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Open Access Protocol
Bi-modal stimulation in the treatment of
tinnitus: a study protocol for an
exploratory trial to optimise stimulation
parameters and patient subtyping
Shona D'Arcy,1 Caroline Hamilton,1 Stephen Hughes,1 Deborah A Hall,2,3
Sven Vanneste,4 Berthold Langguth,5,6 Brendan Conlon1,7,10,8
To cite: D'Arcy S, Hamilton C, Abstract
Hughes S, et al. Bi-modal Strengths and limitations of this study
Introduction Tinnitus is the perception of sound in the
stimulation in the treatment of absence of a corresponding external acoustic stimulus.
tinnitus: a study protocol for ►► The main strength of this study is that it is a large
Bimodal neuromodulation is emerging as a promising
an exploratory trial to optimise two-site, triple-blinded, randomised trial that will
treatment for this condition. The main objectives of this
stimulation parameters and provide exploratory evidence of the relevance of
patient subtyping. BMJ Open study are to investigate the relevance of interstimulus
stimulation parameters on the clinical efficacy of
2017;7:e018465. doi:10.1136/ timing and the choices of acoustic and tongue stimuli
different bimodal stimulation parameters and will
bmjopen-2017-018465 for a proprietary bimodal (auditory and somatosensory)
inform future trial design.
neuromodulation device, as well as to explore whether
►► Prepublication history for ►► The study comprehensively characterises patients
specific subtypes of patients are differentially responsive for subtyping and this will refine candidature for the
this paper is available online.
To view these files, please visit to this novel intervention for reducing the symptoms of intervention.
the journal online (http://dx.doi. chronic tinnitus. ►► Among the limitations of this study are the variability
org/10.1136/bmjopen-2017- Methods and analysis This is a two-site, randomised, in duration between screening and enrolment
018465). triple-blind, exploratory study of a proprietary and the selection of the investigated stimulation
neuromodulation device with a pre–post and 12-month parameters.
Received 4 July 2017 follow-up design. Three different bimodal stimulation
Revised 10 August 2017 ►► The online recruitment process may inadvertently
parameter sets will be examined. The study will enrol 342 introduce participant selection bias.
Accepted 23 August 2017
patients, split 80:20 between two sites (Dublin, Ireland
and Regensburg, Germany), to complete 12 weeks of
treatment with the device. Patients will be allocated to one
of three arms using a stepwise stratification according research, clinical, health service and patient communities
to four binary categories: tinnitus tonality, sound level through publications in peer-reviewed and popular science
tolerance (using loudness discomfort level ofDownloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
Open Access
success.3 Systematic reviews highlight a lack of double- investigate whether subtypes of patients are differentially
blind, randomised, controlled studies or quality clinical responsive to this novel intervention. Safety data will also
evidence supporting the efficacy of acoustic stimulation be collected and reported. Additional feasibility outcomes
in treating tinnitus.4 This has led researchers to inves- concern methodological and procedural uncertainties
tigate approaches to treating tinnitus that go beyond when this novel medical device is prescribed and fitted in
acoustic stimulation. a large sample of patients.
