EUROPEAN UROLOGY 61 (2012) 917925

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Platinum Priority Benign Prostatic Hyperplasia

Editorial by Christopher R. Chapple on pp. 926927 of this issue

Monotherapy with Tadalafil or Tamsulosin Similarly Improved

Lower Urinary Tract Symptoms Suggestive of Benign Prostatic
Hyperplasia in an International, Randomised, Parallel,
Placebo-Controlled Clinical Trial

Matthias Oelke a,*, Francois Giuliano b, Vincenzo Mirone c, Lei Xu d, David Cox d, Lars Viktrup d
a
Department of Urology, Hannover Medical School, Hannover, Germany; b Department of Physical Medicine and Rehabilitation, Raymond Poincare Hospital,
University of Versailles Saint Quentin en Yvelines, Garches, France; c Department of Obstetrical-Gynecological Science and Reproductive Medicine, University
of Naples Federico II, Naples, Italy; d Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

Article info Abstract

Article history: Background: Tadalafil improved lower urinary tract symptoms (LUTS) suggestive of
Accepted January 9, 2012 benign prostatic hyperplasia (BPH; LUTS/BPH) in clinical studies but has not been
Published online ahead of evaluated together with an active control in an international clinical study.
Objective: Assess tadalal or tamsulosin versus placebo for LUTS/BPH.
print on January 18, 2012 Design, setting, and participants: A randomised, double-blind, international, placebo-
controlled, parallel-group study assessed men 45 yr of age with LUTS/BPH, Interna-
Keywords: tional Prostate Symptom Score (IPSS) 13, and maximum urinary ow rate (Qmax) 4 to
15 ml/s. Following screening and washout, if needed, subjects completed a 4-wk
Benign prostatic hyperplasia
placebo run-in before randomisation to placebo (n = 172), tadalal 5 mg (n = 171), or
Erectile dysfunction tamsulosin 0.4 mg (n = 168) once daily for 12 wk.
Lower urinary tract symptoms Measurements: Outcomes were assessed using analysis of covariance (ANCOVA) or
Phosphodiesterase type 5 ranked analysis of variance (ANOVA) (continuous variables) and Cochran-Mantel-
inhibitors Haenszel test or Fisher exact test (categorical variables).
Results and limitations: IPSS signicantly improved versus placebo through 12 wk with
Tadalafil tadalal (2.1; p = 0.001; primary efcacy outcome) and tamsulosin (1.5; p = 0.023) and
Tamsulosin as early as 1 wk (tadalal and tamsulosin both 1.5; p < 0.01). BPH Impact Index
signicantly improved versus placebo at rst assessment (week 4) with tadalal (0.8;
p < 0.001) and tamsulosin (0.9; p < 0.001) and through 12 wk (tadalal 0.8, p = 0.003;
tamsulosin 0.6, p = 0.026). The IPSS Quality-of-Life Index and the Treatment Satisfaction
ScaleBPH improved signicantly versus placebo with tadalal (both p < 0.05) but not
with tamsulosin (both p > 0.1). The International Index of Erectile FunctionErectile
Function domain improved versus placebo with tadalal (4.0; p < 0.001) but not tamsu-
losin (0.4; p = 0.699). Qmax increased signicantly versus placebo with both tadalal
(2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). Adverse event proles were
consistent with previous reports. This study was limited in not being powered to directly
compare tadalal versus tamsulosin.
Conclusions: Monotherapy with tadalal or tamsulosin resulted in signicant and
numerically similar improvements versus placebo in LUTS/BPH and Qmax. However,
only tadalal improved erectile dysfunction.
Trial registration: Clinicaltrials.gov ID NCT00970632
# 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Hannover Medical School, Carl-Neuberg-Str. 1,

30625 Hannover, Germany. Tel. +49 511 532 6673; Fax: +49 511 532 3481.
E-mail address: oelke.matthias@mh-hannover.de (M. Oelke).
0302-2838/$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2012.01.013
918 EUROPEAN UROLOGY 61 (2012) 917925

