An interventional study of Active non-invasive vagus nerve stimulation (nVNS) and Sham non-invasive vagus nerve stimulation (nVNS) in Chemotherapy-induced Neuropathy, sponsored by The Hong Kong Polytechnic University. Not yet recruiting at 3 sites in Hong Kong. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-16.
Sponsored by The Hong Kong Polytechnic University · Not applicable, Interventional, and Supportive care
Background: Studies highlight the potential benefits of home-based exercise for cancer survivors with chemotherapy-induced neuropathy (CIN); however, its effectiveness in alleviating CIN-related sensorimotor impairments and symptoms has been inconsistent and generally modest. Non-invasive vagus nerve stimulation (nVNS) has emerged as a promising adjunct for CIN rehabilitation. Preliminary studies suggest that nVNS can enhance the therapeutic effects of exercise-based rehabilitation, leading to greater improvements in sensorimotor impairments. A recent trial found that nVNS alleviated CIN-related pain and improved mental well-being, but did not significantly enhance physical well-being or clinician-rated CIN severity.
Objectives: To evaluate the efficacy, safety, and feasibility of combining home-based exercise with non-invasive vagus nerve stimulation (nVNS) to alleviate chemotherapy-induced neuropathy (CIN) and improve quality of life in cancer survivors.
Design and Subjects: This phase II randomized controlled trial will enroll 60 cancer survivors with established CIN following treatment with platinum compounds or taxanes. Participants will be randomly assigned in a 1:1:1 ratio to one of three groups: exercise with real nVNS (ERS), exercise with sham nVNS (ESS), or usual care.
Interventions: Participants in the experimental groups will engage in a 12-week home-based exercise program, with the ERS group receiving real nVNS and the ESS group receiving sham stimulation.
Study Instruments and Main Outcome Measures: The primary outcome, patient-reported CIN, will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item (EORTC QLQ-CIPN20). Secondary outcomes will include the Total Neuropathy Score-nurse for clinician-reported CIN, the Symptom Distress Scale for general symptoms, functional performance measures (Timed Up and Go Test and 6-Minute Walk Test), and the EORTC QLQ-Core 30-item for quality of life.
Data Analysis and Expected Results: Generalized Estimating Equations will be used for efficacy outcome analysis. It is anticipated that the combined intervention may lead to improvements in CIN, functioning, and quality of life, thereby supporting further research in larger trials.
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Completed a chemotherapy regimen with radical intent that included at least one of the following agents for a minimum of 3 months:
Exclusion Criteria:
Participants will receive active non-invasive vagus nerve stimulation (nVNS) concurrently with a standardized 12-week home-based exercise program after baseline assessment and randomization. The exercise program will include moderate-intensity aerobic walking (30 min daily; initial step goal based on pre-intervention average daily steps; weekly increase of 5-20%) and resistance training, targeting Borg 3-5/10. Active nVNS will be applied to the left cymba concha using tVNS501 at 25 Hz with a pulse width of 250 µs, 30 seconds on and 30 seconds off, and an intensity of 0.25-2.0 mA (maximum tolerable level) during exercise. It will be stopped during rest and after exercise.
Device: Active non-invasive vagus nerve stimulation (nVNS) · Behavioral: Home-based aerobic and resistance exercise program
The ESS group will receive the same 12-week home-based exercise program as the ERS group following baseline assessment and randomization, including moderate-intensity aerobic walking and resistance training. However, the stimulator will deliver a low frequency of 1 Hz at an intensity that elicits only the minimum perceptible sensation, with the aim of inducing a subtherapeutic placebo effect by mimicking active stimulation. Sham stimulation will be administered by the same research associate during the first face-to-face training session, after which participants will self-administer it concurrently with the home-based exercise program.
Device: Sham non-invasive vagus nerve stimulation (nVNS) · Behavioral: Home-based aerobic and resistance exercise program
The UC group will receive routine follow-up and consultation with doctors and/or nurses, without any supplementary information regarding home-based exercise or nVNS during the study period. However, they will have the opportunity to access the home-based exercise program, including a face-to-face session and an instruction booklet containing information regarding only the home-based exercise program, but not nVNS stimulator operation, after completing the final post-intervention assessment at Week 12.
nVNS will be applied to the left auricular region during the 12-week home-based exercise program. The ERS group will receive real stimulation at a frequency of 25 Hz, a pulse width of 250 µs, a pulse-train duration of 30 seconds on and 30 seconds off, and an intensity set at the maximum tolerable level for each participant (0.25-2.0 mA). Stimulation will be stopped during rest and after exercise. A portable device (tVNS501; Changzhou Rishena Medical Device Co., Ltd., Jiangsu, China) will be used to deliver the stimulation. During the first face-to-face training session, a trained research associate will configure the device parameters and position the electrode on the participant's left cymba concha. Subsequently, participants will be trained to self-administer the stimulation during home-based exercise.
The ESS group will undergo sham stimulation using the same device and electrode placement as the ERS group. Sham stimulation will be administered by the same trained research associate during the first face-to-face training session and subsequently self-administered by the participants during the 12-week home-based exercise program. However, the stimulator will be set to deliver a low stimulation frequency of 1 Hz at an intensity that elicits only the minimum perceptible sensation, with the aim of inducing a subtherapeutic placebo effect by mimicking active stimulation. The pulse width will be set to the lowest output of the stimulator, 100 µs, and the pulse-train duration will be 10 seconds on and 50 seconds off, thereby minimizing any potential physiological effects.
