Vagal Nerve Stimulation for POTS

Age: 18 - 65

Sex: Female

Trial Phase: Phase 1

Sponsor: Vanderbilt University Medical Center

Must not be taking: Corticosteroids

Disqualifiers: Pregnancy, Bedridden, Smoking, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 3 study days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how stimulating a nerve in the earlobe, known as transcutaneous vagal nerve stimulation, can help manage symptoms in women with postural tachycardia syndrome (POTS). The trial examines how this stimulation, alone or combined with one of two medications (galantamine or pyridostigmine), affects heart rhythm, symptoms when standing, and inflammation. Participants will experience different treatment combinations over three days. Women aged 18-45 who have had POTS for more than six months and experience a rapid heart rate upon standing might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

If you are taking any medication that affects the autonomic system or inflammation, you would need to stop them before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that transcutaneous vagal nerve stimulation (tVNS) is generally easy for people to handle. This non-invasive method avoids major side effects that some medications cause. Early results indicate that tVNS can help reduce heart rate spikes in people with postural tachycardia syndrome (POTS).

Pyridostigmine, used with tVNS in this study, is commonly prescribed for POTS. Research indicates it is well tolerated over long-term use, though some may experience mild side effects like stomach cramps or diarrhea.

Galantamine, another medication being tested, is considered safe for other conditions. Studies have shown it can be used long-term without causing major problems or increasing tumor risk in animal studies.

Overall, earlier research has shown both the medications and the nerve stimulation to be quite safe. Participants in the trial will be closely monitored to ensure their safety and well-being. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about vagal nerve stimulation for treating POTS (Postural Orthostatic Tachycardia Syndrome) because it offers a novel approach compared to traditional treatments like beta-blockers or medications such as fludrocortisone. Unlike these standard treatments that often focus on managing heart rate and blood volume, vagal nerve stimulation targets the nervous system directly, potentially offering a new mechanism to alleviate symptoms. This approach involves using electrical impulses to stimulate the vagus nerve, which plays a crucial role in regulating heart rate and blood pressure. This technique could offer faster symptom relief and a different pathway to manage POTS, sparking interest in its potential benefits over current therapies.

What evidence suggests that this trial's treatments could be effective for POTS?

Research has shown that transcutaneous vagal nerve stimulation (tVNS) can help reduce fast heart rates in people with POTS. Some participants in this trial will receive tVNS, which studies have shown to slow heart rates compared to sham treatments. Another treatment option in this trial is pyridostigmine, which has improved symptoms for many POTS patients, with up to 52% of those who tolerated it experiencing relief. Although less research exists on galantamine specifically for POTS, it is also being tested in this trial alongside tVNS due to its effects on the nervous system. These treatments show promise for managing POTS symptoms by influencing heart rhythm and the nervous system. ^{1 2 6 7 8}

Who Is on the Research Team?

Italo Biaggioni, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

This trial is for women aged 18-45 with Postural Tachycardia Syndrome (POTS), experiencing a rapid heartbeat upon standing. Participants must have had POTS symptoms for over 6 months and be able to consent. Excluded are those pregnant, with conditions explaining POTS, bed/chair-ridden individuals, or anyone on medications affecting autonomic function who can't stop them before the study.

Inclusion Criteria

I am a woman aged 18-45 with POTS, experiencing a rapid heart rate increase when standing.

Subjects able and willing to provide informed consent

Exclusion Criteria

I do not have conditions like smoking, diabetes, obesity, infections, or cancer that could affect study results.

I cannot stop taking medication that affects my body's automatic processes or inflammation for the study.

Pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 study days

1-2 visits (in-person)

Treatment

Participants receive transcutaneous vagal nerve stimulation and medications (galantamine, pyridostigmine, or placebo) with tilt table tests

3 study days

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

What Are the Treatments Tested in This Trial?

Interventions

• Galantamine
• Pyridostigmine
• Sham Vagal Stimulation
• Vagal Stimulation

Trial Overview The study tests electrical stimulation of a nerve in the earlobe and its effects combined with galantamine or pyridostigmine pills compared to placebo in controlling heart rhythm and reducing symptoms when standing in POTS patients. It involves screening plus three testing days over five days total.