1. Introduction the bladder, prostate, urethra, and supporting vasculature

Benign prostatic hyperplasia (BPH) is a histologic diagnosis
characterised by smooth muscle and epithelial cell prolif-
eration in the prostate transition zone leading to nonma-
lignant prostate enlargement. It is widely recognised that
BPH is not the exclusive cause of lower urinary tract
symptoms (LUTS) [1,2]. However, clinical drug trials often
enrol men based in part on a clinical diagnosis of non-
neurogenic LUTS suggestive of BPH (LUTS/BPH).
The prevalence of bothersome LUTS/BPH increases with
age, and epidemiologic and pathophysiologic links between
LUTS/BPH and erectile dysfunction (ED) have been demon-
strated [3,4]. Medical therapy for LUTS/BPH currently
consists of a-blockers, 5a-reductase inhibitors, or combi-
nation therapy [1,2]. Although efficacious, these therapies
have the potential for side-effects relating to sexual
dysfunction [5]. Tadalafil is a phosphodiesterase type 5
(PDE5) inhibitor (PDE5-I) widely approved for the treat-
ment of ED. Several placebo-controlled studies in men with
LUTS/BPH have demonstrated improvements in Interna-
tional Prostate Symptom Scores (IPSS) with tadalafil [610].
Tadalafil was recently approved in the United States for
treatment of signs and symptoms of BPH (LUTS/BPH) and
for the treatment of coexisting LUTS/BPH and ED. Although
the mechanisms for improvements in LUTS with PDE5
inhibition have yet to be fully clarified, proposed con-
[(Fig._1)TD$IG]tributors include inhibition of PDE5 isoenzymes present in
and consequent increases in intracellular nitric oxidecyclic
guanosine monophosphate concentration, relaxation of the
smooth muscle cells in these structures, improved blood
perfusion, and reduced afferent signalling from the
urogenital tract [1115].
The primary objective of this study was to compare the
effect of tadalafil 5 mg once daily with placebo on LUTS/
BPH. Given that the a-blocker tamsulosin is often a first-line
treatment for LUTS/BPH, tamsulosin was included as an
active control, with a secondary objective of comparing
tamsulosin 0.4 mg once daily with placebo. Although not
designed for statistical testing of noninferiority or superi-
ority between tadalafil and tamsulosin, the study was
adequately powered for the comparison of each active
treatment with placebo. This study provides for the first
time data for both tadalafil and tamsulosin from a single
large, randomised, placebo-controlled, international study.
2. Patients and methods
A double-blind, placebo- and active-controlled, parallel-design trial was
conducted at 44 urology sites in Australia, Austria, Belgium, France,
Germany, Greece, Italy, Mexico, The Netherlands, and Poland. Following
screening (and a 4-wk wash-out for BPH, overactive bladder, or ED drugs,
as needed), participants began a 4-wk single-blind placebo lead-in period,
followed by randomisation (1:1:1 ratio) to once-daily tadalal 5 mg,
tamsulosin 0.4 mg, or placebo for 12 wk (Fig. 1). Dosing was to occur

Visit 1 Screened
Screening/washout, (n = 652)
Weeks 8 to 4

Visit 2
Placebo lead-in,
Weeks 4 to 0 Randomised
(n = 511)
Visit 3
Randomisaon/ Placebo Tadalafil 5 mg Tamsulosin 0.4 mg*
Baseline, Week 0 (n = 172) (n = 171) (n = 168)

Discontinued, no. (%) Discontinued, no. (%) Discontinued, no. (%)

Visit 4 AE AE AE
Week 1 2 (1.2) 2 (1.2) 1 (0.6)
Entry criteria not met Entry criteria not met Entry criteria not met
0 (0) 2 (1.2) 2 (1.2)
Lost to follow-up Lost to follow-up Lost to follow-up
Visit 5 3 (1.7) 0 (0) 2 (1.2)
Week 4 Perceived lack of efficacy Perceived lack of efficacy Perceived lack of efficacy
3 (1.7) 0 (0) 0 (0)
Protocol violation Protocol violation Protocol violation
8 (4.7) 5 (2.9) 8 (4.8)
Visit 6
Sponsor decision Sponsor decision Sponsor decision
Week 8
1 (0.6) 0 (0) 1 (0.6)
Subject decision Subject decision Subject decision
7 (4.1) 6 (3.5) 4 (2.4)
Visit 7
Week 12 or early Completed 12 wk Completed 12 wk Completed 12 wk
disconnuaon (n = 148 [86.0%]) (n = 156 [91.2%]) (n = 150 [89.3%])

