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Keywords:

  • β3-adrenoceptor agonist;
  • efficacy;
  • mirabegron;
  • overactive bladder;
  • safety

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Objective

  • To evaluate the efficacy and safety of the β3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB).

Patients and Methods

  • This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥ 8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks.
  • The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King's Health Questionnaire.
  • Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram.

Results

  • A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups.
  • At final assessment, mirabegron was significantly superior to placebo in terms of mean [sd] change from baseline in number of micturitions/24 h (–1.67 [2.212] vs -0.86 [2.354]; P < 0.001) and mean [sd] change from baseline in number of urgency episodes/24 h (–1.85 [2.555] vs –1.37 [3.191]; P = 0.025), incontinence episodes/24 h (–1.12 [1.475] vs –0.66 [1.861]; P = 0.003), urgency incontinence episodes/24 h (–1.01 [1.338] vs –0.60 [1.745]; P = 0.008), and volume voided/micturition (24.300 [35.4767] vs 9.715 [29.0864] mL; P < 0.001).
  • The incidence of AEs in the mirabegron group was similar to that in the placebo group. Most AEs were mild and none were severe.

Conclusions

  • Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population.

Abbreviations
OAB

overactive bladder

QoL

quality of life

KHQ

King's Health Questionnaire

AE

adverse event

ECG

electrocardiogram

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Overactive bladder (OAB) is a highly prevalent symptom syndrome [1-3] that substantially affects health-related quality of life (QoL) [4, 5]. The current pharmacological approach to treating OAB mainly involves antimuscarinic agents, but the use of these agents is limited in some individuals because of suboptimum efficacy or bothersome adverse events (AEs), including dry mouth, blurred vision and constipation [6]. Alternative approaches to managing OAB have focused on β-adrenoceptors, which have a recognised role in mediating the relaxation of bladder smooth muscle [7]. Three β-adrenoceptor subtypes have been identified in the human detrusor, but it is the β3-adrenoceptor subtype that is responsible for promoting its relaxation and urine storage [8-11], and this may also inhibit the activity of the bladder afferent nerves [12-15]. Agents that selectively activate the β3-adrenoceptor subtype, such as mirabegron, could treat the symptoms of OAB via a mechanism of action that is distinct from antimuscarinic therapies [16].

The rationale for the present study is based on the results of a Japanese phase II dose-finding study (NCT00527033), in which three doses of mirabegron (25 mg, 50 mg and 100 mg) demonstrated significant improvements in micturition variables and incontinence episodes compared with placebo, with no clinically significant safety concerns, even at the highest dose. In this Japanese phase III study, a mirabegron dose of 50 mg was selected to assess efficacy (superiority) and safety compared with both placebo and a tolterodine-treated group (without testing).

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

The present phase III study was a randomised, double-blind, placebo- and tolterodine-controlled, parallel-group, multicentre comparison in a Japanese population with OAB. Men or women aged ≥20 years, with OAB symptoms for ≥24 weeks, entered an initial 2-week, single-blind, placebo run-in period. Key OAB-related exclusion criteria included a diagnosis of genuine stress incontinence, an average total daily urine volume >3000 mL during the 3-day pre-treatment micturition diary period, and a post-void residual urine volume of at least 100 mL when measured before treatment. At formal enrolment, patients who completed the run-in period and had on average ≥8 micturitions/24 h and ≥1 urgency episode/24 h and/or ≥1 urgency incontinence episode/24 h, confirmed using 3-day micturition diaries, were randomised to receive oral once-daily placebo, mirabegron 50 mg, or tolterodine tartrate 4 mg for 12 weeks. A 2-week post-treatment observation follow-up period was established to confirm safety. The total study duration was 16 weeks, consisting of: a 2-week placebo run-in period (visit 1 [week –2] and visit 2 [baseline]); a 12-week treatment period (visit 3 [week 4], visit 4 [week 8], visit 5 [week 12]); and a 2-week follow-up period (visit 6 [week 14]). All patients gave signed informed consent before the observational run-in period. The trial was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board at each study site.

