Clinical Application of Vagus Nerve Stimulation Combined With Immunoregulatory T Cells in Alleviating Aromatase Inhibitor-Induced Pain

The goal of this clinical trial is to learn whether transcutaneous auricular vagus nerve stimulation, also called taVNS, can help relieve aromatase inhibitor-related joint and muscle pain in adult women with hormone receptor-positive breast cancer.

The main questions this study aims to answer are:

1. Does taVNS reduce pain caused by aromatase inhibitor treatment?
2. Does taVNS improve quality of life, mood symptoms, and the need for pain medicine?
3. What side effects or medical problems occur during treatment?

Researchers will compare active taVNS with sham stimulation. Participants in both groups will receive mild electrical stimulation around the ear, but the sham stimulation will be applied to an area not expected to activate the vagus nerve.

Participants will:

1. Be randomly assigned to active taVNS or sham stimulation
2. Receive one 30-minute treatment session every day for 28 days
3. Complete pain, mood, and quality-of-life questionnaires before treatment, after treatment, and during follow-up
4. Report pain medicine use and any side effects
5. Provide small blood samples to measure inflammatory markers, T-cell profiles, and tumor markers

Participants will be followed for up to 6 months after treatment. For some participants who do not have enough pain relief after taVNS, an optional second-stage study may be offered. In this stage, participants may receive low-dose interleukin-2, also called IL-2, by injection every other day for 2 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; Pain Alleviation; Aromatase Inhibitor Associated Musculoskeletal Symptoms (AIMSS)
• Intervention / Treatment: Device: transcutaneous auricular vagus nerve stimulation; Device: sham stimulation

• Study Type: Interventional
• Enrollment (Estimated): 216
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yi Feng, M.D; Phone Number: +86-010-88325590; Email: fengyi@pkuph.edu.cn
• Study Contact Backup: Name: Pei Li, M.D; Phone Number: +86-13126762029; Email: pli@stu.pku.edu.cn

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100044
      • Peking University People's Hospital
      • Contact: Pei Li, M.D; Phone Number: +86-13126762029; Email: pli@stu.pku.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Female participants aged over 18 years;
2. Patients with pathologically confirmed stage I-III primary breast cancer;
3. Patients who have recovered from systemic symptoms related to surgery, radiotherapy, or chemotherapy;
4. Patients with estrogen receptor- and/or progesterone receptor-positive breast cancer who are receiving aromatase inhibitor therapy and have aromatase inhibitor-related musculoskeletal pain, with a score greater than 3 on the Worst Pain item of the Brief Pain Inventory (BPI-WP);
5. Patients who have received aromatase inhibitor therapy for more than 30 days and are expected to continue treatment for more than 1 year;

6. Patients who voluntarily agree to participate in this study and sign the informed consent form.

   For participants receiving combined IL-2 treatment, the following additional criterion applies:

7. Pain relief rate of less than 50% after taVNS treatment and a lower peripheral blood Treg count than before treatment.

Exclusion Criteria:

1. Patients with advanced breast cancer;
2. Patients with other significant organ dysfunction, such as major cardiovascular disease, diabetes mellitus, or hyperthyroidism;
3. Patients with other cancers;
4. Patients with a history of fracture or surgery around the painful joint area within the past 6 months;
5. Patients currently receiving corticosteroids or opioid therapy;
6. Patients with contraindications to vagus nerve stimulation;
7. Patients who are unable to communicate normally, such as those with cognitive impairment or hearing impairment;

8. Patients who have participated in another clinical trial within the past 1 month.

   For participants receiving combined IL-2 treatment, the following additional exclusion criteria apply:

