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)

Abstract

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.