Efficacy of Transcutaneous Vagus Nerve Stimulation Paired With Tailor-Made Notched Music Therapy Versus Tailor-made Notched Music Training for Chronic Subjective Tinnitus

Study Overview
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Brief Summary
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This clinical study is a prospective, multicenter, randomized, controlled, double-blind clinical study. Sun Yat Sen Memorial Hospital of Sun Yat sen University was the central unit, and Nanjing First Hospital, Sun Yat Sen people's Hospital, Guanfzhou Panyu central Hospital and Zhuhai integrated traditional Chinese and Western medicine hospital were the cooperative units. In this study, 388 patients with chronic subjective tinnitus were recruited. In view of chronic subjective tinnitus, a common ear disease, the study gave the patients three months of treatment with transcutaneous vagus nerve stimulation paired with tailor-made notched music therapy or tailor-made notched music training alone. By comparing the changes of subjective scale scores related to tinnitus before and after treatment in patients receiving two different therapies, such as THI, VAS, BAI, BDI, PSQI, to evaluate the efficacy of the two therapies, so as to judge whether transcutaneous vagus nerve stimulation paired with tailor-made notched music therapy is better than tailor-made notched music training alone. In addition, the study will continue to follow up the patients after the treatment for one year to observe the difference in the long-term sustained efficacy of the two therapies. This clinical study will also evaluate the two therapies from the perspective of compliance and safety, and explore the factors that affect the efficacy of the two therapies.

Detailed Description
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Unified rules for filling in case report forms： All case report forms must be completed by designated and trained researchers. Two data managers independently input and proofread the data in duplicate. The data manager will modify, confirm and enter the data according to the scales written by participant. The locked data file will not be changed. Use medical terms / concepts to record AES . The type, degree, occurrence time, duration, treatment measures and treatment process shall be recorded in detail. Sample size estimation: △ THI≥ 7 points in the comparison between groups indicates that the difference in efficacy has clinical significance, the superiority margin is established. The pre-test results showed that △ THI = -10.2 points, SD = 10.0 points in the two groups after the treatment. According to unilateral inspection standard α= 0.025, inspection efficacy 1- β= 0.80, using two sample t-test to estimate the sample size, the results show that at least 155 subjects are included in each group. Further estimation was made according to the loss of follow-up rate of 20%. Finally, at least 194 subjects (388 persons in total) should be included in each group. PASS 21.0.03 (NCSs, LLC, Kaysville, Utah, USA) is adopted for the above calculation. Plan for missing data： If the subject uses the drugs, treatment or surgery prohibited in the protocol, the subject will no longer meet the conditions of the clinical study and will be deemed to have withdrawn from the study. If the event occurs before 3 months of treatment, the subject's data will no longer be used for statistical analysis of subsequent data. If the event occurs in the follow-up period after the completion of treatment, the data of the subject before and after treatment shall be retained. The data in the follow-up period shall be regarded as missing data and filled with corresponding methods for full analysis set analysis. For the missing data caused by the loss of follow-up, this study will use the method of multiple imputation to estimate the missing value. The research subjects who failed in screening will provide corresponding treatment according to their own conditions and clinical guidelines. These subjects will not be included in the clinical study. Statistical analysis plan: When considering the influence of baseline, the continuous variables were analyzed by covariance analysis, and the qualitative indicators were tested by CMH test or logistic regression. Primary analysis： Using covariance analysis to compare the different changes of THI scores between two groups after 3-month treatment, controlled for age and baseline THI. Secondary analysis： Using covariance analysis to compare the different changes of VAS, BAI, BDI, PSQI scores between two groups after 3-month treatment, controlled for age and baseline values corresponding to each scale. Using a repeated measure ANOVA to compare the different changes of THI, VAS, BAI, BDI, PSQI between two groups at 3, 6 and 12 follow-up visits. Using Chi square test or Fisher exact test to compare the different efficient rate between two groups after 3-month treatment. Exploratory analysis: Using multiple linear regression analysis to explore the factors affecting the short-term and long -term efficacy of the two treatments, such as age, hearing loss threshold, tinnitus loudness, tinnitus frequency and so on. Using Independent two sample t-test or nonparametric analysis to compare the differences in EEG- or fMRI-related indicators between two groups. Safety analysis: Using Pearson's chi-square test to compare the difference of adverse event incidence rate between two groups.

