Critical analysis of phase II and III randomised
control trials (RCTs) evaluating efficacy and
tolerability of a β3-adrenoceptor agonist
(Mirabegron) for overactive bladder (OAB)
Marta Rossanese, Giacomo Novara*, Ben Challacombe†, Alessandro Iannetti*,
Prokar Dasgupta† and Vincenzo Ficarra
Department of Experimental and Clinical Medical Sciences, Urology Unit, University of Udine, Udine, *Department of
Surgical, Oncologic and Gastrointestinal Sciences, Urologic Unit, University of Padua, Padua, Italy, and †King's Health
Partners, London, UK
To critically analyse available phase II and III randomised
control trials (RCTs) reporting clinical data about the efficacy
and tolerability of Mirabegron (a β3-adrenoceptor agonist) in
the treatment of overactive bladder (OAB) syndrome. A
review of the literature was performed in September 2013
using the MEDLINE database. A ‘free text’ protocol was used
for the search strategy using ‘overactive bladder’ and
‘Mirabegron’ as keywords. Subsequently, the searches were
pooled and limited to phase II and III RCTs. Two phase II and
five phase III RCTs were selected and analysed. The available
phase II studies showed the efficacy and tolerability of
different doses of Mirabegron compared with placebo.
Moreover, a dose-ranging study showed that 50 mg once daily
should be considered the most promising dose for clinical use.
The 12-week phase III studies confirmed the effectiveness of
Mirabegron to significantly reduce the mean number of
incontinence episodes/24 h and the mean number of
micturitions/24 h compared with placebo. A post hoc analysis
confirmed that favourable results with Mirabegron were
reported both in patients with OAB who were antimuscarinic
Introduction
Overactive bladder (OAB) is a syndrome characterised by the
presence of urgency, with or without urinary incontinence
usually with increased daytime or night-time frequency [1].
OAB is a very prevalent condition in both female and male
patients, and it is more common in older adults compared
with the general population. Moreover, OAB syndrome
adversely affects patient’s health-related quality of life
(HRQL) inducing depression, social isolation and decreased
levels of activity, especially in presence of urgency
incontinence [2].
BJU Int 2015; 115: 32–40
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naïve and in those who had discontinued prior antimuscarinic
therapy. Moreover, a phase III trial showed the safety and
tolerability of 12-month treatment of Mirabegron.
Discontinuation due to adverse events was low both using the
50 and 100 mg dose of Mirabegron. Mirabegron is the first
of a new class of drugs for the treatment of OAB able to
influence non-voiding activity and produce an increased
storage capacity and inter-void interval. Recently
published phase II and III RCTs have shown that the
β3-adrenoceptor-selective agonist, Mirabegron, is an effective
and safe drug for the symptomatic treatment of OAB
syndrome. Mirabegron represents a valid medical option
both for patients with OAB who are antimuscarinic naïve, as
well as in those where antimuscarinics are ineffective or not
tolerated.
Keywords
Mirabegron, overactive bladder, antimuscarinics
Currently, antimuscarinic drugs (i.e. Darifenacin,
Fesoterodine, Oxybutynin, Solifenacin, Tolterodine, and
Trospium) are the first-line drug therapy for OAB; they block
muscarinic M2/M3 receptors located on the urothelium,
interstitial and detrusor muscle cells, and afferent nerves [3].
Meta-analyses of randomised controlled trials (RCTs) have
shown that antimuscarinics provide significant clinical benefit
for OAB symptoms [4]. However, >60% of patients
discontinue antimuscarinic therapy over a 12-month period.
Inadequate symptom control and/or intolerable adverse effects
(e.g. dry mouth, constipation) represent the most common
factors inducing the discontinuation of therapy [5].
© 2014 The Authors
BJU International © 2014 BJU International | doi:10.1111/bju.12730
Published by John Wiley & Sons Ltd. www.bjui.org

