Dapoxitene Study

EURURO-2898; No of Pages 12
european urology xxx (2009) xxxxxx
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Sexual Medicine
Dapoxetine 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, Franc ois Giuliano d
a
CETPARP/Le grand Hunier, Lille, France Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA c Johnson & Johnson Pharmaceutical Services, L.L.C., Raritan, NJ, USA d Hospital, Garches, France AP-HP, Neuro-Urology-Andrology, Raymond Poincare
b
Article info Article history: Accepted January 13, 2009 Published online ahead of print on January 21, 2009 Keywords: Dapoxetine Distress Intravaginal ejaculatory latency time Premature ejaculation Perceived control over ejaculation Selective serotonin reuptake inhibitor
Abstract
Background: Dapoxetine 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 efcacy 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: Dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (13 h before intercourse) for 24 wk. Measurements: Stopwatch-measured IELT, Premature Ejaculation Prole (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 signicantly with dapoxetine versus placebo at week 12 and week 24 ( p < 0.001 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: Dapoxetine signicantly improved all aspects of PE and was generally well tolerated in this broad population. # 2009 Published by Elsevier B.V. on behalf of European Association of Urology.
* Corresponding author. Centre ETPARP, 3, Rue Carolus, 59000 Lille, France. Tel. +33 3 20 93 50 70; Fax: +33 3 20 93 98 46. E-mail address: jacques@buvat.org (J. Buvat).
0302-2838/$ see back matter # 2009 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eururo.2009.01.025
Please cite this article in press as: Buvat J, et al., Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries, Eur Urol (2009), doi:10.1016/j.eururo.2009.01.025
1.
Introduction
Dapoxetine, 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.
2.1.
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 nalized. Subjects took study medication 13 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 centers 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.
2.4.
Outcome measures
Patients and methods

Objective
This trial evaluated the efcacy and safety of long-term (6 mo) treatment with prn dapoxetine 30 mg and dapoxetine 60 mg in men with PE in 22 countries.
2.2.
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 difculty, 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.
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 Prole (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 denition of clinical benet 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.
2.5.
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.
2.3.
Study design 2.6. Safety assessments
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,
Safety was evaluated based on the incidence, severity, and type of AEs and withdrawals because of AEs. Holter monitoring (rst 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,
Table 1 Outcome measures Outcome measure

Premature Ejaculation Prole Perceived control over ejaculation Satisfaction with sexual intercourse Personal distress related to ejaculation Interpersonal difculty related to ejaculation
Question
Over the past month, was your control over ejaculation during sexual intercourse: Over the past month, was your satisfaction with sexual intercourse: 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 difculty in your relationship with your partner? Compared to the start of the study, would you describe your premature ejaculation problem as:
Scores and response options

0: 1: 2: 3: 4: 0: 1: 2: 3: 4: Very poor Poor Fair Good Very good Not at all A little bit Moderately Quite a bit Extremely
Clinical global impression of change in premature ejaculation
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 benet of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial [published online ahead of print 18 November 2008]. BJU Int. doi:10.1111/j.1464-410X.2008.08165.x, available at http://www3.interscience.wiley.com/journal/119816734/grouphome/home.html [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].
2.7.
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 xedsequence 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% signicance level. A longitudinal analysis of average IELT was performed using a mixed-effects model with an unstructured variancecovariance matrix that included treatment group, pooled center, baseline average IELT stratum, and treatment-by-time interaction as xed 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 rst 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-dened level of clinical benet 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.
3.1.
Results
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.
3.2. 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
Table 2 Baseline demographic and clinical characteristics Characteristic

