Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)

EUROPEAN UROLOGY 65 (2014) 587–596

available at www.sciencedirect.com journal homepage: www.europeanurology.com

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 Bu¨ttner i,* a

Vita Salute San Raffaele University, Milan, Italy; b University of Western Ontario, London, Ontario, Canada; c Universita¨tsklinikum 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

Hoˆpital 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. The EU-ACME credits will then be attributed automatically.

* 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. Bu¨ttner).

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.

589

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

590

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.

591

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)

592

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 Bu¨ttner 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, Bu¨ttner, 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, Bu¨ttner. Drafting of the manuscript: Bu¨ttner, Henneges. Critical revision of the manuscript for important intellectual content: Montorsi, Brock, Stolzenburg, Mulhall, Moncada, Patel, Chevallier, Krajka, Henneges, Dickson, Bu¨ttner. Statistical analysis: Henneges. Obtaining funding: Bu¨ttner. Administrative, technical, or material support: None. Supervision: Bu¨ttner, Henneges. Other (specify): None. Financial disclosures: Hartwig Bu¨ttner 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 Bu¨ttner are employees of Eli Lilly. Drs. Bu¨ttner 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 Hu¨tz, 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 Mu¨ller, University Hospital Zu¨rich, Zu¨rich; 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 Lie`ge, Lie`ge; 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, Hoˆpital Universitaire Care´meau, Nıˆmes; Beatrice Cuzin, Hopital Edouard Herriot, Lyon; Marian Devonec, Claude Bernard University, Hoˆpital Lyon-Sud, Pierre-Be´nite; Philippe Lecorvoisier, CHU Henri Mondor, Creteil; Alain Ruffion, Centre Hospitalier Lyon Sud, Pierre Be´nite; Nicolas Terrier, Hoˆpital Albert Michallon, Grenoble; Germany: Markus Graefen, Martini-Klinik am UKE GmbH, Hamburg; Peter Hammerer, Klinik fu¨r Urologie und Uroonkologie, Sta¨dtisches Klinikum Braunschweig gGmbH, Braunschweig; Joachim Noldus, Katholisches Krankenhaus Marienhospital Herne, Universita¨tsklinikum der Ruhr-Universita¨t Bochum, Herne; Matthias Oelke, Hanover Medical School, Hannover; Martin Schostak, Universita¨tsklinikum Magdeburg, Magdeburg; Manfred Wirth, Universita¨tsklinikum Carl Gustav Carus, Dresden; Ju¨rgen Zumbe´, 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; Jose´ Jara-Rascon, Hospital General Universi˜ on, Madrid; Maria Jose Requena Tapia, tario Gregorio Maran Hospital Universitario Reina Sofia, Co´rdoba; Enrique Lledo˜ on, Garcia, Hospital General Universitario Gregorio Maran Madrid; Antonio Martin Morales, Complejo Hospitalario Carlos Haya, Malaga; Jose Martı´nez Jabaloyas, Universitario de Valencia Hospital, Valencia; Juan Ignacio Martı´nezSalamanca, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid; Marı´a Paz Martı´n Torres, Hospital Universitario Doce de Octubre, Madrid; Rafael Prieto Castro, Hospital Universitario Reina Sofia, Co´rdoba; 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. References [1] Heidenreich A, Bastian PJ, Bellmunt J, et al. Guidelines on prostate cancer. European Association of Urology Web site. http://www. uroweb.org/gls/pdf/08%20Prostate%20Cancer_LR%20March% 2013th%202012.pdf. Accessed June 27, 2013. [2] Salonia A, Burnett AL, Graefen M, et al. Prevention and management of postprostatectomy sexual dysfunctions. Part 1: choosing the right patient at the right time for the right surgery. Eur Urol 2012;62: 261–72. [3] Salonia A, Burnett AL, Graefen M, et al. Prevention and management of postprostatectomy sexual dysfunctions part 2: recovery and preservation of erectile function, sexual desire, and orgasmic function. Eur Urol 2012;62:273–86. [4] Ficarra V, Novara G, Ahlering TE, et al. Systematic review and metaanalysis of studies reporting potency rates after robot-assisted radical prostatectomy. Eur Urol 2012;62:418–30. [5] Montorsi F, Nathan PH, McCullough A, et al. Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial. J Urol 2004;172:1036–41. [6] Hatzimouratidis K, Burnett AL, Hatzichristou D, McCullough AR, Montorsi F, Mulhall JP. Phosphodiesterase type 5 inhibitors in postprostatectomy erectile dysfunction: a critical analysis of the basic science rationale and clinical application. Eur Urol 2009;55: 334–47. [7] Nathan PH, McCullough AR, Levine LA, et al. Randomized, doubleblind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Impot Res 2008;20: 479–86. [8] Montorsi F, Brock G, Lee J, et al. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 2008;54: 924–31. [9] Mulhall JP, Burnett AL, Wang R, et al. A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy. J Urol 2013;189:2229–36. [10] Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999;54:346–51. [11] Salomon G, Isbarn H, Budaeus L, et al. Importance of baseline potency rate assessment of men diagnosed with clinically localized prostate cancer prior to radical prostatectomy. J Sex Med 2009;6: 498–504. [12] Nelson C, Alphs HH, Rabbani F, et al. Insights into the impact of nerve-sparing status during radical prostatectomy: validation of a nerve sparing scoring system. J Urol 2009;181(Suppl 4):370.

