Efficacy and Treatment Satisfaction with On-Demand Tadalafil (Cialis W )inmenwitherectiledysfunction

European Urology European Urology 46 (2004) 362 369 Efficacy and Treatment Satisfaction with On-Demand (Cialis W )inmenwitherectiledysfunction René Skoumal a, Juza Chen b, Krzysztof Kula c, Jan Breza d, Nicolae Calomfirescu e, Bruce R. Basson f, Vladimir Kopernicky f, a Urocentrum Brno, Brno, Czech Republic b Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv, Israel c Medical University of Lodz, Lodz, Poland d Urologicka Klinika Fnsp L. Derera, Bratislava, Slovak Republic e Uro-Andro-Med, Bucharest, Romania f Eli Lilly and Company, Area Medical Center Vienna, Eli Lilly Regional Operations, Barichgasse 40 42, 1030 Vienna, Austria Accepted 28 April 2004 Available online 31 May 2004 Abstract Objective: (Cialis 1 ) is an inhibitor of phosphodiesterase type 5, which mediates relaxation of vascular smooth muscle in the corpus cavernosum thus facilitating erection. The purpose of this multicentre, randomized, double-blind, parallel group, placebo-controlled study was to evaluate efficacy and treatment satisfaction of ondemand Cialis in men with mild-to-severe erectile dysfunction (ED). Methods: Following a 4-week treatment-free run in period, patients stratified into three severity groups by the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score were randomized to receive either placebo or Cialis 20 mg taken on demand over a 12-week period. Efficacy endpoints were change from baseline in IIEF EF domain scores, responses to Sexual Encounter Profile diary (SEP) questions, and responses to the Global Assessment Questions (GAQ). Treatment satisfaction was evaluated using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire in two of seven participating countries where validated translations were available. Results: Of the 443 men who entered the trial, 409 (mean age, 52 years) formed the intent-to-treat population. Mean baseline demographics and ED severity measures were balanced between treatment groups except for a higher percentage of patients naïve to sildenafil in the tadalafil group compared to placebo (50% versus 36%). The percentage of patients in each IIEF EF severity class (mild, moderate and severe) was 47%, 30% and 23% for placebo patients and 48%, 29% and 23% for tadalafil patients, respectively. was significantly superior to placebo on all primary efficacy measures (IIEF EF domain scores, SEP15, GAQ1; p < 0:001); notably 64% of tadalafil patients achieved a normal IIEF EF domain score at endpoint compared to 16% of placebo patients ( p < 0:001). Of the 185 patients completing the EDITS questionnaire (137 receiving Cialis and 48 receiving placebo), tadalafil-treated patients had a median EDITS score of 84 (95%CI 80, 86), which was significantly higher than the median score for placebo-treated patients of 41 (95%CI 32, 59; p < 0:001; Wilcoxon test). The proportion of patients satisfied with treatment (defined as final EDITS score greater than 50) was 87% for the tadalafil-treated group and 46% for the placebo-treated group (p < 0:001; exact test). Adverse events were significantly more common with tadalafil than placebo ( p < 0:01) and included primarily headache (7.2% versus 1.9%) and flushing (4.6% versus 0%). One patient discontinued tadalafil treatment due to back pain. Conclusion: In men with mild-to-severe ED, tadalafil 20 mg significantly improves erectile function, demonstrates superior treatment satisfaction relative to placebo, and is well tolerated. This is the first study to yield efficacy data Corresponding author. Tel. þ43 1 71178 605; Fax: þ43 1 71178 259. E-mail address: kopernicky@lilly.com (V. Kopernicky). 0302-2838/$ see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.04.026

