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Unification of treatments and interventions for tinnitus patients (UNITI): a study protocol for a multi-center randomized clinical trial

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Background Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and assessments or applications of intervention targeting only a single organ level. Combinatory treatment approaches, potentially targeting multiple systems as well as treatment personalization might provide remedy and enhance treatment responses. The aim of the present study is to systematically examine established tinnitus therapies both alone and in combination in a large sample of tinnitus patients. Further it wants to provide the basis for personalized treatment approaches by evaluating a specific decision support system developed as part of an EU-funded collaborative project (Unification of treatments and interventions for tinnitus patients; UNITI-project). Methods/ Study design This is a multi-center parallel-arm randomized clinical trial conducted at five different clinical sites over the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counselling, hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated. Assessments and interventions are harmonized over the involved clinical sites. The primary outcome measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory. Discussion Results and conclusions from the current study might not only provide an essential contribution to combinatory and personalized treatment approaches in tinnitus but could also provide more profound insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus. Trial registration ClinicalTrials.gov: NCT04663828. Registered on 11. December 2020
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Unication of treatments and interventions for
tinnitus patients (UNITI): a study protocol for a
multi-center randomized clinical trial
Stefan Schoisswohl ( stefanschoisswohl@yahoo.de )
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg https://orcid.org/0000-0003-3633-999X
Berthold Langguth
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Martin Schecklmann
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Benjamin Boecking
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Christopher Cederroth
Karolinska Institutet Institutionen for fysiologi och farmakologi
Dimitra Chalanouli
EXCELYA
Rilana Cima
KU Leuven: Katholieke Universiteit Leuven
Sam Denys
KU Leuven: Katholieke Universiteit Leuven
Juliane Dettling-Papargyris
Terzo-Institute for Applied Hearing Research
Alba Escalera-Balsera
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Juan Manuel Espinosa-Sanchez
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Alvara Gallego-Martinez
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
E Giannopoulou
Page 2/32
EXCELYA
Leyre Hidalgo-Lopez
hospital universitario virgen de las nieves, Granada, Spain
Michael Hummel
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Dimitris Kikidis
National and Kapodistrian University of Athens, Hippocratein General Hospital, Athens
Michael Koller
University Hospital Regensburg: Universitatsklinikum Regensburg
Jose Antonio López Escámez
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Steven Marcrum
University Hospital Regensburg: Universitatsklinikum Regensburg
Nikolaos Markatos
National and Kapodistrian University of Athens
Juan Martin-Lagos
Hospital Universitario San Cecilio
Maria Martinez-Martinez
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Marta Martinez-Martinez
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Maria Mata Ferron
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Birgit Mazurek
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Nicolas Mueller-Locatelli
Hospital Universitario San Cecilio
Patrick Neff
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Kevin Oppel
Terzo Institute for Applied Hearing Research
Patricia Perez-Carpena
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
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Paula Robles-Bolivar
GENYO: Centro Pzer - Universidad de Granada - Junta de Andalucia de Genomica e Investigacion
Oncologica
Matthias Rose
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Tabea Schiele
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Axel Schiller
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Jorge Simoes
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Sabine Stark
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Susanne Staudinger
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Alexandra Stege
Charité Universitätsmedizin Berlin: Charite Universitatsmedizin Berlin
Nicolas Verhaert
KU Leuven: Katholieke Universiteit Leuven
Winfried Schlee
University of Regensburg Department of Psychiatry and Psychotherapy: Klinik und Poliklinik fur
Psychiatrie und Psychotherapie der Universitat Regensburg
Research Article
Keywords: tinnitus, treatment, hearing aids, cognitive behavioral therapy, sound therapy, structured
counseling, multi-center, RCT
DOI: https://doi.org/10.21203/rs.3.rs-573232/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License. 
Read Full License
Page 4/32
Abstract
Background
Tinnitus represents a relatively common condition in the global population accompanied by various
comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or
cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus
phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus
patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and
assessments or applications of intervention targeting only a single organ level. Combinatory treatment
approaches, potentially targeting multiple systems as well as treatment personalization might provide
remedy and enhance treatment responses. The aim of the present study is to systematically examine
established tinnitus therapies both alone and in combination in a large sample of tinnitus patients.
Further it wants to provide the basis for personalized treatment approaches by evaluating a specic
decision support system developed as part of an EU-funded collaborative project (Unication of
treatments and interventions for tinnitus patients; UNITI-project).
Methods/ Study design:
This is a multi-center parallel-arm randomized clinical trial conducted at ve different clinical sites over
the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counselling,
hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a
combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated.
Assessments and interventions are harmonized over the involved clinical sites. The primary outcome
measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory.
Discussion
Results and conclusions from the current study might not only provide an essential contribution to
combinatory and personalized treatment approaches in tinnitus but could also provide more profound
insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus.
Trial registration:
ClinicalTrials.gov: NCT04663828. Registered on 11. December 2020
Background
Following a recent multidisciplinary consensus, tinnitus is termed as “
the conscious awareness of a tonal
or composite noise for which there is no identiable corresponding external acoustic source
” [1] whereby
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a continuous perception over 6 months constitutes a chronication [2]. Frequent causes for the
emergence of tinnitus range from noise trauma, presbyacusis to intake of ototoxic medication, potentially
provoking pathological neural alterations in the central auditory pathway [3]. Approximately 10-15% of
the global adult population are affected by this phantom sound perception [4], whereas 2-3% are
particularly suffering from tinnitus [5,6]. In many cases tinnitus generates a high level of suffering and
can be accompanied by various comorbidities such as depression, anxiety or sleep disorders [7–10],
explicitly dened as tinnitus disorder [1]. Currently there is no general treatment respectively a cure for
tinnitus existent. Available treatment approaches cover a broad spectrum of interventions from
pharmacology [6], neurostimulation [11], cochlear implants [12] to different sound therapies [13,14] or
hearing aids [15,16]. While the European guidelines for tinnitus [17] give a weak recommendation for the
application of amplication devices in tinnitus patients with hearing loss, there is currently no explicit
recommendation for pharmacological interventions or neurostimulation [17]. Up to now, cognitive
behavioral therapy approaches exhibit the best body of evidence for the treatment of tinnitus [18,19] with
a strong recommendation according to European guidelines [17]. Even though tinnitus research has been
impressively expanded over the past decade, the majority of studies suffers from methodological
shortcomings such as heterogeneous patient samples, imprecisely dened therapeutic interventions,
relatively small sample sizes as well as a lack of predened primary outcomes and data analysis
strategies [20,21]. Beyond tackling these limitations in prospective studies, interdisciplinary multi-center
randomized clinical trials (RCT) could help to further increase the validity and interpretability of results.
The complexity of tinnitus with a wide variety of phenotypes and different etiologies plus the uncertainty
about underlying pathophysiological processes make the quest in nding an appropriate treatment rather
dicult [3,22]. In most of the studies only a subgroup of patients exhibits improvement to a certain
intervention ranging from 1% to more than 35%. However, currently none of the treatment approaches has
sound and universal ndings [23]. Thus a common treatment for all tinnitus subtypes is most unlikely,
highlighting the necessity of so-called precision medicine or rather personalized treatment concepts in
tinnitus [24,25]. A potential proceeding would be the identication of demographic or tinnitus-related
characteristics, potentially capable to predict a patients response to a certain type of intervention [26].
