Novel Therapeutics in Posttraumatic Stress Disorder (PTSD): A Randomized Clinical Trial of Mifepristone
Condition: Stress Disorders, Post-Traumatic
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Intervention: Mifepristone Oral Tablet [Korlym]; Placebo Oral Tablet
Intervention description: 2 Mifepristone 300 MG Oral Tablets once daily (600mg total) for 7 days; 2 Placebo Oral Tablets once daily for 7 days
Intervention MeSH terms: Mifepristone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking description: Double blinded Placebo-controlled
Enrollment: 81.0
Sex: Male
Minimum age: 18 Years
Maximum age: 89 Years
Healthy volunteers: No
Keywords: Stress Disorders, Post-Traumatic; Mifepristone; Veterans; Clinical Trial

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.
    

Eligibility 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.