EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) - Post-Trial Follow-up (PTFU)

The University of Oxford require access to NHS England Data for the purpose of the following clinical trial:

The Study of Heart & Kidney Protection with Empagliflozin (EMPA-KIDNEY)

The following is a summary of the aims of the trial provided by the University of Oxford:

“The EMPA-KIDNEY randomized trial compares empagliflozin (a drug belonging to the class of medication called SGLT-2 (sodium glucose co-transport 2) inhibitors which reduce blood sugar levels in people with diabetes) 10mg once daily versus matching placebo in participants with established chronic kidney disease (CKD) with or without diagnosed diabetes mellitus.

The primary aim of the study is to investigate the effect of empagliflozin on kidney disease progression or cardiovascular death versus placebo on top of standard of care in patients with pre-existing CKD. The main inclusion criterion was participants with CKD who are at risk of their condition progressing.

The EMPA-KIDNEY initial results were e-published in 2022 and demonstrated that among a wide range of patients with CKD, who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than for participants in the placebo group. The trial website provides an animation (designed for participants) explaining the results in full (https://www.empakidney.org/news/empagliflozin-reduces-the-risk-of-kidney-disease-progression-or-cardiovascular-death-in-people-with-chronic-kidney-disease).

Following the on-treatment phase of the trial (which ended in July 2022), participants are being followed up indirectly for a further 2-years (ending in July 2024). The purpose of this new Data Sharing Agreement (DSA) for the EMPA-KIDNEY Post-trial Follow-up (PTFU) phase is to request information on participant deaths.”

The following NHS England Data will be accessed:

• Demographics – necessary to ensure that the EMPA-KIDNEY dataset is as complete and accurate as possible. This is important as one of the primary outcomes is cardiovascular death. If new deaths are identified (i.e. deaths not previously reported by the site), the fact and date of death will be reported to sites to assist them with identifying deceased participants and find medical records relating to their death held locally

The level of the Data will be identifiable – necessary for the purposes of linkage validation. Returning NHS number and date of birth to the University of Oxford enables the Study Team to ensure that the linkage process is robust and accurate. These identifiers will not be used for analysis.

The Data will be minimised as follows:

• Limited to ≤1133 participants recruited by consent into the EMPA-KIDNEY trial in England and Wales

• Limited to data between 19th May 2019 (when recruitment began) and date of data linkage by NHS England (expected before 30th June 2024)

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.

Although Boehringer Ingelheim International GmbH (BI) is the regulatory sponsor of the EMPA-KIDNEY trial, BI will not carry out any controllership activities in relation to the Data covered by this Agreement. By working with a commercial sponsor, the EMPA-KIDNEY trial has been able to provide results for this important research more quickly than conducting the trial solely within the University of Oxford.

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

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

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

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

This processing is in the public interest as the results from the trial may inform doctors’ decisions about the management of their patients, and could lead to substantial improvements in the health of people with kidney disease.

The funding is provided by BI. The funding is specifically for the trial described. Funding for the PTFU work is in place until 30/06/2024.

BI own the patent for empagliflozin and provided a supply of study treatment for the trial. It is likely that BI are benefiting financially from the successful relabelling and remarketing of empagliflozin that was in part due to the EMPA KIDNEY results. This may also be the case should the PTFU results data show continued benefit to patients, but it is unlikely that the PTFU results will be submitted for a change to the label (as the label already has a full indication for adults with CKD).

The University of Oxford also receive support from the UK Medical Research Council and British Heart Foundation (BHF) to run trials, by providing core funding to the Nuffield Department of Population Health (NDPH) at the University of Oxford.

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

NHS England have conducted an assessment of how the commercial interests are proportionately balanced with the benefits to the health and social care system and to the interests of the data subjects, and are satisfied that the public benefit is proportionate to any potential commercial benefits. The results from this trial may result in CKD patients having access to new drug treatments that could improve their health, or avoid worsening disease and death.

The EMPA-KIDNEY trial is overseen by a Steering Committee chaired by members of the University of Oxford, and composed of academics from the contributing regions and employees of BI. The Steering Committee is not involved in the detailed conduct of the trial within each country, such as this linkage activity. There will be no Steering Committee decisions around the use of NHS England Data for the PTFU phase.

A Public and Patient Involvement (PPI) panel was conducted prior to the start of EMPA-KIDNEY. Participants from the UK HARP-III trial (a University of Oxford renal trial that recruited participants with CKD) were asked to participate and they agreed that the use of data in the way that the EMPA-KIDNEY Study Team proposed for EMPA-KIDNEY was reasonable. The PPI panel were also asked about linkage of participants to central registries, and this was considered acceptable.

The University of Oxford will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth and a unique person ID) for the cohort to be linked with NHS England Data.

NHS England will provide the relevant records from the Demographics dataset to the University of Oxford. The Data will contain directly identifying data items including NHS Number and Date of Birth which are required for the purposes of validating linkage. This enables the Study Team to ensure that the linkage process is robust and accurate.

The Data will not be transferred to any other location.

The Data will be stored on servers at the University of Oxford.

The Data will be accessed onsite at the premises of the University of Oxford, and will be accessed by authorised personnel via remote access.

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).

Remote processing will be from secure locations within England and Wales. The data will not leave England and Wales at any time.

Access is restricted to employees of the University of Oxford. Access is granted on a “need to know” basis on the instruction of the Information Asset Owner for the EMPA-KIDNEY trial. Only personnel involved in the EMPA-KIDNEY trial will have access to the Data under this Agreement.

Boehringer Ingelheim International GmbH (BI) is not permitted to access the Data.

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

The Data will not be linked with any other data.