Patients unresponsive and/or intolerant to antimuscarinic
drugs and without significant improvement after behavioural
interventions could be candidates for second-line therapy
using Botulinum toxins, intravesical vanilloid or sacral nerve
neuromodulation [6].
Recently, a new class of oral drug has emerged, which
induces a direct relaxation of detrusor smooth muscle via
stimulation of bladder β3-adrenoceptors and has been
approved by the USA Food and Drugs Administration (FDA)
and European Medicines Agency (EMEA) for treatment of
OAB. In the USA and Canada, the recommended starting
dose is 25 mg once daily, with an option to increase to
50 mg. In Europe and Japan, the recommended dose is 50 mg
once daily with 25 mg dose reserved for special populations
(e.g. those with renal or hepatic impairment). Initial efficacy
and tolerability data have been reported in five phase III
RCTs [7–11].
The objective of the present review was to perform a critical
analysis of the available phase II and III RCTs reporting
clinical data concerning the effectiveness and tolerability of
Mirabegron in the treatment of OAB syndrome.
Methods
A review of the literature was performed in September 2013
using the Medical Literature Analysis and Retrieval System
Online (USA National Library of Medicine’s life science
database; MEDLINE). A ‘free text’ protocol was used for the
search strategy. Specifically, the terms ‘overactive bladder’ and
‘Mirabegron’ were used as keywords through all the fields of
the records. Subsequently, the searches were pooled and
limited to phase II and III RCTs. No temporal limits were
used. In addition, other significant studies cited in the
reference lists of the selected papers were considered. Three
of the authors individually reviewed all the abstracts of the
retrieved studies to select the papers that were relevant to the
review topic. Specifically, all the full-test studies including data
of efficacy (changes in incontinence episodes/24 h; changes
in micturitions/24 h; level of urgency; changes in urgency
incontinence episodes/24 h; night-time micturitions/24 h,
changes in volume voided/micturition, urgency episodes/24 h),
and complications (overall rates of adverse events [AEs],
withdrawals due to AEs, dry mouth rate, constipation, acute
urinary retention, vision abnormality, headache etc.) of
Mirabegron were considered. Data were extracted separately
and independently by two of the authors and were
cross-checked.
Results
Of 81 retrieved records, we selected and included in the
present review a total of 18 studies. Specifically, 11 papers
evaluating mode of action and/or pharmacological
Efficacy and tolerability of mirabegron for OAB
characteristics of Mirabegron [12–22], two papers described
phase II trials [23,24] and four papers reported phase III
trials [7–10]. Moreover, we added a new RCT [11] and an
extensive sponsored review of the Literature reporting
some original data not previously reported in the available
RCTs [25].
Mode of Action and Pharmacological
Characteristics
The activation of the micturition reflex is distension of the
bladder, an activity mediated by the stimulation of
myelinated Aδ fibres and unmyelinated C-fibres. If bladder
compliance is increased, the response to distensions is
reduced. Thus, it is necessary to have a greater filling volume
to recruit afferent activity sufficient to initiate micturition, so
the voiding reflex will be delayed. One determinant of
bladder compliance is spontaneous bladder activity during
filling [12]. Experimental studies have shown that
spontaneous bladder activity is reduced by β3-adrenoceptor
agonists [13,14]. Although all three β-adrenoceptor subtypes
(β1, β2 and β3) have been identified in the human detrusor,
the β3-adrenoceptor has been found to be the prevalent
subtype [15,16]. Thus, the β3-adrenoceptor appears to be an
important new therapeutic target for OAB. Indeed,
Mirabegron is a β3-adrenoceptor-selective agonist approved
for treatment of OAB in Japan (Betanis®), USA
(Myrbetriq®) and Europe (Betmiga®), that induces a
detrusor relaxation and a bladder afferent activity inhibition
with a consequent increase in urine storage. At the molecular
level, there are two hypotheses that could explain how the
β3-adrenoceptor mediates relaxation in the human bladder.
The first is that β3-adrenoceptor activation leads to the
opening of big-conductance calcium-activated potassium
channels [17]. The second is that stimulation of the
β3-adrenoceptor results in an activation of adenylyl cyclase,
with the subsequent formation of cyclic adenosine
monophosphate (cAMP) [18]. Mirabegron is rapidly
absorbed after oral administration, the time to maximum
plasma concentration (Tmax) being ≈3 h [19,20]. Mirabegron
is highly lipophilic, and is metabolised in the liver via
multiple pathways, but mainly by cytochrome P450 (i.e.
CYP3A4 and CYP2D6). Inhibitory effects of monoclonal
antibodies against CYP2D6 were small, showing that
CYP3A4 is the primary CYP enzyme responsible for in vitro
oxidative metabolism of Mirabegron, with a minor role of
CYP2D6. Therefore, CYP2D6 substrates with a ‘narrow
therapeutic index’ should be used with caution and
will require titration when prescribed together with
Mirabegron. Interestingly, in the perspective of a potential
co-administration of Mirabegron with tamsulosin (a
CYP2D6 and CYP3A4 substrate), we must take into
consideration that the maximum plasma concentrations of
the drug (Cmax) and area-under-the-curve (AUC) of this
© 2014 The Authors
BJU International © 2014 BJU International 33
Review
α-blocker increased by 60%. Mirabegron has minimal
or no effect on other frequently used drugs, e.g.
oral contraceptives containing ethinyl oestradiol and
levonorgestrel, solifenacin (CYP3A4 substrates), warfarin
(substrate for CYP2C9), metformin and digoxin. It circulates
in plasma as the uncharged active form and as inactive
metabolites. Most of an administered dose is excreted in the
urine, mainly as the unchanged form, and one-third is
recovered in faeces, almost entirely as the unchanged form
[21]. The terminal elimination half-life is about 23–25 h
[19,20]. Effects of food intake on the pharmacokinetic
properties of Mirabegron have been assessed in a
single-dose, randomised, cross-over study in healthy
adults. In this study Mirabegron oral controlled-absorption
system (OCAS) 50 or 100 mg was administrated orally to
healthy adults in the fasted state or after a high- or low-fat
breakfast. Mirabegron OCAS exhibited a greater reduction
in plasma exposure after a low-fat meal compared with a
high-fat meal. However, the effects of food seen in this
study do not warrant a dose adjustment in clinical
practice [22].
Clinical Experiences with Mirabegron
Phase II studies
In 2013, Chapple et al. [23] reported the results of a
randomised, double-blind, double-dummy, parallel group,
placebo and active-controlled phase IIa proof-of-concept
study. After a placebo run-in period, 262 patients with OAB
symptoms were randomised into four groups: placebo,
Mirabegron 100 mg twice-daily (BID), Mirabegron 150 mg
BID and Tolterodine 4 mg extended-release (ER) once-daily
for 4 weeks. The primary endpoint was the change from
baseline to end-of-treatment in the mean number of
micturition episodes/24 h. Secondary endpoints included
changes in the mean volume voided/micturition; the mean
number of urinary incontinence episodes/24 h, urgency
urinary incontinence episodes/24 h, and urgency
episodes/24 h. Moreover, the authors tested urgency severity,
nocturia, and HRQL profile. Mirabegron resulted in a
statistically significant improvement in the mean number of
micturitions/24 h compared with the placebo group (−2.19 for
Mirabegron 100 mg BID and −2.21 for Mirabegron 150 mg
BID vs −1.18 for placebo; P ≤ 0.01). For the secondary
endpoints, only Mirabegron 150 mg BID resulted in a
statistically significant increase in the mean volume
voided/micturition in comparison with placebo (32.7 vs
10.5 mL; P ≤ 0.05). Compared with placebo, Mirabegron
resulted in statistically significant improvements in
incontinence episodes (−1.0 vs −2.2 episodes/24 h for
100 mg; P ≤ 0.01); urgency incontinence episodes (−1.1 vs
−2.1 episodes/24 h for 100 mg; P ≤ 0.05); and it showed
statistical significant reductions in urgency episodes (−1.0 vs
© 2014 The Authors
34 BJU International © 2014 BJU International
−2.3 episodes/24 h for both doses; P ≤ 0.05) and nocturia
episodes (−0.2 vs −0.6 episodes/24 h for 100 mg; P ≤ 0.01).
Treatment-related AEs were comparable for the Mirabegron
and placebo treatment groups. Specifically, dry mouth
prevalence was 3.1% in both Mirabegron arms and 4.7% in
the Tolterodine arm. Mirabegron 150 mg BID caused a not
clinically relevant (5 beats/min) mean increase from baseline
in pulse rate [23].
The previous proof-of-concept study was followed by a phase
IIb, 12-week, double-blinded trial randomising 928 patients in
the following groups: Mirabegron OCAS 25, 50, 100 or 200 mg
once-daily, placebo or Tolterodine ER 4 mg once-daily [24].
The primary endpoint was the change from baseline to
end-of-treatment in the mean number of micturition
episodes/24 h. The secondary endpoints included changes
in the mean volume voided/micturition, incontinence
episodes/24 h, urgency incontinence episodes/24 h, urgency
episodes/24 h, level of urgency and nocturia episodes. Patients
recruited in the Mirabegron groups showed a statistically
significant reduction in the mean number of micturitions/24 h
vs placebo (−1.9, −2.1, −2.1, and −2.2 micturitions/24 h for
Mirabegron 25, 50, 100, 200 mg, respectively vs −1.4
micturitions/24 h for placebo; P ≤ 0.05). Moreover, the trial
showed statistically significant advantages in favour of
Mirabegron groups for most of evaluated secondary
endpoints (P < 0.05 for all comparisons). Interestingly the
treatment-emergent AEs were similar to placebo for all
treatment groups. The discontinuation rate due to AEs
was 3% for placebo and 2.4–5.3% for the different doses of
Mirabegron. There was a small but significant increase in
mean pulse rate after Mirabegron 100 and 200 mg, although
that was not associated with a clinically significant increase
in cardiovascular AEs. There were no differences between
treatment groups for electrocardiogram (ECG) parameters,
systolic or diastolic blood pressure and laboratory parameters
[24]. According to the results of this dose-ranging study the
most promising dose for clinical use was considered 50 mg
once daily. Indeed, the 100 mg is not a marketed dose and the
25 mg one is currently recommended as starting dose only in
the USA.
Recently, Nitti et al. [26] investigated urodynamics parameters
in men with LUTS and BOO treated with Mirabegron. In all,
200 male patients were randomised to receive placebo (65);
Mirabegron 50 mg (70) or Mirabegron 100 mg (65). The
primary urodynamic parameters assessed were the change
from baseline to end-of-treatment in maximum urinary flow
rate (Qmax) and detrusor pressure at Qmax (PdetQmax). The study
was designed to test the non-inferiority of Mirabegron 50 or
100 mg to placebo. The study showed that the β3-adrenoceptor
agonist Mirabegron did not adversely affect voiding
urodynamics parameters, such as the Bladder Contractility
Index and Bladder Voiding Efficiency compared with placebo
after 12 weeks of treatment [26].
 Efficacy and tolerability of mirabegron for OAB

