Long-term Effects of Transcutaneous Vagal Nerve Stimulation on Postural Orthostatic Tachycardia Syndrome (POTS)

Not Applicable

• Conditions: Autonomic Dysfunction; Syncope, Postural; Orthostatic Intolerance; Postural Tachycardia Syndrome; Physical Disability
• Interventions: Device: Transcutaneous vagal nerve stimulation (tVNS); Other: Placebo; Device: Home daily transcutaneous vagal nerve stimulation

• Registration Number: NCT04632134
• Lead Sponsor: Istituto Clinico Humanitas

Brief Summary

Postural Orthostatic Tachycardia Syndrome (POTS) is characterized by symptoms of chronic orthostatic intolerance such as fatigue, lightheadedness, dizziness, palpitations and by pronounced tachycardia upon standing.

The aims of the present research study are to test whether a daily transcutaneous vagal nerve stimulation (tVNS) performed for 14 consecutive days may improve heart rate response and reduce disabling symptoms while standing.

Detailed Description

Postural Orthostatic Tachycardia Syndrome (POTS) is characterized by symptoms of chronic orthostatic intolerance such as fatigue, lightheadedness, dizziness, palpitations and by pronounced tachycardia without hypotension upon standing. In healthy volunteers, transcutaneous vagal nerve stimulation (tVNS) may result in increased cardiac vagal activity and reduced vascular sympathetic drive with minimal, if any, side effects. It is possible to hypothesize that any therapeutic intervention aimed at increasing cardiac vagal modulation might result in clinical improvement of the disease.

The aim of the study are to evaluate the medium-term effects of tVNS, performed every day for a 14 days on cardiovascular autonomic profile and symptoms intensity in POTS patients.

Study and General Design

Phase 1- Enrollment:

23 POTS patients, older than 18 years of age, will be consecutively enrolled. Each POTS patient will undergo complete medical evaluation at the time of enrollment, which will take place seven days before baseline recordings (i.e. Control day, see below), in order to individually optimize the tVNS amplitude and get patients familiarized with both the tVNS procedure and the clinical laboratory environment. On the same day, 30-minute continuous tVNS will be delivered to the patients under rigorous medical and hemodynamic supervision to exclude any kind of short term adverse effects.

Transcutaneous vagal nerve stimulation (tVNS) will be performed using a noninvasive battery powered Transcutaneous Electrical Nerve Stimulation device (Nemos ©; Cerbomed, Germany). Electrical stimulation will be delivered by external electrodes through the skin surface at the conca of right external ear. Electrical current will be applied continuously with a pulse width of 200 μs and pulse frequency of 25 Hz, differently from previous protocols. Stimulation amplitude will be adjusted between 0.1-6 milliampere (mA), to a maximal amplitude level without causing patient discomfort.

Phase 2 Sham tVNS and Effective tVNS:

In every subject continuous ECG, beat by beat non-invasive arterial pressure (Nexfin device), respiratory activity by thoracic piezoelectric belt will be recorded while supine and during 75° head-up tilt (rest-tilt protocol). After positioning the tVNS electrodes in the right ear but without delivering tVNS (Sham tVNS), above mentioned signals will be recorded for 10 minutes while supine, for 15 minutes during 75° head-up tilt. The same protocol will be repeated during stimulation amplitude will be adjusted to maximal tolerable level as assessed in Phase 1 (effective acute tVNS).

The Composite Autonomic Symptom Scale (COMPASS 31) COMPASS 31 will be used to quantify the following autonomic symptoms: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, urinary and pupillomotor dysfunction symptoms .

Phase 3-Home daily stimulation:

Thereafter, every patient will be provided with a Nemos© device and electrodes for home daily stimulation. Daily stimulation will consist of 4 hours of stimulation organized as 4 sessions each lasting 1 hour, to be applied at the patient's convenience.

Phase 4- Post- 14-day tVNS. After 14 days of home daily tVNS, all the patients will undergo the rest-tilt protocol described in Phase 2.

