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Novel Therapeutics in Posttraumatic Stress Disorder (PTSD): A Randomized Clinical Trial of Mifepristone

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ClinicalTrials.gov Identifier: NCT01739335
Recruitment Status : Completed
First Posted : December 3, 2012
Results First Posted : January 24, 2018
Last Update Posted : January 24, 2018
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:

Posttraumatic stress disorder (PTSD) is a common and disabling psychiatric disorder for Veterans. Left untreated or under-treated, it can become a chronic condition associated with significant distress, depression, aggression, family disruption, substance abuse and an increased risk of morbidity and mortality. Considerable advances were made in the treatment of PTSD in recent years; however, psychopharmacological treatments have been shown to be largely ineffective for Veterans with PTSD.

To address this gap, this proposal seeks to test an innovative treatment approach in PTSD - pharmacological manipulation of the body's major stress system (the hypothalamic-pituitary-adrenal (HPA) axis) with mifepristone. At high doses mifepristone is a glucocorticoid receptor (GR) antagonist with peripheral and central nervous system effects, making it a compound of interest in the treatment of stress related disorders. There is abundant evidence of enhanced GR sensitivity in Veterans with PTSD which is thought to underlie some of the symptoms of PTSD and associated disturbances in mood and cognition. There is also evidence that short-term mifepristone treatment has sustained beneficial effects on mood, cognition and sleep disturbance in some neuropsychiatric conditions (major depression, bipolar disorder, primary insomnia). The purpose of the study is to examine the effects of mifepristone to determine if it is efficacious in improving PTSD symptoms and associated clinical outcomes.

To achieve these objectives, the investigators propose to conduct a Phase IIa, multi-site, double-blind, placebo controlled trial of mifepristone in male Veteran outpatients with chronic PTSD through the VA's Cooperative Clinical Trial Award program. The investigators propose to enroll 90 subjects at multiple VA sites based on an estimated attrition rate of 20%. Eligible Veterans will be randomly assigned to the treatment of mifepristone (600 mg/day) or placebo for one week and followed for up to three months. The investigators will also describe the effects of mifepristone on several other clinical parameters including PTSD symptomology, depression severity, sleep quality, and functional impairment. Several measures of neuroendocrine functioning will also be obtained to explore the relationship of plasma cortisol and adrenocorticotropic hormone (ACTH) levels to clinical response and the time to addition of rescue medications.


Condition or disease Intervention/treatment Phase
Stress Disorders, Post-Traumatic Drug: Mifepristone Oral Tablet [Korlym] Drug: Placebo Oral Tablet Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double blinded Placebo-controlled
Primary Purpose: Treatment
Official Title: Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone
Actual Study Start Date : November 19, 2012
Actual Primary Completion Date : September 19, 2016
Actual Study Completion Date : November 16, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Mifepristone
'Mifepristone Oral Tablet [Korlym] (2 x 300mg =600 mg total, once daily, at bedtime) for 7 days
Drug: Mifepristone Oral Tablet [Korlym]
2 Mifepristone 300 MG Oral Tablets once daily (600mg total) for 7 days
Other Name: Korlym

Placebo Comparator: Placebo
Placebo Oral tablet (2 sugar pills, once daily, at bedtime) for 7 days
Drug: Placebo Oral Tablet
2 Placebo Oral Tablets once daily for 7 days
Other Name: Sugar pill




Primary Outcome Measures :
  1. Percentage of Clinical Responders at 4-week Follow-up [ Time Frame: week 4 ]
    A clinical responder at 4-week is defined as a participant who achieves a 30% or greater reduction in CAPS total score (past week symptom status) from baseline to 4-week follow-up. The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. The CAPS total score (ranges 0 - 136) is the sum of 17 PTSD symptoms (each symptom is the sum of the frequency score (ranges 0-4) and the intensity score (ranges 0-4)) in the three different symptom subcategories (intrusive/re-experiencing (0-40), avoidance/numbing (0-56) and hyperarousal (0-40)). The higher is the CAPS total score, the worse is the PTSD symptom. Higher percentage of responders indicate a better drug effect in treating PTSD symptoms.


