Efficacy and safety of onabotulinumtoxinA in patients with overactive bladder: subgroup analyses by sex and by serum prostate-specific antigen levels in men from a randomized controlled trial

Abstract

Purpose: We aimed to assess onabotulinumtoxinA treatment outcomes by sex in patients with overactive bladder (OAB) and then explore the impact of serum prostate-specific antigen (PSA) levels in men.

Methods: Patients inadequately managed with OAB medications were randomized to receive single-dose onabotulinumtoxinA (100 U) or placebo intravesical injection in a phase III trial in Japan. We performed subgroup analyses by sex and post-hoc subgroup analyses using male PSA categories.

Results: In women (n = 186), onabotulinumtoxinA demonstrated statistically significant and clinically relevant improvements in all urinary symptoms at Week 12. In men with lower PSA (< 1.5 ng/mL, n = 40), onabotulinumtoxinA also showed numerically greater reductions in urinary symptom frequency than placebo; the between-group differences (onabotulinumtoxinA minus placebo) in change from baseline in the average daily number at Week 12 for urinary incontinence (UI), urgency UI, micturition, urgency, and nocturia were - 1.43, - 1.79, - 2.81, - 2.45, and - 0.32 episodes, respectively. In men with higher PSA (≥ 1.5 ng/mL, n = 22), onabotulinumtoxinA did not reduce urinary symptom frequency. Some patients treated with onabotulinumtoxinA showed elevated post-void residual urine volume at Week 2 (≥ 200 mL): 4 of 91 women, none of the men with lower PSA and 3 of 11 men with higher PSA.

Conclusions: OnabotulinumtoxinA was efficacious and well tolerated in women and in men with lower PSA levels. Given our post-hoc subgroup analyses which suggested that onabotulinumtoxinA treatment is a good treatment option for OAB males with lower PSA levels, future studies having prostate volume data with larger sample size are warranted to verify our findings. CLINICALTRIALS.

Gov identifier: NCT02820844 (first posted July 1, 2016). https://ichgcp.net/clinical-trials-registry/NCT02820844 .

Keywords: Men; OnabotulinumtoxinA; Overactive bladder; Prostate-specific antigen; Randomized controlled trial.

Conflict of interest statement

OY has received consultancy fees from Astellas, GlaxoSmithKline, Kissei, Kyorin, Nippon Shinyaku, Pfizer, and Taiho, as well as grants from Astellas, Eisai, Kissei, Taiho, and Takeda. MH has received consultancy fees from GlaxoSmithKline. TY has received grants from Astellas, Kyorin, and Taiho. YS has no conflicts of interest. KF, KK, TN, AU and TM are employees of GlaxoSmithKline.

© 2021. The Author(s).

Figures

Fig. 1

Plots for the change from baseline up to Week 12 in the average daily number of urinary incontinence (UI) episodes. Values: adjusted mean; error bars: standard error. Data by sex were analyzed using a mixed model for repeated measures (MMRM) with treatment, site, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as fixed effects. The data by prostate-specific antigen (PSA) categories were analyzed using an MMRM with PSA category, treatment-by-PSA category interaction, and treatment-by-PSA category-by-visit interaction as fixed effects in addition to the above fixed effects. When it is assumed that the treatment difference for UI were − 1.79 or − 1.43 and 3.5 for its standard deviation (SD), post-hoc power with 39 participants using two-sample t-test will be 34% and 24% power at the two-sided significance level of 5% to detect treatment differences in men with lower PSA. Here, − 1.79 and 3.5 are the effect size and SD assumed in the study protocol for the overall population, respectively, and − 1.43 is the observed treatment difference adjusted mean in men with lower PSA levels

Fig. 2

Forest plots for the between-group differences in the change from baseline at Week 12 for urinary symptoms and patient-reported outcomes. Closed square: analyses by sex, closed circle: analyses by prostate-specific antigen (PSA) categories. Values: adjusted mean; error bars: 95% confidence interval. The data for urinary incontinence (UI) and urgency urinary incontinence (UUI) by sex were analyzed using a mixed model for repeated measures (MMRM) with treatment, site, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as fixed effects, whereas other data for urinary symptoms by sex were analyzed using an MMRM with the baseline frequency of UUI episodes (≤ 9 or ≥ 10 per 3 days) in addition to the above fixed effects. The data for the urinary symptoms by PSA categories were analyzed using an MMRM with above the fixed effects by adding the PSA category, treatment-by-PSA category interaction and treatment-by-PSA category-by-visit interaction as fixed effects. The data for the patient-reported outcomes by sex were analyzed using analysis of covariance (ANCOVA) with terms for treatment, site, baseline value, and baseline frequency of UUI episodes (≤ 9 or ≥ 10 per 3 days) as fixed effects. The data for the patient-reported outcomes by PSA categories were analyzed using ANCOVA with terms for treatment, site, baseline value, the baseline frequency of UUI episodes (≤ 9 or ≥ 10 per 3 days), PSA category and treatment-by-PSA category interaction as fixed effects