Safety and efficacy of vibegron in pediatric patients with treatment-resistant nocturnal enuresis: a multicenter retrospective study

Introduction

Background

Nocturnal enuresis (NE) is a common chronic condition in children, affecting approximately 10–15% of those aged 5–10 years, with an annual spontaneous remission rate of approximately 15% (1). The first-line treatment for NE is urotherapy, a behavioral intervention that includes education on normal bladder function, lifestyle modifications such as fluid management and scheduled voiding, and bowel management. According to the International Children’s Continence Society (ICCS), urotherapy is considered the foundation of treatment prior to pharmacological intervention. In children who did not achieve adequate response to urotherapy, the first-line active treatments include desmopressin and enuresis alarm therapy (1). If these therapies are not successful, anticholinergics are commonly used in clinical practice for suspected bladder overactivity. Despite these established modalities, 20–40% of children demonstrated inadequate response and require additional interventions (2,3). NE substantially influences psychosocial development and health-related quality of life, and treatment resistance further increases the burden on families and healthcare providers (3,4). In Japan, anticholinergic agents are commonly used as second-line pharmacotherapy for children who demonstrate inadequate response to initial treatment (5). However, a substantial proportion of patients exhibit resistance to anticholinergic therapy, highlighting the need for alternative treatment options. Alternative treatments for refractory cases have been explored. Imipramine, a tricyclic antidepressant, was traditionally considered the primary pharmacological treatment. However, it has been relegated to third-line therapy due to concerns about potential cardiac adverse effects (tachycardia, QTc prolongation) that require monitoring in pediatric populations. Recent evidence has shown that desmopressin + imipramine has significantly superior complete response (CR) rates compared with desmopressin + oxybutynin [68% vs. 5%, odds ratio (OR): 42.5, P<0.001]. This finding is attributed to imipramine’s central noradrenergic mechanism, which enhances arousal, rather than to its peripheral anticholinergic effects (6). The use of complementary approaches, including acupuncture, herbal medicine, and Tuina (Chinese therapeutic massage), particularly in Asian populations, has been investigated. Based on a systematic review of acupuncture modalities (7), moxibustion [risk ratio (RR): 1.47, P=0.004], acupoint injection (RR: 1.45, P=0.02), and laser acupuncture [standardized mean difference (SMD): −0.69, P=0.001] led to improvements compared with control interventions. However, all data obtained were rated as having very low quality. These nonpharmacological options may be interesting for families seeking alternative treatments. Nevertheless, high-quality evidence regarding their efficacy against treatment-resistant NE (TR-NE) remains limited. β3-adrenoceptor agonists are an established treatment for overactive bladder (8), being advantageous compared with anticholinergics given their more favorable side-effect profile, particularly a lower risk of constipation and dry mouth (9). These agonists relax the detrusor smooth muscle without affecting voiding function, potentially offering therapeutic benefits in patients with NE accompanied by detrusor overactivity (8).

Rationale and knowledge gap

Several studies have investigated the use of β3-adrenoceptor agonists in pediatric patients with voiding dysfunction. Mirabegron has demonstrated efficacy in children with neurogenic detrusor overactivity in an open-label phase III trial (10) and comparable effectiveness to solifenacin with better tolerability in pediatric idiopathic overactive bladder (11). A recent randomized controlled trial by Mansour et al. demonstrated that mirabegron significantly improved lower urinary tract symptoms in children with non-neurogenic overactive bladder who were resistant to standard urotherapy, showing superior efficacy and better tolerability compared with solifenacin. Although evidence for mirabegron use in NE remains limited, its favorable safety profile and efficacy in pediatric overactive bladder suggest potential applicability in desmopressin-resistant cases, warranting further investigation (12). The preliminary findings of Fujinaga et al. indicated that vibegron, a novel selective β3-adrenoceptor agonist, reduced enuretic episodes in children with anticholinergic-resistant NE (13); however, evidence specific to NE remains limited. This retrospective multicenter study helps address this gap by providing the largest pediatric dataset to date on vibegron and exploring different treatment strategies. These preliminary findings may inform future prospective studies and contribute to developing optimized management approaches for TR-NE.

Research gap and study rationale

Recent studies have revealed the efficacy of β3-adrenoceptor agonists for pediatric lower urinary tract dysfunction. However, there are still several critical research gaps in the literature. First, existing studies on vibegron (13,14) in children have been limited to small, single-center cohorts. Hence, they lack the statistical power to detect significant differences between treatment approaches or identify optimal patient selection criteria. Second, no large-scale studies have systematically compared different vibegron treatment strategies, specifically switching from failed therapies versus add-on approaches versus dual or triple combination regimens to guide evidence-based clinical decision-making. Finally, larger-scale real-world safety data from multicenter studies are required to establish evidence-based clinical guidelines.