One approach that has been increasingly investigated in
the last decade is invasive and non-invasive neuromodula-
tion of brain structures and networks involved in tinnitus Methods and analysis
generation.5 6 Neuromodulation is defined as the process Trial design
of inhibition, stimulation, modification, regulation or The Treatment Evaluation of Neuromodulation for
alteration of electrical activity in the central, periph- Tinnitus (TENT-A) study is a two-site, randomised,
eral or autonomic nervous systems.7 It is the science of triple-blind, exploratory study examining three different
how electrical stimulation can modulate nervous system bimodal stimulation parameter sets. The treatment dura-
functionality for therapeutic benefit. Neuromodulation tion is 12 weeks and patients are followed up at 6 weeks, 6
approaches of the central nervous system for the treat- months and 12 months post-treatment cessation. TENT-A
ment of tinnitus include repetitive transcranial magnetic will be conducted at two sites: Wellcome Trust-HRB
stimulation, transcranial direct current stimulation Clinical Research Facility, St. James’s Hospital, Dublin,
and epidural stimulation of temporal, temporoparietal Ireland and Tinnituszentrum Regensburg, University of
and frontal brain areas. All of these approaches have Regensburg, Germany. The protocol was independently
resulted in reduction of tinnitus handicap in a subgroup reviewed and approved by Research Ethics Committees
of patients.8–11 In addition, neuromodulation employing of the Tallaght Hospital/St James’ Hospital (Ref: 2016–
cranial nerve stimulation has been investigated for 03-List 11) and the University Clinic Regensburg (Ref:
tinnitus treatment in humans12 13. 16-101-0186). The trial sponsor is Neuromod Devices
To date, a limited number of uncontrolled pilot studies Limited. The trial was registered on ClinicalTrials.gov on
have been conducted to assess the safety and initial effi- 27 January 2016 (Identifier: NCT02669069, Pre-results).
cacy of neuromodulation employing cranial nerve stim- The first patient was consented in 22 March 2016 with
ulation for tinnitus. These have included invasive vagus the last visit planned for May 2018. Our reporting follows
nerve stimulation (VNS),14 non-invasive stimulation of standard protocol items for clinical trials defined in the
the vagus nerve15 16 and non-invasive cervico-trigeminal SPIRIT 2013 Statement.21
nerve stimulation (CTNS).12 13 While VNS demonstrated
promising results in animals,17 human studies have Eligibility criteria
demonstrated mixed results.14 16 18 Human studies using Eligible patients will be aged 18–70 years at screening;
non-invasive CTNS have demonstrated promising initial self-report having experienced tinnitus for >3 months and
efficacy.12 13 However, these results should be considered 40 dB HL in at least one measurement frequency in
powered sample size is needed. This study protocol the range 0.25–1.00 kHz, or of >80 dB HL in at least one
represents the first important step towards that goal. measurement frequency in the range 2.0–8.0 kHz. Exclu-
sions also include those patients who began wearing a
Hypothesis and aims hearing aid within the last 90 days, those with any type
The main objectives of the study described here are to of electro-active implantable device (eg, vagal nerve
investigate the relevance of interstimulus timing and stimulator, cochlear implant or a cardiopacemaker)
the choices of acoustic and tongue stimuli in order to and those with the following conditions that can be
optimise bimodal neuromodulation parameters for this comorbid with tinnitus: Ménière’s disease, loudness
treatment. Exploratory analyses will be conducted to discomfort level for sounds presentedDownloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
Open Access
level (SL), temporomandibular joint disorder (TMJ) the stimulus intensities are logged in the device’s memory
and anxiety determined by a score >120 out of 160 on for subsequent analysis.
the state-trait anxiety inventory (STAI).22 23 Moderate The somatosensory stimulus intensity is configured for
to severe dementia as indicated by a score 70 dB HL hearing loss at any frequency, the upper MML is a psychoacoustic estimate of the lowest level of
bound of stimulus intensity control is limited for reasons broadband noise required to minimally mask the patient’s
of safety noise dosage. The treatment device reverts to the tinnitus.28 The stimulus is normally presented ipsilaterally
default stimulus intensities at the start of each new treat- (tinnitus ear), or if tinnitus is present in both ears, the
ment session. Any adjustments made by the patients to stimulus is presented binaurally or to the ear with the
Table 1 Stimulation parameter set for the three parallel arms
Temporal relationship with somatosensory
Auditory stimulation stimulation
Arm 1 Sequence of tones mixed with a broadband noise that is Somatosensory pulses are synchronised with the tones
spectrally modified to compensate for any hearing loss
