Patient‐reported outcomes with the β3‐adrenoceptor agonist mirabegron in a phase III trial in patients with overactive bladder

Aims

To assess patient‐reported outcomes (PROs) in patients with overactive bladder (OAB) receiving the novel β₃‐adrenoceptor agonist mirabegron.

Methods

Data from a randomised, double‐blind, controlled phase III trial in 1,987 patients aged ≥18 years with OAB symptoms for ≥3 months were analysed. Patients received placebo, mirabegron 50 or 100 mg/day, or tolterodine extended release (ER) 4 mg orally once daily for 12 weeks after a 2‐week placebo run‐in. Prespecified analysis of PROs (changes in OAB Questionnaire [OAB‐q], Patient Perception of Bladder Condition [PPBC], and Work Productivity and Activity Impairment: Specific Health Problem [WPAI‐SHP] instrument) in patients treated with mirabegron 50 mg/day, tolterodine ER 4 mg/day or placebo is reported. Post‐hoc analyses of OAB‐q, PPBC and the Treatment Satisfaction‐Visual Analogue Scale (TS‐VAS) in patients who were incontinent at baseline are also reported.

Results

Significant improvements over placebo in OAB‐q coping and concern from baseline to final visit were observed with mirabegron 50 mg/day. No significant improvements in these parameters were observed with tolterodine ER 4 mg/day. Mirabegron 50 mg/day significantly increased the proportion of patients showing a PPBC improvement over placebo. Mirabegron 50 mg/day also produced greater improvements in WPAI‐SHP presenteeism and greater reductions in absenteeism and overall work impairment than placebo or tolterodine ER 4 mg/day. The impact of mirabegron 50 mg/day treatment on PROs in the incontinent population appears to be greater than that in the overall OAB population.

Conclusions

At the approved dose of 50 mg/day, mirabegron significantly improves OAB patients' perception of disease and quality of life, independent of whether they are incontinent at baseline. Neurourol. Urodynam. 35:987–994, 2016. © 2015 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.     

A proof‐of‐concept study: Mirabegron,a new therapy for overactive bladder

Aims

To evaluate the potential of mirabegron, a selective β3‐adrenoceptor agonist, for treatment of overactive bladder (OAB) symptoms.

Methods

A multicenter, randomized, double‐blind, double‐dummy, parallel group, placebo and active‐controlled, Phase 2, proof‐of‐concept study was conducted. Eligible patients (n = 314) were enrolled into a single‐blind, 2‐week placebo run‐in period followed by a randomized, double‐blind, placebo‐controlled treatment period. Patients received mirabegron 100 or 150 mg twice‐daily (BID), placebo or tolterodine 4 mg extended release (ER) once‐daily for 4 weeks. Primary endpoint was change from baseline to end‐of‐treatment in mean number of micturition episodes per 24 hr. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes per 24 hr; severity of urgency; nocturia, and quality of life measures. Safety parameters included adverse events, laboratory tests, electrocardiogram parameters and post‐void residual volume.

Results

Mirabegron 100 and 150 mg BID resulted in a statistically significant improvement versus placebo in mean change from baseline to end‐of‐treatment in the primary endpoint of micturition frequency (2.2 micturitions/24 hr vs. 1.2 micturitions/24 hr for both doses, adjusted P ≤ 0.01 for both comparisons). Mirabegron had a statistically significant effect versus placebo for most secondary endpoints, including quality of life variables. Despite a small increase in pulse rate, mirabegron demonstrated good safety and tolerability.

Conclusions

Mirabegron was efficacious and well tolerated in patients with OAB symptoms and heralds the first of a new class of oral pharmacological therapy for OAB for more than 30 years. Neurourol. Urodynam. 32:1116–1122, 2013. © 2013 Wiley Periodicals, Inc.     

Mirabegron 50 mg once‐daily for the treatment of symptoms of overactive bladder: An overview of efficacy and tolerability over 12 weeks and 1 year