Fig. 1 Disposition of subjects. Subject Consolidated Standards of Reporting Trials (CONSORT) diagram.
AE = adverse event.
* One subject randomised to tamsulosin did not take at least one dose of study drug and was excluded from the efficacy analyses.
 EUROPEAN UROLOGY 61 (2012) 917925
approximately 30 min after eating (per tamsulosin dosing recommenda-
tions [16]). The trial was performed in accordance with applicable laws
and regulations, good clinical practices, and ethical principles as described
in the Declaration of Helsinki. Institutional review boards for each site
approved the trial. All men provided written informed consent before
initiating any trial procedure. Enrolment began in December 2009, and the
last subject completed the study in January 2011.
Eligible men were 45 yr of age who had had LUTS/BPH for >6 mo at
screening and with IPSS 13 and maximum urinary ow rate (Qmax) 4 to
15 ml/s prior to the placebo lead-in period; subjects with improvements
in IPSS or Qmax during placebo lead-in were not excluded. Compliance
70% during the placebo lead-in was required for randomisation. Men
could not have used nasteride or dutasteride within 3 or 6 mo,
respectively. Other inclusion and exclusion criteria were as described
previously [9] in addition to tamsulosin-specic exclusions of men with
planned cataract surgery; history of symptomatic orthostatic hypotension
(especially upon initial a-blocker administration); or recurrent dizziness,
vertigo, loss of consciousness, or syncope.
Efcacy measures included IPSS (primary measure) [17], BPH Impact
Index (BII) [18], and International Index of Erectile FunctionErectile
Function Domain (IIEF-EF) [19]. A week 1 IPSS (mIPSS) used questions
beginning with Since your last visit. IPSS storage and voiding
subscores, nocturia question (question 7), and IPSS Quality-of-Life
(QoL) Index were also assessed. Measures were assessed at baseline and
end point (12 wk or end of therapy) and also at screening, 1 and 4 wk for
IPSS, and 4 wk for BII. The Patient and Clinician Global Impression of
Improvement (PGI-I and CGI-I, respectively) instruments [20,21] and the
subject-rated Treatment Satisfaction ScaleBPH (TSS-BPH) [22], evalu-
ated from 0% (greater) to 100% (lower) satisfaction, were administered at
end point.
Uroowmetry was performed using standard calibrated devices at
the screening, baseline, and end point visits. Valid Qmax measurements
required prevoid total bladder volume (assessed by ultrasound) of 150
to 550 ml and voided volume (Vvoid) of 125 ml. Screening uro-
owmetry was interpreted by investigators to assess eligibility; baseline
and end point uroowmetry were interpreted by a blinded central
reader and used for analyses. Bladder capacity was calculated post hoc as
the sum of Vvoid and postvoid residual (PVR) volume.
Safety was evaluated based on subject-reported adverse events (AE),
PVR, clinical laboratory parameters (haematology, chemistry, and
urinalysis), and vital signs. Treatment-emergent AEs (TEAE) were those
rst reported or worsening after randomisation.
Randomisation was stratied by baseline LUTS severity, geographic
region, and patient query regarding prior ED diagnosis (yes or no). The
primary efcacy objective was evaluating the change in total IPSS from
baseline to end point for tadalal versus placebo. Efcacy was analysed
in all randomised subjects who started double-blind study drug. At least
151 subjects per treatment arm provided an estimated 80% power to
detect a placebo-adjusted mean treatment difference in IPSS of 2.0
(assuming a standard deviation of 6 and a projected nonevaluable rate of
5%). The study was not powered to demonstrate noninferiority of
tadalal to tamsulosin or for direct comparisons between active
treatment arms.
Continuous efcacy measures, uroowmetry, and PVR were evaluated
as change from baseline (randomisation) to week 12/last-observation-
carried-forward (LOCF) end point. Analyses for 1 or 4 wk did not use LOCF
imputation. Continuous efcacy measures were assessed using analysis of
covariance (ANCOVA), with terms for treatment group, region, and
baseline, and baseline-by-treatment interaction and treatment-by-region
interaction (removed where p  0.1).
A xed-sequence testing procedure was implemented to control type
I error in analyses of primary and key secondary outcomes for tadalal
using the following prespecied order: total IPSS at end point, total IPSS
after 4 wk, BII at end point, mIPSS after 1 wk, and BII after 4 wk. Statistical
919
signicance was interpreted only if results of the preceding analysis
were signicant at the 0.05 level. Results were presented independent of
the xed sequence, as all end points tested under this procedure
achieved statistical signicance. All other efcacy analyses (including all
tamsulosin results) were assessed at the 0.05 signicance level without
adjustment for multiplicity.
PGI-I and CGI-I treatment group differences were analysed using the
Cochran-Mantel-Haenszel test adjusted for baseline LUTS severity. TSS-
BPH treatment group differences were analysed using the van Elteren
test for differences in medians stratied by region.
Treatment group differences for AEs were analysed using Fisher
exact tests. Changes from baseline to end of therapy in Qmax, PVR, and
clinical laboratory parameters were analysed using a ranked analysis of
variance (ANOVA) with a term for treatment group. Treatment group
differences for average urinary ow rate (Qave), Vvoid, and bladder
capacity were performed as post hoc analyses.
3. Results
Of 652 subjects screened, 511 were randomised (safety
population), and 510 started study drug (efficacy popula-
tion); 88.8% of subjects completed the study (Fig. 1).
Treatment groups were well balanced concerning demo-
graphic and clinical characteristics (Table 1). Mean age was
64 yr of age (10.2% 75 yr of age), and most patients were
from Europe (71%). At randomisation, IPSS was 20 in 30%
of subjects, and Qmax was <10 ml/s in 54%.
The change from baseline to week 12 (LOCF) relative to
placebo in total IPSS was statistically significant for both
tadalafil and tamsulosin ( p = 0.001 and p = 0.023, respec-
tively; Fig. 2A; Table 2). Least squares mean (LSmean) plus
or minus standard error (SE) differences in IPSS versus
placebo were significant for both tadalafil and tamsulosin at
1 wk (mIPSS: 1.5  0.5; p = 0.003 and 1.5  0.5; p = 0.005,
respectively) and 4 wk (2.2  0.6; p < 0.001 and 2.3  0.6;
p < 0.001, respectively; Fig. 3A). Based on prespecified
subgroup analysis, there was no significant treatment by
previous a-blocker therapy interaction ( p = 0.230) with
respect to changes in total IPSS. Changes in IPSS subscores
and nocturia are shown in Table 2.
Differences from placebo in BII were statistically
significant for both tadalafil and tamsulosin ( p = 0.003
and p = 0.026, respectively; Fig. 2B). Differences from
placebo in BII were also significant at 4 wk for both
tadalafil and tamsulosin (LSmean  SE: 0.8  0.2;
p < 0.001 and 0.9  0.2; p < 0.001, respectively; Fig. 3B).
For the IPSS QoL Index, significant improvements
compared with placebo at 12 wk were reported with tadalafil
( p = 0.022) but not tamsulosin ( p = 0.546; Table 3). The TSS-
BPH overall satisfaction score at end point was significantly
lower (indicating higher satisfaction) in the tadalafil group
compared with placebo ( p = 0.005), driven by greater
satisfaction with efficacy ( p = 0.003; data not shown). There
was no significant difference between tamsulosin and
placebo in TSS-BPH overall satisfaction ( p = 0.457) or
satisfaction with efficacy ( p = 0.409; data not shown).
Between-treatment group differences compared to
placebo in the distribution of subjects over the PGI-I and
CGI-I response categories were significant for tadalafil
(PGI-I: p = 0.001; CGI-I: p = 0.004) but not for tamsulosin
920 EUROPEAN UROLOGY 61 (2012) 917925

