Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries

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1 european urology 55 (2009) available at journal homepage: Sexual Medicine for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries Jacques Buvat a, *, Fisseha Tesfaye b, Margaret Rothman c, David A. Rivas b, François Giuliano d a CETPARP/Le grand Hunier, Lille, France b Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA c Johnson & Johnson Pharmaceutical Services, L.L.C., Raritan, NJ, USA d AP-HP, Neuro-Urology-Andrology, Raymond Poincaré Hospital, Garches, France Article info Article history: Accepted January 13, 2009 Published online ahead of print on January 21, 2009 Keywords: Distress Intravaginal ejaculatory latency time Premature ejaculation Perceived control over ejaculation Selective serotonin reuptake inhibitor Abstract Background: is being developed for the on-demand treatment of premature ejaculation (PE). Previous clinical trials have demonstrated its safety and efficacy. Objective: To evaluate the long-term efficacy and safety of dapoxetine in men with PE. Design, setting, and participants: This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N = 1162) 18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for 6 mo, with an intravaginal ejaculatory latency time (IELT) 2 min in 75% of intercourse episodes at baseline. Intervention: 30 mg or dapoxetine 60 mg or placebo on demand (1 3 h before intercourse) for 24 wk. Measurements: Stopwatch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs). Results and limitations: The study was completed by 618 men. Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9 min, 3.2 min, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine versus placebo at week 12 and week 24 ( p < for all). The most common AEs were nausea, dizziness, diarrhea, and headache. AEs led to discontinuation in 1.3%, 3.9%, and 8.2% of subjects with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively. Limitations of this study included the exclusion of men who were not in long-term monogamous relationships. Conclusions: significantly improved all aspects of PE and was generally well tolerated in this broad population. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Centre ETPARP, 3, Rue Carolus, Lille, France. Tel ; Fax: address: jacques@buvat.org (J. Buvat) /$ see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 958 european urology 55 (2009) Introduction, a short-acting selective serotonin reuptake inhibitor (SSRI), is being developed for the asneeded (prn) treatment of premature ejaculation (PE). Because it is rapidly absorbed and eliminated after oral administration [1], dapoxetine is wellsuited to prn administration. Results from previous trials demonstrated significant improvements in intravaginal ejaculatory latency time (IELT), perceived control over ejaculation ( control ), satisfaction with sexual intercourse ( satisfaction ) [2], and ejaculation-related personal distress ( distress ) and interpersonal difficulty [3], which are components of the PE diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) [4]. 2. Patients and methods 2.1. Objective This trial evaluated the efficacy and safety of long-term (6 mo) treatment with prn dapoxetine 30 mg and dapoxetine 60 mg in men with PE in 22 countries Subjects Men 18 yr of age and in a stable monogamous relationship for 6 mo were eligible if they met the DSM-IV-TR criteria for PE for 6 mo, indicated at least moderate PE-related distress or interpersonal difficulty, and reported an IELT of 2 min in 75% of evaluable events during a 4-wk screening/baseline period. Subjects were not paid, but may have received travelexpense reimbursement. Exclusion criteria included history of medical or psychiatric illness; uncontrolled hypertension or cardiac impairment; medical events associated with the onset of PE; erectile dysfunction (ED; currently treated for ED or score <21 on the Erectile Function Domain of the International Index of Erectile Function [IIEF]) or other forms of sexual dysfunction; partner sexual dysfunction; known hypersensitivity to SSRIs or serotonin norepinephrine reuptake inhibitors; and concomitant use of SSRIs, tricyclic antidepressants, or other disallowed medications during the study. Other forms of PE therapy (pharmacologic or behavioral) were prohibited. Alcohol consumption was limited to two drinks per day Study design This randomized, double-blind, parallel-group, placebocontrolled trial was conducted at 130 centers in Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, the Czech Republic, Finland, France, Germany, Hungary, Israel, Italy, Mexico, the Netherlands, Norway, Poland, Portugal, South Africa, Spain, Sweden, and the United Kingdom. It consisted of a prerandomization phase (screening visit and 