Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men

Transcription

EURURO-5034; No. of Pages 10
EUROPEAN UROLOGY XXX (2013) XXX–XXX
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Platinum Priority – Benign Prostatic Hyperplasia
Editorial by XXX on pp. x–y of this issue
Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men
with Voiding and Storage Lower Urinary Tract Symptoms:
Results from a Phase 2, Dose-finding Study (SATURN)
Philip Van Kerrebroeck a,*, François Haab b, Javier C. Angulo c, Viktor Vik d, Ferenc Katona e,
Alberto Garcia-Hernandez f, Monique Klaver f, Klaudia Traudtner f, Matthias Oelke g
a
Maastricht University Medical Centre, Maastricht, The Netherlands;
d
Thomayer Hospital, Prague, Czech Republic;
g
Hannover Medical School, Hannover, Germany
e
b
Hôpital Tenon, Paris, France;
c
Hospital Universitario de Getafe, Madrid, Spain;
Josa Andras Hospital, Nyiregyhaza, Hungary; f Astellas Pharma Europe B.V., Leiden, The Netherlands;
Article info
Abstract
Article history:
Accepted March 8, 2013
Published online ahead of
print on March 19, 2013
Background: Storage symptoms are often undertreated in men with lower urinary tract
symptoms (LUTS).
Objective: To evaluate the combination of an antimuscarinic (solifenacin) with an a-blocker
(tamsulosin) versus tamsulosin alone in the treatment of men with LUTS.
Design, setting, and participants: A double-blind, 12-wk, phase 2 study in 937 men with
LUTS (3 mo, total International Prostate Symptom Score [IPSS] 13, and maximum urinary
flow rate 4.0–15.0 ml/s).
Intervention: Eight treatment groups: tamsulosin oral controlled absorption system (OCAS)
0.4 mg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6 or 9 mg plus tamsulosin OCAS 0.4 mg; or
placebo.
Outcome measurements and statistical analysis: The primary efficacy end point was change
from baseline in total IPSS. Secondary end points included micturition diary and quality-oflife (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline
storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone
versus combination therapy, due to the small sample size of the solifenacin monotherapy and
placebo subgroups.
Results and limitations: Combination therapy was associated with significant improvements
in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study
population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS
storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in
a subpopulation of men with two or more urgency episodes per 24 h (Patient Perception of
Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24 h at baseline
(storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone
( p 0.05 for the dose–response slope, all variables). Combination therapy was well tolerated,
and adverse events were consistent with the safety profiles of both compounds.
Conclusions: Solifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total
study population but offered significant efficacy and QoL benefits over tamsulosin OCAS
monotherapy in men with both voiding and storage symptoms at baseline. Combination
therapy was well tolerated.
ClinicalTrials.gov identifier: NCT00510406
Keywords:
Lower urinary tract symptoms
Overactive bladder
Tamsulosin OCAS
Solifenacin
Storage symptoms
Voiding symptoms
# 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
* Corresponding author. Department of Urology, Maastricht University Medical Centre, PO Box 5800,
6202 AZ Maastricht, The Netherlands. Tel. +31 433 877 258; Fax: +31 433 875 259.
E-mail address: [email protected] (P. Van Kerrebroeck).
0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
http://dx.doi.org/10.1016/j.eururo.2013.03.031
Please cite this article in press as: Van Kerrebroeck P, et al. Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with
Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN). Eur Urol (2013),
2
1.
Introduction
level of storage symptoms. All patients underwent ultrasound evaluation of prostate size (transrectal preferred), although no minimum or
Lower urinary tract symptoms (LUTS) include voiding,
storage, and postmicturition symptoms. In men, these are
conventionally associated with benign prostatic hyperplasia (BPH) or benign prostatic obstruction; however, they
often cannot be attributed to physiologic changes to the
prostate, thus treatment guidelines focus on symptom
management [1].
Despite a high prevalence of storage symptoms in
studies in men with LUTS, the symptoms are commonly
undertreated [2,3]. Moreover, under- or inappropriate
treatment for storage LUTS is more common in men than
in women: In an analysis of claims data from >7.2 million
US patients aged >45 yr with overactive bladder (OAB),
pharmacologic therapy was prescribed to 17.1% of men
versus 28.6% of women ( p < 0.001) [4].
a-Blocker monotherapy (eg, tamsulosin) is usually
considered the first-line therapy for moderate to severe
male LUTS [1]. However, symptom control with these
agents may be variable, especially in men with predominant
storage symptoms. Current European Association of Urology treatment guidelines suggest that antimuscarinics (eg,
solifenacin) can be added to a-blockers to manage storage
symptoms that persist after a-blocker monotherapy [1], and
a number of studies support the benefit of a-blocker plus
antimuscarinic combination treatment [5].
We report the results of a phase 2 study, Solifenacin and
Tamsulosin in Males with Lower Urinary Tract Symptoms
Associated with Benign Prostatic Hyperplasia (SATURN),
that evaluated the efficacy and safety of different doses of
an antimuscarinic (solifenacin) in combination with an
a-blocker (tamsulosin in an oral controlled absorption
system [OCAS] formulation) in men with LUTS. The results
of this study were expected to establish the most useful
clinical dose of combination therapy for further evaluation
in the phase 3 Study of Solifenacin Succinate and
Tamsulosin Hydrochloride OCAS in males with moderate
to severe storage lower urinary tract symptoms (NEPTUNE).
maximum prostate size was specified for inclusion in the study. Patients
were excluded if they had a postvoid residual (PVR) volume >200 ml,
evidence of a symptomatic urinary tract infection, a known history or
diagnosis of specific urinary conditions (including urinary retention),
previous surgery of the bladder neck or prostate, or any other relevant
medical history as determined by the investigator.
2.2.
Treatments
After a 2-wk placebo run-in period, patients were randomised to
placebo, tamsulosin OCAS 0.4 mg monotherapy, solifenacin 3, 6, or 9 mg
plus tamsulosin OCAS 0.4 mg, or dose-matched solifenacin monotherapy
(2:4:4:4:4:1:1:1 randomisation ratio) (Fig. 1). As it was expected that the
optimal dose of solifenacin in men with LUTS would be lower than in
OAB, the 3- and 6-mg doses were selected from a safety perspective. The
9-mg dose was included to provide information about the dose–
response curve at the higher end of the dose range. The approved dose of
tamsulosin OCAS for LUTS was used.
