NATRIX - SBP - Recruitment Agreement - DSA 1 - ≥40 and ≤85 years : A Phase 2B Randomised, Double-Blind, Placebo-Controlled Study to evaluate the efficacy, safety and pharmocokinetics of a multiple dose regimen of REGN5381.

Quality by Randomization Ltd, trading as Protas requires access to NHS England data for the purpose of inviting individuals who match the eligibility criteria for the study (detailed below) to take part in the NATRIX-SBP study.

The following is a summary of the aims of NATRIX-SBP, provided by Protas.

The primary objective of this study is to understand whether ‘REGN5381’ - a monthly injection which aims to reduce high blood pressure - is useful in lowering blood pressure in patients with hypertension. This research is important because it may help doctors and scientists to improve treatment for people who have high blood pressure around the world.

High blood pressure affects around 11.8 million adults in England. This condition increases the risk of heart disease and strokes, which are among the leading causes of death in the UK.

High blood pressure is often unrecognised and undertreated, with the World Health Organization estimating that only 1 in 5 adults with high blood pressure have it under control, highlighting the need for new medicines that make treatment straightforward.

NATRIX-SBP is a phase IIb randomised, placebo controlled, double blind clinical trial which will be conducted by Regeneron in collaboration with Protas to evaluate a potential treatment for uncontrolled high blood pressure (REGN5381). The effectiveness and safety of REGN5381 and how it works in the body will be tested. The study will recruit 732 participants in England through GP practices.

REGN5381 is a monthly injection which aims to reduce high blood pressure which is not currently controlled by the participant’s medication. REGN5381 is an antibody. An antibody is a type of protein that the immune system makes to fight infection. Scientists are now able to use antibodies to combat other diseases. REGN5381 can attach to and activate a protein called natriuretic peptide receptor 1 (NPR1). Activation of NPR1 lowers blood volume and leads to water and salt removal from the body. This aims to lower blood pressure.

The study investigates REGN5381 at two doses (300mg, 100mg) versus placebo. People with a systolic blood pressure ≥130 mm who are taking at least one blood pressure medication (between the ages of 40-85 years old) or at least three medications for high blood pressure (between the ages of 30-39 years old) may be eligible to take part. The study lasts for 27 weeks, and participants will need to attend around 7 appointments.

Objective 1: (for which the NHS England data will be used)

To identify individuals who meet the eligibility criteria and invite those individuals to take part in the study. For the NATRIX-SBP Study to achieve its objectives, 750 people will need to be recruited.

To recruit this number of individuals, it is expected that 40,000 individuals will need to be invited to the NATRIX-SBP Study using the NHS DigiTrials Recruitment service. NHS England may identify further eligible individuals to be contacted about NATRIX-SBP, should the recruitment target not be met.

Objective 2: (NHS England data will not be used for this objective)

To evaluate the efficacy of REGN5381 relative to placebo in lowering blood pressure after multiple dose administrations in participants with uncontrolled hypertension

Objective 3: (NHS England data will not be used for this objective)

To assess the efficacy of REGN5381 relative to placebo in lowering blood pressure after multiple dose administrations in participants with:

1. Baseline evidence of reduced kidney function (defined as stage 3 CKD -GFR 30 to 59 ml/min/1.73m2)

2. Baseline evidence of apparent resistant hypertension (defined as being on ≥3 anti-hypertensive therapies)

- Evaluate the durability of effects of REGN5381 on blood pressure

- To characterize the pharmacokinetics of REGN5381 following single and repeated subcutaneous (SC) administrations of REGN5381

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

• Hospital Episode Statistics

o Admitted Patient Care

• Demographics

• Medicines Dispensed in Primary Care (NHSBSA)

The level of the Data will be identifiable – necessary because the third-party messaging provider require enough information to be able to contact potential participants.

INCLUSION CRITERIA:

Limited to individuals identified by NHS England as meeting the following criteria:

• ≥40 and ≤85 years on a stable regimen of ≥1 anti-hypertensive therapies for at least 1 month at the time of screening

Geographical minimisation by limiting data to candidates with a registered address within vicinity of the eight trial sites (locations currently planned in Greater Manchester, Liverpool, Newcastle, Carlisle, Bromsgrove, Coventry and 2 in Greater London)

The NATRIX-SBP does have additional Inclusion and Exclusion criteria as detailed in the study protocol. These criteria cannot be identified using NHS England data, therefore will be applied during the screening of interested candidate.

NHS DigiTrials tech team will produce a cohort using the clinical criteria the trial provided (which is applied to every cohort), and the demographic criteria that trial provides on a per-cohort basis.

