A Study To Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Oral Doses of GSK557296 in a Study in Men With Premature Ejaculation

Study Overview
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Brief Summary
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To determine if an on demand dosing of 50 mg or 150 mg of GSK557296 demonstrates superior efficacy with respect to duration of intra vaginal ejaculatory latency time (IELT) during an 8 week study period compared to placebo in men with primary premature ejaculation. An assessment of the safety and tolerability of all doses of GSK557296 will be performed as well as an assessment for change in the Index of Premature Ejaculation (IPE) from baseline and at the end of the 8 weeks of treatment. During the active treatment period study participants will be limited to a maximum of 40 doses of GSK557296, or placebo, spilt as 20 doses for both 4 week intervals.

Official Title
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A Phase II Study to Evaluate: Delay in Intravaginal Ejaculatory Latency Time (IELT), Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Oral Doses of GSK557296 in a Randomized, Double Blind, Placebo-Controlled, Parallel Group Study in Men With Premature Ejaculation

Conditions
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Premature Ejaculation

Intervention / Treatment
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* Drug: GSK557296
* Drug: GSK557296
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males with primary PE, according to the ISSM Consensus Definition. Defined as, 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, such as distress, bother, frustration and/or the avoidance of sexual intimacy Stable heterosexual relationship, with a single non pregnant, nonlactating female partner using adequate contraception (as confirmed by oral questioning of male study subject) in a relationship of greater than >4 months duration. This same partner will be the one with whom the subject makes and records all IELT attempts during the duration of the study. Aged between 18 and 50 years (i.e. subjects must not have completed their 50th year birthday at the time of screening, but can turn 50 years during the course of the study). The subject must make at least four attempts at sexual intercourse on four separate days during the untreated run in period. The average intravaginal ejaculatory latency time must be <65 seconds based on the study-provided stop watch assessments Exclusion Criteria: A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result and positive HIV antibody and or confirmatory ELISA test at screening. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Previous or Current Medical Conditions Erectile dysfunction (defined as IIEF-EF domain score < 22) Active or recent (< 6 months) history of prostatitis, as determined by patient symptoms or treatment seeking for newly diagnosed or flare of symptoms related to previously diagnosed prostatitis. Any unstable medical, psychiatric or substance abuse disorder that in the opinion of the investigator is likely to affect the subject's ability to complete the study or precludes the subject's participation in the study. Presence of penile anatomical abnormalities (e.g. penile fibrosis or Peyronie's disease) that in the opinion of the investigator would significantly impair sexual performance. Prior implantation of penile implant for erectile dysfunction Primary hypoactive sexual desire. Spinal cord injury. History of seizures, within last 6 months. History of prostate cancer treated or untreated. History of prostatectomy or prostate procedures for any cause. Clinically significant chronic hematological disease which may lead to priapism such as sickle cell anemia, multiple myeloma or leukemia. Significant active peptic ulceration. Presence of the following conditions prior to screening: myocardial infarction, coronary bypass surgery, coronary artery angioplasty, unstable angina, clinically evident congestive heart failure, cardiac pacemaker, or cerebrovascular accident. Cardiac arrhythmia: significant cardiac arrhythmia shown on screening ECG, or a known or suspected history of significant cardiac arrhythmias within six months prior to screening. i.e., pre-existing syndromes, sinus pause > 3 seconds, non-sustained ventricular tachycardia (3 consecutive ectopic beats), sustained ventricular tachycardia (30 consecutive ectopic beats), sustained supraventricular tachycardia (30 consecutive ectopic beats), accessory pathway tachycardia, bradycardia (heart rate < 50 beats per minute), atrial flutter, atrial fibrillation, ectopic pacemaker, sick sinus syndrome, ventricular block (second or third degree), or bundle branch block. Uncontrolled atrial fibrillation/flutter (ventricular response rate less than or equal to 100 bpm) at the screening visit (Visit 1). History of