BERKELEY, CA (UroToday.com) - Oral pharmacological treatment options for overactive bladder (OAB) include antimuscarinics as first-line therapy.[1,2] However, OAB patients may have a suboptimal response or find that antimuscarinic therapy is limited by associated adverse events (AEs), with dry mouth the most common and bothersome AE.[3,4] For these patients there has not been another class of oral therapeutic agents available. Therefore, there is a need for a new treatment option for OAB that is effective and well tolerated.
A new mechanism of action has been proposed to treat OAB by stimulating the beta 3-adrenergic receptor (b3-AR) which induces detrusor relaxation, increasing inter-void interval and bladder storage capacity.[5,6] Mirabegron is a b3-AR agonist that has been developed for the treatment of OAB, and it is the first drug in this class to be approved for the treatment of OAB symptoms.
The purpose of this study was to assess the efficacy, safety, and tolerability of mirabegron 50 mg and 100 mg once daily in a multinational and multicenter randomised double-blind, parallel-group placebo-controlled and tolterodine extended-release (ER) comparator trial in OAB patients. The tolterodine ER control served to place the efficacy and safety of mirabegron in context with that of an established antimuscarinic OAB treatment
We enrolled > 2 300 adults with an average micturition frequency of eight or more times per day and at least three episodes of urgency, with or without incontinence, in a three day period. After a two-week single- blind placebo run in period, patients were allocated to the arms of the study. Patients completed a paper micturition diary for a three-day period, before clinic visits, at baseline and at weeks 4, 8, and 12 (final visit) and quality of life assessments, including the OAB Questionnaire (OAB-q), the Patient Perception of Bladder Condition (PPBC), and the Treatment Satisfaction-Visual Analog Scale (TS-VAS). Safety parameters included adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, and post void residual volume.
After placebo run in, a total of 1 978 patients were randomised to mirabegron 50 mg (n=497), mirabegron 100mg (n= 498) or tolterodine extended release (ER) 4mg (n= 495) orally once a day for the 12 week study period. There were co–primary efficacy end points of a change from baseline to final visit in the mean number of incontinence episodes and micturitions per 24 h. The primary comparison was between mirabegron and placebo with a secondary comparison between tolterodine and placebo.
The mirabegron 50-mg and 100-mg groups showed statistically significant reductions in the mean number of incontinence episodes per 24 h compared with placebo (mean decreases of 1.57 and 1.46 for mirabegron 50 mg and 100 mg, respectively, vs 1.17 for placebo; p < 0.05 for both comparisons). Similarly, statistically significant reductions were demonstrated with mirabegron 50 mg and 100 mg with a change in the mean number of micturitions per 24 h (mean decreases of 1.93 and 1.77 for mirabegron 50 mg and 100 mg, respectively, vs 1.34 for placebo; p < 0.05 for both comparisons). Improvements in co–primary efficacy end points were also observed with tolterodine ER but these did not reach statistical significance compared with placebo (p = 0.11 for both).
For the key secondary efficacy end points, statistically significant reductions in the number of incontinence episodes and micturitions per 24 h were evident at week 4 (first measured time point) for both doses of mirabegron compared with placebo (p < 0.05 for both comparisons), which was maintained over time (weeks 8 and 12). Compared with placebo, all active treatment groups achieved statistically significant improvements from baseline in mean volume voided per micturition ( p < 0.05). The mirabegron 50 mg group achieved a statistically significant improvement from baseline to final visit in the mean number of episodes with urgency (grade 3 or 4) per 24 h.
The incidence of treatment-emergent AEs (TEAEs) was similar across the placebo, mirabegron 50 mg and 100 mg, and tolterodine ER 4-mg groups. Importantly, the incidence of dry mouth, reported to be an important factor for determining persistence with antimuscarinic agents  in the mirabegron 50 mg and 100 mg groups was similar to placebo (2.8%, 2.8%, and 2.6%, respectively). Hence the tolerability profile of mirabegron offers the potential to improve persistence with OAB treatment in clinical practice.
This therapy did not exhibit any significant cardiac AEs. The overall incidence of adjudicated cardiovascular events was similar in placebo- and mirabegron-treated patients, and slightly higher in tolterodine-treated patients. This supports the cardiovascular safety of mirabegron in this patient population.
Limitations of this study were the 12-week follow up, and the fact that around 50% of the study population had previously discontinued prior antimuscarinic treatment for various reasons, including lack of efficacy, which may have diminished the magnitude of the tolterodine treatment effect.
Mirabegron represents a new class of treatment for OAB, with proven efficacy and good tolerability. It offers promise as an effective oral agent for the treatment of OAB with a distinct efficacy/tolerability balance.
- Chapple CR, Khullar V, Gabrie l Z,Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008;54:543–62.
- Yamaguchi O, Nishizawa O, Takeda M, et al.. Clinical guidelines for overactive bladder. Int J Urol 2009;16:126–42.
- D’Souza AO, Smith MJ, Miller LA, Doyle J, Ariely R. Persistence, adherence, and switch rates among extended-release and immedi- ate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm 2008;14:291–301.
- Benner JS, Nichol MB, Rovner ES, et al.. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 2010;105: 1276–82.
- Kumar V, Templeman L, Chapple CR, Chess-Williams R. Recent developments in the management of detrusor overactivity. Curr Opin Urol 2003;13:285–91.
- Yamaguchi O. b3-adrenoceptors in human detrusor muscle. Urology 2002;59(5 Suppl 1):25–9.
Vik Khullar BSc, MD, FRCOG, AKC and Rhiannon Bray, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.