Personalised Pharmacometabolomic-guided Strategy Trial to Optimise Treatment for Hypertension

Trial design and setting:

HYPERMARKER is a proof-of-concept, pragmatic, adaptive, open-label strategy trial embedded in routine clinical practice with stratified individual patient randomisation. The setting is secondary care, including four hospital sites in four countries (Germany, the Netherlands, Spain and the United Kingdom). Potential participants can be identified at sites from referrals, hospital clinics, ambulatory care centres, during hospital admissions by their care team or members of the research team contracted at the site. Eligibility should be confirmed by medically-qualified personnel. Except for the enrolment process and optional final blood test, the trial can be managed remotely, or with in-person visits as preferred by sites and participants.

The intervention will combine metabolomic and clinical data using machine learning to provide additional information clinical investigators may utilise in their choice of blood pressure-lowering medication class for individual patients (pharmacometabolomic approach). The trial is organised into two phases to iterate and improve the pharmacometabolomic approach, and ensure that all patients included in the trial have access to the intervention. In the first phase, participants will be randomised to usual standard of care (group A) for treatment selection, or initial pharmacometabolomic approach (group B). In the second phase, participants originally randomised to group A will have their medications re-reviewed by the clinical investigator with access to the latest iteration of the pharmacometabolomic approach. Similarly, those originally randomised to group B will also potentially benefit from updates to the pharmacometabolomic approach during the course of the trial.

The range of drugs considered by the pharmacometabolomic approach are well-established hypertension medications that are the core basis of usual standard of care for hypertension treatment. All prescription decisions are made by the local Investigator who should be clinically-qualified with a license to practice and prescribe.

Enrolment:

HYPERMARKER is a pragmatic clinical trial, and patients will be recruited by opportunity within the recruitment period for each site. After written informed consent, the participant will be randomised and a blood sample collected to assess their metabolomic profile. Patient demographics, medical and medication history, comorbidity burden and patient-reported outcomes are collected. The study team will set up the home blood pressure monitoring device, demonstrate to the participant, and connect it to their own mobile device. Each participant will be asked to capture at least one week of home blood pressure measurements following randomisation. Patients, clinicians and study researchers will be able to access blood pressure values and trends using the secure online trial portal.

Randomisation and treatment allocation:

Timing: Participants can only be randomised after all eligibility criteria have been confirmed and informed consent is documented.

Process: Randomisation will be stratified by site (four sites), participant age (18-69 \& ≥70 years), and baseline SBP (SBP 140-159mmHg or ≥160mmHg), allocating the participants 1:1 to either Group A (initial standard of care) or Group B (up-front pharmacometabolomic approach). Investigators will randomise participants directly through the online trial platform using the Research Electronic Data Capture (REDCap) system.

Concealment of allocation: As an open-label trial, both the Investigator and participant will be aware of the allocation after randomisation, with the Investigator responsible for informing the participant about the randomised allocation.

Procedure where a participant withdraws from the trial: If a participant withdraws then their randomisation code cannot be reused. If a participant withdraws, they can be replaced.

Follow-up:

Group A Any changes or additional medication(s) will be initiated by the Investigator after the participant has completed at least one week of home blood pressure measurements. Choice of therapy will be left to the Investigator based on their usual clinical approach, and without the additional pharmacometabolomic information. Four weeks of blood pressure readings, and patient reported outcomes (PROs) completion will be requested of each participant. In the second phase, investigators are provided with the output from the latest iteration of the pharmacometabolomic approach when making their own clinical decision on what medication to prescribe. The participant is then requested to complete a further 4-weeks of blood pressure readings, and PRO completion regardless of any therapy change.

Group B The output from the pharmacometabolomic approach will be communicated within a 4-6 week period to investigators. Clinical staff will then be expected to prescribe therapy of their own choosing, ideally aligning with the pharmacometabolomic approach if deemed clinically appropriate. Four weeks of blood pressure measurements, and PRO completion will be requested of each participant. In the second phase, Clinical Investigators will receive an update from the latest iteration of the pharmacometabolomic approach and may choose to change the prescribed medication if clinically appropriate. A further 4-weeks of blood pressure measurements as well as PRO completion will be requested of participants requested regardless of any therapy change.

Blood pressure monitoring:

Participants will be requested to complete at least 3 days of blood pressure measurements at home per monitoring week. Each day consists of two readings in the morning and in the evening. Participants will receive notifications via the study app as they move through monitoring periods and by way of reminder to ensure readings are collected.

Patient Reported outcomes questionnaires:

Questionnaires can be sent by text message or email invitation and completed on a web-browser hosted by the online trial platform system - REDCap using any electronic device/system (Phone, tablet, laptop or desktop PC). Participants receive programmed reminders to complete the questionnaires.

The following questionnaires will be collected:

Quality of life: The EuroQOL EQ-5D-5L questionnaire will be collected at baseline, and following each phase of the trial.

Healthcare resource utilisation: This questionnaire collects data relevant to direct and indirect healthcare utilisation and will be collected at baseline, and following each phase of the trial.

Adherence questionnaire: Participants will be asked about whether they are taking the suggested anti-hypertensive medication and if they have any perceived adverse reactions. It will be collected following each phase of the trial. Socioeconomic \& Demographic questionnaire. This questionnaire will be optional for participants and sent at baseline.

Dietary intake: A dietary intake questionnaire will be completed by participants at site using an electronic device/system (Phone, tablet, laptop or desktop PC). Questionnaires will be hosted by myfood24 (Dietary Assessment Ltd), for sites in the UK and collect data regarding participants food and drink consumption from the previous 24hrs.

End of trial:

Each participant will be asked to attend their local research site to have an optional blood sample to assess changes in their metabolomic profile; this is for research purposes only and will not contribute to clinical care. The end of study for each participant is defined as the date of the last patient-reported blood pressure or patient-reported outcome.

Public and Patient Involvement in the study design and methodology:

A patient and public involvement (PPI) group with representatives from all four trial site countries have reviewed the trial design and content of key trial documents such as the protocol, participant information leaflet, participant information video and the informed consent form. The PPI group have also tested the at home blood pressure device and mobile application as well as patient-reported outcome questionnaires. Changes including to the content, delivery platform and design have been made following PPI feedback to ensure participants will understand and accept what will happen to them in the study.