Secondary Outcome Measures :
  1. Percentage of Clinical Responders at 12-week Follow-up (End of Study) [ Time Frame: week 12 ]
    A clinical responder at 12-week is defined as a participant who achieves a 30% or greater reduction in CAPS total score (past week symptom status) from baseline to 12-week follow-up. The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. The CAPS total score (ranges 0 - 136) is the sum of 17 PTSD symptoms (each symptom is the sum of the frequency score (ranges 0-4) and the intensity score (ranges 0-4)) in the three different symptom subcategories (intrusive/re-experiencing (0-40), avoidance/numbing (0-56) and hyperarousal (0-40)). The higher is the CAPS total score, the worse is the PTSD symptom. Higher percentage of responders indicate a better drug effect in treating PTSD symptoms.

  2. Change in CAPS Total Score From Baseline to 4-week and 12-week [ Time Frame: baseline to 4-week ]
    The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. The CAPS total score ranges 0 to 136, which is the sum of 17 PTSD symptoms (each symptom is the sum of the frequency score (ranges 0-4) and the intensity score (ranges 0-4)) in the three different symptom subcategories (intrusive/re-experiencing (0-40), avoidance/numbing (0-56) and hyperarousal (0-40)). A higher CAPS total score indicates worse PTSD symptoms. A positive change score indicates an increased CAPS total score (i.e., worse PTSD symptoms) at 4-week (12-week) compared to its baseline value, while a negative change score indicates an opposite direction.


Other Outcome Measures:
  1. Change in CAPS Intrusive Symptom Scores From Baseline to 4-Week and 12-Week [ Time Frame: baseline to 4-Week and 12-Week ]
    The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. Its intrusive symptom subscale (ranges 0 - 40) is the sum of 5 PTSD symptoms (each ranges 0 - 8) in the intrusive/re-experiencing symptom subcategory. A higher intrusive symptom score indicates worse PTSD symptoms. A positive change score indicates an increased intrusive symptom score (i.e., worse PTSD symptoms) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

  2. Change in CAPS Avoidance Symptom Scores From Baseline to 4-Week and 12-Week [ Time Frame: baseline to 4-Week and 12-Week ]

    The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. Its avoidance symptom subscale (ranges 0 - 56) is the sum of 7 PTSD symptoms (each ranges 0 - 8) in the avoidance/emotional numbing symptom subcategory. A higher avoidance symptom score indicates worse PTSD symptoms. A positive change score indicates an increased avoidance symptom score (i.e., worse PTSD symptoms) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

    The higher is the avoidance/emotional numbing PTSD subscale score, the worse is the PTSD symptom.


  3. Change in CAPS Hyperarousal Symptom Scores From Baseline to 4-Week and 12-Week [ Time Frame: baseline to 4-Week and 12-Week ]
    The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. Its hyperarousal symptom subscale (ranges 0 - 40) is the sum of 5 PTSD symptoms (each ranges 0 - 8) in the hyperarousal symptom subcategory. A higher hyperarousal symptom score indicates worse PTSD symptoms. A positive change score indicates an increased hyperarousal symptom score (i.e., worse PTSD symptoms) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

  4. Change in Depression (Measured by the BDI Total Score) From Baseline to 4-Week and 12-Week [ Time Frame: baseline to 4-Week and 12-Week ]
    The Beck Depression Inventory (BDI) total score (ranges 0-63) is the sum of 21 items (each item rated on a 4-point scale of 0 to 3) relating to symptoms of depression, cognitions, and physical symptoms. The BDI total score measures the overall severity of depression. The higher the BDI total score, the more severe the depression. A positive change score indicates an increased BDI total score (i.e., more severe depression) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

  5. Changes in PTSD Symptom Severity (Measured by the Stressful Life Total Score From the PTSD Checklist) From Baseline to 4-Week and 12-Week [ Time Frame: baseline to 4-Week and 12-Week ]
    Stressful life total score (ranges 17-85) is the sum of the severity ratings of the 17 PTSD-related symptoms (each symptom is rated on a 5-point scale of 1=not at all to 5=extremely) over the past week. It evaluates the extent to which responders have been "bothered" by the symptoms of PTSD. The higher stressful life score indicates more stressful life events. A positive change score indicates an increased stressful life total score (i.e., more stressful life events) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

