Feasibility and Expansion Trial of Transcutaneous Vagus Nerve Stimulation (tVNS) for Immune-Related Fatigue in Patients Receiving Immune Checkpoint Inhibitors

This is a single-arm, open-label feasibility and expansion study evaluating transcutaneous vagus nerve stimulation (tVNS) as a supportive care intervention for immune-related fatigue in patients receiving immune checkpoint inhibitor therapy.

Eligible participants are adults with advanced or metastatic solid tumors who are currently receiving immune checkpoint inhibitors and experiencing clinically significant fatigue. Participants will self-administer tVNS at home once daily for 60 minutes over a 6-week intervention period using a non-invasive auricular stimulation device.

The primary objective is to evaluate feasibility, defined as adherence to the prescribed tVNS regimen. Secondary objectives include assessment of safety and tolerability, as well as changes in fatigue severity and health-related quality of life. Exploratory objectives include evaluation of changes in autonomic function, measured by heart rate variability, and inflammatory biomarkers obtained from blood samples.

Participants will complete study visits at baseline, Week 3, and Week 6, which include patient-reported outcome measures, adverse event assessments, and biospecimen collection. Heart rate variability will be continuously monitored using a wearable device throughout the intervention period.

This study is designed to generate feasibility and preliminary clinical and biological data to inform the design of future randomized trials evaluating tVNS as a treatment for immune-related fatigue.

• Participants will self-administer transcutaneous vagus nerve stimulation (tVNS) at home using a non-invasive auricular stimulation device for 60 minutes per day over a 6-week period. Participants will (Device): Participants will self-administer transcutaneous vagus nerve stimulation (tVNS) at home using a non-invasive auricular stimulation device for 60 minutes per day over a 6-week period. Participants will continue standard cancer therapy, including immune checkpoint inhibitors, during the study. Study assessments will include adherence monitoring, adverse event evaluation, patient-reported outcomes, and collection of blood samples and physiologic data.

Primary outcomes

• Feasibility of Daily tVNS Use [Up to 6 weeks]: Feasibility will be assessed based on adherence to the prescribed tVNS regimen. Feasibility is defined as the proportion of participants who complete at least 80% of prescribed tVNS sessions over the 6-week intervention period, as measured by concordance between participant-reported use and device-recorded usage.

Secondary outcomes

• Safety and Tolerability of tVNS [Up to 6 weeks]: Safety and tolerability will be assessed by the incidence, severity, and relatedness of adverse events occurring during the 6-week intervention period, graded according to CTCAE version 5.0.
• Change in Fatigue Severity (FACIT-F) [Baseline to 6 weeks]: Fatigue severity will be assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Changes in scores from baseline to Week 6 will be evaluated.
• Change in Health-Related Quality of Life (EORTC QLQ-C30) [Health-related quality of life will be assessed using the EORTC QLQ-C30 global health status scale. Changes from baseline to Week 6 will be evaluated.]: Health-related quality of life will be assessed using the EORTC QLQ-C30 global health status scale. Changes from baseline to Week 6 will be evaluated.
• Change in Heart Rate Variability [Baseline to 6 weeks]: Autonomic function will be assessed using heart rate variability (HRV) derived from wearable device data collected throughout the 6-week intervention period. Changes in HRV metrics over time will be explored.
• Change in Inflammatory Biomarkers [Baseline to 6 weeks]: Blood samples will be collected to assess circulating inflammatory biomarkers (e.g., cytokines such as IL-6, TNF-alpha, and C-reactive protein). Changes from baseline to Week 6 will be explored.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age 18 years or older
* Histologically confirmed advanced or metastatic solid tumor
* Receiving immune checkpoint inhibitor therapy and completed at least two cycles
* Clinically significant fatigue (FACIT-F score ≤ 34)
* ECOG performance status 0-2
* Life expectancy of at least 3 months
* Ability to provide informed consent
* Access to a smartphone or tablet

Exclusion Criteria:

* Current or planned chemotherapy, targeted therapy, or radiation during the 4-week intervention period.
* Have received targeted therapy in the last 2 weeks
* Have received chemotherapy or radiation therapy in the last 4 weeks
* Symptomatic brain metastases defined as active neurologic complaint (headache, blurry vision, neurologic deficits or other symptom requiring treatment with steroids)
* Long term steroid use >10 mg prednisone equivalent daily
* Active autoimmune disease requiring systemic immunosuppression
* Implanted electronic medical devices (e.g., pacemakers, defibrillators)
* History of epilepsy or vagal hypersensitivity
* Known arrhythmia or bradycardia (Baseline HR < 50 bpm)
* Open wounds or dermatologic issues at the stimulation site
* Pregnancy or breastfeeding
* Participation in other fatigue-focused intervention trials
* Severe uncontrolled psychiatric illness (PHQ-9 >20)