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

doi:10.1016/j.eururo.2009.01.025

European Urology

Volume 55, Issue 4, April 2009, Pages 957-968

https://doi.org/10.1016/j.eururo.2009.01.025 Get rights and content

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 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

Dapoxetine 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 < 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 significantly improved all aspects of PE and was generally well tolerated in this broad population.

Introduction

Dapoxetine, a short-acting selective serotonin reuptake inhibitor (SSRI), is being developed for the as-needed (prn) treatment of premature ejaculation (PE). Because it is rapidly absorbed and eliminated after oral administration [1], dapoxetine is well-suited 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].

Section snippets

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

Subjects

Of 1162 subjects randomized (December 2004 to October 2006), 53% completed the study (Fig. 1). Efficacy measures were analyzed using the intent-to-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 (SD) IELT increased significantly from 0.9

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

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

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Cited by (177)

The Unfinished Business of Defining Premature Ejaculation: The Need for Targeted Research
2022, Sexual Medicine Reviews
Fifteen years have passed since the International Society of Sexual Medicine first established the 3-pronged criteria for premature ejaculation (PE): a short ejaculation latency, lack of ejaculatory control, and bother/distress. Although the process of establishing valid criteria for any condition or disorder is an ongoing one, a dearth of targeted research on these criteria has hindered professional societies from updating and revising them.
To review and critique existing criteria used in the diagnosis of PE, to identify specific problems with them, and to recommend studies that will address shortcomings.
Each of the PE criteria was evaluated and compared against standard procedures for establishing validated measures. Following each analysis, targeted research to address the gaps has been recommended.
Each PE criterion has shortcomings and each can be improved by using standard validation procedures, as noted by the targeted research outcomes. Professional societies can play an important role by encouraging broad participation in research that generates new and relevant data supporting, validating, or challenging the existing criteria.
The concepts underlying the diagnostic criteria for PE have both broad consensus and functional utility. Nevertheless, much of the research investigating PE has uncritically adopted these criteria without concomitantly recognizing their limitations. These limitations prevent determining accurate prevalence rates, interpreting research findings with confidence, and establishing efficacious treatment outcomes.
Rowland DL, Althof SE, McMahon CG. The Unfinished Business of Defining Premature Ejaculation: The Need for Targeted Research. Sex Med Rev 2022;10:323–340.
Efficacy of Dapoxetine in the Treatment of Patients With Lifelong Premature Ejaculation as an Alternative to Sertraline Therapy
2022, Sexual Medicine
Before dapoxetine was approved for the treatment of lifelong premature ejaculation (LPE) in China, daily dosing with off-label sertraline was common.
To investigate the efficacy of dapoxetine in the treatment of patients with LPE as an alternative to sertraline therapy.
This prospective study included LPE patients who previously attempted treatment with sertraline and who agree to receive dapoxetine therapy in our hospital from January 2020 to March 2021. Patients who received any PE therapy in the two months prior to the dapoxetine therapy were excluded. All patients received dapoxetine 30 mg (taken 1–3 hours before sexual intercourse) for 12 weeks, and they were not taking sertraline during the trial.
Data on their intravaginal ejaculatory latency time and premature ejaculation profile were recorded before and after the dapoxetine treatment. Clinical Global Impression of Change scores and data on Treatment-Emergent adverse events were collected after treatment.
A total of 144 patients with LPE completed this study; including 64 patients who reported that previous sertraline treatment was satisfactory (group A) and 80 patients for whom previous sertraline therapy was unsatisfactory in treating PE (group B). Both groups experienced significantly increased intravaginal ejaculatory latency time. Dapoxetine therapy was reported satisfactory by 67.5% of patients with LPE in whom sertraline therapy unsatisfactory according to their Clinical Global Impression of Change score, which was not different from those who reported this result in group A (62.5%). Similar outcomes were also reported for premature ejaculation profile and treatment-emergent adverse events.
