Effects of Tadalafil Treatment on Erectile Function Recovery

EUROPEAN UROLOGY 65 (2014) 587–596
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Platinum Priority – Sexual Medicine
Editorial by Arthur L. Burnett on pp. 597–598 of this issue
Effects of Tadalafil Treatment on Erectile Function Recovery
Following Bilateral Nerve-sparing Radical Prostatectomy:
A Randomised Placebo-controlled Study (REACTT)
Francesco Montorsi a, Gerald Brock b, Jens-Uwe Stolzenburg c, John Mulhall d,
Ignacio Moncada e, Hitendra R.H. Patel f, Daniel Chevallier g, Kazimierz Krajka h,
Carsten Henneges i, Ruth Dickson j, Hartwig Büttner i,*
a
Vita Salute San Raffaele University, Milan, Italy; b University of Western Ontario, London, Ontario, Canada; c Universitätsklinikum Leipzig, Leipzig, Germany;
d
Memorial Sloan-Kettering Cancer Centre, New York, NY, USA; e Hospital La Zarzuela, Madrid, Spain; f University Hospital North Norway, Tromso, Norway;
g
Hôpital Universitaire Archet 2, Nice, France; h Uniwersyteckie Centrum Kliniczne, Gdansk, Poland; i Lilly Deutschland GmbH, Bad Homburg, Germany; j Eli
Lilly Canada Inc., Toronto, Ontario, Canada
Article info
Abstract
Article history:
Accepted September 28, 2013
Published online ahead of
print on October 13, 2013
Background: The potential rehabilitative and protective effect of phosphodiesterase
type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy
(NSRP) remains unclear.
Objective: The primary objective was to compare the efficacy of tadalafil 5 mg once
daily and tadalafil 20 mg on demand versus placebo taken over 9 mo in improving
unassisted erectile function (EF) following NSRP, as measured by the proportion of
patients achieving an International Index of Erectile Function-Erectile Function domain
(IIEF-EF) score 22 after 6-wk drug-free washout (DFW). Secondary measures included
IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length.
Design, setting, and participants: Randomised, double-blind, double-dummy, placebocontrolled trial in men 68 yr of age with adenocarcinoma of the prostate (Gleason 7)
and normal preoperative EF who underwent NSRP at 50 centres from nine European
countries and Canada.
Interventions: 1:1:1 randomisation to 9 mo of treatment with tadalafil 5 mg once daily,
tadalafil 20 mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label
tadalafil once daily (all patients).
Outcome measurements and statistical analysis: Logistic regression, mixed-effects
model for repeated measures, and analysis of covariance, adjusting for treatment,
age, and country, were applied to IIEF-EF scores 22, SEP-3, and penile length.
Results and limitations: Four hundred twenty-three patients were randomised to
tadalafil once daily (n = 139), on demand (n = 143), and placebo (n = 141). The mean
age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients
in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF
scores 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo
were 1.1 (95% confidence interval [CI], 0.6–2.1; p = 0.675) and 0.9 (95% CI, 0.5–1.7;
p = 0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF
score improvement significantly exceeded the minimally clinically important difference
(MCID: DIIEF-EF 4) in both tadalafil groups; for SEP-3 (MCID 23%), this was the case
for tadalafil once daily only. Treatment effects versus placebo were significant for
Keywords:
Clinical trials
Erectile dysfunction
Nerve-sparing prostatectomy
Penile function
Phosphodiesterase type 5
inhibitors
Prostate cancer
Radical prostatectomy
Rehabilitation
Tadalafil once a day
Please visit
www.eu-acme.org/
europeanurology to read and
answer questions on-line.
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then be attributed
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* Corresponding author. Lilly Deutschland GmbH, Medical Department, Werner-Reimers Straße 2-4,
61352 Bad Homburg, Germany. Tel. +49 6172 273 2059; Fax: +49 6172 273 2522.
E-mail address: [email protected] (H. Büttner).
0302-2838/$ – see back matter # 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
http://dx.doi.org/10.1016/j.eururo.2013.09.051
588
EUROPEAN UROLOGY 65 (2014) 587–596
tadalafil once daily only (IIEF-EF: p = 0.016; SEP-3: p = 0.019). In all groups, IIEF-EF and
SEP-3 decreased during DFW but continued to improve during open-label treatment. At
month 9 (EDT), penile length loss was significantly reduced versus placebo in the
tadalafil once daily group only (LS mean difference 4.1 mm; 95% CI, 0.4–7.8; p = 0.032).
Conclusions: Tadalafil once daily was most effective on drug-assisted EF in men with
erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once
daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not
improved after cessation of active therapy for 9 mo.
Trial registration: ClinicalTrials.gov identifier NCT01026818.
# 2013 Published by Elsevier B.V. on behalf of European Association of Urology.
1.
Introduction
eligibility criteria were historical prostate-specific antigen (PSA) levels
<10 ng/ml; a Gleason score 7 (on biopsy); no significant cardiovascular
Nerve-sparing radical prostatectomy (NSRP) is a commonly
used treatment for clinically localised prostate cancer (PCa)
in patients with a life expectancy 10 yr [1]. Notwithstanding improvements in surgical techniques, erectile
dysfunction (ED) is a common sequela of NSRP [2–4].
Phosphodiesterase type 5 inhibitors (PDE5-Is) are
generally well tolerated and effective in the treatment of
ED following NSRP [2,3,5], although they are less effective in
the post-NSRP population compared with the general
population [6], and the optimal time-point for starting
PDE5-I treatment is undetermined.
To date, three randomised controlled trials (RCTs) have
evaluated the impact of the early use of PDE5-Is in men with
ED following NSRP. Nightly administration of sildenafil for
36 wk, starting 4 wk after surgery, markedly increased the
return of normal spontaneous erections; the study was
stopped early, because it was expected not to meet its
primary end point [7]. Vardenafil treatment for 9 mo,
starting within 2 wk after surgery, was efficacious when
used on demand but had no significant effect on unassisted
erectile function (EF) after drug-free washout (DFW) [8]. In
a recent study, 3 mo of treatment with avanafil 100 or
200 mg on demand significantly improved drug-assisted EF
after prostatectomy, but no sustained effect on unassisted
EF was assessed [9].