Phase III studies
Three 12-week [7–9], one 16-week [11] and one 52-week [10]
RCTs were retrieved. Table 1 shows the patients’ characteristics
of those enrolled in the available 12-week phase III RCTs.
Tables 2 and 3 summarise primary and secondary outcomes of
previous RCTs.
Nitti et al. [7] conducted a double-blind, placebo-controlled
trial for 12 weeks in a USA registrational trial. The authors
randomised 1329 patients with OAB symptoms in to three
groups: placebo, Mirabegron 50 or 100 mg once daily. The
co-primary efficacy endpoints were the changes from
baseline to final visit in the mean number of incontinence
episodes/24 h and changes from baseline to final visit in
the mean number of micturitions/24 h. At 4 weeks after
treatment, both the Mirabegron 50 and 100 mg groups
showed statistically significant reductions in the mean (SD)
number of incontinence episodes/24 h [−1.47 (0.11) and
−1.63 (0.12) for Mirabegron 50 mg and 100 mg, respectively
vs −1.13 (0.11) for placebo; P ≤ 0.05] and in mean (SD)
number of micturitions/24 h [−1.66 (0.13) and −1.75 (0.14)
for Mirabegron 50 and 100 mg, respectively vs −1.05 (0.13)
for placebo; P ≤ 0.05) compared with placebo. Moreover,
both the 50 and 100 mg Mirabegron groups had significantly
greater increases from baseline to final visit in the mean
(SD) volume voided/micturition, at 18.2 (2.44) and 18
(2.47) mL for Mirabegron 50 and 100 mg, respectively vs 7
(2.41) mL for placebo (P ≤ 0.05). Significant improvements
in additional secondary endpoints (level of urgency, urge
incontinence episodes/24 h, urgency episodes/24 h and
nocturia episodes/24 h) were reported in both Mirabegron
groups in comparison with placebo. Also in this phase III
RCT the percentages of AEs were similar between the
Mirabegron 50/100 mg and the placebo group, at 51.6%,
46.9% and 50.1%, respectively. The most frequent reported
AEs in the 50 and 100 mg Mirabegron groups were
hypertension (6.1% and 4.9%, respectively), UTI (2.7%
and 3.7%, respectively), headache (3.2% and 3%,
respectively), and nasopharyngitis (3.4% and 2.5%,
respectively) [7].