The University of Oxford will retain the Data until sites have confirmed any deaths that the EMPA-KIDNEY Study Team report to them. Identifiers received from NHS England will be destroyed after validation of deaths. The University of Oxford will not be destroying the identifiers held directly from participants.

The Data received from NHS England will be used as follows:

• Information on deaths will be crosschecked with the trial database. If new deaths are identified (i.e. deaths not previously reported by the site), the fact and date of death will be reported to sites to assist them with identifying deceased participants and find medical records relating to their death held locally.

• NHS England death Data will not be entered into the trial database, or used for analysis. In the event that an unreported death is identified, the site responsible for the participant will be prompted to check their records (which include access to the NHS Spine) and to report the death into the study database via the web-based system, as they would do routinely for deaths reported in other ways (e.g. via a relative or other healthcare provider).

The expected outputs of the processing will be:

• Lay summaries of important results to be shared with the public via the trial website https://www.empakidney.org/

• Submission to a major peer-reviewed journal (for both the main PTFU results and associated health economic outputs)

• Presentations at relevant scientific meetings e.g., the World Congress in Nephrology, American Society of Nephrology, European Renal Association.

• Open lectures to the public.

• Posters

• 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 (previously Twitter) account (@oxford_ndph).

• Advice to government (including NHS England).

The 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.

The University of Oxford plans to present results at the American Society of Nephrology in October 2024. The corresponding publication should be issued in Q4 2024. Results from the Health Economic analysis are intended to be published by Q1 2025.

The EMPA-KIDNEY initial results (reported at the American Society of Nephrology in November 2022) found that:

• Among a wide range of patients with Chronic Kidney Disease (CKD) those treated with empagliflozin experienced significantly lower rates of CKD progression and death from cardiovascular causes compared to the placebo group. (N Engl J Med 2023; 388:117-127).

• Empagliflozin slows the rate of progression of CKD levels among all types of patients including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor. (Lancet Diabetes Endocrinol 2024;12:39-50)

The EMPA-KIDNEY initial results showed that participants in the empagliflozin arm have less occurrence of illness and death than those in the placebo arm. Data from EMPA-KIDNEY was evaluated along with data from other similar trials, and as a result of this, empagliflozin (under the brand name Jardiance) was approved for use in certain kidney patients by:

• The European Medicines Agency (EMA) in June 2023.

• The Medicines and Healthcare products Regulatory Agency (MHRA) in early September 2023

• The US Food and Drug Administration (FDA) on 21 September 2023.

The National Institute for Health and Care Excellence (NICE) issued guidance in December 2023 recommending empagliflozin as an add-on treatment for eligible adults with CKD (https://www.nice.org.uk/guidance/ta942).

These recommendations are leading to the implementation of these important findings into clinical practice for people living with CKD.

The findings of the post-trial follow-up (PTFU) phase are expected to contribute to evidence-based decision-making by organisations such as those stated above; local decision-makers such as doctors; and patients by helping to increase the quality of the trial data by identifying any participant deaths not otherwise reported. The findings should help to inform best practice to improve the treatment and outcomes of CKD patients with or without diagnosed diabetes mellitus.

The use of the Data could:

• lead to the identification or improvement of treatments or interventions to improve health and care outcomes.

• inform decisions on how to effectively allocate and evaluate funding according to health needs.

• support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work).

Chronic kidney disease (CKD) is common. In high-income countries, the prevalence of CKD is about 10% and is likely to increase as average population age rises and diabetes mellitus becomes more prevalent. Cardiovascular risk also increases progressively as kidney function declines. This means that results from the EMPA-KIDNEY trial are relevant to many people around the world, and their healthcare providers.

Following the initial findings of the EMPA-KIDNEY trial, the further expected benefits of conducting this research include:

1. IMPACT ON KIDNEY PATIENTS

The EMPA-KIDNEY PTFU results will provide valuable information on whether the benefits of taking empagliflozin persist, and quantify the full effect of 2 years of treatment over 4 years. Patients with kidney disease can have substantially reduced quality of life, especially when the disease has progressed. The EMPA-KIDNEY PTFU results will extend the knowledge of treatment effects of empagliflozin in the longer term which has the potential to improve patient lives. The findings should impact international clinical practice guidelines.

2. HEALTHCARE COSTS

HEALTH ECONOMICS

An important component of evaluating the benefits and value of empagliflozin is to determine its cost-effectiveness. To do this, the University of Oxford will perform an EMPA-KIDNEY health economic analysis. PTFU data are required to estimate the full cost saving by preventing the need for dialysis.

UK

CKD has major effects on the health of those diagnosed, and in its most advanced stages incurs major costs to the NHS. This is because, although only 0.1-0.2% of the UK population receive renal replacement therapy, regular dialysis costs the NHS £30,000 per patient per year. When combined with the costs of managing earlier stage of CKD and its complications, the disease was estimated to cost £1.4 billion each year (2009-2010 estimate: https://pubmed.ncbi.nlm.nih.gov/22815543/). Delaying the progression of CKD could result in significant savings for healthcare providers such as the NHS.

GLOBALLY

- EMPA-KIDNEY is an international trial of participants with CKD at risk of progression recruited from 8 countries in Europe, North America, and Asia. The proposed health economic analytical framework intends to evaluate the cost effectiveness of empagliflozin from the perspectives of the UK and US health systems, drawing on the overall trial evidence. The PTFU results data will be valuable for this process.

- To estimate cost-effectiveness in other countries (including countries that did not participate in the trial) an extrapolation model based on the trial data will be made available to permit further evaluations of cost-effectiveness of empagliflozin in other countries. In this way, the PTFU results data will contribute to improve healthcare for kidney patients globally.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to CKD patients.

Yielded Benefits is not a requirement for new applications.