In the current study, we aimed to evaluate the effect of
the early use of the long-acting PDE5-I tadalafil (once daily
or on demand) on both assisted and unassisted EF in men
who developed ED after NSRP.
disease, uncontrolled hypertension, diabetes, or endocrine disease;
confirmed bilateral NS prostatectomy (total nerve sparing score [NSS]
4) [12]; no need for adjuvant PCa therapy; and having ED after surgery,
defined by a patient-reported Residual Erection Function (REF) score 3
(‘‘penis is hard enough for penetration but not completely hard’’). The
REF question was based on the validated Erection Hardness Score [13],
which allows ratings from 1 to 4; REF allows an additional rating of 0 for
‘‘penis does not enlarge.’’
2.2.
Study design
This multicentre, phase 4, randomised, double-blind, three-arm, parallelgroup study was conducted in accordance with the Declaration of
Helsinki; appropriate ethical review boards approved the study protocol.
The study consisted of a screening period (including NSRP surgery); a
9-mo, double-blind, double-dummy, placebo-controlled treatment
period; a 6-wk DFW period; and a 3-mo, open-label treatment period.
Key visits occurred at randomisation (baseline, within 6 wk after NSRP), at
the end of double-blind treatment (EDT; month 9), washout (month 10.5;
primary end point), and open-label treatment (month 13.5). Supplemental
Figure 1 displays the detailed study design. At baseline, patients were
randomised 1:1:1 to oral treatment with tadalafil once daily, tadalafil on
demand, or placebo using an interactive voice response system and
stratified by age group and country. Matching placebo tablets identical to
the 5-mg and 20-mg tadalafil tablets were used to ensure that the blinded
regimen was identical for all treatment groups. During double-blind
treatment, patients received tadalafil 5 mg once daily (plus placebo on
demand), tadalafil 20 mg on demand (plus placebo once daily), or placebo
(once daily plus on demand). For on demand dosing, patients were
permitted to take up to three tablets per week (and no more than one per
day). During DFW, patients received no study drug. During the open-label
period, all patients received tadalafil 5 mg once daily.
2.
Patients and methods
2.3.
2.1.
Patients
The primary objective was to evaluate the efficacy of tadalafil 5 mg once
Outcome measures
daily and tadalafil 20 mg on demand compared with placebo when taken
Patients were enrolled between November 2009 and August 2011 in 50
over 9 mo in improving unassisted EF, as measured by the proportion of
centres from nine European countries and Canada. All patients signed
patients achieving an IIEF-EF score 22 [14] after the 6-wk DFW period.
written informed consent before study procedures.
Secondary outcomes addressed in this manuscript include the actual
Adult men <68 yr of age at the time of NSRP for organ-confined,
values and changes from baseline in IIEF-EF score, positive responses to
nonmetastatic PCa (cT1c–T2c) were eligible to participate if they had no
Sexual Encounter Profile (SEP) questions, and changes in stretched
history of ED. An International Index of Erectile Function-Erectile
penile length in the flaccid state [15]. Penile length was measured before
Function domain (IIEF-EF) score 22 was required at screening (after
prostatectomy (visit 2) and at EDT (month 9). Visit 2 measurements were
cancer diagnosis, 6 wk before NSRP). This cut-off was considered
taken before administration of any sedatives or anaesthetics.
appropriate because many men with newly diagnosed PCa claim to have
Minimal clinically important differences (MCIDs), defined as
unimpaired EF but have IIEF-EF scores of 22–25 (mild ED) [10]. This
responses exceeding four points of change in IIEF-EF [16] and 23% for
phenomenon may be linked to decreased sexual interest and activity
positive SEP question 3 (SEP-3) responses [17], were evaluated in a post
after biopsy, distress caused by the cancer diagnosis, and anxiety about
hoc analysis. Safety was evaluated based on treatment-emergent
pending surgery during the 4-wk period that the IIEF assesses [11]. Other
adverse events (TEAEs) and PSA levels.
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EUROPEAN UROLOGY 65 (2014) 587–596
2.4.
interaction, country, age group, and baseline IIEF-EF score as fixed effects
Statistical analysis
and patient and error as random effects. Least squares (LS) means and
Sample size calculations were based on the assumption that 34% of
95% CIs are given. Interactions for country by treatment and age group by
placebo-treated patients and 54–64% of tadalafil-treated patients (once
treatment were included if significant at the 10% level. Post hoc analysis
daily and on demand) would achieve an IIEF-EF score 22 after DFW [7,8].
of covariance (ANCOVA) for SEP-3 included terms for treatment, country,
A sample size of 412 randomised patients provided 84% power to detect a
and age group. Change in penile length was analysed using ANCOVA,
20% difference in proportions in the two pairwise comparisons of tadalafil
including treatment, country, baseline value, age group, and NSS as
(once daily and on demand) versus placebo (20% drop-out rate assumed)
variables. The proportions of patients reporting TEAEs were compared
[18]. Randomisation was stratified by age and country. Efficacy analyses
using a Cochran-Mantel-Haenszel test stratified by country and age
were based on the intent-to-treat population, including all randomised
group. Data were analysed using SAS v.9.2 software (SAS Institute, Cary,
patients with baseline data and at least one postbaseline visit. Safety
NC, USA).
analyses included all patients who received at least one dose of study drug.
The primary efficacy outcome, the proportion of patients reaching an
3.
Results
3.1.