Objective

This multicenter study aimed to evaluate the safety and effectiveness of vibegron in children with TR-NE and to compare different treatment strategies.

Study contributions and organization

The current study can make the following contributions to the literature:

• It is the largest multicenter retrospective cohort research evaluating the safety and efficacy of vibegron in TR-NE (387 patients across 12 institutions);
• Evaluates multiple treatment strategies, including switching from anticholinergics, add-on therapy, dual therapy, and triple therapy combinations;
• Shows that combination therapy targeting multiple pathophysiological mechanisms significantly outperforms monotherapy switching;
• Provides real-world safety and efficacy data with detailed subgroup analyses, offering practical insights for clinical decision-making.

The remainder of this manuscript is organized as follows: Section 2 describes the Methods section, which includes study design, patient selection, treatment protocols, and statistical analyses. Section 3 presents the study results, which include safety outcomes, overall treatment efficacy, and subgroup comparison findings across treatment strategies. Section 4 discusses key findings, compares the results of the current study with those of previous research, explains the mechanisms underlying the observed treatment effects, and acknowledges study limitations. Section 5 presents the conclusion of the study with clinical implications and recommendations for future research. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-573/rc).

Methods

This retrospective observational study was conducted across 12 hospitals and clinics affiliated [12 Institutional Review Board (IRB) approvals in total] with the members of the Japanese Society on Enuresis and Incontinence. The study protocol was approved by the ethics committees of all participating institutions: Showa Medical University Northern Yokohama Hospital, and Showa Medical University Fujigaoka Hospital (approval No. 21-105-B), Juntendo University Urayasu Hospital (approval No. P21-0012-U01), Kansai Medical University Hospital (approval No. 2021370), Fussa Hospital (approval No. 2021-41), Sasaki Clinic (approval No. 0001), Teikyo University Hospital (approval No. 22-003), Ehime University Hospital (approval No. 2205005), Kitano Hospital (approval No. P220300700), Juntendo University Nerima Hospital (approval No. E22-0062), Jin Children’s Clinic (approval No. 0001), Saitama Children’s Medical Center (approval No. 2022-01-015). The current study was retrospective in nature, and the medical records of the patients were reviewed while maintaining the privacy of each individual. Hence, informed consent was not required. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

This study included children aged 5–18 years who received vibegron (50 mg once daily) for refractory NE between November 27, 2018, and December 31, 2021. The following inclusion criteria were standardized: children with NE who did not achieve adequate response (defined as <50% symptom improvement after ≥12 weeks) to the first-line active treatments recommended by the ICCS guidelines (desmopressin and/or enuresis alarm therapy) after urotherapy. Of the 387 patients who were enrolled, 1 patient who dropped out during the first visit was excluded from the safety analysis, and 17 patients who self-discontinued within 1 month were excluded from the efficacy analysis. Finally, 386 patients were included in the safety assessment and 369 in the efficacy evaluation (Figure 1). This study included monosymptomatic NE (MNE) and nonmonosymptomatic NE (NMNE) with daytime urinary incontinence (DUI). Among the enrolled patients, 144 (37.2%) had concurrent DUI, defined as the involuntary loss of urine during daytime that occurred at least once per week, as documented in medical records based on patient/parent reports. Constipation was defined as fewer than three bowel movements per week, as documented in medical records based on the physician’s discretion. Patients who had a neurogenic bladder, developmental disorders, and congenital anomalies of the urogenital tract, had discontinued medication, or dropped out after the first visit were excluded.

Figure 1 Patient flow diagram for safety and efficacy analyses in children with TR-NE treated with vibegron. AC, anticholinergics; DDAVP, desmopressin; TR-NE, treatment-resistant nocturnal enuresis.

Data collection and outcome measures

Baseline information—including sex, age, presence of DUI, constipation, and the number of wet nights during the 4 weeks before treatment—was collected from medical records. The primary outcome was reduction in wet nights per 30 days, categorized using the ICCS criteria into CR (100% reduction or ≤1 wet night/month), partial response (PR: 50–99% reduction), and no response (NR: <50% reduction). This outcome was assessed based on the patient/parent reports of wet nights within 30 days prior to follow-up visits. Due to the study’s retrospective multicenter design, standardized 30-day voiding diaries were not uniformly collected. Data were primarily obtained via history taking documented in medical records. To account for variability in follow-up intervals (ranging from approximately 3 weeks to 2 months, depending on clinic schedules), values were normalized to 30-day equivalents.