2.3.
End points
The primary end point was change in total IPSS from baseline to end of
treatment. Secondary end points included change from baseline to end of
treatment in IPSS voiding and storage subscores, micturition diary
variables (micturition frequency, urgency episodes of Patient Perception
of Intensity of Urgency Scale [PPIUS] grade 3 or 4, urgency incontinence
episodes, and mean volume voided per micturition), and quality-of-life
(QoL) assessments (IPSS-QoL index and Patient Perception of Bladder
Condition [PPBC]). Micturition diaries were completed by patients 3 d
prior to the baseline and assessment visits. The PPIUS is a 5-point,
validated questionnaire used for the judgement of urgency preceding
every void, with episodes being rated from 0 to 4 (0, no urgency; 1, mild
urgency; 2, moderate urgency; 3, severe urgency; 4, urge incontinence)
[6]. The PPBC is a 6-point validated instrument used to judge the general
bladder condition, with patients being asked to rate their symptoms
from 1 (‘‘does not cause me any problems’’) to 6 (‘‘causes me many
severe problems’’) [7]. Safety parameters included patient-reported
adverse events and PVR volume determined by ultrasound.
As solifenacin is expected to treat storage symptoms specifically, the
total urgency and frequency score (TUFS) was evaluated as a post hoc
secondary end point to assess improvements in both frequency and
urgency using a single parameter, calculated as the mean of daily totals
2.
Patients and methods
for all recorded PPIUS urgency grading (0–4) for each diary day. The TUFS
(previously known as total urgency score) has been validated in patients
SATURN was a double-blind, parallel-group, placebo-controlled, multi-
with OAB and LUTS [8,9].
centre, dose-ranging study. The study included a single-blind, 2-wk,
placebo run-in period followed by a randomised, double-blind, placebo-
2.4.
Statistics
controlled, 12-wk treatment period. The study was conducted at
102 centres in 17 European countries, in accordance with the International
Efficacy analyses were carried out in the full analysis set, defined as all
Conference on Harmonisation–Good Clinical Practice guidelines and
patients who received at least one dose of study medication and who had
the principles of the Declaration of Helsinki. All study materials were
a total IPSS at baseline and at least one postrandomisation total IPSS
reviewed and approved by local independent ethics committees, and all
value. Baseline characteristics and safety analyses were reported for the
patients provided written informed consent before screening.
safety set, defined as all patients who received at least one dose of study
2.1.
study drug.
medication and for whom any data were reported after the first dose of
Patients
The primary efficacy analysis was based on a general linear model,
The study enrolled men aged 45 yr who were diagnosed with LUTS
including solifenacin dose and baseline total IPSS as covariates and
with both voiding and storage symptoms. Inclusion criteria included
country as a fixed factor. The dose–response relationship was tested by
total International Prostate Symptom Score (IPSS) 13, a maximum
using parametric statistical modelling to calculate the slope resulting
urinary flow rate (Qmax) of 4.0–15.0 ml/s, with a volume voided during
from the addition of increasing solifenacin doses to tamsulosin OCAS.
free flow 120 ml. Presence of storage symptoms was determined by the
The slope represents the expected increase in change from baseline for
investigator, but there were no specific inclusion criteria regarding the
each increase of 1 mg in the dose of solifenacin (given in combination
3
Fig. 1 – Patient flow in the SATURN study. Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system.
with tamsulosin OCAS), with a significant difference from 0 demonstrating a benefit from increasing the dose of solifenacin added to
tamsulosin OCAS. Additional post hoc efficacy analyses are presented for
voiding symptoms to the overall population but had a
higher level of storage symptoms, demonstrated by greater
frequency and urgency (Table 2).
tamsulosin OCAS alone versus combination therapy in a subpopulation
with two or more urgency episodes per 24 h (PPIUS grade 3 or 4) and
eight or more micturitions per 24 h at baseline, averaged over the 3-d
micturition diary documentation (storage symptoms subgroup). All
statistical comparisons used two-sided tests at the a = 0.05 significance
level. Due to low patient numbers in the subgroup in the solifenacin
monotherapy and placebo arms, the test power of the post hoc analysis
was reduced. Thus, statistical comparisons are presented only for
tamsulosin OCAS alone versus combination therapy.
3.
Results
3.1.
Patients and baseline characteristics
Of 1163 men with LUTS who were screened, 1079 were
enrolled and 937 were randomised (Fig. 1). Baseline
characteristics were similar in all groups (Table 1). Men
included in the post hoc analyses had similar baseline
3.2.
Efficacy
3.2.1.
Primary efficacy end point
Reductions in total IPSS were small in all randomised
groups and similar to placebo, with no significant difference
between combination groups and tamsulosin OCAS alone
(Table 3). Parametric statistical modelling found no
additional benefit from increasing solifenacin doses in
combination with tamsulosin OCAS on the primary end
point, total IPSS in the total study population (dose–
response slope: 0.09; p = 0.1123).
3.2.2.
