Obesity & Overweight
Conditions
Keywords
Obesity & Overweight, Transcutaneous Auricular Vagus Nerve Stimulation, Incretin Receptor Agonists, Non-responders
Brief summary
This is a single-center, randomized, participant-blinded, sham-controlled trial designed to evaluate the adjunctive effect of transcutaneous auricular vagus nerve stimulation (taVNS) in overweight or obese patients who show a suboptimal weight-loss response to incretin receptor agonist therapy. A total of 24 participants will be randomly assigned to receive either taVNS plus tirzepatide 5 mg or sham stimulation plus tirzepatide 5 mg for 12 weeks. The primary objective is to compare the percent change in body weight from baseline to week 12 between the two groups.
Detailed description
This is a prospective, single-center, randomized, participant-blinded, sham-controlled, parallel-group study conducted at the Department of Endocrinology, Nanjing Drum Tower Hospital. The study will enroll 24 overweight or obese participants with a suboptimal weight-loss response, defined as a body weight reduction of no more than 10% after at least 12 weeks of tirzepatide treatment. Eligible participants will be randomized in a 1:1 ratio to the taVNS plus tirzepatide 5 mg group or the sham stimulation plus tirzepatide 5 mg group for 12 weeks. Before and after intervention, all participants will undergo standardized assessments, including lifestyle questionnaires, anthropometric measurements, body composition analysis, autonomic function evaluation, laboratory testing, and assessment of hepatic steatosis and fibrosis. Autonomic function assessment will include heart rate variability, cardiovascular autonomic reflex tests, sudomotor function, and brain MRI. Liver-related assessments will include FibroTouch and liver MRI. During follow-up, body weight will be monitored weekly by telephone or WeChat, waist circumference, hip circumference, and body composition will be reassessed every 4 weeks, and device use will be monitored through an app to ensure adherence and protocol consistency. The primary endpoint is the between-group difference in percent change in body weight from baseline to week 12. Secondary endpoints include changes in body composition and fat distribution, glucose- and lipid-related metabolic parameters, liver function and hepatic steatosis/fibrosis-related parameters, and autonomic function measures. Exploratory analyses will evaluate changes in brain imaging phenotypes after 12 weeks of intervention.
Interventions
DEVICEtranscutaneous auricular vagus nerve stimulation
Participants will receive active transcutaneous auricular vagus nerve stimulation plus tirzepatide 5 mg for 12 weeks. Active stimulation will be delivered to the bilateral cymba conchae, an auricular region innervated by the auricular branch of the vagus nerve. Stimulation will use an intermittent waveform of 15 seconds on and 5 seconds off at 20 Hz, with a pulse width of 0.2 ms. Stimulation intensity will be titrated from 0 mA to a level that produces mild tingling without obvious discomfort, usually 1.0-2.5 mA. Stimulation will be administered twice daily for 30 minutes per session, 5 days per week, for 12 weeks. Tirzepatide will be administered as a subcutaneous injection once weekly.
DEVICESham
Participants will receive sham stimulation in addition to tirzepatide 5 mg for 12 weeks. Sham stimulation will be applied to the bilateral tail of the helix, an auricular site without vagus nerve distribution, whereas active taVNS targets the cymba conchae, which is innervated by the auricular branch of the vagus nerve. The sham group will use the same waveform parameters, stimulation intensity titration, and treatment schedule as the active group, namely twice daily for 30 minutes per session, 5 days per week, for 12 weeks. Tirzepatide will be administered as a subcutaneous injection once weekly.
Sponsors
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Only participants are masked in this trial. Participants are randomly assigned to active taVNS plus tirzepatide 5 mg or sham stimulation plus tirzepatide 5 mg. To maintain masking, sham stimulation uses the same device, similar stimulation procedures, and the same treatment schedule as active stimulation, but is applied to a non-vagal auricular site (the left tail of the helix). Randomization codes are generated by an independent unblinded team and allocation is concealed using sealed, opaque envelopes. Emergency unblinding materials are prepared and securely retained.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Individuals with obesity, or overweight accompanied by at least one weight-related comorbidity (e.g., hypertension or fatty liver disease), who have been receiving tirzepatide therapy for at least 12 weeks and have achieved ≤10% weight loss during treatment; 2. Willingness to provide written informed consent.