Official Title
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Efficacy of Transcutaneous Vagus Nerve Stimulation Paired With Tailor-Made Notched Music Therapy Versus Tailor-made Notched Music Training for Chronic Subjective Tinnitus: A Multicenter, Randomized, Double-blind, Controlled Clinical Trial

Conditions
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Tinnitus, Subjective, Vagus Nerve Stimulation, Music Therapy, Double-Blind Method, Female, Male, Humans, Treatment Outcome

Intervention / Treatment
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* Device: Transcutaneous Vagus Nerve Stimulation Paired with Tailor-Made Notched Music Therapy
* Device: Tailor-made Notched Music Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with tinnitus as the main complaint: the patients subjectively feel the sound in the ear or deep part of the head without internal or external sound stimulation, and therefore seek medical treatment Chronic (≥ 6 months) and tonal tinnitus Age 18-60 Tinnitus frequency is 125-8000 Hz Hearing threshold at each frequency shall not exceed 70 dB HL Exclusion Criteria: Patients with conductive deafness, history of middle ear surgery, pulsatile tinnitus caused by vascular distortion and tinnitus caused by Meniere disease History of head trauma, central nervous system diseases, mental diseases and drug abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The subjects included in the study are randomized by a unified randomization center. The randomization center will number the subjects with the random number table generated by the computer, and then arrange them in the order of number. The subjects will be randomly divided into groups in turn, and the subjects in the groups will be numbered with the random number table. The first half of the subjects with a larger number in the groups will be divided into the experimental group (tVNS paired with TMNMT), and the rest into the control group (TMNMT).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transcutaneous Vagus Nerve Stimulation Paired with Tailor-Made Notched Music Therapy<br>The participants receive 30 minutes / time, 4 times / day, continuous 3 months of auditory tVNS combined with TMNMT. The stimulation intensity used in each course was set to the highest level that the patient could tolerate. The participants listen to the tailor-made notched music at the same time. | Device: Transcutaneous Vagus Nerve Stimulation Paired with Tailor-Made Notched Music Therapy<br>* The pulse frequency of vagus nerve stimulation is 25 Hz, the pulse width is 200 US, and the intensity is 1-10 mA. Tailor-made notched music is produced by filtering a frequency band of 1/2 octave width centered at the individual tinnitus frequency. When two sides of tinnitus frequencies are different, each side of music are filtered respectively, according to the different tinnitus frequency. When only have unilateral tinnitus or bilateral tinnitus in the same central frequency, both sides of music are filtered with the same tinnitus frequency. The tVNS and TMNM begin at the same time during treatment.<br>|
| Active Comparator: Tailor-made Notched Music Training<br>Similarly, 30 minutes / time, 4 times / day, continuous 3 months of TMNMT is received every day. The setting of parameters and the selection of music were the same as those in the experimental group. At the beginning of TMNMT, 10 s of sham stimulation set according to the standard of the experimental group is given. | Device: Tailor-made Notched Music Training<br>* Tailor-made notched music is produced by filtering a frequency band of 1/2 octave width centered at the individual tinnitus frequency. When two sides of tinnitus frequencies are different, each side of music are filtered respectively, according to the different tinnitus frequency. When only have unilateral tinnitus or bilateral tinnitus in the same central frequency, both sides of music are filtered with the same tinnitus frequency. At the beginning of TMNMT, 10 seconds sham vagus nerve stimulation is output, whose parameters are as same as experimental group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Tinnitus Handicap Inventory (THI) scores for short-term efficacy assessment | Difference in the change of THI scores between two groups after 3-month treatment. The THI evaluates the severity of tinnitus in terms of emotion and function. The global scores of THI range from 0 (no disability) to 100 (serve disability). | From baseline to 3-month follow-up visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in scores of Visual Analog Scale (VAS) for short-term efficacy assessment | Difference in the change of VAS scores between two groups after 3-month treatment. The total VAS scores range from 0 (negligible) to 10 (too nosiy to tolerate), reflecting the loudness of tinnitus patients feel. | From baseline to 3-month follow-up visit | 
| Changes in scores of Beck Anxiety Inventory (BAI) for short-term efficacy assessment | Difference in the change of BAI scores between two groups after 3-month treatment. The total BAI scores range from 0 (normal) to 63 (serve anxiety), reflecting the degree of anxiety. | From baseline to 3-month follow-up visit | 
