide arm have less occurrence of illness & death than those in the placebo arm), and the drug is successfully relabelled and remarketed, it is likely that Novo Nordisk will benefit financially from this. However, the primary aim of the study is to improve the health of people with T2DM by providing reliable evidence about the benefits and harms or oral semaglutide.

The ASCEND PLUS trial is overseen by a Steering Committee of 19 people chaired by members of the University of Oxford, and composed of academics from the contributing regions, lay members and 4 employees of Novo Nordisk. The Steering Committee has an advisory and oversight capacity for making major organisational and policy decisions and providing scientific advice. Its purpose is to determine the strategy of the trial and oversee its delivery.

There will be no Steering Committee decisions around the use of NHS England data. The ratified Steering Committee Charter prevents the possibility that Novo Nordisk members could unilaterally influence the publication of results.

Two lay members were recruited to the trial Steering Committee (TSC) and attended the first TSC meeting in June 2021 and subsequent meetings, ensuring patient and public involvement in the high-level strategic decisions for the trial.

The trial has convened the ASCEND PLUS Public Advisory Group (ASCEND PLUS PAG), a diverse group of patients and the public, to input into the whole life-cycle of the trial. The ASCEND PLUS PAG give feedback, advice and opinions across different aspects of the trial including recruitment materials, participant questionnaires, website development, strategies to maintain participant adherence and engagement, and dissemination of the trial results.

The Study Team is undertaking continued involvement and engagement by the ASCEND PLUS PAG to ensure that all those living with diabetes in mainland UK are represented in the trial and to encourage and support participant retention.

During the active recruitment period the cohort will be increasing and the Study Team will update the cohort provided to NHS England quarterly. Once recruitment has completed, the Study Team will update the cohort quarterly to remove any participants who have withdrawn. There will be no further additions after the recruitment finishes. The cohort will include participants who are eligible at screening, have provided written informed consent and entered the pre-randomisation run-in period. The Study Team have a regulatory requirement to report adverse events that occur during the run-in period as participants are taking active treatment. Any participants who are not randomised will be subsequently withdrawn from the cohort.

As part of this Data Sharing Agreement, to enable data linkage, the Study Team will send NHS England the cohort with the following identifiers:

• Study ID (unique participant identifier)

• NHS Number

• Date of Birth

NHS England will provide the relevant records from the following datasets on a quarterly frequency:

• HES APC – plus 5-years historical data

• HES CC

• HES OP

• ECDS (replaces HES A&E)

• Demographics

• Civil Registrations and Mortality

• Medicine dispensed in Primary Care (NHSBSA data) – plus 5-years historical data

• Diagnostic Imaging Dataset (DID)

NHS England will provide the relevant records from the following datasets on an annual frequency:

• National Diabetes Audit (NDA) – plus 5-years historical data

• Cancer – plus historical data

When new participants are added to the cohort, NHS England will provide the relevant records from the following datasets for each new participant::• HES APC, NHSBSA and NDA - back to 1 April 2018

• Cancers - all history

Historical data is necessary to help confirm that events that occur during the trial are new outcomes.

NHS England data will provide the relevant records from the HES, ECDS, deaths, cancer, demographics, NHSBSA, DIDs, and NDA datasets to University of Oxford. The data returned to NDPH will contain directly identifying data items including NHS Number and Date of Birth which are required to verify the cohort linkage and to link the data at record level with data already held by the University of Oxford.

Identifiable data is necessary for the purpose of data linkage and quality assurance of that linkage. The Data includes a range of detailed information that is necessary for analysis of the safety and effectiveness of the treatment.

Identifying data will need to be retained to enable further data linkages, such as that which will take place under this DSA. In addition, it is NDPH policy to retain research data for at least 25-years after the end of the trial as per the 2014 Clinical Trials Regulation (EU) No 536/2014: https://eur-lex.europa.eu/eli/reg/2014/536/oj.

The Data will be accessed by authorised personnel via remote access. The Data will be stored and remain on the servers at the University of Oxford at all times.

The data will not be transferred to any other location.

All information is stored securely on servers at the University of Oxford.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The data will not leave the England at any time.

Access is restricted to individuals within the NDPH of the University of Oxford who have authorisation from the Information Asset Owner. All such individuals are substantive employees of the University of Oxford.

