Heart Failure With Preserved Ejection FractionTRANSFERNCT05789147
Transcutaneous Vagus Nerve Stimulation in Heart Failure
A study testing Active tVNS in people with Heart Failure With Preserved Ejection Fraction and Heart Failure With Midrange Ejection Fraction, run by Istituti Clinici Scientifici Maugeri SpA at 1 site in Italy.
Trial summary
Several studies have shown that alterations in autonomic nervous system function are implicated in the onset and progression of numerous cardiovascular diseases. Direct stimulation of the vagus nerve by means of a sleeve placed around the vagus nerve represents one of the methodologies proposed in the field of… Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Heart Failure With Preserved Ejection Fraction, Heart Failure With Midrange Ejection Fraction
- What is being tested?
- Active tVNS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 29 participants
- Where
- 1 siteItaly
- Study dates
- 15 Jun 2020to 31 Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Heart failure patients with moderately reduced or preserved ejection fraction
- Sinus rhythm
- New York Heart Association (NYHA) Class II-III
Who cannot join
- Patients with implanted cardiac device (ICD, CRT),
- Patients with recent (< 3 months) cardiac surgery,
- Patients with recent (< 3 months) myocardial infarction,
- Patients with recent (< 3 months) revascularization
- Patients with an indication for cardiac surgery within the next 6 months.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: EffecTs of tRanscutaneous vAgus Nerve Stimulation in Heart Failure Patients With Moderately rEduced or preseRved Left Ventricular Function
Several studies have shown that alterations in autonomic nervous system function are implicated in the onset and progression of numerous cardiovascular diseases. Direct stimulation of the vagus nerve by means of a sleeve placed around the vagus nerve represents one of the methodologies proposed in the field of neuromodulation. This study, which is proposed as a pilot study for further application of the method in subjects with cardiovascular disease aims to verify and consolidate evidence on cardiovascular autonomic effects in patients with heart failure. Vagal stimulation will be achieved noninvasively by applying an external stimulator to the auricular site.
Read the detailed description
The autonomic nervous system (ANS), through the interaction between the sympathetic and vagal systems, plays a key role in modulating the cardiovascular system. Multiple experimental data and clinical studies have shown that alterations in the activity of the ANS - characterized by a predominant sympathetic modulation associated with reduced vagal modulation - are implicated in the onset and progression of numerous cardiovascular diseases. For example, both an increase in sympathetic activity and a reduction in vagal activity are associated with an increased risk of death after myocardial infarction and heart failure, and a further reduction in vagal activity has been shown to precede the phases of hemodynamic instability (1 -2).
Over the last few years, the modulation of the ANS through the implantation of devices has emerged as a new frontier for the treatment of heart failure (3). Although there is a wide interest in the scientific community for the potential represented by this therapeutic modality, nevertheless the different devices for neuromodulation therapy are implantable devices (whose application requires an invasive procedure) and therefore not free from risks and complications.
Direct stimulation of the vagus nerve by means of a sleeve positioned around the vagus nerve in its right or left cervical portion and controlled by a pacemaker, represents one of the methods proposed in the field of neuromodulation (4).
As for vagal stimulation, this can also be achieved non-invasively by applying an external stimulator in the ear (5). Transcutaneous nerve stimulation is a widely used procedure for the treatment of refractory epilepsy, while there is still limited experience evaluating its cardiovascular effects. Preliminary data in healthy volunteers have shown that: a) transcutaneous vagal stimulation, through the auricle, is able to activate the afferent vagal pathway up to the nucleus of the solitary tract (6), b) non-invasive stimulation of the vagus nerve is able to reduce sympathetic outflow (7). Recent clinical experience suggests its role also in the control of paroxysmal atrial fibrillation (8).
Therefore, non-invasive vagus nerve stimulation could be a promising therapeutic option in the cardiovascular field.
This study aims to evaluate the effects of long-term transcutaneous vagus nerve stimulation (tVNS) on autonomic parameters and other available physiological biomarkers that reflect long-term adjustment of autonomic neural regulation and to correlate the magnitude of the response to the baseline autonomic profile. A preliminary set of experiments will be conducted on healthy subjects to define the best tVNS protocol (in terms of frequency and site of stimulation) to induce acute changes in the autonomic profile.
