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Platinum Priority – Brief CorrespondenceEditorial by Maurizio Serati and Fabio Ghezzi on pp. 15–16 of this issue

Efficacy of the b3-adrenoceptor Agonist Mirabegron for the

Treatment of Overactive Bladder by Severity of Incontinence at

Baseline: A Post Hoc Analysis of Pooled Data from Three

Randomised Phase 3 Trials

Christopher Chapple a,*, Vik Khullar b, Victor W. Nitti c, Jeffrey Frankel d, Sender Herschorn e,Mathilde Kaper f, Mary Beth Blauwet g, Emad Siddiqui h

a Department of Urology, Royal Hallamshire Hospital, Sheffield, UK; b St Mary’s Hospital, Imperial College, Urogynaecology Department, London, UK;c NYU Langone Medical Center, New York, NY, USA; d Seattle Urology Research Center, Seattle, WA, USA; e Department of Surgery/Urology, University

of Toronto, Toronto, Ontario, Canada; f Department of Biostatistics, Astellas Pharma Global Development, Leiden, The Netherlands; g Department of

Biostatistics, Astellas Pharma Global Development, Northbrook, IL, USA; h Astellas Pharma Europe Ltd, Chertsey, Surrey

Article info

Article history:Accepted June 30, 2014

Keywords:

Correlation analysis

Efficacy

Incontinence

Mirabegron

Overactive bladder

Severity

Abstract

The b3-adrenoceptor agonist mirabegron is approved for treatment of the symptoms ofoveractive bladder (OAB). Incontinence can be the most bothersome of OAB symptoms.Hence, we conducted a post hoc analysis of pooled data from three randomised, double-blind, placebo-controlled, 12-wk, phase 3 studies of mirabegron to evaluate the efficacyof mirabegron 50 mg in incontinent OAB patients and in subgroups of patients stratifiedby severity of incontinence at baseline (an average of two or more [FAS-I�2 subgroup] orfour or more [FAS-I�4 subgroup] incontinence episodes per 24 h at baseline, where FAS-Iis the full analysis set-incontinence population) and to determine correlations betweenmeasures of efficacy and disease severity. Mirabegron 50 mg resulted in statisticallysignificant improvements from baseline to final visit versus placebo in mean number ofincontinence episodes, micturitions, and urgency episodes per 24 h and mean volumevoided per micturition in the pooled incontinent population and in the FAS-I�2 and FAS-I�4 subgroups. Treatment effect versus placebo for incontinence and urgency episodesincreased with increasing severity of incontinence at baseline. Moderate correlationswere seen between improvement in both frequency of incontinence episodes andmicturitions and baseline incontinence and micturition frequency, respectively, withmirabegron 50 mg and placebo.Patient summary: Incontinence can be the most bothersome of OAB symptoms;mirabegron 50 mg once daily is effective for treatment of OAB symptoms in incontinentpatients, and its effect increases with increasing severity of incontinence.

# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Royal Hallamshire Hospital, Glossop Road, SheffieldS10 2JF, UK. Tel. +44 0114 2797841; Fax: +44 0114 271 1901.

ple@shef.ac.uk (C. Chapple).

E-mail address: c.r.chap

http://dx.doi.org/10.1016/j.eururo.2014.06.0520302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 1 1 – 1 412

The efficacy and tolerability of the b3-adrenoceptor agonist

mirabegron for the treatment of the symptoms of overactive

bladder (OAB) have been demonstrated in three large-scale,

randomised, double-blind, placebo-controlled, 12-wk, phase

3 studies [1–3] in which the co–primary end points were

mean change from baseline to final visit (end of treatment) in

mean number of incontinence episodes per 24 h and mean

number of micturitions per 24 h. In addition, in a pooled

analysis of these three studies, mirabegron 50 mg and

100 mg were associated with statistically significant

improvements compared with placebo in the co–primary

end points and the key secondary outcome measures of mean

Fig. 1 – Adjusted mean change from baseline to end of treatment in (A) numb(C) number of urgency episodes per 24 h; and (D) volume voided per micturiti(FAS-I) populations and subgroups with an average of two or more (FAS-II2) obaseline diary (pooled data). Note that results for mean number of incontinenpresented previously in the primary reporting of this pooled efficacy data [4] ayThe total FAS-I comprised patients who reported one or more incontinence ep*p < 0.001 for pairwise comparison with placebo within a stratified analysis ofan ANCOVA model for the other three normally distributed end points. All mobaseline value as a covariate.CI = confidence interval; SE = standard error.

number of urgency incontinence episodes per 24 h, mean

number of urgency episodes per 24 h, and level of urgency

( p < 0.05 for all comparisons) [4].