Table 1 Baseline characteristics of all randomised subjects

Placebo (n = 172) Tadalal 5 mg (n = 171) Tamsulosin 0.4 mg (n = 168)

Age, yr, mean (range): 63.7 (45.988.6) 63.5 (45.183.1) 63.5 (45.583.4)
65, no. (%) 95 (55.2) 96 (56.1) 96 (57.1)
>65 to <75, no. (%) 54 (31.4) 62 (36.3) 56 (33.3)
75, no. (%) 23 (13.4) 13 (7.6) 16 (9.5)
Race, no. (%):
White 131 (76.2) 130 (76.0) 131 (78.0)
Black or African American 0 1 (0.6) 0 (0)
American Indian/Alaska Native* 41 (23.8) 40 (23.4) 37 (22.0)
Region, no. (%):
Europe 123 (71.5) 121 (70.8) 120 (71.4)
Non-Europe 49 (28.5) 50 (29.2) 48 (28.6)
BMI, kg/m2, mean (range) 28.1 (19.240.2) 27.1 (17.243.4) 27.9 (18.339.0)
LUTS severity, no. (%):
Mild (IPSS <8) 6 (3.5) 3 (1.8) 4 (2.4)
Moderate (IPSS 8 to <20) 112 (65.1) 120 (70.2) 115 (68.5)
Severe (IPSS 20) 54 (31.4) 48 (28.1) 49 (29.2)
IPSS total, mean  SD 17.4  6.0 17.2  4.9 16.8  5.3
IPSS storage subscore, mean  SD 7.3  3.2 6.8  2.7 7.1  3.0
IPSS voiding subscore, mean  SD 10.1  4.1 10.5  3.5 9.8  3.5
IPSS nocturia question, mean  SD 2.2  1.2 2.1  1.1 2.1  1.1
BII, mean  SD 5.0  3.3 4.8  2.8 4.7  3.1
Qmax category, no. (%):
<10 ml/s 79 (45.9) 92 (53.8) 105 (62.5)
1015 ml/s 69 (40.1) 63 (36.8) 53 (31.5)
>15 ml/s 18 (10.5) 12 (7.0) 7 (4.2)
Previous therapies (within 12 mo prior to screening), no. (%):
a-blocker therapy 45 (26.2) 41 (24.0) 43 (25.6)
Other LUTS/BPH therapy 8 (4.7) 6 (3.5) 9 (5.4)
ED therapy 23 (13.4) 21 (12.3) 21 (12.5)
ED history, no. (% Yes) 120 (69.8) 121 (70.8) 116 (69.0)
Sexually active with a female partner, no. (% yes) 145 (84.3) 143 (83.6) 139 (82.7)
PSA (ng/ml), mean  SD 2.0  1.7 2.1  1.8 1.9  1.6

BMI = body mass index; LUTS = lower urinary tract symptoms; IPSS = International Prostate Symptom Score; SD = standard deviation; BII = Benign Prostatic
Hyperplasia Impact Index; Qmax = maximum urinary ow rate; LUTS/BPH = lower urinary tract symptoms suggestive of benign prostatic hyperplasia;
ED = erectile dysfunction; PSA = prostate-specic antigen.
*
Subjects enrolled in Mexico self-reported their race as American Indian/Alaska Native.