- Conditions
- Heart Failure With Preserved Ejection Fraction, Heart Failure With Midrange Ejection Fraction
- Being tested
- Active tVNS, Sham tVNS
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Active tVNSDevice
It is a non-invasive transcutaneous electrical stimulation of the auricular branch of the vagus nerve which innervates the skin of the human ear. These nerve fibers project directly to the solitary tract nucleus (NTS) in the brain stem (6).
Sham tVNSDevice
Sham stimulation is obtained by placing the stimulation electrode at the level of the earlobe. The stimulation is therefore administered and perceived in an area not innervated by vagal fibers.
| Study group | Role | What they receive |
|---|---|---|
| active tVNS | Active comparator | Patients randomized to active treatment will be instructed to receive the stimulation at the tragus Receives: Device: Active tVNS |
| sham tVNS | Placebo comparator | Patients randomized to active treatment will be instructed to receive the stimulation at the ear lobe Receives: Device: Sham tVNS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Heart Rate
beats/min
Measured: 6 months
Secondary outcomes (1)
Baroreflex Sensitivity
ms/mmHg
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2023
- Study start15 Jun 2020
- Primary completion30 Sep 2024
- Study completion31 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Heart Failure With Preserved Ejection FractionStudies of the same condition, open and under way.
- More trials run by Istituti Clinici Scientifici Maugeri SpAThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized controlled study to evaluate the effects of 6-month tVNS (1 hour/day) in heart failure patients on autonomic biomarkers.
- Masking
- None (open label)
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- Istituti Clinici Scientifici Maugeri SpA
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05789147
- Sponsor's protocol ID
- CE 2182
- Other IDs
- RF-2016-02364803
- Acronym
- TRANSFER
- Status last verified
- Jan 2025
- First submitted
- 28 Feb 2023
- Last updated
- 30 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998 Feb 14;351(9101):478-84. doi: 10.1016/s0140-6736(97)11144-8.
PubMed 9482439Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, Pozzoli M, Opasich C, Tavazzi L. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation. 1997 Nov 18;96(10):3450-8. doi: 10.1161/01.cir.96.10.3450.
PubMed 9396441Schwartz PJ, La Rovere MT, De Ferrari GM, Mann DL. Autonomic modulation for the management of patients with chronic heart failure. Circ Heart Fail. 2015 May;8(3):619-28. doi: 10.1161/CIRCHEARTFAILURE.114.001964. No abstract available.
PubMed 25991804Klein HU, Ferrari GM. Vagus nerve stimulation: A new approach to reduce heart failure. Cardiol J. 2010;17(6):638-44.
PubMed 21154273Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II. Headache. 2016 Feb;56(2):259-66. doi: 10.1111/head.12650. Epub 2015 Sep 18.
PubMed 26381725Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015 May-Jun;8(3):624-36. doi: 10.1016/j.brs.2014.11.018. Epub 2014 Dec 6.
PubMed 25573069Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16.
PubMed 25164906Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, Lockwood D, Lazzara R, Po SS. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015 Mar 10;65(9):867-75. doi: 10.1016/j.jacc.2014.12.026.
PubMed 25744003Maestri R, Pinna GD. POLYAN: a computer program for polyparametric analysis of cardio-respiratory variability signals. Comput Methods Programs Biomed. 1998 Apr;56(1):37-48. doi: 10.1016/s0169-2607(98)00004-2.
PubMed 9617526Pinna GD, Maestri R, Torunski A, Danilowicz-Szymanowicz L, Szwoch M, La Rovere MT, Raczak G. Heart rate variability measures: a fresh look at reliability. Clin Sci (Lond). 2007 Aug;113(3):131-40. doi: 10.1042/CS20070055.
PubMed 17381425Pinna GD, Maestri R, Raczak G, La Rovere MT. Measuring baroreflex sensitivity from the gain function between arterial pressure and heart period. Clin Sci (Lond). 2002 Jul;103(1):81-8. doi: 10.1042/cs1030081.