Treatment strategy and subgroup classification

Although this study focuses on evaluating the overall efficacy and safety of vibegron, a secondary exploratory analysis was conducted to assess differences in treatment strategy. Patients were retrospectively classified based on insufficient response to prior therapy into an add-on group in which vibegron was combined with existing therapy (e.g., desmopressin, enuresis alarm, or anticholinergics), and a switch group in which patients were transitioned from prior anticholinergic agents to vibegron. The treatment strategy was selected based on the discretion of the attending physician.

For secondary analysis, patients were categorized into the switch group (n=160) and the add-on group (n=209). The add-on group was further subdivided based on the type of concurrent therapy: desmopressin (DDAVP) addition (n=63), alarm addition (n=26), anticholinergic addition (n=39), dual therapy addition (DDAVP or alarm + anticholinergics, n=50), and triple therapy (DDAVP + alarm + anticholinergics) with vibegron (n=31). These subgroup analyses were exploratory and intended to generate hypotheses for future prospective studies.

Safety assessment

Adverse events were assessed at the first outpatient visit after starting vibegron and in subsequent follow-ups. All events were collected through spontaneous reporting, regardless of the type or severity. The median duration of vibegron use was 245 [interquartile range (IQR), 126–484] days, enabling the assessment of both early and delayed adverse effects in pediatric patients. Medication compliance, calculated as the percentage of prescribed doses taken over 30 days, was assessed during follow-up visits based on patient/parent reports and via a review of prescribing records.

Statistical analysis

Descriptive statistics were calculated for baseline characteristics and treatment outcomes. Continuous variables were presented as mean ± standard deviation or median and IQR, as appropriate. Categorical variables were presented as counts and percentages. The Wilcoxon rank-sum test was conducted for continuous variables, whereas Pearson’s chi-square test was employed for categorical variables. For comparisons between the add-on and switch groups (secondary analysis), P values <0.05 were considered significant. Effect sizes were calculated for between-group comparisons using Cohen’s d and odds ratios with 95% confidence intervals (95% CI), where appropriate. Given the exploratory nature of subgroup analyses, no correction for multiple comparisons was applied. To evaluate treatment safety, the number needed to harm (NNH) was estimated. All analyses were conducted using JMP Pro version 18 (SAS Institute Inc., Cary, NC, USA).

Results

Study population and baseline characteristics

A total of 387 children with refractory NE received vibegron therapy during the study period. One patient dropped out at the first outpatient visit after starting medication and was excluded from the safety analysis. An additional 17 patients self-discontinued treatment within 1 month and were excluded from the efficacy analysis, resulting in 386 patients enrolled for safety assessment and 369 patients for treatment efficacy evaluation (Figure 1).

Table 1 presents the baseline demographic and clinical characteristics. The study population comprised 288 boys (74.4%) and 99 girls (25.6%), with a mean age of 8.4±2.0 years and a mean body weight of 27.8±8.9 kg. Moreover, 78 (20.2%) patients experienced constipation, and 144 (37.2%) had DUI. The mean duration from the first visit to vibegron treatment initiation was 471.9±483.6 days, confirming that all patients had TR-NE. The median duration of vibegron use was 245 (IQR, 126–484) days. In total, 366/369 patients had available data on medication compliance, and three patients with missing compliance records were excluded from the analysis. The adherence rates were as follows: 100% in 239 (65.3%) patients, 90–99% in 63 (17.2%), 50–89% in 63 (17.2%), and <50% in 1 (0.3%). Overall, 302 (82.5%) patients had an adherence rate of ≥90%.

Treatment efficacy

As regards overall treatment response, 64 (17.3%) patients achieved CR, 131 (35.5%) achieved PR, and 174 (47.2%) showed NR. The mean reduction in bedwetting episodes was 7.1±7.7 days per 30 days from baseline.

Subgroup analysis by treatment strategy

Marked differences in treatment outcomes were observed between treatment strategies (Table 2). The alarm addition subgroup demonstrated the highest efficacy, with wet nights decreasing from 14.7±7.5 to 4.4±4.2 days per 30 days, representing a 71.6% reduction. This subgroup achieved a CR rate of 27% and the lowest NR rate of 15%. The triple therapy group also exhibited favorable outcomes, with a 61.6% reduction in wet nights and a 26% CR rate. Among the dual therapy combinations, the DDAVP + anticholinergic + vibegron subgroup (n=33) achieved a 58.3% reduction in wet nights with 27% CR. Meanwhile, the DDAVP + alarm + vibegron subgroup (n=17) exhibited a 63.8% reduction rate and the highest CR rate (42%). In contrast, patients who switched from anticholinergics and those receiving DDAVP addition demonstrated more modest improvements, with 40.1% and 42% reductions in wet nights, respectively. Only 11% of the patients in the switch group achieved CR, whereas the DDAVP addition group had a 7% CR rate.