(PGI-I: p = 0.114; CGI-I: p = 0.452; Table 3). In the tadalafil
group, more subjects and their clinicians perceived
improvements in LUTS at end point compared to the
placebo group.
In comparison to placebo, LSmean  SE change from
baseline to end point in the IIEF-EF domain in men with ED
[(Fig._2)TD$IG]
who were also sexually active (approximately 60% of subjects)
was significant with tadalafil (4.0  1.0; p < 0.001), whereas
the LSmean change with tamsulosin was not (0.4  1.0;
p = 0.699).
Improvements in Qmax were significantly greater than
placebo with tadalafil ( p = 0.009) and with tamsulosin

Fig. 2 Differences from placebo in (A) total International Prostate Symptom Score and (B) Benign Prostatic Hyperplasia Impact Index. Numbers represent
least squares mean treatment difference (95% confidence interval) versus placebo in the change from baseline to 12 wk (last-observation-carried-
forward) and corresponding p values from analysis of covariance.
IPSS = International Prostate Symptom Score; BII = Benign Prostatic Hyperplasia Impact Index; LS = least squares.
 EUROPEAN UROLOGY 61 (2012) 917925 921

Table 2 International Prostate Symptom Score (IPSS) total, storage, and voiding subscores and nocturia question (IPSS question 7)

Placebo (n = 172) Tadalal 5 mg (n = 171) Tamsulosin 0.4 mg (n = 167)

IPSS total: n = 172 n = 171 n = 165

Change from baseline, LS mean  SE 4.2  0.5 6.3  0.5 5.7  0.5
Change vs placebo, LS mean  SE (95% CI) 2.1  0.6 (3.3 to 0.8) 1.5  0.6 (2.8 to 0.2)
p value 0.001 0.023
Storage subscore* n = 172 n = 171 n = 165
Change from baseline, LS mean  SE 1.6  0.2 2.2  0.2 2.2  0.2
Change vs placebo, LS mean  SE (95% CI) 0.6  0.3 (1.1 to 0.0) 0.6  0.3 (1.1 to 0.0)
p value 0.055 0.055
Voiding subscore** n = 172 n = 171 n = 165
Change from baseline, LS mean  SE 2.6  0.3 4.1  0.3 3.5  0.3
Change vs placebo, LS mean  SE (95% CI) 1.5  0.4 (2.4 to 0.7) 1.0  0.4 (1.8 to 0.1)
p value <0.001 0.026
Nocturia questiony n = 172 n = 171 n = 165
Change from baseline, LS mean  SE 0.3  0.1 0.5  0.1 0.5  0.1
Change vs placebo, LS mean  SE (95% CI) 0.2  0.1 (0.4 to 0.0) 0.2  0.1 (0.4 to 0.0)
p value 0.080 0.118

IPSS = International Prostate Symptom Score; LS = least squares; SE = standard error; CI = condence interval.
*
IPSS questions 2 + 4 + 7.
**
IPSS questions 1 + 3 + 5 + 6.
y
IPSS question 7.

[(Fig._3)TD$IG]

A 0 B 0.0
Placebo Placebo
LS Mean Change from Baseline

Tadalafil 5 mg
LS Mean change from Baseline

-1 Tadalafil 5 mg
Tamsulosin 0.4 mg Tamsulosin 0.4 mg
-0.5
-2
BPH Impact Index
IPSS Total

-3

-4
* -1.0

*
-5 * * *
*
-1.5 *
-6
* * *
-7 -2.0
0 1 4 12 /EP 0 4 12 /EP

Duration of Treatment (weeks) Duration of Treatment (weeks)

Fig. 3 Changes from baseline in (A) total International Prostate Symptom Score and (B) Benign Prostatic Hyperplasia Impact Index. Data represent the
least squares mean change plus or minus standard error.
LS = least squares; EP = end point; ANCOVA = analysis of covariance.
* p < 0.05 versus placebo based on ANCOVA.

