Analyzing Female Trauma Exposed Responses to a Medication

A growing body of literature suggests that stress-related disorders such as PTSD are
associated with chronically increased activity of CNS circuits that utilize
corticotropin-releasing factor (CRF), a neuropeptide involved in mediating the
neuroendocrine, immune, autonomic, and behavioral responses to stress. CRF1 receptor
antagonists exert significant dampening effects on this system, but have never been
investigated in patients with PTSD. The investigators at Mount Sinai School of Medicine
(MSSM) and the National Institute of Mental Health (NIMH) Intramural Research Program have
conducted a Phase II proof-of-concept clinical trial of a neurokinin-1 antagonist provided
by GlaxoSmithKline (GSK). In this investigation, we will conduct a 2-site (Emory and MSSM),
6-week, randomized, double-blind, placebo-controlled, parallel-arm, fixed dose trial
evaluating the efficacy, safety, and tolerability of GSK561679 for 154 female adult
outpatients with PTSD. The San Francisco Department of Veterans Affairs Medical Center
(SFVAMC) was added as a site in July 2012. SFVAMC will enroll 40 female adult outpatients
with PTSD.

We propose to investigate the efficacy of the highly specific CRF1 antagonist GSK561679 in
PTSD in a placebo-controlled clinical trial. GSK561679 has not been approved by the Food and
Drug Administration for the treatment of any condition. Furthermore, we propose to
longitudinally investigate whether certain biological surrogate markers (neuroendocrine,
neurophysiology, genotyping) are predictive of treatment response. If a patient is already
taking medication for PTSD and has achieved therapeutic response, she will not be tapered
off effective medication(s) to participate in this study, and will not be eligible for the
study. Taper and discontinuation of medications in preparation for this study will only
occur in those patients who are not responding to medication treatment for PTSD.

Preclinical and clinical literature also exists which implicates both hypothalamic and extra
hypothalamic CRF in stress-related insomnia and the regulation of non-rapid eye movement
delta sleep. There is preliminary evidence that blocking CRF signaling results in an
immediate improvement in stress-related sleep disturbances. Disturbed sleep is the most
prevalent symptom endorsed by PTSD patients. It is potentially debilitating in many domains
of functioning, and it is an outcome that can be objectively and precisely measured with
sleep EEG. Therefore, an exploratory aim of this study will be to investigate the impact of
GSK561679 on objective measures of sleep continuity and quantitative sleep EEG using
ambulatory polysomnography. All subjects enrolled at SFVAMC who meet inclusion and exclusion
criteria for the study will be given the option of having their sleep monitored throughout
the study

Inclusion Criteria:

- Female between 18-65 years of age

- Able to provide consent and willing to participate in research

- PTSD duration of illness at least 3 months

- Negative Urine toxicology test

- Agrees to use protocol-defined effective birth control method

Exclusion Criteria:

- 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

- Subject has a documented history of hepato-biliary disease including a history of, or
positive laboratory results for hepatitis

- Subject requires ongoing treatment with medications that are prohibited per protocol

- Subject has a stool positive for occult blood.

- Pregnancy or lactation