A Phase III, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicentre Study to Assess the Efficacy and Safety of the β3 Adrenoceptor Agonist, Mirabegron, in Patients With Symptoms of Overactive Bladder
TL;DR: Mirabegron 25 mg and 50 mg were associated with significant improvements in efficacy measures of incontinence episodes and micturition frequency and well tolerated vs placebo.
About: This article is published in Urology.The article was published on 2013-08-01. It has received 218 citations till now. The article focuses on the topics: Mirabegron & Overactive bladder.
Citations
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TL;DR: This guideline provides a clinical framework for the diagnosis and treatment of non-neurogenic overactive bladder and identifies first through third line treatments as well as non-FDA approved, rarely applicable and treatments that should not be offered.
643 citations
Cites methods from "A Phase III, Randomized, Double-bli..."
...(2013) reported findings from a pre-specified pooled efficacy and safety analysis using data from the USA/Canada Phase III trial,(131) the Europe/Australia Phase III trial,(130) and the Europe/USA/Canada Phase III trial.(132) Mirabegron at doses of 50 and 100 mg once daily significantly reduced incontinence episodes per day (50 mg: -1....
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TL;DR: This guideline amendment focused on four topic areas: mirabegron, peripheral tibial nerve stimulation, sacral neuromodulation and BTX-A.
640 citations
TL;DR: The previous European Association of Urology (EAU) guidelines on urinary incontinence comprised a summary of sections of the 2009 International Consultation on Incontinence as mentioned in this paper, and a decision was made in 2010 to rewrite these guidelines based on an independent systematic review carried out by the EAU guidelines panel.
351 citations
TL;DR: Data is presented on the efficacy, safety, and tolerability of mirabegron in studies conducted to date that demonstrate a different mechanism of action from antimuscarinic agents.
Abstract: Aims
Mirabegron, the first β3-adrenoceptor agonist to enter clinical practice, has a different mechanism of action from antimuscarinic agents. This review presents data on the efficacy, safety, and tolerability of mirabegron in studies conducted to date.
Methods
All clinical data on mirabegron that are currently in the public domain are included, including some in-press manuscripts.
Results
In Phase III clinical trials in patients with overactive bladder (OAB), mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating the symptoms of OAB, including micturition frequency, urgency incontinence, and urgency. Significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition were seen as early as the first assessment (week 4) for mirabegron 50 and 100 mg, and were maintained throughout treatment. Responder analyses showed a significant improvement with mirabegron 50 and 100 mg in terms of dry rates, ≥50% reduction in mean number of incontinence episodes/24 hr, and the proportion of patients with ≤8 micturitions/24 hr at final visit. The benefit of mirabegron 50 and 100 mg was also evident in patients ≥65 years of age, and in both treatment-naive patients and those who previously discontinued antimuscarinic therapy. These data therefore demonstrate a clinically meaningful benefit with mirabegron in the objective endpoints of OAB. Assessment of measures of health-related quality of life and treatment satisfaction showed that patients perceived treatment with mirabegron as meaningful. In OAB clinical trials of up to 12 months mirabegron appeared to be well tolerated. The most common adverse events (AEs) observed with mirabegron in clinical trials of up to 12 months were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to placebo, and was between three and fivefold less than for tolterodine extended release 4 mg. Since dry mouth is the most bothersome AE associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients.
Conclusions
In Phase III clinical trials, mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating symptoms of OAB and, at doses of 50 and 100 mg, demonstrated significant improvements versus placebo on key secondary endpoints, as early as the first assessment (week 4), and these were maintained throughout treatment. In OAB clinical trials of up to 12 months, mirabegron appeared to be well tolerated. Neurourol. Urodynam. 33:17–30, 2014. © 2013 Wiley Periodicals, Inc.
227 citations
Cites background or methods or result from "A Phase III, Randomized, Double-bli..."