R. Skoumal et al. / European Urology 46 (2004) 362 369 363 on tadalafil in an Eastern European population of men with erectile dysfunction, and the first to measure satisfaction with the EDITS questionnaire in any study population of men with this condition using tadalafil. # 2004 Elsevier B.V. All rights reserved. Keywords: ; Cialis 1 ; Erectile dysfunction; Patient satisfaction 1. Introduction Erectile dysfunction (ED) is defined by the National Institutes of Health as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance [1]. While published data is currently unavailable for prevalence of ED in Eastern European men, a number of studies have found that 19 to 55% of European males between the ages of 18 and 80 had some degree of ED [2], with the prevalence increasing with advancing age. The focus of ED therapy has turned to oral treatments in recent years, particularly those targeting phosphodiesterase type 5 (PDE-5). The first approved compound to inhibit PDE-5 was sildenafil, which has demonstrated efficacy and safety in clinical trials for ED [3,4]. More recently, the efficacy and safety of other inhibitors of PDE-5, tadalafil and vardenafil, have been established and reported [5]. Data presented thus far show that tadalafil is a safe and efficacious drug for the treatment of ED [6]. In particular, tadalafil is unique in its extended period of effectiveness. Porst et al. [7] have reported a greater proportion of successful intercourse attempts up to 36 hours post-tadalafil dose compared to placebo. A variety of medical, psychological and lifestyle factors have been implicated in the etiology of ED [8,9,2], leading to a negative impact on self-esteem, quality of life and interpersonal relationships [1]. Certainly, with the availability of an increasing variety of treatment options, patient satisfaction with treatment is arguably an important consideration in the maintenance of a particular treatment choice. This study was undertaken to evaluate the effect of on-demand tadalafil on efficacy, treatment satisfaction, and safety in a large population of men from Central and Eastern Europe and the Eastern Mediterranean with a broad range of functional severity and etiology of ED. 2. Methods 2.1. Study population This multicenter, randomized, double-blind, parallel, placebocontrolled study (H6D-VI-LVEQ) was conducted in accordance with Good Clinical Practice and International Conference on Harmonization guidelines, and conformed with the Declaration of Helsinki. Seven countries participated in the study including Czech Republic, Poland, Slovakia, Israel, Hungary, Lebanon and Romania. Written informed consent was obtained from all patients prior to the performance of any protocol-specific procedure. Men at least 18 years of age with a history of ED (defined as a consistent change in the quality of erection that adversely affects the patient s satisfaction with sexual intercourse) of at least three months were eligible for the study. All patients had to anticipate having the same female sexual partner throughout the study for consistency in recording responses to efficacy questionnaires. Patients presenting with ED of any functional severity (mild, moderate or severe) and of any etiological classification (psychogenic, organic or mixed) were eligible for enrollment. Disease etiology was defined subjectively according to each investigator s clinical opinion. Exclusion criteria were: ED caused by premature ejaculation or untreated endocrine disease; failure to achieve erection after pelvic surgery including radical prostatectomy (except bilateral nerve-sparing); significant penile deformity or penile implant; clinically significant renal or hepatic insufficiency; poorly controlled diabetes (hemoglobin A 1c >13%); unstable cardiovascular diseases (e.g. unstable angina, recent myocardial infarction or coronary intervention, evidence of congestive heart failure, new significant conduction defect, or uncontrolled hypertension); recent history of significant central nervous system injuries; and history of HIV infection. Exclusion of patients with prior ineffective treatment with sildenafil was at the discretion of the investigators. Concomitant use of other therapies for ED was not allowed. 