Patients enrolled in each of these studies could be

incontinent or continent at baseline with varying symptom

severity and therefore were representative of a real-world

population of OAB patients. However, incontinence is among

the most troublesome symptoms and is associated with the

greatest impairment of quality of life [5]. Hence, we

conducted a post hoc analysis to determine the effect of

mirabegron 50 mg once daily compared with placebo on

frequency of micturitions and urgency episodes and volume

er of incontinence episodes per 24 h; (B) number of micturitions per 24 h;on with mirabegron 50 mg and placebo. Full analysis set–incontinencer four or more (FAS-II4) incontinence episodes per 24 h in the 3-dce episodes per 24 h in the pooled FAS-I populations have beennd are displayed for purposes of comparison.isodes in the 3-d baseline micturition diary.covariance (ANCOVA) model for evaluation of incontinence episodes anddels included treatment group, sex, and study as fixed factors and

E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 1 1 – 1 4 13

voided per micturition in the subgroup of the pooled phase 3

population that was incontinent at baseline (note that these

outcomes were previously analysed in the total, continent

plus incontinent, OAB population [4]). We also evaluated the

effect of mirabegron 50 mg once daily compared with

placebo on incontinence, urgency, micturition frequency,

and volume voided per micturition in OAB patients stratified

by baseline severity of incontinence. Finally, we conducted a

correlation analysis between measures of treatment re-

sponse and measures of baseline severity to gain greater

insight into the treatment response pattern of mirabegron.

The analysis set (the full analysis set–incontinence [FAS-I])

comprised all randomised patients who received one or more

doses of study drug; who reported one or more micturition

measurements and one or more incontinence episodes in

a 3-d micturition diary at baseline; and who reported one

or more micturition measurements in at least one postbase-

line diary (baseline demographic data are shown in the

Supplement). For the pooled analysis, the efficacy data for

each of the placebo and mirabegron 50 mg arms of all three

studies were pooled. The pooled FAS-I populations were

then stratified into subgroups with an average of two or

more (FAS-I�2 subgroup) or four or more (FAS-I�4 subgroup)

incontinence episodes per 24 h in the 3-d baseline diary.

Pearson correlation coefficients were derived between

two measures of efficacy—change from baseline to final visit

in mean number of incontinence episodes per 24 h and

mean number of micturitions per 24 h—and three measures

of disease severity at baseline—mean numbers of micturi-

tions per 24 h, incontinence episodes per 24 h, and urgency

episodes per 24 h.

There were 878 and 862 patients in the pooled placebo

and mirabegron 50 mg FAS-I groups, respectively. At

baseline, approximately 52% of the pooled placebo group

(n = 457) and the mirabegron 50 mg group (n = 449) were in

the FAS-I�2 subgroup, whereas approximately 23% of the

pooled placebo group (n = 194) and the mirabegron 50 mg

group (n = 198) were in the FAS-I�4 subgroup.

Table 1 – Correlation analysis of different measures of treatment respmeasures of baseline severity (continuous measurements; pooled data

Measure of treatment response Measure of baselineseverity

Change from baseline to final visit in mean:

Number of incontinence episodes/24 h (FAS-I) Incontinence frequency

Number of incontinence episodes/24 h (FAS-I) Number of urgency episode

(Grade 3 or 4)/24 h

Number of incontinence episodes/24 h (FAS-I) Micturition frequency

Number of micturitions/24 h (FAS) Micturition frequency

Number of micturitions/24 h (FAS) Number of urgency episode

(Grade 3 or 4)/24 h

Number of micturitions/24 h (FAS-I) Incontinence frequency

FAS = full analysis set; FAS-I = full analysis set-incontinence.

Mirabegron 50 mg resulted in statistically significant

improvements from baseline to final visit relative to

placebo in mean number of incontinence episodes per

24 h, mean number of micturitions per 24 h, mean number

of urgency episodes per 24 h, and mean volume voided per

micturition in the FAS-I population ( p < 0.001; Fig. 1).

Statistically significant improvements from baseline to final

visit for mirabegron 50 mg relative to placebo in these four

outcomes were also seen in the FAS-I�2 and FAS-I�4

subgroups. The adjusted mean change from baseline in

incontinence episodes per 24 h and urgency episodes per

24 h in both the pooled placebo and mirabegron 50 mg

groups was smallest in the total FAS-I population and

increased to a maximum in the FAS-I�4 subgroup. This

translated to an increasing treatment effect size for the

outcomes of incontinence and urgency frequency, relative

to placebo, with increasing severity of incontinence at

baseline (Fig. 1). For micturition frequency and volume

voided per micturition, there was little variation in adjusted

mean change from baseline for either the pooled placebo

or mirabegron 50 mg groups or for treatment effect size

relative to placebo with baseline number of incontinence

episodes per 24 h (Fig. 1).

Correlations for change from baseline to final visit in

both mean number of incontinence episodes per 24 h and

mean number of micturitions per 24 h with measures of

disease severity at baseline were statistically significant for

the pooled placebo and mirabegron 50 mg groups (Table 1).

