Vagal Nerve Stimulation for POTS

Age: 18 - 65

Sex: Female

Trial Phase: Phase 1

Sponsor: Vanderbilt University Medical Center

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

Compensation: Varies

Number of Visits: 4

Duration: 3 study days

11 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to investigate how the electrical stimulation of a nerve in the skin of the earlobe (transcutaneous vagal nerve stimulation), alone or in combination with two medications (galantamine and pyridostigmine), affects the way the autonomic (involuntary) nervous system controls heart rhythm, symptoms on standing, and inflammatory markers in female patients with postural tachycardia syndrome (POTS). The study consists of 2 parts: a screening (1-2 study days), and 3 testing days. The study will take 5 days total and about 16 participants will be screened for the study. The investigators estimate 13 will be eligible to participate in all of the study days.

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.

What data supports the effectiveness of vagal nerve stimulation as a treatment for POTS?

Research shows that vagal nerve stimulation can improve heart function and quality of life in heart failure patients and reduce seizures in epilepsy patients, suggesting it might help with POTS by improving heart rate variability and autonomic balance. ^{1 2 3 4 5}

Is vagal nerve stimulation generally safe for humans?

Vagal nerve stimulation (VNS) is generally considered safe, but it can have side effects like voice changes, cough, and headaches. Serious issues like infections and heart rate changes can occur, especially with surgically implanted devices, but newer non-invasive methods improve safety. ^{6 7 8 9 10}

How is vagal nerve stimulation different from other treatments for POTS?

Vagal nerve stimulation (VNS) is unique because it involves continuous electrical stimulation of the vagus nerve, which is different from typical drug treatments. This method is already used for conditions like epilepsy and depression, suggesting it may offer a novel approach for POTS by potentially improving heart rate variability and other autonomic functions. ^{3 11 12 13 14}

Research Team

Italo Biaggioni, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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 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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Chronic cervical vagal stimulation. Mechanisms of action and clinical relevance for heart failure]. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for epilepsy: a review. [2014]

3. England pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation improves severely impaired heart rate variability in a patient with Lennox-Gastaut-Syndrome. [2022]

4. Norway pubmed.ncbi.nlm.nih.gov

[Vagal nerve stimulation in children with drug-resistant epilepsy]. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Vagal stimulation for heart failure: background and first in-man study. [2016]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Case of Vagal Nerve Stimulator-Induced Stridor After Anterior Cervical Diskectomy and Fusion-Induced Vocal Cord Paralysis. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Adverse events in children receiving intermittent left vagal nerve stimulation. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. [2019]

11. United States 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. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study. [2007]

13. United States pubmed.ncbi.nlm.nih.gov

Intraoperative nerve stimulation during vagal nerve stimulator placement. [2023]

14. Netherlands 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. [2011]