How Is the Trial Designed?

Group I: Pyridostigmine with vagal/sham stimulation Experimental Treatment 3 Interventions

Patients will receive a single oral dose of pyridostigmine pill 30 mg, and 1.5-2 hours later they will have two tilt table tests: one with vagal stimulation and one with sham vagal stimulation

Group II: Placebo pill with vagal/sham stimulation Experimental Treatment 3 Interventions

Patients will receive a single oral dose of placebo sugar pill, and 1.5-2 hours later they will have two tilt table tests: one with vagal stimulation and one with sham vagal stimulation

Group III: Galantamine with vagal/sham stimulation Experimental Treatment 3 Interventions

Patients will receive a single oral dose of galantamine pill 8 mg, and 1.5-2 hours later they will have two tilt table tests:one with vagal stimulation and one with sham vagal stimulation

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Published Research Related to This Trial

In a study of 46 patients undergoing vagal nerve stimulation (VNS) surgery, stimulation of the vagal nerve consistently induced vocal cord responses, confirming the effectiveness of intraoperative monitoring.

The most sensitive area of the vagal nerve was identified in the medial middle region, allowing for lower stimulation thresholds (median 0.2 mA), which could improve the safety and efficacy of VNS procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraoperative nerve stimulation during vagal nerve stimulator placement. Kamada, C., Enatsu, R., Kanno, A., et al.[2023]

In a study of 60 Norwegian children with difficult-to-treat epilepsy, 72% reported positive effects from vagal nerve stimulation (VNS) after an average follow-up of 2.5 years, with 63% experiencing decreased seizure frequency or severity.

The side effects of VNS were generally mild, with 50% of patients reporting minor side effects, indicating that VNS is a relatively safe and effective additional treatment option for children with refractory epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Vagal nerve stimulation in children with drug-resistant epilepsy]. Bremer, A., Eriksson, AS., Røste, GK., et al.[2015]

In a review of 111 patients who received vagus nerve stimulation (VNS) for refractory epilepsy, three cases of intraoperative bradycardia were observed during device testing, but no adverse cardiac events occurred postoperatively.

Despite the initial bradycardia during testing, all three patients experienced reduced seizure frequency after starting VNS therapy, indicating that VNS is safe and effective for managing epilepsy even when bradycardia is noted during the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. Ardesch, JJ., Buschman, HP., van der Burgh, PH., et al.[2022]

Vagus nerve stimulation (VNS) is effective for treating refractory epilepsy and depression, but traditional methods involve surgical implantation, which carries risks such as infection and bradycardia.

New non-invasive VNS systems eliminate the need for surgery, improving safety and tolerability, and allowing patients to administer stimulation on demand, potentially expanding its use in various medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Ben-Menachem, E., Revesz, D., Simon, BJ., et al.[2022]

Vagus nerve stimulation (VNS) is a promising treatment for patients with refractory epilepsy, specifically demonstrated in a case of Lennox-Gastaut Syndrome (LGS).

In this patient, VNS led to an improvement in heart rate variability (HRV), suggesting potential benefits beyond seizure control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation improves severely impaired heart rate variability in a patient with Lennox-Gastaut-Syndrome. Koenig, SA., Longin, E., Bell, N., et al.[2022]

In a study of 138 patients with refractory epilepsy, vagus nerve stimulation (VNS) led to a significant average reduction of 51% in monthly seizure frequency over a mean follow-up of 44 months, demonstrating its efficacy as an adjunctive treatment.

The responder rate, defined as patients experiencing at least a 50% reduction in seizures, was 59%, with 9% of patients achieving complete seizure freedom, indicating that VNS can provide substantial benefits for many patients with difficult-to-treat epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. De Herdt, V., Boon, P., Ceulemans, B., et al.[2007]

Repeated vagal nerve stimulation (VNS) in rats showed significant antidepressant and anxiolytic effects, comparable to the effects of standard antidepressants desipramine and sertraline, as measured by behavioral tests.

