taVNS in Veterans With Knee OA (AVAHCS) (taVNS)

September 3, 2026 updated by: VA Office of Research and Development

Optimizing Home-Based Auricular Vagus Nerve Stimulation for Pain, Function, and Inflammation in Veterans With Knee Osteoarthritis: A Randomized Pilot Dose-Finding Study (AVAHCS) (F4845-C)

The objectives of this study are to identify an optimal transcutaneous auricular vagus nerve stimulation (taVNS) dosing regimen for pain relief and anti-inflammatory effects in Veterans with knee osteoarthritis (OA), compared to corticosteroid injection (CSI), and lay the groundwork for future combinatorial therapies with cell-based approaches. The population for this study is Veterans with osteoarthritis (OA). This single-center, randomized pilot study will enroll participants with knee OA, who will be allocated to CSI (n=10), high-dose taVNS (n=15; 1-2 hours/day, 7 days/week), or low-dose taVNS (n=15; 30-60 min/day, 3 days/week) for 12 weeks. Synovial fluid and blood samples will be collected at baseline, 4, and 12 weeks for biomarker analysis (pro-inflammatory cytokines: TNF-, IL-6, IL-1 ; anti-inflammatory mediators: IL-10, TGF-). The approximate study duration for each individual participant is 12 weeks of treatment with assessment visits at baseline, one month, and three months. Participants will be recruited at the Atlanta VA. The anticipated total enrollment is 40 participants. No specimens or data will be banked for future research use. Informed consent will be obtained from participants in person via signatures on written informed consent forms.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This pilot study will be the first to test home-based taVNS against corticosteroid injections (CSI) in knee osteoarthritis (KOA) to assess their effects on pain, function, and serum/synovial fluid pro and anti-inflammatory biomarkers. Adult participants diagnosed clinically and/or radiographically with KOA (n=40) will be randomized to CSI (n=10) or 12 weeks of taVNS (high dose n=15; low dose n=15) and assessed pre-procedure and at 1- and 3-month timepoints. The following outcome measures will be assessed: PEG-3, DVPRS, NIH-PROMIS, KOOS, and Central Sensitization Inventory. In addition, biomarker levels in the serum and synovial fluid will be measured at baseline, 1- and 3-month timepoints.

This study will be the first to 1) directly compare taVNS against gold-standard CSI, 2) examine taVNS effects on cytokines in knee OA as compared to CSI, 3) target an ideal taVNS dosing strategy for knee OA, and 4) utilize Parasym , a home-based taVNS device previously shown to reduce heart failure symptoms and decrease TNF- 17 that has been classified as non-significant risk (NSR) by the FDA. The investigators are therefore testing a novel veteran-centric, nonpharmacological intervention for knee OA; taVNS with Parasym offers a safe, self-administered alternative to opioids and invasive procedures, with minimal side effects and high potential for real-world implementation in the Veteran population.

Aim 1: Identify an ideal taVNS dosing regimen for analgesic effects. (30-60 minutes per day, 3 days per week 4,17 versus 1-2 hours per day, 7 days per week17 for 12 weeks) on clinical improvements in pain and function. Hypothesis for Aim 1: Pain (primary outcome), measured by the PEG-3 (3-item scale assessing pain intensity, interference with activity, and enjoyment of life)18 and DVPRS (assesses pain intensity + interference with activity, sleep, mood, stress)19 and function (secondary outcome) measured by the KOOS (Knee Injury and Osteoarthritis Outcome Score)20 and NIH PROMIS measures21 will be more improved in those undergoing high-dose taVNS (n=15) than vs. low-dose taVNS (n=15) or CSI (n=10). Central sensitization inventory will also be collected to evaluate it as a co-variate in predicting and monitoring treatment response.

Aim 2: Evaluate taVNS dose-dependent modulation of biomarkers associated with inflammation in Aim 1 participants. Synovial fluid and peripheral blood will be obtained pre-procedure and at 4- and 12-weeks following initiation of therapy. Hypothesis for Aim 2: taVNS results in greater reductions in pro-inflammatory cytokines (e.g., TNF- , IL-6, IL-1 ) and increased levels of anti-inflammatory mediators (e.g., IL-10, TGF- ) in synovial fluid and peripheral blood compared to CSI. The investigators expect that the higher dose group will demonstrate more pronounced changes in anti-inflammatory biomarkers as compared to low dose taVNS or CSI.

This study addresses a critical need for innovative, non-opioid OA therapies and supports the CReATE Motion Center's mission to advance regenerative therapies for Veterans. Based on results of this study, the investigators will choose the taVNS dosing strategy that best enhances clinical and anti-inflammatory effects. This pilot study has the potential to advance a novel, non-pharmacological approach to pain relief and functional recovery in a population with high unmet needs and is a critical first step to our understanding of dose optimization in taVNS for knee OA-related pain, function, and anti-inflammatory effects.

