W. Wallace Dinsmore and Michael G. Wyllie Royal Victoria Hospital, Belfast, and Plethora Solutions Ltd, London, UK

Transcription

1 . JOURNAL COMPILATION 29 BJU INTERNATIONAL Sexual Medicine, EJACULATORY LATENCY, CONTROL AND SEXUAL SATISFACTION IN MEN WITH PE DINSMORE and WYLLIE BJUI BJU INTERNATIONAL improves ejaculatory latency, control and sexual satisfaction when applied topically 5 min before intercourse in men with premature ejaculation: results of a phase III, multicentre, double-blind, placebo-controlled study W. Wallace Dinsmore and Michael G. Wyllie Royal Victoria Hospital, Belfast, and Plethora Solutions Ltd, London, UK Accepted for publication 28 January 29 Study Type Therapy (RCT) Level of Evidence 1b OBJECTIVES To determine the effect of applied topically 5 min before intercourse on the Index of Premature Ejaculation (IPE) and intravaginal ejaculatory latency time (IELT) of men with lifelong premature ejaculation (PE) defined according to the International Society of Sexual Medicine (ISSM) definition; secondary objectives were to evaluate the safety and tolerability of in patients with PE, and their sexual partners. PATIENTS AND METHODS Men aged >18 years, in stable heterosexual, monogamous relationships, and with lifelong PE diagnosed according to both the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) criteria and the ISSM definition, consented (together with their partners) to enter the baseline period of the study. Patients who documented an IELT of 1 min with two or more of the first three sexual encounters during the 4-week baseline period were randomized, in a 2:1 ratio, to receive double-blind treatment with (three actuations of spray each containing 7.5 mg lidocaine and 2.5 mg prilocaine applied 5 min before intercourse) or placebo for 3 months. Patients completed IPE and Premature Ejaculation Profile (PEP) questionnaires at entry and at monthly clinic visits, and recorded stopwatch-timed IELT during each sexual encounter. Patients rated the quality of their orgasms on a 5-point scale at baseline and at the end of the treatment period, and rated the study medication on a 4-point scale. Safety was assessed by collecting adverse event data. RESULTS In all, 3 men with PE were randomized from 31 centres in Europe. The geometric mean (range) IELT over the 3-month treatment period increased from a baseline of.6 min in both groups to 3.8 ( ) and 1.1 ( 15.) min in the and placebo groups, respectively. Adjusting for treatment-group imbalances, this represents a 6.3-fold and 1.7-fold increase in adjusted geometric means. There were significantly greater increases in the scores for the IPE domains of ejaculatory control and sexual satisfaction in the group than in the placebo group, with a mean (SEM) 7. (.59)- point difference between treatments in change from baseline in the IPE domain for ejaculatory control and a 5.9 (.57)- point difference in change from baseline in the IPE domain for sexual satisfaction (both P <.1). This was supported by improvements in all secondary endpoints. At the end of the treatment period 66% of patients rated as good or excellent. was well tolerated and no systemic adverse events were reported. Localized treatment-related adverse events were reported by 2.6% and 3.1% of patients and partners, respectively. CONCLUSION applied topically 5 min before intercourse improved ejaculatory latency and significantly improved ejaculatory control and sexual satisfaction, factors relevant for acceptance of a PE treatment by both patient/physician and regulatory authorities. was well tolerated by both patients and partners, with no systemic side-effects and a low incidence of localized effects, and was rated favourably by most users. therefore appears to offer significant advantages over other therapies in development for the treatment of PE. KEYWORDS, TEMPE, premature ejaculation, topical treatment, prilocaine, lidocaine INTRODUCTION A precise definition of premature ejaculation (PE) is important in terms of evaluating the results of clinical trials and registration of new therapies with regulatory authorities. To this end, a contemporary, evidencebased definition of lifelong PE was recently developed by a consensus group in association with the International Society for Sexual Medicine (ISSM) [1]. The ISSM definition states that PE is A male sexual dysfunction characterized by ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration; and inability to delay ejaculation on all or nearly all vaginal penetrations; and negative personal consequences, 94 JOURNAL COMPILATION 29 BJU INTERNATIONAL 13, doi:1.1111/j x x