Secondary efficacy end points
Numeric improvements in micturition diary variables were
observed for solifenacin monotherapy versus placebo and
for combinations of solifenacin with tamsulosin OCAS
4
Table 1 – Baseline characteristics for all men participating in the SATURN study (total population; safety set)
Variable
Age, yr
Ethnicity, no. (%)
White
Black
Other
Weight, kg
Height, m
BMI, kg/m2
Estimated prostate
weight, g
PVR volume, ml
Placebo
(n = 92)
Soli 3 mg
(n = 43)
Soli 6 mg
(n = 43)
Soli 9 mg
(n = 43)
TOCAS 0.4
mg
(n = 177)
Soli 3 mg +
TOCAS 0.4 mg
(n = 179)
Soli 6 mg +
TOCAS 0.4 mg
(n = 178)
Soli 9 mg +
TOCAS 0.4 mg
(n = 175)
65.0 (8.3)
65.2 (8.0)
65.2 (8.1)
65.3 (7.7)
65.0 (7.9)
65.4 (8.2)
65.7 (8.0)
66.0 (6.5)
92 (100)
0
0
82.9 (14.7)
1.73 (0.08)
27.9 (5.0)
41.8 (21.3)
43 (100)
0
0
88.3 (12.9)
1.76 (0.06)
28.6 (3.3)
39.4 (16.5)
43 (100)
0
0
82.7 (13.4)
1.73 (0.06)
27.5 (4.0)
40.3 (15.0)
41 (95.3)
0
2 (4.7)
81.1 (14.4)
1.72 (0.06)
27.4 (4.0)
37.2 (11.8)
176 (99.4)
0
1 (0.6)
82.6 (14.4)
1.74 (0.07)
27.2 (4.1)
40.0 (19.1)
178 (99.4)
1 (0.6)
0
84.4 (13.6)
1.74 (0.07)
27.8 (3.9)
37.9 (15.2)
178 (100)
0
0
85.6 (13.0)
1.75 (0.07)
28.0 (3.7)
39.2 (14.7)
175 (100)
0
0
85.0 (13.5)
1.75 (0.08)
27.9 (4.2)
40.1 (16.6)
34.0 (32.8)
52.2 (45.4)
45.3 (39.4)
43.0 (34.3)
35.7 (38.2)
43.2 (44.7)
38.6 (37.7)
43.4 (42.5)
BMI = body mass index; PVR = postvoid residual; Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system.
All values are given as mean (standard deviation) unless otherwise indicated.
Table 2 – Baseline efficacy parameters for all men participating in
the SATURN study and for the subgroup of patients with voiding
and storage symptoms (full analysis set)
Efficacy measure
Total study
population
(n = 919)
Storage symptoms
subgroupz
(n = 282)
Total IPSS
IPSS voiding
IPSS storage
Urgency episodes per 24 h
(PPIUS grade 3 or 4)
Micturitions per 24 h
TUFS per 24 h
IPSS QoL
Qmax, ml/s
18.3 (4.1)
10.3 (3.2)
7.9 (2.5)
2.56 (3.06)
19.2 (4.1)
10.4 (3.3)
8.8 (2.4)
5.24 (2.72)
10.16 (2.69)
18.83 (9.59)
3.8 (1.1)
10.24 (2.20)
11.40 (2.37)
26.63 (7.13)
4.1 (1.1)
10.26 (2.10)
IPSS = International Prostate Symptom Score; PPIUS = Patient Perception of
Intensity of Urgency Scale; QoL = quality of life; Qmax = maximum urinary
flow rate; TUFS = total urgency and frequency score.
All values are given as mean (standard deviation).
z
Patients in the tamsulosin oral controlled absorption system monotherapy
or combination therapy groups with two or more urgency episodes per 24 h
(PPIUS grade 3 or 4) and eight or more micturitions per 24 h at baseline.
versus placebo and tamsulosin OCAS alone in the total study
population (Table 3). Decreases from baseline to end of
treatment in micturition frequency and TUFS, and increases
in voided volume per micturition were significantly greater
with increasing solifenacin dose plus tamsulosin OCAS
versus tamsulosin OCAS monotherapy (dose–response
slopes: 0.07, p = 0.0008; 0.15, p = 0.044; and 2.84,
p < 0.0001, respectively).
3.3.
Post hoc efficacy analyses
As improvements in storage symptoms were observed in
the total population, a post hoc subgroup analysis was
based on the extent of storage symptoms at baseline in
patients receiving tamsulosin OCAS alone or in combination
with solifenacin. The study had strict inclusion criteria for
voiding symptoms, but not for storage symptoms, and half
of these patients had only minor storage symptoms (fewer
than one urgency episode per 24 h [PPIUS grade 3 or 4] or
fewer than eight micturitions per 24 h). These patients
experienced little or no additional benefit from combination therapy compared with tamsulosin OCAS monotherapy, but patients in the storage symptoms subgroup with
two or more urgency episodes per 24 h (PPIUS grade 3 or 4)
and eight or more micturitions per 24 h at baseline showed
clear improvements in storage parameters with solifenacin
plus tamsulosin OCAS over tamsulosin OCAS alone. In
this latter subgroup, there were significant improvements
in IPSS storage subscore (Fig. 2c), number of urgency
episodes (PPIUS 3 and 4), micturition frequency, voided
volume, and TUFS (Fig. 2d) (Table 4). Compared with
tamsulosin OCAS monotherapy, combination treatment
was associated with numeric improvements in total IPSS
(Fig. 2a), but there were no improvements in IPSS voiding
subscore (Fig. 2b).
3.4.
Quality of life
In the study population as a whole, addition of solifenacin to
tamsulosin OCAS did not produce additional improvements
in IPSS-QoL index or PPBC. However, the post hoc
subanalysis showed additional improvements with combination therapy versus tamsulosin OCAS monotherapy in
QoL variables in men in the storage symptoms subgroup
(Fig. 3a and 3b).
3.5.
Safety
Combination therapy was well tolerated, and most adverse
events were of mild or moderate intensity (Table 5). The
types of adverse events were in line with the known safety
profiles of each individual drug. The most common adverse
events in all treatment groups containing solifenacin with
or without tamsulosin OCAS were dry mouth and
constipation. Treatment-related dry mouth was reported
in a total of 47 (8.8%) patients in the combination-therapy
groups, compared with 4 (2.3%) with tamsulosin OCAS
monotherapy, 8 (6.2%) with solifenacin monotherapy, and
none with placebo (Table 5).
5
Table 3 – Changes from baseline to end of treatment in International Prostate Symptom Score and micturition diary variables for the total
study population (full analysis set)
Variable
Placebo
Soli
3 mg
Total IPSS
89
42
Patients, no.
Baseline value
17.4 (3.5)
19.5 (4.9)
6.3 (5.9)
7.4 (5.9)
Change
Urgency episodes per 24 h (PPIUS grade 3 or 4)z
Patients, no.
64
29
3.61 (2.97)
4.73 (3.90)
Baseline value
1.34 (2.58)
1.68 (2.96)
Change
Micturitions per 24 h
Patients, no.
88
42
9.72 (2.68)
10.15 (2.69)
Baseline value
0.93 (2.31)
1.01 (2.01)
Change
Urgency incontinence episodes per 24 hz
Patients, no.
