Efficacy of TAC-302 for patients with detrusor underactivity and overactive bladder: a randomized, double-blind, placebo-controlled phase 2 study

Masaki Yoshida, Momokazu Gotoh, Osamu Yokoyama, Hidehiro Kakizaki, Tomonori Yamanishi, Osamu Yamaguchi, Masaki Yoshida, Momokazu Gotoh, Osamu Yokoyama, Hidehiro Kakizaki, Tomonori Yamanishi, Osamu Yamaguchi

Abstract

Purpose: This multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluated the efficacy and safety of TAC-302, a novel drug that restores neurite outgrowth, in patients with detrusor underactivity (DU) and overactive bladder (OAB).

Methods: After 2-4 weeks of observation, patients were randomized 2:1 to receive oral TAC-302 200 mg or placebo twice daily for 12 weeks. The primary endpoint was detrusor contraction strength, estimated by bladder contractility index (BCI) for males and projected isovolumetric pressure 1 (PIP1) for females. Secondary endpoints included changes in bladder voiding efficiency (BVE) and safety.

Results: Seventy-six patients were included (TAC-302, n = 52; placebo, n = 24). The mean (standard deviation [SD]) BCI for males was 64.6 (16.6) at baseline and 75.2 (21.1) at week 12 (p < 0.001) with TAC-302 (n = 27), and 61.3 (16.6) and 60.5 (16.7) (p = 0.82) with placebo (n = 11). The respective mean (SD) PIP1 for females was 18.8 (6.6) and 29.4 (9.4) (p < 0.001) with TAC-302 (n = 15), and 20.6 (7.5) and 25.5 (9.6) (p = 0.14) with placebo (n = 7). TAC-302 significantly increased BCI in males and BVE in both sexes. TAC-302 efficacy on OAB was not clearly shown. The incidences of adverse events (AEs), serious AEs, and AEs leading to dose interruption were similar between groups; no adverse drug reactions occurred.

Conclusion: Considering the significant effects on BCI in males and BVE in both sexes, TAC-302 may benefit patients with DU.

Registration: ClinicalTrials.gov Identifier NCT03175029 registered 6/5/2017.

Keywords: Bladder voiding efficiency; Detrusor underactivity; Overactive bladder; TAC-302; Underactive bladder.

Conflict of interest statement

M. Yoshida has received consultancy fees from Taiho Pharmaceutical Co., Ltd. and speaker fees from KYORIN Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Astellas Pharma Inc., Ferring Pharmaceuticals Co., Ltd., and Pfizer Inc. M. Gotoh has received consultancy fees from Taiho Pharmaceutical Co., Ltd., Lilium Otsuka Co., Ltd., and speaker fees from Astellas Pharma Inc., Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Ferring Pharmaceuticals Co., Ltd., and Glaxo Smith Kline Plc. O. Yokoyama has received consultancy fees from Taiho Pharmaceutical Co., Ltd., Glaxo Smith Kline Plc., and Astellas Pharma Inc. and speaker fees from Glaxo Smith Kline Plc., Astellas Pharma Inc., and Kissei Pharmaceutical Co., Ltd. H. Kakizaki has received consultancy fees from Taiho Pharmaceutical Co., Ltd., and Astellas Pharma Inc., and speaker fees from Astellas Pharma Inc., Kissei Pharmaceutical Co., Ltd., Pfizer Inc., KYORIN Pharmaceutical Co., Ltd., and Ferring Pharmaceuticals Co., Ltd. T. Yamanishi has received consultancy fees from Taiho Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Pfizer Inc., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Nippon Shinyaku Co., Ltd., Nihon Kohden Corp., and Coloplast Corp. O. Yamaguchi has received consultancy fees from Astellas Pharma Inc., Taiho Pharmaceutical Co., Ltd., and Ferring Pharmaceuticals Co., Ltd., and speaker fees from Astellas Pharma Inc.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
a Shows the results for increased BCI in male patients before and after treatment in each group. p values for baseline vs week 12 were calculated using the Paired t test. In contrast, Fig. 1b compares the difference between the TAC-302 group and the placebo group in the amount of change in BCI at 12 weeks. p values for BCI change from baseline for TAC-302 vs placebo were calculated using both the Student’s t test and ANCOVA. Figures 2a, b, as in a and b, show the evaluation of PIP1 in female patients. The horizontal line in the middle of each box indicates the median; the × indicates the mean; the ○ indicates individual data; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box extend to the data point furthest from the box that is still within 1.5 × (75th percentile to 25th percentile) the box. ANCOVA analysis of covariance, BCI bladder contractility index
Fig. 2
Fig. 2
a PIP1 at baseline and week 12. b Change in PIP1 (females only) from baseline. The horizontal line in the middle of each box indicates the median; the × indicates the mean; the ○ indicates individual data; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box extend to the data point furthest from the box that is still within 1.5 × (75th percentile to 25th percentile) the box. p values for baseline vs week 12 were calculated using the Paired t test, and p values for PIP1 change from baseline for TAC-302 vs placebo were calculated using both the Student’s t-test and ANCOVA. ANCOVA analysis of covariance, PIP1 projected isovolumetric pressure 1
Fig. 3
Fig. 3
Change from baseline in BVE according to baseline post void residual volume: a ≥ 50 mL, b ≥ 100 mL (FAS). P-values were calculated using the Student’s t test (TAC-302 vs placebo). BVE bladder voiding efficiency, FAS full analysis set

