E UROPEAN UROLOGY XXX (2013) XXX–XXX - EU …eu-acme.org/europeanurology/upload_articles/Van... · · 2014-04-30from a Phase 2, Dose-finding Study (SATURN) Philip ... E UROPEAN

EURURO-5034; No. of Pages 10

Platinum Priority – Benign Prostatic HyperplasiaEditorial 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,*, Franc ois 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; b Hopital Tenon, Paris, France; c Hospital Universitario de Getafe, Madrid, Spain;d Thomayer Hospital, Prague, Czech Republic; e Josa Andras Hospital, Nyiregyhaza, Hungary; f Astellas Pharma Europe B.V., Leiden, The Netherlands;g Hannover Medical School, Hannover, Germany

E U R O P E A N U R O L O G Y X X X ( 2 0 1 3 ) X X X – X X X

ava i lable at www.sc iencedirect .com

journa l homepage: www.europea nurology.com

Article info

Article history:Accepted March 8, 2013Published online ahead ofprint on March 19, 2013

Keywords:

Lower urinary tract symptoms

Overactive bladder

Tamsulosin OCAS

Solifenacin

Storage symptoms

Voiding symptoms

Abstract

Background: Storage symptoms are often undertreated in men with lower urinary tractsymptoms (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 withLUTS (�3 mo, total International Prostate Symptom Score [IPSS] �13, and maximum urinaryflow 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; orplacebo.Outcome measurements and statistical analysis: The primary efficacy end point was changefrom baseline in total IPSS. Secondary end points included micturition diary and quality-of-life (QoL) parameters. Post hoc subgroup analyses were performed by severity of baselinestorage symptoms, with statistical comparisons presented only for tamsulosin OCAS aloneversus combination therapy, due to the small sample size of the solifenacin monotherapy andplacebo subgroups.Results and limitations: Combination therapy was associated with significant improvementsin micturition frequency and voided volume versus tamsulosin OCAS alone in the total studypopulation; improvements in total IPSS were not significant. Statistically significant improve-ments in urgency episodes, micturition frequency, total urgency score, voided volume, IPSSstorage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed ina subpopulation of men with two or more urgency episodes per 24 h (Patient Perception ofIntensity 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 totalstudy population but offered significant efficacy and QoL benefits over tamsulosin OCASmonotherapy in men with both voiding and storage symptoms at baseline. Combination

rattifi

ed by Elsevier B.V. on behalf of European Association of Urology.

therapy was well toleClinicalTrials.gov iden

# 2013 Publish

* Corresponding author. De6202 AZ Maastricht, The NE-mail address: p.vankerreb

Please cite this article in press as: Van Kerrebroeck P, et al. EfficacVoiding and Storage Lower Urinary Tract Symptoms: Results frohttp://dx.doi.org/10.1016/j.eururo.2013.03.031

0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalhttp://dx.doi.org/10.1016/j.eururo.2013.03.031

ed.er: NCT00510406

partment of Urology, Maastricht University Medical Centre, PO Box 5800,etherlands. Tel. +31 433 877 258; Fax: +31 433 875 259.

[email protected] (P. Van Kerrebroeck).

y and Safety of Solifenacin Plus Tamsulosin OCAS in Men withm a Phase 2, Dose-finding Study (SATURN). Eur Urol (2013),

f of European Association of Urology.

http://dx.doi.org/10.1016/j.eururo.2013.03.031

mailto:[email protected]



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1. Introduction

Lower urinary tract symptoms (LUTS) include voiding,

storage, and postmicturition symptoms. In men, these are

conventionally associated with benign prostatic hyperpla-

sia (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 Urolo-

gy 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).

2. Patients and methods

SATURN was a double-blind, parallel-group, placebo-controlled, multi-

centre, dose-ranging study. The study included a single-blind, 2-wk,

placebo run-in period followed by a randomised, double-blind, placebo-

controlled, 12-wk treatment period. The study was conducted at

102 centres in 17 European countries, in accordance with the International

Conference on Harmonisation–Good Clinical Practice guidelines and

the principles of the Declaration of Helsinki. All study materials were

reviewed and approved by local independent ethics committees, and all

patients provided written informed consent before screening.

