Dataset Information

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

ABSTRACT:

Aims

SYNERGY II was a 12-month phase III trial in patients with overactive bladder (OAB) symptoms that investigated the safety and efficacy of the combination of mirabegron and solifenacin in comparison with each monotherapy. This analysis evaluated the trial findings using four age subgroups (<65, ?65, <75, and ?75 years).

Methods

Eligible patients were ?18 years with symptoms of "wet" OAB (urinary frequency and urgency with incontinence) for ?3 months. Patients were randomized to receive once-daily solifenacin succinate and mirabegron (5?mg/50?mg; combination), solifenacin succinate, or mirabegron (4:1:1). Safety evaluations: treatment-emergent adverse events (TEAEs), vital signs, and electrocardiogram, post-void residual volume, and laboratory assessments. Primary efficacy variables: change from baseline to end of treatment in number of incontinence episodes/24?h and micturitions/24?h.

Results

Of 1794 patients (full analysis set), 614 (34.2%) and 168 (9.4%) were ?65 and ?75 years old, respectively. Overall, 856 (47.2%) patients experienced ?1 TEAE. Higher TEAE incidences were typically observed for the combination versus both monotherapies (eg, constipation) and in the older versus younger age groups (eg, urinary tract infection). Increases in mean pulse rate from baseline of >1?bpm were noted in the combination and mirabegron younger age groups only. No clinically significant findings were observed in the other safety parameters. The efficacy variables improved with all treatments and the greatest improvements were typically observed with combination therapy.

Conclusions

Mirabegron and solifenacin combination therapy was a well-tolerated and effective treatment for patients with OAB symptoms irrespective of their age.

SUBMITTER: Mueller ER

PROVIDER: S-EPMC6850571 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

Mueller Elizabeth R ER van Maanen Rob R Chapple Christopher C Abrams Paul P Herschorn Sender S Robinson Dudley D Stoelzel Matthias M Yoon Sang J SJ Al-Shukri Salman S Rechberger Tomasz T Gratzke Christian C

Neurourology and urodynamics 20190115 2

<h4>Aims</h4>SYNERGY II was a 12-month phase III trial in patients with overactive bladder (OAB) symptoms that investigated the safety and efficacy of the combination of mirabegron and solifenacin in comparison with each monotherapy. This analysis evaluated the trial findings using four age subgroups (<65, ≥65, <75, and ≥75 years).<h4>Methods</h4>Eligible patients were ≥18 years with symptoms of "wet" OAB (urinary frequency and urgency with incontinence) for ≥3 months. Patients were randomized t ...[more]

PMID: 30644570

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Project description:BackgroundPatients with overactive bladder (OAB) experience sudden, intense urges to urinate, which may include urge urinary incontinence and nocturia. Pharmacotherapy includes β3-adrenergic receptor agonists such as mirabegron; however, mirabegron contains a label warning for cytochrome P450 (CYP) 2D6 inhibition, making coadministration with CYP2D6 substrates require monitoring and dose adjustment to avoid unintended increases in substrate concentration.ObjectiveTo understand the codispensing patterns of mirabegron among patients using ten predefined CYP2D6 substrates with and before mirabegron dispensing.MethodsThis retrospective claims database analysis used the IQVIA PharMetrics® Plus Database to assess codispensing of mirabegron with ten predefined CYP2D6 substrate groups identified on the basis of medications most frequently prescribed in the United States, those with high susceptibility to CYP2D6 inhibition, and those with evidence for exposure-related toxicity. Patients had to be ≥ 18 years old before initiation of the CYP2D6 substrate episode that overlapped with mirabegron. The cohort entry period was November 2012 to September 2019, and the overall study period was 1 January 2011 to 30 September 2019. Comparisons of patient profiles at dispensing were made between time periods with and before mirabegron use in the same patient. Descriptive statistics were used to assess the number of exposure episodes, total duration of exposure, and median duration of exposure of CYP2D6 substrate dispensing with and before mirabegron.ResultsCYP2D6 substrate exposure periods totaling ≥ 9000 person-months were available before overlapping exposure to mirabegron for all ten CYP2D6 substrate cohorts. Median codispensing duration for chronically administered CYP2D6 substrates was 62 (interquartile range [IQR] 91) days for citalopram/escitalopram, 71 (105) days for duloxetine/venlafaxine, and 75 (115) days for metoprolol/carvedilol; median codispensing duration for acutely administered CYP2D6 substrates was 15 (33) days for tramadol and 9 (18) days for hydrocodone.ConclusionsIn this claims database analysis, the dispensing patterns of CYP2D6 substrates with mirabegron displayed frequent overlapping of exposure. Thus, a need exists to better understand the outcomes experienced by patients with OAB who are at increased risk for drug‒drug interactions when taking multiple CYP2D6 substrates concurrently with a CYP2D6 inhibitor.

Project description:AIMS/OBJECTIVES:In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and ?3 -adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation. METHODS:OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV-related treatment-emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters. RESULTS:The frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], -0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (-0.93 mm Hg [0.38], -0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (-1.28 mm Hg [0.38], -0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds). CONCLUSION:The comparable frequency of CV-related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined.

Project description:OnabotulinumtoxinA and mirabegron have recently gained marketing authorisation to treat symptoms of overactive bladder (OAB).To evaluate the relative efficacy of mirabegron and onabotulinumtoxinA in patients with idiopathic OAB.Network meta-analysis.A search of 9 electronic databases, review documents, guidelines and websites.Randomised trials comparing any licensed dose of onabotulinumtoxinA or mirabegron with each other, anticholinergic drugs or placebo were eligible (19 randomised trials were identified). 1 reviewer extracted data from the studies and a second reviewer checked the data. Candidate trials were assessed for similarity and networks were developed for each outcome. Bayesian network meta-analysis was conducted using both fixed-effects and random-effects models. When there were differences in mean baseline values between mirabegron and onabotulinumtoxinA trials they were adjusted for using network meta-regression (NMR).No studies directly comparing onabotulinumtoxinA to mirabegron were identified. A network was created for each of the 7 outcomes, with 3-9 studies included in each individual network. The trials included in the networks were broadly similar. Patients in the onabotulinumtoxinA trials had more urinary incontinence and urgency episodes at baseline than patients in the mirabegron trials and these differences were adjusted for using NMR. Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency and urination. NMR supported the results of the network meta-analysis.In the absence of head-to-head trials comparing onabotulinumtoxinA to mirabegron, this indirect comparison indicates that onabotulinumtoxinA may be superior to mirabegron in improving symptoms of urinary incontinence, urgency and urinary frequency in patients with idiopathic OAB.

Dataset Information

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

Aims

Methods

Results

Conclusions

Publications

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

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