Age, yr Mean (SD) Race, n (%) White Black Asian Other Average IELT, min Mean (SD)
Placebo (n = 385)
40.1 (9.98)
Dapoxetine 30 mg (n = 388)
39.6 (9.53)
40.5 (9.62)
317 6 16 46
(82) (2) (4) (12)
331 4 11 42
(85) (1) (3) (11)
331 5 10 43
(85) (1) (3) (11)
0.9 (0.51)
0.9 (0.50)
0.9 (0.49)
Baseline average IELT stratum, n (%) 0.5 min 100 (26) 1 min 236 (62) >12 min 144 (38) >2 min 2 (1) Missing values 3 (1) Perceived control over ejaculation, n (%) 0 (very poor) 178 (46) 1 (poor) 182 (48) 2 (fair) 22 (6) 3 (good) 1 (<1) 4 (very good) 0 Missing 2 (1) Satisfaction with intercourse, n (%) 0 (very poor) 83 (22) 1 (poor) 139 (36) 2 (fair) 113 (30) 3 (good) 41 (11) 4 (very good) 7 (2) Missing 2 (1) Personal distress related to ejaculation, n (%) 0 (not at all) 3 (1) 1 (a little bit) 23 (6) 2 (moderately) 87 (23) 3 (quite a bit) 178 (46) 4 (extremely) 94 (24) Missing 0 Interpersonal difculty related to ejaculation, n (%) 0 (not at all) 73 (19) 1 (a little bit) 107 (28) 2 (moderately) 93 (24) 3 (quite a bit) 86 (22) 4 (extremely) 26 (7) Missing 0 SD = standard deviation; IELT = intravaginal ejaculatory latency time. Percentages may not sum to 100% due to rounding.
98 240 142 3 3
(25) (62) (37) (1) (1)
105 235 151 1 2
(27) (61) (39) (<1) (1)
192 169 23 2 0 2
(50) (44) (6) (1) (1)
197 165 25 2 0 0
(51) (42) (6) (1)
82 150 108 37 9 2
(21) (39) (28) (10) (2) (1)
72 164 112 34 7 0
(19) (42) (29) (9) (2)
6 31 82 177 92 0
(2) (8) (21) (46) (24)
4 27 103 171 84 0
(1) (7) (26) (44) (22)
85 100 99 77 27 0
(22) (26) (26) (20) (7)
76 132 91 74 16 0
(20) (34) (23) (19) (4)
(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 < 0.001 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.
Fig. 1 Subject disposition.
3.3.
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)
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).
3.4. 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 = 0.003 for dapoxetine 30 mg vs placebo at week 16; p 0.001 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 mans 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 < 0.001 for both) and week 24 end points (60.0% and 68.6%, respectively, vs 47.8% with placebo; p < 0.001 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 < 0.001 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.
3.5. 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,
Table 3 Outcomes in men with baseline IELT of =0.5 min, =1 min, and the overall population
Outcome measure Placebo Baseline IELT 0.5 min Dapoxetine 30 mg Dapoxetine 60 mg Placebo Baseline IELT 1 min Dapoxetine 30 mg Dapoxetine 60 mg Overall population (IELT 2 mina) Placebo Dapoxetine 30 mg Dapoxetine 60 mg
Arithmetic mean IELTb n, baseline Mean (SD), baseline n, end point Mean (SD), week 24 end point p value vs placebo Geometric mean IELTc n Mean (SE), baseline Mean (SE), week 24 end point p value vs placebo
100 0.3 (0.13) 91 0.8 (1.7)
98 0.3 (0.14) 94 1.5 (2.06) 0.019
105 0.3 (0.14) 98 1.8 (2.04) <0.001
236 0.5 (0.26) 210 1.3 (2.12)
240 0.6 (0.27) 226 2.5 (5.26) 0.002
235 0.5 (0.28) 216 2.8 (3.66) <0.001
382 0.9 (0.51) 339 1.9 (2.89)
385 0.9 (0.50) 363 3.1 (4.88) <0.001
387 0.9 (0.49) 355a 3.5 (3.80) <0.001
88 0.3 (1.06) 0.4 (1.11)
86 0.3 (1.06) 0.9 (1.13) <0.001
94 0.2 (1.08) 1.2 (1.11) <0.001
205 0.5 (1.04) 0.7 (1.07)
218 0.5 (1.04) 1.3 (1.07) <0.001
212 0.4 (1.05) 1.7 (1.07) <0.001
332 0.7 (1.04) 1.1 (1.06)
355 0.7 (1.04) 1.8 (1.06) <0.001
350 0.7 (1.04) 2.3 (1.06) <0.001
Geometric Mean IELT fold increase at the week 24 end pointc n 88 Fold increase (SE) 1.5 (1.09) p value vs placebo
86 3.4 (1.12) <0.001
94 5.0 (1.11) <0.001
205 1.5 (1.06)
218 2.8 (1.07) <0.001
212 3.9 (1.07) <0.001
332 1.5 (1.05)
355 2.5 (1.05) <0.001
350 3.3 (1.05) <0.001
Achieved composite PRO criteria for clinical benet at the week 24 end pointd Total n n (%) p value vs placebo 93 6 (6.5) 95 19 (20.0) 0.024 95 32 (33.7) <0.001 212 18 (8.5) 227 49 (21.6) <0.001 214 74 (34.6) <0.001 346 45 (13.0) 359 91 (25.3) <0.001 353 131 (37.1) <0.001
Achieved one-category increase in satisfaction with sexual intercourse at the week 24 end pointe Total n 94 95 95 n (%) 25 (26.6) 42 (44.2) 50 (52.6) p value vs placebo 0.017 <0.001 Achieved one-category decrease in personal distress related to ejaculation at the week 24 end pointf Total n n (%) p value vs placebo 93 32 (34.4) 95 51 (53.7) 0.016 95 67 (70.5) <0.001
213 61 (28.6)
227 100 (44.1) <0.001
214 117 (54.7) <0.001
347 124 (35.7)
359 174 (48.5) <0.001
353 197 (55.8) <0.001
213 87 (40.8)
227 131 (57.7) <0.001
214 146 (68.2) <0.001
347 166 (47.8)
360 216 (60.0) <0.001
353 242 (68.6) <0.001
Achieved a CGI rating of better or much better at the week 24 end pointg Total n 94 94 n (%) 7 (7.4) 17 (18.1) p value vs placebo 0.048
95 31 (32.6) <0.001
214 22 (10.3)
226 57 (25.2) <0.001
214 75 (35.0) <0.001
347 54 (15.6)
359 110 (30.6) <0.001
352 138 (39.2) <0.001
IELT = intravaginal ejaculatory latency time; SD = standard deviation; SE = standard error; PRO = patient-reported outcome; CGI = clinical global impression of change. 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.
a
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-
Table 4 Treatment-emergent adverse events occurring in I2% of subjects Adverse event Placebo (n = 385)
Total Nausea Headache Dizziness Diarrhoea Somnolence Insomnia Fatigue Nasopharyngitis Dry mouth Inuenza Anxiety Blood pressure increased Erectile dysfunction Vomiting Dyspepsia Hyperhidrosis Abdominal pain Asthenia Back pain 148 11 32 10 6 4 12 8 13 2 10 2 1 8 2 5 2 1 1 6 (38.4) (2.9) (8.3) (2.6) (1.6) (1.0) (3.1) (2.1) (3.4) (0.5) (2.6) (0.5) (0.3) (2.1) (0.5) (1.3) (0.5) (0.3) (0.3) (1.6)
Subjects, n (%) Dapoxetine 30 mg (n = 388)