2.2. Study design This study was powered based on the primary objective of efficacy, however it is unique in its comparison of both treatment satisfaction using the EDITS questionnaire and erectile function in patients treated with tadalafil and placebo. After signing informed consent and meeting inclusion criteria, patients began a 4-week treatment-free run-in period during which they were required to make at least 4 attempts at sexual intercourse. For all patients who reported previous ED treatment at baseline, the following question was asked: Has the treatment improved the patient s erections?. After the run-in period, patients meeting enrollment criteria continued in the study and baseline IIEF was measured. Patients were then stratified by the IIEF Erectile Function (EF) domain score (mild ED: 17, moderate ED: 11 16, and severe ED: 1 10) and geographic region, and randomly assigned within each severity group to treatment in a 3:1 (20 mg tadalafil: placebo) ratio. Visits to the physician took place at 4-week intervals over 12 weeks. Patients received 30 tablets of study medication at each visit except the final visit and were instructed to take a maximum of one tablet daily as needed. Efficacy was measured using the IIEF scale, which was culturally and linguistically validated for all participating countries [11], at each 4-weekly visit, and with the GAQ at the final visit or early discontinuation. The GAQ consisted of two questions: (1) Has the treatment you have been taking during this study improved your erections?, and (2) If yes, has the treatment improved your

364 R. Skoumal et al. / European Urology 46 (2004) 362 369 ability to engage in sexual activity? Patients also recorded efficacy information after each sexual encounter by answering 5 yes/no questions in their Sexual Encounter Profile (SEP) diaries. Of primary interest for this study were responses to SEP Question 2: Were you able to insert your penis into your partner s vagina? and SEP Question 3: Did your erection last long enough for you to have successful intercourse? Treatment satisfaction was assessed using the patient version of the EDITS questionnaire, a validated 11-item instrument to assess ED treatment satisfaction with a final score ranging from 0 (extremely low) to 100 (extremely high) [10]. The EDITS was administered to patients at the last visit or at early discontinuation in two of the seven participating countries (Czech Republic and Poland) where validated translations of the questionnaire were available. Vital signs and adverse events were recorded at each visit. 2.3. Data analysis 2.3.1. General Data were analyzed on an intent-to-treat (ITT) basis. Efficacy analyses included patients with baseline and at least one postbaseline measure. Endpoint analyses used each patient s last observed post-baseline value. Safety analyses included all ITT patients. All hypothesis testing was two-sided using the 0.05 level of significance, and 95% confidence intervals were used. The study had >90% power for the following effect sizes (ratio of treatment difference to standard deviation): IIEF ¼ 1.03, SEP2 ¼ 0.74, and SEP3 ¼ 0.97. Analyses were conducted using the SAS statistical package version 8.02 for windows (SAS Institute, Cary, NC, USA). 2.3.2. Imputation For total IIEF domain scores where <30% of individual questions were missing, the mean was imputed for missing responses but was set to missing if 30% of individual questions were missing. For SEP questions 1 5, a no on any question meant all subsequent questions were set to no for that encounter. 2.3.3. Disposition and safety Protocol completion rates and frequencies of adverse events were compared between treatments using exact tests. Vital signs were analyzed using repeated measures analysis with a term for treatment and an autoregressive covariance matrix. 2.3.4. Efficacy For IIEF domains, analysis of covariance (ANCOVA) models of last observation carried forward (LOCF), endpoint, and change from baseline included terms for baseline, treatment group, investigative site, and baseline-by-treatment-group interaction (if p-value <0.1). The percent of patients with IIEF EF scores <26 at baseline who reached a score 26 (lower limit of normal range) at endpoint were compared using exact tests. SEP percent success rates were calculated for each patient at baseline and post-baseline periods. Endpoint and change from baseline SEP scores were modeled using ANCOVA with baseline disease severity category (mild: IIEF EF 17; moderate: IIEF EF 11 16; and severe: IIEF EF 1 10), treatment, and the baseline disease severity by treatment group interaction. Stepwise logistic regression models were used to compare GAQ1 and 2 response rates between treatments (forward and backward selection; p < 0:10 to enter or stay; treatment always included). The investigated parameters included age, country, baseline disease severity, prior improvement with ED therapy, etiology, and baseline SEP2 and SEP3 severity. 