Introduction
Overactive bladder (OAB) is characterized by episodes of a strong, sudden urge or need to urinate immediately (urgency), usually accompanied by frequency and nocturia with or without urge urinary incontinence (UUI) [
1,
2]. This common and chronic condition can have a profound impact on patient’s lives by causing embarrassment, impairing daily functioning and relationships, and in some cases requiring patients to plan their lives around accommodating their symptoms [
3‐
5]. Accordingly, OAB has been shown to negatively affect health-related quality of life (QoL) and contribute to symptoms of anxiety and depression [
6‐
8]. Among patients with OAB, the severity of OAB symptoms is positively correlated with the severity of anxiety and depression symptoms [
9,
10].
Goals of treatment for OAB include improving not only symptom control but also patient QoL [
2]. Standard regulatory endpoints, including reductions in bothersome symptoms (frequent micturitions, urgency episodes, and UUI episodes), are typically collected and reported in clinical trials of OAB [
11‐
15]. Although clinical trials are increasingly including patient-reported outcomes (PROs) to measure symptoms and impact on daily functioning [
11‐
14,
16,
17], it is important to individualize goal setting with the understanding that improvements in symptoms and QoL observed in large clinical trials may not necessarily translate to meaningful changes for individual patients. Assessing the magnitude of improvement in bothersome symptoms that is considered relevant from the patient perspective represents an important step toward establishing the ability of interventions to produce meaningful changes. For example, even small improvements in OAB symptoms, such as reduction in micturition frequency by one or two episodes, may be considered meaningful by an individual patient. Several trials of OAB medications have incorporated responder rates in an effort to demonstrate rates of clinically meaningful change based on predefined endpoints [
12,
14,
17‐
19].
Vibegron is a selective β
3-adrenergic receptor agonist approved for treatment of OAB in adults [
20]. In the 12-week, phase 3 EMPOWUR trial, vibegron significantly reduced micturitions and UUI episodes (coprimary endpoints), as well as urgency episodes (key secondary endpoint), vs placebo (
P < 0.01 each) [
21]. Compared with placebo, vibegron was also associated with significantly greater improvement in PROs, including the OAB questionnaire (OAB-q) and Patient Global Impression scores [
17]. Statistically significantly greater proportions of patients receiving vibegron vs placebo were classified as responders at week 12 for coping scores and symptom bother scores based on a 10-point minimally important difference (MID) for OAB-q subscales.
The current analysis used an anchor-based approach to interpret the meaningfulness of reductions in clinical trial endpoints observed in the EMPOWUR trial and to demonstrate treatment effects in the proportion of patients achieving meaningful change in OAB endpoints, with the threshold predefined based on categories of improvement on the Patient Global Impression of Change (PGI-C).
Discussion
In the phase 3 EMPOWUR trial, vibegron 75 mg demonstrated consistent mean improvements across clinically relevant OAB symptoms, including micturition frequency, urgency episodes, and UUI episodes compared with placebo [
21]. The clinical relevance of these improvements is supported by significant changes in PROs with vibegron vs placebo, including improvements in the OAB-q subscales and PGI-C [
17].
In response to a regulatory request, the current analyses were performed to provide validation for the clinical meaningfulness of co-primary and key secondary efficacy endpoints from the EMPOWUR trial. Associations between median percentage changes in frequency of average daily micturitions, urgency episodes, and UUI episodes and PGI-C categories were moderate to strong, further supporting use of the PGI-C in deriving responder definitions [
26]. Notably, the cutoff values used were comparable to or greater than those identified as representing minimally important differences in an analysis that employed anchor- and distribution-based methods using data from the phase 2, 8-week, randomized, placebo- and active-controlled trial [
27]. These responder definitions derived from the phase 2 trial allowed prespecifying phase 3 responder definitions in EMPOWUR. In the current analysis, significantly more patients receiving vibegron vs placebo in EMPOWUR achieved meaningful reductions in micturitions, urgency episodes, and UUI episodes that were associated with patient-perceived improvement according to PGI-C. Results of this analysis are strongly supportive of the clinical meaningfulness of the co-primary and key secondary endpoint results from the EMPOWUR trial. In addition, qualitative interview results identified micturition frequency, urgency, and leakage as the most bothersome symptoms, providing further support for the content validity of the patient voiding diary and efficacy endpoints used in the phase 3 EMPOWUR trial of vibegron in patients with OAB [
21]. In addition, such interviews supported the responder definitions for UUI and urgency episodes that were prespecified in EMPOWUR as key secondary endpoints.