2.1. Patients

The study enrolled men aged �45 yr who were diagnosed with LUTS

with both voiding and storage symptoms. Inclusion criteria included

total International Prostate Symptom Score (IPSS) �13, a maximum

urinary flow rate (Qmax) of 4.0–15.0 ml/s, with a volume voided during

free flow �120 ml. Presence of storage symptoms was determined by the

investigator, but there were no specific inclusion criteria regarding the


level of storage symptoms. All patients underwent ultrasound evalu-

ation of prostate size (transrectal preferred), although no minimum or

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

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

with OAB and LUTS [8,9].

2.4. Statistics

Efficacy analyses were carried out in the full analysis set, defined as all

patients who received at least one dose of study medication and who had

a total IPSS at baseline and at least one postrandomisation total IPSS

value. Baseline characteristics and safety analyses were reported for the

safety set, defined as all patients who received at least one dose of study

medication and for whom any data were reported after the first dose of

study drug.

The primary efficacy analysis was based on a general linear model,

including solifenacin dose and baseline total IPSS as covariates and

country as a fixed factor. The dose–response relationship was tested by

using parametric statistical modelling to calculate the slope resulting

from the addition of increasing solifenacin doses to tamsulosin OCAS.

The slope represents the expected increase in change from baseline for

each increase of 1 mg in the dose of solifenacin (given in combination



Fig. 1 – Patient flow in the SATURN study. Soli = solifenacin; TOCAS = tamsulosin oral controlled absorption system.

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with tamsulosin OCAS), with a significant difference from 0 demon-

strating a benefit from increasing the dose of solifenacin added to

tamsulosin OCAS. Additional post hoc efficacy analyses are presented for

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


voiding symptoms to the overall population but had a

higher level of storage symptoms, demonstrated by greater

frequency and urgency (Table 2).

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



Table 2 – Baseline efficacy parameters for all men participating inthe SATURN study and for the subgroup of patients with voidingand storage symptoms (full analysis set)

Efficacy measure Total studypopulation(n = 919)

Storage symptomssubgroupz

(n = 282)

Total IPSS 18.3 (4.1) 19.2 (4.1)

IPSS voiding 10.3 (3.2) 10.4 (3.3)

IPSS storage 7.9 (2.5) 8.8 (2.4)

Urgency episodes per 24 h

(PPIUS grade 3 or 4)

2.56 (3.06) 5.24 (2.72)

Micturitions per 24 h 10.16 (2.69) 11.40 (2.37)

TUFS per 24 h 18.83 (9.59) 26.63 (7.13)

IPSS QoL 3.8 (1.1) 4.1 (1.1)

Qmax, ml/s 10.24 (2.20) 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.

Table 1 – Baseline characteristics for all men participating in the SATURN study (total population; safety set)

Variable Placebo(n = 92)

Soli 3 mg(n = 43)

Soli 6 mg(n = 43)

Soli 9 mg(n = 43)

TOCAS 0.4mg

(n = 177)

Soli 3 mg +TOCAS 0.4 mg

(n = 179)


(n = 178)


(n = 175)

Age, yr 65.0 (7.9) 65.4 (8.2) 65.7 (8.0) 66.0 (6.5) 65.0 (8.3) 65.2 (8.0) 65.2 (8.1) 65.3 (7.7)

Ethnicity, no. (%)

White 92 (100) 43 (100) 43 (100) 41 (95.3) 176 (99.4) 178 (99.4) 178 (100) 175 (100)

Black 0 0 0 0 0 1 (0.6) 0 0

Other 0 0 0 2 (4.7) 1 (0.6) 0 0 0

Weight, kg 82.9 (14.7) 88.3 (12.9) 82.7 (13.4) 81.1 (14.4) 82.6 (14.4) 84.4 (13.6) 85.6 (13.0) 85.0 (13.5)

Height, m 1.73 (0.08) 1.76 (0.06) 1.73 (0.06) 1.72 (0.06) 1.74 (0.07) 1.74 (0.07) 1.75 (0.07) 1.75 (0.08)

BMI, kg/m2 27.9 (5.0) 28.6 (3.3) 27.5 (4.0) 27.4 (4.0) 27.2 (4.1) 27.8 (3.9) 28.0 (3.7) 27.9 (4.2)

Estimated prostate

weight, g

41.8 (21.3) 39.4 (16.5) 40.3 (15.0) 37.2 (11.8) 40.0 (19.1) 37.9 (15.2) 39.2 (14.7) 40.1 (16.6)

PVR volume, ml 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.



