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This study is a 24-week, single-center, randomized, double-blind, sham-controlled, parallel-group clinical trial. A total of 38 patients with type 2 diabetes and mild cognitive impairment were enrolled and randomly assigned in a 1:1 ratio to either the treatment group (receiving active transcutaneous auricular vagus nerve stimulation) or the sham control group (receiving sham transcutaneous auricular vagus nerve stimulation). The primary objective of this study is to evaluate the potential disease-modifying effects of transcutaneous auricular vagus nerve stimulation on cognitive impairment in patients with type 2 diabetes.
This study is a 24-week, single-center, randomized, double-blind, sham-controlled, parallel-group clinical trial aimed at investigating the potential disease-modifying effects of transcutaneous auricular vagus nerve stimulation (taVNS) on cognitive impairment in 38 patients with type 2 diabetes mellitus (T2DM) complicated by mild cognitive impairment. Participants will be randomly assigned in a 1:1 ratio to receive either active taVNS (stimulation frequency: 20 Hz pulses for 10 seconds and 100 Hz pulses for 50 seconds per minute; 30 minutes per session, twice daily) or sham stimulation for 5 days per week. All participants will continue to receive treatment based on their original glucose-lowering therapies. The primary objective of the study is to evaluate improvements in cognitive function, while secondary endpoints include structural and functional brain changes, metabolic improvements, neurodegenerative biomarkers, and safety outcomes.
Participants will undergo comprehensive cognitive and metabolic assessments at baseline, followed by a safety visit at Week 12 to monitor adverse events, treatment adherence, and metabolic parameters. The comprehensive evaluation at Week 24 will include cognitive assessments, neuroimaging, and metabolic profiling. During the study period, investigators will conduct weekly follow-ups via telephone or WeChat, and participants will attend monthly in-clinic visits to complete examinations such as capillary blood glucose, blood pressure, and heart rate, as well as to be inquired about treatment adherence and adverse reactions. All rationales for decision-making and efficacy evaluations must be thoroughly documented.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| active taVNS | Experimental | After disinfecting the stimulation sites (cymba conchae, cavum conchae, and earlobe), the auricular stimulation electrodes will be attached. For the active stimulation group, the actual functional electrodes delivering the current are positioned at the cymba conchae and cavum conchae. The stimulation parameters are set as follows:(1) Dense-disperse wave, with a stimulation frequency consisting of 20 Hz pulses for 10 seconds and 100 Hz pulses for 50 seconds per minute, and a pulse width of 0.2 ms ± 30%;(2) Stimulation intensity ranging from 4 to 6 mA, adjusted according to the individual patient's tolerance;(3) 30 minutes per session, twice daily;(4) 5 days per week, for 24 weeks. |
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| sham taVNS | Sham Comparator | After disinfecting the stimulation sites (cymba conchae, cavum conchae, and earlobe), the auricular stimulation electrodes will be attached. For the sham stimulation group, the actual functional electrodes delivering the current are positioned at the earlobe. The stimulation parameters are set as follows:(1) Dense-disperse wave, with a stimulation frequency consisting of 20 Hz pulses for 10 seconds and 100 Hz pulses for 50 seconds per minute, and a pulse width of 0.2 ms ± 30%;(2) Stimulation intensity ranging from 4 to 6 mA, adjusted according to the individual patient's tolerance;(3) 30 minutes per session, twice daily;(4) 5 days per week, for 24 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| active transcutaneous auricular vagus nerve stimulation | Device | After disinfecting the stimulation sites (cymba conchae, cavum conchae, and earlobe), the auricular stimulation electrodes will be attached. For the active stimulation group, the actual functional electrodes delivering the current are positioned at the cymba conchae and cavum conchae. The stimulation parameters are set as follows:(1) Dense-disperse wave, with a stimulation frequency consisting of 20 Hz pulses for 10 seconds and 100 Hz pulses for 50 seconds per minute, and a pulse width of 0.2 ms ± 30%;(2) Stimulation intensity ranging from 4 to 6 mA, adjusted according to the individual patient's tolerance;(3) 30 minutes per session, twice daily;(4) 5 days per week, for 24 weeks. |
| Measure | Description | Time Frame |
|---|---|---|
| Montreal Cognitive Assessment Scale (MoCA) score | The MoCA is a comprehensive endpoint focusing on the cognitive domain. It integrates multidimensional assessments of core cognitive functions (including subscale scores for visuospatial/executive function, naming, attention, language, abstraction, delayed recall, and orientation), yielding a total score range of 0-30.The calculation formula is:MoCA Score = Subscale Scores+ Educational Correction(Note: If the participant's formal education is ≤12 years, 1 point is added to the sum of the subscale scores, with the maximum total score capped at 30).Lower MoCA scores indicate more severe global cognitive impairment in the participant. | Baseline, and Week 24 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in score of Mini-Mental State Examination (MMSE) | The MMSE contains a total of 30 items that assess orientation, registration, attention and calculation, recall, and language, with a score range from 0 to 30. Generally, a higher MMSE score reflects a better cognitive function. | from baseline to week 24 of treatment |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jianguo Ruan, MD | Contact | 86-25-83-106666 | medrjg@163.com |