During the single-blind placebo run-in period, patients received one mirabegron placebo tablet and one tolterodine placebo capsule (one tablet and one capsule total) once daily. At formal enrolment, patients were randomised in a 1:1:1 ratio using a block size of six to receive: one mirabegron 50 mg tablet and one tolterodine placebo capsule (active mirabegron 50 mg group); one mirabegron placebo tablet and one tolterodine 4 mg capsule (active tolterodine group); and one mirabegron placebo tablet and one tolterodine placebo capsule (placebo group).

Micturition variables, including the number of urgency episodes/24 h and incontinence episodes/24 h, and volume voided/micturition, were assessed using patient micturition diaries and were evaluated in the full analysis set population (patients who took study medication at least once and provided data for at least one variable before and after initiation of the treatment period). The QoL scores were evaluated in the QoL analysis set population (patients in the full analysis set for whom at least one domain score could be calculated and who had taken the study medication for at least 14 days) using the King's Health Questionnaire (KHQ) [17].

The primary efficacy endpoint was based on the change from baseline (visit 2) to final assessment (visit 5) in the mean number of micturitions/24 h. Secondary efficacy variables, based on the change from baseline to final assessment, were: the mean number of urgency episodes/24 h; mean number of urinary incontinence episodes/24 h; mean number of urgency incontinence episodes/24 h; mean number of nocturia episodes, mean volume voided/micturition; and mean change in QoL domain scores on the KHQ.

A patient micturition diary was completed during the 3-day period immediately before specified visits (visits 2 [baseline], 3, 4 and 5 [final assessment]) or at the time of withdrawal from the study. Patients completed the KHQ at baseline and final assessment, or at the time of withdrawal from the study.

The safety assessment was based on AEs, laboratory tests (haematology, blood chemistry and urine analysis), vital signs, 12-lead electrocardiogram (ECG), and post-void residual urine volume and was performed in the safety analysis set population (patients who took the study medication at least once during the treatment period).Treatment-related AEs that were considered to have a relationship with the study treatment were defined as adverse drug reactions. Routine laboratory tests and vital signs (i.e. sitting blood pressure and pulse rate) were assessed at visits 1, 2, 3, 4 and 5 (or withdrawal); vital signs were also assessed at follow-up (visit 6). ECG and post-void residual urine volume were performed at visits 1, 2 and 5 (or at withdrawal from the study).

The planned sample size of 990 patients (330 in each treatment group) was based on the results from a 12-week dose-finding phase II study (178-CL-045; NCT00527033), which demonstrated a change from baseline to end of study in the mean (sd) number of micturitions/24 h of −1.18 (2.155) and −2.12 (2.383) in the placebo and mirabegron 50 mg group, respectively. Assuming a standard deviation of 2.4, the number of patients per group necessary to demonstrate superiority to placebo would be 137 at a two-sided significance level of 5% and a power of 90%. As for the secondary analysis variable, the change in mean number of incontinence episodes/24 h, when estimating the number of patients per group (power 90%) using simulation through resampling with replacement, the number of patients needed would be 180. Assuming that ∼60% of the patients in the analysis set would have urinary incontinence, 300 patients would be necessary in the analysis set. The same target sample size was used for the comparator drug tolterodine.

For the primary efficacy endpoint, a two-sample t-test was used to compare mirabegron with placebo for change from baseline in mean number of micturitions/24 h at final assessment. The Wilcoxon rank-sum test was used for the secondary efficacy variables related to incontinence and the two-sample t-test for the other secondary endpoints and the KHQ. A two-sided significance level of 5% was used for the primary and secondary endpoints. For each efficacy variable, the differences in the change from baseline to final assessment between the placebo and the respective treatment groups and the two-sided 95% CI of the difference were calculated using anova, with treatment group as a factor and baseline as a covariate. Tolterodine was used as an active comparator, without testing for non-inferiority of efficacy and safety.

