Auricular Vagal Nerve Stimulation for Hypermobile Ehlers-Danlos Syndrome

NCT05212129 | Recruiting FDA Device

• 1 other identifier: 1541191
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Change in gastrointestinal symptoms as assessed by the instrument Patient Assessment of upper Gastrointestinal Symptom Severity Index (PAGI-SYM)

  Instrument assessing upper gastrointestinal symptoms including symptoms of gastroparesis; score range 0-100 with higher scores indicating worse symptoms

  Change from baseline total PAGI-SYM score at end of therapy (6 weeks)

Secondary Outcomes (3)

• Change in gastric motor function as assessed by gastric MRI

  Change from baseline at end of therapy (6 weeks)

• Change in Body Perception Questionnaire (BPQ) total score

  Change from baseline at end of therapy (6 weeks)

• Change in vagal efficiency measurements

  Change from baseline at end of therapy (6 weeks)

Study Arms (2)

Treatment Arm A (hEDS)

ACTIVE COMPARATOR

(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)

Other: Acoustic vagal nerve stimulation (aVNS) treatment

Treatment Arm B (ANS Dysfunction)

EXPERIMENTAL

(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.

Device: Percutaneous vagal nerve stimulation (pVNS) device

Interventions

Acoustic vagal nerve stimulation (aVNS) treatment OTHER

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.

Also known as: Safe and Sound Protocol

Treatment Arm A (hEDS)

Percutaneous vagal nerve stimulation (pVNS) device 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).

Also known as: percutaneous electrical nerve field stimulation

Treatment Arm B (ANS Dysfunction)

Eligibility Criteria

• Age: 10 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.
• Severe dermatological condition or active infection of external or middle ear
• Implanted electrical device
• Hearing impaired
• Sight impaired without correction
• Seizure disorder
• 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

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• University College, London: collaborator
• Indiana University: collaborator

Study Sites (1)

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

RECRUITING

Related Publications (5)

• Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):148-157. doi: 10.1002/ajmg.c.31539. Epub 2017 Feb 1.

  PMID: 28145606 BACKGROUND

• Kovacic K, Chelimsky TC, Sood MR, Simpson P, Nugent M, Chelimsky G. Joint hypermobility: a common association with complex functional gastrointestinal disorders. J Pediatr. 2014 Nov;165(5):973-8. doi: 10.1016/j.jpeds.2014.07.021. Epub 2014 Aug 20.

  PMID: 25151198 BACKGROUND

• Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003 Jul;115(1):33-40. doi: 10.1016/s0002-9343(03)00235-3.

  PMID: 12867232 BACKGROUND

• Kovacic K, Hainsworth K, Sood M, Chelimsky G, Unteutsch R, Nugent M, Simpson P, Miranda A. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol. 2017 Oct;2(10):727-737. doi: 10.1016/S2468-1253(17)30253-4. Epub 2017 Aug 18.

  PMID: 28826627 BACKGROUND

• Porges SW, Davila MI, Lewis GF, Kolacz J, Okonmah-Obazee S, Hane AA, Kwon KY, Ludwig RJ, Myers MM, Welch MG. Autonomic regulation of preterm infants is enhanced by Family Nurture Intervention. Dev Psychobiol. 2019 Sep;61(6):942-952. doi: 10.1002/dev.21841. Epub 2019 Mar 13.

  PMID: 30868570 BACKGROUND

MeSH Terms

Conditions

Gastrointestinal Diseases; Ehlers-Danlos syndrome type 3; Postural Orthostatic Tachycardia Syndrome

Interventions

Therapeutics

Condition Hierarchy (Ancestors)

Digestive System Diseases; Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases

Study Officials

• Katja Karrento, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Katja Karrento, MD

CONTACT

(414) 266-3690; kkarrento@mcw.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Treatment Arm A is masked (double-blinded). Treatment Arm B is not masked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Participants enrolled in either Treatment Arm A (randomized to active vs sham therapy) or Treatment Arm B at the same time throughout the enrollment process.

Study Record Dates

• First Submitted: November 2, 2021
• First Posted: January 27, 2022
• Study Start: April 5, 2021
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)