218 64 25 30 15 15 10 22 21 9 18 11 2 8 5 6 7 3 9 8 (56.2) (16.5) (6.4) (7.7) (3.9) (3.9) (2.6) (5.7) (5.4) (2.3) (4.6) (2.8) (0.5) (2.1) (1.3) (1.5) (1.8) (0.8) (2.3) (2.1)
265 119 53 52 44 28 27 26 24 17 16 12 12 12 12 10 10 9 4 4 (68.1) (30.6) (13.6) (13.4) (11.3) (7.2) (6.9) (6.7) (6.2) (4.4) (4.1) (3.1) (3.1) (3.1) (3.1) (2.6) (2.6) (2.3) (1.0) (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). Dapoxetine was generally well tolerated. Adverse events appeared early in treatment, were usually dose-dependent, generally did not lead to
10
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]. Dapoxetine-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.
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 conicts of interest, including specic nancial interests and relationships and afliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/afliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents led, 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 nancial 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 NCT00229073 (available at www.clinicaltrials.gov).
5.
Conclusions
Dapoxetine 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.
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;46:3019. [2] Pryor JL, Althof SE, Steidle C, et al. Efcacy and tolerability of dapoxetine in the treatment of premature ejaculation: integrated analysis of two randomized, double-blind, placebo-controlled trials. Lancet 2006; 368:92937.
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[3] Kaufman JM, Rosen RC, Mudumbi RV, Tesfaye F, Hashmonay R, Rivas D. Treatment benet of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial. BJU Int. In press. doi:10.1111/j.1464410X.2008.08165.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;2:35867. [7] Giuliano F, Patrick DL, Porst H, et al. Premature ejaculation: results from a ve-country European observational study. Eur Urol 2008;53:104857. [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;179:4312.
[9] McMahon CG, Althof S, Waldinger MD, et al. An evidencebased denition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Denition of Premature Ejaculation. BJU Int 2008;102:33850. [10] McMahon CG. Clinical trial methodology in premature ejaculation observational, interventional, and treatment preference studiespart IIstudy design, outcome measures, data analysis, and reporting. J Sex Med 2008;5:181733. [11] Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. Geometric mean IELT and premature ejaculation: appropriate statistics to avoid overestimation of treatment efcacy. J Sex Med 2008;5:4929. [12] Shabsigh R, Patrick DL, Rowland DL, Bull SA, Tesfaye F, Rothman M. Perceived control over ejaculation is central to treatment benet in men with premature ejaculation: results from phase III trials with dapoxetine. BJU Int 2008;102:8248. [13] McKillop C. Interview with Dr Francois Giuliano. New avenues in the pharmacological treatment of premature ejaculation. Eur Urol 2007;52:12547. [14] Modi NB, Nath R, Wang B, Rivas D, Gupta S. Dapoxetine has no effects on hemodynamics or electrocardiographic assessments [abstract]. J Sex Med 2008;5:901.
Editorial Comment on: Dapoxetine 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 LAquila, 67100 LAquila, 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 riskbenefit 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.
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References
[1] Buvat J, Tesfaye F, Rothman M, Rivas DA, Giuliano F. Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries. Eur Urol. In press. doi:10.1016/j.eururo.2009.01.025. [2] Jannini EA, Lenzi A. Ejaculatory disorders: epidemiology and current approaches to denition, classication and subtyping. World J Urol 2005;23:6875. [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: 198202. [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;90:64729. [5] Jannini EA, Simonelli C, Lenzi A. Sexological approach to ejaculatory dysfunction. Int J Androl 2002;25:31723.
DOI: 10.1016/j.eururo.2009.01.026 DOI of original article: 10.1016/j.eururo.2009.01.025

