BACKGROUND: Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects.
OBJECTIVE: The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy.
DESIGN, SETTING, AND PARTICIPANTS: A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo.
INTERVENTION: A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10mg plus mirabegron 25 or 50mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10mg, or mirabegron 25 or 50mg), or placebo.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24h, incontinence episodes per 24h, and urgency episodes per 24h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters.
RESULTS AND LIMITATIONS: Compared with solifenacin 5mg monotherapy, all combinations with solifenacin 5 or 10mg significantly improved MVV, with adjusted differences ranging from 18.0ml (95% confidence interval [CI], 5.4-30.0) to 26.3ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy.
CONCLUSIONS: Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo.
PATIENT SUMMARY: To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability.
Written by:
Abrams P, Kelleher C, Staskin D, Rechberger T, Kay R, Martina R, Newgreen D, Paireddy A, van Maanen R, Ridder A. Are you the author?
Bristol Urological Institute, Southmead Hospital, Bristol, UK; Guys and St Thomas' Hospitals, London, UK; Tufts University School of Medicine, Boston, MA, USA; II Department of Gynaecology, Medical University, Lublin, Poland; RK Statistics Ltd., Bakewell, UK; Astellas Pharma BV, Leiden, The Netherlands.
Reference: Eur Urol. 2014 Feb 19. pii: S0302-2838(14)00131-6.
doi: 10.1016/j.eururo.2014.02.012
PubMed Abstract
PMID: 24612659
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