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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 interventions 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 counseling, 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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S T U D Y P R O T O C O L Open Access
Unification of Treatments and Interventions
for Tinnitus Patients (UNITI): a study
protocol for a multi-center randomized
clinical trial
Stefan Schoisswohl
1*
, Berthold Langguth
1
, Martin Schecklmann
1
, Alberto Bernal-Robledano
2
,
Benjamin Boecking
3
, Christopher R. Cederroth
4
, Dimitra Chalanouli
5
, Rilana Cima
6
, Sam Denys
7,8,9
,
Juliane Dettling-Papargyris
10
, Alba Escalera-Balsera
11
, Juan Manuel Espinosa-Sanchez
2,11
, Alvaro Gallego-Martinez
11
,
Efi Giannopoulou
5
, Leyre Hidalgo-Lopez
12
, Michael Hummel
13
, Dimitris Kikidis
14
, Michael Koller
15
,
Jose A. Lopez-Escamez
2,11,16
, Steven C. Marcrum
17
, Nikolaos Markatos
14
, Juan Martin-Lagos
18
,
Maria Martinez-Martinez
2,11
, Marta Martinez-Martinez
2,18
, Maria Mata Ferron
2,11
, Birgit Mazurek
3
,
Nicolas Mueller-Locatelli
18
, Patrick Neff
1,19
, Kevin Oppel
10
, Patricia Perez-Carpena
2,11
, Paula Robles-Bolivar
11
,
Matthias Rose
20
, Tabea Schiele
3
, Axel Schiller
1
, Jorge Simoes
1
, Sabine Stark
3
, Susanne Staudinger
1
,
Alexandra Stege
13
, Nicolas Verhaert
7,8,9
and Winfried Schlee
1
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
interventions 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).
© The Author(s). 2021, corrected publication 2022. Open Access This article is licensed under a Creative Commons Attribution
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and indicate if changes were made. The images or other third party material in this article are included in the article's Creative
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Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need
to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.
0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence: stefanschoisswohl@yahoo.de
1
Department of Psychiatry and Psychotherapy, University of Regensburg,
Universitaetsstraße 84, 93053 Regensburg, Germany
Full list of author information is available at the end of the article
Schoisswohl et al. Trials (2021) 22:875
https://doi.org/10.1186/s13063-021-05835-z
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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
counseling, 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.
Keywords: Tinnitus, Treatment, Hearing aids, Cognitive behavioral therapy, Sound therapy, Structured counseling,
Multi-center, RCT
Background
Following a recent multidisciplinary consensus, tin-
nitusistermedasthe conscious awareness of a tonal
or composite noise for which there is no identifiable
corresponding external acoustic source[1]wherebya
continuous perception over 6 months constitutes a
chronification [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 1015% of the global
adult population are affected by this phantom sound
perception [4], whereas 23% are particularly suffer-
ing from tinnitus [5,6]. In many cases, tinnitus gen-
erates a high level of suffering and can be
accompanied by various comorbidities such as depres-
sion,anxiety,orsleepdisorders[710], explicitly de-
fined as tinnitus disorder [1]. Currently, there is no
general treatment respectively a cure for tinnitus ex-
istent. Available treatment approaches cover a broad
spectrum of interventions from pharmacology [6],
neurostimulation [11], cochlear implants [12]todif-
ferent sound therapies [13,14] or hearing aids [15,
16]. While the European guidelines for tinnitus [17]
give a weak recommendation for the application of
amplification 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 ap-
proaches exhibit the best body of evidence for the
treatment of tinnitus [18,19] with a strong recom-
mendation according to European guidelines [17].
Even though tinnitus research has been impressively
expanded over the past decade, the majority of stud-
ies suffers from methodological shortcomings such as
heterogeneous patient samples, imprecisely defined
therapeutic interventions, relatively small sample sizes,
and a lack of predefined primary outcomes and data
analysis strategies [20,21]. Beyond tackling these limita-
tions in prospective studies, interdisciplinary multi-center
randomized clinical trials (RCT) could help to further in-
crease the validity and interpretability of results.
The complexity of tinnitus with a wide variety of phe-
notypes and different etiologies plus the uncertainty
about underlying pathophysiological processes make the
quest in finding an appropriate treatment rather difficult
[3,22]. In most of the studies, only a subgroup of pa-
tients exhibits improvement to a certain intervention
ranging from 1% to more than 35%. However, currently
none of the treatment approaches has sound and univer-
sal findings [23]. Thus a common treatment for all tin-
nitus subtypes is most unlikely, highlighting the
necessity of so-called precision medicine or rather per-
sonalized treatment concepts in tinnitus [24,25]. A po-
tential proceeding would be the identification of
demographic or tinnitus-related characteristics, poten-
tially capable to predict a patients response to a cer-
tain 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
focuses mainly on a single target of the underlying
pathophysiology. At best, tinnitus treatments should in-
tegrate all involved components/ systems [27]; hence, a
combination of different therapeutic approaches could
provide further remedy. Studies focusing on combin-
atory interventions range from combinations of hearing
aids with sound generators [2830], simultaneous sound
and somatosensory stimulations [31,32], application of
counseling together with tinnitus masking termed tin-
nitus retraining therapy [13,22,33,34], to brain stimula-
tion in combination with relaxation [35] as well as
Schoisswohl et al. Trials (2021) 22:875 Page 2 of 16
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multimodal therapies [36,37], though past studies are
not capable to provide a clear superiority of combined
interventions. A systematic examination of several differ-
ent single and combinational interventions is currently
not available, highlighting the need for more profound
investigations in this regard.
The present study protocol describes the methodo-
logical procedure of the UNITI-RCT (Unification of
Treatments and Interventions for Tinnitus Patients
Randomized Clinical Trial), which constitutes the
centerpiece of the EU-funded UNITI project. The pri-
mary objective of the UNITI project is the development
of a computational model to predict patientsresponses
to distinct treatments in order to facilitate personalized
therapies in tinnitus. For a detailed overview of goals
and procedures of the UNITI project, see Schlee et al.
