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Supplement
Overview of design of studies
Studies 046 (NCT00689104) [1], 047 (NCT00662909) [2] and 074 (NCT00912964) [3] were of
similar design, except that the assessed doses of mirabegron varied across trials (Figure 1)
and tolterodine extended release (ER) 4 mg was included as an active-control arm in Study
046 only. Male and female patients aged ≥18 years with OAB symptoms for ≥3 months were
enrolled in all studies. Following a 2-week, single-blind, placebo run-in period to determine
baseline symptoms and patient eligibility, patients were randomised if, during a 3-day
micturition diary period, they recorded ≥8 micturitions/24 h and ≥3 urgency episodes –
based on a grade of 3 or 4 on the Patient Perception of Intensity and Urgency Scale (PPIUS
[4]) – with or without urgency incontinence. Patients with stress incontinence or mixed
incontinence with stress predominance at screening were excluded as were those who had
an average total daily urine volume >3000 ml.
Patients were randomised to receive once-daily oral placebo, mirabegron 25 mg
(Study 074 only), mirabegron 50 mg (Studies 046, 047 and 074), mirabegron 100 mg (Studies
046 and 047), or tolterodine ER 4 mg (Study 046 only) for 12 weeks using a computergenerated randomisation scheme. In the pooled analysis of these studies [5], efficacy data
for the placebo and mirabegron 50 mg treatment arms from all three studies were pooled,
and efficacy data for the mirabegron 100 mg treatment arms from the two studies in which
that dose was used, were pooled; the mirabegron 25 mg and tolterodine ER 4 mg treatment
arms that were represented in only one study were not included in the pooled analysis. In
this post-hoc analysis, only the placebo and mirabegron 50 mg treatment arms were used.
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Efficacy endpoints
Co-primary endpoints in all three studies were change from baseline to final visit in the
mean number of incontinence episodes/24 h and mean number of micturitions/24 h.
Secondary efficacy endpoints in all three studies included change from baseline to final visit
in mean volume voided, mean level of urgency (based on PPIUS), mean number of urgency
episodes (PPIUS grade 3 or 4)/24 h, and the mean number of urgency incontinence
episodes/24 h. These were recorded in a patient micturition diary over a 3-day period prior
to clinic visits which occurred at baseline and Weeks 4, 8 and 12/Final Visit (or end of
treatment, defined as last on-treatment assessment for patients who did not complete the
Week 12 visit).
Statistical analyses
The safety analysis set (SAF) comprised all randomised patients who took ≥ 1 dose of
double-blind study drug; the full analysis set (FAS) comprised SAF patients who had ≥ 1
micturition measurement at baseline and ≥ 1 post-baseline micturition measurement; the
FAS-incontinence (FAS-I) set comprised FAS patients who reported ≥ 1 incontinence episode
at baseline. In the original analyses of each Phase III study and in the original pooled
analysis, all efficacy outcome measures were evaluated in the FAS (continent and
incontinent patients) except for number of incontinence episodes/24 h and number of
urgency incontinence episodes/24 h which were evaluated in the FAS-I (i.e. only incontinent
patients). This post-hoc analysis is concerned with the subset of the total patient population
that is incontinent at baseline; therefore data is presented for the FAS-I population. Thus,
for the efficacy outcomes of micturitions/24 h, urgency episodes/24 h and volume
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voided/micturition, this post-hoc analysis represents the first analysis of these data in the
FAS-I population. In contrast, results for mean number of incontinence episodes/24 h have
been presented previously in the pooled FAS-I populations and are displayed again here for
comparison purposes.
Pooled FAS-I groups were stratified into subgroups with an average of ≥2 or ≥4
incontinence episodes/24 h in the 3-day baseline diary (these cut-offs were empirically
defined based on previous data), in order to assess the efficacy of mirabegron by a
categorical measure of disease severity at baseline (for brevity, these groups are referred to
as FAS-I≥2 and FAS-I≥4).
Analysis of the pooled total FAS-I and incontinent subgroups was performed using
Analysis of Covariance (ANCOVA) with treatment group, sex and study as fixed factors and
baseline value as a covariate. Based on the ANCOVA, least squares mean estimates and twosided 95% confidence intervals for mean changes from baseline were derived within
treatment groups and between the mirabegron 50 mg treatment group and placebo.
ANCOVA was used to derive p-values for the comparisons of the normally distributed
variables of mean number of micturitions/24 h; mean number of urgency episodes/24 h and
mean volume voided/micturition. As change from baseline in mean number of incontinence
episodes does not appear to be normally distributed, a stratified rank ANCOVA was used to
derive p-values for the comparison of this variable.