Such predictive markers could facilitate a so-called Decision Support System (DSS), which could assist
clinicians in selecting the most promising tinnitus treatment on an individual patient level [20].
Currently available tinnitus treatments mostly aim at different systems and domains e.g., the auditory
system (AS) or the central nervous system (CNS) respectively focus mainly on a single target of the
underlying pathophysiology. At best, tinnitus treatments should integrate all involved components/
systems [27], hence a combination of different therapeutic approaches could provide further remedy.
Studies focusing on combinatory interventions range from combinations of hearing aids with sound
generators [28–30], simultaneous sound and somatosensory stimulations [31,32], application of
counseling together with tinnitus masking termed tinnitus retraining therapy [13,22,33,34], to brain
stimulation in combination with relaxation [35] as well as multimodal therapies [36,37]. Though, past
studies are not capable to provide a clear superiority of combined interventions. A systematic
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examination of several different single and combinational interventions is currently not available,
highlighting the need for more profound investigations in this regard.
The present study protocol describes the methodological procedure of the UNITI-RCT (Unication of
Treatments and Interventions for Tinnitus Patients – Randomized Clinical Trial), which constitutes the
centerpiece of the EU-funded UNITI-project. The primary objective of the UNITI-project is the development
of a computational model to predict patients’ responses to distinct treatments in order to facilitate
personalized therapies in tinnitus. For an detailed overview of goals and procedures of the UNITI-project
see Schlee et al., 2021 [38].
Objectives
The attempt of the UNITI-RCT is to not only overcome the shortcomings of previous studies, but also
pave the way for personalized medicine approaches in tinnitus. For this purpose a multi-center parallel-
arm RCT, implemented and harmonized among ve clinical sites across the EU, combining and
investigating selected existing therapies evaluated in the European guidelines for tinnitus [17], is
conducted. The main objective of the UNITI-RCT is (1) to scrutinize if a combinational therapy is more
effective than a single therapy for the treatment of chronic tinnitus. Additionally, (2) the outcomes of each
utilized intervention will be compared against each other; (3) several treatment groups will be formed and
analyzed based on whether participants received a certain treatment type alone or in combination with
another treatment, (4) whether participants received a certain type of intervention at all (either alone or in
combination) and (5) whether the received interventions targeted on one or two organ levels - the ear or
the CNS (ear- vs. brain-mediated interventions). Moreover, (6) the development of a specic DSS, which
will be based on demographic, psychological, audiological, electrophysiological and genetic parameters,
for patient-specic data-driven treatment suggestions [39] will be validated over the course of the UNITI-
RCT.
Methods
For the reporting of the methodological approach of the UNITI-RCT, the SPIRIT guidelines have been used
[40].
Study design
The study is designed as a multi-center RCT which investigates the effect of four different tinnitus
therapy approaches applied as single or combinatory treatments over a time period of 12 weeks in 500
patients with mild to severe tinnitus distress. The clinical trial has been registered at ClinicalTrials.gov
(NCT04663828; trial registration dataset in the supplemental material) and will be completed in ve
different clinical sites across the European Union.
University of Regensburg, Regensburg, Germany (RCT coordinator)
Charité – Universitaetsmedizin Berlin, Berlin, Germany
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Ethniko Kai Kapodistriako Panepistimo Athinon, Athens, Greece
Servicio Andaluz de Salud/ Hospital Universitario San Cecilio, Granada, Spain
Katholieke Universiteit Leuven, Leuven, Belgium
Sample size determination/ effect size calculation
Since there is no reliable data for the main purpose of the study (single vs. combinational treatment)
available from which an effect size for sample calculation can be deduced, literature from a stepped-care
approach involving counseling, sound therapy and CBT was used for this purpose [18]. This study
exhibited an effect size of 0.52 after eight months when a stepped-care approach including a
combination of treatments was contrasted against treatment as usual. This approach is not fully
comparable to the current RCT (single vs. combinational treatment), as also treatments with much lower
effect sizes are included in the current study (hearing aids, sound therapy, structured counselling), effect
size was estimated conservatively as about 0.26. With a signicance level of 5% and a power of 80%
(two-sided test) the necessary sample size is 468. Taking also drop-outs into account, the aim is to
investigate a total sample size of N = 500.
Study population
As already mentioned above a total number of 500 participants will be investigated in the course of this
RCT. Each of the ve clinical sites has the objective to examine n = 100 patients with chronic subjective
tinnitus for the RCT with respect to specic inclusion and exclusion criteria. Potential candidates will be
recruited via media advertising (according to local regulations) as well as on an individual basis at the
clinical sites through e.g., information sheets, word of mouth or in conversations with medical staff. In
order to be eligible for participation, potential participants have to meet the following criteria as outlined
in table 1.
Outcome measures and assessments
All measures, assessments and documentations are harmonized among the clinical sites. Besides the
below listed standardized measures and assessments, participants’ comorbidities as well as concomitant
treatments and medications will be recorded. All types of medication (even over-the-counter drugs), which
have been ingested within the last three months before screening respectively up to the time of study
starting, and which will be ingested during the study are documented with respect to dose, administration
as well as begin and stop date. Further, all types of treatments which have been performed within the last
three months before screening respectively up to the time of study starting and/ or will be performed
during the course of the trial are documented with respect to frequency and begin/ stop date.
Primary Outcome
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The primary outcome of the current RCT is focused on the domain tinnitus distress. Changes in tinnitus
distress with respect to the applied interventions will be assessed via the total score of the Tinnitus
Handicap Inventory (THI) [41].
Secondary Outcome
Several other standardized tinnitus- and health-related questionnaires will be used as secondary
outcomes in the course of this RCT:
Tinnitus Functional Index (TFI) [42]
Mini Tinnitus Questionnaire (mini-TQ) [43]
Tinnitus numeric rating scales (NRS) [44]
World Health Organization – Quality of Life abbreviated (WHOQoL-Bref;
https://www.who.int/healthinfo/survey/WHOQOL_BREF.pdf?ua=1)
Clinical Global Impression Scale - Improvement (CGI-I) [45]
Patient Health Questionnaire for Depression (PHQ-D/PHQ-9) [46,47]
Sample description and other measures
European School of Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ) [48]
Tinnitus Sample Case History Questionnaire (TSCHQ) [49]
Questionnaire on Hypersensitivity to Sound (GUF) [50]
Big Five Inventory-2 (BFI-2) [51]
Montreal Cognitive Assessment (MoCA) [52]
Social Isolation Electronic Survey (SOISES) [53] – a subset of 11 questions sensitive for tinnitus
distress change will be used, further designated as Mini-SOISES
Attitudes Towards Amplication Questionnaire (ATAQ) – a subset of questions (baseline: 8; end of
treatment: 7) associated with hearing aids taken from the Attitudes towards Loss of Hearing
Questionnaire (ALHQ) [54]
Fear of Tinnitus Questionnaire (FTQ) [55]
Electrophysiological measures
Two types of electrophysiological measures are performed in the course of this RCT – auditory brain
stem responses (ABR) and auditory middle latency responses (AMLR). ABRs represent the synchronized
neural activity along the auditory pathway evoked by a serial presentation of acoustic stimuli (e.g.,
clicks). ABR is considered to be a robust electrophysiological method to assess the functional integrity of
the auditory pathways. Normally, up to ve waves occur in the ABR response. The wave I of the ABR
reects activity of the spiral ganglion cells at the distal part of the eighth auditory nerve, the wave II from
the globular cells in the cochlear nucleus, the wave III is generated by the cochlear nucleus spherical cells
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and globular cells and wave IV and wave V are generated from the medial superior olive and its
projections to the nuclei in the lateral lemniscus and the inferior colliculus [56]. These
electrophysiological responses are typically less than a microvolt in amplitude [57,58]. AMLRs are
typically composed of a set of positive (P-waves) and negative (N-waves) waves. AMLRs are sensitive
potentials for the processing of low frequency tones. The difference found between the behavioral
auditory threshold and the electrophysiological threshold is of approximately 10 dB [59]. Further, they
may be used for the investigation of functional integrity in the auditory pathway or the assessment of
non-organic hearing loss. Both measures will be recorded with four external electrodes placed over the
forehead and behind the ear during the presentation of standardized acoustic signals while patients are
lying in a quiet room. Measurements will be performed by trained medical and/ or study staff. These
measurements will not be used as outcome measures, but will be analyzed as potential prognostic
factors for treatment response.
