Safety and effectiveness of mirabegron in male patients with overactive bladder with or without benign prostatic hyperplasia: A Japanese post‐marketing study

Abstract Objectives The aim of this post hoc analysis from the Japanese mirabegron surveillance program was to investigate the safety and effectiveness of mirabegron in male patients with overactive bladder (OAB) symptoms with/without concomitant benign prostatic hyperplasia (BPH). Methods This 12‐week study included patients who were starting mirabegron treatment for the OAB symptoms of urinary urgency, daytime frequency, and urgency urinary incontinence. Patients were stratified according to BPH diagnosis, and patients with BPH were stratified into those who did/did not receive BPH‐specific treatment. Assessments included adverse drug reactions (ADRs), residual urine volume evaluations, and total Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom Score‐Quality of Life (IPSS‐QoL) measurements. Results Of 4540 male patients, 3176 (70.0%) had been diagnosed with BPH. Mean age was slightly higher in patients with BPH (74.7 ± 8.41 years) versus patients without BPH (71.0 ± 12.13 years). Overall, 66/1364 (4.84%), 170/2588 (6.57%), and 35/569 (6.15%) patients without BPH, with BPH + treatment, and with BPH + no treatment, respectively, experienced ≥1 ADR. No patients without BPH and 21/3176 (0.66%) patients with BPH experienced a urinary retention ADR. No significant changes from baseline to week 12 in residual volume were noted. Mirabegron was judged to be an effective treatment for 990/1296 (76.4%) patients without BPH, 1935/2491 (77.7%) patients with BPH + treatment, and 421/538 (78.3%) patients with BPH + no treatment. Significant decreases in total OABSS and IPSS‐QoL were observed for all groups. Conclusions Mirabegron was a well‐tolerated and effective treatment for patients with OAB symptoms with or without BPH in this post‐marketing study.


| INTRODUCTION
The occurrence of overactive bladder (OAB) syndrome can have a substantial impact on patients' quality of life (QoL), including affecting work productivity, anxiety, and increased healthcare usage. 1,2 OAB is a prevalent condition, and two epidemiological studies have estimated that 12% of the Japanese population exhibit OAB symptoms. 3,4 In both of these surveys, a slightly higher prevalence was noted for men compared with women. Patients with severe benign prostatic hyperplasia (BPH) typically experience higher levels of pain, more anxiety, and greater negative effects on their usual activities than patients with milder symptoms. 5 The coexistence of BPH with OAB could therefore have a substantial impact on the QoL of men with both conditions. 6 Several pharmacological approaches are recommended for treating patients with BPH and OAB symptoms. Current Japanese guidelines recommend various pharmacological agents, including α 1 -adrenoreceptor antagonists (α 1 -blockers; such as tamsulosin), phosphodiesterase 5 inhibitors (such as tadalafil), and 5α-reductase inhibitors (such as dutasteride) for treating patients with BPH. 7 In terms of OAB symptoms, potential treatment options in Japan include antimuscarinics or the β3-adrenoreceptor agonists, mirabegron and vibegron. [7][8][9] Antimuscarinics are associated with specific anticholinergic side effects, including dry mouth and constipation, 10 and the β3-adrenoreceptor agonists may circumvent these effects through their distinct mechanism of action. [11][12][13] A few initial clinical studies have been conducted that have examined the safety and effectiveness of mirabegron in male patients with OAB symptoms and BPH. The MATCH and PLUS studies both showed that add-on mirabegron treatment was more effective than add-on placebo in men with residual OAB symptoms who were receiving tamsulosin for lower urinary tract symptoms (LUTS). 14,15 An integrated analysis of five phase 3 trials found that similar improvements in urgency, frequency, and incontinence were observed with mirabegron and the antimuscarinic solifenacin in a population of male patients with OAB symptoms. 16 In the same analysis, approximately 37% of the population had a history of LUTS associated with BPH or benign prostatic enlargement and 22% were receiving treatment with an α 1 -blocker. 16 The present study was conducted to assess the safety, effectiveness, and appropriate use of mirabegron in patients with OAB symptoms in the routine clinical environment. 17 The primary analysis from this study found that mirabegron was a well-tolerated and effective treatment for Japanese patients with OAB symptoms in the real-world setting. Using the findings from this study, this post hoc analysis was conducted to examine the safety and effectiveness of mirabegron in male patients with OAB symptoms with or without BPH. In particular, the occurrences of urinary retention and the concomitant use of α 1 -blockers were specifically investigated.