14
7
Baseline value
1.75 (2.07)
1.38 (1.25)
0.96 (1.03)
1.38 (1.25)
Change
TUFS per 24 h
87
40
Patients, no.
Baseline value
18.21 (9.06)
21.21 (12.12)
3.13 (7.67)
4.37 (8.62)
Change
Volume voided per micturition, ml
88
42
Patients, no.
Baseline value 186.44 (65.65) 174.83 (60.99)
Change
6.36 (42.79)
19.32 (38.92)
Soli
6 mg
Soli
9 mg
TOCAS
0.4 mg
Soli 3 mg +
TOCAS 0.4 mg
Soli 6 mg +
TOCAS 0.4 mg
Soli 9 mg +
TOCAS 0.4 mg
42
18.1 (4.0)
6.0 (5.4)
42
20.2 (5.2)
6.3 (7.5)
176
18.0 (3.8)
7.7 (5.6)
179
18.7 (4.0)
7.8 (5.7)
176
18.1 (4.0)
7.7 (5.2)
173
17.9 (4.0)
6.6 (6.1)
31
3.48 (3.15)
1.21 (2.45)
29
4.67 (3.28)
1.61 (2.77)
110
3.88 (3.38)
1.59 (2.92)
125
3.58 (2.72)
1.52 (2.38)
118
3.47 (3.10)
2.14 (2.75)
112
3.56 (2.76)
1.61 (3.08)
42
9.83 (2.17)
1.09 (2.28)
42
10.41 (3.14)
1.33 (2.20)
175
10.07 (2.60)
1.04 (1.79)
179
10.45 (2.80)
1.67 (2.27)
174
10.22 (2.73)
1.74 (2.11)
171
10.12 (2.59)
1.70 (2.05)
12
1.31 (1.61)
0.83 (1.16)
7
1.05 (1.47)
0.76 (1.42)
24
1.34 (1.74)
0.67 (1.77)
30
1.29 (1.06)
0.86 (1.00)
27
1.62 (1.91)
1.46 (1.89)
31
0.91 (0.81)
0.48 (1.16)
41
18.54 (8.87)
3.54 (6.66)
42
20.76 (10.64)
4.44 (7.50)
167
19.07 (9.46)
3.68 (7.29)
175
19.56 (9.09)
5.05 (7.24)
172
18.49 (9.67)
5.37 (7.51)
164
18.64 (8.92)
4.69 (7.99)
42
166.89 (55.51)
23.69 (31.65)
42
177.15 (67.58)
6.54 (52.42)
175
175.55 (54.96)
13.58 (44.64)
179
171.06 (51.96)
20.86 (42.80)
174
177.12 (60.88)
32.37 (40.42)
171
179.71 (53.84)
38.38 (47.78)
IPSS = International Prostate Symptom Score; PPIUS = Patient Perception of Intensity of Urgency Scale; Soli = solifenacin; TOCAS = tamsulosin oral controlled
absorption system; TUFS = total urgency and frequency score.
All values are given as mean (standard deviation).
z
Only subjects with at least one episode at baseline were included.
Fig. 2 – Adjusted (least square) mean changes from baseline to end of treatment in (a) total International Prostate Symptom Score (IPSS) (n = 282), (b) IPSS
voiding subscore (n = 282), (c) IPSS storage subscore (n = 282), and (d) total urgency and frequency score (TUFS) per 24 h (n = 280) in the storage symptoms
subgroup* (full analysis set). P values are for combination therapy versus tamsulosin oral controlled absorption system (TOCAS).
Soli = solifenacin; NS = not statistically significant.
* IPSS I13, maximum urinary flow rate 4.0–15.0 ml/s, two or more urgency episodes per 24 h (Patient Perception of Intensity of Urgency Scale grade 3 or
4), and eight or more micturitions per 24 h at baseline.
6
Table 4 – Changes from baseline to end of treatment in International Prostate Symptom Score and micturition diary variables for the storage
symptoms subgroup (full analysis set)
TOCAS 0.4 mg
Total IPSS (n = 282)
19.1 (4.2)
Mean (SD) baseline
Adjusted mean change from baseline
5.68
–
Estimated difference vs TOCAS (95% CI)
p
–
Urgency episodes per 24 h (PPIUS grade 3 or 4)* (n = 280)
5.81 (3.13)
Mean (SD) baseline
1.62
–
p
–
Micturitions per 24 h (n = 280)
11.37 (2.24)
Mean (SD) baseline
0.93
p
Urgency incontinence episodes per 24 h* (n = 92)
0.44 (1.22)
Mean (SD) baseline
0.65
–
–
p
TUFS per 24 h (n = 280)
27.50 (7.39)
Mean (SD) baseline
4.76
–
–
p
Volume voided per micturition, ml (n = 280)
Mean (SD) baseline
155.46 (47.22)
14.50
–
p
–
Soli 3 mg +
TOCAS 0.4 mg
Soli 6 mg +
TOCAS 0.4 mg
Soli 9 mg +
TOCAS 0.4 mg
19.6 (4.3)
6.48
0.81 (2.52, 0.91)
0.3553
19.0 (3.9)
6.81
1.13 (2.90, 0.64)
0.2108
19.0 (4.0)
7.40
1.72 (3.48, 0.04)
0.0553
–
0.18
(0.36, 0.00)
0.0522
4.84 (2.43)
1.68
0.06 (0.94, 0.82)
0.8893
5.29 (2.95)
2.76
1.14 (2.04, 0.23)
0.0138
5.13 (2.36)
2.43
0.81 (1.71, 0.09)
0.0772
–
0.12
(0.21, 0.03)
0.0128
11.56 (2.25)
1.83
0.90 (1.59, 0.21)
0.0112
11.35 (2.53)
1.89
0.96 (1.68, 0.25)
0.0086
11.29 (2.51)
2.33
1.40 (2.11, 0.68)
0.0001
–
0.14
(0.21, 0.06)
0.0003
0.42 (0.86)
0.89
0.24 (0.81, 0.33)
0.4115
0.62 (1.45)
1.33
0.68 (1.28, 0.09)
0.0249
0.34 (0.70)
1.06
0.41 (1.01, 0.19)
0.1776
–
0.06
(0.12, 0.01)
0.0793
26.23 (6.32)
6.54
1.79 (4.24, 0.67)
0.1533
26.93 (8.04)
8.69
3.93 (6.47, 1.39)
0.0026
25.97 (6.88)
8.84
4.08 (6.61, 1.54)
0.0017
–
0.48
(0.74, 0.21)
0.0004
157.96 (42.72)
20.96
6.46 (7.85, 20.78)
0.3746
155.97 (44.72)
24.68
10.18 (4.64, 25.01)
0.1775
172.85 (44.59)
36.01
21.51 (6.61, 36.41)
0.0048
Slope
–
2.27
(0.72, 3.81)
0.0042
CI = confidence interval; IPSS = International Prostate Symptom Score; PPIUS = Patient Perception of Intensity of Urgency Scale; SD = standard deviation;
Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system; TUFS = total urgency and frequency score.
