Study objectives
As stated in the study protocol [1], the objectives of the UNITI-RCT are to examine whether:
(1) combination therapy is more effective than a single therapy for the treatment of chronic tinnitus;
(2) the effectiveness of the ten investigated interventions differs from each other;
(3) for the four treatment types (SC, ST, HA, CBT) the combination with another treatment is superior to the treatment alone;
(4) a certain type of intervention either alone or in combination is superior to other treatments;
(5) a combination of treatments targeting both the auditory system and the central nervous system are superior to treatments targeting only either the ear or the brain.
(6) the development of a Decision Support System (DSS), where machine learning will be used to deliver personalized suggestions for interventions aiming to maximize its efficacy.
This SAP describes how objectives 1–5 will be evaluated. All these objectives are testing for superiority of one or several treatment types over the others. The first objective, which focuses on comparing the effects of single and combinatorial treatments in general and independent from the specific intervention, will be considered the main objective to be addressed by UNITI-RCT. The development of the DSS (objective 6) will be described elsewhere.
Table 1
Overview of the planned analyses to address the objectives of the UNITI-RCT.
| Objective | Description of comparison | Contrasted groups | Primary Outcome | Secondary Outcome |
| 1 | Single versus combined | (CBT, ST, SC, HA) versus (CBT + HA, CBT + ST, CBT + SC, ST + HA, ST + SC, SC + HA) | THI change at final visit (week 12) compared to baseline | THI at interim (week 6) compared to baseline | THI at Follow Up I (week 36) compared to baseline | THI at Follow Up II (week48) compared to baseline | CGI-I at various time points (interim visit, and follow-ups at weeks 36 and 48) | TFI, Mini TQ, NRS, WHO-QoL Bref, PHQ-9, PHQ9 at various time points (interim visit, and follow-ups at weeks 36 and 48) | Dropouts, Treatment compliance |
| 2 | All ten treatment arms | CBT, ST, SC, HA, CBT + HA, CBT + ST, CBT + SC, ST + HA, ST + SC, SC + HA versus each other |
| 3 | SC single versus combined | SC versus (SC + CBT, SC + ST, SC + HA) |
| ST single versus combined | ST versus (ST + SC, ST + CBT; ST + HA) |
| HA single versus combined* | HA versus (HA + SC, HA + CBT; HA + ST) |
| CBT single versus combined | CBT versus (CBT + SC, CBT + ST, CBT + HA) |
| 4 | SC versus no SC | (SC, CBT + SC, ST + SC, SC + HA) versus (CBT, ST, HA, CBT + HA, CBT + ST, ST + HA) |
| ST versus no ST | (ST, CBT + ST, ST + HA, ST + SC,) versus (CBT, SC, HA, CBT + HA, CBT + SC, SC + HA) |
| HA versus no HA* | (HA, CBT + HA, ST + HA, SC + HA) versus (CBT, ST, SC, CBT + ST, CBT + SC, ST + SC) |
| CBT versus no CBT | (CBT, CBT + HA, CBT + ST, CBT + SC) versus (ST, SC, HA, ST + HA, ST + SC, SC + HA) |
| 5 | Combination of brain and ear targeting treatments | (CBT + HA, CBT + ST, ST + SC, SC + HA) versus (CBT, ST, SC, HA, CBT + SC, ST + HA) |
Table legend: CBT: cognitive behavior therapy; ST: sound therapy; SC structured counseling; HA: hearing aids (CBT and HA, CBT and ST, CBT and SC, ST and HA, ST and SC, SC and HA). *: only patients from the strata with HA indication are included in this analysis.
Patient Population
Each center aims to enroll 100 patients for the RCT, for a total number of 500 patients with chronic subjective tinnitus (ie., lasting for at least six months). At all sites, potential candidates are recruited via media advertising (according to local regulations) as well as on an individual basis at the clinical sites through e.g., information sheets, word of mouth, or conversations with medical staff.
Inclusion And Exclusion Criteria
Tables 2 and 3 summarize the inclusion and exclusion criteria for UNITI-RCT.