2.3.5. Satisfaction EDITS scores were analyzed using an ANCOVA model specified using backwards selection ( p < 0:10 to stay; treatment always included). The parameters included age, country, baseline IIEF EF domain severity (mild: 17, moderate: 11 16, and severe: 1 10), baseline SEP2 and SEP3, etiology, prior sildenafil use, duration of ED, smoking, and alcohol consumption. Treatment by prior sildenafil use interaction was explicitly explored. Medians and the Wilcoxon signed-rank test between treatments were also reported due to the skewed distributions of final EDITS scores. Pearson s correlation coefficients were calculated between the average EDITS score and final IIEF score in each of the five domains (orgasmic function, erectile function, overall satisfaction, intercourse satisfaction, sexual desire). 3.Results 3.1. Subjects A total of 409 patients were randomized to treatment, 305 to tadalafil and 104 to placebo (mean age, 52 years; range, 21 82 years; Table 1). The two groups were well balanced for most baseline characteristics, including age, etiology, ED duration, and IIEF EF domain score class. However, a greater proportion of tadalafil patients were naïve to sildenafil compared to placebo patients. The number of patients in each IIEF EF severity class (mild, moderate and severe) was 47%, 30% and 23% for placebo patients and 48%, 29% and 23% for tadalafil patients, respectively. The number of patients who participated for each of the seven countries was as follows: Czech Republic: 128; Hungary: 51; Israel: 38; Lebanon: 36; Poland: 66; Romania: 31; Slovakia: 59. Ninety-five percent (290/305) of tadalafil-treated patients and 92% (96/ 104) of placebo-treated patients completed the study. Of the 23 discontinuations, 1 tadalafil and 0 placebo patients discontinued due to an adverse event, which was back pain ( p ¼ 1:000), while 5 placebo patients and 0 tadalafil patients discontinued due to lack of efficacy ( p ¼ 0:002). Other reasons for discontinuation included lost to follow-up (6 tadalafil, 2 placebo); patient decision (4 tadalafil, 1 placebo); and protocol violation (4 tadalafil). patients took significantly more doses during the study period than placebo patients (3.9 versus 2.9 doses per week for tadalafil and placebo, respectively; p < 0:001), despite similar time on the study (94.8 versus 92 days; p ¼ 0:091). 3.2. International Index of Erectile Function therapy significantly improved IIEF scores and resulted in significantly higher endpoint IIEF scores across all five IIEF domains: Erectile Function, Intercourse Satisfaction, Orgasmic Function, Sexual Desire

R. Skoumal et al. / European Urology 46 (2004) 362 369 365 Table 1 Baseline demographic and clinical characteristics Characteristic (n ¼ 104) 20mg(n ¼ 305) Age years (Mean with 95%CI) 52 (49, 54) 52 (51, 53) Etiology (n) Psychogenic 19 (18%) 46 (15%) Organic 29 (28%) 89 (29%) Mixed 56 (54%) 170 (56%) ED duration (n) <3 months 1 (1%) a 0 (0%) 3 to <6 months 10 (10%) 25 (8%) 6 to <1 year 10 (10%) 43 (14%) 1 year 83 (80%) 237 (78%) IIEF EF Score (Mean with 95%CI) 15.9 (14.8, 17.0) 15.3 (14.6, 15.9) IIEF EF Severity Class (n) 17 30 b 49 (47%) 145 (48%) 11 16 31 (30%) 89 (29%) 1 10 24 (23%) 71 (23%) Mean per patient yes response to SEP2 (% with 95%CI) 57 (50, 65) 53 (49, 57) Mean per patient yes response to SEP3 (% with 95%CI) 21 (18, 24) 25 (19, 31) Improvement with previous sildenafil treatment (n) Yes 66 (63%) 144 (47%) No 1 (1%) 8 (3%) No previous sildenafil treatment 37 (36%) 153 (50%) Improvement with any previous ED treatment (n) Yes 73 (70%) 159 (52%) No 4 (4%) 18 (6%) No previous ED treatment 27 (26%) 128 (42%) Pre-existing conditions (n) Hypertension 31 (30%) 98 (32%) Diabetes 9 (9%) 43 (14%) Prostatic hyperplasia/hypertrophy 11 (11%) 19 (6%) Hypercholesterolemia 9 (9%) 31 (10%) Hyperlipidemia 3 (3%) 16 (5%) a This patient was enrolled despite not fulfilling the inclusion/exclusion criteria. Since data were analyzed on an intent-to-treat basis, the patient was kept in the analysis. b Patients were included based on a history of erectile dysfunction (defined as a consistent change in the quality of erection that adversely affects the patient s satisfaction with sexual intercourse); erectile dysfunction was not based on IIEF scores. Subsequent assessment of erectile dysfunction by the IIEF at baseline revealed that a small proportion of patients, that is, 9/305 (3%) for tadalafil and 5/104 (5%) for placebo, had an erectile function domain score 26 or greater. and Overall Satisfaction, when compared to placebo ( p < 0:001, all; Table 2). Of the tadalafil-treated patients with baseline IIEF EF score <26, 64% (188/ 292) achieved a normal score (26) at endpoint, compared to 16% (16/97) of placebo patients ( p < 0:001) with significant differences seen across all baseline IIEF EF severity classes (mild, moderate and severe; Fig. 1). For IIEF Erectile Function Domain, previous sildenafil use was not a significant covariate and the inclusion of this term did not result in any significant adjustment of the results (no change for tadalafil; increase of 0.2 for placebo). 3.3. Sexual Encounter Profile -treated patients reported a significantly greater proportion of successful penetrations than placebo treated patients ( p < 0:001; SEP question 2, Fig. 2). Data adjusted for baseline severity class was 87% and 53% for tadalafil and placebo, respectively. -treated patients also reported a significantly greater proportion of successful intercourse completions than placebo-treated patients ( p < 0:001; SEP question 3, Fig. 2). Data adjusted for baseline severity class was 73% and 34% for tadalafil and placebo, respectively. For SEP2 and SEP3, adjusting for previous sildenafil use lead to only minor changes (1% and 2% increases in SEP2 and SEP3) in the placebo group. The results remained statistically significant. -treated patients had a significantly higher endpoint and a greater change from baseline compared to placebo for the remaining SEP questions related to achievement of an erection, satisfaction of erection

366 R. Skoumal et al. / European Urology 46 (2004) 362 369 Table 2 Mean IIEF domain scores Measure (n ¼ 102) 20mg (n ¼ 301) p-value Erectile function Baseline 16.0 (14.8, 17.1) 15.3 (14.7, 15.9) Endpoint 17.4 (15.9, 18.9) 25.1 (24.5, 25.8) <0.001 Change 1.4 (0.1, 2.8) 9.8 (9.0, 10.6) <0.001 Intercourse satisfaction Baseline 7.4 (6.9, 7.9) 7.3 (7.1, 7.6) Endpoint 8.8 (8.2, 9.4) 12.1 (11.8, 12.4) <0.001 Change 1.4 (0.8, 2.1) 4.7 (4.4, 5.1) <0.001 Orgasmic function Baseline 6.6 (6.1, 7.2) 6.3 (6.0, 6.7) Endpoint 6.9 (6.3, 7.4) 8.6 (8.4, 8.9) <0.001 Change 0.2 ( 0.4, 0.8) 2.3 (1.9, 2.6) <0.001 Sexual desire Baseline 6.6 (6.3, 6.9) 6.6 (6.4, 6.8) Endpoint 6.6 (6.3, 7.0) 7.7 (7.5, 7.9) <0.001 Change 0.0 ( 0.3, 0.4) 1.1 (0.9, 1.3) <0.001 Overall satisfaction Baseline 4.7 (4.3, 5.1) 4.4 (4.2, 4.6) Endpoint 5.4 (4.9, 5.9) 8.1 (7.8, 8.3) <0.001 Change 0.7 (0.2, 1.2) 3.7 (3.4, 4.0) <0.001 Data are means with 95%CI. p-values represent between-group comparisons. hardness and overall satisfaction with the sexual experience (SEP questions 1, 4 and 5; all p < 0:001). 3.4. Global Assessment Questions Of the tadalafil-treated men, 86% reported an improvement in their erections compared to 33% of placebo-treated men ( p < 0:001; GAQ question 1). Percentage of patients 80 60 40 20 0 26% 72% 10% 65% 17-25 11-16 1-10 Baseline IIEF EF Domain Score 9% Fig. 1. Percentage of patients achieving a normal IIEF EF Domain Score (26) at endpoint categorized by baseline ED severity (mild: 17 25; moderate: 11 16; severe: 1 10). Patients with an IIEF EF Domain Score of 26 at baseline are not included. p < 0:001 compared with patients receiving placebo. 