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

Обзор

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.

Вмешательства

• Устройство 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.
• Устройство 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.

Первичные конечные точки

• The pain relief rate of patients at the end of the 4-week treatment period [Срок оценки: From enrollment to the end of treatment at 4 weeks.]

Вторичные конечные точки (8)

• Pain relief rate at follow-up [Срок оценки: At 1, 2, 3, and 6 months after completion of treatment.]
• Dosage of analgesic drugs [Срок оценки: At 1, 2, 3, and 6 months after completion of treatment.]
• Depression scores [Срок оценки: At 1, 2, 3, and 6 months after completion of treatment.]
• Anxiety scores [Срок оценки: At 1, 2, 3, and 6 months after completion of treatment.]
• Quality of life score [Срок оценки: At 1, 2, 3, and 6 months after completion of treatment.]
• Plasma inflammatory marker levels [Срок оценки: Baseline, immediately after completion of treatment, and 6 months after completion of treatment.]
• The proportion of T cells in the blood [Срок оценки: Baseline, immediately after completion of treatment, and 6 months after completion of treatment.]
• The count of T cells in the blood [Срок оценки: Baseline, immediately after completion of treatment, and 6 months after completion of treatment.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

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

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University People's Hospital — Пекин

Публикации

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• 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
• 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
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• 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 Tria PMID 36355371
• 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. PMID 27500725
• 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

Идентификаторы

NCT: NCT07593365 · 2026PHB256-001 · 82571385

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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