The home-based exercise program includes aerobic and resistance training at moderate intensity (modified Borg 3-5/10). Aerobic: daily walking 30 min, initial step goal based on pre-intervention average daily steps, increased by 5-20% each week for 12 weeks, with self-monitoring of Borg and weekly follow-up guidance. Resistance: upper- and lower-body elastic band exercises (shoulder flexion/extension, horizontal abduction, elbow flexion/extension, heel raises, partial squats), 1-2 sets of 6 repetitions per set, completed within 1 minute, with 1-1.5 minutes of rest between sets, for a total of up to 30 minutes, progressing to a maximum of 15 repetitions per set. Participants receive an instruction booklet, three elastic bands, and a wrist pedometer. A 60-min face-to-face training session is delivered by a trained research associate at a study hospital, a university teaching room, or the participant's home.
Patient-Reported Chemotherapy-Induced Neuropathy as Assessed by the Chinese Version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20)
The Chinese version of the EORTC QLQ-CIPN20 will be utilized to assess patient-reported chemotherapy-induced neuropathy. This 20-item questionnaire is an effective tool recommended by the National Cancer Institute for evaluating the CIPN phenotype, which includes sensory, motor, and autonomic symptoms in clinical trials. Both the Chinese and English versions demonstrate good internal consistency (Cronbach's α = 0.78-0.90), test-retest reliability (r = 0.73-0.84), and responsiveness to change (Cohen's d = 0.42-1.42).
Time frame: From enrollment to the end of treatment at Week 12.
Clinician-Reported Chemotherapy-Induced Neuropathy as Assessed by the Total Neuropathy Score-Nurse (TNSn)
The TNSn will be used. This tool includes three symptom-related questions that evaluate sensory symptom distribution, motor symptom impact, and autonomic symptom presence, along with assessments of vibration and pinprick sensations. Each symptom and sign is rated on a scale from 0 to 4, with higher scores indicating more severe conditions. The TNSn has been validated in clinimetric studies, showing a Minimal Clinically Important Difference of 2.79 points.
Time frame: At baseline (before intervention), Week 6, and Week 12 after randomization.
General Symptoms as Assessed by the Symptom Distress Scale (SDS)
The SDS will be used to assess general symptoms, including nausea, loss of appetite, insomnia, pain, fatigue, constipation and diarrhea, concentration difficulties, and changes in physical appearance. The scale employs a 5-point Likert-type scoring system, where 1 indicates normal symptom levels and 5 represents the highest degree of distress. Total scores range from 10 to 50, with higher scores reflecting greater symptom distress. Previous studies have shown that the SDS has acceptable internal consistency, with Cronbach's α values between 0.71 and 0.88.
Time frame: At baseline (before intervention), Week 6, and Week 12 after randomization.
Timed Up and Go Test
The TUGT measures dynamic balance and mobility by timing how long it takes a participant to rise from a seated position, walk three meters, turn around, walk back, and sit down. Participants will perform the task twice, and the average time will be recorded.
Time frame: At baseline (before intervention), Week 6, and Week 12 after randomization.
6-Minute Walk Test
The 6MWT evaluates endurance and physical performance by measuring the distance participants can walk at their usual speed for six minutes along a flat corridor, with the total distance recorded in meters. This test quantitatively reflects functional performance and exercise capacity, making it relevant for this population.
Time frame: At baseline (before intervention), Week 6, and Week 12 after randomization.
Health-Related Quality of Life as Assessed by the Chinese Version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
The EORTC QLQ-C30 will be used to assess health-related quality of life. Previous studies indicate moderate to good test-retest reliability (r = 0.54-0.86) and person separation reliability (r = 0.47-0.89) for both the English and Chinese versions.
Time frame: At baseline (before intervention), Week 6, and Week 12 after randomization.
Recruitment rate
Defined as the number of eligible participants who provide informed consent and are randomized, divided by the total number of eligible patients identified, multiplied by 100.
Time frame: Through study completion, an average of 2 years.
Retention rate
Defined as the percentage of enrolled patients who complete both the baseline and all follow-up assessments.
Time frame: Through study completion, an average of 2 years.
Acceptability as Assessed by the Chinese version of the Patients' Global Impression of Change
The Chinese version of the PGIC is a single-item, 7-point numerical rating scale ranging from 1 to 7 that assesses participants' subjective perceptions of improvement and satisfaction after receiving the study intervention.
Time frame: At Week 12 (post-intervention)
Adherence to aerobic exercise
Adherence to the prescribed aerobic exercise, measured by the number of steps taken per day.
Time frame: Daily during the 12-week intervention period, from randomization through Week 12.
Adherence to resistance exercise
Adherence to the prescribed resistance exercise, measured as the duration of exercise performed in minutes.
Time frame: During the 12-week intervention period, from randomization through Week 12.
Adherence to nVNS or sham stimulation
Adherence to the assigned nVNS or sham stimulation, measured as the duration of completed prescribed stimulation sessions in minutes.
Time frame: During the 12-week intervention period, from randomization through Week 12.
Number of Participants Experiencing Treatment-Related Adverse Events, as Assessed Using the NCI-CTCAE Version 5.0
Participants will be asked to report any adverse effects occurring during their participation in the study. The type, onset, and duration of each adverse effect will be recorded on a standardized form in accordance with the NCI-CTCAE Version 5.0 guidelines.
Time frame: During the 12-week intervention period, from randomization through Week 12.
Plan to share: Yes — All individual participant data underlying the results reported in the publication will be made available.
Supporting information: Study protocol, Statistical analysis plan
Time frame: Beginning 3 months and ending 3 years after the publication of results
Access criteria: Upon reasonable request to the Principal Investigator, individual participant data may be shared, provided that the requester submits a proposal describing the planned analyses and signs a data-sharing agreement. Requests and supporting documents should be submitted to the Principal Investigator at robbie-m.wang@polyu.edu.hk
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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