Audiometric and tinnitometric measures
Otological examinations will be executed according to state-of-the-art medical practice. Audiological and/
or tinnitometric assessments will be conducted by responsible medical and/ or trained study staff with a
standard clinical audiometer. Pure tone air-conduction and bone-conduction audiometry will be recorded
according to the guidelines from the British Society of Audiology - http://www.thebsa.org.uk/wp-
content/uploads/2014/04/BSA_RP_PTA_FINAL_24Sept11_MinorAmend06Feb12.pdf. Individual tinnitus
characteristics such as pitch and loudness will be determined via the presentation of different
frequencies (or narrow band noise in the case of noise-like tinnitus). Participants have to decide which
stimulus is closer to their tinnitus percept in a forced choice paradigm. Two different pure tones with a
difference of two octaves (1 kHz and 4 kHz) will be consecutively presented and patients have to select
the frequency which is closer to their tinnitus pitch (not intensity). Next, the selected frequency plus a
different frequency closer to the one selected (one octave difference) will be presented and patients have
to make the same decision again. The procedure goes on, keeping the closest frequency for the next
round, until patients conrm the same frequency three times. In each round, different neighboring
frequencies are presented. Frequencies used include 250, 500, 1000, 2000, 3000, 4000, 6000 and 8000
Hz, presented at 20 dB above the individual hearing level of the respective frequency.
Subsequently, tinnitus loudness is determined by the comparison of the determined tinnitus frequency at
different loudness levels starting from the individual hearing level. (5 dB steps).
The procedures are conducted in one ear in case of unilateral (contralateral to tinnitus percept) or
symmetric bilateral tinnitus and in two ears in cases of asymmetric tinnitus.
In order to assess patients minimum masking level, a narrow band noise centered at the previously
dened tinnitus frequency is presented in an ascending way (5 dB steps, starting from individuals hearing
threshold) ipsilateral to the tinnitus percept until an adequate level to cover the patients’ tinnitus is
reached.
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The phenomenon of a brief tinnitus percept suppression following acoustic stimulation is termed residual
inhibition [60] and will be evaluated via thirty seconds and two-minute presentations of a pure tone and a
broad band noise in accordance with the determined individual tinnitus frequency.
Blood samples
Blood samples are taken once before treatment start on a voluntary basis and are therefore not
mandatory for trial participation. Participants are informed about blood sample collection and how their
samples will be handled in detail (with respect to EU and country-specic regulations). The blood
samples are sent to the Center for Genomics and Oncological Research (GENyO), Universidad de Granada
(Granada, Spain) and the plasma samples to the Karolinska Institutet (Stockholm, Sweden) for further
analysis of genetic parameters and plasma proteins respectively. Both laboratories are part of the UNITI
consortium [38]. Storage, shipping and analysis of participants biological samples are done according to
the EU GDPR (2016/679) as well as country specic legislations.
Peripheral blood samples from patients included in the clinical trial will be obtained in EDTA coated
tubes. After centrifugation at 1500g during 10 min, plasma and cellular fractions will be separated.
Plasma will be immediately frozen at -80 degrees to prevent protein degradation.
DNA isolation and genome sequencing
DNA will be isolated from the buffy coat by the QIAamp DNA blood Mini kit (QIAGEN), according to the
manufacturer’s protocol. DNA quality will be assessed by absorbance measurements (Nanodrop 2000c,
ThermoScientic) and by 260/280 and 230/260 indexes to determine protein and salt content. DNA
concentration will be determined by a uorimetric method (Qubit) and Quant-iT technology (Invitrogen)
and DNA integrity will be evaluated in 1% agarose gels and by Bioanalyzer technology [61].
For whole genome sequencing, DNA libraries will be prepared by using the Truseq DNA PCR-free kit (350
bp). DNA will be sequenced in an Ilumina NovaSeq 6000 sequencing platform 150 paired-end reads (150
x 2 bp) with a throughput 30x (90 Gb/sample). Bioinformatic analysis will include alignment and
mapping of raw data to the latest updated reference genome (GRCh38.p13), preprocessing of FASTQ and
generation of BAM les, variant calling to obtain VCF les following GATK Best Practices guidelines, and
annotation using Ensemble Variant Effect Predictor.
Analyzing the whole genome using next-generation sequencing delivers a base-by-base view of all
genomic alterations, including single nucleotide variants (SNV), small insertions and deletions, and large
structural variations (copy number changes). Paired-end whole-genome sequencing involves sequencing
both ends of a DNA fragment, which increases the likelihood of alignment to the reference and facilitates
detection of genomic rearrangements, repetitive sequences, and gene fusions. Gene burden tests will be
used to compare burden of loss of function SNV and structural variants in synaptic genes in patients with
tinnitus, using Non-Finnish European dataset from gnomAD v3 as population database to estimate allelic
frequencies [62].
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Protein analyses
Protein biomarkers for patients included in the RCT will be initially assessed by a Proximity Extension
Assay (PEA) from O’LINK. Control groups will include subjects with and without hearing loss. PEA
multiplex analysis in 500 tinnitus cases and 2728 non tinnitus control blood samples from the STOP
study (https://stop.ki.se/) will be performed. An immune response biomarker panel directed against 96
proteins implicated in inammatory diseases will be used, since several studies have found inammation
to be involved in various forms of hearing loss. Therefore, inammatory biomarkers could potentially be
associated with tinnitus. Standard biostatistical analyses will be performed, including basic descriptive
and univariate statistics as well as Receiver Operating Characteristics curves.
Genetic and blood biomarkers will serve as a basis for determining tinnitus subtypes and evaluating
persons treatment response at the clinical sites through the procedure.
Treatment conditions
Four different types of interventions will be included in the present RCT. Two of them mainly target on the
auditory aspects of tinnitus (sound therapy; hearing aid), whereas the other two especially target the CNS
(structured counseling; cognitive behavioral therapy). Each intervention will be harmonized among the
participating clinical sites in view of procedure, technical equipment and trained research staff. This will
be achieved via specic Standard Operation Procedure documents and a detailed step-by-step description
of procedures as well as the conduction of dedicated workshops from leading experts in the particular
eld for each intervention. Hereinafter, the used interventions are described.
