Analyzing Female Trauma Exposed Responses to a Medication

Study Overview
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Brief Summary
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This purpose of this study is to look at the safety of the experimental drug GSK561679 as well as its effects on PTSD symptoms, thinking and memory, startle reaction, stress hormones, and mental health symptoms in comparison to placebo (an inactive substance).

Detailed Description
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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

Official Title
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CRF Receptor Antagonist for PTSD and Related Sleep Disturbances in Women

Conditions
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Stress Disorders, Post-traumatic

Intervention / Treatment
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* Drug: GSK561679
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK561679<br>GSK561679, oral administration, 350mg/day, 6 week administration | Drug: GSK561679<br>* GSK561679, oral administration, 350mg/day, 6 week administration<br>* Other names: CRF1 antagonist;|
| Placebo Comparator: Placebo<br>Placebo compound treatment for comparison with IP | Drug: Placebo<br>* Placebo compound treatment for comparison with IP<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy, Measured by Change in the Clinician-Administered PTSD Scale (CAPS) Score | The CAPS is a semi-structured clinical interview providing a measure of the severity of PTSD symptoms. A severity score is calculated by summing the frequency and intensity scores for each of the 17 DSM-IV criteria symptoms. The severity of symptoms is rated on a scale from 0-4, where, 0 = Absent, 1 = Mild/subthreshold; 2 = Moderate/ threshold, 3 = Severe/markedly elevated and 4 = Extreme/ incapacitating. Scores may range from 0 (no symptoms) to 136 (severe symptoms). Change is the difference in scores between baseline and 6 weeks. | Baseline, 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy, Measured by Response Rate of at Least 50% Improvement in CAPS Score at the End of 6 Weeks as Compared to Baseline | The number of participants that showed at least a 50% reduction in CAPS scores from their baseline visit at the end of 6 weeks were measured as having a response to the treatment. The CAPS is a semi-structured clinical interview providing a measure of the severity of PTSD symptoms. A severity score is calculated by summing the frequency and intensity scores for each of the 17 DSM-IV criteria symptoms. Scores may range from 0 (no symptoms) to 136 (severe symptoms). | Baseline, Week 6 | 
| Efficacy, Measured by Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Score | The MADRS is a ten-item clinician-administered questionnaire used to measure the severity of depressive symptoms in patients with depressive disorders. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Change is the difference in scores between baseline and 6 weeks. | Baseline, Week 6 | 
| Safety, Measured by the Number of Subjects That Experienced an Adverse Event | The occurrence of adverse events will be recorded at the end of 6 weeks. | Baseline, Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep, Stress disorders, Post-traumatic