PubMed 12095408Maestri R, Pinna GD, Robbi E, Cogliati C, Bartoli A, Gambino G, Rengo G, Montano N, La Rovere MT. Impact of optimized transcutaneous auricular vagus nerve stimulation on cardiac autonomic profile in healthy subjects and heart failure patients. Physiol Meas. 2024 Jul 17;45(7). doi: 10.1088/1361-6579/ad5ef6.
PubMed 39016202
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- EffecTs of tRanscutaneous vAgus Nerve Stimulation in Heart Failure Patients With Moderately rEduced or preseRved Left Ventricular Function
- ClinicalTrials.gov ID
- NCT05789147
- Acronym / sponsor ID
- TRANSFER / CE 2182
- Conditions
- Heart Failure With Preserved Ejection Fraction, Heart Failure With Midrange Ejection Fraction
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 29 participants (actual)
- Lead sponsor
- Istituti Clinici Scientifici Maugeri SpAUniversity, hospital or other
- Study start
- 15 Jun 2020 (actual)
- Primary completion
- 30 Sep 2024 (actual)
- Study completion
- 31 Dec 2024 (actual)
- First posted
- 29 Mar 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Several studies have shown that alterations in autonomic nervous system function are implicated in the onset and progression of numerous cardiovascular diseases. Direct stimulation of the vagus nerve by means of a sleeve placed around the vagus nerve represents one of the methodologies proposed in the field of neuromodulation. This study, which is proposed as a pilot study for further application of the method in subjects with cardiovascular disease aims to verify and consolidate evidence on cardiovascular autonomic effects in patients with heart failure. Vagal stimulation will be achieved noninvasively by applying an external stimulator to the auricular site.
Detailed description
The autonomic nervous system (ANS), through the interaction between the sympathetic and vagal systems, plays a key role in modulating the cardiovascular system. Multiple experimental data and clinical studies have shown that alterations in the activity of the ANS - characterized by a predominant sympathetic modulation associated with reduced vagal modulation - are implicated in the onset and progression of numerous cardiovascular diseases. For example, both an increase in sympathetic activity and a reduction in vagal activity are associated with an increased risk of death after myocardial infarction and heart failure, and a further reduction in vagal activity has been shown to precede the phases of hemodynamic instability (1 -2).
Over the last few years, the modulation of the ANS through the implantation of devices has emerged as a new frontier for the treatment of heart failure (3). Although there is a wide interest in the scientific community for the potential represented by this therapeutic modality, nevertheless the different devices for neuromodulation therapy are implantable devices (whose application requires an invasive procedure) and therefore not free from risks and complications.
Direct stimulation of the vagus nerve by means of a sleeve positioned around the vagus nerve in its right or left cervical portion and controlled by a pacemaker, represents one of the methods proposed in the field of neuromodulation (4).
As for vagal stimulation, this can also be achieved non-invasively by applying an external stimulator in the ear (5). Transcutaneous nerve stimulation is a widely used procedure for the treatment of refractory epilepsy, while there is still limited experience evaluating its cardiovascular effects. Preliminary data in healthy volunteers have shown that: a) transcutaneous vagal stimulation, through the auricle, is able to activate the afferent vagal pathway up to the nucleus of the solitary tract (6), b) non-invasive stimulation of the vagus nerve is able to reduce sympathetic outflow (7). Recent clinical experience suggests its role also in the control of paroxysmal atrial fibrillation (8).
Therefore, non-invasive vagus nerve stimulation could be a promising therapeutic option in the cardiovascular field.
This study aims to evaluate the effects of long-term transcutaneous vagus nerve stimulation (tVNS) on autonomic parameters and other available physiological biomarkers that reflect long-term adjustment of autonomic neural regulation and to correlate the magnitude of the response to the baseline autonomic profile. A preliminary set of experiments will be conducted on healthy subjects to define the best tVNS protocol (in terms of frequency and site of stimulation) to induce acute changes in the autonomic profile.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Randomized controlled study to evaluate the effects of 6-month tVNS (1 hour/day) in heart failure patients on autonomic biomarkers.
