Comparison of Optimal Hypertension Regimens

In the UK, current NICE (National Institute for Health and Clinical Excellence) guidance stratifies hypertension treatment according to age and self-defined ethnicity (SDE). Different initial monotherapies are recommended for all those aged over 55 years, and for younger black compared to white individuals. However, there is no recommended stratification for combination therapy. The evidence based supporting the current guidance on SDE stratification is limited, and there is a specific lack of data from UK based populations.

Stratification based on SDE has a number of limitations and an alternative approach is stratification based on ancestry informative markers (AIM). There are genetic polymorphisms, which show substantially different frequencies between populations from different geographical regions, and can predict geographical ancestry with remarkable accuracy. AIM are thus more likely to capture the genetic component of variation in drug response in ethnically diverse population.

Metabolomic profiling of plasma and urine may provide complementary information to AIM, as differences between individuals will reflect both genetic and environmental influences. To address these issues the investigators intend to compare the variation in response to antihypertensive drug treatments in three SDE cohorts, and relate this to variation in AIM and metabolomic profiles. Our objective is to test the validity of current NICE guidance on antihypertensives stratification based on SDE, to provide evidence about SDE stratification for dual therapy, and to examine whether more effective personalisation of antihypertensive treatment, can be achieved using AIM and/or metabolomic profiling.

An assessment of patient stratification based on AIM phenotypes against SDE will enable the selection of optimal and more effective choices of anti-hypertensive treatments from currently existing first line drugs (and combinations of) and ultimately reduce the attrition of antihypertensive therapies.

Output from the trial will provide the first perspective evidence for best treatment choice according to SDE for white, black and asian populations in the UK. This should reduce the number of consultations; time required to achieve optimal blood pressure control and the contribution to between hypertension control in the UK.

Patients in the trial will be enrolled on a monotherapy or dual therapy regime depending on their history of hypertension. The monotherapy group of patients will enter a randomised, open-label, three-treatment three-period cross over trial.

The dual therapy group of patients will enter a randomised, open-label, four-treatment four-period cross over trial.

Randomisation, for each crossover design, will be stratified by three SDE groups.

The duration for individual participants will be approximately 24 (monotherapy) or 32 weeks (dual therapy)

The hypertensive medication used in this trial are:

Amlodipine 5 or 10mg, Chlortalidone 25mg, Amiloride 10mg, Lisinopril 10 or 20mg,

Participants on the dual therapy treatment arm will have a total of 11 visits including screening/enrolment (visit 1) and baseline visit (visit 2)

Participants on the monotherapy treatment arm will have a total of 9 visits including screening/enrolment (visit 1) and baseline visit (visit 2)

A total number of 1320 participants will be enrolled in the study across participating sites, so that approximately 660 participants in each therapy regime (approximately 220 participants per ethnic group) complete the trial.

An optional skin-sodium investigation will be conducted at selected sites only where capacity and capability to complete the sub study investigations is demonstrated. The sub study aims to recruit up to 60 participants who have already given consent for the main AIM HY INFORM Trial. Consent for the optional sub-study will be obtained separately.

The investigation comprises two optional assessments: a skin biopsy and a sodium magnetic resonance imaging (23Na MRI) scan. Both assessments will be used to quantify skin sodium levels. Participants in the mono and dual therapy arms can elect to have the skin biopsy, the MRI scan, or both, at the baseline visit. Participants in the mono therapy arm only, can elect to have the skin biopsy, the MRI scan, or both, following completion of the amlodipine (A) and chlortalidone (C) study arms. The additional measurements are not anticipated to take more than approximately 2 hours.

Inclusion criteria

To be included in the trial the participant must:

• Have given written informed consent to participate
• Be aged 18 to 65 years inclusive
• Self-Define Ethnicity: participants should SELF IDENTIFY into 1 of the three groups below:

White White British White Irish Any other white background

Black or Black British Black Caribbean Black African Any other black background

Asian or Asian British Asian Indian Asian Pakistani Asian Bangladeshi Any other Asian background

• Be hypertensive defined as:- Mono-therapy rotation

• currently untreated with EITHER an ABPM day time average blood pressure ≥ 135mmHG (systolic) or ≥ 85mmHg (diastolic) OR Home BP measurements using a validated device based on the average of 10 blood pressure readings of ≥135 mmHg (systolic) or ≥85 mmHg (diastolic)
• Patients who may be taking antihypertensive drugs at sub therapeutic doses or in ineffective combinations, and who are felt likely to be controllable on a study drug and willing and able to be washed out, at the discretion of the CI (Chief Investigator) / PI (Principal Investigator), can enter the trial if they meet the above criteria.

Dual therapy rotation

a.Treated hypertensive receiving one to three antihypertensive drugs with a blood pressure (ABPM daytime average blood pressure or Home BP as in a.) between 135 or 200 mmHg (systolic) AND between 85 or 110 mmHg (diastolic).

Exclusion criteria

The presence of any of the following will mean participants are ineligible:

• Participant does not fit into one of the defined ethnic groups e.g. Mixed
• Pregnant or breastfeeding women
• Known or suspected secondary hypertension
• Significant sensitivity or contraindications to any of the study medications
• Participants taking lithium or are regularly consuming non-steroidal anti-inflammatory drugs at variable doses
• Requirement to take any of the study drugs continuously e.g. ACEi and heart failure
• Any clinically significant hepatic impairment
• Any clinically significant kidney impairment
• Concurrent participation in another clinical trial using systemic vasoactive medications or medications known to interact with the study drugs (participation in another study as part of the AIM HY mechanistic or social science programme will not be an exclusion criterion)
• Patients who are deemed unsuitable by the investigator on clinical grounds