[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 superiority
RCT, implemented and harmonized among five 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 ther-
apy is more effective than a single therapy for the treat-
ment 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 an-
other treatment, (4) whether participants received a cer-
tain type of intervention at all (either alone or in
combination), and (5) whether the received interventions
targeted on one or two organ levelsthe ear or the CNS
(ear- vs. brain-mediated interventions). Moreover, (6)
the development of a specific DSS, which will be based
on demographic, psychological, audiological, electro-
physiological, and genetic parameters, for patient-
specific 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 in-
vestigates the effect of four different tinnitus therapy ap-
proaches 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 reg-
istered at ClinicalTrials.gov (NCT04663828; trial regis-
tration dataset in the supplemental material) and will be
completed in five different clinical sites across the Euro-
pean Union.
(1) University of Regensburg, Regensburg, Germany
(RCT coordinator)
(2) Charité Universitaetsmedizin Berlin, Berlin,
Germany
(3) Ethniko Kai Kapodistriako Panepistimo Athinon,
Athens, Greece
(4) Hospital Universitario Virgen de las Nieves/Hospital
Clinico Universitario San Cecilio, Granada, Spain
(5) 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 involv-
ing counseling, sound therapy, and CBT was used for
this purpose [18]. This study exhibited an effect size of
0.52 after 8 months when a stepped-care approach in-
cluding 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 counseling), and effect size
was estimated conservatively as about 0.26. With a sig-
nificance 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 par-
ticipants will be investigated in the course of this RCT.
Each of the five clinical sites has the objective to exam-
ine n= 100 patients with chronic subjective tinnitus for
the RCT with respect to specific 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., in-
formation sheets, word of mouth, or in conversations
with medical staff. In order to be eligible for participa-
tion, potential participants have to meet the following
criteria as outlined in Table 1.
Outcome measures and assessments
All measures, assessments, and documentations are har-
monized among the clinical sites. Besides the below
listed standardized measures and assessments,
Schoisswohl et al. Trials (2021) 22:875 Page 3 of 16
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participantscomorbidities as well as concomitant treat-
ments and medications will be recorded. All types of
medication (even over-the-counter drugs), which have
been ingested within the last 3 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, and begin and stop date.
Further, all types of treatments which have been per-
formed within the last 3 months before screening re-
spectively 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
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:
(1) Tinnitus Functional Index (TFI) [42]
(2) Mini Tinnitus Questionnaire (Mini-TQ) [43]
(3) Tinnitus numeric rating scales (NRS) [44]
(4) World Health Organization Quality of Life
abbreviated (WHOQoL-Bref; https://www.who.int/
healthinfo/survey/WHOQOL_BREF.pdf?ua=1)
(5) Clinical Global Impression Scale - Improvement
(CGI-I) [45]
(6) Patient Health Questionnaire for Depression (PHQ-
D/PHQ-9) [46,47]
Sample description and other measures
(1) European School of Interdisciplinary Tinnitus
Research Screening Questionnaire (ESIT-SQ) [48]
(2) Tinnitus Sample Case History Questionnaire
(TSCHQ) [49]
(3) Questionnaire on Hypersensitivity to Sound (GUF)
[50]
(4) Big Five Inventory-2 (BFI-2) [51]
(5) Montreal Cognitive Assessment (MoCA) [52]
(6) Social Isolation Electronic Survey (SOISES) [53]a
subset of 11 questions sensitive for tinnitus distress
change will be used, further designated as Mini-
SOISES
(7) Attitudes Towards Amplification 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]
(8) Fear of Tinnitus Questionnaire (FTQ) [55]
Electrophysiological measures
Two types of electrophysiological measures are per-
formed in the course of this RCTauditory brain stem
responses (ABR) and auditory middle latency responses
(AMLR). ABRs represent the synchronized neural activ-
ity along the auditory pathway evoked by a serial
Table 1 Eligibility criteria
Inclusion criteria Exclusion criteria
- Primary complaint tinnitus
- Chronic tinnitus (6 months)
- Age between 18 and 80 years
- A score of 18 in the Tinnitus Handicap Inventory (THI; [41] - at least
mild tinnitus distress
- A score of > 22 in the Montreal Cognitive Assessment (MoCa; [52])-
absence of mild cognitive impairment
- Ability and willingness to use the UNITI mobile applications on
smartphones
- Openness to use a HA (if indication and allocation to HA group)
- Ability to understand and consent to the research (hearing ability,
intellectual capacity)
- Ability to participate in all relevant visits (no plans for, e.g., long-term
holidays or pregnancy
a
)
- Existing drug therapies with psychoactive substances (e.g.,
antidepressants or anticonvulsants) must be stable for at least 30 days at
the beginning of the therapeutic intervention. The drug therapy should
remain constant during the course of the study. Necessary changes do
not constitute an exclusion criterion per se, but need to be recorded.
- 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)
- Menieres 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
b
a
Due to specific standards of the local ethics committee at the clinical site in Granada, Spain , with respect to the conduction of RCTs, all female participants will
be tested with regard to an existing pregnancy
b
If a HA has already been worn 3 months before screening, eligible candidates are allowed to participate, but are automatically assigned to the group with no
HA indication
Schoisswohl et al. Trials (2021) 22:875 Page 4 of 16
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presentation of acoustic stimuli (e.g., clicks). ABR is con-
sidered to be a robust electrophysiological method to as-
sess the functional integrity of the auditory pathways.
Normally, up to five waves occur in the ABR response.
The wave I of the ABR reflects activity of the spiral gan-
glion cells at the distal part of the eighth auditory nerve,
the wave II from the globular cells in the cochlear nu-
cleus, the wave III is generated by the cochlear nucleus
spherical cells 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 re-
sponses are typically less than a microvolt in amplitude
[57,58]. AMLRs are typically composed of a set of posi-
tive (P-waves) and negative (N-waves) waves. AMLRs
are sensitive potentials for the processing of low-
frequency tones. The difference found between the be-
havioral 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 standard-
ized acoustic signals while patients are lying in a quiet
room. Measurements will be performed by trained med-
ical and/ or study staff. These measurements will not be
used as outcome measures, but will be analyzed as po-
tential 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 respon-
sible 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 dif-
ferent 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 differ-
ence of two octaves (1 kHz and 4 kHz) will be consecu-
tively presented and patients have to select the
frequency which is closer to their tinnitus pitch (not in-
tensity). Next, the selected frequency plus a different fre-
quency 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 clos-
est frequency for the next round, until patients confirm
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 dif-
ferent loudness levels starting from the individual hear-
ing level (5 dB steps).