4-wk baseline period); a 24-wk double-blind treatment phase; and a 1-wk, randomized, double-blind withdrawal phase (results reported elsewhere [5]). During the treatment phase, subjects were randomized 1:1:1 to receive dapoxetine 30 mg or dapoxetine 60 mg or placebo using a computer-generated randomization schedule (assigned and coded using an interactive voice response system). Blind was not broken until all subjects had completed the study and the database had been finalized. Subjects took study medication 1 3 h before anticipated sexual intercourse and returned to the study site every 4 wk. Subjects were to report adverse events (AEs) when they occurred; AEs were actively solicited at each visit. The protocol was reviewed by each center s Institutional Review Board (IRB) in accordance with the Code of Federal Regulations and IRB policies and was conducted according to the guidelines for Good Clinical Practice. All participants provided signed written informed consent Outcome measures The primary end point was stopwatch-measured IELT (held by the partner), reported for each intercourse episode. Patient-reported outcome (PRO) measures included the Premature Ejaculation Profile (PEP) and clinical global impression of change (CGI; Table 1) [6,7]. Men and their partners completed the male and female versions of the PEP, respectively (partner results reported elsewhere [8]), and the CGI at baseline and at week 4, week 8, week 12, week 16, week 20, and week 24. A composite PRO definition of clinical benefit was applied based on the percentage of subjects achieving an increase of greater than or equal to two categories in control and a decrease of greater than or equal to one category in distress at week 12 and week 24. Other end points were the percentages of men with a decrease of greater than or equal to one category in distress or an increase of greater than or equal to one category in satisfaction Sample size determination A sample size of 258 subjects per treatment group (N = 774) provided 90% power (two-sided a = 0.05), to detect a 1-min difference in mean IELT between placebo and dapoxetine 60 mg (assuming a common standard deviation [SD] of 3.5 min) and a 25.9% difference between dapoxetine 60 mg and placebo on the composite PRO criterion. Assuming a 40% discontinuation rate (calculated based on 30% from previous 12-wk trials [standard error = 0.9%] and adding 10% to account for the longer study duration), target enrollment was 1300 subjects Safety assessments Safety was evaluated based on the incidence, severity, and type of AEs and withdrawals because of AEs. Holter monitoring (first dose; 10 min before to 3 h after), changes in clinical laboratory results (each 4-wk visit), and vital signs (from baseline to study end point) were also assessed. Known SSRI class effects were monitored at baseline and at week 4, week 12, and week 24 using the Beck Depression Inventory, IIEF,

3 european urology 55 (2009) Table 1 Outcome measures Outcome measure Question Scores and response options Premature Ejaculation Profile Perceived control over ejaculation Satisfaction with sexual intercourse Over the past month, was your control over ejaculation during sexual intercourse: Over the past month, was your satisfaction with sexual intercourse: 0: Very poor 1: Poor 2: Fair 3: Good 4: Very good 0: Not at all 1: A little bit 2: Moderately 3: Quite a bit 4: Extremely Personal distress related to ejaculation Interpersonal difficulty related to ejaculation Over the past month, how distressed were you by how fast you ejaculated during sexual intercourse? Over the past month, to what extent did how fast you ejaculated during sexual intercourse cause difficulty in your relationship with your partner? Clinical global impression of change in premature ejaculation Compared to the start of the study, would you describe your premature ejaculation problem as: 3: Much worse 2: Worse 1: Slightly worse 0: No change 1: Slightly better 2: Better 3: Much better Adapted with permission of John Wiley & Sons from Kaufman JM, et al. Treatment benefit of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial [published online ahead of print 18 November 2008]. BJU Int. doi: /j x x, available at [3]. Hamilton Anxiety Scale, Montgomery-Asberg Depression Rating Scale, and the Barnes Akathisia Rating Scale; results will be presented separately. Safety assessments from the withdrawal phase are reported elsewhere [5] Statistical analysis Average IELT (arithmetic mean; within-subject average of all IELT measurements over 4 wk) was compared between groups at week 12 and week 24 using the last postbaseline observation carried forward approach, with an analysis of covariance that included treatment effect, pooled center, and baseline average IELT (1 min vs >1 min) stratum as factors and