...Adjusted mean change from baseline ( SE) by time point in the mean number of incontinence episodes/24hr for the pooled placebo, mirabegron 25, 50, and 100mg groups (FAS-I) in SCORPIO,(32) ARIES,(33) and CAPRICORN.(34) This figure has been adapted, in part, from Figure 3 from Nitti et al....
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...Adjustedmean change from baseline ( SE) by time point inmean number of micturitions/24hr for the pooled placebo, mirabegron 25, 50, and 100mg groups (FAS) in SCORPIO,(32) ARIES,(33) and CAPRICORN.(34) This figure has been adapted in part, from Figure 4 from Nitti et al....
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...Mirabegron 25mg demonstrated numerically greater improvements on the 3 urgency assessments versus placebo; however, reduction from baseline to weeks 4 and 8 in mean urgency incontinence episodes/24hr was the only urgency assessment achieving statistical significance.(34) Primary and secondary efficacy data from a prespecified pooled analysis of these three studies are presented in Figures 2–4....
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...Overviewof design of SCORPIO,(32) ARIES,(33) andCAPRICORN.(34) This figure has beenadapted fromFigure 1 fromNitti et al....
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...001).(34) As regards observations at earlier timepoints, mirabegron 50mg demonstrated significantly greater improvements versus placebo in change to week 4 in mean number of incontinence episodes/24hr (P< 0....
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TL;DR: Combination therapy improved OAB symptoms and had similar safety and acceptability and all combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo.
196 citations
References
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TL;DR: Once daily mirabegron in a 50 or 100 mg dose is an effective treatment for overactive bladder symptoms with a low occurrence of side effects.
386 citations
TL;DR: Mirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability and Statistically significant improvements were also observed in other key efficacy end points and QoL outcomes.
382 citations
TL;DR: An in‐depth review of drugs that are available for the treatment of common conditions, written by two of the leading authorities in the world, Paul Abrams and Karl‐Erik Andersson, on the topic of overactive bladder and antimuscarinic agents.
Abstract: Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as alpha(3)-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.
357 citations
TL;DR: In this paper, the authors evaluated patient-reported reasons for discontinuing antimuscarinic prescription medications for overactive bladder (OAB) by using latent class analysis (LCA) and the Lo-Mendell-Rubin likelihood statistical test.
Abstract: Study Type – Symptom prevalence (prospective cohort) Level of Evidence 1b
OBJECTIVE
To evaluate patient-reported reasons for discontinuing antimuscarinic prescription medications for overactive bladder (OAB).
PATIENTS AND METHODS
A phase 1 screening survey was sent to a representative sample of 260 000 households in the USA to identify patients using antimuscarinic agents for OAB. A detailed phase-2 follow-up survey was sent to 6577 respondents with one or more antimuscarinic prescriptions for OAB in the 12 months before the phase 1 survey. The follow-up survey included questions about demographics, clinical characteristics, antimuscarinic use, beliefs about OAB, treatment expectations, OAB symptom bother, and pre-coded reasons for discontinuation. Patients who reported discontinuing one or more OAB medication during the 12 months before phase 2 were grouped by reason, using latent class analysis (LCA); the Lo-Mendell-Rubin likelihood statistical test was used to determine the number of classes. Conditional probabilities of reasons for discontinuation were calculated for each class. Multivariable logistic regression was used to assess the influence of demographic and clinical characteristics on class assignment.
RESULTS
In all, 162 906 (63%) and 5392 (82%) useable responses were returned in phases 1 and 2, respectively; the demographics were similar in respondents and nonrespondents in both phases. In all, 1322 phase 2 respondents (24.5%) reported discontinuing one or more antimuscarinic drugs during the 12 months before phase 2. LCA identified two classes (Lo-Mendell-Rubin statistic, P = 0.01) based on reasons for discontinuation. Most respondents (89%) reported discontinuing OAB medication primarily due to unmet treatment expectations and/or tolerability; many respondents in this class switched to a new antimuscarinic agent. A smaller group (11%) indicated a general aversion to taking medication. Age, sex, race, income, and history of incontinence were not predictive of class assignment.