The Study Team need to link to all study participants at person record level with other Electronic Health Registries (which may include):

• NHS Central Register (NHSCR) - Scotland

• Public Health Scotland (PHS) - Scotland

• Digital Health & Care Wales (DHCW) - Wales

• Secure Anonymised Information Linkage (SAIL) – Wales

• Healthcare Quality Improvement Partnership (HQIP) – England & Wales

• National Institute for Cardiovascular Outcomes Research (NICOR) – England & Wales

• UK Renal Registry

Researchers from the NDPH of the University of Oxford will analyse the data for the purposes described above.

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

The Study Team will not provide or otherwise make available the NHS England registry data to any third party or allow use of it or them by or on behalf of any third party, in whole or in part, whether by way of sale, resale, loan, transfer, hire or any other form of exploitation except and exclusively in the following circumstances:

1. In circumstances where there may be a need to contact an individual participant’s GP or other medical professionals for further clarification about a medical event or death to support the medical event coding process undertaken by the Study Team.

2. In circumstances when a Medicines and Healthcare products Regulatory Agency (MHRA) inspector, may see an individual record with a medical event or death recorded, which may have been supplied by NHS England.

3. When the trial is required to provide de-identified data to the MHRA as part of the annual regulatory reporting procedures. These reports contain counts of serious adverse events including hospitalisations and deaths among the trial participants. Small numbers cannot be suppressed in these regulatory reports.

There are no contractual obligations to provide record level data to anyone until the Study Team are contractually required to share data with Novo Nordisk 1-year before the end of study (data sharing is anticipated in 2027). The University of Oxford is not permitted to share NHS England Data, included Manipulated Data, with Novo Nordisk. The University of Oxford intend to share Derived Data with Novo Nordisk but must first request a review by NHS England and must receive written confirmation from NHS England that the dataset to be shared has been verified as meeting the criteria for Derived Data.

The following details the expected outputs of the processing:

• Results will be communicated directly to trial participants. The Study Team plan to distribute plain English results co-developed by the ASCEND Patient Advisory Group (PAG) to surviving study participants by mail and shared with the public via the trial website. (https://www.ascend-plus-trial.org/).

• Submissions to peer reviewed journals such as the New England Journal of Medicine and the Lancet, with the next publication expected Q4 2028.

• Presentations at appropriate conferences such as the American Diabetes Association, the American Heart Association, the European Society of Cardiology and the International Clinical Trials Methodology.

• Posters displayed at departmental, national and international conferences (as above)

• Summaries of key findings will be placed on the study website and disseminated through Oxford University Communications channels.

• Press/media engagement and other public promotion of the research (e.g. via the Nuffield Department of Population Health website (https://www.ndph.ox.ac.uk/), or X (formerly Twitter) account (@oxford_ndph).

• Open lectures and talks

• Advice to government (including NHS England).

No individuals will be identified in any study reports.

It is anticipated that the results from ASCEND PLUS will inform National and International guidelines. Examples of these guidelines could include the NICE guideline “Type 2 diabetes in adults: management” (https://www.nice.org.uk/guidance/ng28), the American Diabetes Association Standards of Medical Care in Diabetes guidelines (https://professional.diabetes.org/content-page/practice-guidelines-resources), and the diabetes guidelines from the European Society of Cardiology and the European Association for the Study of Diabetes. ASCEND PLUS could also potentially contribute to NICE guidelines such as the “Cardiovascular disease: risk assessment and reduction, including lipid modification” [https://www.nice.org.uk/guidance/cg181] as did the ASCEND trial (another NDPH diabetes trial, and the predecessor of ASCEND PLUS).

Any outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived e.g. the HES analysis guide.

University of Oxford’s contract with Novo Nordisk prohibits Novo Nordisk from preventing any publication that the Steering Committee has approved, even if trial results are negative.

According to Diabetes UK (https://www.diabetes.org.uk/), in February 2022 4.3 million people in the UK had a diagnosis of diabetes and this number is rising each year.

