Vagal Nerve Stimulation for Ehlers-Danlos Syndrome

Overseen By Monica Grimm, BA

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Medical College of Wisconsin

Must not be taking: CNS drugs, Alcohol

Disqualifiers: Organic disease, Developmental delay, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing two non-invasive treatments that stimulate the vagus nerve to help patients with Hypermobile Ehlers-Danlos Syndrome (hEDS) and Postural Orthostatic Tachycardia Syndrome (POTS). These patients often have severe stomach problems and issues with body regulation. The treatments aim to improve the function of the vagus nerve, which could reduce their symptoms and improve their quality of life. Non-invasive vagus nerve stimulation (nVNS) has been explored as a treatment for various conditions, including gastroparesis and functional dyspepsia, showing potential benefits in improving symptoms and gastric functions.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are taking a new drug affecting the central nervous system within two weeks before joining, you cannot participate. Also, if your medication explains your symptoms, you will be excluded from the study.

What data supports the effectiveness of the treatment Acoustic Vagal Nerve Stimulation (aVNS) Treatment, Percutaneous Vagal Nerve Stimulation (pVNS) Device for Ehlers-Danlos Syndrome?

Research shows that vagal nerve stimulation (VNS) can help reduce pain and inflammation, as seen in conditions like chronic pain syndromes and erosive hand osteoarthritis. This suggests that similar treatments like pVNS might also be beneficial for managing symptoms in Ehlers-Danlos Syndrome. ^{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 complications, especially when surgery is involved. Common issues include voice changes, cough, and headaches, while more serious problems like infections and heart rhythm changes can occur during surgical implantation. Newer non-invasive VNS methods are safer as they don't require surgery. ^{6 7 8 9 10}

How does the Vagal Nerve Stimulation treatment for Ehlers-Danlos Syndrome differ from other treatments?

Vagal Nerve Stimulation (VNS) for Ehlers-Danlos Syndrome is unique because it uses a device to send electrical impulses to the vagus nerve, which is different from typical treatments that might focus on managing symptoms with medication or physical therapy. This approach is less invasive than traditional surgery and offers a novel way to potentially improve symptoms by targeting nerve function directly. ^{4 6 9 11 12}

Research Team

Katja Kovacic, MD

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

This trial is for children aged 10-18 with hypermobile Ehlers-Danlos Syndrome (hEDS) and related gastrointestinal or autonomic symptoms, who speak English and have a Beighton score of at least 4/9. It excludes those with seizure disorders, significant anemia, hearing impairment, complex medical conditions explaining their symptoms, recent CNS drug treatments, pregnancy, substance abuse issues, severe skin infections around the ear or incompatible implanted devices.

Inclusion Criteria

Information from our previous studies of patients with stomach and digestive issues who don't have a specific condition called hEDS will be used for comparison.

Kids between 10 and 18 years old

Kids who speak English and don't have another reason for their symptoms.

Exclusion Criteria

Refusal of blood collection or to provide DNA sample

You have a history of seizures.

You have severe anemia or a medical condition that makes drawing blood unsafe.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive non-invasive vagal nerve stimulation therapies for 6 weeks

6 weeks

Regular visits for therapy administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Acoustic Vagal Nerve Stimulation (aVNS) Treatment
• Percutaneous Vagal Nerve Stimulation (pVNS) Device

Trial Overview The study tests two non-invasive vagal nerve stimulation therapies: percutaneous (pVNS) and acoustic (aVNS), to see if they can alleviate gastrointestinal symptoms in children with hEDS and Postural Orthostatic Tachycardia Syndrome by improving gastric function and autonomic signaling.

Participant Groups

Group I: Treatment Arm B (ANS Dysfunction) Experimental Treatment 1 Intervention

(n=30) patients with concerns for ANS dysfunction (with or without hEDS) will receive auricular percutaneous vagal nerve stimulation (pVNS) therapy. Additional sub-study option: 15-20 subjects will undergo gastric MRI and (those who consent to it) will also participate in a biobank blood sample collection study.

