The Statistical Analysis Plan for the Unification of Treatments and Interventions for Tinnitus Patients Randomized Clinical Trial (UNITI-RCT)

Abstract

Background Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potential increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. Methods Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavior therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in 4 treatment arms with single treatment and 6 treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. Discussion The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. Trial registration ClinicalTrials.gov NCT04663828 (https://clinicaltrials.gov/ct2/show/NCT04663828). The trial is ongoing. Date of registration: December 11, 2020. The main RCT analyses will start by the end of December 2022 and will include data from patients who have finished their treatment by the 19th of December 2022.

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

“…In addition, a per-protocol analysis was conducted on all patients who met the requirements for treatment compliance as defined in the SAP (N = 185). 31 The analysis of the primary objective was performed in the ITT population to test the clinical efficacy of combination treatments against single treatments. Further comparisons between single versus combination treatments for all 4 single treatments separately (CBT single vs.…”

“…In addition, a per-protocol analysis was conducted on all patients who met the requirements for treatment compliance as defined in the SAP (N = 185). 31…”

“…Further comparisons between single versus combination treatments for all 4 single treatments separately (CBT single vs. combined, HA single vs. combined, SC single vs. combined, ST single vs. combined) as well as comparisons between all ten treatment arms were performed. 14,31 To address all objectives, mixed effect models were applied (with REML using the R package) 32 by considering the outcome as the response variable and including the corresponding objective, time point (baseline, interim visit, final visit, and follow-up), and objective-by-time interaction as fixed effects, including centre and subject ID as random intercepts. The models were adjusted for the following covariates: age, sex, educational attainment, hearing aid indication, and PHQ-9 baseline scores.…”

“…Detailed information about the trial rationale, design, methodological approaches, and statistical analysis strategies are published in the study protocol (link: https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05835-z) and statistical analysis plan (SAP). 14,15 The study was approved by local ethics committees at every clinical site independently. Further, all authors vouch for the completeness and correctness of the data, adherence of the trial to the study protocol, 14 as well as adherence of data analysis strategies to the SAP.…”

“…Further, all authors vouch for the completeness and correctness of the data, adherence of the trial to the study protocol, 14 as well as adherence of data analysis strategies to the SAP. 15 A detailed list of author contributions can be found in the Supplementary Appendix.…”