baseline average IELT as a covariate. A fixedsequence stepwise multiple test procedure with a priori ordered hypotheses was used to control family-wise type I error. All tests were two-sided and conducted at the 5% significance level. A longitudinal analysis of average IELT was performed using a mixed-effects model with an unstructured variance covariance matrix that included treatment group, pooled center, baseline average IELT stratum, and treatment-by-time interaction as fixed effects and subject intercept and time as random effects. Given the recent emphasis on IELT in the diagnosis of PE (ie, IELT of about 1 min in the ISSM criteria) [9,10], IELT analyses included men with baseline IELT 2 min (a priori; all men), 1.0 min (a priori), and 0.5 min (post hoc). Geometric mean IELT (post hoc), a measure of central tendency, was calculated as the nth root of the product of all IELT measurements, where n is the number of IELT measurements. The geometric mean was obtained by first computing the arithmetic mean of the logarithmic transformed values of the IELT measurements, then using exponentiation to return to the original scale. Geometric means are always less than arithmetic means, unless all data points are the same value. Because it is less affected by outliers, some now recommend that geometric mean IELT be reported for all PE studies (discussed elsewhere [11]). Cochran-Mantel-Haenszel tests were used to evaluate differences between treatments at week 12 and week 24 in the rates of achieving a composite PRO-defined level of clinical benefit and in the CGI, with adjustment for baseline average IELT stratum and pooled center. Each PEP measure was compared between groups with an analysis of variance model that included factors for treatment group, pooled center, and baseline average IELT stratum. 3. Results 3.1. Subjects Of 1162 subjects randomized (December 2004 to October 2006), 53% completed the study (Fig. 1). Efficacy measures were analyzed using the intentto-treat principle. Baseline demographic and clinical characteristics were similar across groups (Table 2). Missing data result from lack of report by the subject Intravaginal ejaculatory latency time Mean average IELT was greater with dapoxetine than with placebo after the first dose and at all subsequent time points (all p 0.001; Fig. 2). Mean

4 960 european urology 55 (2009) Table 2 Baseline demographic and clinical characteristics Characteristic Placebo (n = 385) 30 mg (n = 388) 60 mg (n = 389) Age, yr Mean (SD) 40.1 (9.98) 39.6 (9.53) 40.5 (9.62) Race, n (%) White 317 (82) 331 (85) 331 (85) Black 6 (2) 4 (1) 5 (1) Asian 16 (4) 11 (3) 10 (3) Other 46 (12) 42 (11) 43 (11) Average IELT, min Mean (SD) 0.9 (0.51) 0.9 (0.50) 0.9 (0.49) Baseline average IELT stratum, n (%) 0.5 min 100 (26) 98 (25) 105 (27) 1 min 236 (62) 240 (62) 235 (61) >1 2 min 144 (38) 142 (37) 151 (39) >2 min 2 (1) 3 (1) 1 (<1) Missing values 3 (1) 3 (1) 2 (1) Perceived control over ejaculation, n (%) 0 (very poor) 178 (46) 192 (50) 197 (51) 1 (poor) 182 (48) 169 (44) 165 (42) 2 (fair) 22 (6) 23 (6) 25 (6) 3 (good) 1 (<1) 2 (1) 2 (1) 4 (very good) Missing 2 (1) 2 (1) 0 Satisfaction with intercourse, n (%) 0 (very poor) 83 (22) 82 (21) 72 (19) 1 (poor) 139 (36) 150 (39) 164 (42) 2 (fair) 113 (30) 108 (28) 112 (29) 3 (good) 41 (11) 37 (10) 34 (9) 4 (very good) 7 (2) 9 (2) 7 (2) Missing 2 (1) 2 (1) 0 Personal distress related to ejaculation, n (%) 0 (not at all) 3 (1) 6 (2) 4 (1) 1 (a little bit) 23 (6) 31 (8) 27 (7) 2 (moderately) 87 (23) 82 (21) 103 (26) 3 (quite a bit) 178 (46) 177 (46) 171 (44) 4 (extremely) 94 (24) 92 (24) 84 (22) Missing Interpersonal difficulty related to ejaculation, n (%) 0 (not at all) 73 (19) 85 (22) 76 (20) 1 (a little bit) 107 (28) 100 (26) 132 (34) 2 (moderately) 93 (24) 99 (26) 91 (23) 3 (quite a bit) 86 (22) 77 (20) 74 (19) 4 (extremely) 26 (7) 27 (7) 16 (4) Missing SD = standard deviation; IELT = intravaginal ejaculatory latency time. Percentages may not sum to 100% due to rounding. (SD) IELT increased significantly from 0.9 min at baseline to 1.9 min (SD = 2.89 min), 3.1 min (SD = 4.88 min), and 3.5 min (SD = 3.80 min) with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively, at the week 24 end point (both p < vs placebo; week 24 end point and change from baseline; Table 3). Similarly, geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively, at the week 24 end point (Table 3); geometric mean fold increases were 1.5, 2.5, and 3.3, respectively. Among men with baseline IELT 1 min and 0.5 min (Table 3), mean average and geometric IELT were significantly ( p < 0.05) greater with dapoxetine than with placebo at the week 24 end point; geometric mean fold increases were also significantly ( p < 0.001) higher with dapoxetine compared with placebo in these baseline IELT strata.