Patient disposition and baseline characteristics
IIEF-EF score 22 after DFW, was treated as a binary variable (missing
values imputed as failure). The proportion of patients achieving this
target was assessed using pairwise comparisons (tadalafil once daily
versus placebo, tadalafil on demand versus placebo). Odds ratios (ORs)
and 95% confidence intervals (CIs) were derived from a logistic
regression model, including treatment group, country, and age group
as explanatory variables. A closed gatekeeping strategy based on the
Bonferroni-Hommel procedure [19] was used to control the type 1 error
at a two-sided 0.05 level (largest p value tested first at 0.05; if failed,
second test at 0.025). The primary logistic regression was repeated for
the proportion of patients achieving IIEF-EF scores 22 at EDT and openlabel periods. IIEF-EF score changes from baseline and proportions of
positive responses to SEP questions were analysed using a mixed-effect
model for repeated measures (MMRM), assuming an unstructured
covariance structure and including visit, treatment, treatment-by-visit
[(Fig._1)TD$IG]
Screening
Of 583 patients screened, 423 were randomised to doubleblind treatment: 139 (32.9%) to tadalafil once daily, 143
(33.8%) to tadalafil on demand, and 141 (33.3%) to placebo.
Overall, 41 (29.5%) patients in the tadalafil once daily group,
31 (21.7%) in the tadalafil on demand group, and 36 (25.5%)
in the placebo group discontinued the study, most
frequently because of violation of entry criteria (23.1%),
patient decision (22.2%), and adverse events (19.4%; Fig. 1).
The efficacy and safety analyses included 422 patients
(tadalafil once daily: 139; tadalafil on demand: 142;
placebo: 141). One patient assigned to tadalafil on demand
Screening failures: n = 160
Entry criteria not met: n = 105
Patient decision:
n = 49
Protocol deviation:
n=3
Adverse event:
n=2
Physician decision: n = 1
Screened: n = 583
Randomised: n = 423
Tadalafil once daily: n = 139
Double-blind
treatment period
Discontinuations:
n = 25
Adverse event:
n = 10
Patient decision:
n=7
Lack of efficacy:
n=3
n=3
Lost to follow-up:
Entry criteria not met: n = 2
Tadalafil once daily: n = 114
Drug-free washout
Completers
Tadalafil once daily: n = 98
Discontinuations:
Protocol deviation:
Lost to follow-up:
Tadalafil as needed: n = 112
Fig. 1 – Patient disposition (Consolidated Standards of Reporting Trials flowchart).
Discontinuations:
n = 26
Entry criteria not met: n = 7
Lack of efficacy:
n=6
Adverse event:
n=4
Lost to follow-up:
n=4
Patient decision:
n=3
Protocol deviation:
n=2
Placebo: n = 115
Discontinuations:
n=5
Patient decision:
n=2
Entry criteria not met: n = 1
Lack of efficacy:
n=1
Physician decision: n = 1
Tadalafil as needed: n = 117
Discontinuations:
n=7
Entry criteria not met: n = 2
Lack of efficacy:
n=1
n=1
Lost to follow-up:
n=1
Protocol deviation:
Patient decision:
n=2
Placebo: n = 141
Discontinuations:
n = 21
Entry criteria not met: n = 9
Adverse event:
n=6
Patient decision:
n=3
Lack of efficacy:
n=2
Protocol deviation:
n=1
Tadalafil as needed: n = 122
Discontinuations:
n=9
Entry criteria not met: n = 2
Lack of efficacy:
n=2
n=1
Adverse event:
n=1
Lost to follow-up:
Physician decision: n = 1
Sponsor decision:
n=1
Patient decision:
n=1
Tadalafil once daily: n = 105
Open-label
Tadalafil 5 mg
once daily
Tadalafil as needed: n = 143
Discontinuations:
n=7
Entry criteria not met: n = 2
Lack of efficacy:
n=2
Lost to follow-up:
n=2
n=1
Death:
Placebo: n = 108
n=5
n=3
n=2
Discontinuations:
Lost to follow-up:
Protocol deviation:
Patient decision:
Placebo: n = 105
n=3
n=1
n=1
n=1
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EUROPEAN UROLOGY 65 (2014) 587–596
Table 1 – Baseline characteristics
Variable
Age, yr
Mean (SD)
Age group, no. (%)
<61 yr
61–68 yr
Ethnicity, no. (%)
White
Othera
BMI, kg/m2
Mean (SD)
NSRP approach, no. (%)
Open surgery
Conventional laparoscopy
Robot-assisted laparoscopy
Other
Total NSS, categorised, no. (%)
Perfect (2)
Not perfect (>2)
Tadalafil once daily
(n = 139)
Tadalafil as needed
(n = 143)
Placebo
(n = 141)
58.6 (5.07)
57.5 (5.91)
57.6 (5.69)
82 (59.0)
57 (41.0)
85 (59.4)
58 (40.6)
91 (64.5)
50 (35.5)
137 (98.6)
2 (1.4)
141 (98.6)
2 (1.4)
138 (97.9)
3 (2.1)
26.6 (2.97)
26.9 (2.93)
27.1 (3.08)
68
29
31
11
65
31
41
6
56
28
44
13
(48.9)
(20.9)
(22.3)
(7.9)
117 (84.2)
22 (15.8)
(45.5)
(21.7)
(28.7)
(4.2)
116 (81.1)
27 (18.9)
(39.7)
(19.9)
(31.2)
(9.2)
113 (80.1)
28 (19.9)
BMI = body mass index; NSRP = nerve-sparing radical prostatectomy; NSS = nerve-sparing score; SD = standard deviation.
Other ethnicities included American Indian/Alaska native, Asian, and African/Caribbean heritage.
a
did not receive study drug and was excluded. Baseline
characteristics were similar between treatment groups
(Table 1). Overall, patients’ mean age was 57.9 yr (standard
deviation [SD]: 5.58 yr).
3.2.
Erectile function recovery after nerve-sparing radical
prostatectomy
3.2.1.
International Index of Erectile Function–Erectile Function
tadalafil groups but not in the placebo group (95% CI for
placebo included 4; Fig. 3). The treatment effect versus
placebo was statistically significant for tadalafil once daily
only (once daily minus placebo: LS mean: 2.8 [95% CI,
0.8–4.8], p = 0.007) but was not sustained after DFW (no
significant treatment group differences). During open-label
tadalafil once daily treatment, LS mean IIEF-EF scores
increased again, significantly exceeding the MCID in all
three treatment groups.
domain
3.2.2.
