Stress Disorders, Post-traumatic
Conditions
Keywords
Stress disorders, Post-traumatic, Sleep
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).
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
Interventions
DRUGGSK561679
GSK561679, oral administration, 350mg/day, 6 week administration
DRUGPlacebo
Placebo compound treatment for comparison with IP
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy, Measured by Change in the Clinician-Administered PTSD Scale (CAPS) Score | 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
| Measure | Time frame | Description |
|---|---|---|
| Efficacy, Measured by Response Rate of at Least 50% Improvement in CAPS Score at the End of 6 Weeks as Compared to Baseline | 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). |
| Efficacy, Measured by Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Score | 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. |
| Safety, Measured by the Number of Subjects That Experienced an Adverse Event | Baseline, Week 6 | The occurrence of adverse events will be recorded at the end of 6 weeks. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from Emory University School of Medicine, Mount Sinai School of Medicine, Baylor College of Medicine, and the San Francisco VA Medical Center between January 2010 and June 2014.
Pre-assignment details
Subjects stopped psychotropic medications (w/ the exception of zolpidem, eszopiclone, and zaleplon for insomnia) w/in 2 weeks (6 weeks for fluoxetine) of Visit 1. Patients on ineffective psychotropic medications tapered off by the patients' prescribing doctor. 150 subjects did not proceed to randomization due to meeting exclusionary criteria.
Participants by arm
| Arm | Count |
|---|---|
| GSK561679 GSK561679, oral administration, 350mg/day, 6 week administration
GSK561679: GSK561679, oral administration, 350mg/day, 6 week administration | 63 |
| Placebo Placebo compound treatment for comparison with IP
Placebo: Placebo compound treatment for comparison with IP | 65 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 3 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | Protocol Violation | 0 | 4 |
| Overall Study | Withdrawal by Subject | 3 | 8 |
Baseline characteristics
| Characteristic | GSK561679 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 63 Participants | 65 Participants | 128 Participants |
| Region of Enrollment United States | 63 participants | 65 participants | 128 participants |
| Sex: Female, Male Female | 63 Participants | 65 Participants | 128 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 63 | 55 / 65 |
| serious Total, serious adverse events | 1 / 63 | 1 / 65 |
Outcome results
Primary
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.
Time frame: Baseline, 6 weeks
Population: Intent to treat analysis was performed using maximum likelihood estimation with mixed models to include all observations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK561679 | Efficacy, Measured by Change in the Clinician-Administered PTSD Scale (CAPS) Score | -26.02 score on a scale | Standard Deviation 22.28 |
| Placebo | Efficacy, Measured by Change in the Clinician-Administered PTSD Scale (CAPS) Score | -27.33 score on a scale | Standard Deviation 19.76 |
Secondary
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.
Time frame: Baseline, Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK561679 | Efficacy, Measured by Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Score | -7.83 Score on a scale | Standard Deviation 9.32 |
| Placebo | Efficacy, Measured by Change in the Montgomery-Asberg Depression Rating Scale (MADRS) Score | -5.98 Score on a scale | Standard Deviation 9.1 |
Secondary
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).
Time frame: Baseline, Week 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK561679 | Efficacy, Measured by Response Rate of at Least 50% Improvement in CAPS Score at the End of 6 Weeks as Compared to Baseline | 14 participants |
| Placebo | Efficacy, Measured by Response Rate of at Least 50% Improvement in CAPS Score at the End of 6 Weeks as Compared to Baseline | 18 participants |
Secondary
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.
Time frame: Baseline, Week 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK561679 | Safety, Measured by the Number of Subjects That Experienced an Adverse Event | 55 participants |
| Placebo | Safety, Measured by the Number of Subjects That Experienced an Adverse Event | 55 participants |