Comparative analysis between treatment approaches

When comparing the two main treatment approaches, the add-on group demonstrated significantly superior outcomes to the switch group (Table 3). The add-on group achieved a greater reduction in wet nights from baseline (8.1±7.6 vs. 6.3±7.5 days, P=0.009; Cohen’s d =0.24, small effect size) and a higher percentage reduction (56.9% vs. 40.1%, P<0.001). The combined response rate (complete + PR) was significantly higher in the add-on group than in the switch group (62% vs. 42%, OR =2.28, 95% CI: 1.50–3.48; P<0.001).

Safety assessment

Four patients (1.0%) experienced adverse events that required discontinuation of vibegron (Table 4). All affected patients were male, aged 6.8–9.1 years, and were receiving concomitant solifenacin treatment. The reported adverse events included rotatory dizziness (n=1), worsening constipation (n=1), and rash (n=2). Three adverse events occurred within the first month of treatment, whereas one case of rash developed after 1–2 months. All adverse events resolved promptly upon discontinuation of vibegron, and no serious adverse events were reported during the study period. The NNH was 100, indicating excellent tolerability in the pediatric population.

Discussion

Key findings

This retrospective multicenter study demonstrated that vibegron, a β3-adrenoceptor agonist, exhibited a favorable safety profile and significant efficacy in treating TR-NE in Japanese children and adolescents. The findings offer substantial evidence for the clinical utility of this novel therapeutic approach in a challenging patient population where conventional treatments have proven insufficient.

Treatment efficacy

This study uncovered the clinically meaningful therapeutic benefits of vibegron therapy. Overall, 52.8% of the patients achieved a significant clinical response (≥50% reduction in wet nights), with 17.3% achieving CR and 35.5% achieving PR according to the ICCS criteria. The mean reduction in bedwetting episodes of 7.1±7.7 days per 30 days represents a substantial improvement in this treatment-resistant population. These results are consistent with the findings of previous smaller studies. Fujinaga et al. (13) reported a 56% improvement rate in 17 children with TR-NE, supporting the efficacy observed in our larger cohort. The effectiveness of vibegron can be attributed to its distinct mechanism of action: β3-adrenoceptor agonists directly relax the detrusor smooth muscle without affecting voiding function (14), potentially offering therapeutic benefits in patients who have demonstrated resistance to anticholinergic therapy.

Treatment strategy analysis: add-on versus switch versus triple therapy

The subgroup analysis revealed critical insights regarding optimal treatment strategies. The add-on group demonstrated significantly superior outcomes to the switch group (56.9% vs. 40.1% reduction in wet nights, P<0.001), indicating that combining vibegron with existing therapies is more effective than switching from anticholinergics to vibegron monotherapy. This finding aligns with current clinical evidence indicating that anticholinergic monotherapy or simple medication switches often provide limited efficacy in NE, particularly in treatment-resistant cases (5,8). However, the add-on group may have shown some residual responsiveness to previous treatments, which could have influenced the observed superiority. Although the results support the add-on strategy, prospective validation controlling for baseline response status is warranted. The superior performance of combination approaches reflects the multifactorial pathophysiology of NE, which typically requires interventions targeting multiple mechanisms simultaneously. Most notably, the combination approaches had superior outcomes compared with monotherapy. The alarm addition subgroup achieved the highest reduction in wet nights (71.6%), and the DDAVP + alarm + vibegron combination had the highest CR rate (42%). Triple therapy (vibegron + desmopressin + alarm + anticholinergic), which represents a comprehensive four-drug regimen, achieved a reduction rate of 61.6% and a CR rate of 26%. These findings support the hypothesis that β3-adrenoceptor agonists and anticholinergics can improve bladder function via distinct pathways, creating synergistic therapeutic effects (15). The combination of desmopressin (which addresses nocturnal polyuria), anticholinergics (which reduce detrusor overactivity), and vibegron (which facilitates β3-mediated bladder relaxation) targets multiple pathophysiological mechanisms simultaneously. This may explain the favorable outcomes observed in treatment-resistant cases. Notably, the superior performance of DDAVP + alarm + vibegron over DDAVP + anticholinergic + vibegron underscores the importance of behavioral interventions via alarm therapy in addition to pharmacological interventions. Previous meta-analyses have demonstrated that desmopressin–alarm combination therapy achieves higher response rates and lower relapse rates than monotherapy, with significant relative risk improvements (16,17). Although this study did not directly assess relapse rates after therapy cessation, the inclusion of alarm therapy—known to reduce relapse compared with desmopressin monotherapy—may contribute to greater long-term treatment persistence and sustainability. The lower-than-expected response rates with vibegron + desmopressin further emphasize the critical importance of behavioral interventions in treatment-resistant cases.