5 european urology 55 (2009) Fig. 1 Subject disposition Patient-reported outcomes All PEP measures improved significantly ( p < 0.001) with dapoxetine versus placebo beginning at week 4 (Fig. 3). Improvements from baseline in control and satisfaction were significantly greater with dapoxetine than with placebo at all time points ( p < 0.05). Changes from baseline in distress and interpersonal difficulty were significantly greater with dapoxetine than with placebo at most time points, including the week 24 end point ( p < 0.05). For the CGI measure, significantly more subjects receiving dapoxetine 30 mg and dapoxetine 60 mg reported that their PE was at least better (30.6% and 39.2%, respectively, vs 15.6% with placebo; Table 3) at the week 24 end point. Similar results were seen at week 12. Among men with baseline IELT of 1 min or 0.5 min, a significantly ( p < 0.05)

6 962 european urology 55 (2009) Fig. 2 Mean average intravaginal ejaculatory latency time (IELT) over time. SD = standard deviation; P = placebo. greater proportion reported that their PE was at least better with dapoxetine compared with placebo (Table 3) Assessment of treatment benefit More subjects met the composite PRO definition of clinical benefit with dapoxetine 30 mg and dapoxetine 60 mg than with placebo at the week 24 end point ( p < 0.001; Table 3). Similar results were seen at week 12 (27.3% and 34.0% with dapoxetine 30 mg and dapoxetine 60 mg, respectively, vs 12.1% with placebo; p < 0.001). More subjects met these criteria with dapoxetine versus placebo beginning at week 4 and continuing through week 24 ( p = for dapoxetine 30 mg vs placebo at week 16; p for all other comparisons). Previous analyses indicated that this composite definition is useful for assessing treatment benefit and corresponds with improvements in IELT, satisfaction, and the man s perception of his condition [12]. Among subjects from all treatment groups achieving this response at the week 24 end point, mean (SD) IELT was 5.98 (6.34) min (mean geometric fold increase, 5.08). Furthermore, 67.4% and 71.9% reported good or very good control and satisfaction, respectively, and 80.1% and 89.1% reported not at all or a little bit of distress and interpersonal difficulty, respectively. These outcomes approach those of men without PE from a European observational study [7], in which mean (SD) IELT was 10.0 (6.88 min), 78.4% and 91.6% reported good or very good control and satisfaction, respectively, and 68.2% and 91.3% reported not at all for distress and interpersonal difficulty, respectively. Significantly more subjects receiving dapoxetine 30 mg and dapoxetine 60 mg compared with placebo reported a decrease of greater than or equal to one category in distress at the week 12 (63.1% and 65.4%, respectively, vs 46.1% with placebo; p < for both) and week 24 end points (60.0% and 68.6%, respectively, vs 47.8% with placebo; p < for both; Table 3). Significantly more subjects experienced an increase of greater than or equal to one category in satisfaction following treatment with dapoxetine 30 mg or dapoxetine 60 mg than with placebo (48.5% and 55.8%, respectively, vs 35.7% with placebo; p < for both). Among men with a baseline IELT of 1 min or 0.5 min (Table 3), significantly ( p < 0.05) more men achieved composite PRO-defined clinical benefit with dapoxetine versus placebo at the week 24 end point. Similarly, significantly ( p < 0.05) more men in these groups achieved either a decrease of greater than or equal to one category in distress or an increase of greater than or equal to one category in satisfaction with dapoxetine than with placebo Safety Adverse events were reported by 38.4%, 56.2%, and 68.1% of men receiving placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively. Similar to previous studies [2], the most common treatmentemergent AEs with dapoxetine were nausea, dizziness, diarrhea, and headache (Table 4). Nausea with dapoxetine 30 mg and dapoxetine 60 mg was usually mild (69% and 62%, respectively) and intermittent. The most common AE leading to discontinuation was nausea (0.3%, 1.0%, and 2.6% with placebo,