Arm 2 Sequence of tones mixed with a broadband noise that is Somatosensory pulses are temporally aligned with the
spectrally modified to compensate for any hearing loss tones with varying short delays
Arm 3 Sequence of tones mixed with a broadband noise with the Somatosensory pulses are temporally aligned with the
spectral range outside the regions normally associated with tones with varying long delays
sensorineural hearing loss
D'Arcy S, et al. BMJ Open 2017;7:e018465. doi:10.1136/bmjopen-2017-018465 3Downloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
Open Access
predominate sound. TLM will be assessed by presenting Advertisements on regional and national radio stations
a 1 kHz tone29 contralateral to the predominant tinnitus and in regional and national newspapers will invite indi-
ear or if tinnitus is equally loud in both sides or localised viduals with tinnitus, who are interested in participating
in the head, the stimuli will be presented to the ear with in a clinical study for tinnitus, to register their interest on
better hearing or randomly selected. The stimulus will be dedicated recruitment websites. The recruitment website
increased in 1 dB increments until the patient confirms provides information on the study and how to proceed
that it is equal in loudness to their tinnitus. Finally, a VAS with registration. Once they register their interest, candi-
will be employed for patients to rate the current loudness dates will be provided with a UIC and an accompanying
of their tinnitus, with 0 equating to ‘not loud at all’ and 10 personal identification number and be directed to an
equating to ‘extremely loud’, as the endpoints anchors.30 eligibility assessment website. The eligibility assessment
Safety data on adverse events (AEs) and serious adverse comprises an online survey, hosted by SurveyGizmo,
events (SAEs) will be captured throughout the trial. where those interested can find out about the require-
An AE is defined as any unfavourable and unintended ments of participating in the study. Candidates will answer
sign, symptom or disease, temporarily that may or may a scripted set of general prescreening questions on age,
not be related to the medical device. It will be rated as duration of tinnitus, oral piercings, other current medical
minor, major or serious and related or unrelated to the conditions including TMJ disorder and Ménière’s disease
device by the TENT-A Medical Review Board. An SAE is and involvement in medicolegal cases. This is not part
defined as an AE that led or might have led to the death of the formal screening because no personal or medical
or serious deterioration in the state of health of a patient. details will be taken, but it is intended to manage the
Treatment-related AEs are those judged by the principal large numbers of candidates expected to respond to the
investigator at each site to be possibly caused by the treat- advertising campaign and anticipated high screen failure
ment under investigation. The principal investigator will rate. Candidates who meet the inclusion criteria at this
remain vigilant for signs of possible treatment-related stage will be provided with a patient information leaflet
changes in oral health (eg, irritations in the oral cavity or and informed consent via email or post and invited to a
discomfort between the tongue tip and dental retainers screening visit at the local site.
or metal fillings) and the impact of tinnitus (indicated by
the THI and TFI). Patient timeline
Stopping criteria are defined as patients demonstrating The schedule of clinical research activities is illustrated
a worsening in THI and MML of an increase in THI of 7 in table 2 and briefly comprises seven visits to the clin-
points and an increase in MML of 5.3 dB. Treatment-re- ical site, plus two telephone calls during the period of
lated changes in hearing thresholds that are considered device usage. The various assessments are completed by
an AE are a deterioration from screening to endpoint a multidisciplinary team including: audiologists, medical
of 15 dB in a minimum of two adjacent test frequencies doctors, physiotherapist, research nurses and research
(0.25–8 kHz) in either ear that cannot be explained by associates.
conductive hearing problem or a recent excessive noise The initial objective of the screening visit is to obtain
exposure. written informed consent to determine whether the
Additionally, feasibility outcomes include: reasons for patient satisfies the remaining eligibility criteria and to
exclusion at the screening visit, number of patients who obtain initial outcome measures, patient characteristics
were eligible at the screening appointment but declined and audiological profile. This information is employed
to participate further, number of patient withdrawals in the subtype classification of patients, the stratified
after device fitting, proportion of incomplete patient random allocation process and for device configuration,
datasets at each scheduled visit, patients’ compliance with described below.
