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.

This study will test the hypothesis of whether an antagonist at the corticotropin releasing factor type 1 receptor (i.e. GSK561679) is superior to placebo in reducing symptoms of PTSD. The study is being conducted at 2 sites in the United States: a site at Emory University, and one at Mount Sinai School of Medicine. About 150 women outpatients aged 21 to 65 who currently suffer from PTSD will be enrolled. Study participation could last for up to about 12 weeks.

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.

Primary efficacy outcome measure for the study will be the Clinician-Administered PTSD scale (CAPS).

Secondary efficacy outcome measure will include the Montgomery-Asberg Depression Rating Scale (MADRS).

Safety measures will include adverse event recording at every visit, clinical laboratory measures, vital sign parameters, electrocardiograms (ECGs), and physical examinations.

• Drug: GSK561679
  GSK561679, oral administration, 350mg/day, 6 week administration
  Other Name: CRF1 antagonist
• Drug: Placebo
  placebo compound treatment for comparison with IP
  Other Name: sugar pill/placebo

• Placebo Comparator: Placebo
  placebo compound for 6 weeks
  Intervention: Drug: Placebo
• Active Comparator: GSK561679
  investigational medication
  Intervention: Drug: GSK561679

Inclusion Criteria:

• Female between 21-65 years of age
• Able to provide consent and willing to participate in research
• Fulfills 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:

1. Lifetime or current diagnosis of schizophrenia or other psychotic disorder, bipolar disorder, OCD, or current Axis I disorder [(except for major depression secondary to the PTSD, dysthymia, depression NOS and anxiety disorders (panic disorder, social phobia, GAD, specific phobia)]
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 for studies unrelated to PTSD, or 1 month for studies related to PTSD
3. Current evidence or history of significant unstable medical illness or organic brain impairment, including stroke, 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.
4. Patients who in the investigator's judgment pose a current suicidal or homicidal risk
5. DSM-IV substance abuse or dependence within the past 90 days. Subject has a positive test for illegal substances.
6. Diagnosis of anorexia nervosa or bulimia in the past year.
7. 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 bilirubin > 1.5 x ULN, unless consistent with presumed or diagnosed Gilbert's disease
8. Subject has taken systemic corticosteroids within 2 weeks of the Randomization Visit
9. 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.
10. Subject who is likely to require the use of the following medications: Chronic (for more than 2 weeks), regular NSAID use. Any use of aspirin (including low dose)
11. 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.
12. 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.
13. Subject has a stool positive for occult blood.
14. Pregnancy or lactation*
15. 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).
16. Previous treatment with CRF1 receptor antagonist
17. Any laboratory abnormality that in the investigator's judgment is considered to be clinically significant (blood pressure, ECG, TSH, LFT, etc.)
18. Patients who are receiving exposure-based psychotherapy that targets PTSD symptoms
19. Current or planned litigation or other actions related to secondary gain regarding the traumatic event

20. 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:

    • QTc > 450 msec;
    • any cardiac condition or ECG evidence that the investigator feels may predispose the subject to ischemia or arrhythmia; or
    • any ECG abnormality that, in the investigator's judgment, may pose a potential safety concern