Skin Sodium and Salt Sensitivity of Blood Pressure (INTREPID)

Investigating the Relevance of Skin Sodium and Salt Sensitivity of Blood Pressure in Determining the Response to Anti-Hypertensive Drugs (INTREPID)

Eating too much salt raises blood pressure and the risk of having a heart attack or stroke. The investigators do not fully understand why salt raises blood pressure, but storage of sodium in the body, particularly in the skin, may be important. For this reason, the investigators wish to study the link between skin sodium, blood pressure and cardiovascular risk in patients with high blood pressure, of different ethnicities, using techniques such as skin biopsy and magnetic resonance imaging (MRI). The results will provide detailed information on skin sodium storage and help us better understand the effects of blood pressure medications on these mechanisms. Ultimately, the investigators aim to develop personalized treatment guidelines for clinical use.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypertension
• Intervention / Treatment: Drug: Amlodipine; Drug: Chlortalidone

Detailed Description

The physiological basis of salt sensitivity of blood pressure (SSBP) is poorly understood, and determining which patients have SSBP is not straightforward. Furthermore, determining salt sensitivity requires direct intervention tracking changes in blood pressure after salt challenge or depletion over several days. This makes identifying salt-sensitive individuals impractical in a clinical setting, hindering its application. It is crucial that the investigators elucidate the underlying mechanisms of salt-sensitivity, and through this understanding develop a biomarker of SSBP for clinical use.

From a review of recent studies it appears that in the short-term, accumulation of skin sodium during high salt intake attenuates the blood pressure response, while in the long-term, high skin sodium levels indicate a tendency for SSBP, hypertension and elevated cardiovascular risk. The reasons for this are not clear and merit further investigation. By refining methods for quantification of skin sodium and expanding its use in hypertension research, the clinicians can improve patient assessment, treatment prescription, and disease monitoring.

Using skin biopsy and sodium MRI provides a unique opportunity to study skin sodium handling and SSBP during antihypertensive treatment, and can provide insights into why hypertensives and certain ethnic groups have a higher incidence of SSBP. Sodium MRI may also help increase our understanding of the mechanisms by which diuretics work, both systemically and in the kidney and provide a way to identify salt-sensitive individuals for targeted clinical intervention.

Hypotheses:

1. Skin sodium decreases with salt-dependent (diuretic) treatments but not salt-independent (calcium channel blocker) treatments.
2. Diuretic-induced reductions in skin sodium correlate with reductions in blood pressure.
3. Skin sodium is higher in populations traditionally known to be more salt sensitive, such hypertensive patients of black ethnicity.

Patients will be enrolled on to a randomised, open-label, two-treatment two-period crossover treatment. The hypertensive medication used in this study are Amlodipine 5 or 10mg and Chlortalidone 25mg.

The duration for individual participants will be approximately 16 weeks. Participants will have a total of 7 visits including screening/enrolment (visit 1) and baseline visit (visit 2).

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Irene Sambath; Phone Number: 01223 256621; Email: irene.sambath@nhs.net

Study Locations

• United Kingdom
  • Cambridge, United Kingdom
    • Addenbrooke's Hospital
    • Contact: Irene Sambath; Email: cuh.intrepid@nhs.net
  • London, United Kingdom
    • St Thomas' Hospital
    • Contact: Luca Faconti

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Have given written informed consent to participate
2. Aged 18 or above

3. Be hypertensive defined as:

   1. Currently untreated with an ABPM day time average blood pressure or average home blood pressure of ≥135 mmHg (systolic) or ≥85 mmHg (diastolic)

      OR

   2. Patients who are 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/PI, can enter the study if they meet the above criteria.

Exclusion Criteria:

1. Uncontrolled blood pressure ≥ 180/110mmHg
2. Known or suspected secondary hypertension
3. Pregnant or breastfeeding women
4. Significant sensitivity or contraindications to any of the study medications
5. Participants taking lithium or are regularly consuming non-steroidal anti-inflammatory drugs at variable doses
6. Requirement to take any of the study drugs continuously e.g. ACEi and heart failure
7. Any clinically significant hepatic impairment
8. Any clinically significant kidney impairment
9. Concurrent participation in another clinical trial or study using systemic vasoactive medications or medications known to interact with the study drugs
10. Patients who are deemed unsuitable by the investigator on clinical grounds e.g. an abnormal heart rhythm due to Atrial Fibrillation (AF)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Open label arm 1; Participants will be randomised to AB sequence of drugs A: 1 to 2 weeks of Amlodipine 5mg followed by 6 to 7 weeks of Amlodipine 10mg B: Approximately 8 weeks of 25mg Chlortalidone	Drug: Amlodipine; Amlodipine 5mg and Amlodipine 10mg will be one of the study drugs the patients will receive.; Drug: Chlortalidone; Chlortalidone 25mg will be one of the study drugs the patients will receive.
Other: Open label arm 2; Participants will be randomised to BA sequence of drugs B: Approximately 8 weeks of 25mg Chlortalidone A: 1 to 2 weeks of Amlodipine 5mg followed by 6 to 7 weeks of Amlodipine 10mg	Drug: Amlodipine; Amlodipine 5mg and Amlodipine 10mg will be one of the study drugs the patients will receive.; Drug: Chlortalidone; Chlortalidone 25mg will be one of the study drugs the patients will receive.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Skin sodium	This is planned for all participants	Approximately 8 weeks after receiving each treatment up to week 16 which will be the study completion week
Concentration of Skin Potassium	This is planned for all participants	Approximately 8 weeks after receiving each treatment up to week 16 which will be the study completion week
Systolic blood pressure	This is planned for all participants	All study visits - every 4 weeks up to week 16 which will be the study completion week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI skin sodium concentration	This is planned for all participants	Approximately 8 weeks after receiving each treatment up to week 16 which will be the study completion week
Concentration of Skin glycosaminoglycans	This is planned for all participants	Approximately 8 weeks after receiving each treatment up to week 16 which will be the study completion week
Diastolic blood pressure	This is planned for all participants	All study visits - every 4 weeks up to week 16 which will be the study completion week
Body weight	This is planned for all participants	Body weight measurement will be performed at baseline only.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sodium MRI of kidney	This is planned for patients who consent to sodium imaging of kidney	Approximately 8 weeks after receiving each treatment up to week 16 which will be the study completion week

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: King's College London
• Investigators: Principal Investigator: Ian Wilkinson, Cambridge University Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 17, 2023
• First Submitted That Met QC Criteria: July 27, 2023
• First Posted (Actual): August 4, 2023

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular; Blood Pressure; Heart Disease; Salt Sensitivity; Skin Sodium
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Sodium Chloride Symporter Inhibitors; Amlodipine; Chlorthalidone
• Other Study ID Numbers: A096461

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No