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Background Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. Methods Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. Discussion The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. Trial registration ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis.

Tinnitus is defined as the conscious awareness of a tonal or composite noise in the absence of a corresponding external acoustic source. This international multicentre, parallel-arm, superiority, randomised controlled trial investigated whether combination therapies are superior to single interventions in the treatment of chronic subjective tinnitus. Tinnitus patients were recruited from five clinical sites across the EU and randomly assigned using a web-based system, stratified by their hearing and distress level, to single or combination treatment of 12 weeks. Cognitive-behavioural therapy, hearing aids, app-based structured counselling, or app-based sound therapy were administered either alone or as a combination of two treatments resulting in ten treatment arms. App-based treatments were delivered without direct contact or guidance from clinicians. The primary outcome was the difference in the change from baseline to week 12 in the total score of the Tinnitus Handicap Inventory (THI) between single and combination treatments in the intention-to-treat population. All statistical analysis were performed blinded to treatment allocation. 674 patients of both sexes aged between 18 and 80 years were screened for eligibility. 461 participants (190 females) with chronic subjective tinnitus and at least mild tinnitus handicap were enroled, 230 of which were randomly assigned to single and 231 to combination treatment. Least-squares mean changes from baseline to week 12 were −11.7 for single treatment (95% confidence interval [CI], −14.4 to −9.0) and −14.9 for combination treatments (95% CI, −17.7 to −12.1), with a statistically significant group difference ( p  = 0.034). Cognitive-behavioural therapy and hearing aids alone had large effect sizes, which could not be further increased by combination treatment. No serious adverse events occurred. In this trial involving patients with chronic tinnitus, all treatment arms showed improvement in THI scores from baseline to week 12. Combination treatments showed a stronger clinical effect than single treatment, however, no clear synergistic effect was observed when combining treatments. Instead, we observed a compensatory effect, where a more effective treatment offsets the clinical effects of a less effective treatment. ClinicalTrials.gov Identifier: NCT04663828. Chronic tinnitus is often treated with cognitive-behavioural therapy, hearing aids, counselling, or sound therapy, but their combined benefit is unclear. Here, the authors show, in a multicentre randomised trial, that combination treatments improve tinnitus scores more than single therapies, though benefits appear compensatory rather than synergistic.

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.

Purpose To describe the clinical, audiological, and psychometric features observed in patients with chronic tinnitus and rare variants in the ANK2 gene. Methods We report a case series of 12 patients with chronic tinnitus and heterozygous variants in the ANK2 gene. Tinnitus phenotyping included audiological (standard and high-frequency audiometry, Auditory Brainstem Responses (ABR) and Auditory Middle Latency Responses (AMLR)), psychoacoustic and psychometric assessment by a Visual Analog Scale (VAS) for tinnitus annoyance, the Tinnitus Handicap Inventory (THI), the test on Hypersensitivity to Sound (THS-GÜF), the Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale (HADS) and the Montreal Cognitive Assessment (MoCA). Results All patients reported a persistent, unilateral noise-type tinnitus, mainly described as white noise or narrowband noise. Seven patients (58%) were considered to have extreme phenotype (THI score > 76), and all patients reported some degree of hyperacusis (THS-GÜF score > 18 in 75% of patients). Seven patients scored MoCA < 26, regardless of the age reported, suggesting a mild cognitive disorder. ABR showed no significant differences in latencies and amplitudes between ears with or without tinnitus. Similarly, the latencies of Pa, Pb waves, and NaPa complex in the AMLR did not differ based on the presence of tinnitus. However, there were statistical differences in the amplitudes of Pa waves in AMLR, with significantly greater amplitudes observed in ears with tinnitus. Conclusion Patients with ANK2 variants and severe tinnitus exhibit an endophenotype featuring hyperacusis, persistent noise-like tinnitus, high-frequency hearing loss, and decreased amplitudes in AMLR. However, anxiety, depression, and cognitive symptoms vary among individuals.