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 combina-

tion therapy compared with tamsulosin OCAS monother-

apy, 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 combi-

nation 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).



Fig. 2 – Adjusted (least square) mean changes from baseline to end of treatment in (a) total International Prostate Symptom Score (IPSS) (n = 282), (b) IPSSvoiding 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 symptomssubgroup* (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 or4), and eight or more micturitions per 24 h at baseline.

Table 3 – Changes from baseline to end of treatment in International Prostate Symptom Score and micturition diary variables for the totalstudy population (full analysis set)

Variable Placebo Soli3 mg

Soli6 mg

Soli9 mg

TOCAS0.4 mg




Total IPSS

Patients, no. 89 42 42 42 176 179 176 173

Baseline value 17.4 (3.5) 19.5 (4.9) 18.1 (4.0) 20.2 (5.2) 18.0 (3.8) 18.7 (4.0) 18.1 (4.0) 17.9 (4.0)

Change �6.3 (5.9) �7.4 (5.9) �6.0 (5.4) �6.3 (7.5) �7.7 (5.6) �7.8 (5.7) �7.7 (5.2) �6.6 (6.1)

Urgency episodes per 24 h (PPIUS grade 3 or 4)z

Patients, no. 64 29 31 29 110 125 118 112

Baseline value 3.61 (2.97) 4.73 (3.90) 3.48 (3.15) 4.67 (3.28) 3.88 (3.38) 3.58 (2.72) 3.47 (3.10) 3.56 (2.76)

Change �1.34 (2.58) �1.68 (2.96) �1.21 (2.45) �1.61 (2.77) �1.59 (2.92) �1.52 (2.38) �2.14 (2.75) �1.61 (3.08)

Micturitions per 24 h

Patients, no. 88 42 42 42 175 179 174 171

Baseline value 9.72 (2.68) 10.15 (2.69) 9.83 (2.17) 10.41 (3.14) 10.07 (2.60) 10.45 (2.80) 10.22 (2.73) 10.12 (2.59)

Change �0.93 (2.31) �1.01 (2.01) �1.09 (2.28) �1.33 (2.20) �1.04 (1.79) �1.67 (2.27) �1.74 (2.11) �1.70 (2.05)

Urgency incontinence episodes per 24 hz

Patients, no. 14 7 12 7 24 30 27 31

Baseline value 1.75 (2.07) 1.38 (1.25) 1.31 (1.61) 1.05 (1.47) 1.34 (1.74) 1.29 (1.06) 1.62 (1.91) 0.91 (0.81)

Change �0.96 (1.03) �1.38 (1.25) �0.83 (1.16) �0.76 (1.42) �0.67 (1.77) �0.86 (1.00) �1.46 (1.89) �0.48 (1.16)

TUFS per 24 h

Patients, no. 87 40 41 42 167 175 172 164

Baseline value 18.21 (9.06) 21.21 (12.12) 18.54 (8.87) 20.76 (10.64) 19.07 (9.46) 19.56 (9.09) 18.49 (9.67) 18.64 (8.92)

Change �3.13 (7.67) �4.37 (8.62) �3.54 (6.66) �4.44 (7.50) �3.68 (7.29) �5.05 (7.24) �5.37 (7.51) �4.69 (7.99)

Volume voided per micturition, ml

Patients, no. 88 42 42 42 175 179 174 171

Baseline value 186.44 (65.65) 174.83 (60.99) 166.89 (55.51) 177.15 (67.58) 175.55 (54.96) 171.06 (51.96) 177.12 (60.88) 179.71 (53.84)

Change 6.36 (42.79) 19.32 (38.92) 23.69 (31.65) 6.54 (52.42) 13.58 (44.64) 20.86 (42.80) 32.37 (40.42) 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.



