Vagustim™ Transcutaneous Auricular Vagus Nerve Stimulation Devices

This study will be a double-blind, sham-controlled trial with 20 participants evaluating Vagustim™'s sham method as a placebo. Participants will be randomized to the active treatment group or the sham treatment group and undergo a one-time 10-minute taVNS treatment. Blood samples will be obtained immediately prior to treatment and two hours post-treatment to evaluate circulating cytokine levels. Participants will have blood samples obtained immediately prior to taVNS and two hours post-treatment. A one-time taVNS treatment will be performed with the assistance of an unblinded research coordinator. The investigator will not be present during treatment to ensure double blinding. Blood samples will be sent for cytokine testing.

The Vagustim™ Individual Device is a 134mm x 70mm x 25 mm device that provides targeted vagus nerve stimulation via an in-ear or clip-on electrode. Please see below for exact pulse stimulation parameters and programming:

• Waveform: Symmetrical biphasic rectangular waveform.
• Frequency Range: Adjustable from 1 Hz to 100 Hz.
• Pulse Width: Configurable between 50 µs and 1000 µs.
• Intensity: Adjustable up to 10 mA with fine-tuned increments for patient-specific needs.
• Stimulation Modes: Bilateral (both ears) or unilateral (one ear) stimulation.
• Power Supply: Operates on 2xAA batteries for portability and reliability.
• Connectivity: Bluetooth Low Energy 4.2 for seamless app integration.
• Construction: Durable materials suitable for repeated professional use in clinical environments.
• Duration of implant or exposure: 10 minutes
• Frequency of exposure: Once during study visit

Participants are randomized (1:1) using REDCap as used by the Biostatistics randomization team, , a web-based HIPAA compliant software package. A stratified blocked randomization will be utilized based on age in order to ensure a similar age distribution in each arm of the study (sham and active treatment). The trial will be double blinded to the investigators and participants. To avoid potential bias, the randomizer(s) at each site cannot be physicians who will conduct physical exams to evaluate study participants or members of the research team who will have contact with the study data. There will be one to two designated trainers who will distribute the intervention device based on randomization assignment in a blinded fashion. As the trainer may be able to determine who is in the working device group from the reaction of the participant, this trainer will be independent (not an investigator) and will not have access to study related data/outcomes or be involved in the analysis. Unblinding will occur after all participants have completed their study visits.

taVNS Group: The intensity setting for pulse amplitude will be adjusted to the participant's tolerance (if a sensation is felt) This will involve slowly and incrementally increasing the intensity until the patient states they feel the electrical stimulation.

Sham group: The sham device will be programmed by the company to deliver 10 seconds of stimulation at the beginning treatment session. Externally, the sham device will look identical to the taVNS device. This sham method was chosen for its potential to more closely mimic true stimulation sensation and minimize unblinding. To evaluate the feasibility of this sham methodology, cytokine testing pre-treatment and 2 hours post-treatment. Cytokine testing pre-treatment and 2 hours post-treatment will determine cytokine responses to evaluate feasibility as a sham methodology for future clinical trials.

Subjects may withdraw from the study at any time without prejudice to their care. They may also be discontinued from the study at the discretion of the Investigator for lack of adherence to study treatment or visit schedules or AEs. The Investigator may also discontinue subjects who violate the study plan, or to protect the subject for reasons of safety or for administrative reasons. It will be documented whether or not each subject completes the clinical study.

If the Investigator becomes aware of any serious, related adverse events after the subject completes, withdraws or is discontinued from the study, they will be recorded in the source documents and on the CRF. Refer to previous subsection for data to be collected at the time of discontinuation of study intervention and follow-up and for any further evaluations that need to be completed.

The pilot trial are not powered to determine statistically significant differences in efficacy endpoints comparing taVNS with sham therapy. Sample sizes were chosen to appropriately assess the changes in TNFalpha in sham and treatment devices to determine if Vagustim can be used as placebo device.

This study is considered a pilot study, paving the way for larger, more definitive trials. Pilot studies often use smaller sample sizes to gather preliminary data and refine study procedures before investing in a larger trial.