Stress Disorders, Post-Traumatic
Conditions
Keywords
PTSD, Anxiety Disorder, Corticotropin releasing factor, Women
Brief summary
This study will test the hypothesis of whether an antagonist at the corticotropin releasing factor type 1 (CRF1) receptor (i.e. GSK561679) is superior to placebo in reducing symptoms of post-traumatic stress disorder (PTSD).
Detailed description
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. 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.
Interventions
DRUGGSK561679
GSK561679, oral administration, 350mg/day, 6 week administration
DRUGPlacebo
Matching placebo, oral administration, 1 pill/day for 6 weeks
Sponsors
Icahn School of Medicine at Mount Sinai
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Female between 21-65 years of age * Able to provide consent and willing to participate in research * Fulfills Diagnostic and Statistical Manual of Mental Disorders, 4th edition (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
* Lifetime or current diagnosis of schizophrenia or other psychotic disorder, bipolar disorder, obsessive compulsive disorder (OCD), or current Axis I disorder \[(except for major depression secondary to the PTSD, dysthymia, depression not otherwise specified (NOS) and anxiety disorders (panic disorder, social phobia, generalized anxiety disorder (GAD), specific phobia)\] * 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 * Current evidence or history of significant unstable medical illness or organic brain impairment, including stroke, central nervous system (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. * Patients who in the investigator's judgment pose a current suicidal or homicidal risk * DSM-IV substance abuse or dependence within the past 90 days. Subject has a positive test for illegal substances. * Diagnosis of anorexia nervosa or bulimia in the past year. * 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 (alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total or direct bilirubin \> 1.5 x ULN, unless consistent with presumed or diagnosed Gilbert's disease) * Subject has taken systemic corticosteroids within 2 weeks of the Randomization Visit * 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. * Subject who is likely to require the use of the following medications: Chronic (for more than 2 weeks), regular nonsteroidal anti-inflammatory drugs (NSAID) use. Any use of aspirin (including low dose) * 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. * 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. * Subject has a stool positive for occult blood. * Pregnancy or lactation * Subjects who, in the opinion of the investigator, would be non compliant with the visit schedule or study procedures (e.g. illiteracy, planned vacations, or planned hospitalizations during the study). * Previous treatment with CRF1 receptor antagonist * Any laboratory abnormality that in the investigator's judgment is considered to be clinically significant (blood pressure, electrocardiogram (ECG), thyroid stimulating hormone (TSH), liver function test (LFT), etc.) * Patients who are receiving exposure-based psychotherapy that targets PTSD symptoms * Current or planned litigation or other actions related to secondary gain regarding the traumatic event * 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: 1. Corrected QT Interval (QTc) \> 450 msec; 2. any cardiac condition or ECG evidence that the investigator feels may predispose the subject to ischemia or arrhythmia; or 3. any ECG abnormality that, in the investigator's judgment, may pose a potential safety concern
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy, Measured by Change in the Clinician-Administered PTSD Scale (CAPS) Score | Baseline, Week 6 | 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 has 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 | 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 University of California San Francisco 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. 139 subjects did not proceed to randomization due to meeting exclusionary criteria.
Participants by arm
| Arm | Count |
|---|---|
| GSK561679 Adult women with DSM-IV-defined PTSD received GSK561679 at a fixed dose of 350 mg/day for 6-weeks | 63 |
| Placebo Adult women with DSM-IV defined PTSD received matching placebo for 6 weeks | 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 |
| 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, Week 6
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
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 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 has 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
Population: Intent to treat analysis was performed with missing subjects considered to be non-responders.
| 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: Week 6
Population: Intent to Treat
| 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 |