Sound Therapy (ST)
Sound therapy will be self-administered on a daily basis and conducted via a dedicated mobile
application for Android and iOS in accordance to the European regulations for medical software (IEC
62304, IEC 82304). This mobile application will contain a set of 64 different stimuli comprised of various
articial and naturalistic sounds and an application of different state-of-the-art lter or modulation
techniques, e.g., amplitude modulated tones or noises [63,64] as well as ltered music [65]. Intensity and
length of sound stimulation can be adjusted by the user. Maximum loudness for all types of sound
stimulation will be 85 dB. Patients’ behavioral data (tinnitus loudness after stimulation) as well as type of
sound, loudness and play duration/ repetitions will be collected for each conducted stimulation. Further,
the time of app usage will be recorded. All personal data will be treated with the upmost condentiality
and multiple efforts will be made in order to pseudo-anonymize the collected data and to protect
participants’ identities. EU General Data Protection Regulation (GDPR, 2016/679) will apply for the mobile
application, which are outlined in the data management plan in the supplemental material.
Hearing aid (HA)
Participants will be stratied according to their hearing function. Patients with a hearing aid indication
will represent one strata and only these patients will be randomized for the option “hearing aid therapy”.
Page 12/32
Conventional commercially available hearing instruments will be utilized with all tinnitus-specic sound
interventions deactivated, in order to disentangle the effect of amplication from the effects of sound
therapy. Specically, all participants were tted bilaterally with mini-behind-the-ear hearing instruments
(Type Signia Pure 312 7X; Sivantos Pte. Ltd., Singapora, Republic of Singapore/ WSAudiology, Lynge,
Denmark), with acoustic coupling achieved via non-custom, non-occluding eartips. Gain assignments
appropriate for each individual’s hearing loss will be applied according to the National Acoustic
Laboratories-Non-Linear 2 generic amplication prescription procedure [66] and veried using probe
microphone measures. As it has been reported that numerous signal processing characteristics might
signicantly affect the impact of amplication on tinnitus, all signal processing features, excepting only
acoustic feedback reduction and impulse noise reduction algorithms, will be deactivated during the 12-
week hearing aid trial. Verication of hearing aid gain assignments and signal processing will be
performed by audiologists, hearing aid acousticians, or trained study personnel, in accordance with the
appropriate practice guideline of the British Society of Audiology
(http://www.thebsa.org.uk/wpcontent/uploads/2018/05/REMS-2018.pdf). Participants will be
encouraged to use their hearing aids for at least 10 hours per day and will be allowed to keep their
hearing devices following successful completion of the RCT.
Structured counseling (SC)
A standardized protocol developed from a team of psychologists will provide structured patient
education, counselling as well as tips for a life with tinnitus on a daily basis. The protocol is oriented
towards recent European Tinnitus Guidelines [17] and comprised of 12 chapters:
Basic facts about tinnitus
Beginner facts about tinnitus
Beginner facts about the brain and sound perception
Important vocabulary
Myths and misconceptions about tinnitus
Diagnosis of tinnitus
Special types of tinnitus
Therapeutic approaches
Psychology of tinnitus
My behavior and my tinnitus
The science on tinnitus
Switch perspective: How would you advice others?
Structured counseling will be equally implemented via a mobile application on Android and iOS in
compliance with the European regulations for medical software (IEC 62304, IEC 82304) - details can be
found in the data management plan in the supplemental material. At the end of each chapter there will be
Page 13/32
a short quiz to repeat and consolidate the content. Answers and scores of the quizzes as well as time of
app usage will be collected according to the General Data Protection Regulation (GDPR, 2016/679).
Patients will be encouraged to use the specically developed app for structured counseling. However,
alternatively the information contained in the app can also be provided in printed form.
Cognitive behavioral therapy for tinnitus (CBT4T)
A specially designed cognitive behavioral therapy (CBT) program for tinnitus patients will be applied by
psychologist or psychotherapists by training. CBT4T will be performed in weekly face-to-face group
meetings á 1.5-2 hours over the 12-week treatment phase. One face-to-face screening visit will take place
before the group session. The maximum number of participants per group will be six tinnitus patients.
Psychologists and psychotherapists will carry out the CBT4T and are trained by workshops before the
treatment. The theoretical concept and the content of the treatment of CBT4T is based on the concept of
exposure therapy in anxiety disorders or chronic pain (cognitive restructuring via exposition to fear
expectations) and a fear-avoidance model [18,67,68]. Short psychoeducation at the beginning of the
treatment is followed by exposure exercises in group sessions.
Trial procedure
The UNITI RCT will be conducted at the ve clinical sites as well as in patients’ homes. All patients have
to make at least four visits in the respective clinical sites over a period of at least 10 months consisting of
screening, baseline visit, interim assessment, nal visit at treatment end as well as a follow-up visit 36
weeks after the baseline assessment. Patients who will be randomly assigned to CBT4T, have to
additionally participate in a 12 weeks group therapy at the respective clinic. All other treatments are
conducted without local restrictions.
Screening, baseline and treatment start can be performed on the same day. In this case relevant
assessments are only performed once. Furthermore, an additional visit in the screening period can be
added for purposes of screening/ baseline procedures. Prior to the rst screening visit, there will be an
online pre-screening in order to preselect potentially appropriate participants.
The interval between baseline and treatment start should be maximally 4 weeks. If the interval is longer,
an additional visit will be done (without ESIT-SQ, TSCHQ, BFI-2, ATAQ, electrophysiological measurements
or otological examination). Blood samples will be taken before treatment start. Consent for the
participation at the genetic and plasma protein tests is independent from the consent to participation in
the clinical trial. In case of a combinational treatment, the second treatment will start maximum ten
working days after the rst (e.g., HA and CBT4T). Moreover, a facultative additional follow-up assessment
48 weeks after baseline measurements is planned. For each study visit a deviation of +/- 7 days is
permitted. Figure 1 gives an overview of the study procedure, while in table 2 the assessments for all
measurement points are outlined. In the following each visit is shortly described in a chronological order:
Page 14/32
Pre-screening
Due to the investigation of a rather large and specic sample of the tinnitus population, a pre-screening
will precede the actual screening process. This pre-screening is conducted
as an additional layer of the eligibility assessment in the form of an online-based survey and designed to
ensure a more ecient eligibility check (for an overview of study eligibility criteria see table 1). Access to
the pre-screening survey will be provided via an URL-link to interested candidates. Before start of the pre-
screening, candidates will be provided with information about study aim, procedure as well as
participation requirements. Hereinafter, participants have to conrm that they read and understood the
provided information plus that they are willing to participate in the pre-screening process and answer a
series of tinnitus- and health-associated questions. After completion of the pre-screening, patients will get
a six-digits code, have to contact the respective study center and leave their patient-code and phone
number. Within seven days patients will get their results about eligibility and if applicable, information
about the subsequent screening assessment. Eligible candidates who accept the screening assessment
invitation will be sent a Patient Information Leaet and Informed Consent Form (ICF) by regular mail , to
assure they have sucient time to read the provided information and formulate questions ahead of the
screening visit. Candidates who are not eligible to participate in the study will receive suggestions for
treatment options outside the UNITI study.
Screening
Prior to start of the screening, participants will be informed about purpose, procedure and potential risks
or benets of the trial by a member of the local study team and have to give written informed consent.
Consent for the participation in the genetic tests is independent from the consent to participation in the
clinical trial. Informed consent forms plus information sheets for the RCT and the blood analysis can be
found in the supplemental material. Screening will be conducted at the respective clinical sites. During
screening, inclusion and exclusion criteria (cf. table 1) are veried in a clinical face-to-face setting.
Several exclusion criteria are checked once again to verify that there were no changes as compared to
pre-screening. In the course of the screening process participants undergo a set of otological, audiometric
and tinnitometric examinations and have to complete several tinnitus- and health-related questionnaires.