Safety profile

The safety profile was highly favorable, with only 4 out of 386 (1.0%) patients experiencing adverse events requiring treatment discontinuation. All adverse events were mild and resolved promptly upon vibegron discontinuation. This rate compares remarkably well with the results of adult studies of β3-adrenoceptor agonists. Yoshida et al. (9) reported that 27 out of 169 (16.0%) adults with overactive bladder experienced drug-related adverse events during vibegron therapy. The substantially lower incidence of adverse events in our pediatric cohort signifies enhanced tolerability in younger populations, supporting the safety of the standardized 50-mg daily dose across different pediatric age groups and body weights. Although the median observation period of 245 days was shorter than that in adult studies, the markedly lower adverse event rate indicates that vibegron may be particularly well-suited for long-term treatment strategies in children with TR-NE. This favorable safety profile addresses a significant clinical need, as many children require prolonged therapy to achieve sustained improvement. The median duration of vibegron use (245 days) may be prolonged; however, such extended treatment periods are often necessary in treatment-resistant cases to achieve and consolidate response, particularly when multimodal therapy is employed.

Limitations

Several important limitations should be acknowledged. First, the retrospective design prevented standardized objective assessments, including urodynamic studies, maximum voided volume measurements, and postvoid residual volume assessments, which could have provided valuable physiological data to support clinical findings. The study’s retrospective design also limited our ability to ensure standardized 30-day evaluation periods, with actual follow-up intervals ranging from approximately 3 to 8 weeks, depending on clinic schedules and patient attendance. Values were normalized to 30-day equivalents. Moreover, the decision to initiate vibegron and the choice between switch and combination strategies were made based on the discretion of attending physicians rather than by a prospectively defined protocol. This might have introduced heterogeneity across centers. In addition, the reasons for early treatment discontinuation could not be completely documented. Further, some patients who initially responded to the treatment were lost to follow-up beyond 1 month. Therefore, long-term outcomes such as relapse rates and sustained CR could not be systematically assessed. Thus, future prospective studies with structured long-term follow-up should be conducted to evaluate treatment durability. Second, although constipation status was documented at baseline (20.2%), we did not systematically implement or monitor bowel management protocols, nor did we perform stratified analyses according to constipation status. This might have influenced treatment outcomes. Third, changes in concomitant treatments (e.g., discontinuation of alarm therapy) during follow-up were not systematically documented, which might have influenced treatment outcomes. Fourth, although the treatment duration of vibegron (median: 245 days) was documented, we did not systematically assess treatment response at the end of therapy. Treatment efficacy was evaluated at approximately 1 month. However, we could not determine whether the initial responders maintained their response or when CR was first achieved during the treatment course. Therefore, future prospective studies should incorporate the systematic documentation of treatment milestones throughout the whole treatment period. Fifth, although our study intentionally included MNE and NMNE (37.2% with DUI), we did not systematically assess DUI severity or frequency beyond the once-weekly threshold, nor did we systematically evaluate other daytime lower urinary tract symptoms such as urgency and increased daytime frequency. Stratified analyses according to DUI status or daytime symptom profiles were not performed, and this might have provided additional insights into differential treatment responses. Sixth, the relatively short follow-up period (median of 245 days) limited our evaluation of long-term treatment outcomes and detection of potential delayed adverse effects. Seventh, although a fixed dose of 50 mg/day of vibegron was used in this study regardless of body weight or age, future studies should explore the optimal dosing strategy in pediatric populations, potentially adjusting for age, body weight, or bladder capacity. Eighth, the generalizability of the results may be limited by the inclusion of only Japanese patients, requiring validation in more diverse populations and healthcare settings. Finally, the exploratory nature of the subgroup analyses may have been underpowered to detect clinically meaningful differences between some treatment strategies.