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| sham transcutaneous auricular vagus nerve stimulation | Device | After disinfecting the stimulation sites (cymba conchae, cavum conchae, and earlobe), the auricular stimulation electrodes will be attached. For the sham stimulation group, the actual functional electrodes delivering the current are positioned at the earlobe. The stimulation parameters are set as follows:(1) Dense-disperse wave, with a stimulation frequency consisting of 20 Hz pulses for 10 seconds and 100 Hz pulses for 50 seconds per minute, and a pulse width of 0.2 ms ± 30%;(2) Stimulation intensity ranging from 4 to 6 mA, adjusted according to the individual patient's tolerance;(3) 30 minutes per session, twice daily;(4) 5 days per week, for 24 weeks. |
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| Changes in total score of RBANS |
The RBANS (Chinese version) is a brief neuropsychological screening battery with established test-retest reliability and age-appropriate normative data, which consists of 12 task tests assessing 5 cognitive domains, namely immediate memory, visuospatial/ constructional, language, attention and delayed memory, with a score range from 40 to 160. A higher RBANS score reflects a better global cognitive function. |
| from baseline to week 24 of treatment |
| Change in the RBANS index score of immediate memory | The RBANS (Chinese version) is a brief neuropsychological screening battery with established test-retest reliability and age-appropriate normative data. The RBANS includes 12 sub-tests that generate five age-adjusted index scores and a total score. The five indices include immediate memory (consisting of list learning and story memory tests), visuospatial/constructional domain (consisting of figure copying and line orientation tests), language (consisting of picture naming and semantic fluency tests), attention (consisting of digit span and coding tests) and delayed memory (consisting of list recall, story recall, figure recall and list recognition tests). Generally, a higher index score reflects a better cognitive subdomain function. | from baseline to week 24 of treatment |
| Change in the RBANS index score of visuospatial/constructional | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 24 of treatment |
| Change in the RBANS index score of language | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 24 of treatment |
| Change in the RBANS index score of attention | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 24 of treatment |
| Change in the RBANS index score of delayed memory | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 24 of treatment |
| Change in aggregate time to test completion for Trail Making Test (TMT) | The TMT is a validated timed measure of processing speed, which consists of part A and part B (TMT-A and TMT-B). The time limits for performing the TMT-A and TMT-B are 180 and 300 seconds, respectively. Processing speed is estimated by the aggregate time in seconds to complete TMT-A and TMT-B such that less time indicate faster processing speed. | from baseline to week 24 of treatment |
| Change in aggregate time to test completion for Victoria Stroop Color-Word Test | The Victoria Stroop Color-Word Test is a well-known measure of executive function. There are three indices including Stroop-dot, Stroop-word and Stroop-color word in the test. The color task consists of colored dots; the word task comprises ordinary words that are unrelated to the meaning of color; the color-word task consists of words written in color that indicate the meaning of the color, but the color of these words differs from the meaning of the word itself. The participants were asked to quickly read the color of the dots or Chinese words on the cards. The sum of consuming time taken to read the three cards is used as an index of executive function performance. Less time indicates better executive function. | from baseline to week 24 of treatment |
| Change in Total Brain Volume | The change in total brain volume evaluated by structural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. | from baseline to week 24 of treatment |
| Change in Total White Matter Volume | The change in total white matter volume evaluated by structural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. | from Baseline to Week 24 of treatment |
| Change in Total Gray Matter Volume | The change in total gray matter volume evaluated by structural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. | from Baseline to Week 24 of treatment |
| Change in Total White Matter Lesion Volume | The change in total white matter lesion volume evaluated by sturctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. | from Baseline to Week 24 of treatment |
| Change in Cortical Gray Matter Lobar Volumes | The change in cortical gray matter lobar volumes evaluated by sturctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. | from Baseline to Week 24 of treatment |
| Change in Subcortical Nuclei Volumes | The change in subcortical nuclei volumes evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group. | from Baseline to Week 24 of treatment |
| Change in Blood-Based Neurodegeneration Biomarkers | The change in blood-based neurodegeneration biomarkers (includingAmyloid-β (Aβ42/40 ratio), Phosphorylated tau (p-tau217), Glial fibrillary acidic protein (GFAP), and Neurofilament light chain (NfL), etc.）evaluated by Simoa from baseline to Week 76 will be compared between the treatment group and the placebo group. | from Baseline to Week 24 of treatment |
| Change in Heart Rate Variability | Change in heart rate variability from baseline to Week 24 will be assessed using time-domain and/or frequency-domain heart rate variability analysis | from Baseline to Week 24 of treatment |
| Change in Cardiovascular Autonomic Reflex Test Result | Change in cardiovascular autonomic reflex function from baseline to Week 24 will be assessed using standardized cardiovascular autonomic reflex testing | from Baseline to Week 24 of treatment |
| Change in Glycated Haemoglobin (HbA1c) Levels | Change in HbA1c levels from baseline to weeks 24 | from Baseline to Week 24 of treatment |
| Change in fasting insulin | Fasting insulin | from baseline to weeks 24 of treatment |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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