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)

Drake, Marcus; Chapple, Christopher R.; Esen, Ahmet Adil; Athanasiou, Stavros; Cambronero, J.; Mitcheson, David; Herschorn, Sender; Saleem, Tahir; Huang, Moses; Siddiqui, Emad; Stölzel, Matthias; Herholdt, Claire; MacDiarmid, Scott

doi:10.1016/j.eururo.2016.02.030

Cited by 151 publications

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“…This may be related to the reduced treatment effect with combination and solifenacin monotherapy on nocturia, as previously reported. 17 Similar benefits were observed with combination vs solifenacin 5 mg for treatment satisfaction and patients' perception of major improvements in their condition.…”

Section: Discussionmentioning

confidence: 62%

“…This benefit was less pronounced for micturition normalization, corresponding groups in a dose-ranging phase II study of solifenacin 2.5/5/10 mg plus mirabegron 25/50 mg. 29, 30 In the primary analysis of the BESIDE study, the adverse event profile for the combination was consistent with the known profiles for mirabegron and solifenacin with no signal for new adverse events, nor was there any additive/synergistic effect on vital signs with combination. 17 The significant benefit in symptom resolution and positive patient experience in this study suggests that refractory incontinent OAB patients may be more likely to benefit with a combination of mirabegron and solifenacin rather than persisting with solifenacin 5 mg or dose escalating to solifenacin 10 mg.Study limitations included lack of multiplicity adjustment across the PROs and responder analyses, increasing the risk of chance findings. Furthermore, like most OAB trials, the male population was underrepresented.…”

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confidence: 71%

“…Furthermore, the safety profile of the combination was similar to that of mirabegron or solifenacin monotherapy. 17 This analysis assessed whether improvements in objective endpoints translated into improvements in subjective HRQoL endpoints. PROs were investigated using bladder health questionnaires to evaluate HRQoL, treatment satisfaction and each patient's perception of their bladder condition.…”

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confidence: 99%

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Mirabegron as Add-On Treatment to Solifenacin in Patients with Incontinent Overactive Bladder and an Inadequate Response to Solifenacin Monotherapy

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Materials and Methods:Incontinent OAB patients, despite 4-weeks single-blind daily solifenacin 5 mg, were randomized 1:1:1 to double-blind, daily combination (mirabegron 50 mg/solifenacin 5 mg), solifenacin 5 or 10 mg for 12 weeks. Mirabegron dose was increased from 25 mg to 50 mg after week 4. Symptom Bother, health-related quality of life (HRQoL), and patient perception of bladder condition (PPBC) were assessed using respective OAB-q and PPBC questionnaires; responder rates were based on 50% reduction in daily incontinence, zero incontinence episodes and <8 micturitions/24 hours, and minimal important differences in OAB-q and PPBC.Results: Overall 2,174 patients, median age 59 years, were randomized to combination (n=727), solifenacin 5 mg (n=728) or 10 mg (n=719). Symptom Bother, total HRQoL and its subscales (Coping, Concern, and Social) and PPBC were significantly improved with combination vs solifenacin monotherapy (P<0.05). The odds of achieving clinically meaningful improvements in incontinence and micturition frequency, Symptom Bother, HRQoL and PPBC, was significantly higher with combination vs solifenacin monotherapy.The odds (95% CI) of becoming continent was 47% (OR 1.47; 1.17, 1.84; p=0.001) and 28% (OR 1.28; 1.02, 1.61; p=0.033) higher with combination vs solifenacin 5 and 10 mg, respectively. Conclusion:Significantly more patients on combination achieved clinically meaningful improvements in incontinence and micturition frequency, which were accompanied by similar improvements in PPBC, Symptom Bother and HRQoL. BESIDE Responder 3rd draft February 2016 4 Overactive bladder (OAB) is defined by symptoms of urinary urgency, usually accompanied by increased daytime frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. 1,2 Urgency urinary incontinence affects approximately one third of all OAB cases. 3 Compared with continent ("dry") OAB patients, incontinent ("wet") OAB patients experience greatly diminished quality of life (QoL), reporting higher rates of depression, psychological and emotional distress, and social isolation. 4,5 The severity of urgency urinary incontinence is strongly correlated with reductions in QoL,6 suggesting that incontinent OAB patients who are refractory to treatment are likely to be extremely dissatisfied with their QoL. Daily activities are often severely disrupted, and incontinent patients are more likely to require assistance with daily activities, placing an additional financial burden on society. 7 OAB patients are more likely to seek treatment once symptoms affect health-related quality of life (HRQoL), 8 and to persist with treatment if HRQoL improves. 9 Objective efficacy assessments are essential in OAB trials. However, the greatest treatment benefit experienced by patients is likely to be related to improvements in QoL. It is, therefore, equally important to assess subjective, patient-reported outcomes (PROs) including HRQoL and perception of symptoms, and how these correlate wit...