( p = 0.014; Table 4), as were increases in Qave ( p = 0.002 and baseline compared with placebo were observed with both
p = 0.023, respectively). Differences versus placebo were active treatments but were not statistically significant
not statistically significant for Vvoid or bladder capacity. (Table 4).
There were no significant differences between the active
treatment groups and placebo for any TEAE or in the 4. Discussion
incidence of serious AEs or discontinuations because of AEs
(Table 5). The most common TEAEs with tadalafil were In this, the first international, placebo-controlled study
headache (n = 5) followed by nasopharyngitis (n = 5), back evaluating tadalafil or tamsulosin (as an active control) for
pain (n = 4), dizziness (n = 4), and dyspepsia (n = 4), while LUTS/BPH, tadalafil 5 mg once daily for 12 wk resulted in
with tamsulosin the most common events were headache significant and clinically meaningful improvements in
(n = 7) and dizziness (n = 6). One subject in the tamsulosin LUTS/BPH similar to tamsulosin 0.4 mg once daily. Based
group reported two TEAEs related to ejaculatory dysfunc- on analyses of secondary end points, this was also the first
tion (retrograde ejaculation and semen volume decreased). tadalafil study to show significant improvement in LUTS/
There were no clinically significant changes in laboratory BPH after 1 wk and a significant increase in Qmax at 12 wk.
measurements or vital signs. For PVR, mean reductions from In addition, tadalafil but not tamsulosin significantly
922 EUROPEAN UROLOGY 61 (2012) 917925

Table 3 International Prostate Symptom Score Quality of Life Index, Treatment Satisfaction Scale, and Patient or Clinician Global
Impression of Improvement Scores at 12 wk compared to baseline or placebo

Placebo (n = 172) Tadalal 5 mg (n = 171) Tamsulosin 0.4 mg (n = 167)

IPSS QoL Index, LS mean  SE n = 172 n = 171 n = 165

Change from baseline 1.0  0.1 1.3  0.1 1.1  0.1
Change vs placebo (95% CI) 0.3  0.1 (0.6 to 0.0) 0.1  0.1 (0.4 to 0.2)
p value vs placebo 0.022 0.546
TSS-BPH overall n = 158 n = 163 n = 156
Mean  SD 31.7  17.5 26.9  17.7 30.4  16.5
Median 28.9 22.2 28.9
Median difference vs placebo (95% CI) 4.4 (8.9 to 2.2) 2.2 (4.4 to 2.2)
p value vs placebo 0.005 0.457
PGI-I*, no. (%) n = 159 n = 160 n = 157
Very much better 11 (6.9) 17 (10.6) 10 (6.4)
Much better 36 (22.6) 56 (35.0) 48 (30.6)
A little better 53 (33.3) 52 (32.5) 55 (35.0)
No change 51 (32.1) 28 (17.5) 36 (22.9)
A little worse 4 (2.5) 6 (3.8) 8 (5.1)
Much worse 2 (1.3) 1 (0.6) 0 (0)
Very much worse 2 (1.3) 0 (0) 0 (0)
p value vs placebo 0.001 0.114
CGI-I**, no. (%) n = 160 n = 163 n = 157
Very much better 9 (5.6) 16 (9.8) 6 (3.8)
Much better 34 (21.3) 50 (30.7) 38 (24.2)
A little better 57 (35.6) 58 (35.6) 65 (41.4)
No change 51 (31.9) 32 (19.6) 40 (25.5)
A little worse 6 (3.8) 5 (3.1) 7 (4.5)
Much worse 2 (1.3) 2 (1.2) 1 (0.6)
Very much worse 1 (0.6) 0 (0.0) 0 (0)
p value vs placebo 0.004 0.452

IPSS = International Prostate Symptom Score; QoL = quality of life; LS = least squares; SE = standard error; CI = condence interval; TSS-BPH = Treatment
Satisfaction Scale, Benign Prostatic Hyperplasia; SD = standard deviation; PGI-I = Patient Global Impression of Improvement; CGI-I = Clinician Global Impression
of Improvement.
*
For PGI-I, the subject was asked to check the one response that best described how your urinary symptoms are now, compared with how they were before you
began taking medication in this study.
**
For CGI-I, the clinician was asked to rate the total change in your patients symptoms, regardless of whether you feel that the changes are entirely due to drug
treatment. Compared to your patients condition at study entry, how much have your patients urinary symptoms changed?

