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

NCT07593365 | Not Yet Recruiting DMC

• 2 other identifiers: 2026PHB256-00182571385
• Study Type: interventional
• Target: 216
• Locations: 1 country
• Sites: 1

Brief Summary

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. 1.Does taVNS reduce pain caused by aromatase inhibitor treatment?
2. 2.Does taVNS improve quality of life, mood symptoms, and the need for pain medicine?
3. 3.What side effects or medical problems occur during treatment?
4. 4.Be randomly assigned to active taVNS or sham stimulation
5. 5.Receive one 30-minute treatment session every day for 28 days
6. 6.Complete pain, mood, and quality-of-life questionnaires before treatment, after treatment, and during follow-up
7. 7.Report pain medicine use and any side effects
8. 8.Provide small blood samples to measure inflammatory markers, T-cell profiles, and tumor markers

Conditions

Breast Cancer; Pain Alleviation; Aromatase Inhibitor Associated Musculoskeletal Symptoms (AIMSS)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• 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

  At 1, 2, 3, and 6 months after completion of treatment.

• Anxiety scores

  At 1, 2, 3, and 6 months after completion of treatment.

• Quality of life score

  At 1, 2, 3, and 6 months after completion of treatment.

Other Outcomes (2)

• 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.

Study Arms (2)

transcutaneous auricular vagus nerve stimulation group

ACTIVE COMPARATOR

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

sham stimulation group

SHAM COMPARATOR

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

Interventions

transcutaneous auricular vagus nerve stimulation DEVICE

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.

Also known as: taVNS

transcutaneous auricular vagus nerve stimulation group

sham stimulation DEVICE

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.

sham stimulation group

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female participants aged over 18 years;
• Patients with pathologically confirmed stage I-III primary breast cancer;
• Patients who have recovered from systemic symptoms related to surgery, radiotherapy, or chemotherapy;
• 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);
• Patients who have received aromatase inhibitor therapy for more than 30 days and are expected to continue treatment for more than 1 year;
• 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:
• Pain relief rate of less than 50% after taVNS treatment and a lower peripheral blood Treg count than before treatment.

You may not qualify if:

• Patients with advanced breast cancer;
• Patients with other significant organ dysfunction, such as major cardiovascular disease, diabetes mellitus, or hyperthyroidism;
• Patients with other cancers;
• Patients with a history of fracture or surgery around the painful joint area within the past 6 months;
• Patients currently receiving corticosteroids or opioid therapy;
• Patients with contraindications to vagus nerve stimulation;
• Patients who are unable to communicate normally, such as those with cognitive impairment or hearing impairment;
• Patients who have participated in another clinical trial within the past 1 month.
• Severe cardiac or renal disease, or hematologic disease;
• Previous IL-2-related toxic reaction or allergy;
• Use of other biologic agents or immunosuppressive drugs within the past 1 month;
• Any other condition that the investigator considers unsuitable for study participation.

Sponsors & Collaborators

• Peking University People's Hospital: lead
• National Natural Science Foundation of China: collaborator

Study Sites (1)

Peking University People's Hospital

Beijing, Beijing Municipality, 100044, China

Location

Related Publications (14)

• 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.

  PMID: 39680406 BACKGROUND

• 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.

  PMID: 34936380 BACKGROUND

• 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.

  PMID: 35104810 BACKGROUND

• 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.

  PMID: 33852146 BACKGROUND

• 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.

  PMID: 35250032 BACKGROUND

• 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.

  PMID: 36355371 BACKGROUND

• 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.

  PMID: 27500725 BACKGROUND

• 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.

  PMID: 38063922 BACKGROUND

• 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.

  PMID: 30217648 BACKGROUND

• 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.

  PMID: 37587897 BACKGROUND

• 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.

  PMID: 34138761 BACKGROUND

• 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.

  PMID: 26123825 BACKGROUND

• 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.

  PMID: 26782031 BACKGROUND

• 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.

  PMID: 29704066 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Central Study Contacts

Yi Feng, M.D

CONTACT

+86-010-88325590; fengyi@pkuph.edu.cn

Pei Li, M.D

CONTACT

+86-13126762029; pli@stu.pku.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Department

Study Record Dates

• First Submitted: May 5, 2026
• First Posted: May 18, 2026
• Study Start: May 6, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 18, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)