Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE)

Background: Incontinence has a greater detrimental effect on quality of life than other symptoms of overactive bladder (OAB) and is often difficult to treat with antimuscarinic monotherapy. Objective: To evaluate the efficacy and the safety and tolerability of combination (solifenacin 5 mg and mirabegron 50 mg) versus solifenacin 5 or 10 mg in OAB patients remaining incontinent after 4 wk of solifenacin 5 mg. Design, setting, and participants: OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-wk single-blind run-in were randomised 1: 1: 1 to double-blind daily combination or solifenacin 5 or 10 mg for 12 wk. Patients receiving the combination were initiated on mirabegron 25 mg increasing to 50 mg after week 4. Outcome measurements and statistical analysis: The primary end point was a change from baseline to end of treatment (EOT) in the mean number of incontinence episodes per 24 h (stratified rank analysis of covariance [ANCOVA]). Key secondary end points were a change from baseline to EOT in the mean number of micturitions per 24 h (ANCOVA) and number of incontinence episodes noted in a 3-d diary at EOT (mixed-effects Poisson regression). A trial (BESIDE) comparing combination treatment (solifenacin plus mirabegron) with one treatment alone (solifenacin ) tested the superiority of combination versus solifenacin 5 mg, noninferiority (and potential superiority) of combination versus solifenacin 10 mg (key secondary end points), and the safety and tolerability of combination therapy versus solifenacin monotherapy. Results and limitations: A total of 2174 patients were randomised to combination (n = 727), solifenacin 5 mg (n = 728), or solifenacin 10 mg (n = 719). At EOT, combination was superior to solifenacin 5 mg, with significant improvements in daily incontinence (p = 0.001), daily micturitions (p < 0.001), and incontinence noted in a 3-d diary (p = 0.014). Combination was noninferior to solifenacin 10 mg for key secondary end points and superior to solifenacin 10 mg for improving daily micturitions. All treatments were well tolerated. Conclusions: Adding mirabegron 50 mg to solifenacin 5 mg further improved OAB symptoms versus solifenacin 5 or 10 mg, and it was well tolerated in OAB patients remaining incontinent after initial solifenacin 5 mg. Patient summary: In this 12-wk study, overactive bladder patients who remained incontinent despite initial solifenacin 5 mg treatment received additional treatment with mirabegron 50 mg. Combining mirabegron 50 mg with solifenacin 5 mg was superior to solifenacin 5 mg alone in improving symptoms of incontinence and frequent urination, and it was well tolerated. Trial registration: ClinicalTrials.gov NCT01908829. (C) 2016 European Association of Urology. Published by Elsevier B.V.