2 , EJACULATORY LATENCY, CONTROL AND SEXUAL SATISFACTION IN MEN WITH PE such as distress, bother, frustration and/or the avoidance of sexual intimacy. Studies have yet to determine the prevalence of lifelong PE using this new definition, but estimates of prevalence using various less precise definitions are 3 4% of the male population at some time in their lives [2 6]. Behavioural therapy is well established in the treatment of PE and can be successful in certain situations. However, there is currently a wealth of research into various potential treatment targets for pharmaceutical therapy and several potential products are under development, although none as yet have received regulatory approval (reviewed in [7]). Topical therapy is one of the oldest treatments for PE, the theory being that reducing the sensitivity of the glans penis with a desensitizing agent might improve intravaginal ejaculatory latency time (IELT) whilst maintaining the sensations associated with orgasm and ejaculation (reviewed in [8]). Topical anaesthetic creams licensed for local skin anaesthesia have been used successfully to increase IELT when applied to the glans penis a while before intercourse, and are apparently frequently prescribed off-label for this purpose [9]. However, not having been designed for the treatment of PE, there are several problems with the use of topical creams (e.g. the mess, the potentially long waiting time and need to use a condom) which make them less than an ideal treatment. Of the few products in development as a topical treatment for PE, (also known as TEMPE) appears to be the closest to commercial availability. is a topical agent designed specifically for treating PE and consists of a metered-dose aerosol formulation of lidocaine and prilocaine dissolved in a non-chlorofluorocarbon propellant, which also acts as a solvent, forming a eutectic-like mixture [1]. Uniquely, the desensitizing agents in this non-aqueous formulation can penetrate the poorly keratinized modified mucosa of the glans penis, but not the fully keratinized skin of the penile shaft, enabling a localized desensitizing effect [1]. The efficacy of in PE has been tested in two previously published clinical trials [11,12]. In both of these studies, patients were selected according to the subjective Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) definition of PE which does not include a time element [13]. In an open-label pilot study involving 11 men with PE, the mean (range) IELT increased from a baseline of 1.4 ( ) to ( ) min over five consecutive sexual encounters using a prototype of the spray [12]. In a larger phase II double-blind, randomized, multicentre study, the change in geometric mean IELT from baseline to the end of the 1-month treatment phase was 2.4 times higher in the group than in the placebo group (P <.1) [11]. For both these studies, although the mean IELT at baseline was close to 1 min, men with a range of IELTs were permitted to enter the study, including those who would not comply with the latest ISSM definition. Although IELT is an objective measure of ejaculatory function it does not address the impact of therapy on the patients well-being and confidence in their sexual performance, which are important markers of treatment benefit. This can be measured using patientreported outcome (PRO) questionnaires. A PRO is a measurement of any aspect of a patient s health status that comes directly from the patient, without the interpretation of the patient s responses by a physician or anyone else, and therefore uniquely provides evidence of treatment benefit from the patient perspective. Guidance from the regulatory authorities indicates that both objective and PRO methods are required to document improvements in sexual function [14]. For data to be interpreted and evaluated by the regulatory authorities, the PROs used must be both validated and relevant to patients. The present study was designed to incorporate two such validated PROs, the Index of Premature Ejaculation (IPE) [15] and the Premature Ejaculation Profile (PEP) [16]. In both previous studies patients were instructed to apply 15 min before intercourse. However, pharmacokinetic data suggest that the active compounds are absorbed more rapidly, and it was hypothesized that a shorter interval would be likely to be effective [1], thus the interval between application and coitus has been reduced to 5 min in the present study. The primary objective of the present study was to determine the effect of applied topically 5 min before intercourse on the IPE and IELT of men with lifelong PE defined according to the ISSM definition. Secondary objectives were to evaluate the safety and tolerability of in patients with PE, and their sexual partners. PATIENTS AND METHODS Men with PE, and their partners, were recruited from 31 sites across Europe specializing in the treatment of sexual dysfunction, using methods approved by the appropriate study site Institutional Review Boards, including written correspondence, telephone calls, advertising and routine clinic visits. Men in stable heterosexual, monogamous relationships (of 3 months) who were diagnosed with lifelong PE according to both the DSM-IV criteria [13] and the more recent ISSM definition [1], were considered suitable for inclusion in the study providing that both the subject and his partner were aged 18 years and were both willing to provide written informed consent. Patients were not permitted to enter the study if any of the following were present: (i) receipt (by patient or partner) of an investigational drug within 3 days of screening; (ii) erectile dysfunction (ED), defined as a score from the 5-item version of the International Index of Erectile Function (IIEF-5) [17] of 21, unless the low score was (in the opinion of the investigator) entirely related to PE symptoms; (iii) a physical or psychological condition (patient or partner) that would prevent