Our project is designed as a foundational step toward future combinatorial trials pairing taVNS with other therapies for chondroprotection.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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 Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

  • Name: Anna M Ree, BA
  • Phone Number: 202561 (404) 321-6111
  • Email: anna.ree@va.gov

Study Locations

  • United States
    • Georgia
      • Decatur, Georgia, United States, 30033-4004
        • Atlanta VA Medical and Rehab Center, Decatur, GA
        • Contact:
        • Principal Investigator:
          • Anna Woodbury, MD

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Clinical diagnosis of knee osteoarthritis according to the American College of Rheumatology (ACR) criteria, confirmed by radiologic evidence of the same.
  • Moderate to severe knee pain, as assessed by the Defense Veterans Pain Rating Scale (DVPRS), a validated pain scale (score ≥4)
  • Willingness to discontinue current knee osteoarthritis (OA) pain medications (except permitted rescue medication such as acetaminophen/paracetamol) during the trial
  • Ability to provide informed consent and comply with all study procedures
  • Ambulatory and able to attend all study visits

Exclusion Criteria:

  • History or evidence of inflammatory joint disease (e.g., rheumatoid arthritis, spondyloarthropathy), secondary or metabolic causes of arthritis, or significant trauma to the knee within 3 months prior to screening
  • Recent or planned major knee surgery on the index knee (arthroplasty or arthroscopy within 6 months)
  • Received intra-articular corticosteroid or hyaluronic acid injections in the index knee within 12 weeks prior to screening, or systemic corticosteroids within 30 days
  • Contraindications to transcutaneous auricular vagus nerve stimulation (taVNS), such as:

oMetal implants above the neck oActive ear infection, recent ear trauma, or chronic ear/facial pain oPrior vagus nerve surgery (including vagotomy) or ongoing VNS therapy for another condition

  • Severe comorbidities (e.g., uncontrolled liver/kidney disease, active malignancy, uncontrolled hypertension or cardiovascular disease, uncontrolled diabetes with neuropathy)
  • Participation in another interventional clinical trial within the past 2 months
  • Inability to provide informed consent or comply with protocol requirements (e.g., significant cognitive impairment)
  • Any unstable or severe psychiatric disorder that, in the investigator's opinion, would compromise safety or compliance

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Other: Standard-of-care CSI
Participants allotted to this group will receive gold-standard corticosteroid injection (CSI), a standard-of-care option for treating and managing knee osteoarthritis (KOA) pain.
Drug: Methylprednisolone acetate
FDA-approved injection treatment applied to the knee for purposes of KOA pain management.
Other Names:
  • Depo-Medrol, Depo-Medrate, Depo-Medrone, gold-standard corticosteroid injection (CSI)
Active Comparator: Low-dose taVNS
Transcutaneous auricular vagus nerve stimulation (taVNS) is a self-administered, home-based, non-invasive therapy with minimal risk of side effects. Mechanistically, taVNS targets auricular vagal afferents and requires afferent signaling to the nucleus tractus solitarius (NTS) to activate downstream efferent pathways in the central nervous system, including higher brain regions involved in pain processing (Fig 1), exerting anti-nociceptive effects. Participants allocated to this group will receive low-dose taVNS (n=15; 30-60 min/day, 3 days/week) for 12 weeks.
Device: taVNS
Transcutaneous auricular vagus nerve stimulation (taVNS) is a self-administered, home-based, non-invasive therapy with minimal risk of side effects. Mechanistically, taVNS targets auricular vagal afferents and requires afferent signaling to the nucleus tractus solitarius (NTS) to activate downstream efferent pathways in the central nervous system, including higher brain regions involved in pain processing (Fig 1), exerting anti-nociceptive effects.
Other Names:
  • Nurosym
Active Comparator: High-dose taVNS
Transcutaneous auricular vagus nerve stimulation (taVNS) is a self-administered, home-based, non-invasive therapy with minimal risk of side effects. Mechanistically, taVNS targets auricular vagal afferents and requires afferent signaling to the nucleus tractus solitarius (NTS) to activate downstream efferent pathways in the central nervous system, including higher brain regions involved in pain processing (Fig 1), exerting anti-nociceptive effects. Participants allocated to this group will receive high-dose taVNS (n=15; 1-2 hours/day, 7 days/week) for 12 weeks.
Device: taVNS
Transcutaneous auricular vagus nerve stimulation (taVNS) is a self-administered, home-based, non-invasive therapy with minimal risk of side effects. Mechanistically, taVNS targets auricular vagal afferents and requires afferent signaling to the nucleus tractus solitarius (NTS) to activate downstream efferent pathways in the central nervous system, including higher brain regions involved in pain processing (Fig 1), exerting anti-nociceptive effects.
Other Names:
  • Nurosym