COMPASS 31 questionnaire will be administered while supine and during 75° head-up Tilt

Study Timeline

• Study First Submitted: 2019-09-04
• Study Start: 2019-11-10
• Study First Submitted QC: 2020-11-16
• Study First Posted: 2020-11-17
• Status Verified: 2021-06
• Last Update Submitted: 2022-06-29
• Primary Completion: 2022-06-30
• Last Update Posted: 2022-06-30
• Study Completion: 2022-12-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

• Clinical diagnosis of Postural Orthostatic Tachycardia Syndrome
• Older than 18 years

Exclusion Criteria

• Dysautonomias other than POTS
• Neurodegenerative diseases
• History/family history of seizures
• Atrial fibrillation and other relevant cardiac rhythm disturbances
• Chronic inflammatory diseases
• Chronic use on anti-inflammatory drugs
• Diabetes
• Other neurological or psychiatric diseases
• Pacemakers or other electronic implants inserted into the body
• Coronary disorders
• Elevated intracranial blood pressure
• Assumption of drugs facilitating seizures
• Assumption ofpsychiatric drugs
• Alcohol abuse

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Transcutaneous vagal nerve stimulation (tVNS)	Placebo	After positioning the tVNS electrodes in the right ear but without delivering tVNS (Sham tVNS), above mentioned signals will be recorded for 10 minutes while supine, for 15 minutes during 75° head-up tilt. The same protocol will be performed during active tVNS. The tVNS will be performed while 15 minutes in supine position and during 75°head-up Tilt. Thereafter, every patient will be provided with a Nemos© device and electrodes for home daily stimulation. Daily stimulation will consist of 4 hours of stimulation organized as 4 sessions each lasting 1 hour, to be applied at the patient's convenience.
Transcutaneous vagal nerve stimulation (tVNS)	Transcutaneous vagal nerve stimulation (tVNS)	After positioning the tVNS electrodes in the right ear but without delivering tVNS (Sham tVNS), above mentioned signals will be recorded for 10 minutes while supine, for 15 minutes during 75° head-up tilt. The same protocol will be performed during active tVNS. The tVNS will be performed while 15 minutes in supine position and during 75°head-up Tilt. Thereafter, every patient will be provided with a Nemos© device and electrodes for home daily stimulation. Daily stimulation will consist of 4 hours of stimulation organized as 4 sessions each lasting 1 hour, to be applied at the patient's convenience.
Transcutaneous vagal nerve stimulation (tVNS)	Home daily transcutaneous vagal nerve stimulation	After positioning the tVNS electrodes in the right ear but without delivering tVNS (Sham tVNS), above mentioned signals will be recorded for 10 minutes while supine, for 15 minutes during 75° head-up tilt. The same protocol will be performed during active tVNS. The tVNS will be performed while 15 minutes in supine position and during 75°head-up Tilt. Thereafter, every patient will be provided with a Nemos© device and electrodes for home daily stimulation. Daily stimulation will consist of 4 hours of stimulation organized as 4 sessions each lasting 1 hour, to be applied at the patient's convenience.

Primary Outcome Measures

Name	Time	Method
Change of Autonomic symptoms	Change from baseline Autonomic symptoms at 14 days	Autonomic symptoms will be assessed by the Composite Autonomic Symptom Scale (COMPASS 31) questionnaire. This is based on 31 items and a score ranging from 0 to100, 0 being the absence of symptom and 100 the greatest symptom intensity. The COMPASS 31 will be used to quantify the following autonomic symptoms: orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, urinary and pupillomotor dysfunction symptoms.

Secondary Outcome Measures

Name	Time	Method
Change in Heart rate	Change from baseline cardiovascular autonomic profile at 14 days	Change of Cardiovascular autonomic profile
Change in respiration rate	Change from baseline cardiovascular autonomic profile at 14 days	Change of Cardiovascular autonomic profile
Change in blood pressure	Change from baseline cardiovascular autonomic profile at 14 days	Change of Cardiovascular autonomic profile

Trial Locations

Locations (1)

Humanitas Research Hospital; 🇮🇹 Rozzano, Italy