49% Percentage of "Yes" Responses 100 80 60 40 20 0 Baseline Endpoint Baseline Endpoint Baseline Endpoint Baseline Endpoint SEP Question 2 SEP Question 3 Fig. 2. Comparison of placebo and tadalafil mean per patient yes responses for baseline and endpoint to SEP question 2 (successful intercourse insertions) and SEP question 3 (successful intercourse completions) after 12 weeks of treatment. Data are unadjusted means with 95%CI. p < 0:001 for endpoint comparison with placebo. Among patients with improved erectile function, 97% of tadalafil-treated patients and 94% of placebo-treated patients reported improved ability to engage in sexual activity ( p ¼ 0:279; GAQ question 2). This indicates that treatment improves erections relative to placebo, but of those patients who do achieve improvement in erection, the ability to engage in sexual activity is similar. 3.5. Treatment satisfaction Of the 185 patients completing the EDITS questionnaire (137 patients for tadalafil and 48 patients for placebo), tadalafil-treated patients had a median EDITS score of 84 (95%CI 80, 86), which was significantly higher than the median score of 41 for placebo patients (95%CI 32, 59; p < 0:001; Fig. 3). Overall, the proportion of patients satisfied with treatment (defined by Lewis et al. [12] as final EDITS score greater than 50) was 87% for the tadalafil-treated group and 46% for the placebo-treated group ( p < 0:001). The greater proportion of tadalafil patients satisfied with treatment compared to placebo Percentage of patients 40 35 30 25 20 15 10 5 Mean score = 46 Median score = 41 Mean score = 77 Median score = 84 0 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 EDITS Score Fig. 3. Distribution of unadjusted EDITS scores for placebo and tadalafiltreated patients after 12 weeks of treatment.

R. Skoumal et al. / European Urology 46 (2004) 362 369 367 Table 3 Patients with EDITS Score >50 by Disease Severity (n ¼ 48) (n ¼ 137) p-value Mild (17 30) 12 (50%) 63 (89%) <0.001 Moderate (11 16) 8 (53%) 37 (90%) 0.005 Severe (1 10) 2 (22%) 19 (76%) 0.013 patients was evident across ED severities ( p 0:013; Table 3). Previous sildenafil use had no effect on total EDITS scores in tadalafil-treated patients. However, in placebo-treated patients, the EDITS score was significantly lower in previous sildenafil users compared to sildenafil naïve ( p ¼ 0:028). This difference in EDITS scores associated with previous sildenafil treatment in placebo-treated patients was consistent across most of the EDITS questions, with the exception of question 3, How likely are you to continue using this treatment?, question 4, During the past four weeks, how easy was it for you to use this treatment? and question 10, How natural did the process of achieving an erection feel when you used this treatment over the past four weeks?. Correlation coefficients calculated between IIEF and EDITS scores showed that the IIEF Overall Satisfaction, Erectile Function, and Intercourse Satisfaction domain scores had the highest correlations with the EDITS (r ¼ 0:86, 0.84, and 0.80, respectively). Correlations between EDITS and Orgasmic Function (r ¼ 0:62) and Sexual Desire (r ¼ 0:55) domains were lower. 3.6. Safety The most common adverse events for tadalafil were headache (7.2%), flushing (4.6%), back pain (2.3%), influenza (2.0%), and nasal congestion (2.0%, Table 4), reflecting a significant difference between the tadalafil and placebo groups ( p < 0:01). Two tadalafil-treated patients reported serious adverse events (pulmonary embolism, subarachnoid hemorrhage), while none was reported by placebo-treated patients ( p ¼ 1:000). Both of these serious adverse events were considered by the treating physician not to be related to study drug. Table 4 Treatment emergent adverse events occurring in 2% of all patients Adverse event n (%) (n ¼ 104) 20 mg (n ¼ 305) Headache 2 (1.9) 22 (7.2) Flushing 0 (0.0) 14 (4.6) Back pain 1 (1.0) 7 (2.3) Influenza 0 (0.0) 6 (2.0) Nasal congestion 0 (0.0) 6 (2.0) One tadalafil-treated patient withdrew from the study due to back pain. Vital signs were not significantly different between treatment groups for the duration of the study. There were no deaths in this study. 