Table 2
Inclusion criteria of UNITI-RCT as specified in the study protocol [1].
| Inclusion Criteria |
| Tinnitus as the primary complaint |
| Tinnitus lasting at least 6 months |
| Age 18–80 years |
| A score ≥ 18 in the Tinnitus Handicap Inventory at Screening |
| A score greater than 22 at the Montreal Cognitive Assessment (MoCa) |
| Ability and willingness to use the UNITI mobile applications [3] on their smartphones |
| Openness to using a hearing aid (if allocation to the hearing aid stratum) |
| 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) |
| Negative pregnancy test at screening (only at the clinical site in Granada due to specific standards of the local ethics committee) |
| Existing drug therapy with psychoactive substances (e.g., antidepressants, anticonvulsants) must be stable for at least 30 days at the beginning of the therapeutic intervention. The drug therapy should remain constant during the duration of the study. Necessary changes do not constitute an exclusion criterion per se, but need to be recorded. |
Table 3
Exclusion criteria of UNITI-RCT as specified in the study protocol [1].
| Exclusion Criteria |
| Objective tinnitus or heartbeat- synchronous tinnitus as primary complaint |
| Otosclerosis / acoustic neuroma or other relevant ear disorders with fluctuation hearing |
| Present acute infections (acute otitis media, otitis externa, acute sinusitis) |
| Meniere's disease or similar syndromes with the exception of vestibular migraine |
| Serious internal, neurological or psychiatric conditions |
| Epilepsy or other central nervous system disorders (brain tumor, encephalitis) |
| Clinically relevant drug, medication or alcohol abuse up to 12 weeks before study start |
| Severe hearing loss as defined by the inability to communicate properly in the course of the study |
| At least 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 |
Outcomes
The change between the Tinnitus Handicap Inventory (THI) at the final visit and baseline (post - pre) will be used as a primary outcome measure (see Table 1). In addition to the THI, secondary outcome measures are the changes between the final visit and baseline of the tinnitus functional index (TFI [4]), the short version of the tinnitus questionnaire (mini-TQ, [5]), Tinnitus Numeric Rating Scales (NRS, [6]), World Health Organization – Quality of Life abbreviated (WHOQoL-Bref; https://www.who.int/healthinfo/survey/WHOQOL_BREF.pdf?ua=1), Clinical Global Impression Scale - Improvement (CGI-I, [7]), and Patient Health Questionnaire for Depression (PHQ-9, [9]).
Additional measures which are not defined as primary or secondary outcomes but may be used for sample description and additional analyses include: European School of Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ, [13]), tinnitus sample case history questionnaire (TSCHQ, [14]), Questionnaire on Hypersensitivity to Sound (GUF) [8], Big Five Inventory 2 (BFI-2 [15]), Montreal cognitive assessment (MoCA, also used as inclusion criteria, see above [16]), a short version of the Social Isolation Electronic Survey (Mini-SOISES, [10]), attitudes towards amplification questionnaire (ATAQ) which consists of a subset of questions from the Attitudes towards Loss of Hearing Questionnaire (ALHQ, [11]), Fear of Tinnitus Questionnaire (FTQ [12]), and audiometric and tinnitometric measurements (e.g., tinnitus loudness and frequency, maskability with minimum masking levels, and residual inhibition).
Variables Assessment
An overview of all study assessments, and the time points when they were collected is presented in Table 4. The visit window for each study visit was ± 7 days. In addition to the outcome and other clinical measures described above, the assessment included voluntary blood sampling, auditory brainstem response (ABR) and auditory middle-latency responses (AMLR) and recording of concomitant treatment/medication. The collected ABR and AMLR data and blood samples will be addressed in additional analyses to the one described here. Safety measures are otological examination, audiometry, comorbidities, and adverse effects.
Table 4
Overview of assessments for the UNITI-RCT.
| | Pre-screening | Screening | Baseline | Treatment start | Interim visit | Final visit = end of treatment | Follow-up | Additional follow-up |
| ICF | Aa | 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 | | | | | A | A | 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 | | | Bb | | | Bb | | |
| FTQ | | | B | | B | B | B | B |
| MoCA | | A | | | | | | |
| Randomization | | | A | | | | | |
| Blood sampling | | | Bc | | | | | |
| 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 |
Table legend: Table reproduced from [1] (CC BY 4.0). Interim visit: week 6; final visit: week 12; follow-up: week 36; additional follow-up: week 48. A = mandatory; B = voluntary; 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).
*Declaration of consent (ICF) can be digital for the pre-screening.