Fisher's exact test was used to compare the incidence of treatent-related AEs between mirabegron 50 mg and placebo, and the two-sided 95% CI was calculated. Summary statistics were used for measurements of vital signs, laboratory variables and post-void residual urine volume.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

A total of 1139 patients with OAB were randomised to treatment (placebo n = 381; mirabegron 50 mg n = 380; tolterodine 4 mg n = 378), of whom 85 patients withdrew during the treatment period (placebo, n = 31; mirabegron 50 mg, n = 31; tolterodine 4 mg, n = 23 [Fig. 1]). Demographic and baseline OAB characteristics in the full analysis set population (n = 1105) were similar among the three treatment groups with no statistically significant imbalances (Table 1). More than 82% of patients were women, and the patients’ mean age was ∼58 years. More than 95% of patients in the analysis sets were treated for at least 10 weeks, and treatment compliance was ≥98% in all groups.

figure

Figure 1. Disposition of patients.

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Table 1. Patient demographic and other baseline characteristics of the full analysis and quality-of-life analysis set
Study populationTreatment groupP
Placebo: n = 368Mirabegron 50 mg: n = 369Tolterodine 4 mg: n = 368
  1. *Fisher's exact test, two-sample t-test, based on baseline patients’ diaries, §Wilcoxon rank sum test. QoL, quality of life; KHQ, King's Health Questionnaire.

Full analysis set population    
Men n (%)58 (15.8)58 (15.7)64 (17.4)1.000*
Women n (%)310 (84.2)311 (84.3)304 (82.6)
Mean (sd) age, years58.2 (14.18)58.3 (13.88)58.3 (13.69)0.948
Age group, n (%)    
<65 years231 (62.8)233 (63.1)227 (61.7)
≥65 years137 (37.2)136 (36.9)141 (38.3)
Mean (sd) weight, kg55.32 (9.585)55.12 (9.840)56.54 (10.432)0.771
Mean (sd) height, cm156.50 (7.875)156.62 (7.669)157.21 (7.677)0.827
Mean (sd) duration of illness, months76.5 (88.42)70.0 (66.91)75.6 (78.25)0.264
OAB severity (mean number of micturitions), n (%)    
<10122 (33.2)140 (37.9)136 (37.0)
≥10 to ≤15220 (59.8)199 (53.9)202 (54.9)
>1526 (7.1)30 (8.1)30 (8.2)
Type of incontinence, n (%)   
Absence39 (10.6)31 (8.4)39 (10.6)0.352*
Urgency incontinence236 (64.1)230 (62.3)235 (63.9)
Mixed incontinence93 (25.3)108 (29.3)94 (25.5)
Incontinence (visit 2), n (%)    
Absence104 (28.3)103 (27.9)128 (34.8)0.935*
Presence264 (71.7)266 (72.1)240 (65.2)
Mean (sd) post-void residual urine volume, mL8.99 (12.868)8.45 (12.888)10.44 (16.560)0.567
Medical history, n (%)   0.376*
No311 (84.5)302 (81.8)322 (87.5)
Yes57 (15.5)67 (18.2)46 (12.5)
Complications, n (%)    
No92 (25.0)98 (26.6)74 (20.1)0.674*
Yes276 (75.0)271 (73.4)294 (79.9)
Previous medications    
No128 (34.8)136 (36.9)128 (34.8)0.591*
Yes240 (65.2)233 (63.1)240 (65.2)
Concomitant medications    
No105 (28.5)103 (27.9)95 (25.8)0.870*
Yes263 (71.5)266 (72.1)273 (74.2)
Mean (sd) number of micturitions/24 h [n]11.29 (2.748) [n = 368]11.15 (2.650) [n = 369]11.10 (2.567) [n = 368]0.464
Mean (sd) number of urgency episodes/24 h [n]4.42 (2.989) [n = 368]4.27 (2.848) [n = 369]4.13 (2.810) [n = 368]0.488
Mean (sd) number of incontinence episodes/24 h [n]1.91 (1.760) [n = 264]1.99 (2.054) [n = 266]1.89 (1.826) [n = 240]0.920§
Mean (sd) number of urgency incontinence episodes/24 h [n]1.67 (1.366) [n = 258]1.78 (1.752) [n = 254]1.71 (1.571) [n = 230]0.906§
Mean (sd) volume voided/micturition, mL146.791 (44.2336) [n = 366]149.591 (46.3755) [n = 368]145.863 (46.8973) [n = 367]0.403
Mean number of nocturia episodes ± SD1.81 (1.198) [n = 322]1.72 (0.998) [n = 323]1.71 (1.075) [n = 332]0.288
QoL population, mean (sd) baseline KHQ domain scores    
Domain 1: general health perception [n]32.3(18.47) [n = 368]31.9(17.81) [n = 367]33.8(17.92) [n = 366]0.772
Domain 2: incontinence impact [n]49.1 (27.61) [n = 368]47.8 (26.77) [n = 367]49.5 (26.31) [n = 366]0.511
Domain 3: role limitations [n]36.6 (25.21) [n = 368]34.7 (23.70) [n = 367]35.2 (23.15) [n = 366]0.305
Domain 4: physical limitations [n]38.5 (25.79) [n = 368]37.1 (26.48) [n = 367]38.5 (27.04) [n = 366]0.442
Domain 5: social limitations [n]19.8 (22.58) [n = 368]19.4 (22.21) [n = 367]19.6 (20.92) [n = 366]0.816
Domain 6: personal relationships [n]9.3 (17.54) [n = 280]9.9 (18.52) [n = 279]7.9 (15.31) [n = 291]0.708
Domain 7: emotions [n]38.3 (26.16) [n = 368]36.6 (25.08) [n = 367]36.4 (25.40) [n = 366]0.383
Domain 8: sleep/energy [n]29.9 (24.98) [n = 368]27.8 (23.33) [n = 367]29.9 (23.76) [n = 366]0.240
Domain 9: severity measures [n]30.3 (19.48) [n = 368]30.5 (18.65) [n = 367]30.2 (18.44) [n = 366]0.861

