Analyzing Female Trauma Exposed Responses to a Medication (AFTER)

• ClinicalTrials.gov Identifier: NCT01814332
• Recruitment Status: Completed
• First Posted: March 19, 2013
• Results First Posted: April 25, 2016
• Last Update Posted: June 25, 2021
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Stress Disorders, Post-traumatic	Drug: GSK561679; Drug: Placebo	Phase 2

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: CRF Receptor Antagonist for PTSD and Related Sleep Disturbances in Women
• Actual Study Start Date: January 1, 2010
• Actual Primary Completion Date: June 30, 2014
• Actual Study Completion Date: October 31, 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: GSK561679; GSK561679, oral administration, 350mg/day, 6 week administration	Drug: GSK561679; GSK561679, oral administration, 350mg/day, 6 week administration; Other Name: CRF1 antagonist
Placebo Comparator: Placebo; Placebo compound treatment for comparison with IP	Drug: Placebo; Placebo compound treatment for comparison with IP; Other Name: Sugar pill

Outcome Measures

Primary Outcome Measures :

1. Efficacy, Measured by Change in the Clinician-Administered PTSD Scale (CAPS) Score [ Time Frame: Baseline, 6 weeks ]
   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.

Secondary Outcome Measures :

1. Efficacy, Measured by Response Rate of at Least 50% Improvement in CAPS Score at the End of 6 Weeks as Compared to Baseline [ Time Frame: Baseline, Week 6 ]
   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).
2. Efficacy, Measured by Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Score [ Time Frame: Baseline, Week 6 ]
   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.
3. Safety, Measured by the Number of Subjects That Experienced an Adverse Event [ Time Frame: Baseline, Week 6 ]
   The occurrence of adverse events will be recorded at the end of 6 weeks.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

San Francisco VA Medical Center, San Francisco, CA

San Francisco, California, United States, 94121

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Principal Investigator: Thomas C. Neylan, MD; San Francisco VA Medical Center, San Francisco, CA

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01814332
• Other Study ID Numbers: 09S-NIMH-002
• First Posted: March 19, 2013
• Results First Posted: April 25, 2016
• Last Update Posted: June 25, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by VA Office of Research and Development:

Stress disorders, Post-traumatic; Sleep

Additional relevant MeSH terms:

Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Trauma and Stressor Related Disorders; Mental Disorders