Sexual Encounter Profile questions
An overall significant improvement of the percentage of
[(Fig._2)TD$IG]positive responses to SEP-1 and SEP-2 was observed with
35
Paents achieving IIEF-EF Score 22, %
At EDT (month 9), the proportion of patients reaching the
IIEF-EF target (score 22) was significantly higher in
the tadalafil once daily group than in the placebo group
(Fig. 2), while the comparison between tadalafil on demand
and placebo was not statistically significant (once daily vs
placebo: OR: 2.2 [95% CI, 1.2–4.0], p = 0.016; on demand
vs placebo: OR: 1.5 [95% CI, 0.8–2.9], p = 0.210). After 6-wk
DFW (month 10.5, primary end point), none of the
comparisons versus placebo was statistically significant
(once daily vs placebo: OR: 1.1 [95% CI, 0.6–2.1], p = 0.675;
on demand vs placebo: OR: 0.9 [95% CI, 0.5–1.7], p = 0.704).
Thus, the primary objective of the study was not met. After
an additional 3 mo of open-label tadalafil once daily
treatment (month 13.5, all patients), the proportion of
patients achieving IIEF-EF scores 22 had increased in all
three treatment groups. Again, none of the comparisons
versus the placebo group was statistically significant (once
daily vs placebo group: OR: 1.3 [95% CI, 0.8–2.3], p = 0.273;
tadalafil on demand versus placebo group: OR: 1.4 [95% CI,
0.8–2.3], p = 0.259). At month 10.5 only, a statistically
significant age group effect in favour of younger patients
was observed (<61 yr of age vs 61–68 yr of age: OR: 1.92
[95% CI, 1.11–3.33], p = 0.020).
Figure 3 shows the LS mean changes in IIEF-EF;
unadjusted IIEF-EF scores are provided in Supplemental
Table 1. At EDT, LS mean improvements of IIEF-EF scores
from baseline significantly exceeded the MCID [16] in both
30
Tadalafil OaD
Tadalafil PRN
Placebo
32.4 33.1
p = 0.016
25
Primary: n.s.
27.0
25.2
20
20.9
19.7
19.1
15
16.9
14.2
10
05
00
Month 9
OaD vs
Placebo
PRN vs
Placebo
Month 10.5
Month 13.5
OR (95% CI); p value
2.15 (1.16–3.99); 1.14 (0.63–2.06); 1.34 (0.79–2.28);
0.016
0.675
0.273
1.50 (0.79–2.85); 0.89 (0.48–1.65); 1.35 (0.80–2.29);
0.210
0.704
0.259
Fig. 2 – Percentage of patients achieving an International Index of Erectile
Function-Erectile Function domain score of I22.
CI = confidence interval; IIEF-EF = International Index of Erectile
Function-Erectile Function domain score; OaD = once a day; OR = odds
ratio; n.s. = not significant; PRN = on demand.
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EUROPEAN UROLOGY 65 (2014) 587–596
[(Fig._3)TD$IG]
14
Tadalafil 5 mg OaD
Tadalafil 20 mg PRN
Placebo
Change in IIEF-EF (LS mean)
12
10.6
10
8
*
9.8
7.7
9.0
6.9
6.2
6
6.5
4.3
5.0
4.9
4
5.8
6.0
MCID
3.6
3.6
2
1.4
* p < 0.05 (TAD OaD vs PLC, MMRM)
0
1.0
–2
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
Double-blind
10.0
11.0
Washout
12.0
13.0
Open-label
Month
Fig. 3 – Least-squares mean change in International Index of Erectile Function-Erectile Function domain score over time (error bars present the 95%
confidence interval).*
IIEF-EF = International Index of Erectile Function-Erectile Function domain; LS = least squares; MCID = minimal clinically important difference;
MMRM = mixed-effect model for repeated measures; OaD = once a day; PLC = placebo; PRN = on demand; TAD = tadalafil.
* p value from MMRM.
tadalafil throughout the study ( p = 0.015 and p = 0.018,
respectively; prespecified MMRM). In the tadalafil once
daily group only, the percentage of positive responses was
significantly higher compared with the placebo group, both
at EDT and after open-label treatment (Table 2). For SEP-3,
the difference versus placebo at EDT was also significant in
the tadalafil once daily group only (Fig. 4a and Table 2; LS
mean: 33.7% vs 21.6%; LS mean difference: 12.1% [95% CI,
Table 2 – Proportion of per-patient yes responses to Sexual Encounter Profile questions
LS, %, mean (95% CI)
Tadalafil once daily
(n = 139)
SEP-1: Were you able to achieve at least some erection (some enlargement of the penis)?
Overall p = 0.015
Month 9
67.4 (58.3–76.5)*
Month 10.5
67.8 (58.1–77.5)
Month 13.5
86.2 (77.8–94.5)*
SEP-2: Were you able to insert your penis into your partner’s vagina?
Overall p = 0.018
Month 9
44.0 (35.2–52.8)*
Month 10.5
40.8 (31.2–50.4)
Month 13.5
63.5 (53.9–73.1)*
SEP-3: Did your erection last long enough for you to have successful intercourse?
Overall p = 0.085
Month 9
33.7 (25.5–41.9)*
Month 10.5
28.8 (19.9–37.6)
Month 13.5
52.4 (42.8–62.0)
SEP-4: Were you satisfied with the hardness of your erection?
Overall p = 0.087
Month 9
26.2 (18.9–33.4)*
Month 10.5
16.9 (9.7–24.2)
Month 13.5
42.1 (33.0–51.2)
SEP-5: Were you satisfied overall with this sexual experience?
Overall p = 0.134
Month 9
25.4 (18.3–32.6)*
Month 10.5
16.3 (9.2–23.3)
Month 13.5
40.8 (31.8–49.8)
CI = confidence interval; LS = least squares; SEP = Sexual Encounter Profile.
