Mirabegron versus vibegron in previously untreated female patients with overactive bladder: A randomized, single‐clinic, open‐label trial

This study aimed to assess the efficacy and safety of mirabegron compared with vibegron (both 50 mg once daily) in Japanese female patients with symptoms of overactive bladder (OAB).


| INTRODUCTION
Overactive bladder (OAB) syndrome is characterized by urinary urgency, with or without urgency incontinence, generally accompanied by increased daytime frequency and nocturia in the absence of an obvious condition such as urinary tract infection (UTI). 1 The prevalence of OAB increases with age, 2 and a Japanese survey estimated that 8.1 million adults (12.4%) over the age of 40 years are affected by OAB in Japan. 3 In this study, 37% of participants aged 80 years and older had OAB, compared to only 5% of those aged 40-49 years. 3 The population of Japan is aging at an unprecedented rate, with the percentage of elderly people in Japan exceeding that in all other countries 4 ; in 2021, 28.9% of the Japanese population was 65 years or older, while 14.9% were 75 years or older. 4 Furthermore, OAB is known to have a significant negative impact on quality of life (QoL) 5,6 in elderly individuals and is associated with increased risk of falls, 7 fractures with the use of anticholinergics, 8 depression, 9 and sleep disturbances. 10,11 Anticholinergics and selective β 3 -adrenergic receptor (AR) agonists are the primary drug therapies used to treat OAB symptoms in Japan 12 ; however, they can result in important adverse events (AEs) caused by systemic anticholinergic effects, 13 and there have been reports of poor medication persistence. 14,15 There is also emerging evidence to support an association between cumulative anticholinergic use and the risk of cognitive impairment and dementia, with a recent study reporting an increased risk of dementia (odds ratio [OR]: 1.19-1.65) with using bladder anticholinergics. 16 Another OAB drug target, the β 3 -AR agonist, was developed as an alternative oral therapy and was approved for marketing in Japan in 2011. 17 Vibegron, approved for use in Japan in 2018, is a novel, potent β 3 -AR agonist that is highly selective for the β 3 receptor in vitro. 18 In a recent phase III study conducted in Japan, vibegron demonstrated sustained efficacy versus placebo for all OAB symptoms. 19 Herein, we conducted a prospectively designed randomized controlled trial (RCT) on the safety and efficacy of mirabegron and vibegron in routine clinical settings. This is the first novel study in Japan to examine the efficacy and safety of β 3 agonists in untreated elderly women aged over 70 years with OAB. Further, this is the first headto-head RCT to report the efficacy and safety of mirabegron and vibegron simultaneously.

| Design
This study was designed as a prospective trial involving postmenopausal female patients in a single clinic between December 2019 and September 2022. A randomized, open-label, parallel-group trial design (registration number UMIN000038288) was adopted to compare the safety and efficacy of mirabegron and vibegron. The total study duration was 12 weeks, encompassing a 12-week treatment period. This study was performed in accordance with the Declaration of Helsinki and was approved by the institutional review board of our institute (2019-F I G U R E 1 Patient disposition. FAS, full analysis set; SAF, safety analysis set. 037). Written informed consent was obtained from all participants. Postmenopausal treatment-naïve female OAB patients were included in this study. OAB was diagnosed using the overactive bladder symptom score (OABSS) validated by Homma et al. 3 based on the OABSS definition (a score ≥2 points for Question 3 [urgency] of the OABSS combined with a total score ≥3 points). The OABSS is a four-item questionnaire used to evaluate daytime frequency, nocturia, urgency, and urinary urgency incontinence (UUI) in the past week. Among patients with OAB, those with a UUI score ≥2 were defined as OAB wet, 10,20 and all others were defined as OAB dry. A mean change from baseline to end of treatment (EOT) of 3 or more points on the total OABSS was defined as a minimal clinically important change (MCIC). 21 MCIC was further defined as a mean change from baseline to EOT of 5 points on King's Health Questionnaire (KHQ) 22 domains. 23 The KHQ is a worldwide questionnaire for health-related QoL in patients with OAB.

| Randomization
Patients were randomly allocated to the two treatment groups in a 1:1 ratio. Block randomization, performed by an independent investigator not involved in the actual treatment, was used to generate a random-number sequence by permuted block randomization with a block size of 4 using computer software R (R Foundation for Statistical Computing, Vienna, Austria). Investigators and patients were not blinded to the group allocations.

| Procedure
Patients were randomized to receive oral mirabegron (50 mg) or vibegron (50 mg) once daily for 12 weeks. The 12-week study con-

| Outcomes
The primary efficacy outcome measure was the change in the mean number of OABSSs from baseline to the EOT (Week 12). The T A B L E 1 Baseline demographic and OAB characteristics (full analysis) of the study participants.

| Sample size
No statistical sample-size calculations were conducted. However, a sample size of 44 patients per group resulted in a post hoc power of 24% to detect differences in the mean of 0.7 points, assuming a common SD of 3.0, based on a type I error rate of 5%.
Safety analysis was performed on patients in the safety analysis set (SAF), and efficacy analysis was performed primarily on the full analysis set (FAS). The SAF comprised randomized patients who received one dose of the study drug and underwent a safety measurement. The FAS included SAF patients with at least one efficacy measurement after the initial treatment. The QOL analysis set was defined as FAS for patients for whom at least one domain score could be calculated and who had taken the study drug for at least 28 days.