them from undertaking the study procedures; (iv) significant abnormalities in safety testing results at the screening visit; (v) use of tricyclic antidepressants, monoamine oxidase inhibitors or selective serotonin reuptake inhibitors (SSRIs), for indications other than PE, where the dose has been changed within 4 weeks of screening or where it is planned that the dose will change during the doubleblind treatment period; (vi) use of any treatment for PE, e.g. antidepressant therapy, local anaesthetic spray, intracavernosal injection or psychotherapy within the 4 weeks before screening; (vii) a current history of alcohol or drug abuse (patient or partner); (viii) inability to understand or comply with study procedures; (ix) known drug sensitivity to amide-type local anaesthetics (patient or partner); (x) pregnancy of partner; (xi) partners of child-bearing potential unwilling to use appropriate contraception during the study; (xii) a history of glucose-6- phosphate dehydrogenase deficiency or JOURNAL COMPILATION 29 BJU INTERNATIONAL 941

3 DINSMORE and WYLLIE use of medications that would increase susceptibility to methaemoglobinaemia (patient or partner); (xiii) use of class I (e.g. mexiletine, tocainide) or III (e.g. amiodarone, sotalol) anti-arrhythmic drugs (patient or partner). FIG. 1. Study design. Screening Visit 1 Randomization Visit 2 Entry to open-label phase Visit 5 End of Study Visit 1 An overview of the study design is shown in Fig. 1. Patients and their sexual partners attended a screening visit (visit 1) at which their suitability for participation was determined and the subject had a physical assessment (examination of the glans penis; measurement of heart rate and blood pressure, 12-lead electrocardiogram (ECG) and haematology and biochemistry testing). Patients completed the IPE and PEP questionnaires, and questions to enable diagnosis/classification of ED according to the IIEF-5, and partners completed a PEP questionnaire. Patients suitable for inclusion in the baseline period were those who (as part of the PEP questionnaire) rated their perceived control over ejaculation as poor or very poor, their personal distress related to ejaculation as quite a bit or extremely, their interpersonal difficulty related to ejaculation as quite a bit or extremely and their satisfaction with sexual intercourse as poor or very poor. Couples considered suitable for inclusion underwent a baseline evaluation period of 4 weeks during which they were required to have at least three sexual encounters, separated by an interval of 24 h, and to record the IELT in the diary card provided. At the end of the baseline period, patients completed the IPE and PEP questionnaires and rated the quality of their orgasm in response to the question: In general, how do you rate the orgasm you experience during sexual intercourse? on a 5-point scale ( very poor, poor, satisfactory, good, very good ). Patients with a baseline IELT of 1 min for at least two of the first three sexual encounters were eligible for randomization into the double-blind phase. Eligible patients were randomized in a 2:1 ratio to receive double-blind treatment with or matched placebo for 3 months. metered-dose spray contains 7.5 mg lidocaine and 2.5 mg prilocaine in each actuation. Patients were instructed to apply three sprays (one dose) to cover different regions of the glans penis (after retracting any foreskin), at 5 min before intercourse and to wipe excess spray off with a soft damp Baseline 3 sexual encounters PLACEBO Double-blind Treatment Phase 1 sexual encounter per month cloth before penetration. Patients were instructed to use the spray as often as they wanted, but to leave 24 h between each use and to refrain from activity that leads to ejaculation for 24 h before each use of study medication. Lubricating gels and pessaries were permitted, provided that they did not contain local anaesthetic agents. To fully assess the effect of potential transference of the study drug to the sexual partner, the use of condoms was not permitted. During each sexual encounter, the IELT was measured and recorded in a diary card, together with efficacy and tolerability data. Patients returned to the clinic at monthly intervals (visits 3, 4 and 5) at which the IPE and PEP questionnaires were completed and diary cards reviewed. Also, at visit 5 patients had a safety evaluation, examination of the glans penis, rating of the quality of their orgasms and rating of the study medication in answer to the question What was your opinion of the study medication? on a 4- point scale ( poor, fair, good or excellent ). The patients sexual partners recorded adverse event details and completed partner PEP questionnaires at the end of each phase of the study. At the end of the double-blind treatment phase patients were offered treatment with in an open-label phase, which is ongoing and will be reported separately. The primary objective of the study was to determine the effect of applied topically 5 min before intercourse on the IPE and IELT. Secondary objectives were to evaluate the safety and tolerability of in patients with PE, and their sexual partners. No minimum usage Timescale bar (non-linear): each mark represents one month Based on data from a previous phase II