Statistically significant difference versus placebo, p < 0.05.
*
Tadalafil as needed
(n = 142)
Placebo
(n = 141)
63.9 (55.3–72.4)*
64.2 (55.1–73.4)
79.8 (71.9–87.7)
52.5 (43.6–61.5)
58.9 (49.2–68.6)
75.3 (66.9–83.6)
34.3 (26.0–42.6)
35.0 (25.9–44.1)
56.1 (46.9–65.2)
27.7 (19.1–36.2)
36.3 (26.7–45.9)
50.1 (40.6–59.7)
24.1 (16.4–31.8)
23.0 (14.7–31.4)
45.8 (36.6–55.0)
21.6 (13.6–29.6)
28.5 (19.7–37.4)
40.8 (31.2–50.3)
18.2 (11.3–25.0)
11.7 (4.8–18.6)
35.6 (26.9–44.4)
14.3 (7.3–21.4)
18.9 (11.5–26.2)
30.6 (21.5–39.7)
17.7 (11.0–24.5)
10.5 (3.9–17.2)
35.0 (26.3–43.6)
14.0 (7.1–21.0)
19.1 (12.0–26.2)
29.4 (20.4–38.4)
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EUROPEAN UROLOGY 65 (2014) 587–596
[(Fig._4)TD$IG]
[(Fig._5)TD$IG]
Yes per patient (LS mean), %
70
60
Tadalafil PRN
Placebo
MMRM
p = 0.019
50
Tadalafil OaD
Tadalafil PRN
Placebo
Change from baseline to month 9 (end of RT)
p = 0.066
4
p = 0.415
p = 0.968
Change in penile length
(LS mean), mm
Tadalafil OaD
a
p = 0.327
p = 0.621
40
30
MCID
20
10
33.7
24.1
21.6
28.8
23.0
28.5
52.4
45.8
40.8
0
Month 9
Yes per patient (LS mean), %
b
80
Tadalafil OaD
Tadalafil PRN
ANCOVA
70
60
Month 10.5
p = 0.007
p = 0.992
Month 13.5
0
–2
–2.2
–7.9
–6.3
–4
–6
–8
–10
–12
–14
p = 0.003
p = 0.032
Fig. 5 – Change in penile length (analysis of covariance; error bars present
the 95% confidence interval).
LS = least squares; OaD = once a day; PRN = on demand, RT = randomised,
double-blind treatment.
Placebo
p = 0.010
p = 0.135
p = 0.284
50
40
p = 0.469
3.4.
30
10
Safety
MCID
20
0
33.9 22.9 19.0
34.5 27.4 34.5
55.3 47.9 37.8
Month 9
Month 10.5
Month 13.5
Fig. 4 – Sexual Encounter Profile question 3: per patient yes responses;
(a) mixed-effect model for repeated measures; (b) post hoc analysis of
covariance. Error bars present the 95% confidence interval.
LS = least squares; MCID = minimal clinically important difference;
OaD = once a day; PRN = on demand.
2.0–22.2], p = 0.019; unadjusted data provided in Supplemental Table 1). The percentage of positive SEP-3 responses
significantly exceeded the MCID [17] at EDT in the tadalafil
once daily group only. No significant SEP differences were
observed after DFW. At the end of open-label tadalafil once
daily treatment, the percentage of positive SEP-3 responses
was 52.4% for the tadalafil once daily group versus 45.8% for
the on demand and 40.8% for the placebo group when based
on the prespecified MMRM analysis (differences vs placebo
not statistically significant). The additional post hoc
ANCOVA, however, showed a significant difference between
tadalafil once daily and placebo both at EDT (33.9% vs 19.0%;
p = 0.007) and at the end of open-label treatment (55.3% vs
37.8%; p = 0.010; Fig. 4b). Positive responses to SEP-4 and
SEP-5 were consistent with the results for SEP-3 (Table 2,
MMRM).
3.3.
2
Effect on penile length
Significantly less shrinkage of penile length was observed
in the OaD group compared with placebo at EDT (Fig. 5;
difference once daily minus placebo: LS mean: 4.1 mm
[95% CI, 0.4–7.8], p = 0.032; unadjusted data provided in
Supplemental Table 1). No significant difference was
observed for tadalafil on demand versus placebo (Fig. 5).
There was also no significant effect of NSS (perfect: = 2;
nonperfect: >2) on penile length loss (difference perfect
minus nonperfect: LS mean: 2.1 mm [95% CI, 2.0 to 6.2],
p = 0.314).
At least one TEAE was reported by 39.6%, 43.7%, and 35.5% of
patients in the tadalafil once daily, on demand, and placebo
groups, respectively (overall p = 0.269; Table 3); 2.2%, 2.8%,
and 7.8% reported at least one serious TEAE (overall
p = 0.044). One patient on placebo died from acute
myocardial infarction (not related to study drug). One
patient on open-label tadalafil once daily treatment
experienced a serious ischemic stroke considered to be
related to the study drug by the investigator; no other
serious TEAEs were related to study drug or study
procedures. No more than five patients (4.3%) in any
treatment group had postbaseline PSA levels 0.2 ng/ml at
any time point, with no difference between the treatment
groups.
4.
Discussion
This study is the first RCT of patients with established ED
after NSRP that investigated the effect of early treatment
with tadalafil once daily and on demand on short- and longterm drug-assisted and unassisted EF.