The procedures are conducted in one ear in case of
unilateral (contralateral to tinnitus percept) or symmet-
ric bilateral tinnitus and in two ears in cases of asym-
metric tinnitus.
In order to assess patientsminimum masking level, a
narrow band noise centered at the previously defined
tinnitus frequency is presented in an ascending way (5
dB steps, starting from individuals hearing threshold) ip-
silateral to the tinnitus percept until an adequate level to
cover the patientstinnitus is reached.
The phenomenon of a brief tinnitus percept suppres-
sion following acoustic stimulation is termed residual in-
hibition [60] and will be evaluated via 30-s and 2-min
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-specific regula-
tions). The blood samples are sent to the Center for
Genomics and Oncological Research (GENyO), Univer-
sidad de Granada (Granada, Spain) and the plasma sam-
ples to the Karolinska Institutet (Stockholm, Sweden) for
further analysis of genetic parameters and plasma pro-
teins 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-specific
legislations.
Peripheral blood samples from patients included in the
clinical trial will be obtained in EDTA coated tubes.
After centrifugation at 1500gduring 10 min, plasma and
cellular fractions will be separated. Plasma will be imme-
diately frozen at 80° 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 manufacturers
protocol. DNA quality will be assessed by absorbance
measurements (Nanodrop 2000c, Thermo Scientific) and
by 260/280 and 230/260 indexes to determine protein
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and salt content. DNA concentration will be determined
by a fluorimetric method (Qubit) and Quant-iT technol-
ogy (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 ×
2 bp) with a throughput 30× (90 Gb/sample). Bioinfor-
matic analysis will include alignment and mapping of
raw data to the latest updated reference genome
(GRCh38.p13), preprocessing of FASTQ and generation
of BAM files, variant calling to obtain VCF files follow-
ing GATK Best Practices guidelines, and annotation
using Ensemble Variant Effect Predictor.
Analyzing the whole genome using next-generation se-
quencing delivers a base-by-base view of all genomic al-
terations, including single-nucleotide variants (SNV),
small insertions and deletions, and large structural varia-
tions (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 rear-
rangements, 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 Euro-
pean dataset from gnomAD v3 as population database to
estimate allelic frequencies [62].
Protein analyses Protein biomarkers for patients in-
cluded in the RCT will be initially assessed by a proxim-
ity extension assay (PEA) from OLINK. 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 re-
sponse biomarker panel directed against 96 proteins im-
plicated in inflammatory diseases will be used, since
several studies have found inflammation to be involved
in various forms of hearing loss. Therefore, inflamma-
tory biomarkers could potentially be associated with tin-
nitus. 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 de-
termining tinnitus subtypes and evaluating personstreat-
ment 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 partici-
pating clinical sites in view of procedure, technical
equipment, and trained research staff. This will be
achieved via specific Standard Operation Procedure doc-
uments and a detailed step-by-step description of proce-
dures as well as the conduction of dedicated workshops
from leading experts in the particular field 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 regula-
tions for medical software (IEC 62304, IEC 82304). This
mobile application will contain a set of 64 different stim-
uli comprised of various artificial and naturalistic sounds
and an application of different state-of-the-art filter or
modulation techniques, e.g., amplitude modulated tones
or noises [63,64] as well as filtered music [65]. Intensity
and length of sound stimulation can be adjusted by the
user. Maximum loudness for all types of sound stimula-
tion will be 85 dB. Patientsbehavioral 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 confidentiality and multiple efforts will
be made in order to pseudo-anonymize the collected
data and to protect participantsidentities. 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 stratified according to their hearing
function. Patients with a hearing aid indication will rep-
resent one strata and only these patients will be random-
ized for the option hearing aid therapy.Conventional
commercially available hearing instruments will be uti-
lized with all tinnitus-specific sound interventions deac-
tivated, in order to disentangle the effect of amplification
from the effects of sound therapy. Specifically, all partici-
pants were fitted bilaterally with mini-behind-the-ear
hearing instruments (Type Signia Pure 312 7X; Sivantos
Pte. Ltd., Singapora, Republic of Singapore/ WSAudiol-
ogy, Lynge, Denmark), with acoustic coupling achieved
via non-custom, non-occluding eartips. Gain assign-
ments appropriate for each individuals hearing loss will
be applied according to the National Acoustic
Laboratories-Non-Linear 2 generic amplification pre-
scription procedure [66] and verified using probe micro-
phone measures. As it has been reported that numerous
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signal processing characteristics might significantly affect
the impact of amplification on tinnitus, all signal pro-
cessing features, excepting only acoustic feedback reduc-
tion and impulse noise reduction algorithms, will be
deactivated during the 12-week hearing aid trial. Verifi-
cation of hearing aid gain assignments and signal pro-
cessing will be performed by audiologists, hearing aid
acousticians, or trained study personnel, in accordance
with the appropriate practice guideline of the British So-
ciety of Audiology (http://www.thebsa.org.uk/
wpcontent/uploads/2018/05/REMS-2018.pdf). Partici-
pants will be encouraged to use their hearing aids for at
least 10 h per day and will be allowed to keep their hear-
ing devices following successful completion of the RCT.