**Only for participants who were allocated to a single or combinational treatment with HA.
***Blood samples can be taken at any time point before treatment start
Intervention
Treatment conditions
The main objective of the UNITI RCT is to investigate the effects of four different interventions (SC, ST, HA, CBT) and the combinations of these interventions (CBT + HA, CBT + ST, CBT + SC, ST + HA, ST + SC, SC + HA). Internal standard operation procedures were developed, and workshop training was conducted to ensure harmonization among the participating clinical sites with regard to the procedure, technical equipment, and training of the research staff. A full description of each of the four treatments is available in the study protocol [1].
Randomization And Blinding
Eligible participants are randomly allocated to one of ten treatment arms of single or combinational treatments (see Fig. 1). In the first step, patients will be stratified into two groups according to the severity of their tinnitus distress as measured by the THI. Participants with a THI score greater or equal to 48 are allocated to a “high distress” group, whereas participants with a smaller than 48 are allocated to a “low distress” group. This stratification was performed to capture the tinnitus disorder subtype, which is marked by high tinnitus-related distress[17]. In the second step, the two subgroups of low and high tinnitus distress will be further stratified based on their degree of hearing loss into a subgroup with and without hearing aid indication. This results in four stratification groups, namely: HA indication & low tinnitus distress, HA indication & high tinnitus distress, no HA indication & low tinnitus distress, and no HA indication & high tinnitus distress (cf. Figure 1). An equal ratio of 25 patients per group per clinical site is intended, resulting in a total number of 100 patients per site. Subsequently, in each center, patients are assigned to one of the ten treatment arms according to predefined randomization tables to have appropriate ratios for the planned primary analysis/contrasts (e.g., single vs. combinatory treatment).
Table 5 shows the expected allocation of patients to each of the ten treatment arms considering the proportional ratios of the planned analysis.
Table 5
Expected randomization per center and per treatment.
| | randomized allocation of patients in Athens | randomized allocation of patients in Berlin | randomized allocation of patients in Granada | randomized allocation of patients in Leuven | randomized allocation of patients in Regensburg | Total |
| HA | 12 | 12 | 12 | 12 | 12 | 60 |
| ST | 12 | 12 | 12 | 12 | 12 | 60 |
| SC | 12 | 12 | 12 | 12 | 12 | 60 |
| CBT | 12 | 12 | 12 | 12 | 12 | 60 |
| HA + CBT | 4 | 4 | 4 | 4 | 4 | 20 |
| HA + SC | 4 | 4 | 4 | 4 | 4 | 20 |
| HA + ST | 6 | 6 | 6 | 6 | 6 | 30 |
| SC + CBT | 12 | 12 | 12 | 12 | 12 | 60 |
| ST + SC | 14 | 14 | 14 | 14 | 14 | 70 |
| ST + CBT | 12 | 12 | 12 | 12 | 12 | 60 |
| Total | 100 | 100 | 100 | 100 | 100 | 500 |
The randomization of patients takes place at each clinical site and is monitored centrally. A specific interactive web response system (IWRS) is used to support each clinical site with the randomization of their patients. This facilitates the management of many patients from different sites located in several countries and the monitoring of the multicentric study with a complex design. The distribution across the four strata is centrally monitored during the randomization process. If a recruited and eligible participant quits the RCT participation before randomization, this participant is considered a screening failure. In case an eligible participant is already randomized to a treatment group and quits study participation, this patient is considered a dropout.
The local clinical staff will enter clinical data into a central tinnitus database [6]. Patient-specific data as well as treatment types will be stored with specific pseudo-anonymized codes. The data analysis team (see section timing of analysis) will only have access to the blinded treatment codes stored in the database and will therefore be blinded to the type of treatment participants received. The statistical analysis team will have the treatment codes unblinded only after the analysis is completed by the project coordinators (SSch and WS).
General Principles Of Statistical Analysis
A p-value of < 0.05 will be considered statistically significant and parameter estimates will be presented with two-sided 95% confidence intervals.
Sample Size Calculation
A sample size of 500 participants has been calculated based on conservative estimates of the effect size from previous clinical trials delivering CBT, SC, and ST, with the aim to achieve enough statistical power to address objective 1; see the study protocol [1]. Each of the five centers will recruit 100 patients. 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 for each study site.