The primary objective was not met: Early initiation of
tadalafil (once daily or on demand) had no effect on
unassisted EF at 10.5 mo after NSRP. The proportion of
patients achieving IIEF-EF scores 22 did not differ
significantly between tadalafil once daily or on demand
and placebo after 6-wk DFW. The double-blind treatment
period of 9 mo was possibly too short to achieve optimal EF
recovery, as confirmed by the low recovery rates of 25.2%
with tadalafil once daily, 19.7% with tadalafil on demand,
and 14.2% with placebo at this time point. However, the
proportion of patients who achieved IIEF-EF scores 22
was significantly higher for tadalafil once daily compared
with placebo but not for tadalafil on demand. In previous
studies, rates of 62% and 78% were achieved after 1 yr and 2
yr of daily or every-other-day PDE5-I treatment [20], and
rates of 43% versus 22% were achieved with any PDE5-I
treatment versus no medication after 2 yr [21]. The failure
of tadalafil to improve unassisted EF after DFW at month
10.5 is consistent with a previous RCT of comparable design
593
EUROPEAN UROLOGY 65 (2014) 587–596
Table 3 – Common treatment-emergent adverse events (I2% of patients in any group)
Preferred term
Patients, no. (%)
Tadalafil once daily (n = 139)
Overall
(13.5 mo)
Any TEAE
Headache
Nasopharyngitis
Dyspepsia
Back pain
Myalgia
UTI
Bronchitis
Pain in extremity
Upper abdominal pain
Depression
Hypertension
GI reflux disease
Seasonal allergy
Abdominal discomfort
Anxiety
Urinary incontinence
55
5
5
6
5
5
3
3
3
3
2
2
1
4
0
0
3
(39.6)
(3.6)
(3.6)
(4.3)
(3.6)
(3.6)
(2.2)
(2.2)
(2.2)
(2.2)
(1.4)
(1.4)
(0.7)
(2.9)
(0)
(0)
(2.2)
Double-blind
plus washout
(10.5 mo)
51
5
5
5
5
5
3
3
3
3
2
1
1
4
0
0
3
(36.7)
(3.6)
(3.6)
(3.6)
(3.6)
(3.6)
(2.2)
(2.2)
(2.2)
(2.2)
(1.4)
(0.7)
(0.7)
(2.9)
(0)
(0)
(2.2)
Open
label
(3 mo)
11
1
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
(12.2)
(1.1)
(0)
(1.1)
(0)
(0)
(1.1)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
Tadalafil as needed (n = 142)
Overall
(13.5 mo)
62
12
6
6
5
5
4
1
4
4
3
3
3
0
3
0
0
(43.7)
(8.5)
(4.2)
(4.2)
(3.5)
(3.5)
(2.8)
(0.7)
(2.8)
(2.8)
(2.1)
(2.1)
(2.1)
(0)
(2.1)
(0)
(0)
Double-blind
plus washout
(10.5 mo)
54
11
5
5
5
5
4
1
4
2
3
2
2
0
2
0
0
(38.0)
(7.7)
(3.5)
(3.5)
(3.5)
(3.5)
(2.8)
(0.7)
(2.8)
(1.4)
(2.1)
(1.4)
(1.4)
(0)
(1.4)
(0)
(0)
Open label
(3 mo)
18
2
1
1
1
0
0
0
0
3
0
1
1
0
1
0
0
(17.1)
(1.9)
(1.0)
(1.0)
(1.0)
(0)
(0)
(0)
(0)
(2.9)
(0)
(1.0)
(1.0)
(0)
(1.0)
(0)
(0)
Placebo (n = 141)
Overall
(13.5 mo)
50
7
3
1
4
2
2
4
1
0
1
1
0
0
0
3
0
(35.5)
(5.0)
(2.1)
(0.7)
(2.8)
(1.4)
(1.4)
(2.8)
(0.7)
(0)
(0.7)
(0.7)
(0)
(0)
(0)
(2.1)
(0)
Double-blind
plus washout
(10.5 mo)
46
6
3
1
3
1
2
2
0
0
1
1
0
0
0
3
0
(32.6)
(4.3)
(2.1)
(0.7)
(2.1)
(0.7)
(1.4)
(1.4)
(0)
(0)
(0.7)
(0.7)
(0)
(0)
(0)
(2.1)
(0)
Open label
(3 mo)
11
1
0
0
1
1
0
2
1
0
0
0
0
0
0
0
0
(11.2)
(1.0)
(0)
(0)
(1.0)
(1.0)
(0)
(2.0)
(1.0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
TEAE = treatment-emergent adverse event; UTI = urinary tract infection; GI = gastrointestinal.
investigating early post-NSRP treatment with vardenafil
[8]. Vardenafil given nightly or on demand was also not
superior to placebo after 2 mo of DFW (single blind).
Tadalafil once daily and on demand were effective
throughout the double-blind period as indicated by
IIEF-EF improvements significantly exceeding the respective MCIDs [16,17]; group differences were statistically
significant for tadalafil once daily versus placebo. These
effects on EF were not sustained through DFW, but during
the following open-label treatment with tadalafil once
daily, data suggest that EF continued to improve in all
three treatment groups, as expected for a period between
10.5 mo and 13 mo after NSRP. For SEP-3, which addresses
successful intercourse, the effect of tadalafil once daily
was significant at EDT only. One possible explanation is
that the study may have been too short to achieve a
statistically significant overall effect on SEP-3 because
SEP-1 and SEP-2, which refer to penile tumescence and
penetration, had significantly higher improvements
throughout the study (MMRM) in patients using tadalafil,
but improvements were significant versus placebo at the
end of open-label treatment for the tadalafil once daily
group only. Nevertheless, the proportion of positive SEP-3
responses was approximately 10% higher in the tadalafil
once daily group than in the placebo group at the end of
open-label tadalafil once daily treatment. Although this
effect size was statistically not significant in the prespecified MMRM analysis, it became statistically significant when looking at this specific time point in an
exploratory post hoc ANCOVA analysis (55.3% vs 37.8%;
p = 0.010).
In the previous vardenafil trial, on demand but not
nightly treatment resulted in significant improvement of
IIEF-EF scores and SEP-3 response versus placebo at the
EDT [8]. In our study, treatment effects at the EDT were
significantly superior in the once daily treatment group
only. These contrasting results may result from the
different pharmacokinetic characteristics of the two
PDE5-Is. Pharmacokinetic studies of tadalafil show that
the steady state is reached after 5 d of once daily use,
with accumulation resulting in an area under the
curve and maximum concentration 1.6 times the single
dose [22].