Table 1 Characteristics of patients enrolled in the five available phase III RCTs.

Patients characteristics, % Nitti et al. Khullar et al. Herschorn et al. Chapple et al. Yamaguchi et al.
2013 [7] 2013 [8] 2013 [9] 2013 [10] 2014 [11]

Male 25.7 27.7 31.3 25.9 16.2

Female 74.3 72.2 68.7 74.1 83.7
Aged ≥ 65 years 39.8 37.1 36.9 35.6 37.4
Previous OAB drug NR 47.8 50 NR
Reasons for previous OAB drug discontinuation
Insufficient effects NR 32 67 NR
Poor tolerability NR 12.7 66 NR

NR, not reported.

Table 2 Primary endpoints of available phase III RCTs evaluating Mirabegron 50 and/or 100 mg.

Reference Drug and doses Treatment Primary endpoints

(number of cases) duration,
weeks Mean (SD) change Mean (SD) change
in incontinence in micturitions/24 h
episodes/24 h

Nitti et al. 2013 [7] Mirabegron 50 mg (442) 12 −1.47 (0.11)* −1.66 (0.13)*
Mirabegron 100 mg (433) −1.63 (0.12)* −1.75 (0.14)*
Placebo (453) −1.13 (0.11) −1.05 (0.13)
Khullar et al. 2013 [8] Mirabegron 50 mg (493) 12 −1.62 (0.137)* −1.94 (0.116)*
Mirabegron 100 mg (496) −1.51 (0.128)* −1.75 (0.110)*
Tolterodine ER 4 mg (475) −1.21 (0.137) −1.57 (0.123)
Placebo (494) −1.13 (0.126) −1.37 (0.115)
Chapple et al. 2013 [10] Mirabegron 50 mg (812) 52 −1.01 −1.27
Mirabegron 100 mg (820) −1.24 −1.41
Tolterodine ER 4 mg (812) −1.26 −1.39
Herschorn et al. 2013 [9] Mirabegron 25 mg (432) 12 −1.36 (0.12) −1.65 (0.13)*
Mirabegron 50 mg (440) −1.38 (0.12) −1.60 (0.12)*
Yamaguchi et al. 2014 [11] Mirabegron 50 mg (380) 16 −1.12 (1.47)* −1.67 (2.21)*
Tolterodine 4 mg (378) NR −1.40 (2.17)
Placebo (381) −0.66 (1.86)* −0.86 (2.35)*

NR, not reported; *Statistically significantly superior compared with placebo at the 0.05 level.