| Arm | Type | Receives |
|---|---|---|
| active tVNS | Active comparator | Device: Active tVNSPatients randomized to active treatment will be instructed to receive the stimulation at the tragus |
| sham tVNS | Placebo comparator | Device: Sham tVNSPatients randomized to active treatment will be instructed to receive the stimulation at the ear lobe |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Heart failure patients with moderately reduced or preserved ejection fraction
- Sinus rhythm
- New York Heart Association (NYHA) Class II-III
Key exclusion criteria (5 listed)
- Patients with implanted cardiac device (ICD, CRT),
- Patients with recent (< 3 months) cardiac surgery,
- Patients with recent (< 3 months) myocardial infarction,
- Patients with recent (< 3 months) revascularization
- Patients with an indication for cardiac surgery within the next 6 months.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Active tVNSIt is a non-invasive transcutaneous electrical stimulation of the auricular branch of the vagus nerve which innervates the skin of the human ear. These nerve fibers project directly to the solitary tract nucleus (NTS) in the brain stem (6). | Device | active tVNS |
| Sham tVNSSham stimulation is obtained by placing the stimulation electrode at the level of the earlobe. The stimulation is therefore administered and perceived in an area not innervated by vagal fibers. | Device | sham tVNS |
Primary outcome
Heart Rate
Time frame: 6 months
beats/min
1 secondary outcome
Baroreflex Sensitivity
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2025.
- Background: PubMed 9482439La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998 Feb 14;351(9101):478-84. doi: 10.1016/s0140-6736(97)11144-8.
- Background: PubMed 9396441Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, Pozzoli M, Opasich C, Tavazzi L. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation. 1997 Nov 18;96(10):3450-8. doi: 10.1161/01.cir.96.10.3450.
- Background: PubMed 25991804Schwartz PJ, La Rovere MT, De Ferrari GM, Mann DL. Autonomic modulation for the management of patients with chronic heart failure. Circ Heart Fail. 2015 May;8(3):619-28. doi: 10.1161/CIRCHEARTFAILURE.114.001964. No abstract available.
- Background: PubMed 21154273Klein HU, Ferrari GM. Vagus nerve stimulation: A new approach to reduce heart failure. Cardiol J. 2010;17(6):638-44.
- Background: PubMed 26381725Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II. Headache. 2016 Feb;56(2):259-66. doi: 10.1111/head.12650. Epub 2015 Sep 18.
- Background: PubMed 25573069Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015 May-Jun;8(3):624-36. doi: 10.1016/j.brs.2014.11.018. Epub 2014 Dec 6.
- Background: PubMed 25164906Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16.
- Background: PubMed 25744003Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, Lockwood D, Lazzara R, Po SS. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015 Mar 10;65(9):867-75. doi: 10.1016/j.jacc.2014.12.026.
- Background: PubMed 9617526Maestri R, Pinna GD. POLYAN: a computer program for polyparametric analysis of cardio-respiratory variability signals. Comput Methods Programs Biomed. 1998 Apr;56(1):37-48. doi: 10.1016/s0169-2607(98)00004-2.
- Background: PubMed 17381425Pinna GD, Maestri R, Torunski A, Danilowicz-Szymanowicz L, Szwoch M, La Rovere MT, Raczak G. Heart rate variability measures: a fresh look at reliability. Clin Sci (Lond). 2007 Aug;113(3):131-40. doi: 10.1042/CS20070055.
- Background: PubMed 12095408Pinna GD, Maestri R, Raczak G, La Rovere MT. Measuring baroreflex sensitivity from the gain function between arterial pressure and heart period. Clin Sci (Lond). 2002 Jul;103(1):81-8. doi: 10.1042/cs1030081.
- Results publication: PubMed 39016202Maestri R, Pinna GD, Robbi E, Cogliati C, Bartoli A, Gambino G, Rengo G, Montano N, La Rovere MT. Impact of optimized transcutaneous auricular vagus nerve stimulation on cardiac autonomic profile in healthy subjects and heart failure patients. Physiol Meas. 2024 Jul 17;45(7). doi: 10.1088/1361-6579/ad5ef6.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Active tVNS in people with Heart Failure With Preserved Ejection Fraction and Heart Failure With Midrange Ejection Fraction, run by Istituti Clinici Scientifici Maugeri SpA at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Heart Rate (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05789147, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2025.