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Improvements in Clinical Pain (DVPRS)
Time Frame: Through study completion, average of 9 months
The DVPRS is a pain measurement tool used in the U.S. Military Health System and VA to assess pain intensity and impact on quality of life. It utilizes a numerical rating scale enhanced by words that describe function, sleep, activity, mood, and color-coding to enhance communication. Clinical pain, as measured by the Defense Veterans Pain Rating Scale (DVPRS), will be our primary outcome. This measure is rated on a scale of 0 to 10, with 0 being "no pain" and 10 being "as bad as it could be, nothing else matters". Assessments will be administered at the initial visit (week 1), 4-week follow-up visit, 12-week follow-up visit, and 6-month follow-up visit.
Through study completion, average of 9 months
Concentration of Pro-inflammatory Cytokines (Blood)
Time Frame: Through study completion, average of 9 months
Biomarker analysis (pro-inflammatory cytokines: TNF-α, IL-6, IL-1β) of blood samples, collected at baseline,1-month post-treatment, and 3 months post treatment. The hypothesis is that there will be an increase in anti-inflammatory mediators and decrease in pro-inflammatory cytokines with high-dose taVNS in comparison with the other groups, and that this will correlate with improved clinical outcomes. Specimens will be taken at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months
Concentration of Pro-inflammatory Cytokines (Synovial Fluid)
Time Frame: Through study completion, average of 9 months
Biomarker analysis (pro-inflammatory cytokines: TNF-α, IL-6, IL-1β; anti-inflammatory mediators: IL-10, TGF-β) of synovial fluid, collected at baseline,1-month post-treatment, and 3 months post treatment. The hypothesis is that there will be an increase in anti-inflammatory mediators and decrease in pro-inflammatory cytokines with high-dose taVNS in comparison with the other groups, and that this will correlate with improved clinical outcomes. Specimens will be taken at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months
Concentration of Anti-inflammatory Mediators (Blood)
Time Frame: Through study completion, average of 9 months
Biomarker analysis (anti-inflammatory mediators: IL-10, TGF-β) of blood samples, collected at baseline,1-month post-treatment, and 3 months post treatment. The hypothesis is that there will be an increase in anti-inflammatory mediators and decrease in pro-inflammatory cytokines with high-dose taVNS in comparison with the other groups, and that this will correlate with improved clinical outcomes. Specimens will be taken at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months
Concentration of Anti-inflammatory Mediators (Synovial Fluid)
Time Frame: Through study completion, average of 9 months
Biomarker analysis (anti-inflammatory mediators: IL-10, TGF-β) of synovial fluid and blood samples, collected at baseline,1-month post-treatment, and 3 months post treatment. The hypothesis is that there will be an increase in anti-inflammatory mediators and decrease in pro-inflammatory cytokines with high-dose taVNS in comparison with the other groups, and that this will correlate with improved clinical outcomes. Specimens will be taken at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Changes in Pain Frequency and Intensity (PEG-3)
Time Frame: Through study completion, average of 9 months
The PEG is a 3-item patient-reported measure derived from the Brief Pain Inventory . It assesses average pain intensity, interference with enjoyment of life, and interference with general activity over the past week. Its minimally clinically important difference is 1-2 points. Assessments will be administered at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months
Changes in Knee Pain, Function, and QOL (KOOS-12)
Time Frame: Through study completion, average of 9 months
The KOOS-12 is a 12-item scale that assesses knee pain, function, and quality of life (QOL). Items are rated on a 5-point scale (0=no problems, 4=extreme problems), summed, and converted to a 0-100 scale (0=severe problems, 100=no problems). The KOOS-12 evaluates pain frequency and intensity during common activities (i.e. walking on a flat surface, going up or down stairs, getting in and out of the car), offering a comprehensive view of limitations in activities of daily living (ADLs) attributable to knee pain. The MCID ranges from 14.2 to 21.9 points. Assessments will be administered at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months
Patient Reported Improvements (NIH-PROMIS)
Time Frame: Through study completion, average of 9 months
NIH-PROMIS is a validated, 29-item patient-reported outcome measure assessing health-related quality of life (QOL) across seven domains: anxiety, depression, fatigue, pain interference, physical function, disturbance, and social participation, plus a single pain intensity item. Each domain has four items scored independently, mostly reflecting symptoms over the past seven days (except physical function which is not time bound). This instrument supports the generation of global physical and mental health summary scores, providing an overview of participants' quality of life. Scores are standardized as T-scores (mean 50; standard deviation 10) for ease of interpretation. Minimally important differences ranges from 2 to 6 points across domains, with values of 3 to 5 points commonly cited for pain interference and physical function in musculoskeletal conditions. Assessments will be administered at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months
Treatment Prediction and Monitoring (Central Sensitization Inventory)
Time Frame: Through study completion, average of 9 months
Central sensitization inventory will also be collected to evaluate it as a co-variate in predicting and monitoring treatment response. Assessments will be administered at the initial visit (week 1), 4-week follow-up visit, and 12-week follow-up visit.
Through study completion, average of 9 months

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
VA Office of Research and Development

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Anna Woodbury, MD, Atlanta VA Medical and Rehab Center, Decatur, GA

Publications and helpful links

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Helpful Links

Study record dates

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Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 21, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 3, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 4, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 4, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 3, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • RDX 26-001
  • 5150RX004845-02 (Other Grant/Funding Number: VA RR&D (Create Motion Center))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

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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