  6. Change in Sleep Quality (Measured by the PSQI Total Score) From Baseline to 4-Week and 12-Week [ Time Frame: baseline to 4-Week and 12-Week ]
    The Pittsburgh Sleep Quality Index (PSQI) assesses self-report sleep quality and disturbances. Nineteen individual items generate 7 component scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction. Each component is scored from 0=better to 3=worse. The sum of the 7 component scores yields the PSQI total score (range 0-21) with a higher score indicating a worse sleep quality. A positive change score indicates an increased PSQI total score (i.e., worse sleep quality) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

  7. Change in Anger Level (Measured by the STAXI Total Score) From Baseline to 4-Week and 12-Week [ Time Frame: Baseline to 4-week and 12-week ]
    The State-Trait Anger Expression Inventory (STAXI) total score is the sum of 10 items assessing intensity of anger as an emotional state (State Anger) and the disposition to experience angry feelings as a personality trait (Trait Anger). Each item consists of a 4-point scale (1=not at all, 4=very much) that assess intensity of anger at a particular moment and the frequency of anger experience, expression and control. The STAXI total score ranges from 10 to 40, with a higher score indicating a higher intensity of anger.The sum of the 7 component scores yields the PSQI total score (range 0-21) with a higher score indicating a worse sleep quality. A positive change score indicates an increased STAXI total score (i.e., higher intensity of anger) at 4-week (or 12-week) compared to its baseline value, while a negative change score indicates an opposite direction.

  8. Change in Plasma Cortisol From Baseline to 1-Week [ Time Frame: Baseline to 1-week ]
    Mifepristone will induce acute increase in Cortisol and ACTH levels. Higher Cortisol value indicates higher magnitude of mifepristone's effects on negative feedback inhibition. Cortisol value in placebo group at follow-up visits will remain at the similar level as its baseline magnitude. A positive change value indicates increased cortisol level at 1-week (i.e., higher magnitude on negative feedback inhibition) compared to its baseline value, while a negative change value indicates an opposite direction.

  9. Change in Plasma Cortisol From Baseline to 4-Week [ Time Frame: Baseline to 4-week ]
    Mifepristone will induce acute increase in Cortisol and ACTH levels. Higher Cortisol value indicates higher magnitude of mifepristone's effects on negative feedback inhibition. Cortisol value in placebo group at follow-up visits will remain at the similar level as its baseline magnitude. A positive change value indicates an increased cortisol level at 4-week (i.e., higher magnitude on negative feedback inhibition) compared to its baseline value, while a negative change value indicates an opposite direction.

  10. Change in Adrenocorticotropic Hormone (ACTH) From Baseline to 1-week [ Time Frame: baseline to 1-week ]
    Mifepristone will induce acute increase in Cortisol and ACTH levels. Higher ACTH value indicates higher magnitude of mifepristone's effects on negative feedback inhibition. ACTH value in placebo group at follow-up visits will remain at the similar level as its baseline magnitude. A positive change value indicates an increased ACTH level at 1-week (i.e., higher magnitude on negative feedback inhibition) compared to its baseline value, while a negative change value indicates an opposite direction.

  11. Change in Adrenocorticotropic Hormone (ACTH) From Baseline to 4-week [ Time Frame: Baseline to 4-week ]
    Mifepristone will induce acute increase in Cortisol and ACTH levels. Higher ACTH value indicates higher magnitude of mifepristone's effects on negative feedback inhibition. ACTH value in placebo group at follow-up visits will remain at the similar level as its baseline magnitude. A positive change value indicates an increased ACTH level at 4-week (i.e., higher magnitude on negative feedback inhibition) compared to its baseline value, while a negative change value indicates an opposite direction.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant is a male veteran.
  • Veteran meets the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic criteria for chronic PTSD.
  • Veteran has a CAPS total score (past month symptom status) greater than or equal to 50 at screening.
  • For veterans taking psychotropic medications (i.e., antidepressants, antipsychotics or anxiolytics/sedative-hypnotics), the veteran will be on a stable dose for at least five weeks prior to screening.
  • For veterans not taking psychotropic medication, a minimum of five half-lives must elapse prior to screening since the veteran last took any given psychotropic medication.

