TRAnscutaneous vaGUS Nerve Stimulation in Patients With Chronic Heart Failure (TRAGUS-HF)

To verify the efficacy of transcutaneous vagus nerve stimulation (tVNS) on and autonomic balance in patients with chronic heart failure and reduced (HFrEF) or mildly reduced (HFmrEF) left ventricular ejection fraction. The study hypothesis is that tVNS increases baroreflex gain, with consequent benefits on sympathovagal balance (at short- and mid-term), and on quality of life and bio-humoral parameters (at mid-term).

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure; Heart Failure With Reduced Ejection Fraction; Heart Failure With Midrange Ejection Fraction
• Intervention / Treatment: Device: Active tVNS; Device: Sham tVNS

Detailed Description

Pilot phase: comparing the effects of right- (10-minute) vs. left-sided tVNS (10-minute) on BRS and heart rate variability (HRV) in a subset of patients.

Short-term phase: comparing the effects of active- (10-minute) vs. sham-tVNS (10-minute) on BRS, HRV, and sympathetic nerve activity.

Mid-term phase: comparing the effects of active- (4-week) vs- sham-tVNS (4-week) on BRS, HRV, biomarkers, exercise performance, and cardiac function.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Claudio Passino, MD; Phone Number: 050 3152191; Email: passino@ftgm.it
• Study Contact Backup: Name: Francesco Gentile, MD; Email: fgentile@ftgm.it

Study Locations

• Italy
  • Pi
    • Pisa, Pi, Italy, 56120
      • Michele Emdin
      • Contact: Michele Emdin, MD, PhD; Email: emdin@ftgm.it
      • Sub-Investigator: Francesco Gentile, MD
      • Principal Investigator: Claudio Passino, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria

• Aged ≥18 years;
• Ability to consent to enrollment;
• Diagnosis of chronic heart failure (CHF= and left ventricular ejection fraction <50% according to the latest European guidelines.

Exclusion criteria

• History of acute coronary syndrome within 3 months of enrollment;
• Clinical need to modify CHF therapy during the study;
• History of recurrent syncope, orthostatic hypotension, severe bradycardia (average heart rate <50 bpm), or second or third-degree atrioventricular block;
• Neurological conditions characterized by dysautonomia (e.g., Parkinson's disease);
• Unstable major psychiatric disorders or treatment with psychoactive drugs or drugs that can act on the autonomic nervous system (e.g., antidepressants, antipsychotics, opioids, benzodiazepines);
• Uncontrolled thyroid disorders;
• Active neoplasia;
• Severe renal insufficiency (estimated glomerular filtration rate <15 ml/min/1.73 m2);
• Moderate or severe chronic obstructive pulmonary disease (FEV1/FVC <70% of predicted and FEV1 <70%);
• Liver insufficiency (AST/ALT >100 U/L and/or gamma-GT >150 U/L);
• Participation in other clinical studies in the 3 months preceding;
• Women in pregnancy, breastfeeding, or of childbearing age not following adequate contraception (the woman must agree to abstain from heterosexual intercourse or use at least two effective contraceptive measures such as bilateral tubal ligation, male sterilization, use of hormonal contraceptives that inhibit ovulation, intrauterine devices releasing hormones, copper intrauterine devices; all barrier devices must be used in combination with a spermicidal cream).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active tVNS; The ear clip of the device will be positioned at the level of the patient's tragus delivering current.	Device: Active tVNS; As for the short-term phase, the ear clip of the "Parasym" device (Parasym, London, United Kingdom), containing the stimulation electrode, will be positioned at the level of the patient's tragus, and a 10-minute stimulation will be initiated with a pulse width of 200 μs, a frequency of 30 Hz, and an intensity of one mA lower than the patient's sensitivity threshold. As fort he mid-term phase, a device will be given to the patient, which will be instructed to position the ear clip of the device at the level of the tragus and to set stimulation parameters as established in the laboratory (see above). Each patient will be asked to undergo at least one hour daily stimulation for a period of 4 weeks, reporting on a diary the timing and details of the each session.
Placebo Comparator: Sham tVNS; The ear clip of the device will be positioned at the level of the patient's tragus but not delivering current.	Device: Sham tVNS; As for the short-term phase, the ear clip of the "Parasym" device (Parasym, London, United Kingdom), containing the stimulation electrode, will be positioned at the level of the patient's tragus for 10-minute but no current will be delivered. As fort he mid-term phase, a device (configured to withhold power delivery) will be given to the patient, which will be instructed to position the ear clip of the device at the level of the tragus and to set stimulation parameters as established in the laboratory (see above). Each patient will be asked to undergo at least one hour daily stimulation for a period of 4 weeks, reporting on a diary the timing and details of the each session.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in baroreflex gain (ms/mmHg)	Barorefex gain will be calculated calculated as the ratio between the standard deviation of RR intervals (ms) and systolic blood pressure (mmHg)	10 minutes (short-term effect)
Mean change in baroreflex gain (ms/mmHg)	Barorefex gain will be calculated calculated as the ratio between the standard deviation of RR intervals (ms) and systolic blood pressure (mmHg)	4 weeks (mid-term effect)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change in MSNA burst incidence (bursts/100 heartbeats)	Assessed through peroneal nerve microneurography (as previously detailed in doi: 10.3389/fphys.2022.934372).	10 minutes (short-term effect)
Mean change in peak O2 consumption (mL/Kg/min)	Assessed through cardiopulmonary exercise test	4 weeks (mid-term effect)

Collaborators and Investigators

• Sponsor: Fondazione Toscana Gabriele Monasterio
• Collaborators: Azienda Ospedaliera Città della Salute e della Scienza di Torino

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: February 4, 2024
• First Submitted That Met QC Criteria: April 4, 2024
• First Posted (Actual): April 9, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: TRAGUSHF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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