© 2014 The Authors

BJU International © 2014 BJU International 35
Review

Table 3 Main secondary endpoints of available phase III RCTs evaluating Mirabegron 50 and/or 100 mg.

Reference Drug and doses Treatment Main secondary endpoints

(number of cases) duration,
weeks Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
change change in change change in change in
in level urgency in nocturia volume voided/ urgency
of urgency incontinence episodes micturition, mL episodes/24 h
episodes/24 h

Nitti et al. 2013 [7] Mirabegron 50 mg (442) 12 −0.19 (0.03)* −1.32 (0.10)* −0.57 (0.07)* 18.2 (2.44)* NR
Mirabegron 100 mg (433) −0.21 (0.03)* −1.45 (0.11)* −0.57 (0.06)* 18.0 (2.47)* NR
Placebo (453) −0.08 (0.03) −0.89 (0.10) −0.38 (0.06) 7.0 (2.41) NR
Khullar et al. 2013 Mirabegron 50 mg (493) 12 NR NR NR 24.2 (2.01)* −2.25 (0.15)*
[8] Mirabegron 100 mg (496) NR NR NR 25.6 (2)* −1.96 (0.15)
Tolterodine ER 4 mg (475) NR NR NR 25 (2) −2.07 (0.15)
Placebo (494) NR NR NR 12.3 (1.99) −1.65 (0.15)
Chapple et al. 2013 Mirabegron 50 mg (812) 52 NR NR −0.46 (0.04) 17.5 NR
[10] Mirabegron 100 mg (820) NR NR −0.39 (0.04) 21.5 NR
Tolterodine ER 4 mg (812) NR NR −0.43 (0.04) 18.1 NR
Herschorn et al. 2013 Mirabegron 25 mg (432) 12 −0.22 (0.03) NR NR 12.8 (2.2) −1.68 (0.16)
[9] Mirabegron 50 mg (440) −0.29 (0.03) NR NR 20.7 (2.2)* −1.94 (0.15)
Yamaguchi et al. Mirabegron 50 mg (380) 16 NR −1.01 (1.33)* −0.44 (0.93) 24.3 (35.47)* −1.85 (2.55)*
2014 [11] Tolterodine 4 mg (378) NR NR NR NR NR
Placebo (381) NR −0.60 (1.74)* −0.36 (1.06) 9.71 (29.08)* −1.37 (3.91)*

NR, not reported; *Statistically significantly superior compared with placebo at the 0.05 level.

Table 4 Patient-reported outcomes: comparison between Mirabegron 50 mg and placebo in the phase III RCTs performed in Australia, Canada,
Europe and USA. Placebo values were calculated from reported Mirabegron adjusted means and treatment differences vs placebo data.

Nitti et al. 2013 [7] Khullar et al. 2013 [8] Herschorn et al. 2013 [9]

OAB-q symptom bother

Mirabegron adjusted mean (SE) −17.0 (0.98) −19.6 (0.85) −18.8 (0.9)
Placebo calculated mean 10.8 −14.9 −16
Difference (SE) −6.2 (1.4) −4.7 (1.2) −2.8 (1.26)
HRQL Total
Mirabegron adjusted mean (SE) 14.8 (0.9) 16.1 (0.8) 14.2 (0.8)
Placebo calculated mean 10.7 13.8 13.0
Difference (SE) 4.1 (1.3) 2.3 (1.1) 1.2 (1.12)
OAB-q coping
Mirabegron adjusted mean (SE) 16.9 (1.1) 18.5 (0.9) 16.4 (1.0)
Placebo calculated mean 12.8 15.6 14.7
Difference (SE) 4.1 (1.5) 2.9 (1.3) 1.7 (1.4)
OAB-q concern
Mirabegron adjusted mean (SE) 18.0 (1.0) 18.4 (0.9) 16.2 (0.9)
Placebo calculated mean 12.7 15.8 14.7
Difference (SE) 5.3 (1.5) 2.6 (1.2) 1.5 (1.3)
OAB-q sleep
Mirabegron adjusted mean (SE) 14.6 (1.1) 15.1 (0.9) 14.5 (1.0)
Placebo calculated mean 9.7 13.2 14.1
Difference (SE) 4.9 (1.5) 1.9 (1.2) 0.4 (1.4)
OAB-q social
Mirabegron adjusted mean (SE) 7.4 (0.8) 10.1 (0.7) 7.7 (0.7)
Placebo calculated mean 6 8.7 7.1
Difference (SE) 1.4 (1.1) 1.4 (1.0) 0.6 (1.0)
PPBC
Mirabegron adjusted mean (SE) −0.7 (0.1) −1.0 (0.06) −0.7 (0.06)
Placebo calculated mean 0.5 0.8 −0.7
Difference (SE) −0.2 (0.1) −0.2 (0.08) −0.0 (0.08)
TS-VAS
Mirabegron adjusted mean (SE) 1.6 (0.2) 2.6 (0.1) 1.88 (0.15)
Placebo calculated mean 0.7 1.9 1.05
Difference (SE) 0.9 (0.2) 0.7 (0.2) 0.83 (0.22)

OAB-q, OAB questionnaire; PPBC, Patient Perception of Bladder Condition; TS-VAS,treatment satisfaction visual analogue scale.

