Effects of a CRF1 Receptor Antagonist on Human Startle in Normal Female Volunteers

Objective: This proposal is a part of an integrated project to test the efficacy of a
candidate anxiolytic, a CRF1 receptor antagonist, provided by GlaxoSmithKline (GSK) as part
of The Emory-MSSM-GSK-NIMH Collaborative Mood Disorders Initiative, using fear-potentiated
startle. The anti-fear and anxiolytic activity of a single dose of the highly specific CRF1
antagonist GSK561679 will be evaluated in healthy female subjects using models of phasic
(fear) and sustained (anxiety) aversive states derived from humans and from pre-clinical
studies in rodents.

Study population: The study population will consist of 30 healthy female volunteers, 21-50
years of age, and of diverse racial and ethnic backgrounds.

Design: The study will use a double-blind cross-over design in which each subject will
receive placebo, Alprazolam (1 mg), and a low (50 mg) and high (400 mg) dose of GSK561679. We
will examine the effect of these drugs on the potentiation of startle during anticipation of
no-shock, predictable shock signaled by a discrete threat cue, and unpredictable shock.

Outcome measures: The main outcome measures are the magnitude of the startle reflex and
retrospective anxiety during each condition. Secondary measures will include the skin
conductance response and changes in heart rate, as well as measures of HPA activity.

- INCLUSION CRITERIA:

HEALTHY FEMALE VOLUNTEERS as determined by a responsible physician, based on a medical
evaluation including own and familial medical history, physical examination, psychiatric
history, psychiatric evaluation, laboratory tests and cardiac monitoring. A subject with a
clinical abnormality or laboratory parameters outside the reference range for the
population being studied may be included only if the Investigator agrees that the finding
is unlikely to introduce additional risk factors and will not interfere with the study
procedures.

Females between the ages of 21 and 50 who are free of current psychopathology and free of
past psychopathology of mood and anxiety disorder, psychotic disorder, and substance drug
addiction

Organic central nervous system disorders

Able to give consent

A negative urine toxicology

For females of child-bearing potential, negative pregnancy urine test

For females child-bearing potential, use of two effective birth control methods* for the
duration of the study or abstinence.

Abstinence from ingesting nicotine for at least 6 months before the start of the study.

*See specific criterion for effective birth control methods listed below.

EXCLUSION CRITERIA:

Subjects with an unstable medical disorder or a disorder (including surgical interventions)
that would likely interfere with the action, absorption, distribution, metabolism or
excretion of GSK561679, may pose a safety concern, or interfere with accurate assessment of
safety.

1. Lifetime or current diagnosis of schizophrenia or other psychotic disorder, mood or
anxiety disorder, substance abuse in the last 12 months or lifetime dependence,
alcohol abuse in the last 12 months or lifetime dependence. Current Axis I disorder.
Clear evidence of a first-degree relative with history of psychosis, bipolar disorder
or major depression as determined by the family history interview method;
specifically, participant will know diagnosis or treatment in order to confirm
presence of disorder.

2. Subject is currently participating in another clinical trial in which she is or will
be exposed to an investigational or non-investigational drug or device, or has done so
within the preceding month

3. Current evidence or history of significant unstable medical illness or organic brain
impairment, including stroke, epilepsy, CNS tumor, demyelinating disease, cardiac,
pulmonary, gastrointestinal, renal or hepatic impairment that would likely interfere
with the action, absorption, distribution, metabolism, or excretion of GSK561679.
Abnormal EKG.

4. DSM-IV substance abuse within the past year. Subject has a positive urine test for
illegal drug use.

5. Diagnosis of anorexia nervosa or bulimia

6. Subject has a documented history of hepato-biliary disease including a history of, or
positive laboratory results for hepatitis (hepatitis B surface antigen and/or
hepatitis C antibody), and/or clinically significant hepatic enzyme elevation
including any one of the following enzymes greater than 1.5 times the upper limit of
normal (ULN) value (ALT, AST, ALP, total or direct bil > 1.5 times the ULN, unless
consistent with presumed or diagnosed Gilbert s disease

7. Subject has taken systemic corticosteroids within 2 weeks of the Randomization Visit

8. All prescription or non-prescription medications and herbal remedies are prohibited
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study
medication and until completion of follow-up procedures, unless in the opinion of the
investigator the medication will not interfere with the study procedures or compromise
study safety, e.g. rescue medication. As an exception, acetaminophen, no more than
2g/day, and birth control pills are permitted during the study.

9. Subject who is likely to require the use of the following medications:

- Chronic (for more than 2 weeks), regular NSAID use unless administered
concomitantly with an anti-secretory agent (i.e. proton-pump inhibitor or
histamine-2 receptor antagonist)

- Any use of aspirin (including low dose)

10. Subject has taken non-psychoactive (prescription or non-prescription), dietary, or
herbal products, with a narrow therapeutic index, that are metabolized via the
cytochrome P450 3A4 or 2C9 pathway (warfarin), or transported via OATP1B1 or P-gp,
within 2 weeks (or 5 half-lives, whichever is longer) prior to the Randomization
Visit.

11. Subject has taken other (nonpsychoactive) prescription, nonprescription, dietary, or
herbal products that are potent inducers or inhibitors of the cytochrome P450 3A4
pathway for 2 weeks (or 5 half lives, whichever is longer) prior to the Randomization
Visit.

12. Subject has participated in a study with an investigational drug within the period of
30 days prior to screening for this study

13. Pregnancy or lactation*

14. Subjects who, in the opinion of the investigator, would be noncompliant with the visit
schedule or study procedures (e.g. illiteracy, planned vacations, or planned
hospitalizations during the study).

15. Any laboratory abnormality that in the investigator s judgment is considered to be
clinically significant (blood pressure, ECG, TSH, LFT, etc.)

16. Previous treatment with CRF1 receptor antagonist

17. Allergy to benzodiazepines

18. Medical conditions that would influence psychophysiological responses (e.g.,
cardiovascular disease, previous myocardial infarction, angina, uncontrolled
hypertension).

19. A history of peptic ulcer disease (PUD)

- A serum pregnancy test is performed during the screening. Since this test might
not detect the very early stage of pregnancy (i.e. maximum of 10 day period
between fertilization and implantation), women of child-bearing age are excluded
from the study if they do not use at least two effective birth control methods
for 15 days prior to receiving the study drug. Acceptable methods of birth
control include: a double-barrier method (condoms or diaphragm) combined with
spermicide; hormonal contraceptives plus single barrier (birth control pills,
implants [Norplant] or injections [Depo-Provera]), Intrauterine Device (IUD), or
abstinence (no sexual activity).