A Study With GW597599 And GR205171: Potential New Drugs For The Treatment Of Primary Insomnia

Vestipitant and Vofopitant 2 Day PSG Study for Insomnia

Patients with Primary Insomnia will be treated with GW597599 and GR205171 to evaluate the efficacy in the sleep difficulties associated with insomnia

Inclusion Criteria:

• The subject must be able to read and understand the informed consent form and provide written informed consent, indicating the subjects understanding of the purpose of the study and willingness to comply with all study procedures described in the protocol, including all sleep-laboratory restrictions and procedures.

• Subject is a male or female outpatient, at least 18 years of age and <65 years.

• Diagnosis of primary insomnia, as defined by Diagnostic and Statistical Manual of Mental Disorders-Text Revision (DSM-IV-TR) criteria 307.42. A complaint of difficulty initiating or maintaining sleep or of non-restorative sleep, which lasts for at least 3 months preceding screening along with clinically significant distress or impairment in social, occupational, or other important areas of functioning. The disturbance in sleep does not occur exclusively during the course of another sleep disorder or occur exclusively during the course of another mental disorder. Lastly, the disturbance is not due to the direct physiological effects of a substance or a general medical condition.

• The subjects self-reported sleep history includes at least three months of a usual TST of less than 6 hours, SOL of at least 30 minutes and at least 3 awakening per night in at least 3 nights per week.

• On two screening PSGs (on single-blinded placebo administration at each night):

  • TST between 240 and 390 minutes inclusive on both nights.
  • Mean LPS of 30 minutes or more, but not < 20 minutes on either night.
  • Mean WASO of 60 minutes or more, with neither night < 45 minutes.

• Time in bed between 6.5 and 8.5 hours for at least 5 nights per week over the preceding 3 months

• Bed time between 21.00 and 24.00 hours that does not vary by more than ±2 hour preceding 3 months

• Women of childbearing potential must commit to consistent and correct use of an acceptable method of birth control; GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows:

  • Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses)
  • Child-bearing potential, has a negative serum pregnancy test result at screen and a negative urine dipstick pregnancy test at baseline (prior to study drug administration), and agrees to one of the following:
  • Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject
  • Oral contraceptives (either combined or progestogen only)
  • Double-barrier method of contraception consisting of spermicide with either condom or diaphragm
  • IUD with a documented failure rate of less than 1% per year
  • Complete abstinence from intercourse for two weeks before exposure to the investigational product, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of three days, equivalent to five half lives)

Exclusion Criteria:

• Any clinically significant psychiatric disorder other than primary insomnia as defined by DSM-IV-TR.

  - Subject must not have a Beck Depression Inventory (version II) [Beck, 1996] total score of 29 or greater at the Screening Visit. Patients scoring 17 to 28 must be confirmed by a qualified clinician to not have major depressive illness to be eligible.

• Symptoms/signs that are consistent with any primary sleep disorder other than primary insomnia, e.g., sleep apnea, restless leg syndrome, circadian rhythm sleep disorder.

• History of alcohol, narcotic, benzodiazepine, or other substance abuse or dependence (with the exception of tobacco use) within the past 12 months as defined by DSM-IV-TR.

• Positive urine drug screen (i.e., amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, or opiates) or alcohol breath test at screening. No repeat test allowed.

• Any clinically significant unstable medical or surgical condition (treated or untreated).

• Any history of a clinically significant abnormality of the neurological system (including cognitive disorders or significant head injury) or any history of seizure (excluding febrile seizure).

• Subject has an unstable medical disorder; or a disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of GW597599 or GR205171; or interfere with the accurate assessment of safety or efficacy.

• Subjects having clinically significant abnormalities in haematology, blood chemistry, ECG, urinalysis, physical exam, vital signs, or other protocol-specified screening test which are not resolved by the baseline visit.

• Subjects with a history of clinically significant hepatic, cardiac (e.g. including myocardial infarction), renal, neurologic (e.g. including seizures), cerebrovascular, metabolic or pulmonary disease.

• Any serious medical disorder or condition that would in the Investigator's opinion, preclude the administration of study medication.

• Subjects who have any laboratory value outside the sponsor-specified ranges at the Screening Visit (See Appendix 9: Laboratory Parameters). Testing may be repeated once to see if value returns to within range, but such laboratory value must be resolved by the Screening PSG session (PSG 1/2).

• Subjects who are not euthyroid as evidenced by normal TSH. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit, with no dose changes.

• Known seropositivity for human immunodeficiency virus (HIV).

• Chronic hepatitis B and C, as evidenced by positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody.

• Subjects who have any electrocardiogram (ECG) parameter outside of the Sponsor-specified range (See Appendix 8: ECG Parameters). The ECG maybe repeated once to see if the parameter returns to within range, but any such abnormality must be resolved by the screening PSG session (Visits 2/3).

• Apnea-hypopnea index of 10 or more/hour of sleep on screening PSG Night 1. Subjects failing this criterion on Night 1 Screening PSG should not be screened on Night 2.

• Movement arousal index of 10 or more/hour of sleep on screening PSG Night 1. Subjects failing this criterion on Night 1 Screening PSG should not be screened on Night 2.

• Body mass index of 34 or more at Screening Visit.

• Nightshift or rotating-shift work within the last 2 work weeks or during the study period.

• Planned travel across more than 2 time zones during the study or in the 2 weeks prior to screening.

• Consumption of 300 mg or more per day on average of xanthine-containing beverages (e.g., coffee, cola, tea, chocolate) over the preceding 1 month [NOTE: 12 oz soda = ~50 mg, 7 oz coffee or 2 oz espresso = ~100 mg, 7 oz tea = ~75 mg of caffeine].

• Smoking more than 1 pack of cigarettes per day (20 cigarettes) on average over the preceding 1 month, or inability to stop smoking during the study.

• Typical consumption of more than 7 (women) or 14 (men) alcoholic units in any week, or more than 2 (women) or 3 (men) alcoholic units in any single day, over the preceding 1 month [NOTE: 1 unit = 12 oz beer, 5 oz wine, or 1.5 oz hard liquor].

• Regular intentional napping, i.e., more than 2 naps per week

• Use of any psychotropic medications or other medications, including over-the-counter (OTC) and herbal products, that may affect sleep/wake function within 2 weeks or 5 half-lives (whichever is longer) prior to screening or need to use any of these medications at any time during the study.

• Any history of depot neuroleptic use

• All other (non-psychotropic) drugs metabolised via the P450 3A4 pathway and CYP3A4 inducers/inhibitors must be discontinued from screening and are not allowed for the duration of the study. See the list in Study Reference Manual.

• Subjects (i.e. asthmatics) who have used systemic corticosteroids within 1 week or 5 half-lives (whichever is longer) prior to the screening visit.

• Participation in investigational trial involving NK1 antagonist (including GW679769) in the past or use of any investigational drug within 30 days or 5 half-lives of the study compound or participation in an investigational trial within 30 days prior to the Screening Visit.

• Subjects who have had hypersensitivity or intolerance to NK1 antagonists including GW597599 and GR205171.

• Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures.

• Women having a positive serum HCG pregnancy test at Screening Visit, a positive urine pregnancy dipstick at randomization, or who are lactating or planning to become pregnant within the 3 months following the Screening Visit.

• An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women from the time of the first dose of study medication until 90 days following administration of the last dose of study medication.

• An unwillingness of the male subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as an IUD, oral contraceptives, injectable progesterone, subdermal implants or a tubal ligation if the woman could become pregnant from the time of the first dose of study medication until 90 days following administration of the last dose of study medication.