596

EUROPEAN UROLOGY 65 (2014) 587–596

[13] Mulhall JP, Goldstein I, Bushmakin AG, Cappelleri JC, Hvidsten K. Validation of the erection hardness score. J Sex Med 2007;4:1626–34.

[22] Forgue ST, Patterson BE, Bedding AW, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 2006;61:280–8.

[14] Briganti A, Gallina A, Suardi N, et al. What is the definition of a

[23] Angulo J, Gadau M, Fernandez A, et al. IC351 enhances nitric oxide-

satisfactory erectile function after bilateral nerve sparing radical

mediated relaxation of human arterial and trabecular penile

prostatectomy? J Sex Med 2011;8:1210–7.

smooth muscle [abstract]. Diabetologia 2001;44:A295.

[15] Munding MD, Wessells HB, Dalkin BL. Pilot study of changes in

[24] Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Maylor AM.

stretched penile length 3 months after radical retropubic prosta-

Effects of sildenafil on the relaxation of human corpus cavernosum

tectomy. Urology 2001;58:567–9.

tissue in vitro and on the activities of cyclic nucleotide phosphodi-

[16] Rosen RC, Allen KR, Ni X, Araujo AB. Minimal clinically important differences in the erectile function domain of the International Index of Erectile Function scale. Eur Urol 2011;60:1010–6. [17] Araujo AB, Allen KR, Xiao N, Rosen RC. Minimal clinically important differences in the Vaginal Insertion and Successful Intercourse items of the Sexual Encounter Profile. J Sex Med 2012;9:169–79. [18] Machin D, Campbell MJ, Fayers P, Pinol A. Statistical tables for the design of clinical studies. ed. 3. Oxford, UK: Blackwell; 1998.

esterase isozymes. J Urol 1998;159:2164–71. [25] Vasconcelos JS, Figueiredo RT, Nascimento FL, Damia˜o R, da Silva EA. The natural history of penile length after radical prostatectomy: a long-term prospective study. Urology 2012;80:1293–6. [26] Mostafa ME, Senbel AM, Mostafa T. Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats. Urology 2013;81:1253–60. [27] Park K, Ryu KS, Li WJ, Kim SW, Paick JS. Chronic treatment with a

[19] Dmitrienko A, Bretz F, Westfall PH, et al. Multiple testing method-

type 5 phosphodiesterase inhibitor suppresses apoptosis of corpo-

ology. In: Dmitrienko A, Tamhane AC, Bretz F, editors. Multiple

ral smooth muscle by potentiating Akt signalling in a rat model of

testing problems in pharmaceutical statistics. New York, NY: Chapman and Hall/CRC Press; 2009. p. 35–98.

diabetic erectile dysfunction. Eur Urol 2008;53:1282–9. [28] Berookhim BM, Nelson CJ, Kunzel B, Mulhall JP, Narus JB. A Pro-

[20] Briganti A, Di Trapani E, Abdollah F, et al. Choosing the best

spective Analysis of Penile Length Changes Following Radical Pros-

candidates for penile rehabilitation after bilateral nerve-sparing

tatectomy. British J Urol Int. In press. http://dx.doi.org/10.1111/

radical prostatectomy. J Sex Med 2012;9:608–17.

bju.12443.

[21] Nelson CJ, Scardino PT, Eastham JA, Mulhall JP. Back to baseline:

[29] Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorpo-

erectile function recovery after radical prostatectomy from the

real smooth muscle after radical retropubic prostatectomy. J Urol

patients’ perspective. J Sex Med 2013;10:1636–43.

2004;171:771–4.