Structured counseling (SC)
A standardized protocol developed from a team of psy-
chologists will provide structured patient education,
counseling, and 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:
(1) Basic facts about tinnitus
(2) Beginner facts about tinnitus
(3) Beginner facts about the brain and sound
perception
(4) Important vocabulary
(5) Myths and misconceptions about tinnitus
(6) Diagnosis of tinnitus
(7) Special types of tinnitus
(8) Therapeutic approaches
(9) Psychology of tinnitus
(10)My behavior and my tinnitus
(11)The science on tinnitus
(12)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 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 ac-
cording to the General Data Protection Regulation
(GDPR, 2016/679). Patients will be encouraged to use
the specifically 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 psych-
ologist or psychotherapists by training. CBT4T will be
performed in weekly face-to-face group meetings á 1.5-2
h 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 con-
cept of exposure therapy in anxiety disorders or chronic
pain (cognitive restructuring via exposition to fear ex-
pectations) 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 five clinical
sites as well as in patientshomes. All patients have to
make at least four visits in the respective clinical sites
over a period of at least 10 months consisting of screen-
ing, baseline visit, interim assessment, final visit at treat-
ment end, and a follow-up visit 36 weeks after the
baseline assessment. Patients who will be randomly
assigned to CBT4T have to additionally visit the respect-
ive clinical site twelve times in order to participate in
the CBT sessions. All other treatments are conducted
without local restrictions.
Screening, baseline, and treatment start can be per-
formed on the same day. In this case, relevant assess-
ments are only performed once. Furthermore, an
additional visit in the screening period can be added for
purposes of screening/ baseline procedures. Prior to the
first 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 be-
fore 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 first (e.g., HA
and CBT4T). Moreover, a facultative additional follow-
up assessment 48 weeks after baseline measurements is
planned. If a patient drops out for any reason or wishes
to discontinue the treatment prematurely, there is the
possibility to continue with study visit participation.
For each study visit, a deviation of ± 7 days is permit-
ted. Figure 1gives an overview of the study procedure,
while in Table 2the assessments for all measurement
points are outlined. In the following sections, each visit
is shortly described in a chronological order.
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Pre-screening
Due to the investigation of a rather large and specific
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 efficient eligi-
bility check (for an overview of study eligibility cri-
teria see Table 1). Access to the pre-screening survey
will be provided via a URL link to interested candi-
dates. Before start of the pre-screening, candidates
will be provided with information about study aim,
procedure, and participation requirements. Herein-
after, participants have to confirm 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-digit code, have to contact the
respective study center, and leave their patient-code
and phone number. Within 7 days, patients will get
their results about eligibility and, if applicable, infor-
mation about the subsequent screening assessment.
Eligible candidates who accept the screening assess-
ment invitation will be sent a Patient Information
Leaflet and Informed Consent Form (ICF) by regular
mail, to assure they have sufficient 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 in-
formed about purpose, procedure, and potential risks or
benefits of the trial by a member of the local study team
Fig. 1 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 precedes
the actual screening. Screening and baseline can be performed on the same day. Baseline has to be done at maximum 4 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
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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 ma-
terial. Screening will be conducted at the respective
clinical sites. During screening, inclusion and exclusion
criteria (cf. Table 1) are verified 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, partici-
pants undergo a set of otological, audiometric, and
Table 2 Schedule of assessments
Pre-screening Screening Baseline Treatment
start
Interim
visit
Final visit = end
of treatment
Follow-up Additional
follow-up
ICF A
a
A
Eligibility criteria A A A
ESIT-SQ A
TSCHQ B
Mini TQ A A A A A A B
Tinnitus numeric rating scales A A A A A B
TFI A A A A A B
THI A A A A A A B
WhoQol-BREF A A A A A B
BFI-2 A
CGI-I AA A B
GUF B B B B B B
PHQ-D A A A A A A B
Mini-SOISES A A A A B
ATAQ B
b
B
b
FTQ B B B B B
MoCA A
Randomization A
Blood sampling B
c
Otological examination A A B B
Audiometry A A B B
Loudness match A A B B
Pitch match A A B B
Maskability A A B B
Residual inhibition A B B B
ABR A B B
AMLR A B B
Treatment A A A
Comorbidities A A A A A A B
Concomitant medication/ treatment A A A A A A B
Adverse events A A A B
Amandatory; Bvoluntary; ICF Informed Consent Form; ESIT-SQ European School of Interdisciplinary 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 Health Organization
Quality of Life abbreviated; BFI-2 Big Five Inventory-2; CGI-I Clinical 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 Questionnaire; MoCA Montreal Cognitive Assessment; ABR Auditory Brainstem Response; AMLR Auditory Middle Latency Response
Screening and Baseline 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, baseline measures should be repeated (without ESIT-SQ, TSCHQ, BFI-2, ATAQ,
electrophysiological measurements).
a
Declaration of consent (ICF) can be digital for the pre-screening.
b
Only for participants who were allocated to a single or
combinational treatment with HA.
c
Blood samples can be taken at any time point before treatment start
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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, sev-
eral baseline measures consisting of tinnitus- and health-
related questionnaires and electrophysiological measure-
ments are conducted. Following baseline measurements,
participants are randomly allocated to a treatment group
(please see section Stratification and randomization
below) and informed about the specific treatment they
receive.
Stratification and randomization
Participants will be randomly assigned to one treatment
arm comprised of a single or combinational type of
intervention as exemplified in Fig. 2. Stratification will
be conducted on the basis of two criteria determined
during screening. As a first step, participants will be
stratified according to the degree of tinnitus severity
(Fig. 2, step 1). Based on their THI score [41], partici-
pants 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
stratified into two groups as indicated in step 2 of Fig. 2:
participants with an HA indication and those without an
indication. If eligible participants have already worn a
HA 3 months before screening, they will be automatic-
ally allocated to the stratification group of no HA indica-
tion. 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 final step, participants will be
randomly assigned to one intervention arm (cf. Fig. 2,
step 3). The randomization will be executed per clinical
Fig. 2 Randomization. Eligible participants will be stratified according to their level of tinnitus distress and their level of hearing loss. In a first
step, stratification 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 stratification into one group with and one group without a hearing aid indication. Patients, who are already
wearing a hearing aid for 3 months before screening are automatically allocated to the no hearing aid indication group. In a final step,
participants will be randomly allocated to a treatment arm comprised of single or combinatory interventions
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site and monitored centrally (see section Data manage-
ment and study monitoring). A specific 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 dif-
ferent sites located in several countries and the monitor-
ing of the multicentric study with a complex design. The
distribution across the four strata will be centrally moni-
tored during the randomization process. If a recruited
and eligible participant quits the RCT participation be-
fore 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 allo-
cated to a treatment group per clinical center.