4. Discussion The present study evaluated efficacy and treatment satisfaction of on-demand tadalafil in men with mildto-severe erectile dysfunction (ED). This large, multicenter trial, which encompassed the Czech Republic, Poland, Slovakia, Israel, Hungary, Lebanon and Romania, is the first to assess the efficacy of tadalafil on men with erectile dysfunction in these regions. Further, the study is also novel by being the first, using responses to EDITS, that provides data on patient satisfaction with use of tadalafil in any study population of men with ED. Based on analysis of IIEF, SEP, GAQ1, and EDITS, 12 weeks of treatment with tadalafil 20 mg significantly improved erectile function and produced superior treatment satisfaction relative to placebo in men with mildto-severe ED. As with previous investigations, tadalafil 20 mg was well tolerated. Based on the primary IIEF domain of Erectile Function, mean improvement with tadalafil was reflected by a greater than 8 point change in the IIEF EF domain score compared to placebo. This represents a notable change from baseline for the treated arm despite the relatively mild ED population that was enrolled; a smaller change from baseline might have been expected. These findings are consistent with previous investigations showing that tadalafil improves erectile function relative to placebo [13,14,6]. In addition, of the tadalafil-treated patients with baseline IIEF Erectile Function domain score <26, a significantly greater proportion achieved a normal score at endpoint compared to the placebo patients. For the other domains of IIEF, including Intercourse Satisfaction, Orgasmic Function, Sexual Desire, and Overall Satisfaction, tadalafil-treated patients had a significantly higher endpoint and a greater change from baseline across all domains compared to placebo. The significant improvement in erectile function was also supported by other efficacy measures. Increases in the proportion of positive responses to GAQ and SEP questions concerning patients improvement in erections, ability to penetrate their partner, and ability to maintain erection to successful completion of intercourse were significantly higher for tadalafil-treated patients compared to placebo-treated patients in the current study. To investigate whether the imbalance in prior sildenafil use between treatment groups influenced

368 R. Skoumal et al. / European Urology 46 (2004) 362 369 the results, we tested whether prior sildenafilusewasa significant covariate in the efficacy models. Adjusting for the imbalance in this parameter lead to only minor changes and did not affect the statistical or clinical significance of the findings. These results, in combination with those showing the observed mean improvements on the IIEF Erectile Function domain, provide further support for the efficacy of tadalafil in the treatment of ED. Patients receiving tadalafil had a significantly greater overall satisfaction score based on EDITS than those receiving placebo, which was evident across all degrees of ED severity. This superior treatment satisfaction relative to placebo corresponds to the significantly improved erectile function with tadalafil treatment, as measured by IIEF, SEP and GAQ. Furthermore, based on the SEP questions related to satisfaction of erection hardness and overall satisfaction with the sexual experience in this study, tadalafiltreated patients had a significantly higher endpoint and a greater change from baseline compared to placebo. In the study, previous sildenafil use had no effect on total EDITS scores in tadalafil-treated patients. Interestingly, in placebo-treated patients the EDITS score was significantly lower in previous sildenafil users compared to sildenafilnaïve. This difference in EDITS scores in placebo-treated patients based on previous sildenafil treatment was predominantly due to responses to questions related to overall satisfaction, treatment expectations, treatment timing, confidence, partner satisfaction and erection naturalness (questions 1, 2, 5 9 and 11). One explanation for the lower EDITS scores in these previously exposed placebo patients might be that the patients had previously experienced a therapeutic benefit from PDE-5 inhibition, and thus expected their assigned treatment to provide a similar benefit. Since the placebo response was modest in this study, these patients were not satisfied with the treatment. One limitation of this study is that, while seven countries participated, the