Efficacy, Safety and Tolerability of PSD502 (a Topical Anesthetic) in the Treatment Premature Ejaculation

Efficacy, Safety and Tolerability of PSD502 (a Topical Anesthetic) in the Treatment Premature Ejaculation

A Phase IIb, Multi-center, Randomized, Double-blind, Placebo-controlled Study, With Open-label Follow on, to Evaluate the Efficacy, Safety and Tolerability of PSD502 in Subjects With Premature Ejaculation (PE)

The purpose of this study is to evaluate the effectiveness, safety and tolerability of the investigational drug, PSD502 in subjects with premature ejaculation (PE) The study drug, PSD02, is a metered dose (measured dose), topical (applied to the skin surface) anesthetic (numbing) spray containing a mixture of lidocaine and prilocaine. The study drug will be applied in a spray to the penis prior to intercourse in order to decrease sensitivity in an attempt to delay ejaculation.

Most studies evaluating treatments PE include intravaginal ejaculatory latency time (IELT) in the definition of PE. It has been estimated that PE affects 30-40% of the male population, but is paradoxically a condition for which they are least likely to seek help. Men with PE exhibit abnormal autonomic reflex pathways for the ejaculatory process. These include lower vibratory threshold to ejaculation, shorter bulbocavernous latency time and higher bulbocavernous evoked potentials. Reducing the heightened sensitivity of the glans penis with topical anesthetics might therefore be a way of improving IELT, without adversely affecting the sensation of ejaculation. Although IELT is an objective measure of ejaculatory function it does not address the impact of therapy on patients' well being and confidence in their sexual performance, which are important markers of treatment benefit. Therefore, if IELT is used as a sole efficacy measure it may not fully characterise the treatment benefit to the patient. For this reason, a patient reported outcome (PRO) known as the Index of Premature Ejaculation (IPE) will be used in this study in conjunction with IELT to evaluate efficacy. Thus the combination of the objective measure of ejaculatory latency with the PRO of IPE should be able to provide efficacy data which are representative of clinical benefit to the patient. The use of lidocaine, prilocaine and EMLA® cream as topical anesthetics is well established. Many years of experience of use in large numbers of patients, as well as comprehensive non-clinical safety testing programs for various formulations of lidocaine and prilocaine exist, to support their safety and tolerability. This information, together with the clinical data from 3 studies with PSD502 (ANAE-059-00, PSD502-PE-001, and PSD502-PE-003), suggest that PSD502 may have beneficial effects in reducing penile sensation and prolonging IELT, and its use is unlikely to be associated with significant clinical safety or tolerability concerns. The aim of this study is to provide additional placebo-controlled efficacy data to establish the clinical utility of PSD502 in the treatment of PE. In addition, long term open-label efficacy and safety data will be collected, to further support the registration package for PSD502 in the indication of treatment of PE.

Double-blind Phase: Subjects will be randomised to PSD502 respectively if the patient meets all the entry criteria.

Double-blind Phase: Subjects will be randomised to Placebo respectively if the patient meets all the entry criteria.

PSD502 spray contains a mixture of lidocaine and prilocaine with Norflurane (HFA-134a) is used as both propellant and solvent. A single dose consists of 3 sprays applied to the glans penis. Approximately 5 minutes before intercourse the study spray can be applied and any excess should be wiped off with a damp cloth or tissue. During the initial 3 months double-blind phase of the study subjects should leave at least 24 hours between each dosing During the subsequent 5 months open label Phase of the study subjects may use the spray for up to a maximum of 3 sexual encounters (intercourse) in a 24 hour period. Each sexual encounter (intercourse) when the spray is used must be separated by at least 4 hour period.

The placebo is a metered dose aerosol spray that is identical in appearance to the active treatment and contains the same propellant (norflurane) but has no lidocaine or prilocaine. Approximately 5 minutes before intercourse the study spray can be applied and any excess should be wiped off with a damp cloth or tissue. During the initial 3 months double-blind phase of the study subjects should leave at least 24 hours between each dosing. During the subsequent 5 months open label Phase of the study subjects may use the spray for up to a maximum of 3 sexual encounters (intercourse) in a 24 hour period. Each sexual encounter (intercourse) when the spray is used must be separated by at least 4 hour period.