Please cite this article in press as: Van Kerrebroeck P, et al. Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men withVoiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN). Eur Urol (2013),http://dx.doi.org/10.1016/j.eururo.2013.03.031


Table 4 – Changes from baseline to end of treatment in International Prostate Symptom Score and micturition diary variables for the storagesymptoms subgroup (full analysis set)

TOCAS 0.4 mg Soli 3 mg +TOCAS 0.4 mg



Slope

Total IPSS (n = 282)

Mean (SD) baseline 19.1 (4.2) 19.6 (4.3) 19.0 (3.9) 19.0 (4.0) –

Adjusted mean change from baseline �5.68 �6.48 �6.81 �7.40 �0.18

Estimated difference vs TOCAS (95% CI) – �0.81 (�2.52, 0.91) �1.13 (�2.90, 0.64) �1.72 (�3.48, 0.04) (�0.36, 0.00)

p – 0.3553 0.2108 0.0553 0.0522

Urgency episodes per 24 h (PPIUS grade 3 or 4)* (n = 280)

Mean (SD) baseline 5.81 (3.13) 4.84 (2.43) 5.29 (2.95) 5.13 (2.36) –


Estimated difference vs TOCAS (95% CI) – �0.06 (�0.94, 0.82) �1.14 (�2.04, �0.23) �0.81 (�1.71, 0.09) (�0.21, �0.03)

p – 0.8893 0.0138 0.0772 0.0128

Micturitions per 24 h (n = 280)

Mean (SD) baseline 11.37 (2.24) 11.56 (2.25) 11.35 (2.53) 11.29 (2.51) –


Estimated difference vs TOCAS (95% CI) �0.90 (�1.59, �0.21) �0.96 (�1.68, �0.25) �1.40 (�2.11, �0.68) (�0.21, �0.06)

p 0.0112 0.0086 0.0001 0.0003

Urgency incontinence episodes per 24 h* (n = 92)

Mean (SD) baseline 0.44 (1.22) 0.42 (0.86) 0.62 (1.45) 0.34 (0.70) –


Estimated difference vs TOCAS (95% CI) – �0.24 (�0.81, 0.33) �0.68 (�1.28, �0.09) �0.41 (�1.01, 0.19) (�0.12, 0.01)

p – 0.4115 0.0249 0.1776 0.0793

TUFS per 24 h (n = 280)

Mean (SD) baseline 27.50 (7.39) 26.23 (6.32) 26.93 (8.04) 25.97 (6.88) –


Estimated difference vs TOCAS (95% CI) – �1.79 (�4.24, 0.67) �3.93 (�6.47, �1.39) �4.08 (�6.61, �1.54) (�0.74, �0.21)

p – 0.1533 0.0026 0.0017 0.0004

Volume voided per micturition, ml (n = 280)

Mean (SD) baseline 155.46 (47.22) 157.96 (42.72) 155.97 (44.72) 172.85 (44.59) –

Adjusted mean change from baseline 14.50 20.96 24.68 36.01 2.27

Estimated difference vs TOCAS (95% CI) – 6.46 (�7.85, 20.78) 10.18 (�4.64, 25.01) 21.51 (6.61, 36.41) (0.72, 3.81)

p – 0.3746 0.1775 0.0048 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 mono-

therapy, 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 oftreatment in (a) International Prostate Symptom Score (IPSS) quality oflife (QoL) (n = 281) and (b) Patient Perception of Bladder Condition(PPBC) (n = 280) in the storage symptoms subgroup * (full analysis set). Pvalues are for combination therapy versus tamsulosin oral controlledabsorption system (TOCAS).Soli = solifenacin.* IPSS I13, maximum urinary flow rate 4.0–15.0 ml/s, two ormore urgency episodes per 24 h (Patient Perception of Intensity ofUrgency Scale grade 3 or 4), and eight or more micturitions per24 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 combination-

therapy 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 signifi-

cant 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 ap-

proach 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:


Evaluation of Efficacy and Safety (TIMES) study, neither

tamsulosin nor tolterodine given as monotherapy demon-

strated 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 combina-

tion 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 sub-

scale 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 signifi-

cantly 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 dose-

finding 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 a-

blockers in male patients with LUTS, and they do not

support an increased risk of AUR associated with anti-

muscarinics [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.