7 Table 3 Outcomes in men with baseline IELT of =0.5 min, =1 min, and the overall population Outcome measure Baseline IELT 0.5 min Baseline IELT 1 min Overall population (IELT 2 min a ) Placebo 30 mg 60 mg Placebo 30 mg 60 mg Placebo 30 mg 60 mg Arithmetic mean IELT b n, baseline Mean (SD), baseline 0.3 (0.13) 0.3 (0.14) 0.3 (0.14) 0.5 (0.26) 0.6 (0.27) 0.5 (0.28) 0.9 (0.51) 0.9 (0.50) 0.9 (0.49) n, end point a Mean (SD), week 24 end point 0.8 (1.7) 1.5 (2.06) 1.8 (2.04) 1.3 (2.12) 2.5 (5.26) 2.8 (3.66) 1.9 (2.89) 3.1 (4.88) 3.5 (3.80) p value vs placebo < <0.001 <0.001 <0.001 Geometric mean IELT c n Mean (SE), baseline 0.3 (1.06) 0.3 (1.06) 0.2 (1.08) 0.5 (1.04) 0.5 (1.04) 0.4 (1.05) 0.7 (1.04) 0.7 (1.04) 0.7 (1.04) Mean (SE), week 24 end point 0.4 (1.11) 0.9 (1.13) 1.2 (1.11) 0.7 (1.07) 1.3 (1.07) 1.7 (1.07) 1.1 (1.06) 1.8 (1.06) 2.3 (1.06) p value vs placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Geometric Mean IELT fold increase at the week 24 end point c n Fold increase (SE) 1.5 (1.09) 3.4 (1.12) 5.0 (1.11) 1.5 (1.06) 2.8 (1.07) 3.9 (1.07) 1.5 (1.05) 2.5 (1.05) 3.3 (1.05) p value vs placebo <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Achieved composite PRO criteria for clinical benefit at the week 24 end point d Total n n (%) 6 (6.5) 19 (20.0) 32 (33.7) 18 (8.5) 49 (21.6) 74 (34.6) 45 (13.0) 91 (25.3) 131 (37.1) p value vs placebo <0.001 <0.001 <0.001 <0.001 <0.001 Achieved one-category increase in satisfaction with sexual intercourse at the week 24 end point e Total n n (%) 25 (26.6) 42 (44.2) 50 (52.6) 61 (28.6) 100 (44.1) 117 (54.7) 124 (35.7) 174 (48.5) 197 (55.8) p value vs placebo <0.001 <0.001 <0.001 <0.001 <0.001 Achieved one-category decrease in personal distress related to ejaculation at the week 24 end point f Total n n (%) 32 (34.4) 51 (53.7) 67 (70.5) 87 (40.8) 131 (57.7) 146 (68.2) 166 (47.8) 216 (60.0) 242 (68.6) p value vs placebo <0.001 <0.001 <0.001 <0.001 <0.001 Achieved a CGI rating of better or much better at the week 24 end point g Total n n (%) 7 (7.4) 17 (18.1) 31 (32.6) 22 (10.3) 57 (25.2) 75 (35.0) 54 (15.6) 110 (30.6) 138 (39.2) p value vs placebo <0.001 <0.001 <0.001 <0.001 <0.001 IELT = intravaginal ejaculatory latency time; SD = standard deviation; SE = standard error; PRO = patient-reported outcome; CGI = clinical global impression of change. a Includes all patients, based on the requirement to have IELT 2 min at screening; two (1%), three (1%), and one (<1%) patients in the placebo, dapoxetine 30 mg, and dapoxetine 60 mg groups, respectively, reported IELTs >2 min during the 4-wk baseline period. b Includes subjects in the intent-to-treat population, using the last postbaseline observation carried forward principle. c Includes only subjects who had both baseline and postbaseline average IELT values that are >0, using the last postbaseline observation carried forward principle. d Includes subjects who had both baseline and postbaseline measurements for both control over ejaculation and personal distress over ejaculation, using the last postbaseline observation carried forward principle. e Includes subjects who had both baseline and postbaseline measurements for satisfaction with sexual intercourse, using the last postbaseline observation carried forward principle. f Includes subjects who had both baseline and postbaseline measurements for personal distress related to ejaculation, using the last postbaseline observation carried forward principle. g Includes subjects who had at least one postbaseline measurement for clinical global impression of change, using the last postbaseline observation carried forward principle. european urology 55 (2009)

8 964 european urology 55 (2009) Fig. 3 Premature Ejaculation Profile results over time. Percentages of subjects reporting (a) good or very good control over ejaculation and (b) satisfaction with sexual intercourse or (c) moderately, quite a bit, or extremely in response to the item for personal distress related to ejaculation or (d) to the item for interpersonal difficulty related to ejaculation. P = placebo. dapoxetine 30 mg, and dapoxetine 60 mg, respectively). Serious AEs occurred in 1.0%, 0.8%, and 1.0% of subjects treated with dapoxetine 30 mg and dapoxetine 60 mg and placebo, respectively; most were judged by investigators as not related to treatment and resolved without sequelae. With dapoxetine 30 mg, ventricular tachycardia (mild; n = 1; 7 beats at 129 bpm, 1 unifocal ventricular ectopic beat) and transient ischemic attack (severe; n = 1) were con-