Comparison with similar research

Previous studies have examined the efficacy of vibegron in pediatric lower urinary tract dysfunction and TR-NE. Kitta et al. reported that vibegron improved bladder capacity and compliance without adversely affecting voiding function in children and adolescents with overactive bladder (14). Fujinaga and Onuki found that vibegron, when combined with desmopressin, solifenacin, and a wireless alarm therapy, reduced enuretic episodes in children with refractory NE (18). Our findings are consistent with these reports and expand the evidence base by providing the largest multicenter dataset to date, quantifying comparative outcomes across treatment strategies, and confirming the superior efficacy of triple therapy. The use of mirabegron, which is another β3-adrenoceptor agonist, primarily for overactive bladder and neurogenic detrusor overactivity in pediatric populations, has been evaluated. Soliman et al. reported that mirabegron was comparable to solifenacin in terms of efficacy and had better tolerability in patients with pediatric idiopathic overactive bladder (11). Another report has shown that combination therapy with mirabegron and anticholinergics produces synergistic therapeutic effects. This finding supports the hypothesis that β3-receptor agonists and anticholinergics improve bladder function via distinct pathways (19). Our findings are in accordance with this concept, demonstrating that the application of vibegron as an add-on therapy to existing anticholinergic regimens achieved significant improvements in treatment-resistant cases.

Comparison with mirabegron and literature gaps

Although vibegron and mirabegron are established treatments for adult overactive bladder, data on their use against pediatric NE remain limited. This reflects regulatory approval delays for pediatric indications, traditional reliance on anticholinergics, and the challenges of conducting large-scale trials in heterogeneous treatment-resistant populations. Our study focused on vibegron because it represented real-world practice after its approval in 2018 in Japan. Mirabegron lacked pediatric approval during our study period. The recent randomized controlled trial conducted by Mansour et al. (12) provides important comparative evidence, showing the efficacy of mirabegron in children with non-neurogenic overactive bladder who were resistant to standard urotherapy, demonstrating superior outcomes and better tolerability compared with solifenacin. Future prospective comparative studies would help guide evidence-based therapeutic selection.

Clinical positioning of vibegron

Our multicenter real-world data indicate that vibegron may be considered as an add-on therapeutic option for treatment-resistant cases rather than as first-line monotherapy. The ICCS guidelines (20) recommend combination therapy with anticholinergics and desmopressin in patients with suspected bladder overactivity. However, our study provides preliminary evidence on the potential efficacy of incorporating β3-adrenoceptor agonists. In cases where standard dual therapy with desmopressin and anticholinergics did not achieve adequate improvement, the addition of vibegron resulted in significant clinical response. This finding provides the first large-scale pediatric dataset specifically for vibegron in TR-NE, contributing to the evolving evidence base for multimodal treatment strategies that address the multifactorial pathophysiology of refractory NE.

Emerging technologies and future directions

Recent technological advancements represent promising future directions for the management of NE. Prevoid alerting systems, such as the MyPAD device, use artificial intelligence (AI)-based algorithms (Bi-LSTM-RNN) to detect bladder activity before voiding occurs, achieving a sensitivity of 99% and a specificity of 99.5% (21). This represents a paradigm shift from traditional postvoid alarms to predictive alerting. In addition, wireless alarm devices have demonstrated superior outcomes compared with wired systems, with significantly lower dropout rates (6.1% vs. 20.0%) and higher CR rates (72.9% vs. 39.7%) (22). Our study evaluated established alarm and pharmacological therapies. However, future research should explore the integration of these AI-based prevoid alerting systems with pharmacological approaches such as vibegron, which can potentially enhance treatment outcomes in refractory cases.

Explanations of findings

The observed efficacy of vibegron is likely attributable to its selective β3-adrenoceptor agonism, which relaxes detrusor smooth muscle without impairing voiding. This mechanism may benefit patients with detrusor overactivity or reduced functional bladder capacity, both of which can contribute to TR-NE. The superior outcomes with add-on and triple therapy suggest that addressing multiple pathophysiological mechanisms—detrusor overactivity, nocturnal polyuria, and arousal dysfunction—produces synergistic effects. The high response rate in the alarm addition subgroup underscores the importance of targeting arousal deficits alongside pharmacotherapy. In addition, the low incidence of mild, self-limiting adverse events supports the suitability of vibegron for long-term, multimodal management in pediatric populations. Role of constipation and bowel dysfunction: constipation plays an essential role in the pathophysiology of NE. The ICCS standardization document (2) emphasizes that urotherapy, including bowel management, should be the foundation of treatment prior to pharmacological interventions. Constipation increases bladder overactivity via rectal distension and altered pelvic floor dynamics, and successful treatment of constipation has been shown to improve daytime lower urinary tract symptoms and NE. In our study, 20.2% of patients presented with constipation at baseline. However, systematic bowel management protocols and follow-up of constipation status during vibegron therapy were not standardized across participating centers. In addition, we did not perform subgroup analyses stratified by constipation status to evaluate whether bowel dysfunction modified treatment responsiveness. Hence, future prospective studies should systematically address constipation management and evaluate its impact on pharmacological and combination therapy outcomes.