Group II: Treatment Arm A (hEDS) Active Control 1 Intervention

(n=60) patients who meet criteria for hEDS or Hypermobile Spectrum Disorder (HSD) will receive aVNS (acoustic vagal nerve stimulation) therapy via filtered vocal music sound therapy using the Safe and Sound protocol (randomized 1:1 to active vs sham music; double blind study design)

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

University College, London

Collaborator

Trials

884

Recruited

38,770,000+

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

Findings from Research

Triphasic stimulation (TS) was found to be the most effective pattern for percutaneous electrical stimulation of the auricular vagus nerve (pVNS), requiring less electrical magnitude to achieve comfortable perception levels compared to biphasic (BS) and monophasic (MS) patterns.

The study suggests a shift from empirical methods to a more optimized approach for pVNS settings, as TS demonstrated superior performance in both experimental and numerical models, indicating its potential for more efficient therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data. Kaniusas, E., Samoudi, AM., Kampusch, S., et al.[2021]

The ESTIVAL Study is a randomized, double-blind, sham-controlled trial designed to evaluate the safety and efficacy of transcutaneous vagus nerve stimulation (tVNS) in patients with erosive hand osteoarthritis, involving 156 participants across 18 hospital centers in France.

The primary outcome will measure changes in self-reported hand pain over 12 weeks, with secondary outcomes assessing function, quality of life, and biomarkers, aiming to provide insights into the potential benefits of tVNS for managing pain and inflammation in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation in erosive hand osteoarthritis: protocol for the randomised, double-blind, sham-controlled ESTIVAL trial. Courties, A., Deprouw, C., Rousseau, A., 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]

The ADNS-300 system for vagus nerve stimulation (VNS) was successfully implanted in all three patients, demonstrating its feasibility for therapeutic use and recording of nerve activity.

Two out of three patients experienced a significant reduction in seizure frequency (43% and 40%), indicating that the ADNS-300 system may effectively reduce seizures in refractory epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel implantable vagus nerve stimulation system (ADNS-300) for combined stimulation and recording of the vagus nerve: pilot trial at Ghent University Hospital. El Tahry, R., Raedt, R., Mollet, L., et al.[2012]

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]

Vagal nerve stimulation (VNS) is considered a safe alternative therapy for epilepsy, although it can have rare but significant complications.

The study highlights cases of four patients who were implanted with VNS without prior video-EEG monitoring, suggesting a need for better guidelines on the necessity of this monitoring before VNS implantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Video EEG monitoring prior to vagal nerve stimulator implantation. Attarian, H., Dowling, J., Carter, J., et al.[2019]

In a small study of six very young children (average age 20.5 months) who underwent vagus nerve stimulation (VNS) for epilepsy, 83% experienced a significant reduction in seizure frequency, with 33% becoming seizure-free.

No adverse effects or complications were reported from the VNS procedure, suggesting it is a safe option for treating life-threatening epilepsy in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in children less than 5 years old. Blount, JP., Tubbs, RS., Kankirawatana, P., et al.[2018]

References

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

Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data. [2021]

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

Transcutaneous vagus nerve stimulation in erosive hand osteoarthritis: protocol for the randomised, double-blind, sham-controlled ESTIVAL trial. [2022]

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

Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management. [2018]

4. England pubmed.ncbi.nlm.nih.gov

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

A novel implantable vagus nerve stimulation system (ADNS-300) for combined stimulation and recording of the vagus nerve: pilot trial at Ghent University Hospital. [2012]

6. Japan pubmed.ncbi.nlm.nih.gov

[Surgical complications of vagal nerve stimulation for intractable epilepsy: findings from 26 cases]. [2014]

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

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

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

Video EEG monitoring prior to vagal nerve stimulator implantation. [2019]

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

Outpatient vagus nerve stimulation surgery in patients with drug-resistant epilepsy with severe intellectual disability. [2021]

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

Adverse Events and Complications Associated With Vagal Nerve Stimulation: An Analysis of the Manufacturer And User Facility Device Experience Database. [2023]

11. Germany pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in children less than 5 years old. [2018]

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

Vagal nerve stimulator: a new approach to medically refractory epilepsy. [2005]