In addition, their cognitive abilities will be assessed with the MoCA-test [52].
Baseline
After a successful screening visit and a signed ICF, several baseline measures consisting of tinnitus- and
health-related questionnaires and electrophysiological measurements are conducted. Following baseline
measurements, participants are randomly allocated to a treatment group (please see section stratication
and randomization below) and informed about the specic treatment they receive.
Stratication and Randomization
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Participants will be randomly assigned to one treatment arm comprised of a single or combinational type
of intervention as exemplied in gure 2. Stratication will be conducted on the basis of two criteria
determined during screening. As a rst step participants will be stratied according to the degree of
tinnitus severity (gure 2 step 1). Based on their THI score [41], participants will be allocated to a low
(score < 48) or a high (score 48) tinnitus distress group. Subsequently, the decision will be made,
whether there is an indication for the application of a HA. Accordingly, the two subgroups of low and high
tinnitus distress participants will be stratied into two groups as indicated in step 2 of gure 2:
participants with an HA indication and those without an indication. If eligible participants have already
worn a HA three months before screening, they will be automatically allocated to the stratication group
of no HA indication. An equal ratio between the four strata (HA yes, THI 48; HA no, THI 48; HA yes,
THI < 48; HA no, THI < 48) is intended. In a nal step, participants will be randomly assigned to one
intervention arm (cf. gure 2 step 3). The randomization will be executed per clinical site and monitored
centrally (see section data management and study monitoring). A specic interactive web response
system (IWRS) will help investigators at the clinical sites to randomize their patients. This facilitates the
management of a large number of patients from different sites located in several countries and the
monitoring of the multicentric study with a complex design. The distribution across the four strata will be
centrally monitored during the randomization process. If a recruited and eligible participant quits the RCT
participation before randomization, this participant will be considered as a screening failure. In case an
eligible participant is already randomized to a treatment group and quits study participation, this patient
will be considered as a drop-out. The aim is to have 100 patients randomly allocated to a treatment group
per clinical center.
Interim Assessment
After six weeks of treatment, participants are required to make one interim visit at the clinical site in order
to complete several health- and tinnitus-related questionnaires. Comorbidities, concomitant medication
and treatments as well as potential adverse events are recorded. In case of adverse events directly related
to the treatment, the responsible principle investigator has to make a decision about discontinuation of
the intervention. This can happen at any time during the treatment phase, since participants will be
instructed to get in contact with the staff of the respective clinical site in case of adverse events. This
interim visit can also be conducted online via the UNITI database in order to reduce clinical visits.
Patients will get an URL-link to ll out the corresponding questionnaires. Comorbidities, concomitant
medication and treatments as well as potential adverse events will be assessed telephone call.
Final assessment/ end of treatment
After 12 weeks the treatment phase ends. Health- and tinnitus-related questionnaires are lled out and
several audiometric and tinnitometric measurements are executed.
Follow-up assessments
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The rst follow-up visit will take place 36 weeks after the baseline visit and consist of the same measures
as taken at the nal assessment/ end of treatment. Though, the implementation of all otological,
audiological or electrophysiological measures are not mandatory and can be decided by the clinical sites
individually. An additional facultative follow-up takes place 48 weeks after the baseline visit. Same
measurements are conducted as during the rst follow-up.
Data management and study monitoring
The contract research organization Excelya (www.excelya.com ) will monitor the whole trial and will
perform on-site visits in order to assess the progress of the study and to ensure that it is conducted,
recorded and reported in accordance with the protocol, the timelines, Good Clinical Practice and any other
applicable regulations.
Data collected at the clinical sites will be entered in the UNITI database and treated as securely as
possible and protected according to the latest international guidelines. In terms of data protection,
personal data will be managed according to the EU guidelines. Participants will receive a pseudo-
anonymized code, which will be used during the course of the study. Personal data will be stored at the
respective clinical sites and not entered in the UNITI database. General Data Protection Regulations
(GDPR) from the EU apply for all UNITI mobile applications. Full details of data protection and data
security can be found in the accompanying UNITI data management plan (see supplementary material).
Adverse events
Adverse events (AE) and serious adverse events (SAE) are dened according to Good Clinical Practice §3
(6, 8). Every AE during the study will be documented with respect to start/ nish date, intensity, relation to
intervention, consequences for intervention as well as what actions are taken (e.g., hospitalization). Any
SAE occurring during the treatment phase, will be recorded and reported to the local ethics committee and
the coordinator of the trial within 24 hours. If a patient reports an SAE, the intervention will be
immediately stopped. The study coordinator together with the local principal investigator of the
respective center will decide if the participant should cease the specic treatment and which further
measures are taken.
Risks associated with participation
There is a minor risk, that the interventions used could lead to an increase of subjective tinnitus
symptoms like loudness or unpleasantness. From clinical experiences, temporal increases of symptoms
occur in 10% of cases. In case of tinnitus deterioration or any other adverse event, participants can quit
the intervention without giving reason at any time. If desired they can receive support by trained medical
or psychological experts at the specic clinical site.
Since participants have to visit clinical sites several times (e.g., study visits or CBT4T groups), there might
be a slightly increased risk for a COVID-19 infection. However, safety precautions at the clinical sites
following all country-specic regulations and the fact, that the majority of the interventions can be
Page 17/32
performed at patient`s home (HA and mobile applications) keep the risk very low, nevertheless it cannot
be excluded. Conduction of the study will be done according to the regulations of the present local
hygiene plans at the respective clinical sites. As all offered treatments are well established and as their
safety prole is well known, the potential benets of participating in this study outweigh the potential
risks like a short-term increase of subjective tinnitus symptoms.
Statistical analysis
Statistical analysis will be performed by a dedicated data analysis team blinded towards the type
intervention. Several layers of analysis will be applied, on top of descriptive statistics. As primary
outcome, tinnitus improvement (change in THI score) will be compared between the single treatment and
the combinational treatment arms. Each one of the outcome measures will be compared between groups,
in terms of difference between baseline and nal follow up visit. On top of this, all different groups will be
compared between them. Aim of this comparison is to identify differences between each one of the
groups separately. Outcome measures will be handled as previously described. In addition, patients who
underwent one specic treatment, either as single or part of combinational therapy will be grouped
together, formulating four groups, representing the four different interventions (ST, HAs, CBT4T and SC)
and analyzed accordingly. This analysis will estimate the effectiveness of each one of the interventions,
regardless if they were provided alone or in combination with any other treatment. Furthermore, a
comparison of the subgroup of patients who received an intervention alone versus the subgroup
representing those who underwent the same therapy in combination with any other kind of therapy will be
conducted. For example, patients of the single treatment arm, who only received HA as intervention, will
be compared with patients from the combinational arm who received HA and any other treatment and so
forth. Tinnitus improvement will be compared between ear-mediated (HA, ST) and brain-mediated
(CBT4T, SC) types of interventions.
