Recruiting

Auricular Vagal Nerve Stimulation

Sponsor:

Medical College of Wisconsin

Code:

NCT05212129

Conditions

Functional Gastrointestinal Disorders

Hypermobile Ehlers-Danlos Syndrome

Postural Orthostatic Tachycardia Syndrome

Autonomic Nervous System Disease

Autonomic Nervous System Imbalance

Eligibility Criteria

Sex: All

Age: 10 - 18

Healthy Volunteers: Not accepted

Interventions

Percutaneous vagal nerve stimulation (pVNS) device

Acoustic vagal nerve stimulation (aVNS) treatment

Study Details

Brief summary:

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder characterized by hyperextensible skin, joint hypermobility and additional connective tissue manifestations. For unclear reasons, hEDS is associated with many gastrointestinal (GI) and autonomic nervous system (ANS) complaints such as postural orthostatic tachycardia syndrome (POTS). This study will address the clinical relationship between hEDS/Hypermobile Spectrum Disorders and autonomic regulation and see if there is a benefit of two forms of non-invasive vagal nerve stimulation therapies to reduce GI symptoms in hEDS and POTS. The study will also investigate plausible effects of these nerve stimulation therapies on gastric function and autonomic signaling.

Conditions

Functional Gastrointestinal Disorders

Hypermobile Ehlers-Danlos Syndrome

Postural Orthostatic Tachycardia Syndrome

Autonomic Nervous System Disease

Autonomic Nervous System Imbalance

Study ID

NCT05212129

Start date

Apr 5, 2021

Status verified date

Feb, 2026

Completion date

Dec 31, 2026

Anticipated

Primary completion date

Dec 31, 2026

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 10 - 18

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Children aged 10-18 years old
  • Children with functional upper GI complaints and clinical suspicion for hEDS or HSD as well as a Beighton score of at least 4/9
  • Children with functional upper GI complaints and clinical suspicion for ANS dysfunction
  • De-identified data from our prior studies (IRB #689519 and IRB #1064187) of patients with functional GI disorders who do NOT meet criteria for hEDS will be used as a comparison group
  • Children who are English-speaking and lack other explanation for symptoms
  • Children willing to participate and consent to this study (for children, have a parent willing to participate)

Exclusion Criteria:

A) Exclusion Criteria applying to all participants:

  • Medically complex children or those who take a medication or suffer from a disease that can explain symptoms will be excluded from participation in the study.
  • Adult subjects, children or their parents who have significant developmental delay (will be excluded due to difficulties in accurately completing the questionnaires and assessing symptoms)
  • Patients with findings of organic disease such as peptic ulcer disease, H.pylori gastritis, celiac disease, inflammatory bowel disease, allergic disorders, metabolic disorder or any other chronic condition or medication that may cause chronic GI symptoms will be excluded from the study.
  • Patients who are treated with a new drug affecting the central nervous system in the two weeks prior to enrollment will also be excluded.
  • Pregnancy (evaluating MD screens patients as they normally would during a clinic visit (by questioning) and would only perform urine pregnancy test if clinically indicated (absence of menstrual period or other symptoms concerning for pregnancy)
  • Chronic alcohol/illicit drug use and/or smoking.

B) Exclusion Criteria for subjects undergoing pVNS therapy:

  • Severe dermatological condition or active infection of external or middle ear
  • Implanted electrical device

C) Exclusion Criteria for subjects undergoing aVNS therapy:

  • Hearing impaired
  • Sight impaired without correction
  • Seizure disorder

D) Exclusion Criteria for subjects undergoing gastric motor function sub-study:

  • Patients with pacemakers, metal clips used in previous surgery or other device which are not compatible with MRI scanning
  • Claustrophobia or inability to lie still in the scanner
  • Orthodontic braces or permanent retainers
  • Patients who are unable to tolerate noise produced by the MRI
  • Egg allergy or anticipated inability to complete a standardized egg meal

E) Exclusion Criteria for subjects undergoing HepGI Biobank specimen collection sub-study:

  • Bleeding disorder for the specific biopsies
  • Recent antibiotic usage for fecal sample
  • Significant anemia or clinical status which will not allow safe blood draw required for blood collection
  • Refusal of blood collection or to provide DNA sample
  • Inability or unwillingness on the individual (or parent/legal guardian) to provide clinical or family history.

Study Design

Enrollment

90 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

active comparator: Treatment Arm A (hEDS)

(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)

experimental: Treatment Arm B (ANS Dysfunction)

(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.

Interventions

Percutaneous vagal nerve stimulation (pVNS) device

Subjects in Treatment Arm B will enter a six-week, prospective open label treatment trial with the FDA-approved and commercially available device IB-Stim. This is an ambulatory, neurostimulation device which consists of a battery powered, externally affixed generator with 4 wire leads attached to electrode/needle arrays affixed to the outer ear. The device delivers low voltage (3.2V) stimulation in alternating frequencies for a total of 5 days (around the clock).

Acoustic vagal nerve stimulation (aVNS) treatment

All subjects receiving acoustic therapy via active VNS (aVNS; n=30) or sham VNS (sVNS; n=30) will enter a four-week, randomized, double-blind clinical trial during which they will listen to either computer altered/filtered vocal music (active treatment) that has been designed to stimulate vagal calming vs. regular non-filtered music (sham treatment). The stimuli will mirror the acoustic intervention known as the Safe and Sound Protocol. This protocol has been found to reduce auditory hypersensitivities and calming the autonomic nervous system by increasing vagal regulation of the heart via brainstem ventral vagal complex. The acoustic intervention may be played by an electronic device (i.e. smartphone, tablet, laptop, mp3) and delivered virtually with the help of trained coaches.

Primary outcome measure

  • Change in gastrointestinal symptoms as assessed by the instrument Patient Assessment of upper Gastrointestinal Symptom Severity Index (PAGI-SYM) [ Time Frame: Change from baseline total PAGI-SYM score at end of therapy (6 weeks) ]

Central Contacts and Locations

Central contacts

Katja Karrento, MD

(414) 266-3690kkarrento@mcw.edu

Locations

Medical College of Wisconsin

Recruiting

Milwaukee, Wisconsin, United States, 53226

Contacts

Elaina Schueler, BA

eschueler@mcw.edu

Principal Investigator:

Katja Kovacic, MD

More Information

Sponsor

Medical College of Wisconsin

Last update posted

Feb 13, 2026

Last verified

Feb, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by Medical College of Wisconsin on 2026-02-13.