title: Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony).
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo.
  
  
  METHODS
  Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h 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.
  
  
  CONCLUSIONS
  Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, 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 5 mg, 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 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo.
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  Clinical trials.gov: NCT01340027.
authors.affiliation: Bristol Urological Institute, Southmead Hospital, Bristol, UK. Electronic address: paul.abrams@bui.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Abrams
authors.affiliation: Guys and St Thomas' Hospitals, London, UK.
authors.forename: Con
authors.initials: C
authors.lastname: Kelleher
authors.affiliation: Tufts University School of Medicine, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Staskin
authors.affiliation: II Department of Gynaecology, Medical University, Lublin, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Rechberger
authors.affiliation: RK Statistics Ltd., Bakewell, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Kay
authors.affiliation: Astellas Pharma BV, Leiden, The Netherlands.
authors.forename: Reynaldo
authors.initials: R
authors.lastname: Martina
authors.affiliation: Astellas Pharma BV, Leiden, The Netherlands.
authors.forename: Donald
authors.initials: D
authors.lastname: Newgreen
authors.affiliation: Astellas Pharma BV, Leiden, The Netherlands.
authors.forename: Asha
authors.initials: A
authors.lastname: Paireddy
authors.affiliation: Astellas Pharma BV, Leiden, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: van Maanen
authors.affiliation: Astellas Pharma BV, Leiden, The Netherlands.
authors.forename: Arwin
authors.initials: A
authors.lastname: Ridder
mesh_terms: D000083:Acetanilides / Q000009:adverse effects / Q000627:therapeutic use*; D058667:Adrenergic beta-3 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D004338:Drug Combinations; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000069464:Solifenacin Succinate / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000187:drug effects* / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D014554:Urination / Q000187:drug effects; D014563:Urodynamics / Q000187:drug effects; D064804:Urological Agents / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D004338:Drug Combinations; D018727:Muscarinic Antagonists; D013844:Thiazoles; D064804:Urological Agents; D000069464:Solifenacin Succinate; C520025:mirabegron
keywords: Combination therapy; Mirabegron; Overactive bladder; Solifenacin