References

    1. Resnick NM, Yalla SV. Detrusor hyperactivity with impaired contractile function. An unrecognized but common cause of incontinence in elderly patients. JAMA. 1987;257:3076–3081. doi: 10.1001/jama.1987.03390220074024.
    1. Yamaguchi O, Nomiya M, Andersson K-E. Functional consequences of chronic bladder ischemia. Neurourol Urodyn. 2014;33:54–58. doi: 10.1002/nau.22517.
    1. Yoshida M, Yamaguchi O. Detrusor underactivity: the current concept of the pathophysiology. Low Urin Tract Symptoms. 2014;6:131–137. doi: 10.1111/luts.12070.
    1. Yoshida S, Orimoto N, Tsukihara H, Noma T, Hakozaki A, Sasaki E. TAC-302 promotes neurite outgrowth of isolated peripheral neurons and prevents bladder denervation related bladder dysfunctions following bladder outlet obstruction in rats. Neurourol Urodyn. 2018;37:681–689. doi: 10.1002/nau.23375.
    1. Yoshida S, Noma T, Miyoshi K, Tsukihara H, Orimoto N, Hakozaki A, Sasaki E. Therapeutic effect of TAC-302, a cyclohexenoic fatty alcohol derivative, on bladder denervation-related storage and voiding dysfunctions in rats. Neurourol Urodyn. 2018;37:2106–2113. doi: 10.1002/nau.23571.
    1. Gammie A, Kaper M, Dorrepaal C, Kos T, Abrams P. Signs and symptoms of detrusor underactivity: an analysis of clinical presentation and urodynamic tests from a large group of patients undergoing pressure flow studies. Eur Urol. 2016;69:361–369. doi: 10.1016/j.eururo.2015.08.014.
    1. Nitti VW. Pressure flow urodynamic studies: the gold standard for diagnosing bladder outlet obstruction. Rev Urol. 2005;7:S14–S21.
    1. Tan TL, Bergmann MA, Griffiths D, Resnick NM. Stop test or pressure-flow study? Measuring detrusor contractility in older females. Neurourol Urodyn. 2004;23:184–189. doi: 10.1002/nau.20020.
    1. Yono M, Ito K, Oyama M, Tanaka T, Irie S, Matsukawa Y, Sekido N, Yoshida M, van Till O, Yamaguchi O. Variability of post-void residual urine volume and bladder voiding efficiency in patients with underactive bladder. Low Urin Tract Symptoms. 2021;13:51–55. doi: 10.1111/luts.12325.
    1. Yoshida S, Noma T, Miyoshi K, Tsukihara H, Orimoto N, Hakozaki A, Sasaki E. Therapeutic effect of TAC-302, a cyclohexenoic fatty alcohol derivative, on bladder denervation-related storage and voiding dysfunctions in rats. Neurourol Urodyn. 2018;37(7):2106–2113. doi: 10.1002/nau.23571.

Source: PubMed

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