9 european urology 55 (2009) Table 4 Treatment-emergent adverse events occurring in I2% of subjects Adverse event Subjects, n (%) Placebo (n = 385) 30 mg (n = 388) 60 mg (n = 389) Total 148 (38.4) 218 (56.2) 265 (68.1) Nausea 11 (2.9) 64 (16.5) 119 (30.6) Headache 32 (8.3) 25 (6.4) 53 (13.6) Dizziness 10 (2.6) 30 (7.7) 52 (13.4) Diarrhoea 6 (1.6) 15 (3.9) 44 (11.3) Somnolence 4 (1.0) 15 (3.9) 28 (7.2) Insomnia 12 (3.1) 10 (2.6) 27 (6.9) Fatigue 8 (2.1) 22 (5.7) 26 (6.7) Nasopharyngitis 13 (3.4) 21 (5.4) 24 (6.2) Dry mouth 2 (0.5) 9 (2.3) 17 (4.4) Influenza 10 (2.6) 18 (4.6) 16 (4.1) Anxiety 2 (0.5) 11 (2.8) 12 (3.1) Blood pressure increased 1 (0.3) 2 (0.5) 12 (3.1) Erectile dysfunction 8 (2.1) 8 (2.1) 12 (3.1) Vomiting 2 (0.5) 5 (1.3) 12 (3.1) Dyspepsia 5 (1.3) 6 (1.5) 10 (2.6) Hyperhidrosis 2 (0.5) 7 (1.8) 10 (2.6) Abdominal pain 1 (0.3) 3 (0.8) 9 (2.3) Asthenia 1 (0.3) 9 (2.3) 4 (1.0) Back pain 6 (1.6) 8 (2.1) 4 (1.0) sidered possibly related to treatment. With dapoxetine 60 mg, one subject experienced sinus bradycardia and sinus arrest (both severe; very likely related to treatment) associated with syncope accompanied by loss of consciousness approximately 1 h after dosing on day 1 (prodromal symptom: nausea). Following this event, a protocol amendment required a modified consent form and new patient instructions for minimizing the risk of syncope. Another subject receiving dapoxetine 60 mg experienced syncope accompanied by a loss of consciousness on day 63. All events resolved spontaneously. Both syncope cases resulted in study discontinuation. No reports of syncope with loss of consciousness occurred with dapoxetine 30 mg. Excluding dizziness, cardiovascular AEs occurred in 3.1%, 4.9%, and 8.5% of subjects with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively. No clinically relevant effects on clinical laboratory tests were noted, nor was there any clear effect of dapoxetine on mean supine and standing blood pressure. Safety data from the withdrawal phase are reported elsewhere [5]; briefly, abrupt discontinuation of dapoxetine was not associated with withdrawal syndrome compared with placebo or continued treatment [5]. 4. Discussion This is the most comprehensive study of a pharmacologic treatment for PE conducted to date, including IELT and multiple validated PRO measures, which are significantly different between men with and without PE [7,13]. Arithmetic and geometric mean IELT, an objective measure of pharmacologic effects, confirmed that dapoxetine was superior to placebo regardless of the analysis used or baseline IELT stratum; however, these factors influenced the reported effect (eg, fold increase was inversely proportional to baseline IELT), highlighting the importance of analysis approach and population when comparing IELT data between studies. Because many factors influence IELT, the clinical relevance of PE treatments may best be evaluated using PROs that assess unobservable feelings known only to the man and his partner. All PRO measures improved significantly with dapoxetine versus placebo. Further, significantly more subjects receiving dapoxetine achieved a composite PRO-defined assessment of therapeutic benefit (an increase greater than or equal to two categories in control and a decrease of greater than or equal to one category in distress) compared with placebo, and among these men, improvements in IELT and PEP measures approached those of men without PE from a European observational study [7]. This composite definition of treatment benefit may be useful to clinicians because it captures changes in both patient functioning (control) and feeling (distress), rather than simply reporting a measure of biologic response (IELT). was generally well tolerated. Adverse events appeared early in treatment, were usually dose-dependent, generally did not lead to

10 966 european urology 55 (2009) discontinuation, and were consistent with previous reports [2]. The incidence of AEs was slightly higher than in previous studies (eg, nausea: 1.9%, 8.7%, and 20.1% [2] vs 2.9%, 16.5%, and 30.6% with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively, in the current study), likely because of the longer study duration. Nausea was the most common AE, consistent with previous reports. The incidence of serious AEs was low. Syncope was infrequent; similar events have occurred in other dapoxetine studies [2,3]. -related syncope appears to be vasovagal, benign, and manageable through educational efforts directed toward hydration and recognition of prodromal