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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01739335
First received: November 15, 2012
Last updated: August 19, 2014
Last verified: August 2014
  Purpose

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, the investigators 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 the investigators propose to assess the effects of mifepristone on HPA axis activity and their relationship to treatment outcome and clinical response.

To achieve these objectives, the investigators 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. The investigators 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. In this initial trial we propose to study the effects of mifepristone in veterans with PTSD as monotherapy, rather than as an adjunctive treatment, in order to better detect a signal if there is one.

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 ACTH levels to clinical response and the time to addition of rescue medications.


Condition Intervention Phase
Stress Disorders, Post-Traumatic
Drug: Mifepristone (600 mg/day) or placebo (sugar pill)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Presence or absence of a clinical response, defined as a 30% or greater reduction in total CAPS (past week symptom status) [ Time Frame: Treatment baseline to four weeks ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • Changes in CAPS (past week symptom status) score from baseline to weeks 1, 4, and 12 to capture time by treatment interaction, the proportion of clinical responders at 12 weeks for deciding sustainability, the time to addition of rescue medication to det [ Time Frame: Treatment baseline to weeks 1, 4, and 12 ] [ Designated as safety issue: Yes ]
    The secondary outcome measures will be the changes in CAPS (past week symptom status) score from baseline to weeks 1, 4, and 12 to capture time by treatment interaction, the proportion of clinical responders at 12 weeks for deciding sustainability, the time to addition of rescue medication to determine hazard rates for participants who require additional PTSD pharmacotherapy, and the percentage of AE and SAEs to study safety and tolerability of mifepristone


Estimated Enrollment: 136
Study Start Date: November 2012
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Mifepristone (600 mg/day)
600 mg/day mifepristone for one week
Drug: Mifepristone (600 mg/day) or placebo (sugar pill)
600 mg/day mifepristone or placebo (sugar pill) for one week
Placebo Comparator: Sugar pill
Placebo (sugar pill) for one week
Drug: Mifepristone (600 mg/day) or placebo (sugar pill)
600 mg/day mifepristone or placebo (sugar pill) for one week

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 89 Years
Genders 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 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 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:
  • Veteran has a history of adrenal insufficiency or a morning plasma cortisol level less than 5 mcg/dl at screening.
  • 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.
  • Veteran has diabetes mellitus, an endocrinopathy, or another major medical illness.
  • 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
  • Veteran has prolonged QTc interval >450 msec on ECG at screening.
  • Veteran has hypokalemia at screening (defined as potassium level < 3.5 mEq/L)
  • Veteran has a history of hepato-biliary disease or an AST, ALT greater than 1.5X the ULN.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01739335

Contacts
Contact: Julia A Golier, MD (718) 584-9000 ext 5196 Julia.Golier@va.gov
Contact: Eran Chemerinski (718) 584-9000 ext 5169 Eran.Chemerinski@va.gov

Locations
United States, California
VA San Diego Healthcare System, San Diego, CA Recruiting
San Diego, California, United States, 92161
Contact: Dewleen Baker, MD    858-552-8585 ext 2230    dgbaker@ucsd.edu   
United States, New Mexico
New Mexico VA Health Care System, Albuquerque, NM Recruiting
Albuquerque, New Mexico, United States, 87108-5153
Contact: Gerardo Villarreal, MD    505-265-1711 ext 5942    gerardo.villarreal@va.gov   
United States, New York
James J. Peters VA Medical Center, Bronx, NY Recruiting
Bronx, New York, United States, 10468
Contact: Anthony Rotolo    718-584-9000 ext 6044    Anthony.Rotolo@va.gov   
Principal Investigator: Julia A. Golier, MD         
United States, North Carolina
Durham VA Medical Center, Durham, NC Recruiting
Durham, North Carolina, United States, 27705
Contact: Michael Hertzberg, MD    919-286-0411 ext 7967    michael.hertzberg@va.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Julia A. Golier, MD Department of Veterans Affairs
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01739335     History of Changes
Other Study ID Numbers: MHBA-04-11S
Study First Received: November 15, 2012
Last Updated: August 19, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
Stress Disorders, Post-Traumatic
Mifepristone
Veterans
Clinical Trial

Additional relevant MeSH terms:
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Disease
Anxiety Disorders
Mental Disorders
Pathologic Processes
Mifepristone
Abortifacient Agents, Steroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
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

ClinicalTrials.gov processed this record on September 22, 2014