Patients in the TOCAS monotherapy or combination therapy groups with two or more urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or more
micturitions per 24 h at baseline.
*
Only subjects with at least one episode at baseline were included.
3.6.
Postvoid residual volume
Mean PVR volume increased with increasing solifenacin
dose, both when given alone and in combination with
tamsulosin OCAS. However, differences between solifenacin
doses were less pronounced for the combination-therapy
groups than for the solifenacin monotherapy groups
(Table 6). Increases in PVR volume were not considered
to be clinically relevant and were not accompanied by an
increase in the incidence of acute urinary retention (AUR).
3.7.
Urinary retention
The incidence of AUR was low in all groups and showed no
apparent relationship with increasing solifenacin dose.
There were six cases of AUR (Table 5). Five occurred within
the first 32 d of treatment and four required catheterisation:
one each with solifenacin 9 mg, tamsulosin OCAS monotherapy, solifenacin 3 mg plus tamsulosin OCAS, and
solifenacin 9 mg plus tamsulosin OCAS.
4.
Discussion
This large phase 2 study evaluated the efficacy and safety of
three doses of the antimuscarinic solifenacin (3, 6, and
9 mg) with the standard dose of the a-blocker tamsulosin
OCAS (0.4 mg) in the treatment of men with LUTS with both
voiding and storage symptoms. This description is in line
with current terminology [1]. Historically, patients meeting
the inclusion criteria used in this study have been referred
to as having LUTS associated with BPH, based on their age,
prostate size, and reduced Qmax, although BPH was not
confirmed histologically. In this study, patients were not
selected on the basis of prostate pathology or prostate size;
however, prostate size was enlarged (mean [SD]: 39.5 g
[16.0]; median: 37.0 g), as expected in this population [10].
In this study, combination therapy was not associated
with significant additional benefits in total IPSS in the
overall study cohort when compared with tamsulosin OCAS
alone, while improvements were observed for specific diary
variables, particularly micturition frequency and voided
volume. All three solifenacin plus tamsulosin OCAS
combination-therapy doses were well tolerated, including
the highest solifenacin dose, with side-effect profiles
consistent with those expected for each individual product
[11,12]. There were no clinically meaningful increases in
PVR volume, and the rate of AUR requiring catheterisation
was low in all groups.
The most interesting results from this study are seen in
the post hoc subgroup analysis in patients with two or more
Fig. 3 – Adjusted (least square) mean changes from baseline to end of
treatment in (a) International Prostate Symptom Score (IPSS) quality of
life (QoL) (n = 281) and (b) Patient Perception of Bladder Condition
(PPBC) (n = 280) in the storage symptoms subgroup * (full analysis set). P
values are for combination therapy versus tamsulosin oral controlled
absorption system (TOCAS).
Soli = solifenacin.
* IPSS I13, maximum urinary flow rate 4.0–15.0 ml/s, two or
more urgency episodes per 24 h (Patient Perception of Intensity of
Urgency Scale grade 3 or 4), and eight or more micturitions per
24 h at baseline.
urgency episodes per 24 h (PPIUS grade 3 or 4) and eight or
more micturitions per 24 h at baseline. Despite an inclusion
criterion specifying that patients should have both voiding
and storage LUTS at baseline, only 40% of the men included
in the tamsulosin OCAS monotherapy and combinationtherapy arms had storage symptoms severe enough to
warrant the addition of an antimuscarinic to a-blocker
monotherapy, probably because no specific inclusion
criteria were given for storage symptoms. This subgroup
analysis showed numerically greater improvements in total
IPSS with combination therapy, particularly the two highest
solifenacin doses, than with tamsulosin OCAS alone. In
addition, combination therapy was associated with significant improvements in IPSS storage subscore, urgency
episodes, micturition frequency, TUFS, voided volume,
IPSS-QoL index, and PPBC compared with tamsulosin OCAS
alone. The phase 3 NEPTUNE study of solifenacin/
tamsulosin combination therapy was initiated to confirm
treatment effects in male LUTS, with patients required to
demonstrate voiding and storage symptoms to qualify for
inclusion; TUFS was a primary efficacy end point.
Other studies have evaluated the relatively new approach of adding an antimuscarinic to a-blocker therapy in
men with OAB [13], but variability in their designs makes
them difficult to compare. For example, in the Tolterodine
and Tamsulosin in Men with LUTS Including OAB:
7
Evaluation of Efficacy and Safety (TIMES) study, neither
tamsulosin nor tolterodine given as monotherapy demonstrated significant improvements in patient perception of
treatment benefit [14], whereas significant improvements
were demonstrated with tolterodine plus tamsulosin
combination versus placebo in micturition diary variables,
total IPSS, and IPSS-QoL. No comparison between combination therapy and tamsulosin was made. The study had no
specific inclusion criteria for voiding symptoms and a
criterion of three or more urgency episodes per 24 h (grades
3–5 on the urinary sensation scale) compared with two
or more episodes per 24 h (PPIUS grade 3 and 4) in the
storage symptoms subgroup of the SATURN study, resulting
in higher baseline Qmax values, more severe storage
symptoms, and worse IPSS-QoL scores at baseline, and,
consequently, greater differences from baseline, than in
SATURN [14].