Regression strategies with L1 and/ or L2 penalization alongside random-effect models will also be
applied in order to evaluate which of the factors were determinative for each one of the outcome
measures. This analysis will aim to nd the important parameters for the course in each one of the
domains encountered by each one of the outcome measures
Appropriate statistical methods will be applied (t-test, ANOVA, etc.) under the supervision of
biostatisticians. Descriptive statistics will be visualized. Categorical variables will be compared with chi-
square, whereas repeated measures (pre and post treatment) will be compared with paired t-tests or
repeated measure ANOVAs, in the case of more than two groups, after assumptions testing. Otherwise,
non-parametric tests will be used. Signicance level will be set to 5%. Another objective of this RCT is the
validation of a specic Decision Support System (DSS) per patient. To this end, all cases will be grouped
post-hoc based on whether the treatment they received based on randomization happened to be identical
or not to that suggested by the DSS according to their prole. The two groups will be named DSS aligned
(+) and DSS aligned (-). Whether a patient enters one of the two groups will be a matter of coincidence
and not subject to randomization or actual timely DSS suggestion, since this system will not be ready for
Page 18/32
the RCT start. Evaluation of the DSS will be twofold. Initially, the outcome between DSS aligned (+) and
DSS aligned (-) groups will be compared with use of the outcome measures used in the RCT. Secondly,
the proportion of patients with clinically signicant improvement will be compared between the two
groups, indicating the positive and negative prognostic value of the platform respectively. The statistical
analysis plan for all study data will be nalized before closure of the database and will be published
separately.
Ethics/ ethical aspects
The study procedure has been submitted to or approved by the local ethics committees responsible for
research activities at all investigator clinical sites. Positive evaluated ethic votes for the clinical sites in
Granada, Athens, Berlin and Regensburg (combined ethics approval for clinical sites in Germany) can be
found in the supplemental material (the ethical approval from Leuven is still outstanding). Prior to start of
the study eligible patients have to give written informed consent. Each patient will get detailed and
comprehensive information about the objectives, procedures and interventions of the RCT plus potential
side effects associated with a participation as well as their right to cancel a participation at any time
during the study without any reason or detriment. Participants can request that their study data are
removed from the database and excluded from future analysis. All documentation that is needed for
possible regulatory audits, e.g. the signed ICF, cannot be deleted, even if this is requested by the patient.
Any amendments required to the protocol will be submitted to all local ethics committees.
Discussion
The present study protocol describes an international multi-center RCT for chronic tinnitus using four
different types of interventions (HA, ST, SC, CBT4T), performed either as a single treatment or a
combination of two treatments over the course of 12 weeks.
For many people affected, tinnitus constitutes a massive burden with many potential psychological and
physiological comorbidities [1,69,70], ultimately resulting in lower quality of life [71,72]. The used
interventions in the UNITI-RCT might have the potential for brief or even prolonged tinnitus suppression
as well as to help people to better cope respectively live with their tinnitus.
With its primary objective to not only evaluate single treatments but also the combination among them,
the UNITI-RCT will be the rst proper systematic RCT in tinnitus to scrutinize single and combinatory
interventions in more depth. Given the fact that numerous single-target studies have failed to establish an
effective therapy, the combination of different types of interventions allows a targeting of different
involved organ levels at the same time (AS, CNS) and might manifest in better treatment responses.
Furthermore, the UNITI-RCT attempts to overcome essential limitations of previous studies [20,21]
through a large sample size, harmonized patient selection and screening processes across the ve
participating clinical centers, standardized assessments methods and interventions across the clinical
sites, as well as large-scale data analysis strategies. Previous reviews of tinnitus treatments provide
Page 19/32
evidence that only three past RCTs exceed 250 participants [23], to the best of our knowledge the
currently largest RCT included 492 patients [18]. With the aim to investigate 500 tinnitus patients, the
UNITI-RCT has the attempt to be the largest RCT in tinnitus yet. Importantly, with the UNITI-RCT we also
include the combination of treatments.
Due to tinnitus heterogeneity [24] as well the lack of clarity about pathophysiological processes [73,74] –
up-to-now there is no cure for tinnitus [3,75]. In the majority of studies only a subgroup of tinnitus patients
demonstrate improvement [23]. It has been proposed, that precision medicine approaches should be
tackled by future tinnitus research [21,24]. The UNITI-RCT aims at making a signicant contribution to the
personalization of tinnitus treatments by means of the validation of a specic DSS. The system will be
developed during the UNITI-project [38], in order to support clinicians in choosing the optimal treatment
based on an individual patient`s prole [39]. Such a system and its underlying computational model has
not only the potential to signicantly contribute to our understanding of the tinnitus pathology, but also
improve clinical practice and the way we are trying to treat tinnitus.
It has already been suggested, that mobile applications offer a promising way for tinnitus assessment
and treatment [76–78]. Hence, several specic mobile applications will be developed for the UNITI-RCT
creating the opportunity to signicantly reduce the number of tinnitus-related clinical visits and as such
the necessary health care resources. Moreover, these mobile applications do not only provide an
ecological way to evaluate patients’ tinnitus at many different timepoints with the possibility to track
daily tinnitus uctuations and detailed treatment-related consequences, but also provide maximum
exibility in space and time from a patients’ view – potentially increasing compliance.
Taken together the UNIT-RCT with its multidisciplinary multi-center approach, standardized state-of-the-art
tinnitus interventions and assessments, novel treatment combinations and mobile applications as well as
its major contribution to personalize tinnitus treatments might not only represent a new methodological
benchmark in tinnitus trials but also provide an essential step towards a cure for tinnitus.
Status of the trial
Issue date: 17. May 2021. Protocol version no. 3. The rst stage of patient recruitment started in March
2021 with the online pre-screening. In April 2021, screening and baseline measurements started at the
clinical sites in Berlin and Regensburg. The trial including all mandatory assessments at all involved
clinical sites is due to be nished by the end 2022.
Supplementary Material
SPIRIT checklist
Ethical approvals from Germany, Spain and Athens
Informed consent form – RCT
Information sheet – RCT
Page 20/32
Informed consent form – blood sampling
Information sheet – blood sampling
UNITI data management plan
WHO trial registration dataset
Declarations
Competing interests
The authors declare that they have no conict of interest associated with this publication and there has
been no signicant nancial support that could inuence the conduction of the RCT. The used hearing aid
devices are provided by Sivantos Pte. Ltd/ WSAudiology. The devices for the measurement of acoustic
evoked potentials are provided by Interacoustic A/S. There is no inuence of any company or authority on
the design, conduction, analysis or any other details of this RCT. One employee of Sivantos Pte. Ltd/
WSAudiology is part of the External Advisory Board of the UNITI project [38], but has no inuence on the
conduction of the RCT. The results of the study are only made available to companies or external
authorities via peer-reviewed publications.
Author contributions
The authors BL, WS, MS, BM, JL, DK, RC and SS (Stefan Schoisswohl) are main responsible for the
conceptualization of the study. Author SS (Stefan Schoisswohl) wrote the main manuscript together with
WS, MS and BL. Methodological procedures were written together with corresponding experts of the UNITI
consortium: SM (hearing aid tting); PN, WS (sound therapy); MS (cognitive behavioral therapy); MS, WS
(structured counseling); SM, DK (audiometry and measures of tinnitus characteristics); JS, DK (data
analysis), JL (blood sampling); DK (electrophysiological measurements). All authors read and approved
the nal manuscript.
Funding
The UNITI project has received funding from the European Union’s Horizon 2020 Research and Innovation
Program (grant agreement number 848261).
Consent for publication
Not applicable
Ethics approval and consent to participate
As already mentioned, the study procedure has already been positively evaluated by the local ethics
committees in Granada, Athens, Berlin and Regensburg. The ethical approval documents can be found in
the supplemental material. Prior to study start/ blood sampling, all participants have to give informed
Page 21/32
consent. RCT and blood sampling information sheets and consent forms are available from the
supplemental material.