© 2014 The Authors

36 BJU International © 2014 BJU International

Khullar et al. [8] reported clinical data of the European and
Australian phase III study enrolling patients with symptoms of
OAB for ≥3 months. In all, 1987 patients were randomised to
receive placebo, Mirabegron 50 mg, Mirabegron 100 mg, or
Tolterodine ER 4 mg orally once daily for 12 weeks. Notably,
about half of the randomised patients were previously treated
with anticholinergic drugs. The co-primary efficacy endpoints
were the change from baseline to final visit in the mean
number of incontinence episodes/24 h and the number of
micturitions/24 h. The primary comparison was between
Mirabegron and placebo with a secondary comparison
between Tolterodine ER and placebo. Therefore, the study was
not designed to compare Mirabegron with Tolterodine ER.
Patients treated with Mirabegron 50 or 100 mg reported a
statistically significant reduction in the mean number of
incontinence episodes/24 h, at −1.57 and −1.46 for Mirabegron
50 and 100 mg, respectively, vs −1.17 for placebo (P < 0.05 for
both comparisons). Similarly, patients in both Mirabegron
arms had a statistically significant reduction in the mean
number of micturitions/24 h, at −1.93 and −1.77 for
Mirabegron 50 and 100 mg, respectively, vs −1.34 for placebo
(P < 0.05 for both comparisons). For tolerability, the
prevalence of AEs was similar across the four groups.
Specifically, hypertension was the most common AE. It was
observed in 8.1% of patients treated with Tolterodine ER 4 mg,
in 7.7% of those receiving placebo and in 5.9% and 5.4% in
patients treated with Mirabegron 50 and 100 mg, respectively,
with all the differences being not statistically significant.
Interestingly, the dry mouth rate in the Mirabegron 50 and
100 mg groups were similar to placebo (2.8%, 2.8% and 2.6%,
respectively). Conversely dry mouth was reported by 10.1% of
patients treated with Tolterodine ER [8].
Recently, Khullar et al. [27] published a post hoc analysis of
this RCT evaluating separately the results in patients who had
not received any prior antimuscarinic OAB drugs and those
who had received prior antimuscarinics OAB medications.
The latter group was further subdivided in two subgroups
according to the motivation for discontinuation: (i)
insufficient efficacy; (ii) poor tolerability. Mirabegron 50 and
100 mg showed similar improvements of primary endpoints in
patients with OAB who were antimuscarinic naïve and who
had discontinued prior antimuscarinic therapy.
Herschorn et al. [9] published another phase III study
comparing Mirabegron 25 and 50 mg once daily for 12 weeks
with placebo. Specifically, the Authors randomised 1306
patients to receive placebo, Mirabegron 25 or 50 mg once daily
for 12 weeks. The primary endpoints were changes to final
visit in the mean number of incontinence episodes/24 h
and micturitions/24 h. As compared with placebo, both
Mirabegron doses reported significant reductions in the
number of incontinence episodes/24 , at −1.36 and −1.38 for
Mirabegron 25 and 50 mg, respectively, vs −0.96 for placebo
(P < 0.05 for both comparisons) and in the number of
Efficacy and tolerability of mirabegron for OAB
micturitions/24 h, at −1.65 and −1.60 for Mirabegron 25 and
50 mg, respectively, vs −1.18 for placebo (P < 0.05 for both
comparisons). Mirabegron was well tolerated and overall
incidence of treatment-emergent AEs in the Mirabegron
25 mg (48.6%) and 50 mg groups (47.3%) was similar
to placebo (50.1%). Common AEs in all groups were
hypertension (11.3% for Mirabegron 25 mg, 10.7% for
Mirabegron 50 mg and 8.5% for placebo), nasopharingitis
(3.5% for Mirabegron 25 mg, 5.7% for Mirabegron 50 mg and
3.2% for placebo) and headache (2.1% for Mirabegron 25 mg,
2.7% for Mirabegron 50 mg and 4.4% for placebo) [9].
Yamaguchi et al. [11] published the last of the phase III RCTs
evaluating the efficacy and safety of Mirabegron 50 mg in a
Japanese population with OAB. In all, 1139 patients were
randomised to receive placebo, Mirabegron 50 mg or
Tolterodine 4 mg for 16 weeks. The primary efficacy
endpoint was the change from baseline to final visit in the
mean number of micturitions/24 h. The secondary efficacy
variables were: the mean number of urgency episodes/24 h,
the mean number of urinary incontinence episodes/24 h,
the mean number of urgency incontinence episodes/24 h, the
mean number of nocturia episodes, and the mean volume
voided/micturition. Mirabegron 50 mg once daily showed
significant improvements vs placebo in the mean (SD)
number of micturitions/24 h [−1.67 (2.21) vs −0.86 (2.35);
P < 0.05], urgency episodes/24 h [−1.85 (2.55) vs −1.37
(3.91); P < 0.05], incontinence episodes/24 h [−1.12
(1.47) vs −0.66 (1.86); P < 0.05], urgency incontinence
episodes/24 h [−1.01 (1.33) vs −0.6 (1.74); P < 0.05], and
volume voided/micturition [24.3 (35.47) vs 9.71 (29.08) mL;
P < 0.05]. The overall incidence of treatment-related AEs was
24.5% in the Mirabegron arm, 24% in the placebo arm and
34.9% in the Tolterodine arm. In any treatment group
constipation (3.4% for Mirabegron, 2.6% for placebo and
3.5% for Tolterodine) and dry mouth (2.6% for Mirabegron,
2.9% for placebo and 13.3% for Tolterodine) were the most
common treatment-related AEs. For cardiovascular-related
AEs, their prevalence was low and similar in all the three
arms [11].
Long-term safety and efficacy evaluation of Mirabegron in
OAB was assessed in a phase III RCT published by Chapple
et al. [10] in 2013. In this trial, 2452 patients were randomised
to receive Mirabegron 50 mg, Mirabegron 100 mg or
Tolterodine ER 4 mg orally once daily for 12 months. Notably,
81% of the enrolled patients had participated in previous
Mirabegron phase III 12-week RCTs [7,8]. The primary
objective of this study was to explore the safety and tolerability
of 12-month Mirabegron treatment. The prevalence of AEs
was ≈60% in each group and most AEs were mild or moderate
in severity. Mirabegron 50 and 100 mg, and tolterodine ER
4 mg showed a similar incidence of the most frequent AEs,
including hypertension (9.2%, 9.8% and 9.6% respectively),
constipation (2.8%, 3% and 2.7% respectively) and headache
© 2014 The Authors
BJU International © 2014 BJU International 37
Review