congenital QT prolongation and/or QTc interval >450msec at screening visit (Visit 1) using the Bazett formula. Mean systolic cuff BP > 140 mmHg, as assessed by three measurements taken in sequence within 5-10ming of last measure. Taken with the study subject in a supine position at the screening visit (Visit 1). Mean diastolic cuff BP >90 mmHg, as assess by three measurements taken in sequence within 5-10 minutes of the last measure. Taken with the study subject in a supine position at the screening visit (Visit 1). History of malignancy within the past five years (other than squamous or basal cell skin cancer). Any condition which would preclude sexual activity. Concomitant Medications No concomitant medications maybe used within 7 days of Visit 1 and or at any time during the study including oral medications, vacuum devices, constrictive devices, injections, urethral suppositories, gels, any over-the-counter herbal or non-prescription medications, and products purchased via the internet or mail order pharmacies. During the course of the study concomitant medication use can be considered upon consultation and prior agreement with primary investigator and medical monitor. Specific exceptions for asthmatic patients and patients with allergic rhinitis, who are on stable doses of inhaled or intra nasal agents as prescribed by their health care providers, and who have had no adjustments in their prescribed and or actual use within the last 60 days. Agents which are known or expected to have significant systemic exposures as a result of inhaled or intra-nasal use or to have known CYP3A4 drug-drug interaction potential are not included in this exemption. Subjects who have received any investigational drug (including placebo) within 30 days of the screening visit or 5 half lives of the investigational drug whichever is longer (Visit 1). Abnormal Laboratory Values Subjects who have a serum total testosterone level >25% below the lower limit of normal according to the range of the testing laboratory, when obtained in the morning versus in the afternoon, from screening lab which will need to be evaluated prior to randomization. Subjects with a clinically significant elevation of serum creatinine of > 2.0 when obtained from a screening lab which will need to be evaluated prior to randomization. Subject with a clinically significant elevation of AST of > 126 and/or ALT of > 144 when obtained from a screening lab which will need to be evaluated prior to randomization. Screening PSA > 4.0 ng/ml TSH outside the normal reference ranges at visit 1 Free Triiodothyronine [T3] outside the normal reference ranges at visit 1 Free Thyroxine T4 outside the normal reference ranges at visit 1 Other exclusion criteria Severe chronic or acute liver disease, history of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Subjects with known hypersensitivity to GSK557296 or any component of the investigational medication. Subjects who are illiterate or unable to understand the questionnaires or the subject diary. Subjects who are unwilling or unable to complete the subject diary. Subjects who are unwilling to be randomized to placebo. Subject whose sexual partner is actively trying to conceive, and or is unwilling to use a reliable form of birth control as outlined in Section 8.1 for the duration of the trial. Or whose female partner is breast feeding. Subjects, who in the opinion of the investigator, would be non-compliant with the majority of the visits scheduled or study procedures. History of sensitivity to heparin or heparin-induced thrombocytopenia (for subjects at sites where PK studies are planned). Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 1 month prior to screening. Consumption of seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication, and for the duration of the study. Subjects who have consumed alcohol within 24 hours will have their PK session rescheduled.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>placebo | Drug: placebo<br>* placebo<br>|
| Active Comparator: 50 mg<br>50 mg GSK557296 | Drug: GSK557296<br>* 50 mg GSK557296<br>* Other names: 50 mg;|
| Active Comparator: 150 mg<br>150 mg GSK557296 | Drug: GSK557296<br>* 150 mg GSK557296<br>* Other names: 150 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Intravaginal Ejaculatory Latency Time (IELT) Compared Over All 8 Weeks of Treatment or Until Premature Discontinuation | Male participant needed to make a minimum of 4 attempts at SI and Baseline IELTs were assessed by stop watch measurements for each SI attempt. IELT was the elapsed time from vaginal penetration until ejaculation. On-treatment IELT for each participant was calculated by taking the median IELT from all valid on-treatment IELT attempts. Geometric mean IELT for each treatment was compared using analysis of covariance (ANCOVA). LS mean values and two-sided p-values are from the