A Randomized Clinical Trial of Mifepristone in PTSD

PTSD Clinical Trial

Official title:

Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01946685
• Other study ID #: GOL-11-80
• Status: Recruiting
• Phase: Phase 2
• First received: September 17, 2013
• Last updated: March 30, 2015
• Start date: November 2012
• Est. completion date: June 2016

Study information

• Verified date: March 2015
• Source: James J. Peters Veterans Affairs Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 136
• Est. completion date: June 2016
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 89 Years

Eligibility

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.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• PTSD

Intervention

Drug:
• 600 mg/day Mifepristone

• Placebo

Locations

Country	Name	City	State
United States	James J. Peters VA Medical Center	Bronx	New York

Sponsors (3)

Lead Sponsor	Collaborator
James J. Peters Veterans Affairs Medical Center	Durham VA Medical Center, San Diego Veterans Healthcare System

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CAPS score	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	Four Weeks	No