Noninvasive Bimodal Neuromodulation for the Treatment of Tinnitus: Protocol for a Second Large-Scale Double-Blind Randomized Clinical Trial to Optimize Stimulation Parameters

Brendan Conlon, Caroline Hamilton, Stephen Hughes, Emma Meade, Deborah A Hall, Sven Vanneste, Berthold Langguth, Hubert H Lim, Brendan Conlon, Caroline Hamilton, Stephen Hughes, Emma Meade, Deborah A Hall, Sven Vanneste, Berthold Langguth, Hubert H Lim

Abstract

Background: There is increasing evidence from animal and human studies that bimodal neuromodulation combining sound and electrical somatosensory stimulation of the tongue can induce extensive brain changes and treat tinnitus.

Objective: The main objectives of the proposed clinical study are to confirm the efficacy, safety, and tolerability of treatment demonstrated in a previous large-scale study of bimodal auditory and trigeminal nerve (tongue) stimulation (Treatment Evaluation of Neuromodulation for Tinnitus - Stage A1); evaluate the therapeutic effects of adjusting stimulation parameters over time; and determine the contribution of different features of bimodal stimulation in improving tinnitus outcomes.

Methods: This study will be a prospective, randomized, double-blind, parallel-arm, comparative clinical trial of a 12-week treatment for tinnitus using a Conformité Européenne (CE)-marked device with a pre-post and 12-month follow-up design. Four treatment arms will be investigated, in which each arm consists of two different stimulation settings, with the first setting presented during the first 6 weeks and the second setting presented during the next 6 weeks of treatment. The study will enroll 192 participants, split in a ratio of 80:80:16:16 across the four arms. Participants will be randomized to one of four arms and stratified to minimize baseline variability in four categories: two separate strata for sound level tolerance (using loudness discomfort level as indicators for hyperacusis severity), high tinnitus symptom severity based on the Tinnitus Handicap Inventory (THI), and tinnitus laterality. The primary efficacy endpoints are within-arm changes in THI and Tinnitus Functional Index as well as between-arm changes in THI after 6 weeks of treatment for the full cohort and two subgroups of tinnitus participants (ie, one hyperacusis subgroup and a high tinnitus symptom severity subgroup). Additional efficacy endpoints include within-arm or between-arm changes in THI after 6 or 12 weeks of treatment and in different subgroups of tinnitus participants as well as at posttreatment assessments at 6 weeks, 6 months, and 12 months. Treatment safety, attrition rates, and compliance rates will also be assessed and reported.

Results: This study protocol was approved by the Tallaght University Hospital/St. James's Hospital Joint Research Ethics Committee in Dublin, Ireland. The first participant was enrolled on March 20, 2018. The data collection and database lock are expected to be completed by February 2020, and the data analysis and manuscript submission are expected to be conducted in autumn of 2020.

Conclusions: The findings of this study will be disseminated to relevant research, clinical, and health services and patient communities through publications in peer-reviewed journals and presentations at scientific and clinical conferences.

Trial registration: ClinicalTrials.gov NCT03530306; https://ichgcp.net/clinical-trials-registry/NCT03530306.

International registered report identifier (irrid): DERR1-10.2196/13176.

Keywords: auditory cortex; auditory nerve; bimodal; neuromodulation; pain; plasticity; precision medicine; tinnitus; trigeminal nerve; vagus nerve.

Conflict of interest statement

Conflicts of Interest: BC, CH, SH, EM, and HHL have financial interest and/or are employed by Neuromod Devices Limited. DAH, SV, and BL serve on the Scientific Advisory Board of Neuromod Devices Limited and receive financial compensation for their services to the company.

©Brendan Conlon, Caroline Hamilton, Stephen Hughes, Emma Meade, Deborah A Hall, Sven Vanneste, Berthold Langguth, Hubert H Lim. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 27.09.2019.

Figures

Figure 1
Figure 1
Bimodal sensory neuromodulation device (Lenire) for tinnitus treatment. The system developed by Neuromod Devices (Dublin, Ireland) consists of wireless high-fidelity circumaural headphones that deliver acoustic stimuli, a 32-site surface electrode array (tonguetip) for presenting electrical stimulus patterns to the anterior dorsal surface of the tongue, and a battery-powered controller that coordinates both stimulus modalities.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6789422/bin/resprot_v8i9e13176_fig2.jpg
Hypothesis testing accounting for multiple comparisons. The primary endpoints for the TENT-A2 study correspond to several parallel and serial hypotheses depicted in the figure. A P value of .05 is initially distributed across four hypotheses (H1a, H1b, H1c, H2a), in which the portion of the P value attributed to each hypothesis is indicated by the alpha value. For example, alpha equals 0.55 for H1a, which corresponds to the null hypothesis being rejected if P<.0275 (.55x.05). The null hypothesis for H1a is that there is no between-arm difference in changes in mean Tinnitus Functional Index score from enrollment to interim (6-week timepoint) between parameter setting (PS) 1 and PS6 for the full cohort of participants. The null hypothesis for H1b and H1c is that there is no between-arm difference in changes in mean THI score from enrollment to interim between PS1 and PS6 for the hyperacusis subgroup and high tinnitus symptom severity subgroup, respectively. Both are rejected if P<.01 (.2x.05). The null hypothesis for H2a is that there is no within-arm change in THI from baseline (average of screening and enrolment scores) to interim for the full cohort of participants. H2a is rejected if P<.0025 (.05x.05). Note that the remaining hypotheses (H2b, H2c, H2d, H2e, H2f) can only be tested if the previous hypothesis in the series is rejected. For example, if H2a is rejected, then its portion of the P value (P=.0025) is transferred to H2b for testing. If H2b is rejected, then its portion of the P> value (P=.0025) is transferred to H2c, and so on. Similarly, the arrows shown for the between-arm comparisons indicate that if any of the other hypotheses (for H1a, H1b, or H1c) are successfully rejected, then their portion of the P value is distributed to its neighbors based on the proportion labeled on each arrow. The null hypothesis for the within-arm comparisons (H2a to H2f) is that there is no within-arm change in THI or Tinnitus Functional Index from baseline to interim for the full cohort of participants, hyperacusis subgroup, or high tinnitus symptom severity subgroup. Note that all within-arm comparisons will be based on a two-sided paired (dependent) t test, while all between-arm comparisons will be based on a linear regression with independent variables of treatment arm and THI score at enrollment. Further details on the statistical analysis plan are provided in the Statistical Methods section. BL: baseline, EN: enrollment, IN: interim, Hyp: hyperacusis subgroup (loudness discomfort level <70 dB sensation level at 500 Hz at screening), High-THI: high tinnitus symptom severity subgroup (THI >56 points at screening); TFI: Tinnitus Functional Index; THI: Tinnitus Handicap Inventory.

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