| METHODS
This study (ClinicalTrials.gov: NCT01919047) is one of the postmarketing surveys that encompass the mirabegron surveillance program 18,19 and was planned and conducted in accordance with the Good Post-Marketing Study Practice (GPSP) standards of the Japanese Ministry of Health, Labour, and Welfare (MHLW). 20

| Study design
The methodology for this study has been reported previously. 17 In summary, the overall study included male and female patients who were diagnosed with OAB by their attending physician. Eligible patients were receiving their first administration of mirabegron as a treatment for the OAB symptoms of urinary urgency, daytime frequency, and urgency urinary incontinence. The instigation of mirabegron treatment was at the physician's discretion.
Patients were diagnosed with BPH by their attending physician, and no specific criteria had to be met to confirm a positive diagnosis.
Male patients were stratified on the basis of this diagnosis in the present subanalysis. This methodology was adopted because this investigation was a large noninterventional study within the clinical setting that included data from multiple healthcare facilities. The patients who had been diagnosed with BPH were further stratified into two groups, those who did or did not receive treatment for BPH during the study. BPH treatment was defined as the prescription of an α 1 -blocker and/or 5α-reductase inhibitor, and the use of treatment was at the discretion of the attending physician.
The internet-based post-marketing survey data collection system, PostMaNet, was used to register patients and collect data. Physicians were required to register each patient within 14 days of the start of mirabegron treatment. The registered patients were observed for a 12-week period, and the survey data were entered at the end of this observation period or at discontinuation.

| Study assessments
Patient characteristic data were captured prior to the onset of mirabegron treatment, and concomitant medication usage was acquired during the observation period.
In terms of safety evaluations, the incidence of adverse drug reactions (ADRs), which included abnormal findings from laboratory or other tests, was evaluated throughout the study period. All ADRs were summarized and coded using the Japanese Medical Dictionary for Regulatory Activities (MedDRA; version 17.1). An ADR was defined as an adverse event (AE) that was judged by the physicians to be either potentially related to mirabegron or had an unknown relationship with mirabegron. As the physicians may not have reported all the events that were unrelated to mirabegron treatment in this observational study, ADRs were analyzed rather than AEs. In addition, residual urine volume assessments were conducted at baseline and after 12 weeks of mirabegron treatment (or at discontinuation).
The effectiveness assessments included total Overactive Bladder Symptom Score (OABSS) and International Prostate Symptom Score-Quality of Life (IPSS-QoL) evaluations, which were completed at baseline and after 12 weeks of mirabegron treatment (or at discontinuation). Changes in OAB symptoms were assessed after 12 weeks (or at discontinuation) and compared with baseline symptoms. The general efficacy of mirabegron treatment was subsequently judged to be "effective," "ineffective," or "not evaluable" according to the discretion of the attending physician. An improvement in total OABSS of ≥3 points from baseline was defined as a minimal clinically important change (MCIC). 21

