LLTS for Atrial Fibrillation

(LLT-SPANS Trial)

Overseen By Karrie Meeks

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Oklahoma

Must not be taking: Autonomic medications

Disqualifiers: Stroke, Myocardial infarction, Heart failure, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 15 minutes

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to manage atrial fibrillation (AF) using low-level electrical stimulation on the ear, known as Parasym or Transcutaneous Vagus Nerve Stimulation (tVNS). The researchers aim to determine how different settings of this stimulation affect heart function and stress responses. Participants will be divided into groups to test various frequencies and strengths of stimulation. Ideal candidates include those with paroxysmal atrial fibrillation, heart failure with preserved ejection fraction, or healthy volunteers without heart or nerve-related issues. As an unphased trial, this study offers a unique opportunity to contribute to pioneering research and potentially benefit from innovative treatment strategies.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop your current medications, but it excludes those taking medications that affect autonomic nervous system function.

What prior data suggests that this technique is safe for atrial fibrillation?

Research has shown that low-level transcutaneous vagus nerve stimulation (LLTS) is generally safe and well-tolerated. One study found that most side effects were mild and temporary, with skin irritation being the most common issue, occurring in about 18% of participants. Serious problems were very rare, affecting less than 3% of participants.

Other studies suggest that LLTS can help reduce atrial fibrillation (AF) and improve heart rate variability, which is the variation in time between heartbeats. This indicates that LLTS might benefit heart health without causing significant harm. These findings suggest LLTS could be a safe option for people with AF, although the best treatment settings are still being researched. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the Parasym technique for atrial fibrillation because it offers a non-invasive approach through tragus stimulation, potentially altering heart rate variability. Unlike traditional treatments such as antiarrhythmic drugs or catheter ablation, which can have significant side effects or require invasive procedures, this method uses specific frequencies and amplitudes to stimulate the vagus nerve. The goal is to regulate heart rhythms more naturally, possibly reducing the need for medication or surgery. This innovative approach could provide a safer and more convenient option for patients with atrial fibrillation.

What evidence suggests that LLTS might be an effective treatment for atrial fibrillation?

Research has shown that low-level transcutaneous vagus nerve stimulation (LLTS) can help with atrial fibrillation (AF), a common heart condition. Studies have found that LLTS can shorten and reduce the number of AF episodes. It also lowers inflammation and improves heart rate variability (HRV), an indicator of good heart health. LLTS works by sending small electrical signals to the vagus nerve through the skin, helping to control heart rhythms and reduce inflammation. Early research suggests that LLTS could be a promising non-drug treatment for AF and other heart issues. This trial will explore various LLTS settings, including different frequencies and amplitudes, to determine the most effective use of LLTS for maximum benefit. ^{1 3 4 6 7}

Who Is on the Research Team?

Stavros Stavrakis, MD

Principal Investigator

University of Oklahoma

Are You a Good Fit for This Trial?

This trial is for adults over 21, including healthy individuals and those with Paroxysmal Atrial Fibrillation or Heart Failure with Preserved Ejection Fraction. It's not for those who've had recent strokes or heart attacks, severe heart failure, are pregnant/breastfeeding, have diseases affecting the nervous system, take certain medications, have low ejection fraction in their hearts, frequent fainting spells due to vaso-vagal syncope, a history of vagus nerve surgery (vagotomy), or uncontrolled diabetes/hypertension.

Inclusion Criteria

I am healthy with no heart or autonomic nervous system diseases.

I have heart failure but my heart still pumps well.

I am older than 21 years.

Exclusion Criteria

I have had surgery to cut the nerves to my stomach.

I have had multiple fainting spells due to sudden drops in heart rate and blood pressure.

I am not on medications that affect my nervous system's automatic functions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low-level transcutaneous vagus nerve stimulation (LLTS) with different frequencies and amplitudes for 15 minutes

15 minutes

1 visit (in-person)

Follow-up

Participants are monitored for changes in heart rate variability and brain stem evoked potentials after LLTS

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Parasym

Trial Overview The study tests how different settings of Low-Level Tragus Stimulation (LLTS) affect the autonomic nervous system. Specifically looking at two frequencies (5Hz and 20Hz) and two amplitudes related to pain threshold on heart rate variability and brain stem responses in both healthy volunteers and patients with specific heart conditions.

