Auricular Vagal Nerve Stimulation for Hypermobile Ehlers-Danlos Syndrome

NCT ID: NCT05212129

Last Updated: 2025-05-14

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-05
• Study Completion Date: 2026-12-31

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.

Detailed Description

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 and Hypermobile Spectrum Disorders are associated with many gastrointestinal (GI) and autonomic nervous system (ANS) complaints such as postural orthostatic tachycardia syndrome (POTS). Symptoms are often disabling and associated with poor quality of life and high health care costs. The proposed research will address the following understudied areas: 1) the clinical relationship between hEDS and autonomic regulation, 2) the potential benefit of two forms of non-invasive vagal nerve stimulation (VNS) therapies in reducing functional GI symptoms in hEDS and POTS, and 3) plausible effects of these VNS therapies on gastric motor function and neurohormonal signaling.

Clinical reports document a high co-morbidity between autonomic disorders and hEDS. This prospective study will focus on three major clinical questions: 1) Are there reliable neurophysiological markers associated with hEDS that can provide insights into the 'neural mechanisms' resulting in multisystem co-morbidities? 2) Will innovative intervention techniques designed to enhance autonomic regulation via two non-invasive vagal nerve stimulation techniques (e.g., auricular and acoustic VNS) provide substantial symptom reduction and improve the hEDS patients' quality of life? 3) Can a novel gastric MRI technique capture gastric motor function abnormalities in adolescents with hEDS?

Conditions

Functional Gastrointestinal Disorders; Hypermobile Ehlers-Danlos Syndrome; Postural Orthostatic Tachycardia Syndrome; Autonomic Nervous System Disease; Autonomic Nervous System Imbalance

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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)

Group Type: ACTIVE_COMPARATOR

Acoustic vagal nerve stimulation (aVNS) treatment

Intervention Type: 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.

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.

Group Type: EXPERIMENTAL

Percutaneous vagal nerve stimulation (pVNS) device

Intervention Type: 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).

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).

Intervention Type: DEVICE

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.

Intervention Type: OTHER

Other Intervention Names

percutaneous electrical nerve field stimulation; Safe and Sound Protocol

Eligibility Criteria

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

• 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
• Egg allergy or anticipated inability to complete a standardized egg meal

• 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.

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University College, London

OTHER

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Katja Karrento

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Katja Kovacic, MD

Role: PRINCIPAL_INVESTIGATOR

Medical College of Wisconsin

Locations

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Katja Kovacic, MD

Role: CONTACT

kkovacic@mcw.edu

(414) 266-3690

Monica Grimm, BA

Role: CONTACT

mgrimm@mcw.edu

(414) 266-6111

Facility Contacts

Mychoua Vang, BA

Role: primary

myvang@mcw.edu

References

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.

Reference Type: BACKGROUND

PMID: 28145606 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25151198 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12867232 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28826627 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30868570 (View on PubMed)

Other Identifiers

1541191

Identifier Type: -

Identifier Source: org_study_id