study of in PE [11], it was calculated that 24 3 patients were required to provide 95% power to detect a statistically significant treatment effect on at least one of the endpoints. Unconditionally, there was 95% power to detect a statistically significant doubling in mean IELT for vs placebo at the 5% level of significance and 95% power to detect a statistically significant moderate effect size (Cohen s effect size of.5) difference for vs placebo in the IPE domains of ejaculatory control and sexual satisfaction individually. The co-primary efficacy variables were: (i) the change in mean IELT from baseline during the 3 months of double-blind treatment; (ii) the change in the IPE domain of ejaculatory control from baseline to month 3; (iii) the change in the IPE domain of sexual satisfaction from baseline to month 3. Secondary efficacy variables included the change in the IPE domain of distress from baseline to month 3; the proportions of patients with a mean IELT of >1 min and >2 min during the 3 months of double-blind treatment; subject and partner scores for perceived control over ejaculation, personal distress related to ejaculation, satisfaction with sexual intercourse and interpersonal difficulty related to ejaculation based on the subject PEP at months 1, 2 and 3. To measure IELT, each subject was provided with a stopwatch at the start of the baseline period and instructed that he, or his partner, should time his IELT for each sexual encounter, by starting timing at vaginal penetration and to stop timing at the start of 942 JOURNAL COMPILATION 29 BJU INTERNATIONAL

4 , EJACULATORY LATENCY, CONTROL AND SEXUAL SATISFACTION IN MEN WITH PE FIG. 2. The flow of patients through the study. Excluded (n = 35) Allocated to, n = 2 Received = 191 Not treated = 9 Withdrawals Withdrawn = 18* Adverse event = 2 Withdrawal of consent (subject) = 9 Withdrawal of consent (partner) = 2 Sponsor s decision = 1 Lost to follow-up = 5 Analysed ITT / Safety = 191 Excluded = *Categories are not mutually exclusive Screened n = 335 Randomized (V2) n = 3 Allocation Follow-up Analysis Allocated to placebo, n = 1 Received placebo = 99 Not treated = 1 Withdrawals Withdrawn = 4* Adverse event = Withdrawal of consent (subject) = 3 Withdrawal of consent (partner) = Sponsor s decision = Lost to follow-up = 1 Analysed ITT / Safety = 99 Excluded = dose of study drug during the double-blind treatment phase of the study were included in the analysis of efficacy. The IELT data were log-transformed for analysis and backtransformed for the presentation of results. For patients who withdrew during the study, the mean IELT in the primary analysis was based on the available measurements, with baseline IELT carried forward if this was the only measurement available. The primary analysis of IPE domains was based on lastobservation-carried-forward techniques to replace missing data. The secondary efficacy variables were compared between and placebo using appropriate methods, with no adjustment made for multiplicity of the secondary variables. IPE distress was analysed by analysis of covariance adjusted for centre and baseline distress. The IELT of >1 and >2 min were analysed by logistic regression, adjusted for centre and baseline IELT. Improvement in patient and partner PEP over baseline were analysed by the Cochran-Armitage trend test. The change from baseline in the quality of orgasm rating and the rating of study medication were summarized descriptively. Safety was assessed by collecting adverse event data, the use of concomitant medications as well as the monitoring of heart rate, blood pressure, 12-lead ECG, haematology and biochemistry. Safety data were summarized and presented and descriptive statistics applied as appropriate. ejaculation. Patients were instructed to avoid sexual activity during foreplay that might lead to ejaculation, and to refrain from the use of any pause techniques that might result in the delay of ejaculation during sexual intercourse. The 1-item IPE questionnaire is divided into three domains, i.e. ejaculatory control (four questions), sexual satisfaction (four questions) and distress (two questions), each answered on a 6-point scale [15]. The maximum possible scores for control and satisfaction are 2 points (most control/ satisfaction) and the maximum score for distress is 1 points (least distressed). The separate PEP patients and partner questionnaires each have four questions relating to satisfaction, distress, control and interpersonal difficulty, each answered on a 5-point scale [16] with a maximum score of 5 points for each question. All data were analysed according to a preestablished analysis plan. The co-primary primary efficacy variables were summarized using descriptive statistics and compared between and placebo using analysis of covariance, with factors for centre, treatment and baseline as a covariate. To control the overall level of significance at 5%, a fixed sequence Bonferroni procedure was implemented. This procedure began by testing the IELT variable at the 1.67% level of significance, and then proceeded to test ejaculatory control and sexual satisfaction, in that order, with the level of significance determined by the outcome of the previous test [18]. The primary analysis population was an