The NHS DigiTrials pipeline uses the inclusion and exclusion criteria to create a population of people who would be suitable for invitation to the study. The DigiTrials pipeline then applies the National Data Opt Out and Trial Specific Opt Out to remove people with these applied. After this, a random unique identifier is applied to each person and the population is sorted alphabetically based on this unique identifier. The top portion of records is then used for the purposes of inviting (eg if 3,000 are requested – the top 3,000 records will be progressed on for invite).

Quality by Randomization Ltd (Protas) is responsible for the recruitment of participants to the Natrix_SBP study. Quality by Randomization Ltd (Protas) is the controller of the data used for the purpose of recruitment and is the organisation responsible for ensuring that the data will only be processed for the purpose described.

Regeneron is the research sponsor and is the controller of data collected throughout the study following the recruitment of participants.

The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(f) - processing is necessary for the legitimate interests pursued by 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 domestic law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

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

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

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

NATRIX-SBP is funded by Regeneron. Funding is in place until 23/08/2026.

NHS England are acting as a Processor on behalf of the Protas and are responsible for:

1. Applying the inclusion and exclusion criteria from the invitation request to the datasets to generate a list of invitees

2. Feeding back to Protas the number of invitees actually fulfilled out of the total target population.

3. Removing objections or opt outs (where a national Data opt-out or a study-specific right to object has been registered, as well as special categories of people for whom the data should not be disseminated. The purpose of the restriction is to ensure that patient information that might imply a location is protected.)

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

5. Agreeing with Protas key processing timelines

6. Overseeing performance of Datagraphic Ltd and alerting performance issues to Protas

7. Feeding back to Protas performance in relation to Key Performance Indicators (KPIs) of Datagraphic Ltd and NHS England

8. Where the number of potential invitees is less than the population available, invoking a system to choose invitees at random

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

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

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

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

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

Patient and Public involvement and engagement (PPIE):

The opportunity to contribute towards the development of patient-facing materials for this study was advertised through the British Heart Foundation newsletter and distributed through University of Oxford’s Nuffield Department of Population Health’s communications team to its patient advisory group (PAG). Following review of applications, a panel of 8 public contributors were recruited to review patient-facing materials for NATRIX-SBP (after executing non-disclosure agreements). The contributors have a location spread from Durham to Brighton, with an ethnic diversity of 3 people non-white. They have either personal or carer experience of high blood pressure, and the majority have contributed towards PPIE previously.

At an initial PPIE group meeting a presentation on hypertension was given, followed by brief information on the trial and what was expected of the PPIE panel. There was also an opportunity for them to discuss their experiences with hypertension and public engagement. The contributors were sent all the documents for review (patient information sheets and informed consent forms, 24-hour blood pressure monitoring instructions, the wording for cards and posters, participant invitation letter, text message, withdrawal letter, and patient education materials), and the contributors were given different options to provide feedback, including invitation to attend a group feedback call and/or written feedback in the form of email or marked up document. Feedback was discussed by a cross-functional Protas team and the contributors' suggestions were incorporated into patient-facing materials where appropriate.

During the PPIE group meeting, members of the group were given the opportunity to discuss the following aspects, with the study Chief Investigator and study team:

• key participant information; review of entire suite of intended communications

• wellbeing concerns

• feedback on key ethical issues i.e. discuss the use of confidential patient information without consent

• iterate study documents (not yet including website content)

• use of participant data without consent

• the consenting process

• any commercial involvement

• interaction with the NHS

• intended communications

• engagement with disease/condition specific group

Following the review of patient-facing materials, the PPIE panel were invited to attend a second group meeting with members of the research team, where they could provide their feedback on the group call, or if this method was not preferred, they were also given the opportunity to provided written feedback in the form of email or marked up documents.

All feedback provided by the PPIE panel was reviewed and discussed by a cross-functional Protas team and the contributors' suggestions were incorporated into patient-facing materials where appropriate.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA). Protas will provide to NHS England the core eligibility criteria for those potential participants who will receive invitations. The core eligibility criteria will include the minimum and maximum age, sex, postcode sector, and quantity of individuals within those parameters.

NHS England will use the criteria provided by Protas to identify potential participants who meet the criteria. NHS England will remove any records where a National Data Opt-Out or study-specific opt-out has been registered, as well as special categories of people for whom the data should not be disseminated such as those on a witness protection programme.

NHS England will provide the relevant records of the identified potential participants from the Personal Demographics Service dataset to Datagraphic Ltd. The Data will contain the directly identifying data items (Title, First Name, Surname, Address and Postcode), which are required for the purposes of contacting potential participants. Datagraphic Ltd will also receive additional fields which will enable them to ensure that the correct invitation format and template are used for each round of invitations. Datagraphic Ltd will use Research Ethics Committee-approved template invitation letters.

