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

This study evaluates whether a non-invasive device called transcutaneous vagus nerve stimulation (tVNS) can be safely and feasibly used to help reduce fatigue in patients receiving immunotherapy for cancer. Fatigue is a common and often severe side effect of immune checkpoint inhibitors, and there are currently limited effective treatment options.

In this study, participants will use a small device at home that delivers mild electrical stimulation to the ear for 60 minutes each day over a 6-week period. The study will assess whether patients are able to use the device as prescribed (feasibility), how well it is tolerated, and whether it may improve fatigue and quality of life.

The study will also explore changes in biological markers of inflammation and measures of nervous system function to better understand how tVNS may work. The results of this study will help determine whether this approach should be tested in larger future trials.

Study Overview

• Status: Not yet recruiting
• Conditions: Cancer-related Fatigue
• Intervention / Treatment: 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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 13
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Randall F Holcombe, MD; Phone Number: 1 (802) 656-2021; Email: Randall.holcombe@med.uvm.edu
• Study Contact Backup: Name: Rohit Singh, MD; Phone Number: 1 (802) 656-2021; Email: rohit.singh@uvmhealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Transcutaneous Vagus Nerve Stimulation (tVNS); 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.

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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of Daily tVNS Use	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.	Up to 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of tVNS	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.	Up to 6 weeks
Change in Fatigue Severity (FACIT-F)	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.	Baseline to 6 weeks
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	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.	Baseline to 6 weeks
Change in Inflammatory Biomarkers	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.	Baseline to 6 weeks

Collaborators and Investigators

• Sponsor: University of Vermont Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2030
• Study Completion (Estimated): July 1, 2035

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 7, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Vagus nerve stimulation; Cancer-related fatigue
• Other Study ID Numbers: STUDY00004152/UVMCC2603

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No