general linear model ln(median IELT)= ln(Baseline IELT) + treatment + cluster. A step-down procedure was used to determine if the efficacy of on-demand GSK557296 was superior to placebo. First, the average of the geometric mean IELTs of the pooled 150mg and 50mg doses of GSK557296 was tested against placebo, and if significance was achieved with this global plateau trend test (p < 0.05), then the simultaneous pair wise comparisons of the 150mg and 50mg doses to placebo would occur (each at an alpha level of 0.05). | Up to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean IELT Compared After Each 4-week Treatment Period, or Until Premature Discontinuation | Male participant needed to make a minimum of 4 attempts at SI and Baseline IELTs were assessed by stop watch measurements for each SI attempt. IELT was the elapsed time from vaginal penetration until ejaculation. On-treatment IELT for each participant was calculated by taking the median IELT from all valid on-treatment IELT attempts. Geometric mean IELT for each treatment was compared using analysis of covariance (ANCOVA). LS mean values and two-sided p-values are from the general linear model ln(median IELT)= ln(Baseline IELT) + treatment + cluster. A step-down procedure was used to determine if the efficacy of on-demand GSK557296 was superior to placebo. First, the average of the geometric mean IELTs of the pooled 150mg and 50mg doses of GSK557296 was tested against placebo, and if significance was achieved with this global plateau trend test (p < 0.05), then the simultaneous pair wise comparisons of the 150mg and 50mg doses to placebo would occur (each at an alpha level of 0.05). | Up to Week 8 | 
| Mean IELT Compared After the First Dose of Study Drug or Placebo | Male participants needed to make a minimum of 4 attempts at SI and Baseline IELTs were assessed by stop watch measurements for each SI attempt. IELT was the elapsed time from vaginal penetration until ejaculation. First dose IELT was the IELT value associated with the first valid SI attempt made during the treatment period. For GSK557296 50 mg and 150 mg: LS mean values and two-sided p-values are from the general linear model ln(median IELT)= ln(Baseline IELT) + treatment + cluster using placebo, GSK557296 50 mg and GSK557296 150 mg treatments. A step-down procedure was used to determine if the efficacy of on-demand GSK557296 was superior to placebo. First, the average of the geometric mean IELTs of the pooled 150mg and 50mg doses of GSK557296 was tested against placebo, and if significance was achieved with this global plateau trend test (p < 0.05), then the simultaneous pair wise comparisons of the 150mg and 50mg doses to placebo would occur (each at an alpha level of 0.05). | Up to Week 8 | 
| Mean Change From Baseline in IELT Compared After Each 4-week Treatment Period and Over All 8 Weeks or Until Premature Discontinuation | Male participants needed to make a minimum of 4 attempts at SI and Baseline IELTs were assessed by stop watch measurements for each SI attempt. IELT was the elapsed time from vaginal penetration until ejaculation. Baseline IELT was calculated as the arithmetic mean IELT from valid screening SI attempts. If multiple screening SI attempts were made on the same calendar day, only the IELT from the first attempt was used in the calculation of Baseline IELT. Change from Baseline IELT was calculated by subtracting the Baseline IELT (arithmetic mean IELT from valid screening attempts) from the on-treatment IELT (median IELT from valid on-treatment attempts). Only participants with a Baseline and a post-Baseline IELT value were included. | Baseline and up to Week 8 | 
| Mean Change From Baseline in IELT Compared After the First Dose of Study Drug or Placebo | Male participants needed to make a minimum of 4 attempts at SI and Baseline IELTs were assessed by stop watch measurements for each SI attempt. IELT was the elapsed time from vaginal penetration until ejaculation. First dose IELT was the IELT value associated with the first valid SI attempt made during the treatment period. Baseline IELT was calculated as the arithmetic mean IELT from valid screening SI attempts. If multiple screening SI attempts were made on the same calendar day, only the IELT from the first attempt was used in the calculation of Baseline IELT. Change from Baseline IELT was calculated by subtracting the Baseline IELT (arithmetic mean IELT from valid screening attempts) from the on-treatment IELT (median IELT from valid on-treatment attempts). Only participant with a Baseline IELT and a valid first attempt were included. | Baseline and Week 4 | 
| Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] and From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration [AUC(0-t)] of GSK557296 | The pharmacokinetic (PK ) visit was not needed to take place at visit 2 but supposed to be completed before visit 3. The participants were asked to fast overnight prior to their PK sampling day and the time of their last meal was recorded. | At 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours at visit 2 or within 7 days of randomization | 
