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

Official title

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

Overview

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

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.

Interventions

• Device Transcutaneous Vagus Nerve Stimulation Paired with Tailor-Made Notched Music Therapy
  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 mu
• Device Tailor-made Notched Music Training
  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 stimulat

Primary outcome measures

• Changes in Tinnitus Handicap Inventory (THI) scores for short-term efficacy assessment [Time frame: From baseline to 3-month follow-up visit]

Secondary outcome measures (12)

• Changes in scores of Visual Analog Scale (VAS) for short-term efficacy assessment [Time frame: From baseline to 3-month follow-up visit]
• Changes in scores of Beck Anxiety Inventory (BAI) for short-term efficacy assessment [Time frame: From baseline to 3-month follow-up visit]
• Changes in scores of Beck Depression Inventory (BDI) for short-term efficacy assessment [Time frame: From baseline to 3-month follow-up visit]
• Changes in scores of Pittsburgh sleep quality index (PSQI) for short-term efficacy assessment [Time frame: From baseline to 3-month follow-up visit]
• Changes of Tinnitus Handicap Inventory (THI) scores in the two groups for long-term efficacy assessment [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: From 3-month follow-up visit to 12-month follow-up visit]
• The effective rate of relieving chronic subjective tinnitus in the two groups [Time frame: From baseline to 3-month follow-up visit]
• The difference of functional connectivity based on resting state electroencephalogram (EEG) between the two groups [Time frame: From baseline to 12-month follow-up visit]
• The difference of effective connectivity based on resting state electroencephalogram (EEG) between the two groups [Time frame: From baseline to 12-month follow-up visit]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Piccirillo JF, Rodebaugh TL, Lenze EJ. Tinnitus. JAMA. 2020 Apr 21;323(15):1497-1498. doi: 10.1001/jama.2020.0697. No abstract available. PMID 32176246
• Stockdale D, McFerran D, Brazier P, Pritchard C, Kay T, Dowrick C, Hoare DJ. An economic evaluation of the healthcare cost of tinnitus management in the UK. BMC Health Serv Res. 2017 Aug 22;17(1):577. doi: 10.1186/s12913-017-2527-2. PMID 28830503
• Henry JA, Reavis KM, Griest SE, Thielman EJ, Theodoroff SM, Grush LD, Carlson KF. Tinnitus: An Epidemiologic Perspective. Otolaryngol Clin North Am. 2020 Aug;53(4):481-499. doi: 10.1016/j.otc.2020.03.002. Epub 2020 Apr 30. PMID 32362561
• Langguth B, Elgoyhen AB, Cederroth CR. Therapeutic Approaches to the Treatment of Tinnitus. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:291-313. doi: 10.1146/annurev-pharmtox-010818-021556. Epub 2018 Jul 25. PMID 30044727
• 龚树生 贺 王. 解读美国《耳鸣临床应用指南》 [J]. 中华耳科学杂志, 2016, 14(2): 4
• Stein A, Engell A, Junghoefer M, Wunderlich R, Lau P, Wollbrink A, Rudack C, Pantev C. Inhibition-induced plasticity in tinnitus patients after repetitive exposure to tailor-made notched music. Clin Neurophysiol. 2015 May;126(5):1007-15. doi: 10.1016/j.clinph.2014.08.017. Epub 2014 Sep 6. PMID 25441152
• Okamoto H, Stracke H, Stoll W, Pantev C. Listening to tailor-made notched music reduces tinnitus loudness and tinnitus-related auditory cortex activity. Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1207-10. doi: 10.1073/pnas.0911268107. Epub 2009 Dec 28. PMID 20080545
• Tyler R, Cacace A, Stocking C, Tarver B, Engineer N, Martin J, Deshpande A, Stecker N, Pereira M, Kilgard M, Burress C, Pierce D, Rennaker R, Vanneste S. Vagus Nerve Stimulation Paired with Tones for the Treatment of Tinnitus: A Prospective Randomized Double-blind Controlled Pilot Study in Humans. Sci Rep. 2017 Sep 20;7(1):11960. doi: 10.1038/s41598-017-12178-w. PMID 28931943

Identifiers

NCT: NCT05417711 · 2022-KY-074

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