the device usage as per manufacturer’s instructions and At the enrolment and device fitting visit, a physio-
comparisons of alternative methods for measuring the therapist (Dublin) or medical doctor (Regensburg)
impact of tinnitus and for estimating tinnitus loudness. conducts a comprehensive assessment comprising a
Compliance data will be extracted from log files saved set of 25 predefined cranial manipulations designed to
on the device. For feasibility analysis, compliance rate will diagnose somatic tinnitus.31 We define somatic tinnitus
be expressed as a percentage of logged usage relative to where a patient reports that at least one of the somatic
(i) the expected compliance as per the intended use for manipulations reliably produces a change in the psycho-
the device (a total of 84 hours over the 12-week period), acoustic characteristics of their tinnitus (e.g., in pitch,
and to (ii) a predefined minimum acceptable compli- loudness, localisation, temporal properties and so on).
ance threshold (defined as at least 3 hours average usage Assessments of outcome measures are repeated at the
within a 1-week period, corresponding to a sum total of enrolment visit. Other elements of the visit include an
36 hours of treatment). oral health examination and device training and deploy-
ment. After completing an on-site supervised treatment
Recruitment session, patients return home and self-administer the
Patients will be primarily recruited via media advertising treatment. Patients will be instructed to use the device
and dedicated trial websites in both clinical locations. for two daily 30 min sessions over a 12-week period.
4 D'Arcy S, et al. BMJ Open 2017;7:e018465. doi:10.1136/bmjopen-2017-018465Table 2 Schedule of assessment,
Screening Enrolment and fitting Postallocation
Screening Enrolment Telephone call Interim visit Telephone call Endpoint visit Follow-up Follow-up Follow-up
Time point t - 10wks t=0 t + 3wks t + 6wks t + 9wks t + 12wks t + 18wks t + 38wks t + 64wks
Enrolment
Eligibility screen X
Informed consent X
Allocation X
Training on device usage. X
Review of device usage data log with participant. X
Encourage patient compliance. X X X X
Return device. X
Interventions
Arm 1 X X X X X
Arm 2 X X X X X
Arm 3 X X X X X
Assessments
Medical history X
D'Arcy S, et al. BMJ Open 2017;7:e018465. doi:10.1136/bmjopen-2017-018465
Previous or concomitant medications/illnesses X X X X X X
Tinnitus location & tonality X X X X X X X
Audiometric tests of hearing X X
Loudness Discomfort Level (LDL) X X
Mini-Mental State Examination (MMSE) X
Somatic assessment X
Oral assessment X X
Regensburg Insomnia Scale X X
State-Trait Anxiety Inventory (STAI) X X X
Tinnitus Functional Index (TFI) X X X X X X
Minimum Masking Level (MML) X X X X X X X
Tinnitus Loudness Matching (TLM) X X X X X X X
Tinnitus Handicap Inventory (THI) X X X X X X X
Visual Analogue Scale (VAS) (loudness and X X X X X
Downloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
intrusiveness)
Adverse events X X X X X X
Clinical Global Impression (CGI) (loudness and X X X X X
intrusiveness)
Device usability questionnaire X
Hyperacusis questionnaire X1 X2
wk, week.
1
Open Access
Dublin, 2Germany.
5Downloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com Open Access Figure 1 Anticipated flow of participants through the TENT-A study. TENT-A, Treatment Evaluation of Neuromodulation for Tinnitus. These sessions can be continuous or at different times The purpose of the endpoint visit is to repeat outcome of the day. measures assessments, the oral health examination, an Assessment of outcome measures and safety informa- exit interview and retrieve the device. Three follow-up tion are collected at the interim visit, half way through visits will be conducted to assess the post-cessation effects the 12-week treatment. Compliance will also be assessed of this intervention. and reviewed at the interim visit. Investigators will review the device usage log. Patients with acceptable compli- Sample size ance will be encouraged to continue and patients with The study is powered for a between-arm clinically signif- poor compliance will be encouraged to improve. Compli- icant difference in the mean THI scores from baseline ance phone calls will be conducted at weeks 3 and 9 to to endpoint, where the reported clinically significant encourage patients to continue with device usage and change in THI is 7 points.32 The assumed sample SD is address any technical issues that patients may be having. 12.7 points, as elucidated from a previous study using 6 D'Arcy S, et al. BMJ Open 2017;7:e018465. doi:10.1136/bmjopen-2017-018465
Downloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
Open Access
similar technology,12 resulting in an effect size of 0.55. efficacy will be explored for a series of patient subtypes,
The sample size calculations were performed using split by the stratification variables, while evidence for
MATLAB 2016a, assuming a two-sided significance level sustained effects on the psychological and functional
of 0.016 (0.05 split equally between the three interarm impact of tinnitus will be followed up for 12 months. Addi-
pairwise t-tests), and power of 90%, resulting in a total of tional feasibility measures to inform future trial design
91 patients to be enrolled in each treatment arm, or 114 include: reasons for exclusion, completeness of data
patients per arm to account for an expected drop-out rate collection, attrition rates and patients’ adherence to the
of 20%. In total, 342 patients will be required across the device usage as per manufacturer’s instructions. These
three arms of the study, split 80:20 between the Dublin will be collated using descriptive statistics and reported as
and Regensburg sites, respectively. percentages. We will also evaluate the alternative methods
for estimating tinnitus impact and tinnitus loudness, as
Allocation far as possible using psychometric criteria defined by the
Eligible patients will be randomised, in equal propor-
COnsensus-based Standards for the selection of health
tions, between the three parallel arms (see figure 1).
Measurement INstruments completed in line (COSMIN)
Stratified randomisation will be performed to balance the
checklist.34
influence of several baseline covariates in the post-hoc
Efficacy analyses will focus on investigating (i)
analyses. The stratification covariates are chosen based on
between-arm changes in the THI and TFI outcome
the investigator’s research objectives, namely to elucidate
relative treatment effects on patients with tinnitus with measures from baseline to endpoint, and (ii) within-arm
varying underlying characteristics. Allocation of patients changes in THI and TFI outcome measures from base-
will be stratified across the three intervention arms line to endpoint, for the full cohort and then sequen-
according to four binary categories applied in a stepwise tially testing the subtypes described above using serial
manner: (i) tinnitus tonality, (ii) sound level tolerance gatekeeping to control the family-wise error rate at the
(using loudness discomfort level ofDownloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
Open Access
Dissemination Competing interests SD, CH, SH, and BC are employees and shareholders of the
Findings will be disseminated to relevant research, clinical, Sponsor. BL, SV and DAH act as paid consultants for the Sponsor.
health service and patient communities through publica- Ethics approval Tallaght Hospital / St. James’s Hospital Joint Research Ethics
Committee in Dublin, and Ethics Committee of the University Clinic Regensburg,
tions in peer-reviewed and popular science journals and Germany.
presentations at scientific and clinical conferences.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
Discussion permits others to distribute, remix, adapt, build upon this work non-commercially,
This paper outlines the protocol for a multisite, and license their derivative works on different terms, provided the original work is
randomised, triple-blind, exploratory study designed properly cited and the use is non-commercial. See: http://creativecommons.org/
to explore the effects of different bimodal stimulation licenses/by-nc/4.0/
parameter sets across a number of tinnitus subtypes in © Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
a range of tinnitus clinical subdomains. The results of
expressly granted.
this study will inform the design of future triple-blind
randomised control trials. The main objective is to deter-
mine an optimised bimodal stimulation parameter set,
but we will also explore which patient characteristics References
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Open Access
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D'Arcy S, et al. BMJ Open 2017;7:e018465. doi:10.1136/bmjopen-2017-018465 9Downloaded from http://bmjopen.bmj.com/ on November 8, 2017 - Published by group.bmj.com
Bi-modal stimulation in the treatment of
tinnitus: a study protocol for an exploratory
trial to optimise stimulation parameters and
patient subtyping
Shona D'Arcy, Caroline Hamilton, Stephen Hughes, Deborah A Hall,
Sven Vanneste, Berthold Langguth and Brendan Conlon
BMJ Open 2017 7:
doi: 10.1136/bmjopen-2017-018465
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