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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 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.
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)
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 919
approximately 30 min after eating (per tamsulosin dosing recommenda- signicance was interpreted only if results of the preceding analysis
tions [16]). The trial was performed in accordance with applicable laws were signicant at the 0.05 level. Results were presented independent of
and regulations, good clinical practices, and ethical principles as described the xed sequence, as all end points tested under this procedure
in the Declaration of Helsinki. Institutional review boards for each site achieved statistical signicance. All other efcacy analyses (including all
approved the trial. All men provided written informed consent before tamsulosin results) were assessed at the 0.05 signicance level without
initiating any trial procedure. Enrolment began in December 2009, and the adjustment for multiplicity.
last subject completed the study in January 2011. PGI-I and CGI-I treatment group differences were analysed using the
Eligible men were 45 yr of age who had had LUTS/BPH for >6 mo at Cochran-Mantel-Haenszel test adjusted for baseline LUTS severity. TSS-
screening and with IPSS 13 and maximum urinary ow rate (Qmax) 4 to BPH treatment group differences were analysed using the van Elteren
15 ml/s prior to the placebo lead-in period; subjects with improvements test for differences in medians stratied by region.
in IPSS or Qmax during placebo lead-in were not excluded. Compliance Treatment group differences for AEs were analysed using Fisher
70% during the placebo lead-in was required for randomisation. Men exact tests. Changes from baseline to end of therapy in Qmax, PVR, and
could not have used nasteride or dutasteride within 3 or 6 mo, clinical laboratory parameters were analysed using a ranked analysis of
respectively. Other inclusion and exclusion criteria were as described variance (ANOVA) with a term for treatment group. Treatment group
previously [9] in addition to tamsulosin-specic exclusions of men with differences for average urinary ow rate (Qave), Vvoid, and bladder
planned cataract surgery; history of symptomatic orthostatic hypotension capacity were performed as post hoc analyses.
(especially upon initial a-blocker administration); or recurrent dizziness,
vertigo, loss of consciousness, or syncope. 3. Results
Efcacy measures included IPSS (primary measure) [17], BPH Impact
Index (BII) [18], and International Index of Erectile FunctionErectile Of 652 subjects screened, 511 were randomised (safety
Function Domain (IIEF-EF) [19]. A week 1 IPSS (mIPSS) used questions population), and 510 started study drug (efficacy popula-
beginning with Since your last visit. IPSS storage and voiding
tion); 88.8% of subjects completed the study (Fig. 1).
subscores, nocturia question (question 7), and IPSS Quality-of-Life
Treatment groups were well balanced concerning demo-
(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
graphic and clinical characteristics (Table 1). Mean age was
IPSS, and 4 wk for BII. The Patient and Clinician Global Impression of 64 yr of age (10.2% 75 yr of age), and most patients were
Improvement (PGI-I and CGI-I, respectively) instruments [20,21] and the from Europe (71%). At randomisation, IPSS was 20 in 30%
subject-rated Treatment Satisfaction ScaleBPH (TSS-BPH) [22], evalu- of subjects, and Qmax was <10 ml/s in 54%.
ated from 0% (greater) to 100% (lower) satisfaction, were administered at The change from baseline to week 12 (LOCF) relative to
end point. placebo in total IPSS was statistically significant for both
Uroowmetry was performed using standard calibrated devices at tadalafil and tamsulosin ( p = 0.001 and p = 0.023, respec-
the screening, baseline, and end point visits. Valid Qmax measurements tively; Fig. 2A; Table 2). Least squares mean (LSmean) plus
required prevoid total bladder volume (assessed by ultrasound) of 150
or minus standard error (SE) differences in IPSS versus
to 550 ml and voided volume (Vvoid) of 125 ml. Screening uro-
placebo were significant for both tadalafil and tamsulosin at
owmetry was interpreted by investigators to assess eligibility; baseline
1 wk (mIPSS: 1.5 0.5; p = 0.003 and 1.5 0.5; p = 0.005,
and end point uroowmetry were interpreted by a blinded central
reader and used for analyses. Bladder capacity was calculated post hoc as
respectively) and 4 wk (2.2 0.6; p < 0.001 and 2.3 0.6;
the sum of Vvoid and postvoid residual (PVR) volume. p < 0.001, respectively; Fig. 3A). Based on prespecified
Safety was evaluated based on subject-reported adverse events (AE), subgroup analysis, there was no significant treatment by
PVR, clinical laboratory parameters (haematology, chemistry, and previous a-blocker therapy interaction ( p = 0.230) with
urinalysis), and vital signs. Treatment-emergent AEs (TEAE) were those respect to changes in total IPSS. Changes in IPSS subscores
rst reported or worsening after randomisation. and nocturia are shown in Table 2.