9. Severe cardiac or renal disease, or hematologic disease;
10. Previous IL-2-related toxic reaction or allergy;
11. Use of other biologic agents or immunosuppressive drugs within the past 1 month;
12. Any other condition that the investigator considers unsuitable for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: transcutaneous auricular vagus nerve stimulation group; Electrodes will be placed on specific areas of the participant's left external ear that are mainly innervated by the auricular branch of the vagus nerve. The electrodes will be connected to an electrical stimulation device, and stimulation will be delivered at tolerable intensity using preset study parameters. Treatment will be given once daily for 28 consecutive days.	Device: transcutaneous auricular vagus nerve stimulation; Electrodes will be placed on specific areas of the participant's left external ear that are mainly innervated by the auricular branch of the vagus nerve. The electrodes will be connected to an electrical stimulation device, and stimulation will be delivered at tolerable intensity using preset study parameters. Treatment will be given once daily for 28 consecutive days.; Other Names: taVNS
Sham Comparator: sham stimulation group; Compared with transcutaneous auricular vagus nerve stimulation group, electrodes will be placed on different areas of the participant's left external ear that are not innervated by the auricular branch of the vagus nerve. The electrodes will be connected to an electrical stimulation device, and stimulation will be delivered at tolerable intensity using preset study parameters. Treatment will be given once daily for 28 consecutive days.	Device: sham stimulation; Compared with transcutaneous auricular vagus nerve stimulation group, electrodes will be placed on different areas of the participant's left external ear that are not innervated by the auricular branch of the vagus nerve. The electrodes will be connected to an electrical stimulation device, and stimulation will be delivered at tolerable intensity using preset study parameters. Treatment will be given once daily for 28 consecutive days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The pain relief rate of patients at the end of the 4-week treatment period	From enrollment to the end of treatment at 4 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain relief rate at follow-up		At 1, 2, 3, and 6 months after completion of treatment.
Dosage of analgesic drugs		At 1, 2, 3, and 6 months after completion of treatment.
Depression scores	PHQ-9 is used to measure depression. PHQ-9 ( unabbreviated scale title: Patient Health Questionnaire-9) Minimum Value: 0 Maximum Value: 27 Score Interpretation: Higher scores mean a WORSE outcome. Details:The PHQ-9 is a screening tool for depression. A higher score indicates more severe depressive symptoms. Generally, scores are interpreted as follows: 0-4 (Minimal), 5-9 (Mild), 10-14 (Moderate), 15-19 (Moderately Severe), and 20-27 (Severe) depression.	At 1, 2, 3, and 6 months after completion of treatment.
Anxiety scores	GAD-7 is used to measure anxiety. GAD-7 (unabbreviated scale title: Generalized Anxiety Disorder-7) Minimum Value: 0 Maximum Value: 21 Score Interpretation: Higher scores mean a WORSE outcome. Details:The GAD-7 measures the severity of generalized anxiety disorder. A higher score reflects more frequent and severe anxiety symptoms. Typical interpretations are: 0-4 (Minimal), 5-9 (Mild), 10-14 (Moderate), and 15-21 (Severe) anxiety.	At 1, 2, 3, and 6 months after completion of treatment.
Quality of life score	Quality of life assessed by the EuroQol 5-Dimension 5-Level questionnaire and EuroQol Visual Analogue Scale Description: Quality of life will be assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) and the EuroQol Visual Analogue Scale (EQ VAS). For the EQ-5D-5L descriptive system, scores range from 5 to 25, with higher scores indicating worse health status. For the EQ VAS, scores range from 0 to 100, with higher scores indicating better self-rated health status.	At 1, 2, 3, and 6 months after completion of treatment.
Plasma inflammatory marker levels		Baseline, immediately after completion of treatment, and 6 months after completion of treatment.
The proportion of T cells in the blood		Baseline, immediately after completion of treatment, and 6 months after completion of treatment.
The count of T cells in the blood		Baseline, immediately after completion of treatment, and 6 months after completion of treatment.

Other Outcome Measures

Outcome Measure	Time Frame
Tumor marker levels	Baseline, immediately after completion of treatment, and 6 months after completion of treatment.
Adverse events and serious adverse events	Adverse events and serious adverse events will be recorded throughout the study.

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: National Natural Science Foundation of China

