Single versus combination treatment in tinnitus: an international, multicentre, parallel-arm, superiority, randomised controlled trial

Stefan Schoisswohl (), Laura Basso, Jorge Simoes, Milena Engelke, Berthold Langguth, Birgit Mazurek, Jose Antonio Lopez-Escamez, Dimitrios Kikidis, Rilana Cima, Alberto Bernal-Robledano, Benjamin Böcking, Jan Bulla, Christopher R. Cederroth, Holger Crump, Sam Denys, Alba Escalera-Balsera, Alvaro Gallego-Martinez, Silvano Gallus, Hazel Goedhart, Leyre Hidalgo-Lopez, Carlotta M. Jarach, Hafez Kader, Michael Koller, Alessandra Lugo, Steven C. Marcrum, Nikos Markatos, Juan Martin-Lagos, Marta Martinez-Martinez, Nicolas Müller-Locatelli, Patrick Neff, Uli Niemann, Patricia Perez-Carpena, Rüdiger Pryss, Clara Puga, Paula Robles-Bolivar, Matthias Rose, Martin Schecklmann, Tabea Schiele, Miro Schleicher, Johannes Schobel, Myra Spiliopoulou, Sabine Stark, Susanne Staudinger, Alexandra Stege, Beat Tödtli, Ilias Trochidis, Vishnu Unnikrishnan, Evgenia Vassou, Nicolas Verhaert, Carsten Vogel, Zoi Zachou and Winfried Schlee
Additional contact information
Stefan Schoisswohl: University of Regensburg, Department of Psychiatry and Psychotherapy
Laura Basso: University of Regensburg, Department of Psychiatry and Psychotherapy
Jorge Simoes: University of Twente, Department of Psychology, Health and Technology
Milena Engelke: University of Regensburg, Department of Psychiatry and Psychotherapy
Berthold Langguth: University of Regensburg, Department of Psychiatry and Psychotherapy
Birgit Mazurek: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tinnitus Center
Jose Antonio Lopez-Escamez: University of Sydney, Meniere’s Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute
Dimitrios Kikidis: Head and Neck Surgery, National and Kapodistrian University of Athens, Hippocrateion General Hospital, First Department of Otorhinolaryngology
Rilana Cima: Katholieke Universiteit Leuven, Department of Health Psychology
Alberto Bernal-Robledano: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Benjamin Böcking: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tinnitus Center
Jan Bulla: University of Regensburg, Department of Psychiatry and Psychotherapy
Christopher R. Cederroth: Karolinska Institutet, Department of Physiology and Pharmacology
Holger Crump: Patient Organisation “Hast Du Töne—Leben mit Tinnitus” Bergisch-Gladbach
Sam Denys: Katholieke Universiteit Leuven, Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Leuven
Alba Escalera-Balsera: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Alvaro Gallego-Martinez: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Silvano Gallus: Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Medical Epidemiology
Hazel Goedhart: Tinnitus Hub
Leyre Hidalgo-Lopez: Hospital Universitario Virgen de las Nieves, Department of Mental Health
Carlotta M. Jarach: Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Medical Epidemiology
Hafez Kader: Otto-von-Guericke Universität, Faculty of Computer Science
Michael Koller: University of Regensburg, Center for Clinical Studies
Alessandra Lugo: Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Medical Epidemiology
Steven C. Marcrum: University Hospital Regensburg, Department of Otolaryngology
Nikos Markatos: Head and Neck Surgery, National and Kapodistrian University of Athens, Hippocrateion General Hospital, First Department of Otorhinolaryngology
Juan Martin-Lagos: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Marta Martinez-Martinez: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Nicolas Müller-Locatelli: Hospital Clinico Universitario San Cecilio, Department of Otolaryngology
Patrick Neff: University of Regensburg, Department of Psychiatry and Psychotherapy
Uli Niemann: Otto-von-Guericke Universität, Faculty of Computer Science
Patricia Perez-Carpena: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Rüdiger Pryss: Institute of Clinical Epidemiology and Biometry University of Würzburg
Clara Puga: Otto-von-Guericke Universität, Faculty of Computer Science
Paula Robles-Bolivar: Universidad de Granada, Otology & Neurotology Group CTS495, Instituto de Investigación Biosanitaria, ibs.GRANADA
Matthias Rose: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Internal Medicine and Psychosomatics
Martin Schecklmann: University of Regensburg, Department of Psychiatry and Psychotherapy
Tabea Schiele: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tinnitus Center
Miro Schleicher: Otto-von-Guericke Universität, Faculty of Computer Science
Johannes Schobel: Neu-Ulm University of Applied Sciences, Institute DigiHealth
Myra Spiliopoulou: Otto-von-Guericke Universität, Faculty of Computer Science
Sabine Stark: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Tinnitus Center
Susanne Staudinger: University of Regensburg, Department of Psychiatry and Psychotherapy
Alexandra Stege: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Centrale Biobank Charité (ZeBanC)
Beat Tödtli: Eastern Switzerland University of Applied Sciences, Institute for Information and Process Management
Ilias Trochidis: ViLabs
Vishnu Unnikrishnan: Otto-von-Guericke Universität, Faculty of Computer Science
Evgenia Vassou: Head and Neck Surgery, National and Kapodistrian University of Athens, Hippocrateion General Hospital, First Department of Otorhinolaryngology
Nicolas Verhaert: Katholieke Universiteit Leuven, Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Leuven
Carsten Vogel: Institute of Clinical Epidemiology and Biometry University of Würzburg
Zoi Zachou: Head and Neck Surgery, National and Kapodistrian University of Athens, Hippocrateion General Hospital, First Department of Otorhinolaryngology
Winfried Schlee: University of Regensburg, Department of Psychiatry and Psychotherapy

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-66165-1

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