Randomisation was stratied by baseline LUTS severity, geographic Differences from placebo in BII were statistically
region, and patient query regarding prior ED diagnosis (yes or no). The significant for both tadalafil and tamsulosin ( p = 0.003
primary efcacy objective was evaluating the change in total IPSS from
and p = 0.026, respectively; Fig. 2B). Differences from
baseline to end point for tadalal versus placebo. Efcacy was analysed
placebo in BII were also significant at 4 wk for both
in all randomised subjects who started double-blind study drug. At least
tadalafil and tamsulosin (LSmean SE: 0.8 0.2;
151 subjects per treatment arm provided an estimated 80% power to
detect a placebo-adjusted mean treatment difference in IPSS of 2.0 p < 0.001 and 0.9 0.2; p < 0.001, respectively; Fig. 3B).
(assuming a standard deviation of 6 and a projected nonevaluable rate of For the IPSS QoL Index, significant improvements
5%). The study was not powered to demonstrate noninferiority of compared with placebo at 12 wk were reported with tadalafil
tadalal to tamsulosin or for direct comparisons between active ( p = 0.022) but not tamsulosin ( p = 0.546; Table 3). The TSS-
treatment arms. BPH overall satisfaction score at end point was significantly
Continuous efcacy measures, uroowmetry, and PVR were evaluated lower (indicating higher satisfaction) in the tadalafil group
as change from baseline (randomisation) to week 12/last-observation- compared with placebo ( p = 0.005), driven by greater
carried-forward (LOCF) end point. Analyses for 1 or 4 wk did not use LOCF
satisfaction with efficacy ( p = 0.003; data not shown). There
imputation. Continuous efcacy measures were assessed using analysis of
was no significant difference between tamsulosin and
covariance (ANCOVA), with terms for treatment group, region, and
placebo in TSS-BPH overall satisfaction ( p = 0.457) or
baseline, and baseline-by-treatment interaction and treatment-by-region
interaction (removed where p 0.1).
satisfaction with efficacy ( p = 0.409; data not shown).
A xed-sequence testing procedure was implemented to control type Between-treatment group differences compared to
I error in analyses of primary and key secondary outcomes for tadalal placebo in the distribution of subjects over the PGI-I and
using the following prespecied order: total IPSS at end point, total IPSS CGI-I response categories were significant for tadalafil
after 4 wk, BII at end point, mIPSS after 1 wk, and BII after 4 wk. Statistical (PGI-I: p = 0.001; CGI-I: p = 0.004) but not for tamsulosin
920 EUROPEAN UROLOGY 61 (2012) 917925
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 who were also sexually active (approximately 60% of subjects)
group, more subjects and their clinicians perceived was significant with tadalafil (4.0 1.0; p < 0.001), whereas
improvements in LUTS at end point compared to the the LSmean change with tamsulosin was not (0.4 1.0;
placebo group. p = 0.699).
In comparison to placebo, LSmean SE change from Improvements in Qmax were significantly greater than
baseline to end point in the IIEF-EF domain in men with ED placebo with tadalafil ( p = 0.009) and with tamsulosin
[(Fig._2)TD$IG]
Fig. 2 Differences from placebo in (A) total International Prostate Symptom Score and (B) Benign Prostatic Hyperplasia Impact Index. Numbers represent
least squares mean treatment difference (95% confidence interval) versus placebo in the change from baseline to 12 wk (last-observation-carried-
forward) and corresponding p values from analysis of covariance.
IPSS = International Prostate Symptom Score; BII = Benign Prostatic Hyperplasia Impact Index; LS = least squares.
EUROPEAN UROLOGY 61 (2012) 917925 921
Table 2 International Prostate Symptom Score (IPSS) total, storage, and voiding subscores and nocturia question (IPSS question 7)
IPSS = International Prostate Symptom Score; LS = least squares; SE = standard error; CI = condence interval.
*
IPSS questions 2 + 4 + 7.
**
IPSS questions 1 + 3 + 5 + 6.
y
IPSS question 7.
