LLTS for Atrial Fibrillation

(LLT-SPANS Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Stavros Stavrakis, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: University of Oklahoma

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests a treatment called LLTS, which uses gentle electrical impulses on the ear to help reduce irregular heartbeats and inflammation. It targets healthy volunteers, AF patients, and HFpEF patients. The treatment works by calming the heart and reducing inflammation through vagus nerve stimulation. Low-level tragus stimulation (LLTS) has been shown to significantly reduce atrial fibrillation (AF) burden in patients with paroxysmal AF.

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 data supports the idea that LLTS for Atrial Fibrillation is an effective treatment?

The available research shows that low-level transcutaneous stimulation of the auricular branch of the vagus nerve (LLTS) can help reduce atrial fibrillation. One study mentions that this treatment can suppress the induction and duration of atrial fibrillation in healthy humans. Another study highlights its antiarrhythmic effects, which means it can help prevent irregular heartbeats. While some studies focus on other conditions, like postural tachycardia syndrome, they also suggest that LLTS has beneficial effects in both animals and humans. Overall, the research indicates that LLTS is a promising noninvasive and safe treatment for atrial fibrillation. ^{1 2 3 4 5}

What safety data exists for LLTS for Atrial Fibrillation?

The safety data for LLTS, also known as transcutaneous vagus nerve stimulation (tVNS), indicates that it is generally safe with mild and transient adverse effects. A systematic review and meta-analysis of 177 studies involving 6322 subjects found no significant difference in the risk of adverse events between active tVNS and controls. The most common adverse effects reported were ear pain, headache, and tingling, with no severe adverse events linked to tVNS. Non-invasive VNS systems, like tVNS, improve safety and tolerability compared to surgically implanted devices, which can have more serious adverse events related to implantation. ^{1 6 7 8 9}

Is the treatment Parasym a promising treatment for Atrial Fibrillation?

Yes, Parasym, which involves stimulating the vagus nerve, shows promise as a treatment for Atrial Fibrillation. It is noninvasive, potentially inexpensive, and safe, and it can help reduce the occurrence and duration of Atrial Fibrillation by affecting heart rhythms positively. ^{1 5 10 11 12}

Research Team

Stavros Stavrakis, MD

Principal Investigator

University of Oklahoma

Eligibility Criteria

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.

Treatment Details

Interventions

• Parasym (Behavioural Intervention)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Dr. Scott Rollins

University of Oklahoma

Chief Executive Officer since 2016

PhD in Immunology from the University of Oklahoma

Dr. Ondria Gleason

University of Oklahoma

Chief Medical Officer

MD from the University of Oklahoma College of Medicine

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Vagus nerve stimulation reduces ventricular arrhythmias and increases ventricular electrical stability. [2019]

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

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. [2023]

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

Quantification of acute parasympathetic denervation during cryoballoon ablation by using extracardiac vagal stimulation. [2019]

4. United States 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. [2019]

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

Acupuncture at the auricular branch of the vagus nerve enhances heart rate variability in humans: An exploratory study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

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

Left vagus nerve stimulation for depression: first implantation case post-fDA approval and review of the literature. [2007]

9. Switzerland 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. [2022]

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

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance--The U.S. E-37 Trial. [2022]

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

Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. [2009]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Cardiovascular responses to low-level transcutaneous vagus nerve stimulation. [2021]