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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores two non-invasive nerve stimulation therapies to determine their effectiveness in reducing stomach and nervous system symptoms in individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and related conditions. Participants will receive either sound-based nerve stimulation (Acoustic Vagal Nerve Stimulation, aVNS) or ear-based nerve stimulation (Percutaneous Vagal Nerve Stimulation, pVNS) to evaluate their impact on symptoms like stomach discomfort and nervous system issues, such as dizziness when standing. Children aged 10-18 with ongoing stomach issues and potential hEDS or nervous system problems may be suitable for this trial, particularly if these issues interfere with daily activities. As an unphased trial, this study provides a unique opportunity to explore innovative therapies that could enhance daily life for those affected.

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 prior data suggests that these vagal nerve stimulation therapies are safe for treating hEDS and ANS dysfunction?

Research has shown that treatments like acoustic vagal nerve stimulation (aVNS) and percutaneous vagal nerve stimulation (pVNS) are generally safe and well-tolerated. These methods can influence nerve activity without surgery, often resulting in fewer risks.

For aVNS, a review of studies found it is usually well-tolerated, with no serious side effects reported by participants. Similarly, several studies have tested pVNS, and results suggest it can improve nerve function without causing major side effects.

Both aVNS and pVNS are non-invasive, meaning they don't require surgery, which generally makes them safer than surgical options. While individual experiences may differ, current research provides a reassuring view of their safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Ehlers-Danlos Syndrome (EDS) because they offer a novel approach using vagal nerve stimulation, which is different from traditional management like pain relief and physiotherapy. The acoustic vagal nerve stimulation (aVNS) uses filtered vocal music to target the autonomic nervous system, providing a potentially non-invasive and soothing alternative. Meanwhile, the percutaneous vagal nerve stimulation (pVNS) uses a device to stimulate the vagus nerve through the ear, offering a direct method for autonomic regulation. These methods could offer new hope for managing symptoms by directly targeting nerve pathways, which is a fresh approach compared to conventional treatments.

What evidence suggests that these vagal nerve stimulation therapies could be effective for reducing GI symptoms in hEDS and POTS?

Research suggests that stimulating the vagus nerve, known as vagal nerve stimulation (VNS), could aid conditions affecting automatic functions like heart rate and digestion. In this trial, participants in Treatment Arm A will receive acoustic vagal nerve stimulation (aVNS), which has shown early benefits similar to those in epilepsy treatments, where it helped control nerve signals. This might alleviate symptoms of hypermobile Ehlers-Danlos syndrome (hEDS).

Participants in Treatment Arm B will receive percutaneous vagal nerve stimulation (pVNS). Studies have shown that pVNS can enhance heart function, which is part of the system controlling heart rate and digestion. In other conditions, VNS has reduced pain and swelling, suggesting potential benefits for hEDS patients with automatic nervous system issues. Both treatments in this trial target the vagus nerve to improve nerve function and reduce symptoms. ^{1 2 4 5 6}

Who Is on the Research Team?

Katja Kovacic, MD

Principal Investigator

Medical College of Wisconsin

Are You a Good Fit for This Trial?

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

Information from past studies of patients with stomach and intestine problems who don't have a specific condition will be used for comparison.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05212129

Auricular Vagal Nerve Stimulation for Hypermobile Ehlers- ... This study will address the clinical relationship between hEDS/Hypermobile Spectrum Disorders and autonomic regulation and see if there is a benefit of two ...

2. trials.arthritis.org trials.arthritis.org/trials/NCT05212129

Auricular Vagal Nerve Stimulation for Hypermobile Ehlers ... This study will address the clinical relationship between hEDS/Hypermobile Spectrum Disorders and autonomic regulation and see if there is a benefit of two ...

3. withpower.com withpower.com/trial/phase-syndrome-3-2021-a85d0

Vagal Nerve Stimulation for Ehlers-Danlos Syndrome This trial is testing two non-invasive treatments that stimulate the vagus nerve to help patients with Hypermobile Ehlers-Danlos Syndrome (hEDS)

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8120162/

Auricular Vagus Neuromodulation—A Systematic Review on ... Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06548594

Study Details | NCT06548594 | Out of State - tAN hEDS This clinical trial tests a new ear stimulation method in hEDS patients to determine if it may improve quality of life. Detailed Description. The Ehlers-Danlos ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05212129/auricular-vagal-nerve-stimulation-for-hypermobile-ehlers-danlos-syndrome

Auricular Vagal Nerve Stimulation for Hypermobile Ehlers ... This study will address the clinical relationship between hEDS/Hypermobile Spectrum Disorders and autonomic regulation and see if there is a ...