symptoms. While Holter monitoring was only conducted for 3 h on day 1; results from previous thorough QT studies demonstrated that dapoxetine 60 mg, 120 mg, and 240 mg had no electrocardiographic effects compared with placebo and moxifloxacin (a positive control) [14]. The DSM-IV-TR criteria for PE were utilized in this study, as it was conducted prior to the development of the new ISSM criteria [14]. Investigators categorized subjects as having lifelong or acquired PE; further investigation is needed to evaluate potential differences between these groups. Men with PE not in stable, monogamous relationships, homosexual men, and men with concomitant ED were excluded. Discontinuation was common (47%), but highest among subjects receiving placebo (51% vs 43% and 47% with dapoxetine 30 mg and dapoxetine 60 mg, respectively); factors contributing to discontinuation because of subject choice (24%) may include the long trial duration (6 mo), the burden of evaluations (stopwatch-measured IELT and more than five monthly questionnaires), and the reconsent. Geometric mean IELT analyses, which included subjects with both baseline and end point assessments, suggest that the discontinuation rate did not affect treatment outcomes. 5. Conclusions prolonged IELT, was well tolerated over 24 wk in men from a wide range of cultural backgrounds, and significantly improved all PROs, including control, satisfaction, distress, and interpersonal difficulty. A subset of men achieved composite PRO-defined clinical benefit, and these men reported IELTs and PRO responses that approached those of men without PE from an observational study [7]. These results demonstrate that the benefit of dapoxetine encompasses the overall and relational sexual experience. Author contributions: Jacques Buvat had full access to all of 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: Rivas, Rothman. Acquisition of data: Buvat, Giuliano. Analysis and interpretation of data: Buvat, Giuliano, Rothman, Rivas, Tesfaye. Drafting of the manuscript: Buvat, Giuliano, Rothman, Rivas, Tesfaye. Critical revision of the manuscript for important intellectual content: Buvat, Giuliano, Rothman, Rivas, Tesfaye. Statistical analysis: Tesfaye. Obtaining funding: Rivas. Administrative, technical, or material support: None. Supervision: None. Other (specify): None. Financial disclosures: I certify 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: Buvat and Giuliano are consultants and/or investigators for Johnson & Johnson. Rivas, Rothman, and Tesfaye are employees of Johnson & Johnson. This study was funded by Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ USA. Funding/Support and role of the sponsor: Johnson & Johnson Pharmaceutical Research & Development, LLC provided funding or other financial support and material support for this research and/or work that included the following: design and conduct of the study, management of the data, analysis, interpretation of the data, preparation, review, and approval of the manuscript. Acknowledgment statement: The authors acknowledge editorial support provided by Jason McDonough, PhD, of MedErgy. Trial Registration: Clinicaltrials.gov trial number NCT (available at References [1] Modi NB, Dresser MJ, Simon M, Lin D, Desai D, Gupta S. Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation. J Clin Pharmacol 2006;46: [2] Pryor JL, Althof SE, Steidle C, et al. Efficacy and tolerability of dapoxetine in the treatment of premature ejaculation: integrated analysis of two randomized, double-blind, placebo-controlled trials. Lancet 2006; 368:

11 european urology 55 (2009) [3] Kaufman JM, Rosen RC, Mudumbi RV, Tesfaye F, Hashmonay R, Rivas D. Treatment benefit of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial. BJU Int. In press. doi: /j x x. [4] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition, text revision. Washington, DC: American Psychiatric Association;2000. [5] Giuliano F, Levine SB, Buvat J, et al. Lack of withdrawal syndrome or effects on anxiety with dapoxetine (DPX) for the treatment of premature ejaculation (PE): results from 2 phase III trials [abstract]. Eur Urol Suppl 2008;7: 187. [6] Patrick DL, Althof SE, Pryor JL, et al. Premature ejaculation: an observational study of men and their partners. J Sex Med 2005;2: [7] Giuliano F, Patrick DL, Porst H, et al. Premature ejaculation: results from a five-country