(4.1%, 3.2% and 2.5%, respectively). Dry mouth was
significantly more prevalent in the Tolterodine group
(8.6%) than in the Mirabegron groups (2.8% and 2.3% for
Mirabegron 50 and 100 mg, respectively). Discontinuation due
to AEs was low (6.4%, 5.9% and 6.0% for Mirabegron 50 mg,
Mirabegron 100 mg and Tolterodine, respectively). However,
it must be kept in mind that most of these patients were
previously enrolled in prior phase III RCTs, which may have
selected a population of patients with higher tolerance to AEs
as compared with treatment-naïve patients. For efficacy, the
results reported a relief from OAB symptoms maintained
throughout the 12-month treatment. Specifically, similar
reductions in the adjusted mean change from baseline for the
mean number of micturitions/24 h (−1.27 for Mirabegron
50 mg, −1.41 for Mirabegron 100 mg, and −1.39 for
Tolterodine ER 4 mg), the mean number of incontinence
episodes/24 h (−1.01 for Mirabegron 50 mg, −1.24 for
Mirabegron 100 mg, and −1.26 for Tolterodine ER 4 mg), and
improvements in the mean volume voided/micturition
(17.5 mL for Mirabegron 50 mg, 21.5 mL for Mirabegron
100 mg, and 18.1 mL for Tolterodine ER 4 mg). Therefore, the
study confirmed that for patients with OAB syndrome, a
β3-adrenoceptor agonist offers a better toxicity profile than
antimuscarinics drugs, particularly for typical AEs such as dry
mouth and constipation [10].
Discussion
Mirabegron is the first of a new class of drugs for the
treatment of OAB able to influence non-voiding activity and
producing an increased storage capacity and inter-void
interval. This β3-adrenoceptor agonist demonstrated its
efficacy and tolerability in the context of RCTs performed in
Therefore, further studies on Mirabegron should be planned
considering urgency outcomes as primary endpoints.
Looking at the primary and secondary outcomes, sometimes
the clinical relevance of some observed differences could be
questionable. These considerations are more pertinent when
we consider patient-outcomes (HRQL aspects). Firstly, the
reported results are not homogeneous in the three analysed
trials. Secondly, it is evident how the study reporting the most
favourable impact of the therapy on HRQL is also the one
reporting the poorer placebo response. In other words, the
statistical differences between Mirabegron 50 mg and placebo
for patient-outcomes seems to be influenced more by the
difference in placebo effect than by the difference in
β3-adrenoceptor agonist efficacy (Table 4).
Available phase III studies tested Mirabegron both in
treatment-naïve patients with OAB and in patients who have
discontinued antimuscarinic drugs for insufficient efficacy
and/or poor tolerability. Interestingly, post hoc analyses
confirmed the efficacy of this new drug in both subcategories
of patients [27]. Therefore Mirabegron can be used both in the
setting of failure after anticholinergic therapy and in
treatment-naïve patients with OAB (Fig. 1).
The availability of this drug in the urologists’ arsenal opens
some new interesting questions in the management of patients
with OAB syndrome. First of all, head-to-head comparison
between Mirabegron and anticholinergic drugs aiming at
defining the ideal first-line drug treatment for treatment-naïve
patients with OAB syndrome are lacking. Although, available
clinical trials included patients treated with an active
Fig. 1 Possible utilisation of Mirabegron in the treatment of patients with