EDITS questionnaire was only completed by Czech Republic and Poland since these were the only two countries to have validated translations of the questionnaire. However, this still amounted to a total of 185 patients for comparison. The discontinuation rates observed in the current investigation may also reflect superior patient satisfaction in tadalafil-treated patients compared to placebo. Overall, only 5% of patients receiving tadalafil discontinued for any reason compared with 8% of patients receiving placebo. More specifically, no patient receiving tadalafil discontinued due to lack of efficacy, compared to 5% of placebo-treated patients. In summary, tadalafil 20 mg taken as needed without restrictions on food intake, significantly restored erectile function, demonstrated superior treatment satisfaction relative to placebo, and was well tolerated following 12 weeks of treatment in men with ED across all degrees of severity. Acknowledgements The authors gratefully acknowledge the physicians who participated in this study; namely Drs. Ivo Prochazka, Milan Hora, Vaclav Chaloupka, Ondrej Trojan, Ales Horak, Pavel Navratil, Vladimir Student, Libor Zamecnik, Papp Gyorgy, Toth Csaba, Pajor Laszlo, Romics Imre, Gil Raviv, Itzhak Ben-Zion, Santiago Richter, George Ghazal, Sleiman Merhej, Selim Zeineh, Piotr Trypens, Andrzej Stoklosa, Krzysztof Bar, Zygmunt Dobrowolski, Tiberiu Mogos, Ioan Coman, Jan Vrabec, Ivan Kubis, and Martin Hrivnak. The authors acknowledge Jodie M. 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R. Skoumal et al. / European Urology 46 (2004) 362 369 369 [10] Althof SE, Corty EW, Levine SB, Levine F, Burnett AL, McVary K, et al. EDITS: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urology 1999;53:793 9. [11] Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822 30. [12] Lewis R, Bennett CJ, Borkon WD, Boykin WH, Althof SE, Stecher VJ, et al. Patient and partner satisfaction with Viagra (sildenafil citrate) treatment as determined by the erectile dysfunction inventory of treatment satisfaction questionnaire. Urology 2001;57:960 5. [13] Saenz de Tajada I, Knight JR, Anglin G, Emmick JT. Effects of tadalafil on rectile dysfunction in men with diabetes. Diabetes Care 2002;25:2159 64. [14] Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM, Rosen RC for the IC351 on-demand dosing study group. On-demand IC351 (Cialis TM ) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 2001;13:2 9. Editorial Comment F. Montorsi, Milan, Italy This is an interesting study confirming the efficacy and safety of tadalafil 20 mg used on demand by patients with ED of various severity and aetiology. In my experience there is no doubt that tadalafil ia a great drug and that many patients do appreciate its efficacy and tolerability profile and its peculiar pharmacokinetics. This study however, raises a few points that deserve some comments. 1. The dose used in this study is 20 mg and I agree that this the best dose for the majority of my patients. I usually suggest to use the 10 mg to patients with mild ED and to those with clear psychogenic ED. We should all be aware that starting treatment with the highest available dose goes against the information included in the spc of the drug but I do not really think that there are safety issues with the initial use of the 20 mg dose. I also often use the 5 or 10 mg doses in daily dosing regimens with very satisfactory results in many patients but this a different topic which I believe will become of major interest in the near future. 2. As in other studies, patient previously treated with sildenafil were enrolled by reading with care Table 1, it is clear to me that almost all these patients had responded to sildenafil. At present I would not expect a real failure to any PDE-5 inhibitor to respond to another agent of the same class. 3. Duration of side effects was not measured in this study. This is an information which is still lacking as none of the placebo controlled studies has addressed this issue. In my personal experience the duration of adverse events with tadalafil is not a real concern however I would encourage the company producing the drug to assess this parameter in future studies.