Interim assessment
After 6 weeks of treatment, participants are required to
make one interim visit at the clinical site in order to
complete several health- and tinnitus-related question-
naires. Comorbidities, concomitant medication, and
treatments as well as potential adverse events are re-
corded. In case of adverse events directly related to the
treatment, the responsible principle investigator has to
make a decision about discontinuation of the interven-
tion. This can happen at any time during the treatment
phase, since participants will be instructed to get in con-
tact 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 a URL link to fill out the corre-
sponding 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 filled out, and several
audiometric and tinnitometric measurements are
executed.
Follow-up assessments
The first follow-up visit will take place 36 weeks after
the baseline visit and consists of the same measures as
taken at the final 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 add-
itional facultative follow-up takes place 48 weeks after
the baseline visit. Same measurements are conducted as
during the first follow-up.
Data management and study monitoring
The contract research organization Excelya (www.
excelya.com) will monitor the whole trial and will per-
form 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 Regula-
tions (GDPR) from the EU apply for all UNITI mobile
applications. Full details of data protection and data se-
curity can be found in the accompanying UNITI data
management plan (see supplementary material). Any dis-
closure of study data for scientific purposes will only be
made in anonymous form.
Adverse events
Adverse events (AE) and serious adverse events (SAE)
are defined according to Good Clinical Practice §3 (6, 8).
Every AE during the study will be documented with re-
spect to start/ finish date, intensity, relation to interven-
tion, consequences for intervention, and what actions
are taken (e.g., hospitalization). Any SAE occurring dur-
ing the treatment phase will be recorded and reported to
the local ethics committee and the coordinator of the
trial within 24 h. If a patient reports an SAE, the inter-
vention will be immediately stopped. The study coordin-
ator together with the local principal investigator of the
respective center will decide if the participant should
cease the specific 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 giv-
ing reason at any time. If desired they can receive sup-
port by trained medical or psychological experts at the
specific 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
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all country-specific regulations and the fact that the ma-
jority of the interventions can be performed at patients
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 profile is well known, the potential bene-
fits of participating in this study outweigh the potential
risks like a short-term increase of subjective tinnitus
symptoms.
Statistical analysis
The statistical analysis plan for the study data will be fi-
nalized before all data is collected as well as before the
closure of the UNITI database and will be published sep-
arately. Hence, the following statistical analysis section
provides only a brief excerpt.
Statistical analysis will be performed by a dedicated
data analysis team blinded to the type of intervention.
This will be accomplished by pseudo-anonymizing the
treatment codes, which will only be available to the
center-specific investigator responsible for the
randomization. The final sample size was estimated
through power calculation as already outlined above, to
address the main contrast of interest, that is, whether
there is a statistically significant difference in the pri-
mary outcome when comparing single and combinatory
intervention. Several layers of analysis will be applied, on
top of descriptive statistics. As primary outcome, tin-
nitus improvement (change in THI score) will be com-
pared 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 end of treatment re-
spectively final follow-up visit. On top of this, all differ-
ent groups will be compared among each other. 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 specific treatment, either as single
or part of combinational therapy will be grouped to-
gether, formulating four groups, representing the four
different interventions (ST, HAs, CBT4T, and SC) and
analyzed accordingly. This analysis will estimate the ef-
fectiveness of each one of the interventions, regardless if
they were provided alone or in combination with any
other treatment. Furthermore, a comparison of the sub-
group 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 interven-
tion, will be compared with patients from the
combinational arm who received HA and any other
treatment and so forth. Tinnitus improvement will be
further compared between ear-mediated (HA, ST) and
brain-mediated (CBT4T, SC) types of interventions.
Appropriate statistical methods will be applied (t-test,
ANOVA, etc.) under the supervision of biostatisticians.
Descriptive statistics will be used for the primary and
secondary outcomes, as well as included covariates. Cat-
egorical variables will be compared with chi-square tests,
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
testing for distributional assumptions. Non-parametric
tests will be used if the assumptions of parametric tests,
such as equal variance between groups and Gaussian
distributions, are not met. These tests will be used to
evaluate the primary outcome across timepoints (e.g.,
baseline, interim visit, final visit, follow-up visit). Regres-
sion strategies with random-effect models will also be
applied in order to evaluate which of the factors were
determinative for each one of the outcome measures. To
this end, socio-demographics, as well as questionnaires
quantifying depression and tinnitus-related distress col-
lected at baseline, will be used as covariates. Several
hierarchical models will be created using the lme4 pack-
age in R. The main goal will be to identify which base-
line predictors are associated with the THI score by the
end of treatment. The first set of models will compare
treatments with and without hearing aids (CBT vs. CBT
+ HA, ST vs. ST + HA, SC vs. SC + HAs). The second
set of models will assess the effect of baseline predictors
on the THI by the end of the treatment in single and
combinatorial treatments (SC + CBT, ST + SC, ST +
CBT). Next, individual treatments will be compared
against each other (CBT vs. HA vs. ST vs. SC). Finally,
treatments will be divided into ear-mediated (e.g., HA
and ST) and brain-mediated (e.g., CBT and SC). All
models will have each center encoded as a random fac-
tor. Models will be adjusted with the covariates as de-
scribed above. These analyses will aim to find the
important parameters for the course in each one of the
domains encountered by each one of the outcome mea-
sures. Significance level will be set to 5% for all analyses.
Another objective of this RCT is the validation of a spe-
cific 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 profile. 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 the RCT start. Evaluation of the DSS will be
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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 significant im-
provement will be compared between the two groups,
indicating the positive and negative prognostic values of
the platform respectively.
Ethics/ ethical aspects
The study procedure has been submitted to and ap-
proved by the local ethics committees responsible for re-
search activities at all investigator clinical sites. Positive
evaluated ethic votes for the clinical sites in Granada,
Athens, Berlin, Regensburg, and Leuven (combined eth-
ics approval for clinical sites in Germany) can be found
in the supplemental material. Prior to start of the study
eligible patients have to give written informed consent.