Implications and actions needed

The findings have significant implications for clinical practice and the development of treatment algorithms. For children who demonstrate inadequate response to first-line treatment modalities, vibegron-based regimens offer a viable alternative with a favorable risk-benefit profile. The findings support an add-on strategy rather than sequential medication switches, particularly when PR to conventional treatment has been achieved. The superior outcomes observed with triple therapy imply that clinicians should consider comprehensive multimodal approaches for TR-NE. Rather than pursuing sequential monotherapy trials, incorporating vibegron into existing treatment regimens may yield more efficient and effective outcomes. The safety profile supports its use in pediatric populations, addressing a significant unmet clinical need in this challenging condition. Although the cohort was limited to Japanese children, the pathophysiological mechanisms targeted by vibegron and the combination strategies are broadly applicable. Nonetheless, validation in more ethnically and socioculturally diverse populations is necessary to confirm global generalizability.

Conclusions

This multicenter study provides the largest real-world evidence base for vibegron in TR-NE (n=387 across 12 institutions), addressing critical gaps in the literature. We showed favorable safety [mild adverse events with no serious adverse events: 1.0% (4/386)] and meaningful efficacy (overall response rate: 52.8%), with the addition of alarm therapy achieving superior outcomes (reduction in wet nights: 71.6%) compared with switching monotherapy (40.1%). Based on our systematic comparison of treatment strategies, combination approaches targeting multiple pathophysiological mechanisms significantly outperformed monotherapy switching, providing evidence-based guidance for decisions regarding treatment escalation.

These findings address an important clinical need, effective treatment not only reduces bedwetting symptoms but also prevents psychosocial sequelae, including family conflict and inappropriate disciplinary responses arising from parental frustration, which exacerbate children’s anxiety and depression (23-25). For the research community, this study provides the following: (I) comparative efficacy data that guide treatment protocols; (II) comprehensive subgroup analyses identifying optimal strategies for specific patient populations, and (III) a framework for integrating behavioral and pharmacological approaches. Clinicians can utilize these findings to counsel families about realistic expectations and timely intervention options when first-line therapies are not successful.

Nevertheless, future prospective trials incorporating quality of life assessments, facilitating longer follow-ups for relapse evaluation, and integrating emerging technologies (AI-based alerting systems) should be performed to validate and extend these findings.

