taVNS in Veterans With Knee OA (AVAHCS)

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.

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.

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