The strongest correlation was that for change from baseline

to final visit in mean number of incontinence episodes and

baseline incontinence frequency, with a larger correlation

in the mirabegron 50 mg group than the placebo group. The

next largest correlation was for change from baseline to

final visit in mean number of micturitions and baseline

micturition frequency, with similar correlations for mira-

begron 50 mg and placebo [6]. The correlations between all

other variables were low. This supports the results of the

subgroup analysis, which demonstrates consistent results

onse (with placebo and mirabegron 50 mg once daily) and different)

Treatment arm Pearson’s correlationcoefficient

p-value

Placebo �0.508 <0.001

Mirabegron 50 mg �0.593 <0.001

s Placebo �0.153 <0.001

Mirabegron 50 mg �0.278 <0.001

Placebo �0.154 <0.001

Mirabegron 50 mg �0.159 <0.001

Placebo �0.370 <0.001

Mirabegron 50 mg �0.375 <0.001

s Placebo �0.153 <0.001

Mirabegron 50 mg �0.229 <0.001

Placebo �0.111 0.001

Mirabegron 50 mg �0.091 0.0078

E U R O P E A N U R O L O G Y 6 7 ( 2 0 1 5 ) 1 1 – 1 414

for micturition frequency regardless of number of inconti-

nence episodes at baseline.

These results are consistent with concepts of the OAB

symptom complex [7]. The core symptom of OAB is the

adverse sensory experience of urgency. Urgency leads

directly to increased micturition frequency and, by exten-

sion, to reduced intervoid interval and volume voided per

micturition. Incontinence is separately correlated with

urgency via increased micturition frequency but is multi-

factorial in nature. The b3-adrenoceptor has been shown to

have a role in detrusor relaxation and to facilitate urine

storage through flattening and lengthening of the bladder

base in animal models [8,9]. Hence, it is consistent with its

function as a b3-adrenoceptor agonist that mirabegron has

shown significant improvements in the OAB symptoms

associated with urgency, namely, frequency of urgency

episodes and level of urgency. That mirabegron is also

associated with improvements in micturition frequency

and volume voided per micturition is consistent with the

fact that these symptoms are the direct result of urgency in

the overall symptom complex.

Author contributions: Christopher Chapple had full access to all the data

in the study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Chapple, Nitti, Blauwet, Siddiqui, Frankel,

Kaper, Khullar, Herschorn.

Acquisition of data: Chapple, Nitti, Blauwet, Frankel, Khullar, Herschorn.

Analysis and interpretation of data: Chapple, Nitti, Blauwet, Siddiqui,

Frankel, Kaper, Khullar, Herschorn.

Drafting of the manuscript: Chapple, Nitti, Blauwet, Siddiqui, Kaper,

Khullar, Herschorn.

Critical revision of the manuscript for important intellectual content:

Chapple, Nitti, Blauwet, Siddiqui, Frankel, Kaper, Khullar, Herschorn.

Statistical analysis: Blauwet, Kaper.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: None.

Other (specify): None.

Financial disclosures: Christopher Chapple certifies that all conflicts of

interest, including specific financial interests and relationships and

affiliations relevant to the subject matter or materials discussed in the

manuscript (eg, employment/affiliation, grants or funding, consultan-

cies, honoraria, stock ownership or options, expert testimony, royalties,

or patents filed, received, or pending), are the following: Christopher

Chapple received a grant from Astellas for work related to this paper.

Other financial activities include grants from Allergan, Pfizer, and

Recordati and personal fees from Allergan, American Medical Systems,

Astellas, Lilly, ONO, Pfizer, and Recordati for services as consultant,

researcher, speaker, and trial participant. Sender Hershorn has received

grants from Sunnybrook Research Institute, Allergan, and Pfizer and

personal fees for his participation on advisory boards and for conducting

research from Astellas, Allergan, Pfizer, Merus, and Lilly. Victor Nitti has

received grants from Allergan, Pfizer, Ipsen, and Uroplasty and personal

fees for work as an investigator and advisory board member from

Astellas and Allergan and as an advisory board member from Medtronic,

all for work unrelated to this paper. Vikram Khullar has received grants

from Astellas, Pfizer, and Allergan and personal fees from Astellas and

Allergan. Jeffrey Frankel has received personal fees for acting as

consultant to Pfizer and research payments from Astellas for work

unrelated to this paper. Emad Siddiqui, Mary Beth Blauwet, and Mathilde

Kaper are employees of Astellas.

Funding/Support and role of the sponsor: The studies and post hoc

analyses described in this paper were funded by Astellas Pharma Inc, as

was writing assistance. Astellas Pharma Inc was involved in the design

and conduct of the study and management and analysis of the data.

Acknowledgement statement: Writing assistance was provided by Aideen

Young, PhD, of Envision Scientific Solutions.

Appendix A. Supplementary data

Supplementary data associated with this article can be

found, in the online version, at http://dx.doi.org/10.1016/

j.eururo.2014.06.052.

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