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Auricular Vagal Nerve Stimulation for Hypermobile Ehlers-Danlos Syndrome

Primary Purpose

Functional Gastrointestinal Disorders, Hypermobile Ehlers-Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Percutaneous vagal nerve stimulation (pVNS) device

Acoustic vagal nerve stimulation (aVNS) treatment

About this trial

This is an interventional treatment trial for Functional Gastrointestinal Disorders

Eligibility Criteria

10 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Medical College of WisconsinRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Treatment Arm A (hEDS)

Treatment Arm B (ANS Dysfunction)

Arm Description

(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)

(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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Change in gastric motility function as assessed by gastric MRI motility index

Dynamic gastric MRI measure of gastric contractility as measured by motility index generated by GIQuant software motility index; score range 100-700 with lower scores indicating worse gastric motility

Change in Body Perception Questionnaire (BPQ) total score

Instrument assessing symptoms of autonomic reactivity; raw score range 0-130 with higher score indicating greater autonomic reactivity

Change in vagal efficiency measurements

Metrics of vagal tone extracted from ECG R-R interval data measurements during postural challenges

Change in respiratory sinus arrhythmia measurements

Metrics of vagal tone extracted from ECG R-R interval data measurements during postural challenges

Full Information

NCT ID

NCT05212129

First Posted

November 2, 2021

Last Updated

February 22, 2023

Sponsor

Medical College of Wisconsin

Collaborators

University College, London, Indiana University

1. Study Identification

Unique Protocol Identification Number

NCT05212129

Brief Title

Auricular Vagal Nerve Stimulation for Hypermobile Ehlers-Danlos Syndrome

Official Title

Hypermobile Ehlers-Danlos Syndrome: Efficacy of Non-invasive Vagal Nerve Stimulation and Effects on Brain-Gut Physiology

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 5, 2021 (Actual)

Primary Completion Date

December 31, 2023 (Anticipated)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Medical College of Wisconsin

Collaborators

University College, London, Indiana University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

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?

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

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.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Treatment Arm A is masked (double-blinded). Treatment Arm B is not masked.

Allocation

Randomized

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment Arm A (hEDS)

Arm Type

Active Comparator

Arm Description

Arm Title

Treatment Arm B (ANS Dysfunction)

Arm Type

Experimental

Arm Description

Intervention Type

Device

Intervention Name(s)

Percutaneous vagal nerve stimulation (pVNS) device

Other Intervention Name(s)

percutaneous electrical nerve field stimulation

Intervention Description

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

Other

Intervention Name(s)

Acoustic vagal nerve stimulation (aVNS) treatment

Other Intervention Name(s)

Safe and Sound Protocol

Intervention Description

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 Information:

Title

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

Description

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

Time Frame

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

Secondary Outcome Measure Information:

Title

Change in gastric motility function as assessed by gastric MRI motility index

Description

Time Frame

Change from baseline at end of therapy (6 weeks)

Title

Change in Body Perception Questionnaire (BPQ) total score

Description

Instrument assessing symptoms of autonomic reactivity; raw score range 0-130 with higher score indicating greater autonomic reactivity

Time Frame

Change from baseline at end of therapy (6 weeks)

Title

Change in vagal efficiency measurements

Description

Metrics of vagal tone extracted from ECG R-R interval data measurements during postural challenges

Time Frame

Change from baseline at end of therapy (6 weeks)

Title

Change in respiratory sinus arrhythmia measurements

Description

Metrics of vagal tone extracted from ECG R-R interval data measurements during postural challenges

Time Frame

Change from baseline at end of therapy (6 weeks)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

10 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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: 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Katja Kovacic, MD

Phone

(414) 266-3690

kkovacic@mcw.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Monica Grimm, BA

Phone

(414) 266-6111

mgrimm@mcw.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Katja Kovacic, MD

Organizational Affiliation

Medical College of Wisconsin

Official's Role

Principal Investigator

Facility Information:

Facility Name

Medical College of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Monica Grimm, BA

Phone

414-266-6111

mgrimm@mcw.edu

First Name & Middle Initial & Last Name & Degree

Katja Kovacic, MD

First Name & Middle Initial & Last Name & Degree

Donald Basel, MD

First Name & Middle Initial & Last Name & Degree

Matthew Plunk, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

28145606

Citation

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.

Results Reference

background

PubMed Identifier

25151198

Citation

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.

Results Reference

background

PubMed Identifier

12867232

Citation

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.

Results Reference

background

PubMed Identifier

28826627

Citation

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.

Results Reference

background

PubMed Identifier

30868570

Citation

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.

Results Reference

background

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Auricular Vagal Nerve Stimulation for Hypermobile Ehlers-Danlos Syndrome

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