TAS-303, a selective noradrenaline reuptake inhibitor, is currently at the stage of phase II development for the treatment of stress urinary incontinence (SUI). A randomized, placebo-controlled, double-blind study was conducted with the primary objective of assessing the efficacy, as measured by the percent change in incontinence episode frequency (IEF), of an 8-week TAS-303 treatment course in female patients with SUI compared with that of placebo. The secondary objectives were to assess the efficacy, as measured by the changes in patient global impression of improvement score, incontinence quality of life score, and other scores, and safety, as measured by the occurrence of adverse events (AEs), of TAS-303.

This study included female Japanese patients with SUI, including stress-dominant mixed urinary incontinence (MUI), aged at least 20 years but < 80 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 bladder diary entries before enrollment in the treatment phase proceeded to the treatment phase: mean IEF per 24 hours of ≥ 1 and greater frequency of SUI episodes than of urge urinary incontinence episodes. In this study, after completion of the observation phase for 3 to 4 weeks (placebo given single-blindedly), the patients orally received placebo, TAS-303 3 mg, or TAS-303 6 mg once daily for 8 weeks in the double-blind treatment phase. For the primary analysis of the primary endpoint, the differences between the 6- and 3-mg TAS-303 groups compared with the placebo group were tested using the Student t test with a two-sided significance level of 5% for the entire test.

A total of 256 patients were randomized, and the per protocol set (PPS) consisted of 245 patients (84 in the TAS-303 3 mg group, 80 in the TAS-303 6 mg group, and 81 in the placebo group). The mean IEF was 2.5 to 2.9 times per day in each group. In the TAS-303 3 mg, TAS-303 6 mg, and placebo groups, the numbers of patients with pure SUI and MUI were 63, 61, and 61 and 21, 19, and 20, respectively. The mean percent change in mean IEF per 24 hours from baseline, the primary endpoint in this study, in the PPS was −34.7% in the TAS-303 3 mg group, −35.4% in the TAS-303 6 mg group, and −28.1% in the placebo group at week 8, indicating a greater change in both the 3- and 6-mg TAS-303 groups than in the placebo group. However, the primary analysis failed to demonstrate a statistically significant difference from the placebo group in either group (Table 1). In the analysis in patients with a mean IEF of < 2 times per day in the subanalysis, the mean difference in the percent change in mean IEF from baseline to week 8 in the subanalysis was greater in patients with a mean IEF of < 2 times per day than in all patients. Furthermore, the mean percent change in mean IEF from baseline at week 4 was greater in both the 3- and 6-mg TAS-303 groups than in the placebo group (p < 0.05). In addition, the percentage of patients with dryness (≤ 2.0 g) in the 1-hour pad test at week 8 was 47.5% in the TAS-303 6 mg group and 14.6% in the placebo group, indicating a significant difference between the two groups (Table 2). The incidence of AEs in the 3- and 6-mg TAS-303 groups was similar to that in the placebo, without dose dependency in the incidence and severity of AEs.

Although the primary analysis failed to demonstrate a clear decrease in the percent change in mean IEF at week 8 of 3- or 6-mg TAS-303 treatment, this study suggests a superior effect of TAS-303 to improve urinary incontinence in patients with a mean IEF of < 2 times per day.

The percent change in mean IEF per 24 hours from baseline at week 8, the primary endpoint, was greater, but not statistically significantly, in the 3- and 6-mg TAS-303 groups than in the placebo group. As a superior effect is suggested in mild SUI patients, further research is needed to determine if higher TAS-303 doses for mild SUI patients have potential to improve SUI.