Availability of data and material
Not applicable
Abbreviations
ABR: auditory brain stem response; AE: adverse event; AMLR: auditory middle latency responses; ANOVA:
analysis of variance; AS: auditory system; ATAQ: attitudes towards amplication questionnaire; BFI-2: big
ve inventory-2; CBT4T: cognitive behavioral therapy for tinnitus; CGI-I: clinical global impression scale -
improvement; CNS: central nervous system; DNA: deoxyribonucleic acid; DSS: decision support system;
ESIT-SQ: European school of interdisciplinary tinnitus research screening questionnaire; EU: European
union; FTQ: fear of tinnitus questionnaire; GDPR: general data protection regulations; GUF: questionnaire
on hypersensitivity to sound; HA: hearing aid; ICF: informed consent form; Mini-TQ: mini tinnitus
questionnaire; MoCA: montreal cognitive assessment; PEA: proximity extension assay; PHQ-D: patient
health questionnaire for depression; RCT: randomized clinical trial;SAE: serious adverse event; SC:
structured counseling; SNV: single nucleotide variants; SOISES: social isolation electronic survey; ST:
sound therapy; TFI: tinnitus functional index; THI: tinnitus handicap inventory; TSCHQ: tinnitus sample
case history questionnaire; UNITI: unication of treatments and interventions for tinnitus patients;
WhoQol-BREF: world health organization quality of life - abbreviated
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Tables
Table 1
Eligibility Criteria
Inclusion criteria
imary complaint tinnitus
hronic tinnitus (≥ six months)
ge between 18 and 80 years
score of ≥ 18 in the Tinnitus Handicap Inventory (THI;Newman et al., 1996)– at least mild tinnitus distress
score of > 22 in the Montreal Cognitive Assessment (MoCa;Nasreddine et al., 2005)– absence of mild cognitive
pairment
bility and willingness to use the UNITI mobile applications on smartphones
penness to use a HA (if indication and allocation to HA group)
bility to understand and consent to the research (hearing ability, intellectual capacity)
bility to participate in all relevant visits (no plans for e.g., long-term holidays or pregnancy)
isting drug therapies with psychoactive substances (e.g., antidepressants or anticonvulsants) must be stable for
least 30 days at the beginning of the therapeutic intervention. The drug therapy should remain constant during
e course of the study. Necessary changes do not constitute an exclusion criterion per se, but need to be
corded.
Exclusion criteria
-    Objective tinnitus or heartbeat-synchronous tinnitusas primary complaint
-    Otosclerosis / acoustic neuroma or other relevant ear disorders with fluctuation hearing
-    Present acute infections (acute otitis media, otitis externa, acute sinusitis)
-    Meniere's disease or similar syndromes (but not vestibular migraine)
-    Serious internal, neurological or psychiatric conditions
-    Epilepsy or other disorders of the central nervous system (e.g., brain tumor or encephalitis)
-    Clinically relevant drug, medication or alcohol abuse up to 12 weeks before study start
-    Severe hearing loss – inability to communicate properly in the course of the study
-    One deaf ear
-    Missing written informed consent
-    Start of any other tinnitus related treatments, especially hearing aids, structured counseling,
sound therapy (with special devices; expecting long term effects) or cognitive behavioral therapy in
the last 3 months before the start of the study**
*Due to specific standards of the local ethics committee at the clini cal site in Granada, Spain (Servicio Andaluz de Salud) with
respect to the conduction of RCTs, all female participants will be tested with regards to an existing pregnancy
** If a HA has already been worn three months before screening, eligible candidates are allowed to participate, but are
automatically assigned to the group with no HA indication.
Page 29/32
Table 2
Schedule of assessments
Pre-
Screening
Screening
Baseline
Treatment
Start
Interim
Visit
Final Visit =
End of
treatment
Follow-
up
Additional
Follow-up
A* A   
gibility criteria A A A  
T-SQ  A  
CHQ  B  
ni TQ A A A A A A B
nitus numeric
ng scales
A A A A A B
A A A A A B
A A A A A B
oQol-BREF A A A A A B
-2  A  
I-I   A A A B
F B B B B B B
Q-D A A A A A A B
ni-SOISES  A A A A B
AQ  B** B**  
Q  B B B B B
CA A   
ndomization  A  
od sampling B***  
logical Examination A A B B
diometry A  A B B
dness match A A B B
ch match A A B B
skability A  A B B
idual Inhibition A B B B
R  A B B
LR  A B B
atment   AA A  
morbidities A A AA A A B
ncomitant
dication/ Treatment
A A AA A A B
verse Events A A A B
Page 30/32
A = mandatory, B = voluntary; ICF = Informe d Consent Form; ESIT-SQ = European School of Inte rdisciplinary Tinnitus Research
Screening Questionnaire; TSCHQ = Tinnitus Sample Case History; Mini-TQ =Mini Tinnitus Questionnaire; TFI = Tinnitus
Functional Index; THI = Tinnitus Handicap Inventory; WhoQol-BREF =World Hea lth Organization Quality of Li fe – abbreviated;
BFI-2 = Big Five Inventory-2; CGI-I =Clini cal Global Impression Scale – Improvement; GUF = Questionnaire on Hypersensitivity to
Sound; PHQ-D = Patient Health Questionnaire for Depression; SOISES =Social Isolation Electronic Survey; ATAQ = Attitudes
Towards Amplification Questionnaire; FTQ = Fear of Tinnitus Questionnai re; MoCA = Montreal Cognitive Asse ssment; ABR =
Auditory Brainstem Response; AMLR = Auditory Middle Latency Response.
Screening and Basel ine measurements as well as treatment start can be performed on the same day. In this case all measurements
are only performed once. The baseline should bemaximum 4 weeks before the treatment start, otherwise basel ine measures should
be repeated (without ESIT-SQ, TSCHQ, BFI-2, ATAQ, electrophysiol ogical measurements). *Declaration of consent (ICF) can be
digital for the pre-scree ning. **Only for participants who were allocated to a single or combinational treatment with HA. ***Blood
samples can be taken at any time point before treatment start.
Figures
Figure 1
Page 31/32
Study procedure. An overview of all study visits/ measurement points plus the corresponding time
periods between the visits is illustrated. For each study visit a deviation of +/- 7 days is allowed. In order
to preselect potentially appropriate participants, an online pre-screening preceeds the actual screening.
Screening and baseline can be performed on the same day. Baseline has to be done at maximum four
weeks before treatment start, otherwise there will be an extraordinary visit. An additional follow-up visit
48 weeks after baseline can be conducted on a voluntary basis. Blood samples can be taken at any time
point before treatment start (after informed consent) and is not mandatory for participation in the UNITI-
RCT.
Figure 2
Randomization. Eligible participants will be stratied according to their level of tinnitus distress and their
level of hearing loss. In a rst step stratication will be conducted based on the THI score into a low and
high tinnitus distress group. In the following step 2, participants’ hearing level will be used for
stratication into one group with and one group without a hearing aid indication. Patients, who are
already wearing a hearing aid for three months before screening are automatically allocated to the no
Page 32/32
hearing aid indication group. In a nal step, participants will be randomly allocated to a treatment arm
comprised of single or combinatory interventions.
Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.