intent-to-treat (ITT) population, and all randomized patients receiving at least one RESULTS In all, 3 men with PE were randomized from 31 centres in the UK (37), Czech Republic (121), Hungary (21) and Poland (121). The flow of patients through the screening, baseline and double-blind phases of the study is shown in Fig. 2. At entry to baseline, the groups had similar overall demographics and PE history (Table 1). All patients except three (in the group) were Caucasian and the mean age was 35 years in both groups (SD 9.6 and 11.2, and placebo). Overall, 95% of patients in both groups had lifelong PE and a similar proportion of men in both groups were uncircumcised (94% and 93% in the and placebo groups, respectively). A similar proportion of patients in each group had used previous treatments for PE, the most common being SSRIs or other oral antidepressants, JOURNAL COMPILATION 29 BJU INTERNATIONAL 943

5 DINSMORE and WYLLIE TABLE 1 Demographics of patients at entry to baseline, with the history of PE and previous treatment (191) (99) Variable N (%) Mean (SD) Median (range) N (%) Mean (SD) Median (range) Age, years (9.6) 33. (19 65) (11.2) 33. (2 6) Ethnic origin Caucasian Afro-Caribbean 1 Asian-Indian subcontinent 1 Other 1 Height, cm (7.7) 179. ( ) (7.2) 179. ( ) Weight, kg (14.) 84. ( ) (11.2) 82. ( ) BMI, kg/m (4.) 26. ( ) (3.) 25.5 ( ) PE history and previous treatment History of PE Lifelong PE 182 (95.3) 94 (94.9) Acquired PE 9 (4.7) 5 (5.1) Duration of PE, years (8.7) 1. ( 43.1) (9.).7 ( 38.3) Circumcised, n (%) 12 (6.3) 6 (6.1) Uncircumcised, n (%) 179 (93.7) 92 (92.9) (missing data) 1 (1.) Previous treatment for PE, n (%) Any 59 (3.9) 32 (32.3) Drugs used for treatment of PE Local anaesthetic 12 (6.3) 8 (8.1) Oral SSRI or other antidepressant 47 (24.6) 25 (25.3) Drugs used for treatment of ED Any 6 (3.1) 6 (6.1) Intracavernosal injection 2 (1.) Oral PDE-5 inhibitor 8 (4.1) 6 (6.1) Herbal 1 (.5) Other oral therapy 3 (1.6) 1 (1.) Investigational drug 1 (1.) Other nonpharmaceutical therapy 14 (7.3) 7 (7.1) PDE-5, phosphodiesterase type 5. which had been previously used by 25% of patients in both groups. At baseline both groups had a geometric mean (range) IELT of.6 ( 2.3 and 3.3) in the and placebo groups, respectively, which increased to 3.8 ( ) and 1.1 ( 15.) min in the and placebo groups, respectively, over the full 3-month treatment period (Fig. 3). There was a significant difference between treatments in the change from baseline to month 3, which was measured by the ratio of the adjusted geometric mean IELT to baseline, giving a 6.3- and 1.7-fold increase in IELT in the and placebo groups, respectively (P <.1, 95% CI min at a testing level of.167 due to multiple testing considerations). Baseline scores for the IPE domains of ejaculatory control and sexual satisfaction were similar in both treatment groups. After 3 months, there were significantly greater increases in the scores for both domains in the group than in the placebo group (Table 2 and Fig. 4), with a 7. (SEM.59) point difference between treatments in the change from baseline in the domain for ejaculatory control (P <.1; significant at the.33 testing level) and a 5.9 (.57) point difference in the change from baseline in the domain for sexual satisfaction FIG. 3. Geometric Mean IELT at baseline and over the 3 month treatment period: intent-to-treat population. Geometric mean IELT, min Baseline 3 Month Treatment Period 944 JOURNAL COMPILATION 29 BJU INTERNATIONAL

6 , EJACULATORY LATENCY, CONTROL AND SEXUAL SATISFACTION IN MEN WITH PE Variable (191) (99) Ejaculatory control, n Mean (SD): Baseline score 5.2 (2.) 5.1 (1.8) End of month 3 score* 14.3 (5.1) 7.4 (4.4) Adjusted mean (SEM) change 9.2 (.35) 2.2 (.5) Between-treatment comparison of adjusted mean change, P <.1 Sexual satisfaction, n Mean (SD) Baseline score 7. (2.9) 7.3 (2.9) End of month 3 score* 14.8 (5.) 9.1 (4.6) Adjusted mean (SEM) change 7.8 (.3) 1.9 (.5) Between-treatment comparison of adjusted mean change, P <.1 Distress, n Mean (SD) Baseline score 3.3 (1.7) 3.1 (1.4) End of month 3 score* 7.1 (2.4) 4.5 (2.4) Adjusted mean (SEM) change 4. (.2) 1.2 (.2) Between-treatment comparison of adjusted mean change, P <.1 FIG. 4. Change from baseline to month 3 in adjusted mean IPE scores. Change in adjusted mean IPE score Control Satisfaction IPE Domain Distress (P <.1; significant at the.5 testing level). For secondary efficacy variables, the baseline scores for the IPE domain of distress were similar in both treatment groups, and as for the other two domains, there was a significantly greater increase in the score (representing a reduction in distress) in the group than in the placebo group after 3 months of treatment (Table 2 and Fig. 4), with a mean (SEM) 2.8 (.28) point difference in the change from baseline in this domain (P <.1). Over the 3 months of double-blind treatment, a significantly greater proportion of patients in the group had mean IELTs of >1 min (9% of 191) and >2 min TABLE 2 Change from baseline in IPE scores after 3 months treatment in the doubleblind phase *Last observation was carried forward for patients with missing data after baseline. FIG. 5. Proportion of patients reporting mean IELT >1 min and >2 min over 3 months. % Subjects IELT > 1 min IELT > 2 