Clinical trial NCT01021553: A Study To Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Oral Doses of GSK557296 in a Study in Men With Premature Ejaculation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Premature Ejaculation
Keywords: Proof of Concept
Double Blind
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-11-30
Enrollment: 77
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. 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
2. 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.
3. 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).
4. The subject must make at least four attempts at sexual intercourse on four separate days during the untreated run in period.
5. The average intravaginal ejaculatory latency time must be \<65 seconds based on the study-provided stop watch assessments

Exclusion Criteria:

1. 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.
2. 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

1. Erectile dysfunction (defined as IIEF-EF domain score \< 22)
2. 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.
3. 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.
4. 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.
5. Prior implantation of penile implant for erectile dysfunction
6. Primary hypoactive sexual desire.
7. Spinal cord injury.
8. History of seizures, within last 6 months.
9. History of prostate cancer treated or untreated.
10. History of prostatectomy or prostate procedures for any cause.
11. Clinically significant chronic hematological disease which may lead to priapism such as sickle cell anemia, multiple myeloma or leukemia.
12. Significant active peptic ulceration.
13. 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.
14. 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).
15. History of congenital QT prolongation and/or QTc interval \>450msec at screening visit (Visit 1) using the Bazett formula.
16. 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).
17. 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).
18. History of malignancy within the past five years (other than squamous or basal cell skin cancer).
19. Any condition which would preclude sexual activity.

Concomitant Medications

1. 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.
2. 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

1. 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.
2. 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.
3. 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.
4. Screening PSA \> 4.0 ng/ml
5. TSH outside the normal reference ranges at visit 1
6. Free Triiodothyronine \[T3\] outside the normal reference ranges at visit 1
7. Free Thyroxine T4 outside the normal reference ranges at visit 1

Other exclusion criteria

1. Severe chronic or acute liver disease, history of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
2. Subjects with known hypersensitivity to GSK557296 or any component of the investigational medication.
3. Subjects who are illiterate or unable to understand the questionnaires or the subject diary.
4. Subjects who are unwilling or unable to complete the subject diary.
5. Subjects who are unwilling to be randomized to placebo.
6. 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.
7. Subjects, who in the opinion of the investigator, would be non-compliant with the majority of the visits scheduled or study procedures.
8. History of sensitivity to heparin or heparin-induced thrombocytopenia (for subjects at sites where PK studies are planned).
9. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 1 month prior to screening.
10. 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.
11. Subjects who have consumed alcohol within 24 hours will have their PK session rescheduled.

Primary outcomes:
measure: Mean Intravaginal Ejaculatory Latency Time (IELT) Compared Over All 8 Weeks of Treatment or Until Premature Discontinuation
timeFrame: Up to Week 8
Secondary outcomes:
measure: Mean IELT Compared After Each 4-week Treatment Period, or Until Premature Discontinuation
timeFrame: Up to Week 8
measure: Mean IELT Compared After the First Dose of Study Drug or Placebo
timeFrame: Up to Week 8
measure: Mean Change From Baseline in IELT Compared After Each 4-week Treatment Period and Over All 8 Weeks or Until Premature Discontinuation
timeFrame: Baseline and up to Week 8
measure: Mean Change From Baseline in IELT Compared After the First Dose of Study Drug or Placebo
timeFrame: Baseline and Week 4
measure: 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
timeFrame: At 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours at visit 2 or within 7 days of randomization
measure: Maximum Observed Plasma Concentration (Cmax) of GSK557296
timeFrame: At 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours at visit 2 or within 7 days of randomization
measure: Time of Occurrence of Maximum Observed Plasma Concentration (Tmax) of GSK557296
timeFrame: At 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 hours at visit 2 or within 7 days of randomization
measure: Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and up to follow up (post treatment 48 hours)
measure: Mean Change From Baseline in Heart Rate
timeFrame: Baseline and up to follow up (post treatment 48 hours)
measure: Mean Change From Baseline in Electrocardiogram (ECG) Values
timeFrame: Baseline and up to follow up (post treatment 48 hours)
measure: Number of Participants With Shift From Baseline in Serum Laboratory Values (Clinical Chemistry)
timeFrame: Baseline and up to follow up (post treatment 48 hours)
measure: Number of Participants With Shift From Baseline in Additional Lab Parameters (Free T3, Prostate Specific Antigen [PSA], Thyroid Stimulating Hormone [TSH] and Total Testosterone)
timeFrame: Baseline and up to follow up (post treatment 48 hours)
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline and up to follow up (post treatment 48 hours)
measure: Number of Participants With Dose/Exposure Response Relationship Using PK/Pharmacodynamics (PD) Modeling
timeFrame: Up to Week 8
Other outcomes:
Locations:
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: San Jose
country: United States
facility: GSK Investigational Site
state: California
city: Fort Wayne
country: United States
facility: GSK Investigational Site
state: Indiana
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Bala-Cynwyd
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Shinghal R, Barnes A, Mahar KM, Stier B, Giancaterino L, Condreay LD, Black L, McCallum SW. Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study. J Sex Med. 2013 Oct;10(10):2506-17. doi: 10.1111/jsm.12272. Epub 2013 Aug 12.