At final assessment, mirabegron 50 mg was associated with a significantly greater change from baseline in the mean number of micturitions/24 h compared with placebo (P < 0.001; Fig. 2).The mean (sd) change from baseline in the mean number of micturitions/24 h was –0.86 (2.354) for placebo, –1.67 (2.212) for mirabegron 50 mg and –1.40 (2.176) for tolterodine. The mean [sd] change from baseline to final assessment for the secondary efficacy variables (Figs 2, 3) showed significant improvements for mirabegron vs placebo for number of urgency episodes/24 h (–1.85 [2.555] vs –1.37 [3.191]; P = 0.025); number of incontinence episodes/24 h (–1.12 [1.475] vs –0.66 [1.861]; P = 0.003); number of urgency incontinence episodes/24 h (–1.01 [1.338] vs –0.60 [1.745]; P = 0.008); and volume voided/micturition (24.300 [35.4767] vs 9.715 [29.0864] mL; P < 0.001); but not for number of nocturia episodes (–0.44 [0.933] vs –0.36 [1.062]; P = 0.277). The percentage of subjects with zero incontinence episodes at the final assessment in the placebo, mirabegron and tolterodine groups was 39.4, 50.8 and 48.8%, respectively. All of the primary and secondary efficacy variables showed improvements with mirabegron vs placebo as early as the first assessment (week 4) and these were sustained until the final assessment (Fig. 3).

figure

Figure 2. Mean change from baseline to final assessment for the primary and secondary efficacy endpoints. *P < 0.05, **P < 0.01, *** P < 0.001, based on a two-sample t-test vs placebo for all variables except incontinence and urgency incontinence, for which a Wilcoxon rank sum test was used vs placebo (two-sided significance level of 0.05). NT, not tested.

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figure

Figure 3. Mean change from baseline at each visit in: (A) mean number of micturitions/24 h; (B) mean number of urgency episodes/24 h; (C) mean number of incontinence episodes/24 h; (D) mean number of urgency incontinence incontinence episodes/24 h; (E) mean volume voided/micturition (mL); and (F) mean number of nocturia episodes. *P < 0.05, ***P < 0.001.

