Single versus Combination Treatment in Tinnitus: A Randomized, Multicenter Trial

Background: Tinnitus is associated with a variety of etiologies, 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. Methods: In this multicenter, parallel-arm, randomized controlled clinical trial, patients with chronic subjective tinnitus were randomly assigned to single or combination treatment of 12 weeks each. Cognitive-behavioral therapy, hearing aids, structured counseling and sound therapy were administered either alone or as a combination of two treatments resulting in 10 treatment arms. The primary endpoint was the difference in the change from baseline to week 12 in the total score of the Tinnitus Handicap Inventory between single and combination treatments. Results: Out of 461 enrolled patients 230 were assigned to single and 231 to combination treatment. Least-squares mean changes from baseline to week 12 were -11.7 for single (95% confidence interval [CI], -14.4 to -9.0) and -14.9 for combination treatments (95% CI, -17.7 to -12.1), with a significant between-group difference (p=0.034). Sound therapy alone had the lowest effect size. In contrast, cognitive-behavioral therapy and hearing aids alone had large effect sizes, which could not be further increased by combination treatment. Conclusions: In this trial involving patients with chronic tinnitus, all treatment arms showed improvement in THI scores from baseline to week 12. No clear synergistic effect was observed when combining treatments, but rather a compensatory effect, where a more effective treatment offsets the clinical effects of a less effective treatment. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04663828 ### Clinical Protocols ### Funding Statement This clinical trial received funding from the European Unions Horizon 2020 Research and Innovation Program (grant agreement number 848261) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was independently approved by the following ethics committees: University of Regensburg, Regensburg, Germany (combined ethical approval for clinical sites Berlin and Regensburg); Katholieke Universiteit Leuven, Leuven, Belgium; Ethniko Kai Kapodistriako Panepistimo Athinon, Athens, Greece; Hospital Universitario Virgen de las Nieves/ Hospital Clinico Universitario San Cecilio, Granada, Spain. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced will be made available after successfull publication of the present manuscript.