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EURURO-2898; No of Pages 12

european urology xxx (2009) xxxxxx

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

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Patients and methods

Sample size determination

Study design 2.6. Safety assessments

Table 1 Outcome measures Outcome measure

Scores and response options

Clinical global impression of change in premature ejaculation

european urology xxx (2009) xxxxxx

Table 2 Baseline demographic and clinical characteristics Characteristic

(82) (2) (4) (12)

(85) (1) (3) (11)

(85) (1) (3) (11)

(25) (62) (37) (1) (1)

105 235 151 1 2

(27) (61) (39) (<1) (1)

(50) (44) (6) (1) (1)

(51) (42) (6) (1)

(21) (39) (28) (10) (2) (1)

(19) (42) (29) (9) (2)

(2) (8) (21) (46) (24)

(1) (7) (26) (44) (22)

(22) (26) (26) (20) (7)

(20) (34) (23) (19) (4)

Fig. 1 Subject disposition.

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100 0.3 (0.13) 91 0.8 (1.7)

98 0.3 (0.14) 94 1.5 (2.06) 0.019

105 0.3 (0.14) 98 1.8 (2.04) <0.001

236 0.5 (0.26) 210 1.3 (2.12)

240 0.6 (0.27) 226 2.5 (5.26) 0.002

235 0.5 (0.28) 216 2.8 (3.66) <0.001

382 0.9 (0.51) 339 1.9 (2.89)

385 0.9 (0.50) 363 3.1 (4.88) <0.001

387 0.9 (0.49) 355a 3.5 (3.80) <0.001

88 0.3 (1.06) 0.4 (1.11)

86 0.3 (1.06) 0.9 (1.13) <0.001

94 0.2 (1.08) 1.2 (1.11) <0.001

205 0.5 (1.04) 0.7 (1.07)

218 0.5 (1.04) 1.3 (1.07) <0.001

212 0.4 (1.05) 1.7 (1.07) <0.001

332 0.7 (1.04) 1.1 (1.06)

355 0.7 (1.04) 1.8 (1.06) <0.001

350 0.7 (1.04) 2.3 (1.06) <0.001

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86 3.4 (1.12) <0.001

94 5.0 (1.11) <0.001

205 1.5 (1.06)

218 2.8 (1.07) <0.001

212 3.9 (1.07) <0.001

332 1.5 (1.05)

355 2.5 (1.05) <0.001

350 3.3 (1.05) <0.001

227 100 (44.1) <0.001

214 117 (54.7) <0.001

347 124 (35.7)

359 174 (48.5) <0.001

353 197 (55.8) <0.001

227 131 (57.7) <0.001

214 146 (68.2) <0.001

347 166 (47.8)

360 216 (60.0) <0.001