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Section: Discussionmentioning

confidence: 62%

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Mirabegron as Add-On Treatment to Solifenacin in Patients with Incontinent Overactive Bladder and an Inadequate Response to Solifenacin Monotherapy

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“…β 3 -adrenergic agonists for urgency incontinence-Mirabegron is a β 3 -adrenergic receptor agonist that acts directly on the detrusor muscle. In licensing trials, mirabegron was tested against placebo and tolterodine (an antimuscarinic), and subsequent post-marketing trials tested it against, and in combination with, several anticholinergics 136,137 . Metaanalyses have shown similar efficacy to available anticholinergic drugs, but with a much reduced incidence of dry mouth 138,139 , and lower efficacy than intravesical onabotulinumtoxinA 140 .…”

Section: Medical Interventionsmentioning

confidence: 99%

Urinary incontinence in women

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2017

Nat Rev Dis Primers

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Urinary incontinence symptoms are highly prevalent among women, have a substantial effect on health-related quality of life and are associated with considerable personal and societal expenditure. Two main types are described: stress urinary incontinence, in which urine leaks in association with physical exertion, and urgency urinary incontinence, in which urine leaks in association with a sudden compelling desire to void. Women who experience both symptoms are considered as having mixed urinary incontinence. Research has revealed overlapping potential causes of incontinence, including dysfunction of the detrusor muscle or muscles of the pelvic floor, dysfunction of the neural controls of storage and voiding, and perturbation of the local environment within the bladder. A full diagnostic evaluation of urinary incontinence requires a medical history, physical examination, urinalysis, assessment of quality of life and, when initial treatments fail, invasive urodynamics. Interventions can include non-surgical options (such as lifestyle modifications, pelvic floor muscle training and drugs) and surgical options to support the urethra or increase bladder capacity. Future directions in research may increasingly target primary prevention through understanding of environmental and genetic risks for incontinence.Correspondence to R.C. Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. r.cartwright@imperial.ac.uk. Author contributions Competing interestsThe authors declare no competing interests. Publisher's noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. HHS Public AccessAuthor manuscript Nat Rev Dis Primers. Author manuscript; available in PMC 2018 April 01. Published in final edited form as:Nat Rev Dis Primers. ; 3: 17042. doi:10.1038/nrdp.2017.42. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptUrinary incontinence is the complaint of involuntary loss (leakage) of urine 1 . The condition occurs in both sexes, but is much more frequent in women. Although some overlap in pathophysiology is evident between sexes, incontinence in men is often a consequence of prostatic enlargement or from damage to continence mechanisms during surgery or radiotherapy for prostate cancer. By contrast, incontinence in women is typically related to dysfunction of the bladder or pelvic floor muscles, with such dysfunction often arising during pregnancy or childbirth, or at the time of menopause. This Primer focuses on female urinary incontinence because of its higher prevalence and unique pathophysiology.There are two main subtypes of urinary incontinence: stress incontinence and urgency incontinence. According to the International Urogynecological Association (IUGA) and the International Continence Society (ICS) standard definition, stress incontinence is the complaint of urine leakage in association with coughing, sneezing or physical exertion, whereas urgency incontinence is the comp...

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“…The randomized, double-blind, multicentre, phase 3 BESIDE study showed that add-on therapy with mirabegron 50 mg for 12 weeks provided additional improvements in OAB symptoms for incontinent OAB patients who experience an insufficient response to solifenacin 5 mg compared with solifenacin 5 mg or 10 mg monotherapy. 1 Since antimuscarinics and β3AR agonists are both potentially autonomically active, the BESIDE investigators examined cardiovascular outcomes in this study population, and reported these results at EAU 2016. 2 Key parameters of blood pressure and pulse rate were assessed at screening, baseline, and intervals throughout the study.…”

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confidence: 99%