The aim of the present review article was to summarize the efficacy and tolerability for mirabegron 50 mg over 12 weeks and 1 year versus placebo (SCORPIO) or tolterodine ER 4 mg (SCORPIO and TAURUS). After a 2‐week placebo run‐in, adults with overactive bladder symptoms for ≥3 months were randomized if, during a 3‐day micturition diary period before baseline, they had an average of ≥8 micturitions/24 h and ≥3 urgency episodes. Efficacy end‐points were change from baseline to each study visit and final visit in incontinence, micturitions, volume voided/micturition, urgency incontinence, urgency (grades 3 or 4), level of urgency and nocturia. Additional secondary efficacy variables included patient‐reported outcomes. Safety variables included changes in treatment‐emergent adverse events and vital signs. For SCORPIO, statistically significant improvements from baseline in efficacy variables and patient‐reported outcomes were seen with mirabegron versus placebo from week 4, and were maintained over time. For TAURUS, numerical improvements in efficacy were evident from month 1, and were maintained throughout 12 months. Treatment‐emergent adverse events incidence was similar between groups, except for dry mouth, which was reported by fourfold (SCORPIO) and threefold (TAURUS) more patients taking tolterodine than mirabegron. Mirabegron 50 mg for 12 weeks was associated with statistically significant improvements in objective measures of efficacy and patient‐reported outcomes. At final visit, improvements with mirabegron 50 mg were statistically greater versus placebo. The efficacy profile of mirabegron 50 mg appears to be maintained over 12 months.     

Efficacy of simplified bladder training in patients with overactive bladder receiving a solifenacin flexible‐dose regimen: results from a randomized study

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To compare the efficacy of flexible‐dose solifenacin 5/10 mg with and without simplified bladder training in patients with overactive bladder (OAB) syndrome.

PATIENTS AND METHODS

SOLAR (SOLifenacin Alone and with simplified bladder Re‐training) was a multicentre, prospective, randomized, parallel‐group, open‐label study in patients with OAB. After a 2‐week, single‐blind, placebo run‐in, 643 patients were randomized to treatment with either solifenacin 5 mg once daily (od) alone (323) or 5 mg od combined with simplified bladder training (320) for 8 weeks. At week 8, patients in both groups could request a dose increase to solifenacin 10 mg od for the remaining 8 weeks of the study. The primary efficacy endpoint was the change from baseline in the mean number of micturitions/24 h after 8 weeks. Secondary efficacy measures were the change in micturition frequency and other voiding diary variables at week 16. Patient‐reported outcomes were also assessed, including patient Perception of Bladder Condition, Incontinence Quality of Life, and Treatment Satisfaction using a visual analogue scale score; tolerability was also assessed.

RESULTS

Solifenacin given alone was effective in improving all measures of OAB evaluated in the study. When simplified bladder training was used combined with solifenacin there was a further significant improvement in micturition frequency at week 8, and this difference was maintained through to week 16. The use of simplified bladder training with solifenacin also significantly improved treatment satisfaction at week 16 over the responses to solifenacin given alone. There was no significant difference between the treatment groups at week 16 in urgency, incontinence or other secondary variables measured. The most common adverse event reported was dry mouth in both treatment groups; there was a low rate of discontinuation due to adverse events in the total study group.

CONCLUSION

Combined treatment with solifenacin and simplified bladder training was more effective than solifenacin alone in reducing micturition frequency at weeks 8 and 16, and improving treatment satisfaction at week 16 in patients with OAB. Simplified bladder training did not improve on the benefits of solifenacin alone in the symptoms of urgency or incontinence.     

Effects of a novel β3‐adrenoceptor agonist,AJ‐9677, on relaxation of the detrusor muscle: An in vitro study

Objectives: To examine the relaxant effects of AJ‐9677, a novel β₃‐adrenoceptor agonist, on the isolated rat, monkey and human detrusor muscle. Methods: The isolated detrusor strips of rats, monkeys and humans were mounted in organ baths containing Krebs solution. By the cumulative addition of β‐adrenoceptor agonists (isoproterenol, AJ‐9677, CL 316,243 and salbutamol in rats; isoproterenol, AJ‐9677 and CL 316,243 in monkeys and humans), concentration–relaxation curves were obtained. The maximal relaxation responses and pEC₅₀ values were calculated. In rats, concentration–relaxation curves to isoproterenol and AJ‐9677 were obtained in the presence and absence of propranolol or SR 59230A. Results: Isoproterenol, AJ‐9677, CL 316,243 and salbutamol induced concentration‐dependent relaxation in rats. The rank order of their relaxing potency in the rat detrusor muscle was AJ‐9677 > isoproterenol > CL 316,243 > salbutamol. Isoproterenol and AJ‐9677 also produced a concentration‐dependent relaxation with high potency in monkeys and humans, whilst CL 316,243 had low relaxing potency. According to the antagonist studies in rats, propranolol and SR 59230A caused a rightward shift of the concentration–relaxation curves to isoproterenol or AJ‐9677, respectively. Conclusions: AJ‐9677 has a high relaxant potency on the rat, monkey and human detrusor smooth muscle, and it may have the potential to treat overactive bladder.