| Maximum Observed Plasma Concentration (Cmax) of GSK557296 | The PK visit was not needed to take place at visit 2 but supposed to be completed before visit 3. The participants were asked to fast overnight prior to their PK sampling day and the time of their last meal was recorded. | At 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours at visit 2 or within 7 days of randomization | 
| Time of Occurrence of Maximum Observed Plasma Concentration (Tmax) of GSK557296 | The PK visit was not needed to take place at visit 2 but supposed to be completed before visit 3. The participants were asked to fast overnight prior to their PK sampling day and the time of their last meal was recorded. | At 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours at visit 2 or within 7 days of randomization | 
| Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP were taken in a seated position. If the single measure was outside the cut off value, the mean of three seated measures were taken approximately 5-10 minutes apart was recorded. Baseline value was the latest values obtained on or before the Baseline reference date. Change from Baseline was the value at any visit post-Baseline minus value at Baseline. Per-participant values for all vital sign measures were taken as the mean of all reported values on a given date, regardless of recorded position. | Baseline and up to follow up (post treatment 48 hours) | 
| Mean Change From Baseline in Heart Rate | Heart rate assessment was done in a seated position. If the single measure was outside the cut off value, the mean of three seated measures were taken approximately 5-10 minutes apart was recorded. Baseline value was the latest values obtained on or before the Baseline reference date. Change from Baseline was the value at any visit post-Baseline minus value at Baseline. Per-participant values for all vital sign measures were taken as the mean of all reported values on a given date, regardless of recorded position. | Baseline and up to follow up (post treatment 48 hours) | 
| Mean Change From Baseline in Electrocardiogram (ECG) Values | ECG parameter values for QT interval, QT duration corrected for heart rate by Fridericia's formula (QTc [Fridericia]), QT duration corrected for heart rate by Bazett's formula (QTc [Bazett]), PR Interval and QRS Duration were assessed. The Baseline ECG was the latest ECG recorded on or before the participant's Baseline reference date. Change from Baseline was the value at any visit post-Baseline minus value at Baseline. | Baseline and up to follow up (post treatment 48 hours) | 
| Number of Participants With Shift From Baseline in Serum Laboratory Values (Clinical Chemistry) | Serum laboratory parameters: Albumin, Alkaline phosphatase (AP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Direct bilirubin, Total Bilirubin (T. Bilirubin), Calcium, Chloride, Carbon dioxide content/Bicarbonate (CO2/HCO3), Creatinine, Gamma glutamyl transferase (GGT), Glucose, Potassium, Sodium, Total protein (T. Protein), Urea/Blood urea nitrogen (BUN) and Uric acid were assessed. Baseline laboratory values were the latest values obtained on or before the participant's Baseline reference date. Unscheduled laboratory values were summarized as at-visit values only in the event that an at-visit laboratory value was missing. The values were presented as high, low or normal values shifted from Baseline value. | Baseline and up to follow up (post treatment 48 hours) | 
| Number of Participants With Shift From Baseline in Additional Lab Parameters (Free T3, Prostate Specific Antigen [PSA], Thyroid Stimulating Hormone [TSH] and Total Testosterone) | Baseline laboratory values were the latest values obtained on or before the participant's Baseline reference date. Unscheduled laboratory values were summarized as at-visit values only in the event that an at-visit laboratory value was missing. The values were presented as high, low or normal values shifted from Baseline value. | Baseline and up to follow up (post treatment 48 hours) | 
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. On-treatment adverse events were those started on or after the first dose of study medication and on or before the last dose of study medication. | Baseline and up to follow up (post treatment 48 hours) | 
| Number of Participants With Dose/Exposure Response Relationship Using PK/Pharmacodynamics (PD) Modeling | The relationship between plasma concentrations of GSK557296 and selected endpoints were planned to be explored using appropriate PK/PD models. | Up to Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Proof of Concept, Double Blind