Single versus Combination Treatment in Tinnitus: An International, Multicentre, Parallel-arm, Superiority, Randomised Controlled Trial

Abstract Tinnitus is associated with a variety of aetiologies, phenotypes, and underlying pathophysiological mechanisms, and available treatments have limited efficacy. A combination of treatments, addressing various aspects of tinnitus, might provide a viable and superior treatment strategy. In this international multicentre, parallel-arm, superiority, randomised controlled trial, patients with chronic subjective tinnitus were recruited from five clinical sites across the EU as part of the interdisciplinary collaborative UNITI project. Patients were 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, structured counselling, and sound therapy were administered either alone or as a combination of two treatments resulting in ten treatment arms. 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 enrolled, 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. We observed rather a compensatory effect, where a more effective treatment offsets the clinical effects of a less effective treatment. ClinicalTrials.gov Identifier: NCT04663828 .