Globally, the 10th Edition of IDF Diabetes Atlas estimates that in 2021 there were more than half a billion people living with diabetes, affecting men, women, and children of all ages in every country. The number is projected to more than double to 1.3 billion people in the next 30 years by 2050, with every country seeing an increase. In 2019, diabetes was the direct cause of 1.5 million deaths and 48% of all deaths due to diabetes occurred before the age of 70 (https://www.who.int/news-room/fact-sheets/detail/diabetes).

The data collected from central NHS registries for the ASCEND PLUS study will be used to assess whether there are any benefits or harms of semaglutide during the 5- year treatment phase of the trial helping to provide evidence for the treatment of people with T2DM. Following this, the study will assess whether the treatment provides additional benefits or harms, during the long term follow-up phase of the study (anticipated to be for 20-years after the scheduled treatment period ends).

T2DM is associated with elevated risks of cardiovascular disease and other health conditions. Delaying the severity and onset of these are some of the benefits expected to be found from the study. The conditions for which benefits are anticipate are:

Cardiovascular Outcomes

• Pooled data from observational studies, predominantly conducted in Europe and North America show that the presence of diabetes approximately doubles the risk of vascular outcomes such as coronary heart disease, ischaemic stroke and cardiovascular death while more extreme risks are observed in regions where medications to control glycaemia are not widely available. It is hoped that semaglutide will delay or prevent these outcomes.

Decline in Kidney Function

• Other diabetic complications include kidney disease. It is possible that semaglutide may slow the rate of kidney decline which will improve lives.

Cognitive decline and dementia

• Observational studies have shown that diabetes and obesity are both associated with a 50% increased risk of dementia and a 20% increase in the rate of cognitive decline. These conditions present major health care and social burdens which are worsening globally with increasing lifespan, so using the NHS England data to obtain randomised evidence of the effect of semaglutide therapy on these outcomes would be highly beneficial worldwide.

Vision

• With diabetic retinopathy and diabetic maculopathy being among the most common causes of registerable blindness among working-age adults in the UK. Using NHS England data, ASCEND PLUS study will be able to reliably assess the treatment effects on diabetic retinopathy, macular degeneration and cataracts through linkage to diabetic screening registry information. Visual loss impacts significantly on the quality of life for those people affected, as well as generating financial costs to the NHS ophthalmology services. Therefore the preservation of vision is extremely important.

Informing guidelines

• Oral semaglutide and similar drugs given by injection, are new treatments for diabetes, but clinical trials have only tested them in selected individuals with very high cardiovascular risks. If ASCEND PLUS shows that oral semaglutide is beneficial in a wider range of patients with T2DM (not just those at high cardiovascular risk) then the results could change national and international guidelines. This would mean more patients could be offered the treatment which is of wide public interest and importance to healthcare in general.

Methodology

• The trial should also generate important methodological insights, tools and resources to benefit future research especially using NHS England data linkage.

IMPACTS

1. Impact on patients

If the trial is positive (i.e., participants in the semaglutide arm have less occurrence of illness & death than those in the placebo arm) and the drug is successfully relabelled and remarketed, this should translate to improved outcomes for diabetes patients worldwide. Furthermore, updated guidelines based on the ASCEND PLUS results, if they show benefits of the oral semaglutide, would translate to the treatment being made available to a wider range of patients within the current marketing authorisation, resulting in a reduction in complications of diabetes.

2. Impact on healthcare providers in the UK and Worldwide

Diabetes has major effects on the health of those diagnosed, and incurs major costs to the NHS and health care providers worldwide. Any delay in the progression of the disease could result in improved health for diabetes patients and significant savings for health care providers.

Should ASCEND PLUS provide important new information, the Study Team hopes that data from the results of the trial will inform patients, clinicians and guideline groups globally. It could also provide evidence to submit to regulators for an extension of the current licenced indication in the UK and across the world.

3. Impact on trial design and cost

Other clinical trials run by NDPH such as ASCEND have found that in the UK, routine electronic health data such as that from NHS England, provides a cost-effective method of assessing the impact of treatment on disease. The ASCEND PLUS study design keeps the costs down as it does not need physical trial sites or complex data collection procedures. All interactions with participants will be conducted using innovative patient-centred web-based technology, with limited supplementation by telephone, video call and mailed letters. Study treatment is mailed to participants making it easier for them to participate and less expensive for the Study Team to implement. The design of the ASCEND PLUS study could inform the development of other trials.

Not stated in the register.