| Statistical analyses
All statistical analyses were conducted using SAS version 9.2 or higher (SAS Institute, Cary, North Carolina). To ensure the detection of ADRs occurring at a low frequency, the planned sample size for the overall study was 10 000 patients. 17 In terms of analysis sets, the safety analysis set consisted of patients who had no registration infringements, received mirabegron, were willing to confirm the existence of any ADR, and had ≥1 study visit after the initial receipt of medication within the required contract period. Patients included in the efficacy analysis set had been diagnosed with OAB and were eligible for efficacy assessment according to the attending physicians. Of these, patients who did not have major diseases or conditions that excluded a diagnosis of OAB (abnormal bladder, perivesical abnormalities, prostatic or urethral abnormalities, urinary tract or genital infections, urinary retention, polyuria, or psychogenic pollakiuria), were judged to have OAB based on the OABSS (question 3 score [urgency]: ≥2 points at baseline, total OABSS: ≥3 points at baseline), received mirabegron in accordance with the dosing regimen, and had OABSS results at baseline and week 12 (or at discontinuation) were included in the OABSS analysis set.
The Wilcoxon signed rank test was used to assess the changes from baseline to week 12 in residual urine volume, total OABSS, and IPSS-QoL.

| Study population
The study was conducted from April 2012 to July 2014. Of the 9795 patients included in the overall study, 4588 (46.8%) patients were male. 17 The presence or absence of concomitant diseases was unknown for 48 patients, and therefore 4540 male patients were included in the safety analysis set for this study. Of these, 3176 (70.0%) patients had been diagnosed with BPH. In total, 4343 patients were included in the efficacy analysis set and 1784 were included in the OABSS analysis set.
The demographic data showed that mean age was slightly higher in the patients with BPH (mean ± standard deviation [

| Safety
Slightly higher ADR incidences were observed for the patients with BPH compared with the patients without BPH ( 38.581 ± 16.1597 [15] Concomitant drugs during the observation period, n (%)   Figure 1).

| Effectiveness
As judged by the physicians, mirabegron was considered to be an

| DISCUSSION
The mirabegron surveillance program in Japan has substantially contributed to the quantity of data available that demonstrate the efficacy and safety of mirabegron in the clinical setting. 17 supports the results of previous investigations where urinary retention was reported with an incidence of 0.24% (two patients) in a pooled analysis that investigated the efficacy and safety of mirabegron in male patients with OAB symptoms. 16 Furthermore, no cases of urinary retention were noted in the MATCH study in which men with OAB received either add-on mirabegron or placebo in conjunction with an α 1 -blocker, tamsulosin, for the treatment of LUTS. 14 Only one case of urinary retention was observed following the administration of mirabegron add-on treatment to 43 patients with OAB symptoms and benign prostatic obstruction who were receiving tamsulosin treatment. 22 Owing to the low incidence of lower urinary tract obstructionrelated ADRs noted here, no additional concerns have arisen from this study that require the instigation of further safety measures. However, mirabegron should be administered with caution to patients with clinically significant bladder outlet obstruction, 23 and patients with OAB symptoms and BPH who are receiving the drug should be monitored for signs of urinary retention.
Although slightly higher increases in mean residual volume were observed for the patients with BPH, no statistically significant changes from baseline were noted in this study. However, the highest increases were noted for patients who did not receive treatment, which indicates that the use of BPH treatment may help alleviate any increases in residual volume. The fact that mirabegron was not associated with clinically relevant changes in residual volume is an important observation given that the medication is associated with a lower  reported any substantial changes in post-void residual volume over the mirabegron treatment period. 14,16,25 The overall effectiveness findings from this study showed that mirabegron was a successful treatment for OAB symptoms.
Mirabegron was considered to be an effective treatment for 77.4% of the male patients with OAB who participated in this study, and a very similar result (77.8%) has been reported in a 3-year post-marketing study that is also part of the mirabegron surveillance program. 19 In this study, the use of mirabegron was associated with significant decreases in both total OABSS and IPSS-QoL. In contrast to the above results, no significant difference was noted in total IPSS between the tamsulosin plus mirabegron and the tamsulosin plus placebo groups in the PLUS study. 15 One of the strengths of this study is the high number of patients who were involved in this surveillance. The overall study