Although plasma concentrations have not been directly
correlated with efficacy, a total tadalafil plasma concentration of 55 ng/ml, which approximates 90% enzyme
inhibition in vitro, constituted a reasonable pharmacodynamic target, suggesting the maintenance of these concentrations throughout the dosing interval of 24 h. Therefore,
predicted tadalafil plasma concentrations relative to the
55-ng/ml level provided a pharmacologic rationale for
the 5-mg once daily dose of tadalafil as potentially
efficacious throughout the 24-h dosing interval [23,24].
Because vardenafil has a half-life of 4–5 h only [25], constant
plasma levels probably were not reached with nightly
treatment. Vardenafil would potentially have to be taken in
shorter time intervals to achieve effective steady-state
concentrations [8].
Consistent with IIEF-EF and SEP results, at EDT, there
was a significant protection from penile length loss in the
tadalafil once daily group but not in the tadalafil on
demand group when compared with placebo. Therefore, it
can be hypothesised that patients with postprostatectomy
ED might benefit from protection from structural changes
by chronic inhibition of PDE5 [26,27]. These findings are
also consistent with a recent analysis from the MemorialSloan Kettering Cancer Centre demonstrating that men
using daily PDE5-I treatment had improved penile length
594
EUROPEAN UROLOGY 65 (2014) 587–596
preservation compared with men who did not use
the medication once daily [28]. It is likely that protection
from penile length loss is a surrogate parameter for
preservation of cavernosal integrity, in particular for
smooth muscle [21,22]. Preclinical findings suggest that
chronic low-dose administration of tadalafil is associated
with substantial improvement of the structure of penile
cavernous tissue, with increased smooth muscles and
elastic tissue, decreased fibrous tissue, and functional EF
enhancement [26,27]. An increase in smooth muscle
content has also been observed in patients regularly taking
sildenafil early after radical retropubic prostatectomy [29].
Therefore, our data suggest that the once daily dosing
regimen may have contributed to the maintenance of
cavernosal integrity by protecting against structural
changes as a sequel of neuropraxia.
No new safety signals were detected; one patient
experienced a nonfatal ischemic stroke during open-label
tadalafil once daily treatment. Mean PSA levels did not
differ between treatment groups, indicating that tadalafil
treatment had no impact on biochemical relapse, local
recurrence, or progression of PCa.
Several limitations have to be considered. The binary
IIEF-EF end point resulted in a lower statistical power
compared with continuous end points. Patients were
relatively young and sexually active, and men with certain
comorbid medical conditions (eg, diabetes) were excluded.
Irrespective of treatment, EF naturally recovers over time
following NSRP; this decreased the resolution of the efficacy
measures, as patients in the placebo group also gradually
improved during the study. Also, penile length was
measured up to EDT (month 9) only; it remains unknown
whether the effect was maintained after drug-free washout
(month 10.5), and at the end of open-label tadalafil once
daily treatment (month 13.5), respectively. Finally, patients
with mild ED at screening (IIEF-EF score of 22–25) were
included in the study, and preoperative EF is known to be an
important predictor of functional outcome following NSRP
[16]. However, the reliability of IIEF-EF assessment at
screening (following biopsy and cancer diagnosis) has to be
questioned, in particular because patients had to report no
history of ED as entry criterion. Therefore, the impact of
including men with formally mild ED in this trial remains
speculative.
5.
Conclusions
In men with ED after NSRP, improvements in IIEF-EF and
increased per-patient yes responses to SEP-3 (successful
intercourse) gained during 9 mo of double-blind treatment
with tadalafil once daily were not sustained after 6-wk
DFW. Although the primary end point was not met, the
study suggested that tadalafil once daily was most effective
on drug-assisted EF in men with ED following NSRP
compared with placebo: IIEF-EF improvements at EDT
significantly exceeded the MCID for both tadalafil once daily
and on demand, but only tadalafil once daily significantly
exceeded the MCID for SEP-3, and the treatment effect
versus placebo was statistically significant for tadalafil once
daily only. Moreover, at EDT, there was a significant
protection from penile length loss in the tadalafil once
daily group compared with placebo. These data suggest that
tadalafil once daily treatment may have contributed to the
maintenance of cavernosal tissue integrity, believed to be a
key factor in long-term maintenance of EF. Although the
proportion of patients with IIEF scores 22 and the SEP-3
responses were not statistically different based on the
prespecified MMRM analysis at the end of the DFW period,
patients randomised to tadalafil once daily had a statistically higher response than placebo at the end of open-label
treatment based on ANCOVA analysis. This finding, along
with the reduction in the loss of penile length, raises the
possibility that tadalafil treatment may contribute to the
recovery of EF after prostatectomy.
Author contributions: Hartwig Büttner 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: Montorsi, Büttner, Patel.
Acquisition of data: Montorsi, Brock, Stolzenburg, Moncada, Chevallier,
Krajka.
Analysis and interpretation of data: Montorsi, Brock, Stolzenburg, Mulhall,
Moncada, Patel, Chevallier, Krajka, Henneges, Dickson, Büttner.
Drafting of the manuscript: Büttner, Henneges.
Critical revision of the manuscript for important intellectual content:
Montorsi, Brock, Stolzenburg, Mulhall, Moncada, Patel, Chevallier,
Krajka, Henneges, Dickson, Büttner.
Statistical analysis: Henneges.
Obtaining funding: Büttner.
Administrative, technical, or material support: None.
Supervision: Büttner, Henneges.
Other (specify): None.
Financial disclosures: Hartwig Büttner 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: Drs. Montorsi,
Brock, Stolzenburg, Mulhall, Moncada, and Chevallier have served as
consultants for Eli Lilly. Drs. Montorsi, Brock, Stolzenburg, Moncada, and
Patel have received speaker honoraria from Eli Lilly. Drs. Brock, Moncada,
and Patel have received travel expenses from Eli Lilly. Drs. Henneges,
Dickson, and Büttner are employees of Eli Lilly. Drs. Büttner and Dickson
own Eli Lilly stock.