Exclusion Criteria:

  • Veteran recently continued to engage in a maladaptive pattern of alcohol/substance use and/or abuse (as defined in protocol).
  • Veteran has used potent CYP3A4 inhibitors (fluconazole, ketoconazole, itraconazole, erythromycin, rifampin) and inducers within five half-lives prior to randomization.
  • Veteran is taking simvastatin, lovastatin, fentanyl, pimozide, bupropion, nefazodone, dihydroergotamine, ergotamine, quinidine, sirolimus, tacrolimus, or clarithromycin, cyclosporine, St. John's Wort, diltiazem, verapamil, propranolol, alprazolam, carvedilol or some anticonvulsants (phenytoin, phenobarbital, or carbamazepine) within five half-lives prior to randomization.
  • Veteran is taking oral corticosteroids within five half-lives prior to randomization.
  • Veteran should be free of a major medical illness and medical condition that contraindicate the administration of mifepristone. These include but are not limited to:

    1. Veteran has a history of adrenal insufficiency or a low plasma cortisol level at screening (a.m. level less than 5 mcg/dl or a p.m. level of less than 3 mcg/dl.)
    2. Veteran has a history of severe traumatic brain injury, a history of a stroke, or another neurological illness or injury likely to impact cognitive functioning.
    3. Veteran has diabetes mellitus, an endocrinopathy, or another major medical illness.
    4. Veteran has a history of cardiovascular disease including a history of angina, myocardial infarction or other evidence of coronary artery disease, or congestive heart failure.
    5. Veteran has prolonged QTc interval >450 msec on ECG at screening.
    6. Veteran has hypokalemia at screening (defined as potassium level < 3.5 Milliequivalent Per Liter (mEq/L)).
    7. Veteran has a history of hepato-biliary disease or an aspartate transaminase (AST), alanine transaminase (ALT) greater than 2 times the Upper Limit of Normal (ULN).
    8. Veteran has a history of renal disease or an estimated glomerular filtration rate (GFR) of < 60 ml/min.
  • Veteran has a lifetime diagnosis of schizophrenia, schizoaffective disorder, or type I bipolar disorder.
  • Veteran has a history of attempted suicide within the previous two years or active suicidal ideation within the past month as assessed by the Columbia-Suicide Severity Rating Scare (C-SSRS).
  • Veteran is currently receiving specialized trauma-focused psychotherapy, such as prolonged exposure therapy and cognitive processing therapy.
  • Veteran is not willing to use effective means of birth control during the study.
  • Veteran has a history of allergic reaction to mifepristone.
  • Veteran is found to be unsuitable for study participation at the discretion of the site investigator for any reason.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01739335


Locations
United States, California
VA San Diego Healthcare System
San Diego, California, United States, 92161
United States, New Mexico
Albuquerque VA Medical Center
Albuquerque, New Mexico, United States, 87108
United States, New York
James J. Peters VA Medical Center
Bronx, New York, United States, 10468
United States, North Carolina
Durham VA Medical Center
Durham, North Carolina, United States, 27705
Salisbury W.G. (Bill) Hefner VA Medical Center
Salisbury, North Carolina, United States, 28144
Sponsors and Collaborators
VA Office of Research and Development
Investigators
Principal Investigator: Julia A Golier, MD James J. Peters Veterans Affairs Medical Center

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT01739335     History of Changes
Other Study ID Numbers: MHBA-04-11S
First Posted: December 3, 2012    Key Record Dates
Results First Posted: January 24, 2018
Last Update Posted: January 24, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by VA Office of Research and Development:
Stress Disorders, Post-Traumatic
Mifepristone
Veterans
Clinical Trial

Additional relevant MeSH terms:
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Trauma and Stressor Related Disorders
Mental Disorders
Mifepristone
Coal Tar
Abortifacient Agents, Steroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptives, Oral, Synthetic
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Contraceptives, Postcoital, Synthetic
Contraceptives, Postcoital
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Luteolytic Agents
Menstruation-Inducing Agents
Keratolytic Agents
Dermatologic Agents