SCRATCH-HTN Study: Evaluating Autonomic Neuromodulation Using Trans-cutaneous Vagal Stimulation in Hypertensive Patients

Sham Controlled RCT Evaluating the Safety, Acceptability and Efficacy of Autonomic Neuromodulation Using Trans-cutaneous Vagal Stimulation in Uncontrolled Hypertensive Patients: a Pilot Study

This is a pilot, sham-controlled, double blind, single-site device clinical trial designed to evaluate the safety, acceptability and efficacy of non-invasive autonomic neuromodulation in a cohort of 63 adult patients with uncontrolled high blood pressure.

SCRATCH-HTN trial is a randomised sham-controlled study designed to evaluate the safety, acceptability, and efficacy of trans-cutaneous autonomic neurostimulation (tAN) in a cohort of uncontrolled medicated hypertensive patients.

SCRATCH-HTN trial is designed to test the hypothesis that tAN treatment is safe and acceptable to the patient, improves the control of blood pressure in hypertension and sense of well-being amongst those who are receiving the active treatment as compared to those on sham treatment.

The study will recruit 63 patients with systemic arterial hypertension (male and female aged ≥18 years) who are receiving between one and three oral antihypertensive medications and remain hypertensive with blood pressure (BP) above target levels detailed below in the eligibility criteria. The participants will be randomly allocated to the active (tAN) or sham (sham-tAN) arms of the trial on 2:1 basis, respectively.

The total treatment duration is 12 weeks. Self-administration of 30 min of tAN or sham stimulations once per day for the first two weeks, and then once every week for the rest of the trial period.

Inclusion Criteria:

1. Participant has given written informed consent.

2. Participant has sufficient knowledge of the English language to be able understand the participant information sheet and trial materials including outcome assessments.

3. Participant is aged ≥18 years and <80 years at the time of screening visit.

4. Participant is taking between 1 to 4 antihypertensive medications (inclusive) at time of screening and baseline (randomisation) visit and is willing to adhere to no change in medication during the trial until end of the trial visit (visit 5). (NB. Participant on only one antihypertensive medication should be taking that medication for at least six weeks prior to the screening visit).

5. Participant has confirmed diagnosis of hypertension.

6. Participant meets BP criteria:

   • 24-hour ambulatory BP monitoring (ABPM) at either screening visit or baseline (randomisation) visit, with mean daytime SBP of ≥135 mmHg and <170 mmHg and mean daytime DBP of ≥85 mm Hg and <115 mmHg (N.B. By default, Ambulatory Blood Pressure Monitoring [ABPM] at screening visit will be used at baseline visit. However, if there has been an addition of new medication after participants screening visit, 24-hour ABPM must be repeated at baseline visit).

7. Participant has one or more of the following associated conditions:

   1. Obesity: BMI >30 or waist circumference >94 cm (men) or > 80cm (women). (NB. For participants of South-East Asian/Chinese/Japanese origin these cut-offs are >90 cm (men) or >80 cm (women)).
   2. Type 2 diabetes - controlled or sub-optimally controlled (HbA1c ≤8.5% or ≤69 mmol/mol) on diet and/ or medications except insulin.
   3. Heart rate (average) ≥70 bpm at screening or baseline (randomisation) visit (measurement taken after 5 minutes of rest in a seated position and when finger probe has been placed for a minimum of 30 seconds thereafter) or a heart rate (average) ≥60 bpm at screening or baseline (randomisation) visit if the patient is taking beta-blocker medication.
   4. HbA1c ≥42 mmol/mol or fasting blood glucose (if available) ≥5.6 mmo/L AND either low HDL cholesterol (≤1.03 mmol/L for men and ≤1.29 mmol/L for women) or high triglyceride (triglycerides ≥1.7 mmol/L)
   5. Both low HDL cholesterol (≤1.03 mmol/L for men and ≤1.29 mmol/L for women) AND high triglyceride (triglycerides ≥1.7 mmol/L)
   6. Diagnosed or known case of polycystic ovarian syndrome.

8. Female participants of child-bearing potential (all those below 55 years except if they are surgically sterile, meaning they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy, or formally diagnosed by their doctors to be post-menopausal) must agree to use the acceptable methods of contraception from the time of consent until last follow up visit.

9. Participant is able to communicate satisfactorily with the Investigator and Investigation Site staff, and to participate in, and comply with all clinical study requirements.

10. Participants agrees to have all trial procedures performed and is able and willing to comply with all trial visits and protocol requirements.

Exclusion Criteria:

1. Participant is unable and unwilling to use the AffeX-CT device daily.
2. Participant has a small tragus (ie. the size or shape of the tragus is such that it doesn't allow the application of the ear-clips of the AffeX-CT device for a sustained period of time).
3. Participant has a piercing on the tragus of the ear.
4. Participant is diagnosed with atrial fibrillation or other form of cardiac arrhythmia
5. Participant is known to have chronic kidney disease (CKD) stage 3b or higher or had eGFR <45 ml/min/1.73 m2 in last three months prior to baseline (randomisation) visit.
6. Participant has type 1 diabetes mellitus.
7. Participant has type 2 diabetes mellitus on Insulin or those on oral antidiabetic medications with poor glycaemic control defined as HbA1c above 8.5% (or >69 mmol/mol).
8. Participant has a history of falls or symptoms of orthostatic hypotension in the last 3 months prior to baseline (randomisation) visit.
9. Participant is pregnant, nursing or planning to become pregnant within the next 6 months.
10. Participant suffers from chronic pain and has taken anti-inflammatory drugs for two or more days per week over the last month prior to baseline (randomisation) visit.
11. Participant has clinically significant or symptomatic hypertension-mediated target organ damage such as severe heart failure with NYHA 4, end stage renal damage, medically diagnosed/imaging proven stroke, symptomatic peripheral vascular disease, or severe retinopathy.
12. Participant has a history of stable or unstable angina or had an acute coronary event within 3 months prior to baseline (randomisation) visit or had a myocardial infarction within the last six months of enrolment prior to baseline (randomisation) visit.
13. Participant has a history of renal denervation within last 1 year prior to baseline (randomisation) visit.
14. Participant has a therapeutic implantable electronic/electrical device such as pacemaker, implantable cardioverter-defibrillators (ICDs), implanted vagal stimulators.
15. Participant has history of hospitalization (> 24 hour) for heart failure, or cerebrovascular accidents, or history of stroke diagnosed based on imaging or evidence of specialist diagnosis or any other indirect evidence such as discharge summary or clinical letter (at any time in the past).
16. Participant has mean daytime ABPM pulse pressure ≥ 80 mmHg at screening or baseline (randomisation) visit.
17. Participant has a heart rate <50 bpm at screening or baseline (randomisation) visit (measurement taken after 5 minutes of rest in a seated position and when finger probe has been placed for a minimum of 30 seconds thereafter).
18. Participant has auricular dermatitis.
19. Participant has postural hypotension, defined as a fall > 20mmHg in SBP on standing at 3 minutes (compared with sitting).
20. Participant has a history of hospitalization for hypertensive emergency or urgency in the last six months of enrolment prior to baseline (randomisation) visit.
21. Participant is identified as unsuitable to participate by the CI/Co-Investigator(s) and/or Investigation site team for another reason (e.g., for other medical reasons, laboratory abnormalities, limited life expectancy, etc.).
22. Participants with history of epilepsy and are currently on anti-epileptic medication or those who are not on any anti-epileptic medication but have history of a seizure within last 10 years.