Europe, Australia, Canada, USA and Japan. Specifically, the OAB.

change from baseline to final visit in the mean number of Treatment-näive patients with OAB
incontinence episodes/24 h and micturitions/24 h was
significantly better with Mirabegron than with placebo in all
the available trials [7–11]. The secondary endpoints showed
significant advantages in favour of Mirabegron for change
from baseline to final visit (end of treatment) in the mean Anticholinergic β3-adrenoceptor
volume voided/micturition and for urgency-related outcomes. drugs agonist (Mirabegron)

Although the number of micturition/24 h and the number of

incontinence episodes/24 h (co-primary efficacy variables) are
two relevant aspects of OAB syndrome, the use of the number
of urgency incontinence episodes/24 h and number of urgency Effective and 1. Insufficient efficacy
episodes (Patient Perception of Intensity of Urgency Scale at tolerate 2. Poor tolerability
void of grade 3 and/or 4)/24 h and level of urgency only as treatment
secondary efficacy variables could be considered a potential
drawback of the available studies. Indeed, urgency is
traditionally considered as the driver symptom responsible for
increased frequency and reduced interval between micturition
as well as the reduced volume voided per micturition in the Anticholinergic
definition and characterisation of OAB syndrome [28]. drugs

© 2014 The Authors

38 BJU International © 2014 BJU International

competitor (Tolterodine ER), no study was designed and
powered to show the non-inferiority or superiority of
Mirabegron in comparison with Tolterodine ER. Moreover, no
study compared Mirabegron with other antimuscarinic drugs
currently available in the marketing (e.g. Solifenacin).
Although no definitive conclusion on comparative efficacy of
Mirabegron and anticholinergic drugs can be drawn at
present, tolerability data seems to be significantly in favour of
the β3-adrenoceptor-selective agonist. Indeed, after 12 months
of Mirabegron therapy relevant AEs, such as dry mouth, were
significantly lower than those reported after Tolterodine ER
administration. Secondly, considering the different modes of
action of β3-adrenoceptor-selective agonist and anticholinergic
drugs, it will be important to explore the best sequence of
treatments, as well as the impact of combined therapies.
RCTs evaluating Mirabegron as second-line therapy after
anticholinergics (i.e. the BEYOND study, NCT01638000)
or combined therapies (i.e. the SYMPHONY study,
NCT01340027 and the BESIDE study, NCT01908829) have
already been completed (BEYOND and SYMPHONY studies)
or are already recruiting patients (BESIDE study). Similarly to
the combination of anticholinergic drugs and α-blockers in
male patients with LUTS/BPH, the effectiveness and safety of
the combination of Mirabegron and α-blockers needs
evaluation. Finally, the tolerability profile of this new class of
drugs shown in phase III RCTs must be reconfirmed in the
context of phase IV studies.
Conclusions
Phase III RCTs have highlighted an opportunity to use a new
category of drug in the treatment of OAB syndrome. The
β3-adrenoceptor-selective agonist is more effective than
placebo and more tolerable than anticholinergic drugs.
However, the availability of this new class of drug poses new
questions, which need clarification to better standardise the
therapeutic options in the treatment of patients with OAB
syndrome.
Conflict of Interest
G.N. has been an Advisory Board Member or Speaker for
Astellas, GlaxoSmithKleine, Lilly, Menarini, Nycomed, Pfizer
Inc., Pierre Fabre, and Recordati. V.F. has been an Advisory
Board Member or Speaker for Astellas, Recordati, Lilly, Pfizer,
Bayer and Pierre Fabre.
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Correspondence: Vincenzo Ficarra, Azienda Ospedaliero
Universitaria Santa Maria della Misericordia, Piazzale Santa
Maria della Misericordia 15, Clinica di Urologia, Padiglione 5,
33100 – Udine, Italy.
e-mail: vincenzo.ficarra@unipd.it;
ficarra.vincenzo@aoud.sanita.fvg.it
Abbreviations: AE, adverse event; BID, twice daily (bis in die);
ER, extended-release; HRQL, health-related quality of life;
OAB, overactive bladder; OCAS, oral controlled-absorption
system; PdetQmax, detrusor pressure at Qmax; Qmax, maximum
urinary flow rate; RCT, randomised controlled trial.