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

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.

Fig. 1. Trial profile.

A total of 674 patients were screened, of whom 461 met the trial inclusion criteria and were randomly assigned to one of ten treatment arms comprised of a single treatment or a combination of two treatments out of four different therapy approaches - cognitive-behavioural therapy (CBT), hearing aids (HA), app-based structured counselling (SC) and app-based sound therapy (ST). 230 (49.9%) were assigned to single treatments (CBT, HA, SC, or ST) and 231 (50.1%) were assigned to combination treatments (CBT + HA, CBT + SC, CBT + ST, HA + SC, HA + ST, SC + ST). Patients without hearing aid indication were only randomised to treatments without HA. An extended version of the patient’s flowchart can be found in Fig. S1. Quantity and reasons for trial exclusion during eligibility assessments and trial discontinuation/dropouts can be seen from Tables S1–S5.

Fig. 2. Least-squares mean changes from baseline to interim visit (6w), final visit (12w) and follow-up (36w) in THI total score.

A single (n = 230) and combination (n = 231) treatments; C CBT + HA (n = 17); D CBT + SC (n = 51); E CBT + ST (n = 54); F HA + SC (n = 19); G HA + ST (n = 27); H SC + ST (n = 63); and B Cohen’s d values for all treatment arms (change in THI total score from baseline to final visit). Single treatment arms included: CBT (n = 56), HA (n = 59), SC (n = 56) and ST (n = 59). Total THI scores range from 0 to 100, with higher scores indicating greater severity of tinnitus. Error bars represent 95% confidence intervals. Abbreviations: CBT cognitive-behavioural therapy, HA hearing aids, SC app-based structured counselling, ST app-based sound therapy, THI Tinnitus Handicap Inventory.