| Changes in scores of Beck Depression Inventory (BDI) for short-term efficacy assessment | Difference in the change of BDI scores between two groups after 3-month treatment. The total BDI scores range from 0 (normal) to 63 (serve depression), reflecting the degree of depression. | From baseline to 3-month follow-up visit | 
| Changes in scores of Pittsburgh sleep quality index (PSQI) for short-term efficacy assessment | Difference in the change of PSQI scores between two groups after 3-month treatment. The total PSQI scores range from 0 (sleep well) to 21 (quite poor sleep), reflecting the sleep quality. | From baseline to 3-month follow-up visit | 
| Changes of Tinnitus Handicap Inventory (THI) scores in the two groups for long-term efficacy assessment | Difference in changes of THI between two groups from 3-month follow-up visit to 12-month follow-up visit. The THI evaluates the severity of tinnitus in terms of emotion and function. The global scores of THI range from 0 (no disability) to 100 (serve disability). | From 3-month follow-up visit to 12-month follow-up visit | 
| Changes of Visual Analog Scale (VAS) scores in the two groups for long-term efficacy assessment | Difference in changes of VAS between two groups from 3-month follow-up visit to 12-month follow-up visit. The total VAS scores range from 0 (negligible) to 10 (too nosiy to tolerate), reflecting the loudness of tinnitus patients feel. | From 3-month follow-up visit to 12-month follow-up visit | 
| Changes of Beck Anxiety Inventory (BAI) scores in the two groups for long-term efficacy assessment | Difference in changes of BAI between two groups from 3-month follow-up visit to 12-month follow-up visit. The total BAI scores range from 0 (normal) to 63 (serve anxiety), reflecting the degree of anxiety. | From 3-month follow-up visit to 12-month follow-up visit | 
| Changes of Beck Depression Inventory (BDI) scores in the two groups for long-term efficacy assessment | Difference in changes of PSQI between two groups from 3-month follow-up visit to 12-month follow-up visit. The total BDI scores range from 0 (normal) to 63 (serve depression), reflecting the degree of depression. | From 3-month follow-up visit to 12-month follow-up visit | 
| Changes of Pittsburgh sleep quality index (PSQI) scores in the two groups for long-term efficacy assessment | Difference in changes of PSQI between two groups from 3-month follow-up visit to 12-month follow-up visit. The total PSQI scores range from 0 (sleep well) to 21 (quite poor sleep), reflecting the sleep quality. | From 3-month follow-up visit to 12-month follow-up visit | 
| The effective rate of relieving chronic subjective tinnitus in the two groups | Group effective rate = number of patients in each group who completed 3 months of treatment and whose THI score decreased by ≥ 7 points / number of patients in each group who completed 3 months of treatment. | From baseline to 3-month follow-up visit | 
| The difference of functional connectivity based on resting state electroencephalogram (EEG) between the two groups | The difference of functional connectivity based on resting state electroencephalogram (EEG) in the two groups from baseline to 12-month follow-up visit. The functional connectivity is defined as the correlation between two different brain regions based on coherence or phase synchronization. | From baseline to 12-month follow-up visit | 
| The difference of effective connectivity based on resting state electroencephalogram (EEG) between the two groups | The difference of effective connectivity based on resting state electroencephalogram (EEG) in the two groups from baseline to 12-month follow-up visit. The effective connectivity is defined as the directed functional connectivity between two brain regions based on granger causality analysis. | From baseline to 12-month follow-up visit | 
| The difference of functional connectivity based on functional magnetic resonance imaging (fMRI) between the two groups | The difference of functional connectivity based on functional magnetic resonance imaging (fMRI) in the two groups from baseline to 12-month follow-up visit. The functional connectivity is defined as the Pearson's correlation between two different brain regions. | From baseline to 12-month follow-up visit | 
| The difference of effective connectivity based on functional magnetic resonance imaging (fMRI) between the two groups | The difference of effective connectivity based on functional magnetic resonance imaging (fMRI) in the two groups from baseline to 12-month follow-up visit. The effective connectivity is defined as the directed functional connectivity between two brain regions based on granger causality analysis. | From baseline to 12-month follow-up visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic subjective tinnitus, Tailor-made notched music training, Vagus nerve stimulation, Electroencephalogram, Clinical trial