28-day Repeat Dose and Drug Interaction Study With Orvepitant (GW823296)
28-day Repeat Dose and Drug Interaction Study With Orvepitant (GW823296)
This study is being conducted to obtain information on the safety and tolerability of
 repeated doses of GW823296 for 28 days in healthy male and female subjects. In addition, the
 pharmacokinetics of GW823296 will be evaluated to confirm the doses to be used in Phase II
 efficacy studies. The effect of repeat dose (RD) of GW823296 on CYP3A4 enzyme activity will
 be investigated evaluating the pharmacokinetics of midazolam and urine
 6-?-hydroxycortisol/cortisol ratio.
Inclusion Criteria:

 -  Healthy as determined by a Physician Responsible, based on a medical evaluation
 including history, physical examination, laboratory tests, cardiac monitoring. A
 subject with a clinical abnormality or laboratory variables outside the reference
 range for the population being studied, with the exception of liver transaminases,
 troponin I and TSH, may be included only if the Investigator considers that the
 finding will not introduce additional risk factors and will not interfere with the
 study procedures. Please note that subjects should have liver transaminases, troponin
 I and TSH values within the range specified in the exclusion criteria below.

 -  Women of non-childbearing potential (i.e., physiologically incapable of becoming
 pregnant with documentation of hysterectomy or bilateral ovariectomy >6 months,
 including any female who is postmenopausal. For purposes of this study, postmenopausal
 is defined as one year without menses and confirmed by FSH according to the local
 laboratory ranges at screening) and having a negative serum hCG pregnancy test at
 screening.

 -  No co-morbid Psychiatric Disorders as defined using the Mini International
 Neuropsychiatric Interview (M.I.N.I) scale

 -  Aged 18-65 years, inclusive

 -  A 12-lead ECG and 24-hours Holter ECG at screening showed no abnormalities that in the
 opinion of the Principal Investigator will compromise safety in this study

 -  Body weight >50 kg and body mass index (BMI) within the range 19.0-29.9 kg/m2

 -  Subjects with a history of peptic ulcer disease (PUD) with a known aetiology must
 provide documentation by a gastroenterologist of the aetiology of the PUD and that
 effective treatment was provided with full eradication of ulcers and symptoms. For
 such subjects appropriate steps must also have been taken to minimize reoccurrence
 risk (i.e. if PUD was nonsteroidal anti-inflammatory drug [NSAID] induced, the subject
 should no longer be taking NSAID medications; if cause was Helicobacter pylori [H.
 pylori], the subject should have been appropriately treated). For all subjects,
 regardless of whether there is a positive history of PUD, sites are required to
 document their H. pylori status at screening. Entry into the study is permitted for
 subjects who are seropositive for H. pylori, but treatment is recommended, either
 before or after study participation at the discretion of the Principal Investigator.

 -  Capable of giving written informed consent, which includes compliance with the
 requirements and restrictions listed in the consent form

 -  The subject must be able to read, comprehend and record information.

 -  A signed and dated written informed consent is obtained from the subject.

 -  The subject is available to complete the study.

 Exclusion Criteria:

 -  The subject has screening alanine aminotransferase (ALT) or aspartate aminotransferase
 (AST) >1.5x upper limit of the normal range (ULN); testing may be repeated once to see
 if value returns to within acceptance range but any such laboratory abnormality must
 be resolved by the baseline visit.

 -  Subjects with a troponin I value >0.032 ng/mL at screening are not eligible. Testing
 may not be repeated. The subject should be referred to the treating physician for
 further evaluation, as appropriate.

 -  Subjects with a TSH value above the upper limit of the normal range (ULN) at screening
 are not eligible. The subject should be referred to the treating physician for further
 evaluation, as appropriate. Testing may be repeated once to see whether the value
 returns to within normal range but such abnormality must be resolved before the
 baseline visit.

 -  Subjects found to have stool positive for occult blood. If such a stool was obtained
 without the subject abstaining from red meat for 3 or more days prior to testing, this
 may be repeated once following such abstinence. If that stool is negative for occult
 blood the subject is considered eligible.

 -  Subjects with known or suspected iron deficiency

 -  Subjects with a history of myopathy or rhabdomyolysis

 -  The subject is unable to abstain from strenuous physical activity for 72 hours prior
 to screening, for 72 hours prior first dosing until the last PK sample has been
 collected, and for 72 hours prior to the follow-up visit.

 -  The subject has donated a unit of blood (450 mL) within the previous 60 days or
 intends to donate in the month after completing the study.

 -  The subjects is currently taking regular (or a course of) medication whether
 prescribed or not, including vitamins and herbal remedies, such as St John's Wort. Any
 concurrent medication will not be permitted for 48 hours before admission to the CPRU
 until the end of the study period (follow-up visit).

 -  Typical consumption of more than 14 alcoholic units in any week, or more than 3 (for
 males) or 2 (for females) alcoholic units in any single day, over the month preceding
 the screening visit [NOTE: 1 unit = 8 oz beer, 3 oz wine, or 1 oz hard liquor]

 -  The subject smokes or has smoked in the last 3 months.

 -  The subject has tested positive for Hepatitis C antibody or Hepatitis B surface
 antigen.

 -  The subject has tested positive for HIV-1/2.

 -  The subject has a past history of drug abuse or has tested positive for urine drugs of
 abuse at screening. A minimum list of drugs that will be screened for include
 Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.

 -  Male subject intends to father a child during the study and the 3 months following the
 study

 -  Subjects with a history of eye disease (excluding moderate myopia) or clinically
 relevant eye examination finding, which in the opinion of the study ophthalmologist
 contraindicates their participation in the study

 -  Vulnerable subject (e.g. kept in detention)

 -  Subjects who have had hypersensitivity or intolerance to NK1 antagonists

 -  Subject has a known hypersensitivity against midazolam or against one of the
 excipients of Dormicum® (subjects of Cohorts 2 and 3 only)