Publications and helpful links

General Publications

• Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, Majid A. Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul. 2018 Nov-Dec;11(6):1225-1238. doi: 10.1016/j.brs.2018.08.010. Epub 2018 Aug 23.
• Zhang S, Zhao Y, Qin Z, Han Y, He J, Zhao B, Wang L, Duan Y, Huo J, Wang T, Wang Y, Rong P. Transcutaneous Auricular Vagus Nerve Stimulation for Chronic Insomnia Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2024 Dec 2;7(12):e2451217. doi: 10.1001/jamanetworkopen.2024.51217.
• Zhang Q, Hresko ME, Picton LK, Su L, Hollander MJ, Nunez-Cruz S, Zhang Z, Assenmacher CA, Sockolosky JT, Garcia KC, Milone MC. A human orthogonal IL-2 and IL-2Rbeta system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia. Sci Transl Med. 2021 Dec 22;13(625):eabg6986. doi: 10.1126/scitranslmed.abg6986. Epub 2021 Dec 22.
• Ren Z, Zhang A, Sun Z, Liang Y, Ye J, Qiao J, Li B, Fu YX. Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity. J Clin Invest. 2022 Feb 1;132(3):e153604. doi: 10.1172/JCI153604.
• Miao M, Li Y, Huang B, Chen J, Jin Y, Shao M, Zhang X, Sun X, He J, Li Z. Treatment of Active Idiopathic Inflammatory Myopathies by Low-Dose Interleukin-2: A Prospective Cohort Pilot Study. Rheumatol Ther. 2021 Jun;8(2):835-847. doi: 10.1007/s40744-021-00301-3. Epub 2021 Apr 14.
• Zhang X, Miao M, Zhang R, Liu X, Zhao X, Shao M, Liu T, Jin Y, Chen J, Liu H, Zhang X, Li Y, Zhou Y, Yang Y, Li R, Yao H, Liu Y, Li C, Li Y, Ren L, Su Y, Sun X, He J, Li Z. Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2022 Mar 7;7(1):67. doi: 10.1038/s41392-022-00887-2.
• He J, Chen J, Miao M, Zhang R, Cheng G, Wang Y, Feng R, Huang B, Luan H, Jia Y, Jin Y, Zhang X, Shao M, Wang Y, Zhang X, Li J, Zhao X, Wang H, Liu T, Xiao X, Zhang X, Su Y, Mu R, Ye H, Li R, Liu X, Liu Y, Li C, Liu H, Hu F, Guo J, Liu W, Zhang WB, Jacob A, Ambrus JL Jr, Ding C, Yu D, Sun X, Li Z. Efficacy and Safety of Low-Dose Interleukin 2 for Primary Sjogren Syndrome: A Randomized Clinical Trial. JAMA Netw Open. 2022 Nov 1;5(11):e2241451. doi: 10.1001/jamanetworkopen.2022.41451.
• He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, Jin Y, Gan Y, Hu X, Jia R, Xu C, Hou Z, Leong YA, Zhu L, Feng J, An Y, Jia Y, Li C, Liu X, Ye H, Ren L, Li R, Yao H, Li Y, Chen S, Zhang X, Su Y, Guo J, Shen N, Morand EF, Yu D, Li Z. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016 Sep;22(9):991-3. doi: 10.1038/nm.4148. Epub 2016 Aug 8.
• Yang Y, Zhang R, Zhong Z, Li J, Feng Y. Efficacy of transauricular vagus nerve stimulation for the treatment of chemotherapy-induced painful peripheral neuropathy: a randomized controlled exploratory study. Neurol Sci. 2024 May;45(5):2289-2300. doi: 10.1007/s10072-023-07229-2. Epub 2023 Dec 8.
• Abdullahi A, Wong TWL, Ng SSM. Putative role of non-invasive vagus nerve stimulation in cancer pathology and immunotherapy: Can this be a hidden treasure, especially for the elderly? Cancer Med. 2023 Sep;12(18):19081-19090. doi: 10.1002/cam4.6466. Epub 2023 Aug 17.
• Shi X, Hu Y, Zhang B, Li W, Chen JD, Liu F. Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation. JCI Insight. 2021 Jul 22;6(14):e150052. doi: 10.1172/jci.insight.150052.
• Barbanti P, Grazzi L, Egeo G, Padovan AM, Liebler E, Bussone G. Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open-label study. J Headache Pain. 2015;16:61. doi: 10.1186/s10194-015-0542-4. Epub 2015 Jun 30.
• Arem H, Sorkin M, Cartmel B, Fiellin M, Capozza S, Harrigan M, Ercolano E, Zhou Y, Sanft T, Gross C, Schmitz K, Neogi T, Hershman D, Ligibel J, Irwin ML. Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: the Hormones and Physical Exercise (HOPE) study. J Cancer Surviv. 2016 Aug;10(4):654-62. doi: 10.1007/s11764-015-0511-6. Epub 2016 Jan 19.
• van Hellemond IEG, Geurts SME, Tjan-Heijnen VCG. Current Status of Extended Adjuvant Endocrine Therapy in Early Stage Breast Cancer. Curr Treat Options Oncol. 2018 Apr 27;19(5):26. doi: 10.1007/s11864-018-0541-1.

Study record dates

Study Major Dates

• Study Start (Estimated): May 6, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: May 5, 2026
• First Submitted That Met QC Criteria: May 13, 2026
• First Posted (Actual): May 18, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: 2026PHB256-001; 82571385 (Other Grant/Funding Number: National Natural Science Foundation of China)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: To protect patient privacy and ensure the security of clinical data, the individual participant data (IPD) collected in this study will be used only for scientific analysis and publication related to this trial. No public disclosure, sharing, or uploading to public repositories is planned. Therefore, IPD will not be made available.

Drug and device information, study documents

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