Acknowledgments

The authors thank all participating institutions of the Japanese Society on Enuresis and Incontinence for their cooperation in data collection. We would like to express our sincere gratitude to Dr. Akihiro Kawauchi and Dr. Kazunari Kaneko for their invaluable guidance and advice in the conception and supervision of this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-573/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-573/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-573/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-573/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the ethics committees of all participating institutions: Showa Medical University Northern Yokohama Hospital, and Showa Medical University Fujigaoka Hospital (approval No. 21-105-B), Juntendo University Urayasu Hospital (approval No. P21-0012-U01), Kansai Medical University Hospital (approval No. 2021370), Fussa Hospital (approval No. 2021-41), Sasaki Clinic (approval No. 0001), Teikyo University Hospital (approval No. 22-003), Ehime University Hospital (approval No. 2205005), Kitano Hospital (approval No. P220300700), Juntendo University Nerima Hospital (approval No. E22-0062), Jin Children’s Clinic (approval No. 0001), Saitama Children’s Medical Center (approval No. 2022-01-015). The current study was retrospective in nature, and the medical records of the patients were reviewed while maintaining the privacy of each individual. Hence, informed consent was not required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Butler RJ, Heron J. The prevalence of infrequent bedwetting and nocturnal enuresis in childhood. A large British cohort. Scand J Urol Nephrol 2008;42:257-64. [Crossref] [PubMed]
2. Nevéus T, Fonseca E, Franco I, et al. Management and treatment of nocturnal enuresis-an updated standardization document from the International Children's Continence Society. J Pediatr Urol 2020;16:10-9. [Crossref] [PubMed]
3. Caldwell PH, Nankivell G, Sureshkumar P. Simple behavioural interventions for nocturnal enuresis in children. Cochrane Database Syst Rev 2013;CD003637. [Crossref] [PubMed]
4. Tai BT, Tai TT, Chang YJ, et al. Factors associated with remission of primary nocturnal enuresis and changes of parental perception towards management strategies: A follow-up study. J Pediatr Urol 2017;13:44.e1-9. [Crossref] [PubMed]
5. Tsuji S, Kaneko K. Management of treatment-resistant nocturnal enuresis. Pediatr Int 2023;65:e15573. [Crossref] [PubMed]
6. Shain S, Gitlin J, Pantazis A, et al. Management of the refractory nocturnal enuresis patient to desmopressin in a pediatric population: Desmopressin + oxybutynin vs. desmopressin + imipramine. J Pediatr Urol 2024;20:603.e1-8. [Crossref] [PubMed]
7. Kannan P, Bello UM. The efficacy of different forms of acupuncture for the treatment of nocturnal enuresis in children: A systematic review and meta-analysis. Explore (NY) 2022;18:488-97. [Crossref] [PubMed]
8. Yamaguchi O, Marui E, Kakizaki H, et al. Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int 2014;113:951-60. [Crossref] [PubMed]
9. Yoshida M, Kakizaki H, Takahashi S, et al. Long-term safety and efficacy of the novel β3-adrenoreceptor agonist vibegron in Japanese patients with overactive bladder: A phase III prospective study. Int J Urol 2018;25:668-75. [Crossref] [PubMed]
10. Chapple CR, Cardozo L, Nitti VW, et al. Mirabegron in overactive bladder: a review of efficacy, safety, and tolerability. Neurourol Urodyn 2014;33:17-30. [Crossref] [PubMed]
11. Soliman MG, El-Abd S, El-Gamal OM, et al. Mirabegron versus Solifenacin in Children with Overactive Bladder: Prospective Randomized Single-Blind Controlled Trial. Urol Int 2021;105:1011-7. [Crossref] [PubMed]
12. Mansour I, Hassan A, Farag F, et al. Efficacy and safety of mirabegron compared to Solifenacin in treatment of non-neurogenic overactive bladder in children: a randomized controlled trial. Int Braz J Urol 2025;51:e20240425. [Crossref] [PubMed]
13. Fujinaga S, Watanabe Y, Nakagawa M. Efficacy of the novel selective β3-adrenoreceptor agonist vibegron for treatment-resistant monosymptomatic nocturnal enuresis in children. Int J Urol 2020;27:693-4. [Crossref] [PubMed]
14. Kitta T, Chiba H, Kon M, et al. Urodynamic evaluation of the efficacy of vibegron, a new β3-adrenergic receptor agonist, on lower urinary tract function in children and adolescents with overactive bladder. J Pediatr Urol 2022;18:563-9. [Crossref] [PubMed]
15. Yamaguchi O. Beta3-adrenoceptors in human detrusor muscle. Urology 2002;59:25-9. [Crossref] [PubMed]
16. Chua ME, Silangcruz JM, Chang SJ, et al. Desmopressin Withdrawal Strategy for Pediatric Enuresis: A Meta-analysis. Pediatrics 2016;138:e20160495. [Crossref] [PubMed]
17. Park SJ, Park JM, Pai KS, et al. Desmopressin alone versus desmopressin and an anticholinergic in the first-line treatment of primary monosymptomatic nocturnal enuresis: a multicenter study. Pediatr Nephrol 2014;29:1195-200. [Crossref] [PubMed]
18. Fujinaga S, Onuki Y. Efficacy of vibegron for refractory enuresis after combination therapy with desmopressin, solifenacin, and wireless alarm. Pediatr Int 2022;64:e15248. [Crossref] [PubMed]
19. Blais AS, Nadeau G, Moore K, et al. Prospective Pilot Study of Mirabegron in Pediatric Patients with Overactive Bladder. Eur Urol 2016;70:9-13. [Crossref] [PubMed]
20. Austin PF, Bauer SB, Bower W, et al. The standardization of terminology of lower urinary tract function in children and adolescents: Update report from the standardization committee of the International Children's Continence Society. Neurourol Urodyn 2016;35:471-81. [Crossref] [PubMed]
21. Kuru K, Ansell D, Hughes D, et al. Treatment of Nocturnal Enuresis Using Miniaturised Smart Mechatronics With Artificial Intelligence. IEEE J Transl Eng Health Med 2024;12:204-14. [Crossref] [PubMed]
22. Watanabe T, Ikeda H, Ono T, et al. Comparison of wireless and wired alarm devices for nocturnal enuresis treatment. Pediatr Int 2022;64:e15328. [Crossref] [PubMed]
23. Roccella M, Smirni D, Smirni P, et al. Parental Stress and Parental Ratings of Behavioral Problems of Enuretic Children. Front Neurol 2019;10:1054. [Crossref] [PubMed]
24. Al-Zaben FN, Sehlo MG. Punishment for bedwetting is associated with child depression and reduced quality of life. Child Abuse Negl 2015;43:22-9. [Crossref] [PubMed]
25. Butler RJ. Childhood nocturnal enuresis: developing a conceptual framework. Clin Psychol Rev 2004;24:909-31. [Crossref] [PubMed]