Each patient will get detailed and comprehensive infor-
mation about the objectives, procedures, and interven-
tions of the RCT plus potential side effects associated
with a participation as well as their right to cancel a par-
ticipation at any time during the study without any rea-
son 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, can-
not be deleted, even if this is requested by the patient.
Any changes required to the protocol are discussed and
decided jointly in a dedicated meeting of the responsible
PIs. All amendments will be prepared by the RCT co-
ordinator team in Regensburg and submitted to all local
ethics committees.
Discussion
The present study protocol describes an international
multi-center RCT for chronic tinnitus using four differ-
ent types of interventions (HA, ST, SC, CBT4T), per-
formed 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 physio-
logical 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 evaluate not only single
treatments but also the combination among them, the
UNITI-RCT will be the first proper systematic RCT in
tinnitus to scrutinize single and combinatory interven-
tions in more depth. Given the fact that numerous
single-target studies have failed to establish an effective
therapy, the combination of different types of interven-
tions 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 five participating clinical
centers, standardized assessments methods, and inter-
ventions across the clinical sites, and large-scale data
analysis strategies. Previous reviews of tinnitus treat-
ments provide evidence that only three past RCTs ex-
ceed 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 major-
ity of studies, only a subgroup of tinnitus patients dem-
onstrates improvement [23]. It has been proposed that
precision medicine approaches should be tackled by fu-
ture tinnitus research [21,24]. The UNITI-RCT aims at
making a significant contribution to the personalization
of tinnitus treatments by means of the validation of a
specific 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
patients profile [39]. Such a system and its underlying
computational model has not only the potential to sig-
nificantly 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 treat-
ment [7678]. Hence, several specific mobile applica-
tions will be developed for the UNITI-RCT creating the
opportunity to significantly reduce the number of
tinnitus-related clinical visits and as such the necessary
health care resources. Moreover, these mobile applica-
tions do not only provide an ecological way to evaluate
patientstinnitus at many different timepoints with the
possibility to track daily tinnitus fluctuations and de-
tailed treatment-related consequences, but also provide
maximum flexibility in space and time from a patients
viewpotentially increasing compliance.
Taken together, the UNIT-RCT with its multidiscip-
linary multi-center approach, standardized state-of-the-
art tinnitus interventions and assessments, novel treat-
ment combinations, and mobile applications as well as
its major contribution to personalize tinnitus treatments
might not only represent a new methodological bench-
mark in tinnitus trials but also provide an essential step
towards a cure for tinnitus.
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Status of the trial
Issue date: 04. November 2021. Protocol version no. 3.
The first stage of patient recruitment started in March
2021 with the online pre-screening. In April 2021,
screening and baseline measurements started at the clin-
ical sites in Berlin and Regensburg. In June 2021, these
measurements started at the clinical site in Granada and
Athens as well. The trial including all mandatory assess-
ments at all involved clinical sites is due to be finished
by the end 2022.
Abbreviations
ABR: Auditory brain stem response; AE: Adverse event; AMLR: Auditory
middle latency responses; ANOVA: Analysis of variance; AS: Auditory system;
ATAQ: Attitudes Towards Amplification Questionnaire; BFI-2: Big Five
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: Unification of Treatments and Interventions for Tinnitus
Patients; WhoQol-BREF: World Health Organization Quality of Life -
abbreviated
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1186/s13063-021-05835-z.
Additional file 1. Ethical approvals from Germany, Spain, Greece and
Belgium. Informed consent form RCT. Information sheet RCT.
Informed consent form blood sampling. Information sheet blood
sampling. UNITI data management plan. WHO trial registration dataset.
Authorscontributions
The authors BL, WS, MS, BM, JL-E, 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 ex-
perts of the UNITI consortium: SM (hearing aid fitting); PN, WS (sound ther-
apy); MS (cognitive behavioral therapy); MS, WS (structured counseling); SM,
DK (audiometry and measures of tinnitus characteristics); JS, DK (data ana-
lysis), JL-E (blood sampling); DK (electrophysiological measurements). All au-
thors read and approved the final manuscript.
Funding
The UNITI project has received funding from the European Unions Horizon
2020 Research and Innovation Program (grant agreement number 848261).
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable
Declarations
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, Leuven,
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 consent. RCT and blood sampling information sheets
and consent forms are available from the supplemental material.
Consent for publication
Not applicable
Competing interests
The authors declare that they have no conflict of interest associated with
this publication and there has been no significant financial support that
could influence 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 influence 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 influence 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 details
1
Department of Psychiatry and Psychotherapy, University of Regensburg,
Universitaetsstraße 84, 93053 Regensburg, Germany.
2
Department of
Otolaryngology, Instituto de Investigacion Biosanitaria Ibs.GRANADA, Hospital
Universitario Virgen de las Nieves, Granada, Spain.
3
Tinnitus Center, Charité-
Universitätsmedizin Berlin, corporate member of Freie Universität Berlin und
Humboldt Universität Berlin, Berlin, Germany.
4
Department of Physiology and
Pharmacology, Karolinska Institutet, Stockholm, Sweden.
5
EXCELYA Hungary
Kft., Budakalász, Hungary.
6
Department of Health Psychology, Katholieke
Universiteit Leuven, Leuven, Belgium.
7
Department of Neurosciences,
Research group Experimental Oto-Rhino-Laryngology, University of Leuven,
Leuven, Belgium.
8
Department of Otorhinolaryngology - Head and Neck
surgery, University Hospitals Leuven, Leuven, Belgium.
9
Multidisciplinary
University Center for Speech-Language Pathology and Audiology, University
Hospitals Leuven, Leuven, Belgium.
10
Terzo-Institute for Applied Hearing
Research, ISMA, Sonneberg, Germany.
11
Otology & Neurotology Group CTS
495, Department of Genomic Medicine, GENYO, Center for Genomics and
Oncological Research: Pfizer/University of Granada/Andalusian Regional
Government, PTS Granada, Granada, Spain.
12
Department of Mental Health,
Hospital Universitario Virgen de las Nieves, Granada, Spain.
