taVNS in Veterans With Knee OA (AVAHCS)
ConditionKnee Osteoarthritis
Trial statusNot yet recruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age45-75
SponsorVA Office of Research and Development
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
Disqualifiers
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
Severe comorbidities (e.g., uncontrolled liver/kidney disease, active malignancy, uncontrolled hypertension or cardiovascular disease, uncontrolled diabetes with neuropathy)
Trial design
Design model
Parallel
Treatments tested in this trial
Methylprednisolone acetate
DrugFDA-approved injection treatment applied to the knee for purposes of KOA pain management.
taVNS
DeviceTranscutaneous 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.
Treatment groups
40 Participants
are divided into 3 treatment groupsGroup A: Standard-of-care CSIOther 1 intervention
Group B: Low-dose taVNSActive comparator 1 intervention
Group C: High-dose taVNSActive comparator 1 intervention
Trial outcomes
Primary outcomes
1
Improvements in Clinical Pain (DVPRS)
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.
Time frame
Through study completion, average of 9 months2
Concentration of Pro-inflammatory Cytokines (Blood)
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.
Time frame
Through study completion, average of 9 months3
Concentration of Pro-inflammatory Cytokines (Synovial Fluid)
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.
Time frame
Through study completion, average of 9 months4
Concentration of Anti-inflammatory Mediators (Blood)
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.
Time frame
Through study completion, average of 9 monthsSecondary outcomes
1
Changes in Pain Frequency and Intensity (PEG-3)
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.
Time frame
Through study completion, average of 9 months2
Changes in Knee Pain, Function, and QOL (KOOS-12)
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.
Time frame
Through study completion, average of 9 months3
Patient Reported Improvements (NIH-PROMIS)
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.
Time frame
Through study completion, average of 9 months4
Treatment Prediction and Monitoring (Central Sensitization Inventory)
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.
Time frame
Through study completion, average of 9 monthsSponsors and contacts
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Source ClinicalTrials.gov
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