How Is the Trial Designed?

Group I: Frequency 20Hz; amplitude 1mA below discomfort threshold Experimental Treatment 1 Intervention

Patients will receive tragus stimulation for 15 minutes using the following settings: Frequency 20Hz; amplitude 1mA below discomfort threshold. Continuous ECG will be recorded to assess heart rate variability.

Group II: Frequency 20Hz; amplitude 50% below discomfort threshold Active Control 1 Intervention

Patients will receive tragus stimulation for 15 minutes using the following settings: Frequency 20Hz; amplitude 50% below discomfort threshold. Continuous ECG will be recorded to assess heart rate variability.

Group III: Frequency 5Hz; amplitude 1mA below discomfort threshold Active Control 1 Intervention

Patients will receive tragus stimulation for 15 minutes using the following settings: Frequency 5Hz; amplitude 1mA below discomfort threshold. Continuous ECG will be recorded to assess heart rate variability.

Group IV: Frequency 5Hz; amplitude 50% below discomfort threshold Active Control 1 Intervention

Patients will receive tragus stimulation for 15 minutes using the following settings: Frequency 5Hz; amplitude 50% below discomfort threshold. Continuous ECG will be recorded to assess heart rate variability.

Parasym is already approved in United States, European Union for the following indications:

Approved in United States as gammaCore for:

• Acute treatment and prevention of episodic cluster headache
• Acute treatment of migraine

Approved in United States as VNS Therapy for:

• Epilepsy
• Depression
• Stroke recovery

Approved in European Union as VNS Therapy for:

• Epilepsy
• Depression
• Stroke recovery

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Published Research Related to This Trial

Transcutaneous vagus nerve stimulation (tVNS) significantly reduced postural tachycardia in patients with POTS, showing a mean heart rate increase of 17.6 beats/min in the active group compared to 31.7 beats/min in the sham group after 2 months.

tVNS also led to lower levels of antiadrenergic autoantibodies and inflammatory cytokines, along with improved heart rate variability, indicating its potential as a safe and effective noninvasive treatment for POTS without any reported side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. Stavrakis, S., Chakraborty, P., Farhat, K., et al.[2023]

Extracardiac vagal stimulation (ECVS) effectively quantified acute parasympathetic denervation in 50 patients undergoing cryoballoon ablation for paroxysmal atrial fibrillation, showing significant reductions in cardioinhibitory responses post-procedure.

The study demonstrated that ECVS is a reliable method for assessing vagal denervation, with all patients exhibiting significant decreases in vagal responses after the ablation, indicating its potential utility in monitoring cardiac autonomic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantification of acute parasympathetic denervation during cryoballoon ablation by using extracardiac vagal stimulation. Osório, TG., Coutiño, HE., Iacopino, S., et al.[2019]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Chronic low-level vagal nerve stimulation (VNS) significantly increases inferior vena cava-inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA), which is associated with a reduction in ventricular rate (VR) during atrial fibrillation (AF) in a study involving 6 dogs.

The study found that VNS not only reduced VR from an average of 142 beats per minute to around 120 beats per minute but also caused neural remodeling in the stellate ganglion, indicating potential damage that may influence heart rate control during AF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Vagal Nerve Stimulation on Ganglionated Plexi Nerve Activity and Ventricular Rate in Ambulatory Dogs With Persistent Atrial Fibrillation. Jiang, Z., Zhao, Y., Tsai, WC., et al.[2019]

Transcutaneous vagus nerve stimulation (t-VNS) significantly improved sleep quality in patients with primary insomnia, with a 73% effective rate compared to 27% in the control group after one month of treatment.

The study, involving 30 patients, found no complications associated with t-VNS, indicating it is a safe intervention for treating insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Vagus Nerve Stimulation Could Improve the Effective Rate on the Quality of Sleep in the Treatment of Primary Insomnia: A Randomized Control Trial. Wu, Y., Song, L., Wang, X., et al.[2022]

The AutoStim feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System effectively detected and treated seizures in 31 out of 89 instances during a 3-5 day monitoring period, with 61.3% of those seizures ending during stimulation.