European observational study. Eur Urol 2008;53: [8] Brock G, Buvat J, Giuliano F, et al. Improvement in sexual satisfaction of female partners of men with premature ejaculation (PE) treated with dapoxetine (DPX) [abstract]. J Urol 2008;179: [9] McMahon CG, Althof S, Waldinger MD, et al. An evidencebased definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. BJU Int 2008;102: [10] McMahon CG. Clinical trial methodology in premature ejaculation observational, interventional, and treatment preference studies part II study design, outcome measures, data analysis, and reporting. J Sex Med 2008;5: [11] Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. Geometric mean IELT and premature ejaculation: appropriate statistics to avoid overestimation of treatment efficacy. J Sex Med 2008;5: [12] Shabsigh R, Patrick DL, Rowland DL, Bull SA, Tesfaye F, Rothman M. Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine. BJU Int 2008;102: [13] McKillop C. Interview with Dr Francois Giuliano. New avenues in the pharmacological treatment of premature ejaculation. Eur Urol 2007;52: [14] Modi NB, Nath R, Wang B, Rivas D, Gupta S. has no effects on hemodynamics or electrocardiographic assessments [abstract]. J Sex Med 2008;5:90 1. Editorial Comment on: for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries Emmanuele A. Jannini School of Sexology Department of Experimental Medicine, University of L Aquila, L Aquila, Italy emmanuele.jannini@univaq.it In this well-designed, randomised, double-blind, placebo-controlled multicentre study, Buvat and colleagues clearly demonstrate that dapoxetine is consistently effective in the treatment of premature ejaculation (PE) [1]. The safety profile is an important aspect of this study. The main limitation to the diffusion of offlabel treatment of PE by selective serotonin reuptake inhibitors (SSRIs) and other antidepressants has been the prevalence of side-effects. Due to its particularly short half-life, dapoxetine should have a better safety profile, leading to a risk benefit ratio definitively in favour of the benefits. In fact, dapoxetine was well tolerated in this study: Adverse events appeared early in treatment, were usually dose dependent, and generally did not lead to discontinuation. This is very important information for the clinician treating PE. A partial limitation of the study is that the experimental design does not distinguish between lifelong PE (LL-PE), considered to be neurobiologic and/or genetic in nature, and acquired PE (A-PE) [2], strongly correlated with various psychosocial and organic causes. LL-PE has only very recently been defined, and A-PE is still awaiting a shared definition due to the absence of evidence-based intravaginal ejaculation latency time in these patients. One may expect that dapoxetine, being a serotoninergic drug, is indicated only in patients with LL-PE who are affected by a hypothetic serotonin derangement; I believe that such is not the case. In my clinical experience, not all patients who are successfully treated for prostatitis [3] or hyperthyroidism [4] achieve good ejaculatory control. Many develop a secondary psychologic concern regarding their ability to delay ejaculation that needs counselling and, frequently, pharmacologic treatment with an SSRI. It is also well known that A-PE due to psychosocial aetiologies is often refractory to psychosexologic approaches such as behavioural therapies [5]. Future research may demonstrate that dapoxetine increases the efficacy of psychologic treatments, being effective not only in LL-PE but also in A-PE.

12 968 european urology 55 (2009) References [1] Buvat J, Tesfaye F, Rothman M, Rivas DA, Giuliano F. for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries. Eur Urol 2009;55: [2] Jannini EA, Lenzi A. Ejaculatory disorders: epidemiology and current approaches to definition, classification and subtyping. World J Urol 2005;23: [3] Screponi E, Carosa E, Di Stasi SM, Pepe M, Carruba G, Jannini EA. Prevalence of chronic prostatitis in men with premature ejaculation. Urology 2001;58: [4] Carani C, Isidori AM, Granata A, et al. Multicenter study on the prevalence of sexual symptoms in male hypoand hyperthyroid patients. J Clin Endocrinol Metab 2005;90: [5] Jannini EA, Simonelli C, Lenzi A. Sexological approach to ejaculatory dysfunction. Int J Androl 2002;25: DOI: /j.eururo DOI of original article: /j.eururo