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.
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
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
FDA-approved injection treatment applied to the knee for purposes of KOA pain management.
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.
Atlanta VA Medical and Rehab Center, Decatur, GA
Decatur, Georgia, United States
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 months
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 months
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 months
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 months
Concentration of Anti-inflammatory Mediators (Synovial Fluid)
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.
Time frame: Through study completion, average of 9 months
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 months
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 months
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 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
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 months