Urgency, micturition frequency, and IPSS storage subscale were significantly improved in the 12-wk ADAM
(tolterodine) [15] and ASSIST (solifenacin) [16] trials, in
which patients were taking a stable dose of an a-blocker,
usually tamsulosin, for a minimum of 4 wk before the study,
whereas only urgency was significantly improved in the
VESIcare In Combination with Tamsulosin in OAB Residual
Symptoms (VICTOR) trial [17]. In contrast, the addition of
fesoterodine to a-blocker therapy was shown to significantly improve micturition frequency and symptom bother,
but not urgency episodes [18]. Differences in efficacy results
may be a reflection of differences in the study designs;
however, these studies indicate that antimuscarinics appear
to be efficacious and well tolerated in this patient group,
with low AUR rates [6], consistent with our findings from
the SATURN study.
The SATURN study has several limitations. For this dosefinding study, the three solifenacin doses (3, 6, and 9 mg)
selected for evaluation are lower than the currently
approved doses for OAB (5 and 10 mg). This decision was
made to reflect the potentially different safety profile in
patients with voiding and storage LUTS, a population that,
at the time of study design, was perceived to be more at risk
of adverse events associated with antimuscarinics
(ie, urinary retention). In the meantime, a number of large
studies have been performed using antimuscarinics and ablockers in male patients with LUTS, and they do not
support an increased risk of AUR associated with antimuscarinics [6]. This should allay physicians’ concerns
about an increased risk of AUR with antimuscarinics
in men.
For regulatory reasons, a placebo arm and dose-matched
solifenacin monotherapy arms were included, increasing
the number of treatment groups beyond the scope of a
typical phase 2 study. However, solifenacin monotherapy is
not an adequate treatment for these patients, as it does not
address the prostate-related symptoms experienced by this
population. Results for these arms for the post hoc subgroup
analysis are not shown, as the objective of the study was to
compare combination therapy with tamsulosin, and low
patient numbers in these subgroups prevented statistical
comparisons.
8
Table 5 – Summary of treatment-related adverse events occurring in I1% patients overall and two or more patients in any one group (total
population; safety set)
Adverse events
Placebo
(n = 92)
Any event
Cardiac disorders§
Ear and labyrinth disorders
Vertigo
Eye disorders
Blurred vision
Gastrointestinal disorders
Dry mouth
Constipation
Dyspepsia
Nausea
General disorders and
administration site conditions
Fatigue
Chest pain
Investigations
Nervous system disorders
Dizziness
Headache
Dizziness postural
Renal and urinary disorders
Dysuria
Urinary retention
AUR requiring catheterisationz
Reproductive system and breast
disorders
Retrograde ejaculation
Erectile dysfunction
12
0
1
1
1
0
2
0
1
0
0
0
0
0
3
2
0
2
0
0
0
0
0
2
(13.0)
(1.1)
(1.1)
(1.1)
(2.2)
(1.1)
(3.3)
(2.2)
(2.2)
(2.2)
1 (1.1)
1 (1.1)
Soli 3 mg
(n = 43)
6
0
0
0
0
0
3
2
0
0
1
0
(14.0)
Soli 6 mg
(n = 43)
(2.3)
7
1
0
0
0
0
5
2
4
0
0
1
0
0
0
1 (2.3)
1 (2.3)
0
0
0
0
0
0
1 (2.3)
0
0
0
2 (4.7)
0
0
2 (4.7)
0
0
0
0
0
0
0
0
0
0
0
0
3
2
1
1
1
0
0
0
0
0
1 (2.3)
(7.0)
(4.7)
(2.3)
7
0
0
0
2
2
5
4
0
0
0
1
Soli 9 mg
(n = 43)
(16.3)
(4.7)
(4.7)
(11.6)
(9.3)
(16.3)
(2.3)
TOCAS 0.4 mg
(n = 177)
(2.3)
33
5
3
3
0
0
8
4
2
0
2
3
(7.0)
(4.7)
(2.3)
(2.3)
(2.3)
2
0
2
7
3
2
1
2
0
1
1
4
(11.6)
(4.7)
(9.3)
(18.6)
(2.8)
(1.7)
(1.7)
(4.5)
(2.3)
(1.1)
(1.1)
(1.7)
(1.1)
(1.1)
(4.0)
(1.7)
(1.1)
(0.6)
(1.1)
(0.6)
(0.6)
(2.3)
0
2 (1.1)
Soli 3 mg +
TOCAS 0.4 mg
(n = 179)
26
3
1
1
0
0
12
6
4
3
0
2
0
0
1
3
1
1
0
4
2
2
1
4
(14.5)
(1.7)
(0.6)
(0.6)
(6.7)
(3.4)
(2.2)
(1.7)
(1.1)
(0.6)
(1.7)
(0.6)
(0.6)
(2.2)
(1.1)
(1.1)
(0.6)
(2.2)
2 (1.1)
0
Soli 6 mg +
TOCAS 0.4 mg
(n = 178)
35
2
2
2
6
3
21
18
5
2
0
0
0
0
3
3
2
1
0
1
1
0
0
6
(19.7)
(1.1)
(1.1)
(1.1)
(3.4)
(1.7)
(11.8)
(10.1)
(2.8)
(1.1)
(1.7)
(1.7)
(1.1)
(0.6)
(0.6)
(0.6)
(3.4)
5 (2.8)
0
Soli 9 mg +
TOCAS 0.4 mg
(n = 175)
43
2
0
0
1
0
28
23
5
3
0
4
1
2
2
4
1
2
0
4
1
2
1
4
(24.6)
(1.1)
(0.6)
(16.0)
(13.1)
(2.9)
(1.7)
(2.3)
(0.6)
(1.1)
(1.1)
(2.3)
(0.6)
(1.1)
(2.3)
(0.6)
(1.1)
(0.6)
(2.3)
1 (0.6)
2 (1.1)
AUR = acute urinary retention; Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system.
Data given as number (percentage).
§
Medical Dictionary for Regulatory Activities (MedDRA) system organ classes are shown in bold, MedDRA preferred terms are in non-bold.
z
Not a MedDRA-preferred term.