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Treatment with mirabegron for 12 weeks was associated with significant improvements compared with placebo in seven of the nine QoL domain scores in the KHQ: incontinence impact, role limitations, physical limitations, social limitations, emotions, sleep/energy and severity measures (Fig. 4).

figure

Figure 4. Mean change from baseline in quality-of-life (QoL) scores at the final assessment (QoL analysis set). *P < 0.05, **P < 0.01, ***P < 0.001, based on a two-sample t-test vs placebo (two-sided significance level of 0.05). NT; not tested.

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The overall incidence of treatment-related AEs was similar in the mirabegron (24.5%) and placebo (24.0%) groups, but higher in the tolterodine group (34.9%). Common treatment-related AEs (incidence of ≥2% in any treatment group) are shown in Table 2. The incidence of treatment-related AEs that are associated with antimuscarinic drugs in the placebo, mirabegron and tolterodine groups was as follows: constipation (2.6, 3.4 and 3.5%, respectively), dry mouth (2.9, 2.6 and 13.3%, respectively) and thirst (0.5, 0.0 and 2.1%).The majority of AEs in the mirabegron group were mild in severity. There were no treatment-related serious AEs in the mirabegron group and no deaths were reported in the study.

Table 2. Common treatment-related adverse events (adverse drug reactions) occurring in ≥2% in any treatment group (safety analysis set)
Adverse eventTreatment group
Placebo: n = 379 n (%)Mirabegron 50 mg: n = 379 n (%)Tolterodine 4 mg: n = 375 n (%)
All adverse events91 (24.0)93 (24.5)131 (34.9)
Constipation10 (2.6)13 (3.4)13 (3.5)
Dry mouth11 (2.9)10 (2.6)50 (13.3)
Thirst2 (0.5)0 (0.0)8 (2.1)
Alanine aminotransferase increased5 (1.3)9 (2.4)9 (2.4)
Aspartate aminotransferase increased6 (1.6)6 (1.6)10 (2.7)
Blood creatine phosphokinase increased14 (3.7)10 (2.6)8 (2.1)
γ-glutamyltransferase increased9 (2.4)15 (4.0)6 (1.6)
Blood alkaline phosphatase increased10 (2.6)10 (2.6)6 (1.6)

The incidence of cardiovascular-related AEs (tachycardia, palpitations, increased heart rate, increased blood pressure and ECGs) was low and similar to that for placebo (Table 3).

Table 3. Cardiovascular treatment-related adverse events (safety analysis set)
System organ class Adverse eventTreatment group
Placebo: n = 379Mirabegron 50 mg: n = 379Tolterodine 4 mg: n = 375
  1. ECG, electrocardiogram.

Cardiac disorders, n (%)   
Arrhythmia supraventricular1 (0.3)0 (0.0)0 (0.0)
Left bundle branch block0 (0.0)0 (0.0)1 (0.3)
Right bundle branch block1 (0.3)0 (0.0)0 (0.0)
Palpitations0 (0.0)1 (0.3)0 (0.0)
Sinus arrhythmia0 (0.0)1 (0.3)0 (0.0)
Supraventricular extrasystoles3 (0.8)2 (0.5)2 (0.5)
Tachycardia0 (0.0)1 (0.3)0 (0.0)
Ventricular extrasystoles2 (0.5)0 (0.0)0 (0.0)
Investigations, n (%)   
Blood pressure increased1 (0.3)0 (0.0)2 (0.5)
Heart rate increased0 (0.0)1 (0.3)1 (0.3)
ECG T-wave abnormal0 (0.0)0 (0.0)1 (0.3)
Vascular disorders, n (%)   
Hypertension0 (0.0)1 (0.3)3 (0.8)
Hot flush0 (0.0)0 (0.0)1 (0.3)

Vital signs (pulse rate and blood pressure) and ECG findings in the mirabegron group were generally similar to those in the placebo group. There was a slight elevation in the mean pulse rate for the mirabegron group 4 weeks after initiation of treatment; however, there was no further increase over time, and pulse rate returned to approximately baseline level in the follow-up period. The change in post-void residual urine volume at the final assessment was similar in all treatment groups (0.86 mL for the placebo group, 0.80 mL for the mirabegron group, and 0.44 mL for the tolterodine group).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