Table 5 – Summary of treatment-related adverse events occurring in I1% patients overall and two or more patients in any one group (totalpopulation; safety set)

Adverse events Placebo(n = 92)

Soli 3 mg(n = 43)

Soli 6 mg(n = 43)

Soli 9 mg(n = 43)

TOCAS 0.4 mg(n = 177)


(n = 179)


(n = 178)


(n = 175)

Any event 12 (13.0) 6 (14.0) 7 (16.3) 7 (16.3) 33 (18.6) 26 (14.5) 35 (19.7) 43 (24.6)

Cardiac disorders§ 0 0 0 1 (2.3) 5 (2.8) 3 (1.7) 2 (1.1) 2 (1.1)

Ear and labyrinth disorders 1 (1.1) 0 0 0 3 (1.7) 1 (0.6) 2 (1.1) 0

Vertigo 1 (1.1) 0 0 0 3 (1.7) 1 (0.6) 2 (1.1) 0

Eye disorders 1 (1.1) 0 2 (4.7) 0 0 0 6 (3.4) 1 (0.6)

Blurred vision 0 0 2 (4.7) 0 0 0 3 (1.7) 0

Gastrointestinal disorders 2 (2.2) 3 (7.0) 5 (11.6) 5 (11.6) 8 (4.5) 12 (6.7) 21 (11.8) 28 (16.0)

Dry mouth 0 2 (4.7) 4 (9.3) 2 (4.7) 4 (2.3) 6 (3.4) 18 (10.1) 23 (13.1)

Constipation 1 (1.1) 0 0 4 (9.3) 2 (1.1) 4 (2.2) 5 (2.8) 5 (2.9)

Dyspepsia 0 0 0 0 0 3 (1.7) 2 (1.1) 3 (1.7)

Nausea 0 1 (2.3) 0 0 2 (1.1) 0 0 0

General disorders and

administration site conditions

0 0 1 (2.3) 1 (2.3) 3 (1.7) 2 (1.1) 0 4 (2.3)

Fatigue 0 0 0 0 2 (1.1) 0 0 1 (0.6)

Chest pain 0 0 0 0 0 0 0 2 (1.1)

Investigations 3 (3.3) 0 0 0 2 (1.1) 1 (0.6) 3 (1.7) 2 (1.1)

Nervous system disorders 2 (2.2) 1 (2.3) 2 (4.7) 0 7 (4.0) 3 (1.7) 3 (1.7) 4 (2.3)

Dizziness 0 1 (2.3) 0 0 3 (1.7) 1 (0.6) 2 (1.1) 1 (0.6)

Headache 2 (2.2) 0 0 0 2 (1.1) 1 (0.6) 1 (0.6) 2 (1.1)

Dizziness postural 0 0 2 (4.7) 0 1 (0.6) 0 0 0

Renal and urinary disorders 0 0 0 3 (7.0) 2 (1.1) 4 (2.2) 1 (0.6) 4 (2.3)

Dysuria 0 0 0 2 (4.7) 0 2 (1.1) 1 (0.6) 1 (0.6)

Urinary retention 0 0 0 1 (2.3) 1 (0.6) 2 (1.1) 0 2 (1.1)

AUR requiring catheterisationz 0 0 0 1 (2.3) 1 (0.6) 1 (0.6) 0 1 (0.6)

Reproductive system and breast

disorders

2 (2.2) 1 (2.3) 0 1 (2.3) 4 (2.3) 4 (2.2) 6 (3.4) 4 (2.3)

Retrograde ejaculation 1 (1.1) 0 0 0 0 2 (1.1) 5 (2.8) 1 (0.6)

Erectile dysfunction 1 (1.1) 0 0 1 (2.3) 2 (1.1) 0 0 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)

Placebo(n = 92)

Soli 3 mg(n = 43)

Soli 6 mg(n = 43)

Soli 9 mg(n = 43)

TOCAS 0.4 mg(n = 176)


(n = 179)


(n = 178)


(n = 175)

Baseline, ml 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)

End of treatment, ml 38.7 (47.4) 57.9 (53.0) 68.3 (83.9) 74.5 (84.4) 31.9 (34.9) 49.3 (59.3) 54.9 (71.3) 59.2 (70.8)

Change from baseline, ml 4.6 (41.4) 8.1 (39.7) 26.8 (71.5) 31.8 (83.0) �4.0 (30.2) 6.4 (53.4) 16.9 (59.3) 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

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

the accuracy of the data analysis.