min (74% of 191) than in the placebo group (54% and 22%, respectively, 99 for both; Fig. 5). Therefore the odds of achieving an IELT of >1 or >2 min with were nine times (95% CI ) and 12.8 times (95% CI ) greater than that of achieving the same with placebo (P <.1 for both comparisons). A significantly higher proportion of patients in the group reported improvements of at least one point of all four domains of the PEP questionnaire (perceived control over ejaculation, personal distress related to ejaculation, satisfaction with sexual intercourse and interpersonal difficulty related to ejaculation) at the end month 3 of the placebo-controlled phase (P <.1 for all between-treatment comparisons, Fig. 6). The treatment advantage was also seen at the end of months 1 and 2 for all domains (P <.1 for all between-treatment comparisons, Table 3). The result was very similar for the partner PEP answered by the patients sexual partners, with a significantly higher proportion of partners in the group reporting improvements of at least one point in all four domains of the questionnaire at the end of month 3 (P <.1 for all between-treatment comparisons, Fig. 6). Patients rated the quality of their orgasms at baseline and at the end of month 3 on a 5- point scale. At baseline the two treatment groups had similar ratings with 2.4% (of 186) and 21.4% (of 98) of patients in the and placebo groups, respectively, rating the quality of their orgasms as good or very good. At the end of the 3-month treatment period the rating remained similar in the placebo group (18.6%, of 97), whereas in the group the proportion of patients reporting the quality of their orgasms as good or very good had risen to 61.6% (of 185), as shown in Fig. 7. At the end of the 3-month treatment period patients were asked to rate the study medication on a 4-point scale and the distribution of responses is shown in Fig. 8. Of the patients in the group, 65.9% (of 182) rated the medication as good or excellent, as opposed to 14.6% (of 96) patients in the placebo group. There were no serious adverse events during the study. During the double-blind treatment phase adverse events were reported by a similar proportion of patients in both groups (14 patients in the group, 7.3% of 191) and eight in the placebo group (8.1% of 99). Of these, five adverse events (2.6% of 191) in the group and one (1.% of 99) in the placebo group were considered to be treatment-related (Table 4). All five treatment-related adverse events in the group were in the reproductive system and breast disorders primary system organ class. The most common preferred terms being genital erythema and erectile dysfunction (reported by the patients as loss of erection and disappearance of erection ) each reported by two patients (1.% of 191). Adverse events were reported by 15 sexual partners (7.9% of 191) in the group JOURNAL COMPILATION 29 BJU INTERNATIONAL 945

7 DINSMORE and WYLLIE FIG. 6. Proportion of patients (A) and sexual partners (B) reporting improvement of at least 1 point in PEP domain at the end of month 3 of the double-blind treatment phase. FIG. 7. Proportion of patients rating the quality of orgasm as good or very good : ITT population. % Subjects A Distress Control Satisfaction PEP Domain Interpersonal % Subjects B Distress Control Satisfaction PEP Domain Interpersonal % Subjects Very good Good Baseline End of month 3 FIG. 8. Rating of the study medication by patients at the end of the 3 month treatment period: ITT population. TABLE 3 The proportion of patients, as n (%), with an improvement of at least one category in the PEP at visits in the double-blind phase: ITT population Visit Domain (191) (99) Between treatment comparison Month 1 Distress 152 (8.4) 48 (48.5) all <.1 Control 142 (75.1) 42 (42.4) Satisfaction 149 (78.8) 42 (42.4) Interpersonal difficulty 151 (79.9) 57 (57.6) Month 2 Distress 164 (88.7) 44 (45.4) all <.1 Control 155 (83.8) 28 (28.9) Satisfaction 154 (83.4) 35 (36.1) Interpersonal difficulty 162 (87.6) 57 (58.8) Month 3 Distress 161 (87.5) 41 (42.7) all <.1 Control 162 (88.) 37 (38.5) Satisfaction 162 (88.) 39 (4.6) Interpersonal difficulty 157 (85.3) 61 (63.5) and nine (9.1% of 99) in the placebo group during the double-blind phase. Of these, six partner-reported adverse events (3.1% of 191) in the group were considered to be treatment-related, and none in the placebo group (Table 4). All six treatment-related adverse events in the group were in the reproductive system and breast disorders primary system organ class with the most common preferred term being vulvovaginal burning sensation reported by five sexual partners (2.6% of 191). None of the adverse events reported by patients or their partners were rated as severe and no systemic treatment-emergent adverse events were reported by patients or their sexual partners. The two patients in the group (1.