[(Fig._3)TD$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
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
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 improvement (reviewed in Laydner et al. [24]). Although
BPH symptom impact, and BPH treatment satisfaction at the statistically significant Qmax change in this study could
end point and improved erectile function in those men who be a random finding, a trend towards a dose-response
also reported ED. relationship was reported in a large dose-ranging study
The magnitude of improvement in total IPSS at end point with tadalafil [25], a small increase in Qmax that reached
with tadalafil 5 mg in this study was consistent with several statistical significance was seen with tadalafil 2.5 mg (but
previous reports [7,9,10], and the improvement was also not 5 mg) in another controlled study [10], and a significant
comparable to that seen in previous studies with a-blockers increase in Qmax compared with placebo was observed with
[1] and with tamsulosin 0.4 mg here. Similar numerical another once-daily PDE5-I previously under development
reductions in total IPSS were also reported for tadalafil 5 mg [26]. Compared with previous tadalafil studies, the change
or tamsulosin 0.2 mg once daily in a small pilot study of in Qmax observed here was similar for placebo (1.11.2 ml/s
Korean men with LUTS/BPH [23]. Tadalafil and tamsulosin previously) but greater for tadalafil 5 mg (1.61.7 ml/s
also similarly reduced the impact of symptoms on daily previously) [6,9,10,25]. Although the current study popula-
living (assessed by BII) at 4 and 12 wk. tion did not differ from previous studies for baseline
In contrast with findings for total IPSS and BII, only demographics or clinical characteristics, a greater propor-
tadalafil was significantly superior to placebo on secondary tion of subjects were from Europe. In addition, baseline
measures of satisfaction and improvement, including IPSS Qmax in the active treatment groups (tadalafil 9.9 ml/s and
QoL, global impressions of improvement (CGI-I and PGI-I), tamsulosin 9.4 ml/s) was lower than prior tadalafil studies
and satisfaction with BPH treatment (TSS-BPH). Tadalafil (range for tadalafil 5 mg: 9.811.7 ml/s), which could allow
also significantly improved ED compared with placebo in more room for improvement and thus increase the
sexually active men with ED, while tamsulosin did not. probability of observing an improvement in Qmax. Several
The finding of a significant improvement in Qmax with in vitro studies have reported smooth muscle relaxation in
tadalafil in this study contrasts with the majority of the human bladder neck and prostate when exposed to
previous studies on tadalafil, sildenafil, and vardenafil for PDE5 inhibition [14,27], and the smooth muscle relaxant
LUTS/BPH, which typically identified only a numeric Qmax effect of tadalafil seems to be of similar magnitude as
EUROPEAN UROLOGY 61 (2012) 917925 923
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.
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
alfuzosin [28]. However, it remains unclear whether these novel safety findings in this study, and the most common
in vitro findings translate into the observed small Qmax TEAEs were consistent with the known side-effect profiles
changes seen with tadalafil. Tadalafil at a higher 20-mg of these agents.
daily dose had no significant effect on the bladder outlet A limitation of the present study is that it was not
obstruction (BOO) index in a safety study of men with LUTS/ powered to assess noninferiority or superiority between
BPH; however, these men were not required to have BOO at tadalafil and tamsulosin. Nonetheless, it was fully powered
baseline [29]. In contrast to the small improvements in to individually assess tadalafil or tamsulosin versus
Qmax, which have not reached statistical significance in placebo. Although a minimum clinically relevant noninfer-
most other studies, studies of tadalafil for LUTS/BPH have iority margin for LUTS/BPH treatments has not been clearly
consistently demonstrated significant and clinically mean- established, by conservative estimates, the sample size
ingful IPSS improvement [7,9,10]. This is aligned with required for a noninferiority trial would likely be 2- to
recently updated BPH guidelines stating that there is a poor 4-fold larger than the current study. Although this study
correlation between symptoms and Qmax [1]. There were no 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 other co-authors, interpreted the data and participated in the prepara-
or effects on disease progression; such studies would be of tion, review, and approval of the manuscript.
interest in the future. A prior 1-yr open-label extension
tadalafil study found tadalafil 5 mg once daily to be well Acknowledgment statement: Thomas Melby (an employee of Pharma-
Net/i3, Indianapolis, IN, USA) assisted in the preparation of this
tolerated with maintenance of efficacy [30]. Although the
manuscript. The authors would like to thank the trial participants and
increase in Qmax observed with tamsulosin in this study was
study investigators, without whom this work could not have been
in the range of changes observed in prior tamsulosin studies
performed.
[2], the increase observed with tadalafil was greater than in
prior tadalafil studies. Caution should therefore be exer-
cised in interpreting this finding.
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