Effects of nVNS on Stress Reactivity in IBS (U54: nVNS RCT)

November 3, 2026 updated by: Lin Chang, MD, University of California, Los Angeles

Effects of Non-invasive Vagal Nerve Stimulation on Clinical, Peripheral Biologic, and Brain Measures of Stress Reactivity in Irritable Bowel Syndrome: a Randomized Controlled Trial

Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction that causes abdominal pain and altered bowel habits. Many people with IBS also experience symptoms outside the bowel, such as headaches, widespread pain, poor sleep, anxiety, and depression; these symptoms are especially common in females. This study focuses on stress reactivity (SR), a persistent pattern of stress-system activity that may be linked to autonomic nervous system function, immune activity, the gut microbiome, and brain processing. The investigators will enroll adults with at least moderate IBS symptoms and randomly assign them to 8 weeks of non-invasive vagal nerve stimulation (nVNS) or Usual Care. Participants assigned to nVNS will use a handheld device on the left side of the neck at home twice daily. The investigators will compare changes in IBS severity and other physical symptoms and examine whether baseline or treatment-related changes in blood, stool, heart-rate variability, sex hormones, and brain imaging measures are associated with response. The study will also explore whether treatment effects and predictors differ by sex.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

200

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90024
        • University of California Los Angeles
        • Principal Investigator:
          • Lin Chang, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 18-50 years.
  • Meets Rome V diagnostic criteria for IBS-D or IBS-M.
  • At least moderate IBS symptom severity, defined as IBS-SSS ≥175.
  • For females: premenopausal with generally regular menstrual cycles and willing to complete study visits within the study-specified menstrual-cycle window when feasible.
  • Able to understand and provide informed consent in English.
  • Willing and able to complete questionnaires, biospecimen collection, wearable monitoring, MRI procedures, and randomized study requirements.

Exclusion Criteria:

  • Individuals with obesity (BMI > 30).
  • Evidence or history of another gastrointestinal disease that could explain symptoms, including inflammatory bowel disease or celiac disease, unless adequately excluded by clinical evaluation or prior testing.
  • Pregnancy or a positive pregnancy test.
  • Perimenopausal or postmenopausal status.
  • Previous use in the last 3 months OR current use of hormonal medications, including hormonal contraceptives (i.e. birth control pills, patches, implants, or intrauterine devices (IUDs)) or hormone replacement therapy
  • MRI contraindication, including a non-removable ferromagnetic implant or device, prior significant tattoo-related heating or burns, severe claustrophobia that cannot be managed, or another condition judged unsafe for MRI.
  • Major active psychiatric illness (e.g., schizophrenia, bipolar disorder), significant neurologic or central nervous system disease, or another medical condition that could affect safety, adherence, or interpretation of study outcomes.
  • Current participation in another IBS-specific intervention study or planned initiation of a new IBS-directed treatment during the 8-week randomized period.
  • Contraindication to cervical nVNS or inability to use the device safely.
  • Dermatologic conditions affecting the neck region that would interfere with nVNS placement
  • Any implanted electrical device
  • Any metallic device implanted at or near the neck
  • History of cervical vagotomy
  • Use of another electrical device at the same time (e.g., TENS unit, muscle stimulator) or any portable electronic device
  • Movement disorder
  • Clinically significant hypertension, hypotension, bradycardia, or tachycardia.
  • Cardiac disease or atherosclerotic cardiac disease, including congestive heart failure, known severe coronary artery disease, or recent myocardial infarction within 5 years.
  • Past abdominal surgery (except for appendectomy, cholecystectomy, benign polypectomy, hiatus hernia)
  • Inability or unwillingness to provide informed consent or complete study procedures in English.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: nVNS

Device: Participants will self-administer a transcutaneous cervical nVNS device, Truvaga Plus, which is identical to GammaCore but is rechargeable. Truvaga Plus is classified as a general wellness product that does not require FDA clearance and can be purchased without a prescription (electroCore LLC, Basking Ridge, NJ, USA, letter of support).

Usage: The nVNS will be delivered via two stainless steel contact surfaces that are coated with conductive gel before each treatment. The device will be positioned in parallel with the carotid pulse on the left side of the neck. Two back-to-back 2-minute nVNS stimulations (4 minutes total) will be administered twice daily at home for 8 weeks.