% of 191) who reported loss of/disappearance of erection withdrew due to these adverse events. No patients withdrew due to adverse events reported by their sexual partners. There were no changes of note from baseline to the end of the treatment phase in any of the other safety variables (heart rate, blood pressure, ECG, haematology, biochemistry or physical examination of the penis). DISCUSSION The primary objectives of this study incorporated both IELT as an objective measure of ejaculatory function and the IPE questionnaire as a validated PRO, to evaluate the effect of applied topically 5 min before intercourse, on the patients well-being and confidence in their sexual performance. Men with PE were selected according to the recent ISSM definition including a baseline IELT % Subjects 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % Excellent Good Fair Poor of <1 min (on two or more of the first three sexual encounters) and men with concomitant ED were excluded using the IIEF-5 questionnaire. Importantly, this study also involved the participation of female sexual partners to fully characterize the effect of treatment with on the sexual health and well-being of both partners in a relationship. produced a highly statistically significant increase from baseline in geometric mean IELT over the 3-month treatment period, raising the geometric mean IELT to a clinically meaningful 3.8 min, representing a 6.3-fold increase over baseline and bringing it to within what is generally accepted as the normal range [19,2]. In a recent study using dapoxetine 6 mg daily in men with PE (IELT <2 min at entry), a comparable mean IELT of 3.2 min was achieved after 12 weeks of treatment, although this represented a lower 2.9-fold increase over baseline [21]. It is recognized in the ISSM definition of PE that distress and other negative personal consequences of PE arise from a perception 946 JOURNAL COMPILATION 29 BJU INTERNATIONAL

8 , EJACULATORY LATENCY, CONTROL AND SEXUAL SATISFACTION IN MEN WITH PE Primary system organ class (191) (99) Preferred term Patient-reported Any primary system organ class Total 5 (2.6) 1 (1.) Infections and infestations Total 1 (1.) Tonsillitis 1 (1.) Reproductive system and breast disorders Total 5 (2.6) ED* 2 (1.) Genital burning sensation 1 (.5) Genital erythema 2 (1.) Hypoaesthesia of genital male 1 (.5) Skin and subcutaneous tissue disorders Total 1 (.5) Skin irritation 1 (.5) Partner-reported Any primary system organ class Total 6 (3.1) Reproductive system and breast disorders Total 6 (3.1) Vulvovaginal burning sensation 5 (2.6) Vulvovaginal discomfort 1 (.5) *Preferred term used for spontaneous reports of loss of/ disappearance of erection. A subject with multiple occurrences of an adverse event under one treatment is counted only once in the adverse-event category for that treatment. A subject with multiple adverse events within a primary system organ class is counted only once in the total row. of lack of ejaculatory control, as well as dissatisfaction with ejaculatory latency. The IPE questionnaire consists of 1 questions in three domains (control, distress and sexual satisfaction), which have been shown to correlate well with IELT and can be used in conjunction with IELT to fully characterize the treatment benefit to the patients [15,22]. In previous studies a 2-point increase in ejaculatory control has been used to indicate a treatment benefit (minimum important difference) relevant to patients [23]. However, this was far exceeded in the present study, as produced a change over baseline of 9.2 points for the control domain (representing a 7-point difference between treatments) and 7.8 points for the sexual satisfaction domain (representing a 6-point difference between treatments). There was also a 4-point change over baseline for the distress domain (representing a 2.8-point difference between treatments). The significant differences in change from baseline in both IELT and IPE scores therefore provide data representative of clinical benefit. TABLE 4 Subject- and partnerreported treatment-related adverse events, starting in the double-blind phase This strong treatment effect was further shown by the odds of achieving an IELT of >2 min with, which was times that of achieving the same with placebo. Mean IELTs of >2 min were achieved by 74% (of 191) men using, which is somewhat higher than in the previous small phase II study, where 11 of 2 (55%) men had an IELT of 2 min on two occasions after treatment [11]. This difference can be explained by the much greater power of the present study, together with the more clearly defined selection criteria. A second validated PRO, the PEP questionnaire was also included in this study for use by both patients and their sexual partners, and enabled the evaluation and characterization of the effect of treatment with on the sexual well-being of the female partners of men with PE, as well as the men themselves. The previous phase II study [11] showed a trend in improvements in the sexual health of female partners (using a different questionnaire), but the usage of the study drug was limited to four occasions over one month and was therefore probably insufficient to expect a large change in sexual quality of life. By contrast, the present study shows a clear statistically significant positive improvement in all four dimensions of the PEP for female sexual partners, as well as for the men themselves. It was shown previously [6] that PE has a negative effect on relationships and this study has now confirmed that treating the PE can have a positive effect on how both partners feel about their sexual satisfaction and relationship. In this study, was