After 12 months, patients showed significant improvements in quality of life and seizure severity, with a 50% responder rate, indicating the long-term efficacy and safety of the device in managing drug-resistant partial onset seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance--The U.S. E-37 Trial. Fisher, RS., Afra, P., Macken, M., et al.[2022]

Acupuncture at the auricular branch of the vagus nerve (ABVN) significantly reduced heart rate by approximately 4%-6% and increased heart rate variability (HRV) as measured by SDNN by about 19% in a study of 24 healthy male volunteers.

These results suggest that ABVN acupuncture may activate the parasympathetic nervous system, although the overall effects on other HRV parameters were modest and warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acupuncture at the auricular branch of the vagus nerve enhances heart rate variability in humans: An exploratory study. Boehmer, AA., Georgopoulos, S., Nagel, J., et al.[2022]

In a study involving 23 anesthetized dogs, bilateral low-level vagosympathetic nerve stimulation (LL-VNS) significantly increased the threshold for inducing atrial fibrillation (AF) at various sites, indicating its potential efficacy in suppressing AF triggered by high-frequency stimulation.

The results showed that LL-VNS effectively raised the AF threshold over a 3-hour period, particularly at key sites like the pulmonary veins and atrial appendages, while control dogs without LL-VNS did not exhibit any changes, suggesting that LL-VNS could be a promising intervention for preventing AF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Li, S., Scherlag, BJ., Yu, L., et al.[2009]

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]

Noninvasive transcutaneous stimulation of the auricular branch of the vagus nerve (AB-VNS) significantly reduces spontaneous ventricular arrhythmias in beagle dogs after myocardial infarction, indicating its potential as an antiarrhythmic treatment.

AB-VNS enhances ventricular electrical stability and reduces ventricular interstitial fibrosis, although it does not improve overall cardiac function or reverse structural changes in the heart after 4 weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation reduces ventricular arrhythmias and increases ventricular electrical stability. Nasi-Er, BG., Wenhui, Z., HuaXin, S., et al.[2019]

Transcutaneous low-level vagus nerve stimulation (tVNS) in 15 male volunteers showed significant reductions in left ventricular contractility and output, indicating a potential for cardiac autonomic modulation.

While tVNS reduced heart workload, it also led to increased blood pressure and total peripheral resistance, suggesting a reflex response that needs further investigation to understand its therapeutic implications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular responses to low-level transcutaneous vagus nerve stimulation. Sinkovec, M., Trobec, R., Meglic, B.[2021]

The first case of left vagus nerve stimulation (VNS) after FDA approval showed significant improvement in a patient with treatment-resistant depression, who had previously failed multiple medications and electroconvulsive therapy.

VNS may benefit about one-third of patients with treatment-resistant depression, but it is important for patients to be aware of potential side effects and to have realistic expectations about the treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left vagus nerve stimulation for depression: first implantation case post-fDA approval and review of the literature. Patwardhan, R., Cardenas, R., Myers, D., et al.[2007]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04514757

Transcutaneous (Tragus) Vagal Nerve Stimulation for Post- ... Animal studies have indicated that duration and inducibility of AF can be decreased with intermittent vagus nerve stimulation (VNS). In humans, literature ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12276761/

Efficacy of Transcutaneous Vagus Nerve Stimulation to ... Outcomes assessed across studies included suppression of arrhythmia episodes, changes in heart rate variability, levels of inflammatory markers, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02548754

NCT02548754 | Transcutaneous Electrical Vagus Nerve ... These investigations will establish the first evidence of the long-term effects of LLTS on AF suppression in patients with paroxysmal AF and may provide the ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12231624/

The efficacy of transcutaneous vagus nerve stimulation in ... HRV has the potential to enhance cardiac function, decrease the occurrence of arrhythmias and enhance both mortality outcomes and quality of ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2405500X19309260

TREAT AF (Transcutaneous Electrical Vagus Nerve ... Adherence to the stimulation protocol (≤4 sessions lost per month) was 75% in the active arm and 83% in the control arm (p > 0.05). At 6 months, the median AF ...

6. nature.com nature.com/articles/s41598-022-25864-1

Safety of transcutaneous auricular vagus nerve stimulation ... Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1935861X18302936

Safety and tolerability of Transcutaneous Vagus Nerve ... tVNS has been safe and well tolerated by research participants to date. · The most common side effect of tVNS was skin irritation (in 18.2%). · 35 (2.6%) tVNS ...