In the present phase III study comparing mirabegron 50 mg with placebo (including a tolterodine group, without testing for non-inferiority of efficacy and safety) in Japanese patients with OAB for 12 weeks, mirabegron was shown to have significantly superior efficacy compared with placebo in terms of the change from baseline to final assessment in the mean number of micturitions/24 h (primary endpoint) and in terms of the following secondary efficacy variables: mean number of urgency episodes/24 h; mean number of incontinence episodes/24 h; mean number of urgency incontinence episodes/24 h; and mean volume voided/micturition. The frequency of micturition and incontinence episodes based on micturition diaries are important outcome measures for OAB treatments according to the European Association of Urology guidelines [18], and the impact of mirabegron on the endpoints in the present study confirms the clinical relevance of this new class of drug for the treatment of OAB. In addition, urgency, which is recognised as the key symptom of OAB, was significantly improved with mirabegron. It is unclear why nocturia was not improved significantly with mirabegron compared with placebo, but previous antimuscarinic studies in patients with OAB have reported inconsistent efficacy in treating nocturia [19]. The mean number of nocturia episodes at baseline in the present study was relatively low, which may have contributed to the lack of difference compared with placebo.

Patient-reported outcomes, such as health-related QoL, are useful endpoints to supplement symptom-based assessments in clinical trials of OAB in order to reflect the overall clinical health status [4].The KHQ is considered a reliable and valid tool to assess QoL in men and women with OAB [20]. In the present study there was a significant improvement in QoL with mirabegron vs placebo, as shown by an improvement in seven of nine QoL domains on the KHQ; therefore, mirabegron is effective in controlling the key symptoms of OAB as reflected by improving patients’ QoL.

The present study confirms that the β3-adrenoceptor is an important target in the treatment of OAB symptoms. Stimulation of the β3-adrenoceptor allows detrusor relaxation during the storage phase, with consequent improvement in OAB symptoms [21]. In contrast to antimuscarinic agents, stimulation of the β3-adrenoceptor mediates bladder relaxation that is specific to the storage or filling phase of the micturition cycle, and is unlikely to inhibit bladder contraction during the voiding phase [21]. The observed benefit with mirabegron in reducing urgency in the present study is probably related to its ability to reduce bladder afferent activity via β3-adrenoceptors in both the urothelium and detrusor [12-15, 22-28].

Tolerability is an important aspect in the management of OAB with antimuscarinic agents given the chronic nature of the condition and the well-known side effects associated with antimuscarinic drugs (e.g. dry mouth, constipation or blurred vision). In the present study, the incidence of common (≥2%) treatment-related AEs was similar between the mirabegron and placebo groups. Dry mouth, which is consistently the most common complaint with antimuscarinic therapy [29], occurred frequently in the tolterodine group, but occurred at a similar rate in the mirabegron and placebo groups.The incidence of AEs related to the cardiovascular system was similar between the mirabegron and placebo groups. Compared with placebo, pulse rate increased by ∼2 beats per minute after 4 weeks of treatment with mirabegron and returned to baseline levels 2 weeks after treatment ended. The precise mechanism responsible for the elevation in pulse rate following β3-adrenoceptor stimulation is still unknown. Of the seven patients with pre-existing cardiovascular disease (angina pectoris [n = 3], cardiac valve disease [n = 1], myocardial infarction [n = 1], prinzmetal angina [n = 1], mitral valve prolapse [n = 1]) that were included in this study, only one patient, with angina pectoris, received mirabegron. None of these patients experienced cardiovascular-related AEs during the study.