Intensity: Level is dependent on the patient. They will be instructed to increase the intensity until they feel a strong but comfortable sensation-tingling or a slight lip pull is common. Most users find the ideal intensity between levels 4 and Frequency: 2 sessions, 2x daily; 224 sessions total
Device: Truvaga Plus

Self-administered transcutaneous cervical nVNS device
No Intervention: Usual care

Participants assigned to the Usual Care arm will undergo the same assessments as those in the nVNS arm but will not receive any specific intervention from the project. No restrictions will be placed on participants, except that they will be asked not to start any new therapies for IBS or any new medicines unless deemed necessary by their healthcare provider.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in IBS Severity Scoring System (IBS-SSS)
Time Frame: 8 weeks, from baseline to end of intervention

The IBS-SSS questionnaire is a validated measure of IBS symptom severity and has been shown to be responsive to treatment. The IBS-SSS assesses the severity of abdominal pain, frequency of abdominal pain, severity of abdominal distention, dissatisfaction with bowel habits, and interference of IBS with daily life over a 10-day period. Each of the five categories will receive a score from 0-100, and the total IBSSSS is calculated by taking the sum of these categories (range 0-500, 0 - no symptoms, 500 - very severe symptoms).
8 weeks, from baseline to end of intervention
Change in Patient Health Questionnaire-15 (PHQ-15)
Time Frame: 8 weeks, from baseline to end of intervention

The PHQ-15 is a widely used measure of widespread somatic symptoms over 1 month that is sensitive to treatment effects. The PHQ-15 assess 15 different somatic symptoms (back pain, stomach pain, headaches, chest pain, trouble sleeping, etc.) rated by 0 - not bothered at all to 3 - bothered a lot. The scale is scored as follows: 0-4: Minimal somatic symptom severity, 5-9: Low somatic symptom severity, 10-14: Medium somatic symptom severity, 15-30: High somatic symptom severity.
8 weeks, from baseline to end of intervention
Change in stress reactivity (SR)-related brain phenotypes.
Time Frame: 8 weeks, from baseline to end of intervention

SR-related brain phenotypes will be derived from prespecified MRI measures of brain structure, functional connectivity, and brain activity. MRI data will be collected at baseline and Week 8. The primary imaging analysis will compare baseline-to-Week-8 change in prespecified SR-related brain phenotypes between nVNS and Usual Care.
8 weeks, from baseline to end of intervention

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
IBS Severity Scoring System (IBS-SSS) responder rate
Time Frame: 8 weeks, from baseline to end of intervention

The proportion of participants with IBS who experience a ≥50-point reduction in IBS-SSS score from baseline will be compared between treatment groups. A reduction of at least 50 points represents a clinically meaningful improvement in IBS symptoms. The IBS-SSS questionnaire is a validated measure of IBS symptom severity and has been shown to be responsive to treatment. The IBS-SSS assesses the severity of abdominal pain, frequency of abdominal pain, severity of abdominal distention, dissatisfaction with bowel habits, and interference of IBS with daily life over a 10-day period. Each of the five categories will receive a score from 0-100, and the total IBSSSS is calculated by taking the sum of these categories (range 0-500, 0 - no symptoms, 500 - very severe symptoms).
8 weeks, from baseline to end of intervention
Biologic measures of Stress Reactivity - SNS-Immune gene expression profile
Time Frame: 8 weeks, from baseline to end of intervention

Changes in the sympathetic nervous system (SNS)-immune gene expression profile will be evaluated as a peripheral biologic measure of stress reactivity. Whole-blood SNS-immune gene expression will be measured using mRNA-targeted sequencing. Total RNA will be isolated from whole blood, converted to cDNA using Lexogen QuantSeq 3' FWD, sequenced using Illumina sequencing, mapped to the GRCh38 reference human transcriptome using STAR, and quantified as gene-specific reads per million mapped reads. Baseline-to-Week-8 changes will be compared between nVNS and Usual Care and examined in relation to clinical symptom change. Moderator analyses will also test whether baseline SNS-immune gene expression modifies the treatment response using an SNS-immune measure-by-treatment-by-time interaction.
8 weeks, from baseline to end of intervention
Biologic measures of Stress Reactivity - heart rate variability (HRV)
Time Frame: 8 weeks, from baseline to end of intervention