Amendmend1ethicalapprovalBerlinRegensburg.pdf
Amendmend2ethicalapprovalBerlinRegensburg.pdf
SPIRITchecklist.docx
UNITIcerticateofconsentRCT.pdf
UNITIcerticateofconsentbloodsampling.pdf
UNITIdatamanagementplan.pdf
UNITIinformationsheetRCT.pdf
UNITIinformationsheetbloodsampling.pdf
WHOtrialsregistrationdataset.docx
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Although a wide range of tinnitus management interventions is currently under research and a variety of therapeutic interventions have already been applied in clinical practice, no optimal and universal tinnitus treatment has been reached yet. This fact is to some extent a consequence of the high heterogeneity of the methodologies used in tinnitus related clinical studies. In this manuscript, we have identified, summarized, and critically appraised tinnitus-related randomized clinical trials since 2010, aiming at systematically mapping the research conducted in this area. The results of our analysis of the 73 included randomized clinical trials provide important insight on the identification of limitations of previous works, methodological pitfalls or gaps in current knowledge, a prerequisite for the adequate interpretation of current literature and execution of future studies.
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Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: 1. Further establishment of multicenter and multidisciplinary collaborations; 2. Systematic reviews and syntheses of existing knowledge; 3. Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; 4. The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity.
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Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E-04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E-02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.
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Background: Sound therapy is a clinically common method of tinnitus management. Various forms of sound therapy have been developed, but there are controversies regarding the selection criteria and the efficacy of different forms of sound therapy in the clinic. Our goal was to review the types and forms of sound therapy and our understanding of how the different characteristics of tinnitus patients influence their curative effects so as to provide a reference for personalized choice of tinnitus sound therapy. Method: Using an established methodological framework, a search of six databases including PubMed identified 43 records that met our inclusion criteria. The search strategy used the following key words: tinnitus AND (acoustic OR sound OR music) AND (treatment OR therapy OR management OR intervention OR measure). Results: There are various forms of sound therapy, and most of them show positive therapeutic effects. The effect of customized sound therapy is generally better than that of non-customized sound therapy, and patients with more severe initial tinnitus respond better to sound therapy. Conclusion: Sound therapy can effectively suppress tinnitus, at least in some patients. However, there is a lack of randomized controlled trials to identify effective management strategies. Further studies are needed to identify the most effective form of sound therapy for individualized therapy, and large, multicenter, long-term follow-up studies are still needed in order to develop more effective and targeted sound-therapy protocols. In addition, it is necessary to analyze the characteristics of individual tinnitus patients and to unify the assessment criteria of tinnitus.
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The aim of this study was to investigate the prevalence of tinnitus among adolescents, and the factors known or hypothesized to be associated with tinnitus. Based on random sampling of school types and regions, a nationwide hearing survey of the first-year middle and high school students of South Korea was performed. The subjects underwent an otologic examination followed by pure tone audiometry up to 8 kHz. Questionnaires about the factors associated with hearing and tinnitus were completed by the students and their parents. Among the 1,593 subjects who completed the questionnaire and underwent pure tone audiometry, the prevalence of tinnitus was 46.0% and that of severe tinnitus was 9.1%. Tinnitus was associated with age, female gender, history of ear infection and sinusitis, leisure noise exposure due to karaoke and local-area-network gaming, alcohol consumption, and cigarette smoking. Noticeable hearing loss was not detected but participants with tinnitus complained of difficulty with sound localization, hearing in noise, and verbal working memory and were more susceptible to fatigue. The subjects with tinnitus also suffered more physical and mental health problems than did those without tinnitus. Thus, protection of the ears from noise and appropriate counseling should be considered for adolescents with tinnitus.
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Tinnitus is a common symptom of a phantom sound perception with a considerable socioeconomic impact. Tinnitus pathophysiology is enigmatic and its significant heterogeneity reflects a wide spectrum of clinical manifestations, severity and annoyance among tinnitus sufferers. Although several interventions have been suggested, currently there is no universally accepted treatment. Moreover, there is no well-established correlation between tinnitus features or patients’ characteristics and projection of treatment response. At the clinical level, this practically means that selection of treatment is not based on expected outcomes for the particular patient.
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Tinnitus is the perception of a phantom sound and the patient's reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden, with an estimated prevalence of 10%–20% among the adult population. The EU is funding a new collaborative project entitled “Unification of Treatments and Interventions for Tinnitus Patients” (UNITI, grant no. 848261) under its Horizon 2020 framework. The main goal of the UNITI project is to set the ground for a predictive computational model based on existing and longitudinal data attempting to address the question of which treatment or combination of treatments is optimal for a specific patient group based on certain parameters. Clinical, epidemiological, genetic and audiological data, including signals reflecting ear-brain communication, as well as patients' medical history, will be analyzed making use of existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance validated through a Randomized Clinical Trial (RCT) in which different patient groups will undergo a combination of tinnitus therapies targeting both auditory and central nervous systems. From a scientific point of view, the UNITI project can be summarized into the following research goals: (1) Analysis of existing data: Results of existing clinical studies will be analyzed to identify subgroups of patients with specific treatment responses and to identify systematic differences between the patient groups at the participating clinical centers. (2) Genetic and blood biomarker analysis: High throughput Whole Exome Sequencing (WES) will be performed in well-characterized chronic tinnitus cases, together with Proximity Extension Assays (PEA) for the identification of blood biomarkers for tinnitus. (3) RCT: A total of 500 patients will be recruited at five clinical centers across Europe comparing single treatments against combinational treatments. The four main treatments are Cognitive Behavioral Therapy (CBT), hearing aids, sound stimulation, and structured counseling. The consortium will also make use of e/m-health applications for the treatment and assessment of tinnitus. (4) Decision Support System: An innovative Decision Support System will be implemented, integrating all available parameters (epidemiological, clinical, audiometry, genetics, socioeconomic and medical history) to suggest specific examinations and the optimal intervention strategy based on the collected data. (5) Financial estimation analysis: A cost-effectiveness analysis for the respective interventions will be calculated to investigate the economic effects of the interventions based on quality-adjusted life years. In this paper, we will present the UNITI project, the scientific questions that it aims to address, the research consortium, and the organizational structure.
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As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: “Tinnitus” for the former and “Tinnitus Disorder” for the latter. The proposed definition then becomes “Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder “when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.”. In other words “Tinnitus” describes the auditory or sensory component, whereas “Tinnitus Disorder” reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.
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Tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating for 10-15% of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition. Animal research has revealed that sound paired with electrical somatosensory stimulation can drive extensive plasticity within the brain for tinnitus treatment. To investigate this bimodal neuromodulation approach in humans, we evaluated a noninvasive device that delivers sound to the ears and electrical stimulation to the tongue in a randomized, double-blinded, exploratory study that enrolled 326 adult subjects with chronic subjective tinnitus. Participants were randomized into three parallel arms with different stimulation settings. Clinical outcomes were evaluated over a 12-week treatment period and a 12-month post-treatment phase. For the primary endpoints, participants achieved a statistically significant reduction in tinnitus symptom severity at the end of treatment based on two commonly used outcome measures, Tinnitus Handicap Inventory (Cohen’s d effect size: 0.87 to 0.92 across arms; p<0.001) and Tinnitus Functional Index (0.77 to 0.87; p<0.001). Therapeutic improvements continued for 12 months post-treatment for specific bimodal stimulation settings. Long-term benefits lasting 12 months have not previously been demonstrated in a large cohort for a tinnitus intervention. The treatment also achieved high compliance and satisfaction rates with no treatment-related serious adverse events. These positive therapeutic and long-term results motivate further clinical trials towards establishing bimodal neuromodulation as the first clinically recommended device treatment for tinnitus.