well tolerated by both men and their female partners. No systemic adverse events were reported and only 7.3% of men treated with and 7.9% of sexual partners reported adverse events, with 2.6% and 3.1% of patients and partners, respectively, reporting adverse events considered to be treatment-related. In studies with oral SSRIs and other antidepressants, systemic side-effects such as nausea, diarrhoea, insomnia and headache, leading to treatment discontinuation, are commonly reported [21,24,25]. As would be expected with a topical treatment, the most commonly reported adverse events were localized, but these were generally mild and infrequent. Two patients reported loss of erection and disappearance of erection, which are reported under the preferred term ED (which does not imply a diagnosis of ED), although in both cases the adverse event resulted in study discontinuation. In the previous phase II study with three of 26 men (12%) reported hypoaesthesia. However, in the present study hypoaesthesia was reported by only one of 191 patients (.5%). The difference might be due to the reduction in the interval that the patients were instructed to allow between applying the spray and intercourse, being 15 min in the previous study and 5 min in the present study. It appears that shortening the application interval has enabled a reduction in unwanted desensitizing effects (hypoaesthesia) without compromising efficacy. The most commonly reported adverse events by sexual partners were also localized, but were also mild and infrequent, suggesting JOURNAL COMPILATION 29 BJU INTERNATIONAL 947

9 DINSMORE and WYLLIE minimal transference of the active ingredients to sexual partners. It could be suggested that the topical application of a desensitizing agent to the glans penis might result in a reduction in the sensation of orgasm. However, this was found not to be the case, as resulted in a substantial increase in the proportion of men rating the quality of their orgasms as good or very good, from a baseline of 2% to 6% at the end of the treatment period. The substantial treatment benefits in terms of both ejaculatory latency, and improvements in ejaculatory control and satisfaction, together with the low incidence of sideeffects, is likely to have contributed to the high level of patient acceptability, as shown by most users (66%) who rated the treatment as good or very good after 12 weeks of use. In conclusion, this phase III double-blind, placebo-controlled study has shown that applied topically 5 min before intercourse produced a highly clinically and statistically significant increase from baseline in all three co-primary endpoints, supported by improvements in all secondary endpoints. not only improved ejaculatory latency, but also significantly improved ejaculatory control and sexual satisfaction, factors relevant for acceptance of a PE treatment by both patient/physician and regulatory authorities. was well tolerated by both patients and partners, with no systemic side-effects and a low incidence of localized effects, and was also rated favourably by the majority of users. therefore appears to offer significant advantages over other therapies in development for the treatment of PE. ACKNOWLEDGEMENTS The authors acknowledge the following investigators who recruited patients for this study: From the UK: Dr Hackett, Dr Ralph, Mr Eardley, Dr Savani, Dr Thomas, Dr Abdulhakim; From the Czech Republic: Dr Pavlik, Dr Urban, Dr Milan, Dr Kolomaznik, Dr Koci, Dr Navratil, Dr Janda, Dr Tomastik; From Poland: Dr Ciesielska, Dr Dadej, Professor Darewicz, Dr Depko, Dr Dulko, Dr Jankowska-Wojniak, Professor Kula, Dr Lew-Starowicz, Dr Robacha, Dr Sipinski, Dr Smolinski, Dr Wieczerzak, Dr Wieznowski; From Poland: Dr Nagy, Dr Katona, Dr Fisher. The authors also acknowledge Dr Julia Powell for assistance with medical writing and John Breddy for statistical analysis. CONFLICT OF INTEREST M.G. Wyllie is a Director and shareholder of Plethora Solutions. Prof. W.W. Dinsmore is a consultant to and investigator for Plethora Solutions. REFERENCES 1 McMahon CG, Althof S, Waldinger MD et al. An evidence-based definition of lifelong premature ejaculation. 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10 , EJACULATORY LATENCY, CONTROL AND SEXUAL SATISFACTION IN MEN WITH PE 22 Althof SE, Symonds T. Patient reported outcomes used in the assessment of premature ejaculation. Urol Clin North Am 27; 34: 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 28; 12: Waldinger MD, Zwinderman AH, Olivier B. On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment. Eur Urol 24; 46: Pryor JL, Althof SE, Steidle C et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet 26; 368: Correspondence: Mike Wyllie, Plethora Solutons Ltd., London, UK. j.powell@globalpharma.co.uk Abbreviations: PE, premature ejaculation; ISSM, International Society for Sexual Medicine; IELT, intravaginal ejaculatory latency time; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; PRO, patient-reported outcome; IPE, Index of Premature Ejaculation; PEP, Premature Ejaculation Profile; IIEF, International Index of Erectile Function; SSRI, selective serotonin re-uptake inhibitor; ECG, electrocardiogram; ITT, intent-to-treat. JOURNAL COMPILATION 29 BJU INTERNATIONAL 949