improved measures of LUTS/BPH QoL, global impressions of
BPH symptom impact, and BPH treatment satisfaction at
end point and improved erectile function in those men who
also reported ED.
The magnitude of improvement in total IPSS at end point
with tadalafil 5 mg in this study was consistent with several
previous reports [7,9,10], and the improvement was also
comparable to that seen in previous studies with a-blockers
[1] and with tamsulosin 0.4 mg here. Similar numerical
reductions in total IPSS were also reported for tadalafil 5 mg
or tamsulosin 0.2 mg once daily in a small pilot study of
Korean men with LUTS/BPH [23]. Tadalafil and tamsulosin
also similarly reduced the impact of symptoms on daily
living (assessed by BII) at 4 and 12 wk.
In contrast with findings for total IPSS and BII, only
tadalafil was significantly superior to placebo on secondary
measures of satisfaction and improvement, including IPSS
QoL, global impressions of improvement (CGI-I and PGI-I),
and satisfaction with BPH treatment (TSS-BPH). Tadalafil
also significantly improved ED compared with placebo in
sexually active men with ED, while tamsulosin did not.
The finding of a significant improvement in Qmax with
tadalafil in this study contrasts with the majority of
previous studies on tadalafil, sildenafil, and vardenafil for
LUTS/BPH, which typically identified only a numeric Qmax
improvement (reviewed in Laydner et al. [24]). Although
the statistically significant Qmax change in this study could
be a random finding, a trend towards a dose-response
relationship was reported in a large dose-ranging study
with tadalafil [25], a small increase in Qmax that reached
statistical significance was seen with tadalafil 2.5 mg (but
not 5 mg) in another controlled study [10], and a significant
increase in Qmax compared with placebo was observed with
another once-daily PDE5-I previously under development
[26]. Compared with previous tadalafil studies, the change
in Qmax observed here was similar for placebo (1.11.2 ml/s
previously) but greater for tadalafil 5 mg (1.61.7 ml/s
previously) [6,9,10,25]. Although the current study popula-
tion did not differ from previous studies for baseline
demographics or clinical characteristics, a greater propor-
tion of subjects were from Europe. In addition, baseline
Qmax in the active treatment groups (tadalafil 9.9 ml/s and
tamsulosin 9.4 ml/s) was lower than prior tadalafil studies
(range for tadalafil 5 mg: 9.811.7 ml/s), which could allow
more room for improvement and thus increase the
probability of observing an improvement in Qmax. Several
in vitro studies have reported smooth muscle relaxation in
the human bladder neck and prostate when exposed to
PDE5 inhibition [14,27], and the smooth muscle relaxant
effect of tadalafil seems to be of similar magnitude as
 EUROPEAN UROLOGY 61 (2012) 917925 923

Table 4 Uroflowmetry and postvoid residual volume

Placebo (n = 172) Tadalal 5 mg (n = 171) Tamsulosin 0.4 mg (n = 168)

Qmax, ml/s: n = 147 n = 156 n = 144

Baseline 10.5  4.1 9.9  3.6 9.4  3.3
Mean change 1.2  4.8 2.4  5.5 2.2  4.1
Median change 0.3 1.6 1.6
p value vs placebo 0.009 0.014
Qave, ml/s n = 147 n = 156 n = 145
Baseline 6.1  2.4 5.9  2.1 5.8  2.3
Mean change 0.7  2.7 1.6  3.2 1.3  3.0
Median change 0.1 1.3 0.7
p value vs placebo 0.002 0.023
Vvoid, ml n = 147 n = 156 n = 145
Baseline 270.3  109.2 257.7  94.3 237.6  97.4
Mean change 4.6  110.9 8.2  101.5 21.4  109.3
Median change 0.0 11.0 16.0
p value vs placebo 0.730 0.229
Bladder capacity (ml) n = 147 n = 156 n = 145
Baseline 319.9  122.4 310.0  109.4 297.7  122.0
Mean change 4.2  123.7 3.5  113.8 11.9  130.4
Median change 11.0 8.5 12.0
p value vs placebo 0.969 0.742
PVR (ml) n = 157 n = 163 n = 156
Baseline 50.2  50.9 53.3  50.4 61.5  59.0
Mean change 1.2  56.5 4.6  47.0 10.2  59.2
Median change 0.0 1.0 5.5
p value vs placebo 0.303 0.146

Qmax = maximum ow rate; Qave = average ow rate; Vvoid = voided volume; PVR = postvoid residual volume.
Unless noted otherwise, data are mean plus or minus standard deviation.
Bladder capacity was calculated as Vvoid + PVR. P values are for the differences between placebo and active treatment in ranked transformed change from
baseline assessed by analysis of variance.

Table 5 Adverse events

Placebo Tadalal 5 mg Tamsulosin 0.4 mg p value* p value*

(n = 172) (n = 171) (n = 168) Tadalal Tamsulosin
No. (%) No. (%) No. (%) vs placebo vs placebo

Subjects with one TEAE or more 35 (20.3) 40 (23.4) 40 (23.8) 0.516 0.513
TEAEs:
Headache 2 (1.2) 5 (2.9) 7 (4.2) 0.283 0.101
Nasopharyngitis 8 (4.7) 5 (2.9) 3 (1.8) 0.574 0.219
Back pain 1 (0.6) 4 (2.3) 2 (1.2) 0.215 0.619
Dizziness 3 (1.7) 4 (2.3) 6 (3.6) 0.723 0.332
Dyspepsia 0 4 (2.3) 3 (1.8) 0.061 0.120
Subjects discontinuing because of an AE 2 (1.2) 2 (1.2) 1 (0.6) 1.00 1.00
Subjects with one serious AE or more 0 2 (1.2) 2 (1.2) 0.248 0.243

TEAE = treatment emergent adverse event; AE = adverse event.