The antidepressant effects of VNS were found to depend on serotonergic nerve activity, while noradrenergic nerves also contributed to its anxiolytic effects, indicating a complex mechanism of action for VNS in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serotonergic and noradrenergic pathways are required for the anxiolytic-like and antidepressant-like behavioral effects of repeated vagal nerve stimulation in rats. Furmaga, H., Shah, A., Frazer, A.[2022]

In a study of 24 children undergoing intermittent vagal nerve stimulation over a total of 61 patient years, 15 adverse events were reported, with 13 likely related to the device, indicating a need for careful monitoring during treatment.

Despite the occurrence of adverse events, vagal nerve stimulation was generally well tolerated, and unlike standard drug therapies, these events did not typically require stopping the treatment, although they sometimes led to unexpected surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in children receiving intermittent left vagal nerve stimulation. Murphy, JV., Hornig, GW., Schallert, GS., et al.[2019]

In a study of 48 patients with intractable partial epilepsy, vagus nerve stimulation (VNS) demonstrated a significant reduction in seizure frequency, with a 26% decrease after 1 year, 30% after 5 years, and 52% after 12 years of treatment.

The side effects of VNS were generally mild to moderate, indicating that it is a safe and tolerable option for patients with difficult-to-treat epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Uthman, BM., Reichl, AM., Dean, JC., et al.[2019]

The study identified a specific electrophysiological response called the larynx compound action potential (LCMAP) that occurs approximately 3 ms after vagus nerve stimulation (VNS), which can serve as an objective indicator of effective nerve activation.

LCMAP was successfully recorded in 11 out of 21 rats immediately after surgery, while others required a recovery period, suggesting that monitoring LCMAP could help determine the optimal timing for increasing VNS therapy in patients with refractory epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated assessment of larynx compound muscle action potentials using a self-sizing cuff electrode around the vagus nerve in experimental rats. El Tahry, R., Mollet, L., Raedt, R., et al.[2011]

Citations

1. withpower.com withpower.com/trial/phase-1-tachycardia-8-2017-5de7b

Vagal Nerve Stimulation for POTS · Info for Participants Trial Overview The study tests electrical stimulation of a nerve in the earlobe and its effects combined with galantamine or pyridostigmine pills compared to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8939715/

Transdermal Auricular Vagus Stimulation for the Treatment of ... Previous studies reported that acute stimulation could improve orthostatic tolerance in POTS (Diedrich et al., 2018; Shiffer et al., 2019). However, it is still ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29937049/

Efficacy of Therapies for Postural Tachycardia Syndrome We included 28 studies with at least 4 patients with POTS in which symptomatic response was reported after more than 4 weeks of therapy. This ...

4. frontiersin.org frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1515486/full

Oral medications for the treatment of postural orthostatic ... Ivabradine and midodrine demonstrated the highest rate of symptomatic improvement, while beta-blockers showed the largest reduction in heart ...

5. newsroom.uvahealth.com newsroom.uvahealth.com/2025/07/31/heart-failure-drug-relieves-pots-symptoms-study-finds/

Heart Failure Drug Relieves POTS Symptoms, Study Finds In an analysis of 10 patients with POTS, the researchers found that the drug reduced their heart racing while significantly improving other ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT07189936

Effect of 2-HOBA in Persistent Immune Activation in Long ... The preliminary data show that: 1) LCPOTS subjects have markedly increased circulating doublets compared to controls; 2) T cells in these ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2001/21-169_Reminyl_medr_P4.pdf

21-169 Reminyl Medical Review Part 4 - accessdata.fda.gov In. 24-month carcinogenicity studies in mice and rats no increase in incidental or fatal tumors was associated with galantamine treatment. 2 ...

8. go.drugbank.com go.drugbank.com/drugs/DB00674

Galantamine: Uses, Interactions, Mechanism of Action In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome that was characterized by drowsiness, disorientation, and delirium.