Study concept and design: Van Kerrebroeck, Garcia-Hernandez, Klaver.

Acquisition of data: Van Kerrebroeck, Angulo, Oelke.

Analysis and interpretation of data: Van Kerrebroeck, Angulo, Garcia-

Hernandez, Klaver, Traudtner, Oelke.

Drafting of the manuscript: Van Kerrebroeck, Haab, Angulo, Vik, Katona,

Garcia-Hernandez, Klaver, Traudtner, Oelke.

Critical revision of the manuscript for important intellectual content: Van

Kerrebroeck, Haab, Angulo, Vik, Katona, Garcia-Hernandez, Klaver,

Traudtner, Oelke.

Statistical analysis: Garcia-Hernandez.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Van Kerrebroeck, Klaver.

Other (specify): None.

Financial disclosures: Philip Van Kerrebroeck 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, consultancies,

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

patents filed, received, or pending), are the following: Philip van

Kerrebroeck is a lecturer for Astellas, Ferring, and Medtronic, and member

of an advisory board for Allergan, Astellas, and Ferring. Francois Haab is a

consultant, investigator, and lecturer for Allergan, Astellas, and Pfizer.

Javier Angulo has received educational grants for research from Astellas

and Pfizer and is a lecturer for Astellas, GlaxoSmithKline, and Pfizer.

Matthias Oelke has received lecturer and/or consultant honoraria from

Apogepha, Astellas, GlaxoSmithKline, Eli Lilly and Company, Ethicon,

Ferring, Pfizer, Recordati, and Sophiris and received a research grant

from Astellas. Alberto-Garcia Hernandez, Monique Klaver, and Klaudia

Traudtner are employees of Astellas. Viktor Vik and Ferenc Katona have

nothing to disclose.

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.

Acknowledgement statement: Medical writing and editing assistance for

the preparation of this manuscript was provided by Sophie Berry and

David Hallett at Darwin Healthcare Communications, UK, and funded by

Astellas. The authors would like to acknowledge their colleagues who

recruited patients into the SATURN study: Belgium: Dr. F. Ameye, Dr. J.

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-

Nielsen, Dr. K. Kroyer, Dr. M. Nohr; Finland: Dr. P. Hellstrom, Dr. K.

Lehtoranta, Dr. J. Sairanen, Dr. T. Tammela; France: Dr. J.P. Ansieau, Dr. T.

Billebaud, Dr. R. Claude, Prof. P. Costa, Dr. E. Ghazarossian-Ragni, Prof. E.

Haab, Dr. J.L. Jung, Dr. S. Mallick, Dr. N. Morin, Dr. B. Rabut; Germany: Dr.

T. Benusch, Dr. R. Eckert, Dr. H.P. Fischer, Dr. U. Gerhardt, Dr. W.

Grohmann, Dr. M. Hentschel, Dr. W. Hechelmann, Dr. M. Indig, Dr. W.

Jorger, Dr. T. Kottig, Dr. A. Kublanck, Dr. M. Markov, Dr. B. Mertins, Dr. M.

Voss, Dr. W. Warnack, Dr. J. Willgerodt, Dr. A. Wirger; Great Britain: Mr.

P. Bose, Dr. P. Malone, Dr. R. Pawa, Dr. H. Thomas; Hungary: Dr. F. Katona,

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;

Netherlands: Dr. W.I. Jzerman, Dr. P.J.M. Kil, Dr. J. Oddens, Dr. M. Oelke,

Dr. E.P.M. Roos, Dr. C. van de Beek, Dr. H. Vergunst; Norway: Dr. M.

Marcus, Dr. O. Martin Hoeg; Poland: Prof. K. Bar, Prof. A. Borkowski, Dr. J.


Ciechan, Dr. P. Maciukiewicz, Prof. Z. Wolski; Portugal: Prof. M. Reis;

Russia: Prof. V. Avdoshin, Prof. V. Gomberg, Prof. L.M. Gorilovsky, Dr. A.

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.

Cambronero Santos, Dr. E. Leon Duenas, Dr. J. Morote; Sweden: Dr. E.

Brekkan, Dr. I. Ehren, Dr. M. Hedlund.

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