*
P values are from the Fisher exact test.

alfuzosin [28]. However, it remains unclear whether these
in vitro findings translate into the observed small Qmax
changes seen with tadalafil. Tadalafil at a higher 20-mg
daily dose had no significant effect on the bladder outlet
obstruction (BOO) index in a safety study of men with LUTS/
BPH; however, these men were not required to have BOO at
baseline [29]. In contrast to the small improvements in
Qmax, which have not reached statistical significance in
most other studies, studies of tadalafil for LUTS/BPH have
consistently demonstrated significant and clinically mean-
ingful IPSS improvement [7,9,10]. This is aligned with
recently updated BPH guidelines stating that there is a poor
correlation between symptoms and Qmax [1]. There were no
novel safety findings in this study, and the most common
TEAEs were consistent with the known side-effect profiles
of these agents.
A limitation of the present study is that it was not
powered to assess noninferiority or superiority between
tadalafil and tamsulosin. Nonetheless, it was fully powered
to individually assess tadalafil or tamsulosin versus
placebo. Although a minimum clinically relevant noninfer-
iority margin for LUTS/BPH treatments has not been clearly
established, by conservative estimates, the sample size
required for a noninferiority trial would likely be 2- to
4-fold larger than the current study. Although this study
was of standard duration for trials assessing LUTS/BPH
924 EUROPEAN UROLOGY 61 (2012) 917925
efficacy, it did not address longer-term efficacy of tadalafil
or effects on disease progression; such studies would be of
interest in the future. A prior 1-yr open-label extension
tadalafil study found tadalafil 5 mg once daily to be well
tolerated with maintenance of efficacy [30]. Although the
increase in Qmax observed with tamsulosin in this study was
in the range of changes observed in prior tamsulosin studies
[2], the increase observed with tadalafil was greater than in
prior tadalafil studies. Caution should therefore be exer-
cised in interpreting this finding.
5. Conclusions
Tadalafil 5 mg or tamsulosin 0.4 mg once daily resulted in
significant and similar improvements versus placebo in
LUTS/BPH symptoms as early as 1 wk and throughout the
12-wk treatment period. In addition, tadalafil and tamsu-
losin similarly improved Qmax through 12 wk. However,
only tadalafil resulted in significant improvements in LUTS/
BPH based on secondary measures of QoL and treatment
satisfaction and in erectile function as measured by the
IIEF-EF domain. AEs were few, and the AE profiles of
tadalafil and tamsulosin were consistent with those
previously reported for these drugs.
Author contributions: Matthias Oelke 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: Viktrup, Xu.
Acquisition of data: Oelke, Giuliano, Mirone.
Analysis and interpretation of data: Oelke, Giuliano, Mirone, Xu, Cox,
Viktrup.
Drafting of the manuscript: Oelke, Cox.
Critical revision of the manuscript for important intellectual content: Oelke,
Giuliano, Mirone, Xu, Cox, Viktrup.
Statistical analysis: Xu.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Oelke.
Other (specify): None.
Financial disclosures: I certify that all conicts of interest, including
specic nancial interests and relationships and afliations relevant
to the subject matter or materials discussed in the manuscript
(eg, employment/afliation, grants or funding, consultancies, hono-
raria, stock ownership or options, expert testimony, royalties, or
patents led received, or pending), are the following: Matthias Oelke
has received lecturer and/or consultant honoraria in the eld of LUTS/
BPH from Astellas, GlaxoSmithKline, Eli Lilly and Company, and
Merckle-Recordati. Francois Giuliano is a consultant and lecturer for
Eli Lilly and Company and a consultant and investigator for Bayer-
Schering. Vincenzo Mirone is a consultant, investigator, and speaker
for Eli Lilly and Company and Bayer Health-Care. Lei Xu, David
Cox, and Lars Viktrup are employees and stockholders of Eli Lilly and
Company.
Funding/Support and role of the sponsor: Eli Lilly and Company helped
design and conduct and provided support for this study. Data collection
and management and all statistical analyses were performed and
retained by the sponsor. The corresponding author and coordinating
investigator, Matthias Oelke, together with the Lilly study team and
other co-authors, interpreted the data and participated in the prepara-
tion, review, and approval of the manuscript.
Acknowledgment statement: Thomas Melby (an employee of Pharma-
Net/i3, Indianapolis, IN, USA) assisted in the preparation of this
manuscript. The authors would like to thank the trial participants and
study investigators, without whom this work could not have been
performed.
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