CONCLUSIONS
Expectations about treatment efficacy and side-effects are the most important considerations in discontinuing OAB medications for most patients. Interventions to promote realistic expectations about treatment efficacy and side-effects might enhance adherence.
352 citations
TL;DR: The authors concluded that the two doses of solifenacin improved urgency and other symptoms of the overactive bladder, with an acceptable level of side‐effects.
Abstract: An international, multicentre, randomized double-blind trial is presented. Patients were randomized to treatment with tolterodine, placebo, and two doses of solifenacin. The authors concluded that the two doses of solifenacin improved urgency and other symptoms of the overactive bladder, with an acceptable level of side-effects.
A further phase 3 study into the effect of duloxetine was undertaken to assess whether the previous evidence of efficacy from North America and Europe could be sustained in other parts of the world. In this double-blind placebo-controlled study, the authors found that duloxetine improved continence and quality of life, in keeping with the findings in North America and Europe.
A novel temporary prostatic stent has been evaluated; it looks like the proximal 4-6 cm of a Foley catheter, with a similar proximal balloon to prevent displacement. In this early study it was found to be user-friendly, and to improve symptoms in patients with BOO caused by prostatic enlargement.
OBJECTIVE
To assess in a phase 3a trial the efficacy of solifenacin succinate, a once-daily oral antimuscarinic agent in development at 5-mg and 10-mg dosage strengths, for the treatment of overactive bladder (OAB)) (Yamanouchi Pharmaceutical Co. Ltd, Tokyo, Japan) compared with placebo in patients with symptoms of OAB, i.e. urgency, incontinence, and frequency, with additional objectives being to assess the safety and tolerability of solifenacin and to compare the efficacy and safety of solifenacin with tolterodine 2 mg twice daily.
PATIENTS AND METHODS
The study was an international, multicentre, randomized, double-blind, tolterodine- and placebo-controlled trial conducted at 98 centres. Adult patients with symptomatic OAB for ≥ 3 months were eligible; after a single-blind 2-week placebo run-in period patients were randomized equally to a 12-week double-blind treatment with either tolterodine 2 mg twice daily, placebo, solifenacin 5 mg or 10 mg once daily. Efficacy variables included change from baseline in the mean number of urgency, incontinence and urge incontinence episodes, and change from baseline in voids/24 h and mean volume voided/void.
RESULTS
In all, 1281 patients were enrolled, 1081 randomized and 1077 treated; 1033 were evaluated for efficacy. Compared with placebo, the change from baseline (−1.41, −32.7%) in the mean number of urgency episodes per 24 h was statistically significantly lower with solifenacin 5 mg (−2.85, −51.9%) and 10 mg (−3.07, −54.7%; both P < 0.001), but not with tolterodine (−2.05, −37.9%; P = 0.0511). There was a statistically insignificant decrease in episodes of incontinence with tolterodine (−1.14; P = 0.1122) but a significant decrease in patients treated with solifenacin 5 (−1.42; P = 0.008) and 10 mg (−1.45; P = 0.0038). Compared with placebo (−1.20, −8.1%) the mean number of voids/24 h was significantly lower in patients receiving tolterodine (−1.88, −15%; P = 0.0145), solifenacin 5 (−2.19, −17%) and 10 mg (−2.61, −20%; both P < 0.001). The mean volume voided/void was also significantly higher with all three active treatments (P < 0.001). Solifenacin was well tolerated; compared with placebo (4.9%), dry mouth (the most common side-effect), mostly mild, was reported in 18.6% of patients receiving tolterodine, 14.0% receiving 5 mg and 21.3% receiving 10 mg solifenacin.
CONCLUSION
Solifenacin 5 and 10 mg once daily improved urgency and other symptoms of OAB, and was associated with an acceptable level of anticholinergic side-effects. Solifenacin demonstrated significantly favourable efficacy to side-effect ratio in treating symptomatic OAB.
335 citations