Funding/Support and role of the sponsor: Eli Lilly contributed to the
design and conduct of the study; the collection, management, analysis,
and interpretation of the data; and the preparation, review, and approval
of the manuscript.
Acknowledgment statement: The authors are grateful to all patients
having participated in this trial and to all study investigators (see
Appendix) for their contribution to data acquisition and patient care. We
are indebted to the scientific work of all researchers who laid the
foundation for the design of this trial and whose invaluable reference
works we attempted to synthesize and explain in both rationale and
discussion. A plea of forgiveness is necessary at this point for we are sure
that we might have missed some aspects. We are grateful to Anthony
Beardsworth, Patrick R. Burns, Joaquin Casariego, Gianluca d’Anzeo,
Craig Donatucci, Dapo Ilo, Vladimir Kopernicky, Fernando Marin, James
Michael McGill, Andrea Rossi, David G. Wong, and David Bradley
EUROPEAN UROLOGY 65 (2014) 587–596
Woodward, Eli Lilly and Company, for scientific advice and invaluable
discussions. We thank Clare Barker, Bruce Basson, Ann Gibb, and Pepa
Polavieja, all from Eli Lilly and Company, for statistical support.
Statistical analyses were programmed by PSI CRO LTD, St. Petersburg,
Russia. We thank Annemarie Hütz, Shweta Vaghela, and Karin Helsberg,
Trilogy Writing and Consulting GmbH, Frankfurt, Germany, for providing
medical writing services on behalf of Eli Lilly.
595
Universidad Complutense de Madrid, Madrid; Switzerland:
Marius Cristian Butea-Bocu, Kantonsspital Luzern, Luzern;
Alexander Müller, University Hospital Zürich, Zürich;
United Kingdom: David Chadwick, The James Cook University Hospital, Middlesbrough; Nimish Shah, Addenbrookes
Hospital, Cambridge University Hospitals NHS Foundation
Trust, Cambridge; Sara Stearn, Cambridge University
Hospitals NHS Foundation Trust, Cambridge.
Appendix – List of acknowledged study investigators
Belgium: Robert Andrianne, Centre Hospitalier Universitaire de Liège, Liège; Ignace Billet, AZ Groeninge, Kortrijk;
Alexandre Mottrie, Onze Lieve Vrouwziekenhuis, Aalst;
Hendrik Van Poppel, University Hospitals of the KU Leuven,
Leuven; Canada: Ling DeYoung, St Joseph Health Care,
London, Ontario; Jay C. Lee, University of Calgary, Calgary,
Alberta; Peter J Pommerville, University of British Columbia,
Victoria, BC; France: Pierre Costa, Hôpital Universitaire
Carémeau, Nı̂mes; Beatrice Cuzin, Hopital Edouard Herriot,
Lyon; Marian Devonec, Claude Bernard University, Hôpital
Lyon-Sud, Pierre-Bénite; Philippe Lecorvoisier, CHU Henri
Mondor, Creteil; Alain Ruffion, Centre Hospitalier Lyon Sud,
Pierre Bénite; Nicolas Terrier, Hôpital Albert Michallon,
Grenoble; Germany: Markus Graefen, Martini-Klinik am
UKE GmbH, Hamburg; Peter Hammerer, Klinik für Urologie
und Uroonkologie, Städtisches Klinikum Braunschweig
gGmbH, Braunschweig; Joachim Noldus, Katholisches
Krankenhaus Marienhospital Herne, Universitätsklinikum
der Ruhr-Universität Bochum, Herne; Matthias Oelke,
Hanover Medical School, Hannover; Martin Schostak,
Universitätsklinikum Magdeburg, Magdeburg; Manfred
Wirth, Universitätsklinikum Carl Gustav Carus, Dresden;
Jürgen Zumbé, Klinikum Leverkusen, Leverkusen; Italy:
Giuseppe Ludovico, Miulli Hospital, Acquaviva delle Fonti;
Luigi Da Pozzo, Ospedali Riuniti di Bergamo, Bergamo;
Andrea Salonia, Dipartimento Urologia, IRCCS Ospedale San
Raffaele, Milano; The Netherlands: WJ Levens, Maxima
Medisch Centrum, Veldhoven; Henk van der Poel,
Netherlands Cancer Institute, Amsterdam; John Rietbergen,
Sint Franciscus Gasthuis, Rotterdam; Henk Vergunst,
Canisius-Wilhelmina Ziekenhuis, Nijmegen; Poland:
Andrzej Borkowski, Szpital Kliniczny Dzieciatka Jezus,
Warszawa; Piotr Jarzemski, Jan Biziel University Hospital,
Bydgoszcz; Alicja Klejnotowska, Uniwersyteckie Centrum
Kliniczne, Gdansk; Marek Roslan, Uniwersyteckie Centrum
Kliniczne, Gdansk; Spain: Natalio Cruz, Hospital Virgen del
Rocio, Sevilla; José Jara-Rascon, Hospital General Universitario Gregorio Marañon, Madrid; Maria Jose Requena Tapia,
Hospital Universitario Reina Sofia, Córdoba; Enrique LledoGarcia, Hospital General Universitario Gregorio Marañon,
Madrid; Antonio Martin Morales, Complejo Hospitalario
Carlos Haya, Malaga; Jose Martı́nez Jabaloyas, Universitario
de Valencia Hospital, Valencia; Juan Ignacio Martı́nezSalamanca, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid; Marı́a Paz Martı́n Torres, Hospital
Universitario Doce de Octubre, Madrid; Rafael Prieto
Castro, Hospital Universitario Reina Sofia, Córdoba; Fermin
Rodriguez de Bethencourt, Hospital La Paz, Madrid;
Javier Romero-Otero, Hospital Universitario 12 Octubre,
Appendix B. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.eururo.2013.09.051.
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