Clinical trials of OAB have evaluated clinical meaningfulness of interventions using a variety of approaches. Demonstration of statistically significant effects on PROs—including measures of QoL, patient satisfaction with treatment, and patient perception of improvement—reflect treatment benefits in relation to outcomes of importance from the patient perspective [
11,
13,
14,
17]. Anchor- and distribution-based methods can be used to determine thresholds for responder analyses to demonstrate clinically meaningful improvement in PROs or objective measures [
17‐
19,
28,
29]. Previous studies have reported responder rates based on percentage changes in urgency episodes and/or incontinence episodes [
12,
14,
21]. Notably, a pooled analysis of three randomized, placebo-controlled trials of darifenacin in adults with OAB reported responder rates for a ≥ 50% reduction in urgency episodes (31–34%) and a ≥ 90% reduction in incontinence episodes (27–28%) with darifenacin [
12]; corresponding placebo rates were lower in the darifenacin analyses (23–24% and 17%, respectively), resulting in similar treatment differences vs placebo. The current analysis adds to the literature by identifying cutoff values that are associated with patient perception of meaningful improvement and by demonstrating a significant drug effect based on these cutoff values.
Correlations between OAB symptoms and PROs support the use of PROs as a measure of treatment efficacy and provide an indication of the degree to which improvements in OAB symptoms may predict improvements in patient perceptions and health-related QoL. Analyses of data from several clinical trials of anticholinergics demonstrated that improvements in OAB symptoms over 12 weeks of treatment were significantly correlated with improvements in Patient Perception of Bladder Condition (PPBC) as well as with improvements in health-related QoL [
18,
30‐
33]. Correlation sizes were typically moderate for PPBC and small to moderate for health-related QoL domains.
Patient satisfaction is often driven by patient expectations and by whether the benefits of treatment meet patient goals [
34]. Goal setting is an individualized process that addresses the ways in which a health condition affects the patient’s daily life. Patient goals may refer to improvement in symptoms (e.g., reducing nocturia or urgency), although specific goals may also be stated in relation to activities (e.g., improving sleep quality, being able to walk the dog without needing the toilet) [
4,
34,
35]. Studies have demonstrated statistically significant correlations between goal achievement and patient satisfaction as well as between goal achievement and both patient perception of treatment benefit and health-related QoL among patients with OAB receiving anticholinergic therapy [
35,
36]. Although it is reasonable to expect that the significantly higher response rates achieved with vibegron vs placebo in the current analysis would translate to greater levels of goal attainment and patient satisfaction, further research is warranted.
Placebo-controlled trials are critical to interpretation of OAB treatment effects because of the typically strong placebo and learning effects in clinical trials. In a meta-analysis of 57 randomized, placebo-controlled trials investigating oral pharmacotherapy for OAB, placebo was associated with statistically significant improvements from baseline in mean [95% CI] daily numbers of micturitions (−0.45 [−0.51 to −0.40];
P < 0.001), urgency episodes (−0.50 [−0.62 to −0.40];
P < 0.001), and UUI episodes (−0.46 [−0.55 to −0.38];
P < 0.001) [
37]. The authors noted several potential factors underlying the placebo response including the use of voiding diaries, which may be a form of behavioral therapy; contextual factors; a psychological response to being in a perceived therapeutic situation; effects of information provided to patients during studies; and the dynamic nature of OAB [
37]. Assessing eligibility after patients have completed the voiding diary at screening and during the placebo run-in period, as was done in the EMPOWUR trial, is important to reduce the potential placebo effect associated with maintaining a voiding diary. However, additional factors may contribute to the placebo effect, and it is notable that approximately 24 to 45% of patients receiving placebo in this analysis were classified as responders based on the various cutoff criteria.
Key limitations of the current analysis are that it did not separately analyze patients with OAB wet vs OAB dry. These analyses were not powered to detect statistical significance; sample size calculations were based on the coprimary endpoints. Additionally, the findings represent results from clinical trials, which may not be generalizable to real-world settings where the population is more heterogenous and where lifestyle factors may affect patient perceptions of improvement.
Acknowledgements
We thank the participants of the study.