Exclusion criteria
1. Presence of diseases that may substantially affect body weight homeostasis, including Cushing's syndrome, uncontrolled thyroid disease (thyroid-stimulating hormone \>6.0 mIU/L or \<0.4 mIU/L), malignancy, or similar conditions; 2. Use within the past 3 months of medications, other than incretin receptor agonists, that may significantly affect body weight, including glucocorticoids and antipsychotic agents; 3. Skin infection or damage involving the auricular area; 4. Women planning pregnancy in the near future; 5. Contraindications to MRI, such as metallic prostheses or claustrophobia; 6. Diagnosis of diabetes mellitus; Inability to complete the 12-week intervention period for practical reasons, such as frequent business travel or planned travel.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Body Weight From Baseline | Baseline, 4 weeks, 8 weeks, 12 weeks | Percent change in body weight from baseline to week 12 will be compared between the taVNS plus tirzepatide group and the sham stimulation plus tirzepatide group to evaluate the adjunctive effect of taVNS on weight reduction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Waist Circumference | Baseline, Week 4, Week 8, Week 12 | Change in waist circumference from baseline to Week 4, Week 8, and Week 12 will be assessed using standardized anthropometric measurement. |
| Change in Body Composition and Fat Distribution | Baseline, ,Week 4, Week 8, Week 12 | Changes in body composition and fat distribution will be assessed by body fat percentage using anthropometric measurements and body composition analysis. |
| Change in blood glucose | Baseline, Week 12 | Change in fasting blood glucose from baseline to Week 12 will be assessed using laboratory testing. |
| Change in Hip Circumference | Baseline, Week 4, Week 8, Week 12 | Change in hip circumference from baseline to Week 4, Week 8, and Week 12 will be assessed using standardized anthropometric measurement. |
| Change in Visceral Fat Area | Baseline, Week 4, Week 8, Week 12 | Change in visceral fat area from baseline to Week 4, Week 8, and Week 12 will be assessed using body composition analysis. |
| Change in Glycated Hemoglobin | Baseline, Week 12 | Change in glycated hemoglobin (HbA1c) from baseline to Week 12 will be assessed using laboratory testing. |
| Change in High-Density Lipoprotein Cholesterol | Baseline, Week 12 | Change in high-density lipoprotein cholesterol (HDL-C) from baseline to Week 12 will be assessed using laboratory testing. |
| Change in Low-Density Lipoprotein Cholesterol | Baseline, Week 12 | Change in low-density lipoprotein cholesterol (LDL-C) from baseline to Week 12 will be assessed using laboratory testing. |
| Change in Triglycerides | Baseline, Week 12 | Change in triglycerides from baseline to Week 12 will be assessed using laboratory testing. |
| Change in Controlled Attenuation Parameter | Baseline, Week 12 | Change in controlled attenuation parameter (CAP) from baseline to Week 12 will be assessed using transient elastography. |
| Change in Liver Stiffness Measurement | Baseline, Week 12 | Change in liver stiffness measurement (LSM) from baseline to Week 12 will be assessed using transient elastography. |
| Change in Liver Function | Baseline, Week 12 | Change in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline to Week 12 will be assessed using laboratory testing. |
| Change in Heart Rate Variability | Baseline, Week 12 | Change in heart rate variability from baseline to Week 12 will be assessed using time-domain and/or frequency-domain heart rate variability analysis. |
| Change in Cardiovascular Autonomic Reflex Test Result | Baseline, Week 12 | Change in cardiovascular autonomic reflex function from baseline to Week 12 will be assessed using standardized cardiovascular autonomic reflex testing. |
| Change in Central Autonomic Network Functional Connectivity | Baseline, Week 12 | Change in central autonomic network features from baseline to Week 12 will be assessed using brain MRI-based functional connectivity analysis. |
Countries
China
Contacts
CONTACTYan Bi, MD, PhD
CONTACTTian Wei Gu, MD, PhD
STUDY_DIRECTORYan Bi, MD, PhD
Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Outcome results
None listed