Mean Intravaginal Ejaculatory Latency Time (IELT): Change From Baseline to During 3 Month Double Blind-treatment

To evaluate efficacy of treatment with PSD502 compared with placebo in subjects with PE as measured by: • change in mean IELT from baseline to during the 3 month double-blind treatment Results provide are ratio (over the 3 months/baseline).

To Evaluate Efficacy of Treatment With PSD502 Compared With Placebo in Subjects With PE as measured by: • changes in all 3 IPE domains from baseline to month 3 Ejaculatory control scores range from 4 to 20 with a higher score indicating greater ejaculatory control Sexual satisfaction scores range from 4 to 20 with a higher score indicating greater sexual satisfaction Distress scores range from 2 to 10 with a higher score indicating less distress

Percentage of Subjects With Mean Intravaginal Ejaculatory Latency Time (IELT) > 1 Minute and >2 Minutes During the 3 Months of Double-blind Treatment

Percentage of subjects with mean IELT > 1 minute and >2 minutes during the 3 months of double-blind treatment as measured by the proportion of subjects

Change in the Index of Premature Ejaculation (IPE) Domains of Ejaculatory Control, Distress and Sexual Satisfaction From Baseline to Month 1

Change in the IPE domains of ejaculatory control, distress and sexual satisfaction from Baseline to month 1. Ejaculatory control scores range from 4 to 20 with a higher score indicating greater ejaculatory control Sexual satisfaction scores range from 4 to 20 with a higher score indicating greater sexual satisfaction Distress scores range from 2 to 10 with a higher score indicating less distress

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 month 1. Percentage of subjects with at least a 1 point category improvement in subject PEP domain scores at month 1.

Change in the Index of Premature Ejaculation (IPE) Domains of Ejaculatory Control, Distress and Sexual Satisfaction From Baseline to Month 2

Change in the IPE domains of ejaculatory control, distress and sexual satisfaction from Baseline to month 2 Ejaculatory control scores range from 4 to 20 with a higher score indicating greater ejaculatory control Sexual satisfaction scores range from 4 to 20 with a higher score indicating greater sexual satisfaction Distress scores range from 2 to 10 with a higher score indicating less distress

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 month 2. Proportion of subjects with at least a 1 point category improvement in subject PEP domain scores from baseline to month 2.

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 month 3. Proportion of subjects with at least a 1 point category improvement in subject PEP domain scores from baseline to month 3.

Scores for perceived control over ejaculation, personal distress related to ejaculation, satisfaction with sexual intercourse and interpersonal difficulty related to ejaculation based on the partner PEP at month 3. Proportion of partners with at least a 1 point category improvement in partner PEP domain scores from baseline to month 3.

Inclusion Criteria: Willing and able to provide written informed consent. Male and aged 18 years and over. Diagnosed with PE according to DMS-IV criteria and ISSM definition Diagnosed with lifelong PE Acceptable response to Baseline PEP Subject must be in a stable heterosexual and monogamous relationship and the partner must provide consent Acceptable sexual encounters in the Baseline period. Exclusion Criteria: Subject, or his sexual partner, has received an investigational (non-registered) drug within 30 days of Screening. Subject has erectile dysfunction The subject, or his sexual partner, has a physical or psychological condition that would prevent them from undertaking the study procedures, including, but not limited to, the following: Urological disease Ongoing significant psychiatric disorder not controlled by medication. Subject has safety testing abnormalities at the Screening Visit Subjects taking excluded medications or receiving any treatment for PE Subject, or his sexual partner, has a current history of alcohol or drug abuse, The subject, or his sexual partner, is unlikely to understand or be able to comply with study procedures, for whatever reasons. Subject, or his sexual partner, has known drug sensitivity to amide-type local anesthetics. Subjects with pregnant partners Subject with sexual partners of child-bearing potential and not using appropriate contraception Subject, or his sexual partner, has a history of Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency or use of medications that would increase susceptibility to methemoglobinemia (e.g. anti-malarial agents).

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