A Study To Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Oral Doses of GSK557296 in a Study in Men With Premature Ejaculation
Condition: Premature Ejaculation
MeSH terms: Premature Birth; Premature Ejaculation
Intervention: GSK557296; GSK557296; placebo
Intervention description: 50 mg GSK557296; 150 mg GSK557296; placebo
Intervention MeSH terms: Diketopiperazines
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 77.0
Sex: Male
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: No
Keywords: Proof of Concept; Double Blind

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.