Timing Of Analysis
An initial data exploration is conducted during data collection to ensure the integrity (i.e., the overall completeness and accuracy) of the data stored in the database. No interim analyses are planned. Data preparation, such as data cleaning (e.g., standardizing variable names, encoding categorical variables as factors) and munging will take place for each center after the final visit of the last patient is recorded, as well as plausibility checks. Exploratory data analysis with graphical methods (e.g., histograms, bar-plots, scatterplots, graphical exploration of missing values) will also be conducted for each center after the final visit of the last patient is recorded. The initial and exploratory data analysis, as well as the analysis of the main results, will be carried out by the statistical analysis team [JS, SG, CJ, UN, MSp, ME, NW, LB] with the pseudo-anonymized treatment code, and therefore treatment blindness will be preserved. The main RCT analyses will start by the end of December 2022 and will include data from patients who have finished their treatment by the 19th of December 2022. Secondary outcome analysis is planned to occur when the 48-week follow-up period has been reached for participants included in the primary outcome analysis.
Data Sets To Be Analyzed
The intention-to-treat (ITT) population includes all participants randomized regardless of compliance with the study protocol. Unless otherwise specified, the main analyses will be conducted on an intention-to-treat basis.
Sensitivity analysis: A per-protocol analysis will be conducted to detect potential effects from non-compliance. It will include all subjects who met the requirements for treatment compliance (as described below). The main analysis will be repeated in the per-protocol population to test the robustness of the primary ITT analysis.
Subject Disposition
The flow of participants through the clinical trial stages will be shown with a diagram following the guidelines of the Consolidated Standards Of Reporting Trials (CONSORT) [18]. This will include, for each of the centers the number of participants who were screened, excluded, randomized, dropped out before treatment start (reported per treatment arm), began the intended treatment, dropped out during treatment (reported per treatment arm), completed treatment, and were analyzed for the main objective (reported per treatment arm). Additionally, protocol deviations will be presented alongside reasons.
Participant Characteristics
Baseline participant characteristics will be presented descriptively in a standardized manner as shown in Tables 7 and 8. Participants will be described based on age, sex, education attainment (ESIT-SQ), PHQ-9 scores, THI scores, TFI scores, Mini-TQ scores, WHOQoL-Bref scores, hearing loss (audiometry), and clinical tinnitus characteristics (ESIT-SQ). Descriptive analysis will consist of mean scores followed by standard deviations, as well as medians followed by minimum and maximum values for continuous variables, and frequencies followed by percentages for discrete variables. Descriptive analysis will be available for baseline, interim (6 weeks after baseline), and final visits (12 weeks after baseline). Raw data will also be reported on a longitudinal mean plot together with 95% confidence intervals.
Treatment Compliance/adherence And Protocol Deviations
Compliance with treatment protocols is defined for each treatment arm separately. For combined treatments, failing to meet the criteria for one of the arms is sufficient to identify a patient as failing to comply with the protocol. Table 6 summarizes the definitions for each of the arms. For CBT, meeting one of the two criteria presented below is sufficient to identify a patient as non-compliant.
Table 6
Definitions of non-compliance with treatment protocols.
| Treatment | Definition of non-compliance with treatment protocol |
| CBT | 1) Missing the first and second CBT session 2) participating in less than 6 of the 12 CBT sessions |
| ST | 1) having not played at least once each of the four stimuli categories |
| SC | 1) Not having completed the first six chapters of the SC |
| HA | 1) having used HA for less than 4 hours per day, on average, according to data logging |
Table legend: CBT = cognitive behavior therapy, ST = sound therapy, SC = structured counseling, HA = hearing aid.
The number and percentage of participants compliant with treatment will be presented per treatment group. Compliance is determined by App-use log files (SC, ST), hearing aid log files (HA), and participation in treatment sessions (CBT). Acceptable compliance will be defined as ≥ 50% of the recommended intervention (participation in ≥ 6 CBT sessions including the first two, using HA 4 or more hours per day, on average, according to data logging, having completed at least the first 6 chapters of SC and having played at least once each of the four ST stimuli categories). Withdrawal from/compliance with the randomized intervention will be summarized using the following variables:
-
Number of treatment discontinuations;
-
Number of patients who decided to continue with study visits even though they canceled their treatment;
-
Discontinuation reasons (where available);
-
Compliance with the intervention (in percent), as described above;
All cases of protocol deviations will lead to an exclusion of the respective participant from the main analysis. A list of deviations will be presented in a table including the treatment arm and details of the deviation. Protocol deviations are defined as any deviations from the study protocol [1], non-compliance with inclusion/exclusion criteria as checked during the standard visits (interim and end of treatment visits), non-compliance with treatment protocols, or errors in study conduct.
Concomitant Therapies
Type and frequency of concomitant medication and treatment will be categorized and presented descriptively.