13
Central Biobank
Charité, Charité- Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin und Humboldt Universität Berlin, Berlin, Germany.
14
Department of Otolaryngology, Head and Neck Surgery, National and
Kapodistrian University of Athens, Hippocrateion General Hospital, Athens,
Greece.
15
Center for Clinical Studies, University Hospital Regensburg,
Regensburg, Germany.
16
Department of Surgery, Division of Otolaryngology,
Universidad de Granada, Granada, Spain.
17
Department of Otolaryngology,
University Hospital Regensburg, Regensburg, Germany.
18
Department of
Otolaryngology, Instituto de Investigacion Biosanitaria ibs. GRANADA,
Hospital Universitario Clinico San Cecilio, Granada, Spain.
19
Center for
Cognitive Neuroscience and Department of Psychology, University of
Salzburg, Salzburg, Austria.
20
Department of Psychosomatic and
Psychotherapy, Charité- Universitätsmedizin Berlin, corporate member of
Freie Universität Berlin und Humboldt Universität Berlin, Berlin, Germany.
Received: 28 May 2021 Accepted: 15 November 2021
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... Tinnitus heterogeneity has been identified as a major source of inconsistencies in the literature [9]. Focusing on specific characteristics of tinnitus thus constitutes the first step towards improving tinnitus research reproducibility and comparability, and subsequent design and patient-specific adaptation of treatment strategies [18]. ...
... Beyond these specifics the reproducibility of tinnitus studies is also hindered by the However, there is a general effort in the community to conduct studies with larger cohorts, targeting sub-types of tinnitus in terms of duration or etiology, and to standardise approaches to mitigate the remaining reproducibility issues in tinnitus research [10,18]. ...
... With the sensorimotor-auditory network, we found differences in connectivity with the right paracingulate gyrus (5,26,41), the right middle temporal gyrus (63, À51, 04), and the right precentral gyrus (À50, 4, 15). In the connectivity with the frontoparietal network, differential connectivity between the two groups was found with the right medial frontal gyrus (40,18,34). Coordinates are reported in MNI system after DARTEL registration ( Table 2). ...
Thesis
Tinnitus, the subjective experience of sound outside any external auditory stimulus, is a recognised public health issue, with a 15% prevalence, a high diversity of causes and manifestations, and the potential for severe quality of life impairment. Neuroscientists and clinicians are faced with the challenge of distinguishing tinnitus perception from its associated distress, which is the main target of current treatment options. It is now well established that tinnitus perception involves dysfunctional cerebral activity patterns within and beyond the auditory pathway: tinnitus is increasingly viewed as a complex brain network disorder. Recent findings have linked tinnitus perception of acoustic trauma origin to middle ear dysfunction and identified the parietal operculum, and in particular, its third subdivision (OP3) as determined by cytoarchitectonic findings, as the central representation of this dysfunction.In this thesis, we question the role of OP3 as a potential key region in a cortical network underlying noise-induced tinnitus. First, we explored non-invasive MRI connectivity measures, and then we strove to verify these findings using invasive high spatiotemporal resolution sEEG, and to obtain a direct signature of noise-induced tinnitus in OP3.To examine the role of OP3 as part of a functional brain network, while limiting the heterogeneity and distress-related biases, we focused specifically on a homogenous group of non-bothersome tinnitus participants and conducted a seed-based resting-state fMRI connectivity analysis. The results from this study highlighted a specific connection between OP3 and a dorsal prefrontal region, suggesting the involvement of top-down cognitive control mechanisms in tinnitus, as further discussed in an article published in Brain Connectivity. To establish the position of OP3 within a structural network, and the influence of tinnitus perception on it, we used diffusion MRI and tractography in a bundle-specific approach. We highlighted tinnitus-related differences in white matter tract density along the uncinate fascicle and the inferior fronto-occipital fascicle, evocative of both dorsal and ventral stream alterations, as documented in an article published in NeuroImage: Clinical.The second aim of this thesis was to obtain a form of ground truth evidence of tinnitus perception, thus moving to a higher spectro-temporal scale while preserving spatial resolution. This was provided by using intracranial recordings in three different frameworks. First, we examined the cortico-cortical connectivity of OP3 evoked by low-frequency stimulation as provided by the F-TRACT database. This analysis was published as part of a review article on OP3 with a focus on tinnitus, in Brain Sciences. Then, we questioned the specificities of erroneous sound perceptions separated into hallucinations, resembling tinnitus, and illusions. Here, OP3 was found to be part of both an illusion and a hallucination network of high-frequency modulations, however, hallucinations were found to present a specific involvement of the limbic system. These results, interesting from the point of view of epilepsy, tinnitus, and schizophrenia who share fantom auditory percept semiology, were submitted as a publication in Neurology. Finally, we proposed a pseudo-tinnitus paradigm to provide verification of the main hypothesis of this thesis. Preliminary results provide evidence of the involvement of OP3 in the perception of the percussive stimulus, which is proposed to originate not from the sound processing stream, but from the somatosensory stream of the middle ear. This protocol is ongoing and has received support from the Fondation pour l'Audition to be continued for another year.Taken together, this thesis supports the view that OP3 plays a significant role in tinnitus as part of the network dealing with tinnitus-related somatosensory disturbances, and validates OP3 as a relevant neuromodulation target for tinnitus treatment.
... UNITI is a research and innovation project which aims towards a unification of treatments and interventions for tinnitus [12]. In the context UNITI, a randomized controlled trial (RCT) [13], with the largest number of participants so far in tinnitus research worldwide, is being conducted and all the patient's data are systematically collected and stored in a common repository. All these available data are harmonized and integrated in order to be utilized for the development of a clinical decision support system (CDSS) [14]. ...
... In the context of UNITI's RCT [13] (https://clinicaltrials.gov/ct2/show/NCT04663828), which is currently running, four widely-used interventions for tinnitus and their combination will be included. In more details, these include cognitive behavioral treatment, sound therapy, structured counselling, and hearing aid fitting [12]. ...
