TAS-303, a selective noradrenaline reuptake inhibitor, is in development for the treatment of stress urinary incontinence (SUI) aiming for an effective and safe drug. The present randomized, placebo-controlled, double-blind study was conducted based on the results of an early phase 2 study, which was carried out for an exploratory assessment of the efficacy and safety of TAS-303 3 and 6 mg [1].
The primary objective was to assess the efficacy of TAS-303 18 mg, as measured by the percent change in stress urinary incontinence episode frequency (SUIEF) per 24 hours, by 12-week treatment in female patients with SUI compared with placebo. The secondary objectives were to assess efficacy, as measured by changes in the 24-hour pad weight test, patient reported outcome measures such as the International Consultation on Incontinence Questionnaire – Short Form (ICIQ-SF), Patient Global Impression of Improvement (PGI-I) score, and Incontinence Quality of Life (I-QOL) score; and safety, as measured by the occurrence of adverse events (AEs).

This study included female Japanese patients with SUI, including stress predominant mixed urinary incontinence (MUI), aged at least 20 years who had symptoms of SUI for at least 12 weeks and had positive 1-hour pad test results. Aside from these criteria, patients who met the following criteria based on a 7-day bladder diary entry proceeded to the treatment period: mean SUIEF per 24 hours of ≥ 1. Randomization was undertaken using an interactive web response system and stratified by mean SUIEF <2 or ≥2 per 24 hours at baseline and age <60 years or ≥60 years. In this study, after completion of a single-blind observation period receiving placebo once daily for 3 to 4 weeks, the patients orally received TAS-303 18 mg or placebo once daily for 12 weeks in the double-blind treatment period. The primary endpoint was the percent change in mean SUIEF per 24 hours from baseline to week 12. For the primary analysis of the primary endpoint, the differences between the TAS-303 and the placebo group were evaluated using analysis of covariance (ANCOVA) adjusted by the covariate (baseline urinary incontinence weight measured by 24-hour pad test) with a two-sided significance level of 5%. The sample size was determined to have a minimum of 186 subjects, which provide at least 80% power to detect a treatment difference from placebo of 20% in the percent change in SUIEF and the standard deviation assumed to be 46% for both groups.

A total of 231 patients were randomized, and the per protocol set (PPS) was 221 patients (110 in the TAS-303 group, 111 in the placebo group). The mean age in the TAS-303 group was 53.9 years and 54.2 years in the placebo group. 100/110 (90.9 %) patients were diagnosed as SUI in the TAS-303 group and 103/111 (92.8 %) in the placebo group. The mean SUIEF per 24 hours at baseline was 1.99 and 2.16 in the TAS-303 and placebo group, respectively. The percent change in LS mean SUIEF per 24 hours at week 12 in the PPS was -57.50% in the TAS-303 group and -47.35% in the placebo group (Table 1). The difference between the two groups was -10.16 % (ANCOVA p = 0.047; 95% confidence interval -20.17, -0.14), indicating a significant decrease in the TAS-303 group compared with placebo. As for the secondary endpoints, the change in the mean SUIEF per 24 hours at week 12 was -1.14 in the TAS-303 group and -0.90 in the placebo group. The rate of ≥50% reduction in mean SUIEF per 24 hours at week 12 was 64.5 % in the TAS-303 group and 54.1 % in the placebo group. The mean change in the 24-hour pad test at week 12 was -9.33 g in the TAS-303 group and -7.93g in the placebo group. The mean change in ICIQ-SF at week 12 was -3.0 and -2.8, and the mean change in I-QOL at week 12 was +11.1 and +9.9 in the TAS-303 and placebo group, respectively. More patients in the TAS-303 than in the placebo group rated themselves as “very much better”, “much better” using the PGI-I rating at week 12 (TAS-303 53.6%, placebo 42.3%). The incidence and severity of AEs in the TAS-303 group was similar to that in the placebo.

It was shown that in the TAS-303 group, percent change in mean SUIEF per 24 hours from baseline at week 12 significantly decreased compared to the placebo group. This study suggests that TAS-303 may be an effective and favorable treatment option for SUI by increasing basal urethral pressure.

As a superior effect and safety of this drug is suggested in SUI patients, further research with a larger number of patients is needed to confirm the therapeutic effect in SUI patients.

Takahashi S., et al., Efficacy and safety of the noradrenaline reuptake inhibitor, TAS-303, in women with stress urinary incontinence: Results of a double-blind, randomized, placebo-controlled, early phase II trial. Int J Urol. 2021; 28(1): 82-90.

Continence 2S2 (2022) 100340
DOI: 10.1016/j.cont.2022.100340