: Although both dapoxetine and sertraline are selective serotonin re-uptake inhibitors, dapoxetine therapy is satisfactory in 67.5% of patients with LPE in whom sertraline treatment unsatisfactory, and the effect of dapoxetine was independent of the effect of sertraline.
Liu G, Yin Y, Zhang L. et al., Efficacy of Dapoxetine in the Treatment of Patients With Lifelong Premature Ejaculation as an Alternative to Sertraline Therapy. Sex Med 2021;10:100473.
Advances and Missteps in Diagnosing Premature Ejaculation: Analysis and Future Directions
2022, Journal of Sexual Medicine
There are several problems with diagnostic criteria for premature ejaculation (PE) that lack objectivity, clarity and precision. They hamper accurate determination of PE prevalence estimates, investigations into the etiology of the dysfunction, impact on partners, development of validated Patient Reported Outcomes, regulatory authority oversight, and which men might benefit from specific treatment interventions.
We sought to review, analyze and comment on the evolution of the definitions of PE and offer suggestions for future directions for PE definitions. Our goal is to propose strategies whereby the criterion sets are useful to researchers, clinicians and governmental oversight agencies alike and bring harmony and scientific rigor among the conflicting and confusing definitions.
There are several premature ejaculation definitions published in the peer reviewed medical literature. The PUBMED electronic database from 1970 to 2021 was searched for published definitions. Search terms included the medical subject headings of premature ejaculation, definition and diagnosis. In chronological order, Table 1 lists the various diagnosis and criteria sets for PE. We discuss the process by which constructs, which make up diagnostic criteria sets, are operationalized and validated.
We review definitions of PE beginning with Masters and Johnson's focus on partner orgasmic attainment and move through the nebulous and subjective criterion sets found in the early Diagnostic and Statistical Manuals and International Classification of Disease series, to the more evidenced-based definitions found in International Society of Sexual Medicine, Diagnostic and Statistical Manuals-5 and the American Urological Association (AUA) definitions. Additionally, we discuss how constructs and criteria sets have been adopted to minimize errors of inclusion and exclusion in defining disease/dysfunction.
This manuscript offers a careful chronological analysis of the published definitions of PE. This historical lens allows the reader to perceive the shifting science underlying the development of PE definitions. The manuscript is limited regarding our comments on acquired PE as evidenced-based research is incomplete.
Over the past 50 years there has been considerable forward momentum in defining PE based on well conducted scientific studies. We support the American Urological Association's modification in Intravaginal ejaculatory latency time to 2-minutes for lifelong PE, concur with the 11th revision of the International Classification of Diseases recommendation for changing the terminology from premature ejaculation to early ejaculation. We also recommend ongoing validation of definitions, moving away from the current heterosexist definition of PE based on penile-vaginal sex and urge further population based research into acquired PE to develop stronger evidenced-based criterion sets for this subtype.
Althof SE, McMahon CG, Rowland DL. Advances and Missteps in Diagnosing Premature Ejaculation: Analysis and Future Directions. J Sex Med 2022;19:64–73.
Compliance With Fluoxetine Use in Men With Primary Premature Ejaculation
2019, Journal of Sexual Medicine
Premature ejaculation (PE) is a common sexual dysfunction for which selective serotonin reuptake inhibitors (SSRIs) have been used effectively for treatment. However, compliance with therapy and predictors of long-term SSRI use in the treatment of PE are not well known.
To analyze our experience with drop-out rates with fluoxetine in the primary PE population and to identify predictors of continued use of this agent.