Although antimuscarinic drugs continue to represent the current standard treatment for OAB, with established efficacy and safety profiles, one of their well-known drawbacks is a relatively high prevalence of bothersome side effects. The low persistence rate with antimuscarinics can also be challenging, with ∼50% of patients discontinuing treatment at 3 months [30]. Mirabegron represents the first in a new class of therapy for OAB symptoms for more than three decades. With mirabegron, patients are unlikely to experience the common AEs associated with antimuscarinics. Mirabegron can offer an alternative treatment option for patients with OAB, and has a better tolerability profile.

Evidence from this and three other pivotal phase III studies [31-33], including a pooled analysis of three phase III studies [34], and a 12-month study of efficacy and safety [35] has demonstrated significant improvements with mirabegron, at doses ranging from 25 to 100 mg, in efficacy variables related to incontinence, micturition and urgency, and has demonstrated good tolerability. Together these data support mirabegron as an attractive alternative to antimuscarinic therapy in the management of OAB.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

The study was designed by the study sponsor (Astellas Pharma Inc.) in collaboration with the authors. Data were collected by the investigators at the study centre and were monitored and analysed by personnel at Astellas Pharma Inc. The study and editorial support were funded by Astellas Pharma Inc. Editorial support in the form of assistance with the first draft, collating author comments, and editorial suggestions to draft versions of this manuscript was provided by Emad Siddiqui BSc, MBBS, MRCS, MD (Astellas Pharma Europe Ltd, Surrey, UK) and Stuart Murray from Envision Scientific Solutions. All authors reviewed the initial manuscript draft and contributed to revision of the manuscript.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

O.Y. is a consultant for Astellas, Pfizer, Ferring and Hisamitsu, and a member of the advisory boards of Astellas, and has received grants from Astellas, Kissei and Kyorin and payments for lectures from Astellas, Kyorin, Ono and Kissei. E.M. is a consultant for Astellas relating to the design and statistical analyses of the present study. H.K. is a consultant for Astellas, and has received grants from Astellas, Kissei, Ono, Taiho, Pfizer, GlaxoSmithKline and Asahi Kasei and speaker's honoraria from Astellas, Kissei, Ono, Taiho, Pfizer, GlaxoSmithKline and Asahi Kasei. Y.H. is a consultant for Astellas and Pfizer, and has received grants from Asahi Kasei, Daiichi-Sankyo, GlaxoSmithKline, Kissei, Ono, Kyorin, Taiho, Pfizer and Nippon Shinyaku, and speaker's honoraria from Astellas, Pfizer, Kyorin, Kissei, Ono, Asahi Kasei, Daiichi-Sankyo, GlaxoSmithKline and Taiho.

Y.I. is a consultant for Astellas, Pfizer and Eli Lilly, and has received grants from Astellas, AsahiKasei, Kissei, Ono, Kyorin, Taiho and RaQualia and speaker's fees from Astellas, Asahi Kasei, Kissei, Kyorin, Taiho, Nippon Shinyaku and Pfizer. M.T. is a consultant for Astellas, and has received grants from Astellas, GlaxoSmithKline, Asahi Kasei and Kyorin. O.N. is a consultant for Astellas, and has received grants from Astellas and payments for lectures from Astellas, GlaxoSmithKline and Pfizer. M.G. is a consultant for Astellas, Pfizer, Kyorin and Taiho, and has received grants from Astellas, Pfizer, Kyorin and Taiho and payments for lectures from Astellas, Pfizer, Kyorin and Taiho. M.Y. is a consultant for Astellas Pharm, and study investigator of Meiji Seika Pharm, Nippon Shinyaku, and has received lecture fees from Meiji Seika, Nippon Shinyaku, Astellas, Kissei, Ono Pharm, Pfizer and Kyorin Pharm. O.Y. is a consultant for Astellas, Nippon Shinyaku, Taiho, Ono, Eli Lilly, Meiji Seika and Ferring and has received grants from Astellas, Pfizer, Kissei, Asahi Kasei, Ono, Kyorin and GlaxoSmithKline and payments for lectures from Astellas and Asahi Kasei. N.S. is a consultant for Astellas, has received grants from Astellas and speaker fees from Astellas, Ono, Pfizer, Kyorin and Kissei. Y.I. and S.O. are employees of Astellas.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References