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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Hypertension

Intervention / Treatment
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* Device: Active AffeX-CT device
* Device: Sham AffeX-CT device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has given written informed consent. Participant has sufficient knowledge of the English language to be able understand the participant information sheet and trial materials including outcome assessments. Participant is aged ≥18 years and <80 years at the time of screening visit. Participant is taking between 1 to 3 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). Participant has confirmed diagnosis of hypertension. 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). AND • Mean office BP (which is mean of last two readings from 3 BP recordings) with recorded SBP of ≥140 mmHg and <180 mmHg and DBP ≥90 mmHg and <120 mmHg at screening or baseline (randomisation) visit (either one of the two visits or both). Participant has one or more of the following associated conditions: 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)). Type 2 diabetes - controlled or sub-optimally controlled (HbA1c ≤8.5% or ≤69 mmol/mol) on diet and/ or medications except insulin. 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. 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) 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) Diagnosed or known case of polycystic ovarian syndrome. 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. Participant is able to communicate satisfactorily with the Investigator and Investigation Site staff, and to participate in, and comply with all clinical study requirements. Participants agrees to have all trial procedures performed and is able and willing to comply with all trial visits and protocol requirements. Exclusion Criteria: Participant is unable and unwilling to use the AffeX-CT device daily. 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). Participant has a piercing on the tragus of the ear. Participant is diagnosed with atrial fibrillation or other form of cardiac arrhythmia 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. Participant has type 1 diabetes mellitus. 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). Participant has a history of falls or symptoms of orthostatic hypotension in the last 3 months prior to baseline (randomisation) visit. Participant is pregnant, nursing or planning to become pregnant within the next 6 months. 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. Participant has significant (or symptomatic) target organ damage including symptomatic heart failure, renal damage, symptomatic peripheral vascular disease, or severe retinopathy. 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. Participant has history of renal denervation within 1 year prior to baseline (randomisation) visit. Participant has an implantable electronic/electrical device such as pacemaker, implantable cardioverter-defibrillators (ICDs), implanted vagal stimulators Participant has history of hospitalization for heart failure, cerebrovascular accidents, or stroke (at any time in the past). Participant has mean office pulse pressure ≥ 80 mmHg (mean of the last two of the three readings) at screening or baseline (randomisation) visit. 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). Participant has auricular dermatitis. Participant has postural hypotension, defined as a fall > 20mmHg in SBP on standing at 3 minutes (compared with sitting). Participant has a history of hospitalization for hypertensive emergency or urgency in the last six months of enrolment prior to baseline (randomisation) visit. 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.). 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible participants will be randomised at the baseline visit to either the active (tAN) or sham (sham-tAN) device arm of the trial at a ratio 2:1 ratio.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arm<br>Participants in this arm will receive the active AffeX-CT device. | Device: Active AffeX-CT device<br>* (Trans-cutaneous Autonomic Neurostimulation) tAN treatment will be administered using AffeX-CT device (a device based on a totally TENS unit). AffeX device comprises of a battery-operated control unit, two electrode pairs arranged on ear clips and connected to the control unit with electrical leads. The AffeX device generates an electrical signal that is used to stimulate the nerves that naturally control the output from the sympathetic nervous system.<br>|
| Sham Comparator: Sham arm<br>Participants in this arm will receive the sham (inactive) AffeX-CT device. | Device: Sham AffeX-CT device<br>* Sham Totally TENS device. The device is identical to the active device used in the study, but its only purpose is to act as a placebo. The ear-clip electrodes have been modified so that the electric current is not transmitted to the participant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in average daytime ambulatory Systolic Blood Pressure (SBP) from baseline to the end of treatment. | Daytime SBP values will be obtained with 24hr ABPM | from baseline to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in average daytime ambulatory SBP and Diastolic Blood Pressure (DBP) from baseline and 1 month. | Daytime ambulatory SBP values will be obtained with 24hr ABPM | from baseline to 1 month | 
| Change in average daytime ambulatory DBP from baseline to the end of treatment. | Daytime ambulatory DBP values will be obtained with 24hr ABPM | from baseline to 3 months | 
| Controlled BP at the end of treatment defined as mean daytime ambulatory SBP<135 mmHg and mean daytime ambulatory DBP<85 mmHg. | Daytime ambulatory SBP and DBP will be obtained with 24hr ABPM | from baseline to 3 months | 
| Change in average 24-hour ambulatory SBP and DBP from baseline to the end of treatment. | Daytime ambulatory SBP and DBP will be obtained with 24hr ABPM | from baseline to 3 months | 
| Change in average office SBP and DBP from baseline to 1 month, and from baseline to the end of treatment (3 months). | Daytime ambulatory SBP and DBP will be obtained with a vital signs monitor | baseline to 1 month and baseline to 3 months | 
| Change in average daytime ambulatory HR, and in average night-time ambulatory HR from baseline to the end of treatment. | Daytime and nigh-time ambulatory HR will be obtained with 24hr ABPM | from baseline to 3 months | 
| Change in BP variability defined as the coefficient of variation (SD/mean) of 24-hour ambulatory SBP, and of within-visit office SBP from baseline to the end of treatment. | 24hr ambulatory SBP will be obtained with 24hr ABPM | from baseline to 3 months | 
| Change in Heart Rate (HR) variability defined as the coefficient of variation (SD/mean) of 24-hour ambulatory HR, and of within-visit office HR from baseline to the end of treatment. | 24hr ambulatory HR will be obtained with 24hr ABPM | from baseline to 3 months | 
| Occurrence of a serious adverse event (SAE), fatal or non-fatal, within 3 months. | SAEs will be collected through patient interviews, reporting and monitoring | from baseline to 3 months | 
| The occurrence of a major cardiovascular event (MACE), including myocardial infarction (MI), stroke, and cardiovascular-related mortality within 3 months. | MACE will be collected through patient interviews, reporting and monitoring | from baseline to 3 months | 
| Change in Quality of life between baseline and the end of the treatment (3 months) using the EuroQol Visual Analogue score (0-100), and the EuroQol 5 Dimension (EQ5D) quality of life (QoL) questions. | EQ-5D-5L questionnaire | from baseline to 3 months | 
| Change in sleep quality between baseline and the end of the treatment using the Insomnia Severity Index (ISI), a 7-item questionnaire with each question allowing responses on a 5-point Likert scale from 0-4. Responses summed to give an overall score of 0 | ISI questionnaires | from baseline to 3 months | 
| Adherence to trial therapy, assessed as the proportion of days out of total days in follow-up when therapy was self-administered, and the average daily duration of self-administered therapy over the 3 months of follow-up (90 days). | Study log-book | from baseline to 3 months |