HRV will be evaluated as a peripheral autonomic measure of stress reactivity and compared over the treatment period. HRV will be derived from physiologic data collected using a Fitbit equipped with photoplethysmography sensors that estimate heart rate and intervals between successive beats. Participants will wear the device from baseline through the post-intervention assessment, including during sleep, to characterize longitudinal and circadian HRV. Changes in HRV will be compared between nVNS and Usual Care and correlated with symptom change. Moderator analyses will additionally test whether baseline HRV modifies treatment response through an HRV-by-treatment-by-time interaction.
8 weeks, from baseline to end of intervention
Biologic measures of Stress Reactivity - fecal microbial stress index
Time Frame: 8 weeks, from baseline to end of intervention

Changes in the fecal microbial stress index will be evaluated as a peripheral biologic measure of stress reactivity. The fecal microbial stress index will be derived from stool samples collected at baseline and Week 8 using shotgun metagenomic sequencing. Microbial sequencing data will undergo species-level taxonomic and functional characterization. Baseline-to-Week-8 changes in the microbial stress index will be compared between nVNS and Usual Care and correlated with clinical symptom change.
8 weeks, from baseline to end of intervention
Biologic measures of Stress Reactivity - fecal metabolite stress index
Time Frame: 8 weeks, from baseline to end of intervention

Changes in the fecal metabolite stress index will be evaluated as a peripheral biologic measure of stress reactivity. The fecal metabolite stress index will be derived from stool metabolomic data obtained using LC-MS/MS-based profiling. Baseline-to-Week-8 changes in the metabolite stress index will be compared between nVNS and Usual Care and correlated with clinical symptom change. Moderator analyses will additionally test whether the baseline metabolite stress index modifies treatment response through a metabolite stress index-by-treatment-by-time interaction.
8 weeks, from baseline to end of intervention
Brain changes associated with IBS severity, comorbid symptom scores, and peripheral biologic measures of SR
Time Frame: 8 weeks, from baseline to end of intervention

Examine associations between changes in scores on the SR-related brain phenotype signatures and changes in IBS severity, comorbid symptom scores, and peripheral biologic measures of SR. General linear models will examine associations between baseline-to-Week-8 changes in SR-related brain phenotype signature scores and corresponding changes in IBS-SSS, PHQ-15, HRV, SNS-immune gene expression, and microbial and metabolite stress indices, with adjustment for relevant covariates. Alternative approaches may be used to examine multivariate associations between changes in symptom severity, stress reactivity, comorbidity, and brain connectivity.
8 weeks, from baseline to end of intervention
Change in extraintestinal symptoms in nVNS compared to Usual Care
Time Frame: 8 weeks, from baseline to end of intervention

Predict response (Pre-Post change in extraintestinal symptoms) in nVNS compared to Usual Care. General linear model-based moderator analyses will evaluate whether baseline SR-related brain phenotype scores predict pre- to post-treatment change in extraintestinal symptom severity differently in participants assigned to nVNS versus Usual Care. Models will include baseline SR brain phenotype score, treatment group, the brain phenotype-by-treatment interaction, and prespecified covariates. A significant interaction will indicate differential prediction of treatment response.
8 weeks, from baseline to end of intervention

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Exploratory outcome - Sex differences
Time Frame: 8 weeks, from baseline to end of intervention

Examine whether females with IBS with higher comorbid symptom scores will present with greater changes in SR-related brain signatures following the nVNS intervention compared to male IBS. Exploratory models will examine whether females with IBS with greater baseline comorbid symptom burden demonstrate greater baseline-to-Week-8 changes in SR-related brain signatures following nVNS compared with males with IBS. The moderator analysis includes the comorbid symptom score-by-group interaction, with adjustment for age, BMI, and diet.
8 weeks, from baseline to end of intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, Los Angeles

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health (NIH)

Investigators

  • Principal Investigator: Lin Chang, MD, University of California, Los Angeles

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2026

Primary Completion (Estimated)

December 1, 2031

Study Completion (Estimated)

December 1, 2031

Study Registration Dates

First Submitted

October 20, 2026

First Submitted That Met QC Criteria

November 3, 2026

First Posted (Actual)

November 9, 2026

Study Record Updates

Last Update Posted (Actual)

November 9, 2026

Last Update Submitted That Met QC Criteria

November 3, 2026

Last Verified

November 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-26-1113
  • 2U54DK123755-06A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No plans to share individual participant data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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