Men with primary PE constituted who used fluoxetine and had at least 12 months follow-up constituted the study population. Subjects underwent a comprehensive interview to ascertain self-reported (non-stopwatch) intravaginal ejaculatory latency time (IELT), self-rated control over ejaculation, and personal and patient-reported partner distress due to PE. Patients were treated with fluoxetine 20 mg daily, with the possibility of dose titration up or down based on efficacy and side effects.
The PE parameters of interest included self-reported IELT, self-rated control over ejaculation, personal and partner distress due to PE, and medication adherence.
130 men were included in the study. Dropout rates at 6 and 12 months were 56% and 72%. Self-rated “poor” ejaculatory control decreased from 98%–41% (P < .01), high personal distress from 47%–11% (P < .01), and high partner distress rates from 72%–27% (P < .01). Predictors of continued use at 12 months included high partner distress, being unpartnered, and having a post-treatment IELT ≥5 minutes (P < .01). Overall side effects included headache (5%), dizziness (4%), nausea (5%), nervousness (5%), and sleepiness (8%); however, moderate to severe side effects reported included nausea (2%), sleepiness (2%), headache (2%), and dizziness (2%).
Compliance with SSRIs is a well-described problem in the depression literature, but data are sparse regarding continued use of SSRIs in the treatment of PE.
We report on 12-month compliance with SSRIs for the treatment of PE. Our early compliance rates were more encouraging than what has been reported in the past. However, IELT was self-reported and not measured objectively, and we did not use validated patient-reported outcomes but rather self-reported ejaculatory control and distress levels, which have limitations.
Fluoxetine is an effective agent for the treatment of PE with significant improvement realized in IELT, ejaculatory control, and distress levels for both men and their partners. Despite its efficacy, continued use of fluoxetine beyond 6 months is poor.
Jenkins LC, Gonzalez J, Tal R, et al. Compliance with Fluoxetine Use in Men with Primary Premature Ejaculation. J Sex Med 2020;16:1895–1899.
The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Phase IIb trial (PEDRIX)
2019, Journal of Sexual Medicine
Cligosiban is an orally administered, centrally penetrant oxytocin receptor antagonist being developed to treat premature ejaculation (PE).
To determine the efficacy of 3 dose levels of cligosiban caplets to prolong intravaginal ejaculation latency time (IELT) and improve patient-reported outcomes in men with lifelong PE.
Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts and if they met other diagnostic criteria for lifelong PE. Eligible patients (target 220 evaluable) were randomized to double-blind cligosiban 400, 800, or 1200 mg or matching placebo caplets (to be taken 1 to 6 hours prior to sexual activity). Assessments were conducted at 2, 4, and 8 weeks.
Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, Patient’s Global Impression of Severity, and the Clinical Global Impression of Change.
There were no clinically or statistically significant differences between cligosiban (at any dose level) and placebo for the primary endpoint (change in geometric IELT) or any of the secondary endpoints. Cligosiban was well tolerated with a side-effect profile similar to placebo.
This Phase IIb study failed to demonstrate the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE at doses up to 1200 mg.
This was a Phase IIb, randomized, double-blind, placebo-controlled study that was adequately powered but failed to detect a clinically meaningful or statistical difference in change in IELT between cligosiban at 3 dose levels and placebo. This is in contrast to a similarly designed proof-of-concept study where cligosiban was flexibly dosed at doses up to 800 mg and did demonstrate clinically meaningful and statistically significant changes in efficacy parameters. The reasons for this disparity are not known.
Cligosiban was well tolerated but failed to demonstrate efficacy for the treatment of men with lifelong PE at doses up to 1200 mg.
Althof S, Osterloh IH, Muirhead GJ, et al. The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Phase IIb trial (PEDRIX). J Sex Med 2019; 16:1188–1198.
Correlation between serum tryptophan metabolism and treatment efficacy of dapoxetine in patients with premature ejaculation: A pilot study
2024, Andrology

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

Abstract

Background

Objective

Design, setting, and participants

Intervention

Measurements

Results and limitations

Conclusions

Introduction

Section snippets

Objective

Subjects

Subjects

Intravaginal ejaculatory latency time

Discussion

Conclusions

Lancet

Eur Urol Suppl

J Sex Med

Eur Urol

J Urol

J Sex Med

J Sex Med

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