Pearson’s correlation coefficients were derived between two measures of efficacy –
change from baseline to final visit in mean number of incontinence episodes/24 h and
change from baseline to final visit in mean number of micturitions/24 h and three measures
of disease severity at baseline–mean number of micturitions/24 h, mean number of
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incontinence episodes/24 h and mean number of urgency episodes (grade 3 or 4)/24 h
(making six pairs of correlations).
Study limitations
Post-hoc subgroup analyses have inherent limitations caused by the testing of
multiple subgroups and endpoints and the loss of randomisation [6,7]. Also, in the absence
of standardised and validated criteria for assessment of baseline disease severity, subgroup
analysis of incontinence episodes/24 h at baseline, as in the post-hoc analysis described
here, runs the risk of selection bias. The cut-offs of ≥2 and ≥4 incontinence episodes/24 h
were empirically defined based on previous data. Also, patient numbers are necessarily
reduced through the definition of subgroups; this was particularly the case for the subgroup
with an average of ≥4 incontinence episodes/24 h at baseline. A further limitation is that the
two subgroups are not mutually exclusive, i.e. patients in the FAS-I≥4 group are included in
the FAS-I≥2 group.
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Supplemental Fig. 1 – Overview of the individual phase III studies included in the pooled
analyses
†Screening
from Weeks 3 to 2
n = number of patients randomised
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Supplemental Table 1 – Patient demographics and baseline clinical characteristics by
pooled treatment group (FAS-I)
Placebo
(n=878)
mirabegron
50 mg
(n=862)
694 (80.5)
60.7 (12.5)
Females, n (%)
724 (82.5)
Age (years), mean (SD)
59.9 (13.1)
Race, n (%)
White
806 (91.8)
804 (93.3)
Black or African American
58 (6.6)
41 (4.8)
Asian
8 (0.9)
11 (1.3)
Other
6 (0.7)
6 (0.7)
BMI (kg/m2), mean (SD)
29.5 (6.6)
29.3 (6.3)
Type of OAB*, n (%)
Urgency incontinence
336 (38.3)
352 (40.8)
Mixed stress/urgency incontinence
364 (41.5)
350 (40.6)
Frequency/urgency without incontinence
178 (20.3)
160 (18.6)
Duration of OAB (months), mean (SD)
93.1 (101.9)
87.2 (90.7)
Mean (SD) number of incontinence episodes
2.7 (2.7)
2.7 (2.6)
per 24 hours
Mean (SD) number of micturitions per 24 hours
11.6 (3.2)
11.7 (3.2)
Received previous OAB medication, n (%)
518 (59.0)
506 (58.7)
Reason for previous drug discontinuation, n
(%)†
336 (64.9)
335 (66.2)
Insufficient effect
136 (26.3)
138 (27.3)
Poor tolerability
*Type of OAB was assessed by investigator 2 weeks prior to patient filling out Baseline
micturition diary.
†Patient could choose more than one reason for discontinuation; % of patients with
previous OAB drug only. BMI = body mass index; FAS-I = full analysis set-incontinence; OAB
= overactive bladder; SD = standard deviation
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Supplemental references
1. Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of mirabegron, a β3adrenoceptor agonist, in patients with overactive bladder: results from a randomized
European-Australian phase 3 trial. Eur Urol 2013;63:283–95.
2. Nitti V, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a
randomized phase III trial of mirabegron in patients with overactive bladder. J Urol
2013;189:1388–95.
3. Herschorn S, Barkin J, Castro-Diaz D, et al. A phase III, randomized, double-blind,
parallel-group, placebo-controlled, multicenter study to assess the efficacy and
safety of the beta-3 agonist mirabegron in patients with symptoms of overactive
bladder. Urology 2013;82:313–20.
4. Cartwright R, Srikrishna S, Cardozo L, Robinson D. Validity and reliability of the
patient's perception of intensity of urgency scale in overactive bladder. BJU Int
2011;107:1612-7.
5. Nitti V, Herschorn S, Khullar V, et al. Efficacy of mirabegron in patients with
overactive bladder: a pre-specified pooled analysis of 3 randomized, double-blind,
placebo-controlled, phase III studies. Int J Clin Pract 2013;67:619–32.
6. Magee CD, Byars LA, DeZee KJ. Limitations of subgroup analyses in meta-analysis of
cardiac resynchronization therapy by QRS duration. Arch Intern Med 2012;172:375–
6.
7. Lagakos SW. The challenge of subgroup analyses–reporting without distorting. N Engl
J Med 2006,354:1667–9.
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