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A Randomized Clinical Trial of Mifepristone in PTSD

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ClinicalTrials.gov Identifier: NCT01946685
Recruitment Status : Unknown
Verified March 2015 by Julia A. Golier, M.D., James J. Peters Veterans Affairs Medical Center.
Recruitment status was:  Recruiting
First Posted : September 19, 2013
Last Update Posted : April 1, 2015
Sponsor:
Collaborators:
San Diego Veterans Healthcare System
Durham VA Medical Center
Information provided by (Responsible Party):
Julia A. Golier, M.D., James J. Peters Veterans Affairs Medical Center

Brief Summary:

Posttraumatic stress disorder (PTSD) is a common and disabling psychiatric disorder. Left untreated or under-treated, it can become a chronic condition associated with significant distress, depression, aggression, family disruption, and substance abuse. There is also accumulating evidence that combat-related PTSD is associated with an increased risk of morbidity and mortality. For the welfare of returning veterans with PTSD and their families, it is critical that this disorder is promptly identified and effectively treated. Considerable advances that have been made in the assessment and 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. Thus, blockade of the GR receptor with mifepristone may target unique aspects of PTSD and lead to clinically meaningful improvement in symptoms and cognition. There is preliminary 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). That there can be sustained clinical and neuropsychological effects of mifepristone and normalization of basal HPA axis activity after drug discontinuation in these disorders, has led to the view that mifepristone's actions include recalibration of a dysregulated HPA axis. Accordingly, we propose to study the effects of mifepristone in veterans with chronic PTSD to determine if it is efficacious in improving PTSD symptoms and associated clinical outcomes. To better understand the mechanism of action of mifepristone we propose to assess the effects of mifepristone on HPA axis activity and their relationship to treatment outcome and clinical response.

To achieve these objectives, we propose to conduct a Phase IIa, multi-site, double-blind, placebo controlled trial of mifepristone in veteran outpatients with military-related PTSD through the VA's Cooperative Clinical Trial Award program. We propose to enroll 136 unmedicated male veterans with military related PTSD at four VA sites (Albuquerque, NM, Bronx, NY, Durham, NC, and San Diego, CA). Eligible veterans will be randomly assigned in parallel groups to treatment with 600 mg/day mifepristone or placebo for one week and followed for up to three months. Using statistical selection theory, we propose to determine whether 600 mg of mifepristone yields a sufficiently high proportion of clinical responders after one month to warrant more extensive and definitive research as part of a Phase III trial. Secondarily, we seek to determine the effect of the dose of mifepristone compared to placebo on the trajectory of CAPS scores and the time to addition of rescue medication, as well as compare rates of adverse events and serious adverse events across the three groups. We 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 ACTH levels to clinical response and the time to addition of rescue medications.


Condition or disease Intervention/treatment Phase
PTSD Drug: 600 mg/day Mifepristone Drug: Placebo Phase 2

Detailed Description:

Novel approaches to the treatment of post traumatic stress disorder (PTSD) in veterans are urgently needed. This proposal seeks to test an innovative approach, one that involves careful pharmacological manipulation of the body's major stress system, the hypothalamic-pituitary-adrenal (HPA) axis, using the dose level of the FDA-approved drug, mifepristone (600 mg/day).

We therefore seek to examine the effects of glucocorticoid receptor antagonist, mifepristone (Mifeprex®), on clinical and cognitive outcomes in veterans with posttraumatic stress disorders.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 136 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone
Study Start Date : November 2012
Estimated Primary Completion Date : November 2015
Estimated Study Completion Date : June 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 600 mg/day Mifepristone
600 mg/day Mifepristone for 7 days
Drug: 600 mg/day Mifepristone
Placebo Comparator: Placebo
No active treatment by intervention, supportive treatment avaialble.
Drug: Placebo



Primary Outcome Measures :
  1. CAPS score [ Time Frame: Four Weeks ]
    The primary clinical outcome measure will be the presence or absence of a clinical response, defined as a 30% or greater reduction in total CAPS (past week symptom status) score from baseline to four weeks



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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:

  • Subject is a male combat veteran.
  • Veteran meets DSM-IV diagnostic criteria for chronic PTSD precipitated by combat or another traumatic event which occurred during military service.
  • Veteran has a CAPS total score (past month symptom status) greater than or equal to 50 at screening.
  • Veteran is free of psychotropic medication (a minimum of five half-lives must have elapsed 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, carvedilol or some anticonvulsants (phenytoin, phenobarbital, or carbamazepine)within five half-lives prior to randomization.
  • Veteran is taking oral corticosteroidswithin 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 morning plasma cortisol level less than 5 mcg/dl at screening.
    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 mEq/L)
    7. Veteran has a history of hepato-biliary disease or an AST, ALT greater than 1.5X the ULN.
    8. Veteran has a history of renal disease or an estimated GFR of < 70 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.
  • 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, including the clinical impression that the veteran would be unable to remain free of standard pharmacotherapy for at least one month.

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): NCT01946685


Locations
United States, New York
James J. Peters VA Medical Center Recruiting
Bronx, New York, United States, 10468
Contact: Kirklyn Escondo    718-584-9000 ext 6567    kirklyn.escondo@va.gov   
Sponsors and Collaborators
James J. Peters Veterans Affairs Medical Center
San Diego Veterans Healthcare System
Durham VA Medical Center
Investigators
Study Chair: J Golier, MD James J. Peters Veterans Affairs Medical Center

Responsible Party: Julia A. Golier, M.D., Psychiatry Section Chief, James J. Peters Veterans Affairs Medical Center
ClinicalTrials.gov Identifier: NCT01946685     History of Changes
Other Study ID Numbers: GOL-11-80
First Posted: September 19, 2013    Key Record Dates
Last Update Posted: April 1, 2015
Last Verified: March 2015

Additional relevant MeSH terms:
Mifepristone
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