Table 6 – Mean change in postvoid residual volume from baseline to end of treatment (total population; safety set)
Baseline, ml
End of treatment, ml
Change from baseline, ml
Placebo
(n = 92)
Soli 3 mg
(n = 43)
Soli 6 mg
(n = 43)
Soli 9 mg
(n = 43)
TOCAS 0.4 mg
(n = 176)
Soli 3 mg +
TOCAS 0.4 mg
(n = 179)
Soli 6 mg +
TOCAS 0.4 mg
(n = 178)
Soli 9 mg +
TOCAS 0.4 mg
(n = 175)
34.0 (32.8)
38.7 (47.4)
4.6 (41.4)
52.2 (45.4)
57.9 (53.0)
8.1 (39.7)
45.3 (39.4)
68.3 (83.9)
26.8 (71.5)
43.0 (34.3)
74.5 (84.4)
31.8 (83.0)
35.7 (38.2)
31.9 (34.9)
4.0 (30.2)
43.2 (44.7)
49.3 (59.3)
6.4 (53.4)
38.6 (37.7)
54.9 (71.3)
16.9 (59.3)
43.4 (42.5)
59.2 (70.8)
16.5 (60.0)
Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system.
Data are given as mean (standard deviation).
We recognise that the results of the subgroup analysis,
which provide the most relevant results of the SATURN
study, should be interpreted cautiously, owing to their post
hoc nature in addition to the smaller sample size in the
subgroups, and will need to be confirmed in a preplanned
study in a population of patients with both voiding and
storage symptoms.
5.
Conclusions
Previous studies have suggested benefits from using a
combination-therapy approach to manage male LUTS. Our
study shows that the combination of solifenacin plus
tamsulosin OCAS was not associated with benefit on IPSS in
the total population of patients with male LUTS when
compared with tamsulosin OCAS, while improvements
were observed for specific diary variables, particularly
micturition frequency and voided volume. However, this
combination offered significant efficacy and QoL benefits
versus tamsulosin and was well tolerated in the subgroup of
men with LUTS who had both voiding and moderate to
severe storage symptoms, as shown in a post hoc analysis.
Combination therapy with solifenacin 6 or 9 mg and
tamsulosin OCAS seemed to have the best efficacy and
safety profiles, and these doses have been further assessed
in the phase 3 NEPTUNE study.
Author contributions: Philip Van Kerrebroeck had full access to all the
9
Ciechan, Dr. P. Maciukiewicz, Prof. Z. Wolski; Portugal: Prof. M. Reis;
data in the study and takes responsibility for the integrity of the data and
Russia: Prof. V. Avdoshin, Prof. V. Gomberg, Prof. L.M. Gorilovsky, Dr. A.
the accuracy of the data analysis.
Kornev, Prof. O.B. Loran, Dr. S.H. Al-Shukri, Prof. V.N. Surikov; Slovakia:
Dr. M. Brezovsky, Dr. J. Mikulas, Dr. R. Sokol; Spain: Dr. J. Angulo, Dr. J.
Study concept and design: Van Kerrebroeck, Garcia-Hernandez, Klaver.
Acquisition of data: Van Kerrebroeck, Angulo, Oelke.
Cambronero Santos, Dr. E. Leon Duenas, Dr. J. Morote; Sweden: Dr. E.
Brekkan, Dr. I. Ehren, Dr. M. Hedlund.
Analysis and interpretation of data: Van Kerrebroeck, Angulo, GarciaHernandez, Klaver, Traudtner, Oelke.
References
Drafting of the manuscript: Van Kerrebroeck, Haab, Angulo, Vik, Katona,
Garcia-Hernandez, Klaver, Traudtner, Oelke.
[1] Oelke M, Bachmann A, Descazeaud A, et al. Guidelines on the man-
Critical revision of the manuscript for important intellectual content: Van
agement of male lower urinary tract symptoms (LUTS), incl. benign
Kerrebroeck, Haab, Angulo, Vik, Katona, Garcia-Hernandez, Klaver,
prostatic obstruction (BPO). European Association of Urology Web
Traudtner, Oelke.
Statistical analysis: Garcia-Hernandez.
site. http://www.uroweb.org/gls/pdf/13_Male_LUTS_LR.pdf.
[2] Sexton CC, Coyne KS, Kopp ZS, et al. The overlap of storage, voiding and
Obtaining funding: None.
postmicturition symptoms and implications for treatment seeking in
Administrative, technical, or material support: None.
the USA, UK and Sweden: EpiLUTS. BJU Int 2009;103(Suppl 3):12–23.
Supervision: Van Kerrebroeck, Klaver.
Other (specify): None.
[3] Morant SV, Reilly K, Bloomfield GA, Chapple C. Diagnosis and
treatment of lower urinary tract symptoms suggestive of overactive
bladder and bladder outlet obstruction among men in general
Financial disclosures: Philip Van Kerrebroeck certifies that all conflicts of
practice in the UK. Int J Clin Pract 2008;62:688–94.
interest, including specific financial interests and relationships and
[4] Helfand BT, Evans RM, McVary KT. A comparison of the frequencies
affiliations relevant to the subject matter or materials discussed in the
of medical therapies for overactive bladder in men and women:
manuscript (eg, employment/affiliation, grants or funding, consultancies,
analysis of more than 7.2 million aging patients. Eur Urol 2010;57:
honoraria, stock ownership or options, expert testimony, royalties, or
586–91.
patents filed, received, or pending), are the following: Philip van
[5] Athanasopoulos A, Chapple C, Fowler C, et al. The role of antimus-
Kerrebroeck is a lecturer for Astellas, Ferring, and Medtronic, and member
carinics in the management of men with symptoms of overactive
of an advisory board for Allergan, Astellas, and Ferring. Francois Haab is a
bladder associated with concomitant bladder outlet obstruction: an
consultant, investigator, and lecturer for Allergan, Astellas, and Pfizer.
update. Eur Urol 2011;60:94–105.
Javier Angulo has received educational grants for research from Astellas
[6] Cartwright R, Srikrishna S, Cardozo L, Robinson D. Validity and
and Pfizer and is a lecturer for Astellas, GlaxoSmithKline, and Pfizer.
reliability of the patient’s perception of intensity of urgency scale in
Matthias Oelke has received lecturer and/or consultant honoraria from
Apogepha, Astellas, GlaxoSmithKline, Eli Lilly and Company, Ethicon,
overactive bladder. BJU Int 2011;107:1612–7.
