Evaluation of GSK561679 in Women With Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a chronic and common anxiety disorder that follows
exposure to an overwhelming traumatic event. The majority of patients with PTSD also meet
criteria for other psychiatric disorders and PTSD is associated with an increased risk for
suicide attempts.

PTSD is responsive to psychological and pharmacological treatments, such as selective
serotonin reuptake inhibitors (SSRIs), but response rates rarely exceed 60%, and even fewer
patients (20-30%) achieve clinical remission. Thus, there is a clear need to develop novel
and improved therapeutics for PTSD.

The study is divided into 4 phases:

Phase 1 (Screening): a 1 week no drug screening period to assess study eligibility.

Phase 2 (Pre-Treatment Testing Period): Eligible patients will be enrolled into a 1 week
Testing Phase, which will include neuropsychological and neurophysiological testing as well
as blood draws and electrocardiogram.

Phase 3 (Treatment Period): Eligible patients will be enrolled in a two-armed 6-week period
of double-blind placebo-controlled acute treatment. All subjects who continue to meet
eligibility criteria will be randomized to one of two groups: GSK561679 (at a fixed dose of
350 mg/day) or placebo. Randomization will be performed at a 1:1 ratio into two treatment
groups. Neuropsychological and neurophysiological testing will be repeated after 5 weeks of
the double-blind treatment period.

Phase 4 (Follow-up Period): Safety follow-up visits will be conducted 1 week and 1 month
after the end of the treatment Phase 3.

Inclusion Criteria:

- Female between 21-65 years of age

- Able to provide consent and willing to participate in research

- Fulfills Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)
criteria for primary diagnosis of PTSD

- PTSD duration of illness at least 3 months

- Able to provide consent and willing to participate in research

- CAPS score of ≥ 50 at Screening and Visit 3 (randomization)

- Negative Urine toxicology test

- Agrees to use protocol-defined effective birth control method

- If the patient has a history of peptic ulcer disease (PUD), there is documentation of
the etiology of the PUD and that effective treatment was provided with full
eradication of ulcers and symptoms

Exclusion Criteria:

- Lifetime or current diagnosis of schizophrenia or other psychotic disorder, bipolar
disorder, obsessive compulsive disorder (OCD), or current Axis I disorder [(except
for major depression secondary to the PTSD, dysthymia, depression not otherwise
specified (NOS) and anxiety disorders (panic disorder, social phobia, generalized
anxiety disorder (GAD), specific phobia)]

- 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 for studies unrelated to PTSD, or 1 month for studies
related to PTSD

- Current evidence or history of significant unstable medical illness or organic brain
impairment, including stroke, central nervous system (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.

- Patients who in the investigator's judgment pose a current suicidal or homicidal risk

- DSM-IV substance abuse or dependence within the past 90 days. Subject has a positive
test for illegal substances.

- Diagnosis of anorexia nervosa or bulimia in the past year.

- 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 (alanine transaminase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase (ALP), total or direct bilirubin > 1.5 x ULN, unless consistent
with presumed or diagnosed Gilbert's disease)

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

- Treatment with any other psychoactive medication within 2 weeks of Visit 1, including
all antidepressants, psychoactive herbal or nutritional treatment (St Johns Wort,
SAM-e), lithium, other mood stabilizers, oral antipsychotics, depot antipsychotics
within 12 weeks, beta blockers, thioridazine, pimozide, opiates, anxiolytics, and
sedatives (with the exception of zolpidem, eszopiclone, and zaleplon). Also any
treatment with any medication that the PI judges not acceptable for this study.

- Subject who is likely to require the use of the following medications: Chronic (for
more than 2 weeks), regular nonsteroidal anti-inflammatory drugs (NSAID) use. Any use
of aspirin (including low dose)

- 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.

- Subject has taken other (non-psychoactive) prescription, non-prescription, 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.

- Subject has a stool positive for occult blood.

- Pregnancy or lactation

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

- Previous treatment with CRF1 receptor antagonist

- Any laboratory abnormality that in the investigator's judgment is considered to be
clinically significant (blood pressure, electrocardiogram (ECG), thyroid stimulating
hormone (TSH), liver function test (LFT), etc.)

- Patients who are receiving exposure-based psychotherapy that targets PTSD symptoms

- Current or planned litigation or other actions related to secondary gain regarding
the traumatic event

- Subject has clinical evidence of, or ECG results indicating any of the following at
either screen or Randomization Visit unless repeat ECG shows that the parameter had
returned to within normal range by the Randomization Visit:

1. Corrected QT Interval (QTc) > 450 msec;

2. any cardiac condition or ECG evidence that the investigator feels may predispose
the subject to ischemia or arrhythmia; or

3. any ECG abnormality that, in the investigator's judgment, may pose a potential
safety concern