title: 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: 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.
  
  
  
  To evaluate the efficacy and the safety and tolerability of combination (solifenacin 5mg and mirabegron 50mg) versus solifenacin 5 or 10mg in OAB patients remaining incontinent after 4 wk of solifenacin 5mg.
  
  
  
  OAB patients remaining incontinent despite daily solifenacin 5mg during 4-wk single-blind run-in were randomised 1:1:1 to double-blind daily combination or solifenacin 5 or 10mg for 12 wk. Patients receiving the combination were initiated on mirabegron 25mg increasing to 50mg after week 4.
  
  
  
  The primary end point was a change from baseline to end of treatment (EOT) in the mean number of incontinence episodes per 24h (stratified rank analysis of covariance [ANCOVA]). Key secondary end points were a change from baseline to EOT in the mean number of micturitions per 24h (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 5mg, noninferiority (and potential superiority) of combination versus solifenacin 10mg (key secondary end points), and the safety and tolerability of combination therapy versus solifenacin monotherapy.
  
  
  
  A total of 2174 patients were randomised to combination (n=727), solifenacin 5mg (n=728), or solifenacin 10mg (n=719). At EOT, combination was superior to solifenacin 5mg, 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 10mg for key secondary end points and superior to solifenacin 10mg for improving daily micturitions. All treatments were well tolerated.
  
  
  
  Adding mirabegron 50mg to solifenacin 5mg further improved OAB symptoms versus solifenacin 5 or 10mg, and it was well tolerated in OAB patients remaining incontinent after initial solifenacin 5mg.
  
  
  
  In this 12-wk study, overactive bladder patients who remained incontinent despite initial solifenacin 5mg treatment received additional treatment with mirabegron 50mg. Combining mirabegron 50mg with solifenacin 5mg was superior to solifenacin 5mg alone in improving symptoms of incontinence and frequent urination, and it was well tolerated.
  
  
  
  ClinicalTrials.gov NCT01908829.
authors.affiliation: University of Bristol and Bristol Urological Institute, Bristol, UK. Electronic address: Marcus.Drake@bui.ac.uk.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Drake
authors.affiliation: Royal Hallamshire Hospital and Sheffield Hallam University, Sheffield, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chapple
authors.affiliation: Dokuz Eylül University School of Medicine, İzmir, Turkey.
authors.forename: Ahmet A
authors.initials: AA
authors.lastname: Esen
authors.affiliation: University of Athens Medical School, Athens, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Athanasiou
authors.affiliation: Infanta Leonor Hospital, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cambronero
authors.affiliation: St. Elizabeth's Medical Center, Brighton, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mitcheson
authors.affiliation: Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sender
authors.initials: S
authors.lastname: Herschorn
authors.affiliation: Astellas Pharma Europe Ltd, Chertsey, Surrey, UK.
authors.forename: Tahir
authors.initials: T
authors.lastname: Saleem
authors.affiliation: Astellas Pharma Europe Ltd, Chertsey, Surrey, UK.
authors.forename: Moses
authors.initials: M
authors.lastname: Huang
authors.affiliation: Astellas Pharma Europe Ltd, Chertsey, Surrey, UK.
authors.forename: Emad
authors.initials: E
authors.lastname: Siddiqui
authors.affiliation: Astellas Pharma Global Development, Leiden, The Netherlands.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stölzel
authors.affiliation: Astellas Pharma Europe Ltd, Chertsey, Surrey, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Herholdt
authors.affiliation: Alliance Urology Specialists, Greensboro, NC, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: MacDiarmid
mesh_terms: D000083:Acetanilides / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019233:Retreatment; D000069464:Solifenacin Succinate / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D053201:Urinary Bladder, Overactive / Q000150:complications / Q000188:drug therapy*; D014549:Urinary Incontinence / Q000188:drug therapy* / Q000209:etiology; D014554:Urination / Q000187:drug effects; D064804:Urological Agents / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000083:Acetanilides; D013844:Thiazoles; D064804:Urological Agents; D000069464:Solifenacin Succinate; C520025:mirabegron
keywords: Add-on therapy; Incontinence; Mirabegron; Overactive bladder; Solifenacin