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

The Data will not be transferred to any other location. Datagraphic Ltd will contact individuals as specified by Protas. All potential participants will receive a letter containing their Forename, Surname, address, postcode and an invitation code.

Datagraphic Ltd will send out invitations in approximately 8 batches of letters up to approximately 40000 total mailouts, using an automated system.

The Data will be stored on servers at Datagraphic Ltd.

The Data will be accessed on servers at Datagraphic Ltd.

The Data will not leave England at any time.

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

Protas and other recruiting sites will not have access to NHS England Data as described in this Data Sharing Agreement. Protas and other recruiting sites will not have access to individual’s data unless they are contacted directly by said individual following the mailout.

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

The Data will not be linked with any other data.

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

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

The expected outputs of this Data Sharing Agreement are:

1. Successful contact with eligible participants for the purpose of invitation to participate in the NATRIX-SBP study.

2. Recruitment target reports generated by Protas for delivery to Regeneron and NATRIX–SBP study partners through milestone updates linked to the contract and project plan.

Protas hopes to reach the recruitment target for the NATRIX - SBP study by 22/12/2025.

The outputs that may flow from a subsequent study (not within scope of this Data Sharing Agreement) will be communicated to relevant recipients through the following dissemination channels:

- Updates on the trial website

- Presentations

- Journals / Publications: the results of NATRIX-SBP will be published in a major medical journal

- Conference presentation: the results of NATRIX-SBP may be presented at a major international medical conference

- Study results summary / newsletter

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

No benefits to health or social care are expected as a direct result of the processing of data under this Data Sharing Agreement (DSA) because the sole purpose of this DSA is recruitment of volunteers for participation in the NATRIX-SBP study.

The expected benefits from the planned study (not within scope of this DSA) are:

Hypertension is common, affecting over 1.39 billion people around the world, of whom 75% reside in low and middle-income countries. In the UK, the NHS reports that 30% of adults have Hypertension. According to the Global Burden of Disease, Injuries, and Risk Factors Report 2019, SBP above 110 to 115mm Hg was the leading global factor for attributable deaths, accounting for 10.8 million avoidable deaths each year (mostly due to ischemic heart disease and stroke). Raised blood pressure is often under-recognised and under-treated. An estimated 46% of adults with hypertension are unaware they have the condition, and less than half are diagnosed and treated. The current standard of care in hypertension often requires multiple generic daily oral medications. A key issue with under-treatment is adherence to daily oral pills. Reducing blood pressure across the population would lead to substantial improvements in public health.

The NATRIX-SBP study is a larger than traditional phase 2 trial with a duration of 23 weeks which aims to provide reliable information on a broad range of patients, helping to generalise result more

rapidly. This study will test the BP lowering efficacy (and safety) of the treatment prior to future licencing phase 3 trials for the treatment.

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

If NATRIX-SBP demonstrates that REGN-5381 safely reduces blood pressure, then the data from the trial may lead to regulatory approval for REGN-5381 as a novel treatment for patients with uncontrolled hypertension. As described above, there are many such patients globally and the novel delivery method of REGN-5381 (monthly injection rather than daily tablet) would therefore likely to be attractive to certain groups of patients.

The data from NATRIX-SBP will also inform the development of REGN-5381 for other indications such as heart failure and chronic kidney disease. While the results of NATRIX-SBP would not directly lead to indications in those conditions, they will be very useful in designing future trials in those conditions.

Recruiting individuals into the NATRIX - SBP study, using the NHS DigiTrials recruitment service, is ultimately expected to provide benefits to health and social care by providing the participants for this pivotal trial. FDA guidance on the development of new antihypertensive treatments means that it is feasible to recruit sufficient patients for a pivotal trial in England alone, if effective and efficient recruitment methods are available, such as the NHS DigiTrials recruitment service.

This study will enable researchers to answer key research questions around new treatments for high blood pressure, including:

- What is the blood pressure-lowering efficacy of REGN-5381 at 100 mg every four weeks.

- What is the blood pressure-lowering efficacy of REGN-5381 at 300 mg every four weeks

- What is the safety of REGN-5381 at 100 mg or 300 mg every four weeks

- What are effects of REGN-5381 on kidney function

- What are the pharmacokinetics of REGN-5381 at 100 mg or 300 mg every four weeks

- How effective is REGN-5381 in people with chronic kidney disease or in people already prescribed 3 or more other blood pressure lowering medications

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

Yielded Benefits is not a requirement for new applications.