Conference Paper
Tinnitus is the conscious perception of a phantom sound in absence of an external or internal stimulus. More than 1 in 7 adults in the EU experience tinnitus and for a large proportion of them tinnitus is an intrusive, persistent, and disabling condition, which impairs their life quality. Therefore, tinnitus is posed as a major global burden, which requires a precision-medicine approach in terms of treatments that are tailored to individual patients, due to its high heterogeneity. UNITI is a research and innovation project which aims towards this goal, unifying treatments and interventions for tinnitus. In the context UNITI, a randomized controlled trial (RCT) is being conducted and all the participants' data will be utilized for the development of a clinical decision support system (CDSS). This CDSS will predict the optimal therapeutic intervention for a tinnitus patient based on their profile. In this paper, we present a preliminary study of the CDSS model development process. We describe the available input data, the pre-processing steps conducted, the algorithms tested to model the CDSS' prediction, the models' results, and the future work in the context of this project. The R2 score of the selected model is currently 0.65, indicating that its development process is in the right direction but further tuning and hyperparameter optimization is needed. Clinical Relevance- The proposed model will be integrated in a CDSS aiming at indicating the optimal treatment strategy for a tinnitus patient based their personal profile.
... Such an educational counseling approach aims to promote self-help capacities of the patients and enhance patient empowerment. In principle, educational counseling can be applied as a solitary therapy or in combination with other clinical interventions [12]. ...
Article
Full-text available
Tinnitus is an auditory phantom perception in the ears or head in the absence of a corresponding external stimulus. There is currently no effective treatment available that reliably reduces tinnitus. Educational counseling is a treatment approach that aims to educate patients and inform them about possible coping strategies. For this feasibility study, we implemented educational material and self-help advice in a smartphone app. Participants used the educational smartphone app unsupervised during their daily routine over a period of four months. Comparing the tinnitus outcome measures before and after smartphone-guided treatment, we measured changes in tinnitus-related distress, but not in tinnitus loudness. Improvements on the Tinnitus Severity numeric rating scale reached an effect size of 0.408, while the improvements on the Tinnitus Handicap Inventory (THI) were much smaller with an effect size of 0.168. An analysis of user behavior showed that frequent and intensive use of the app is a crucial factor for treatment success: participants that used the app more often and interacted with the app intensively reported a stronger improvement in the tinnitus. Between study allocation and final assessment, 26 of 52 participants dropped out of the study. Reasons for the dropouts and lessons for future studies are discussed in this paper.
Article
Objective To review current information about diagnosis and management of tinnitus aiming to identify opportunities for achieving a cost-effective, efficient, evidence-based approach that meets the needs of tinnitus sufferers. Data Sources PubMed/MEDLINE. Review Methods In total, 249 relevant published reports were reviewed. Pertinent keywords and MeSH terms identified reports via PubMed and EMBASE. Acknowledged experts were consulted on ways to improve tinnitus management. Conclusions There may be opportunities to improve evaluation and management of patients with tinnitus using modern modes of communication and a multidisciplinary therapeutic approach. Implications for Practice Tinnitus can adversely affect quality of life while being time-consuming and costly to evaluate and manage. Based on both personal experience and the reports of others, patients with tinnitus who choose to see a physician primarily want to know two things: (1) that the tinnitus that is so distressing will not remain at the same level of severity forever and (2) that something can be done to help cope with the tinnitus that is so annoying. Recent advancements in internet communications, social media, information technology, artificial intelligence, machine learning, holistic medical care, mind-body integrative health care, and multidisciplinary approaches in medical therapeutics may be possibly making new ways of meeting the needs of patients with tinnitus.
Article
Full-text available
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.
Article
Full-text available
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.
Article
Full-text available
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.
Article
Full-text available
Tinnitus is a complex and heterogeneous psycho-physiological disorder responsible for causing a phantom ringing or buzzing sound albeit the absence of an external sound source. It has a direct influence on affecting the quality of life of its sufferers. Despite being around for a while, there has not been a cure for tinnitus, and the usual course of action for its treatment involves use of tinnitus retaining and sound therapy, or Cognitive Behavioral Therapy (CBT). One positive aspect about these therapies is that they can be administered face-to-face as well as delivered via internet or smartphone. Smartphones are especially helpful as they are highly personalized devices, and offer a well-established ecosystem of apps, accessible via respective marketplaces of differing mobile platforms. Note that current therapeutic treatments such as CBT have shown to be effective in suppressing the tinnitus symptoms when administered face-to-face, their effectiveness when being delivered using smartphones is not known so far. A quick search on the prominent market places of popular mobile platforms (Android and iOS) yielded roughly 250 smartphone apps offering tinnitus-related therapies and tinnitus management. As this number is expected to steadily increase due to high interest in smartphone app development, a contemporary review of such apps is crucial. In this paper, we aim to review scientific studies validating the smartphone apps, particularly to test their effectiveness in tinnitus management and treatment. We use the PRISMA guidelines for identification of studies on major scientific literature sources and delineate the outcomes of identified studies.
Article
Full-text available
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.
Article
Full-text available
Tinnitus, the perception of sound in the absence of a corresponding sound, and the distress caused by it, is rarely a static phenomenon. It rather fluctuates over time depending on endogenous and exogenous factors. The COVID-19 pandemic is a potential environmental stressor that might influence the individually perceived tinnitus distress. Since not all people are affected by the pandemic in the same way, the situation allows one to identify environmental factors and personality traits that impact tinnitus distress differently. In our study, 122 tinnitus patients were included at two time points: in the year 2018 and during the German lockdown in April 2020. We assessed tinnitus-related distress, depressive symptoms, personality characteristics and the individual perception of the pandemic situation. On average, there was only a small increase of tinnitus distress with heterogeneous changes during the lockdown. People perceiving the situation as generally stressful with increased grief, frustration, stress and nervousness reported the worsening of tinnitus distress. People with high values in neuroticism also reported the worsening of tinnitus distress, while the personality traits extraversion, conscientiousness and openness seemed to be a protection factor. The study identifies factors that influence tinnitus distress change during a pandemic and spots those patients that need specific help in the pandemic situation.
Chapter
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.
Chapter
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.
Chapter
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.
Article
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.