[7] Matza LS, Thompson CL, Krasnow J, Brewster-Jordan J, Zyczynski T,
Ferring, Pfizer, Recordati, and Sophiris and received a research grant
Coyne KS. Test-retest reliability of four questionnaires for patients
from Astellas. Alberto-Garcia Hernandez, Monique Klaver, and Klaudia
with overactive bladder: the overactive bladder questionnaire
Traudtner are employees of Astellas. Viktor Vik and Ferenc Katona have
(OAB-q), patient perception of bladder condition (PPBC), urgency
nothing to disclose.
questionnaire (UQ), and the primary OAB symptom questionnaire
Funding/Support and role of the sponsor: The SATURN study was
conceived and funded by Astellas Pharma Europe B.V. Astellas was
involved in study design, data collection and analysis, and manuscript
preparation, and approved the final version of the manuscript.
(POSQ). Neurourol Urodyn 2005;24:215–25.
[8] Cardozo L, Mikulas J, Amarenco G, Drogendijk T, Compion G. Total
urgency score (TUS) as a measure of frequency and urgency in
SUNRISE. Urology 2010;76(Suppl 3a):592.
[9] Cardozo L, Hessdorfer E, Milani R, Arano P, Dewilde L, Slack M.
Acknowledgement statement: Medical writing and editing assistance for
Solifenacin in the treatment of urgency and other symptoms
the preparation of this manuscript was provided by Sophie Berry and
of overactive bladder: results from a randomized, double-blind,
David Hallett at Darwin Healthcare Communications, UK, and funded by
placebo-controlled, rising-dose trial. BJU Int 2008;102:1120–7.
Astellas. The authors would like to acknowledge their colleagues who
[10] Kaplan SA. Identification of the patient with enlarged prostate:
recruited patients into the SATURN study: Belgium: Dr. F. Ameye, Dr. J.
diagnosis and guidelines for management. Osteopath Med Prim
Braeckman, Dr. P. Van Erps, Prof. W. Oosterlinck, Prof. Dr. B. Tombal, Dr.
B. van Cleynenbreugel, Dr. J. Vanderkerken, Dr. N. Verleyen, Prof. J.J.
Wyndale; Czech Republic: Dr. J. Klecka, Dr. J. Krhut, Dr. J. Liehne, Dr. I.
Pavlik, Dr. V. Viktor, Dr. P. Zhanel; Denmark: Dr. M. Borre, Dr. A. Holm-
Care 2007;1:11.
[11] Wilt TJ, Macdonald R, Rutks I. Tamsulosin for benign prostatic hyperplasia [withdrawn]. Cochrane Database Syst Rev 2003:CD002081.
[12] Luo D, Liu L, Han P, Wei Q, Shen H. Solifenacin for overactive
Nielsen, Dr. K. Kroyer, Dr. M. Nohr; Finland: Dr. P. Hellstrom, Dr. K.
bladder: a systematic review and meta-analysis. Int Urogynecol J
Lehtoranta, Dr. J. Sairanen, Dr. T. Tammela; France: Dr. J.P. Ansieau, Dr. T.
2012;23:983–91.
Billebaud, Dr. R. Claude, Prof. P. Costa, Dr. E. Ghazarossian-Ragni, Prof. E.
[13] Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, Perimenis P,
Haab, Dr. J.L. Jung, Dr. S. Mallick, Dr. N. Morin, Dr. B. Rabut; Germany: Dr.
Barbalias G. Combination treatment with an alpha-blocker plus an
T. Benusch, Dr. R. Eckert, Dr. H.P. Fischer, Dr. U. Gerhardt, Dr. W.
anticholinergic for bladder outlet obstruction: a prospective, ran-
Grohmann, Dr. M. Hentschel, Dr. W. Hechelmann, Dr. M. Indig, Dr. W.
domized, controlled study. J Urol 2003;169:2253–6.
Jorger, Dr. T. Kottig, Dr. A. Kublanck, Dr. M. Markov, Dr. B. Mertins, Dr. M.
[14] Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T,
Voss, Dr. W. Warnack, Dr. J. Willgerodt, Dr. A. Wirger; Great Britain: Mr.
Guan Z. Tolterodine and tamsulosin for treatment of men with
P. Bose, Dr. P. Malone, Dr. R. Pawa, Dr. H. Thomas; Hungary: Dr. F. Katona,
lower urinary tract symptoms and overactive bladder: a random-
Dr. G. Nagy, Prof. Dr. L. Pajor, Dr. G. Rosta, Dr. A. Szabo, Dr. Z. Szabo, Dr. P.
Tenke; Italy: Dr. V. Cicalese, Dr. R. Damiano, Prof. R. Ponchietti;
ized controlled trial. JAMA 2006;296:2319–28.
[15] Chapple C, Herschorn S, Abrams P, Sun F, Brodsky M, Guan Z.
Netherlands: Dr. W.I. Jzerman, Dr. P.J.M. Kil, Dr. J. Oddens, Dr. M. Oelke,
Tolterodine treatment improves storage symptoms suggestive of
Dr. E.P.M. Roos, Dr. C. van de Beek, Dr. H. Vergunst; Norway: Dr. M.
overactive bladder in men treated with a-blockers. Eur Urol 2009;
Marcus, Dr. O. Martin Hoeg; Poland: Prof. K. Bar, Prof. A. Borkowski, Dr. J.
56:534–43.
10
[16] Yamaguchi O, Kakizaki H, Homma Y, et al. Solifenacin as add-on
therapy for overactive bladder symptoms in men treated for lower
urinary tract symptoms—ASSIST, randomized controlled study.
Urology 2011;78:126–33.
[17] Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety
and tolerability of solifenacin add-on therapy to alpha-blocker
treated men with residual urgency and frequency. J Urol 2009;
182:2825–30.
[18] Kaplan SA, Roehrborn CG, Gong J, Sun F, Guan Z. Add-on fesoterodine for residual storage symptoms suggestive of overactive bladder in men receiving alpha-blocker treatment for lower urinary
tract symptoms. BJU Int 2012;109:1831–40.

Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men

Transcription

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