Efficacy and safety of a modified sound therapy for patients with subjective tinnitus (MOST): a multicentre, double-blind, randomised controlled trial.

Background: Tinnitus is a common and often debilitating auditory condition with limited treatment options. While sound therapy is widely used, robust evidence from long-term randomised trials is scarce. We aimed to evaluate the 9-month efficacy and 3-month posttreatment durability of four sound therapies for adults with chronic subjective tinnitus and identify predictors of response. Methods: In this multicentre, double-blind, randomised controlled clinical trial, participants (aged 18-80 years) with chronic subjective tinnitus from three academic hospitals in China were included. Participants were randomly 1:1:1:1 assigned to receive one of four daily 2-h interventions: unmodified music (UM), UM plus pitch-centered narrowband noise (UM + NBN), high-frequency-enhanced music (HFEM), or digital frequency-customised relieving sound (DFCRS). Primary outcome was tinnitus severity assessed by Tinnitus Handicap Inventory (THI). Assessments occurred at baseline, 1, 2, 3, 6, and 9 months, with a 3-month posttreatment follow-up. Two prespecified primary endpoints were defined: (a) complete remission, operationalised as a THI score of 0 at any follow-up visit within the 9-month period. Participants achieving this endpoint were considered clinically cured, and sound therapy was discontinued; or (b) if complete remission was not achieved by the end of 9 months, the magnitude of improvement was defined as the change in THI score from baseline to the 9-month endpoint. The primary analysis followed the intention-to-treat (ITT) principle, This trial is registered with the Chinese Clinical Trial Registry, ChiCTR2000039007. Findings: Between May 14, 2021, and November 30, 2022, 440 participants (median age 45 years [IQR, 35-56]; 222/440 [50·5%] male; median tinnitus duration 13 months [IQR, 7-36]) were enrolled and randomly assigned (UM, n = 111; UM + NBN, n = 110; HFEM, n = 108; DFCRS, n = 111). Baseline characteristics were balanced between the groups. Only one participant in the HFEM group achieved complete remission, with a THI score of 0 at the 6-month follow-up. THI scores significantly decreased over time in all groups (median 50·00 [IQR 36·00-62·00]) at baseline to 9-month follow-up (35·00 [24·00-48·00]; p < 0·0001), with effects sustained posttreatment. Significant group × time interactions occurred (UM: F(5, 618) = 11·45; UM + NBN: F(5, 605) = 7·17; HFEM: F(5, 599) = 8·3; DFCRS: F(5, 619) = 12·65; all p < 0·0001) in all arms. DFCRS demonstrated superior efficacy (parameter estimate -4·37, 95% CI -6·25 to -2·48; p < 0·0001), when compared to UM as reference. No adverse events were reported in any group. Interpretation: In this exploratory trial, personalised acoustic therapy may provide promising efficacy for chronic tinnitus. Although interpretation is tempered by the absence of a blank control arm and objective adherence monitoring, these limitations highlight opportunities for future studies to refine methods and validate treatment benefits more robustly. Funding: The Ministry of Science and Technology, the Shanghai Shenkang Development Centre, the Shanghai Science and Technology Committee, and the National Natural Science Foundation of China.