| Statistical analysis
The least squares mean and two-sided 95% CIs of changes in the primary and secondary efficacy outcome measures from baseline to EOT in the mirabegron and vibegron groups were calculated using an analysis of covariance (ANCOVA) model adjusting for the treatment group, age, and baseline value. The percentage change in OABSS and KHQ score from baseline to EOT achieving MCIC and the percentage of OAB dry and wet at EOT were calculated using a logistic regression model including the same factors as the ANCOVA models, with ORs and 95% CIs comparing the treatment effects between the mirabegron and vibegron groups. Multiple imputations were used for all missing data.
All tests were two-sided, and significance was set at p < .05. All statistical analyses were performed using R and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) software.

| RESULTS
A total of 104 patients were randomized to the two treatment groups   (Figure 2A; Table 2). For the secondary outcomes, the mean change in difference from baseline to EOT in the OABSS domains (daytime frequency, nighttime frequency, urgency, and UUI) is shown in Figure 2 and     (Figures 4A,B, 5A-I, 6A-C, respectively; Table 2) at EOT.
The data on TRAEs are presented in Table S1. The overall incidence of TRAEs was higher in the vibegron group (38.5%) than in the mirabegron group (19.1%) ( p = .047). The incidence of dry mouth was higher in the vibegron group (15.4%) than in the mirabegron group (12.8%), although this difference was not statistically significant. Similarly, the incidence of constipation was higher in the vibegron group (11.5%) than in the mirabegron group (2.1%).
Serious TRAEs were observed in one patient (2.1%) in the mirabegron group and five patients (9.8%) in the vibegron group. The  reported that the change (mean ± SD) in the OABSS from baseline to EOT was À3.6 ± 3.22 for male and female patients <75 years. 24 Another RCT reported that the change in OABSS was À4.51 ± 3.05 (mean age 73.5 years). 25 A recent prospective study using 50 mg vibegron showed that the mean change in OABSS from baseline to EOT was À4.98 for men and women (mean age 73 years). 26 The present study showed that treatment with both mirabegron and vibegron greatly exceeded the MCIC. The higher efficacy observed in this study may have been because the target population was female patients with no prior history of OAB. 27,28 In this study, age was adjusted as a covariate, and logistic analysis was performed to compare each of the nine domains of the KHQ. General health perceptions were significantly improved in the mirabegron group compared with those in the vibegron group, but there were no significant differences between the two groups in other domains. A previous RCT showed that KHQ domains, other than general health perceptions and personal relationships, were significantly improved in those who received 50 mg mirabegron 17 and 50 mg vibegron 19 compared to those in the participants who received the placebo. In this study, general health perceptions significantly improved in the mirabegron group compared with those in the vibegron group, but the results did not take multiplicity into account. Previous studies 17,19 have shown no cases of improvement in general health perceptions, making it difficult to explain whether this is a clinically important difference.
Further research is needed to determine whether the improvement in QoL in clinical trials would differ between the two β 3 -AR agonists in a real-world setting.
Overall, this study showed that the 12-week discontinuation rate due to TRAEs was lower in the mirabegron group than in the vibegron group. The incidence of dry mouth and constipation was lower in the mirabegron group than in the vibegron group. In particular, the presence of serious TRAEs, such as urinary retention, arthralgia, cramps, and dyspnea, also affected drug tolerability. A systematic literature review of 44 RCTs showed that 50 mg mirabegron produced a low rate of dry mouth and constipation, which are the most common AEs resulting in treatment discontinuation with most antimuscarinics. 29 Further, the previous RCT reported that dry mouth and constipation were the most common TRAEs for vibegron, but the incidence of dry mouth was similar to that of placebo. 19 A phase 3 RCT found that vibegron was well tolerated, with a 12-week discontinuation rate of 1.7% compared to 1.1% for placebo. 30 Overall, the AEs observed in the vibegron group in the present study contrasted with our expectations and could not be explained biologically. This remains an unresolved issue that requires further research.
This study has several limitations. First, because two β 3 -AR agonists may be used for longer than 12 weeks, the 12-week treatment period was too short to assess the actual efficacy and to generalize the long-term efficacy, safety, and tolerability of the drug. Second, the sample size was relatively small. Third, the study was conducted at a single institution. Fourth, because this was an open-label trial rather than a placebo-controlled trial, there may be a risk of observer bias.
Further, there were no cases of cardiovascular AEs specific to β 3 agonists because the number of patients was not large enough to perform a SAF. We believe that continued attention should be paid to cardiovascular AEs in order to administer β 3 agonists.
In summary, this was a study of Japanese treatment-naïve postmenopausal female patients with OAB. Our analysis showed that 12 weeks of treatment with 50 mg mirabegron and 50 mg vibegron once daily both improved OAB symptoms, with no significant difference between the two drugs. Safety assessment showed a higher rate of more serious AEs leading to discontinuation in the vibegron group.
A more detailed analysis of the efficacy and safety of the two β 3 -AR agonists should be conducted.