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
Study type: Interventional
Phase: Phase 2

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.
    

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 one dose of the FDA-approved drug,
      mifepristone (600 mg/day).

      The rationale for a treatment trial of mifepristone in PTSD is based on the wealth of
      knowledge available about persistent alterations of the HPA axis in PTSD and their
      interactions with the central and autonomic nervous system and the immune system. The most
      consistent HPA axis findings in PTSD, taken together, suggest there is increased sensitivity
      to the effects of glucocorticoids in the presence of increased central activation of the HPA
      axis. Among the most replicated neuroendocrine findings have been of elevated levels of
      corticotropin-releasing factor (CRF) in the cerebrospinal fluid (CSF), an exaggerated
      cortisol response to emotional stressors, and an exaggerated suppression of cortisol to the
      synthetic glucocorticoid dexamethasone (DEX). The earliest studies of the effects of
      dexamethasone (DEX) using the standard 1.0 mg dose, found that PTSD, unlike major depression,
      was not associated with higher rates of cortisol non-suppression and there was a trend for
      lower cortisol levels post-DEX in PTSD. A lower dose (0.5 mg) was employed to test the
      hypothesis of enhanced suppression of cortisol to DEX in Vietnam Veterans with PTSD, which
      was confirmed. Since then, with few exceptions, greater suppression of cortisol to low-dose
      DEX has been found in PTSD subjects, compared to unexposed and/or trauma-exposed controls
      without PTSD, in diverse samples, including samples of persons exposed to combat, natural
      disasters, domestic violence, the Holocaust, and childhood physical and sexual abuse.
      Furthermore, the extent of cortisol suppression is associated with PTSD symptom severity. The
      finding of a greater down-regulation of lymphocyte GR post-DEX suggests that the
      dexamethasone suppression test (DST) findings may be attributable to more responsive
      glucocorticoid receptors. More recent studies have demonstrated increased suppression of ACTH
      to DEX confirming increased glucocorticoid responsivity at the level of the pituitary. The
      studies of the effects of DEX on HPA axis activity suggest there is enhanced negative
      feedback inhibition of the HPA axis in PTSD. Such inhibition could help to explain why
      despite evidence of central HPA axis activation and an exaggerated response of cortisol to
      stressors and to ACTH stimulation in PTSD, 24-hour basal cortisol levels are not typically
      elevated and indeed are even sometimes low.

      Mifepristone is a selective type II glucocorticoid receptor antagonist with a favorable
      safety profile. It binds to the same site as the synthetic glucocorticoid dexamethasone and
      blocks the negative feedback control of cortisol on the pituitary. Thus, mifepristone,
      because it directly antagonizes the glucocorticoid receptor, which has been found to be more
      sensitive in PTSD in several models, is ideally suited for use in determining the
      pathophysiological significance of increased glucocorticoid receptor sensitivity in PTSD and
      whether its attenuation is of therapeutic value.

      The investigators propose to study the clinical, neuropsychological, and neuroendocrine
      effects of short-term treatment with one dose of mifepristone (600 mg/day) in a
      well-characterized sample of Veterans with PTSD to determine if this treatment is effective
      in achieving a clinical response in PTSD, as well as improving clinical symptoms and quality
      of life. Furthermore, if pulse therapy with mifepristone has sustained effects, it holds out
      the promise of a very different approach to pharmacological treatment, one that may be
      preferable to Veterans who do not want to be on psychopharmacological treatments continuously
      or long-term.

      Primary Objective

      1. To determine whether 600 mg of mifepristone daily for one week in male Veterans with
      chronic PTSD yields a sufficiently high proportion of clinical responders after one month to
      warrant more extensive and definitive research.

      Secondary Objectives

        1. To study the trajectories of Clinician Administered PTSD Scale (CAPS)(CAPS) (past week
           symptom status) scores over the study duration for mifepristone and placebo.

        2. To determine the effect of mifepristone compared to placebo on the time to addition of
           rescue medication.

        3. To determine if a Phase III study is justified.

        4. To compare adverse events (AEs) and serious adverse events (SAEs) in the two groups.

      This Phase IIa clinical trial seeks to enroll 90 eligible male Veterans (assumes 20%
      attrition rate) with chronic PTSD. Participants will be randomly assigned to treatment with
      600 mg/day mifepristone or placebo for one week and assessed for clinical outcomes at one and
      three months follow-up. Eligibility will be based on the inclusion and exclusion criteria
      which are enumerated below and in the Human Participants section. The investigators plan to
      include male Veterans with chronic PTSD who are not receiving psychotropic medication. The
      inclusion and exclusion criteria were selected in order to include as representative a sample
      as possible while also addressing safety concerns. Veterans who are actively suicidal as
      assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) or who have attempted suicide
      within the past two years will be excluded. (If suicidality is identified, the necessary
      steps will be taken to ensure the appropriate clinical care is provided, and the local
      suicide prevention policies implemented.) Veterans with adrenal insufficiency will be
      excluded, as will Veterans with other major medical or neurological illnesses, as they may be
      at increased risk of developing adverse events. Veterans with renal disease/impairment,
      hepatic disease/impairment, cardiac illness (e.g. coronary vascular disease, congestive heart
      failure), or hypokalemia at screening will also be excluded. Since mifepristone use can
      prolong the corrected QT (QTc) interval in a dose-related manner, Veterans with a prolonged
      QTc interval, defined as >450 msec, on the ECG at screening will be excluded. To evaluate QTc
      prolongation post-mifepristone treatment, an ECG will also be performed at both the 3 day
      follow up visit (visit 1.5) and 1 week follow-up visit (week 1, visit 2).

      Participants on potent CYP3A4 inhibitors (fluconazole, ketoconazole, itraconazole,
      erythromycin, rifampin) and some anticonvulsants (e.g., phenytoin, phenobarbital, and
      carbamazepine) will be excluded since these medications impact the metabolism of mifepristone
      (see Risk/Benefit Assessment for details). Due to an increased risk of adverse drug
      reactions, Veterans taking simvastatin, lovastatin, fentanyl, pimozide, bupropion,
      nefazodone, dihydroergotamine, ergotamine, quinidine, sirolimus, carvedilol, propanolol,
      diltiazem, verapamil or tacrolimus will also be excluded. Since the impact of mifepristone on
      the male reproductive system has not been extensively studied, only Veterans willing to use
      effective means of birth control for up to 90 days after mifepristone ingestion will be
      eligible; this will cover the critical period of fetal development.

      Psychotropic medication use is exclusionary at study entry; Veterans who have been previously
      treated with a stable regimen may not be enrolled until a minimum of five half-lives have
      elapsed since the Veteran last took any psychotropic medications. (Sleep aids such as
      trazodone (up to 50 mg/day) or zolpidem (up to 10 mg/day) may be offered to Veterans with
      insomnia on an as-needed basis at the onset of the study.) Major depression and other anxiety
      disorders are not exclusionary since they frequently co-occur with PTSD and it remains
      unclear whether their presence represents true comorbidity, symptom overlap, or severe
      illness. Since mild head trauma is common in the military population in general, excluding
      such participants would diminish the generalizability of the sample; participants with severe
      traumatic brain injury (TBI), defined as an extended period of unconsciousness or amnesia
      following injury, will be excluded. The Ohio State University (OSU) TBI Identification Method
      will be used to assess lifetime history of TBI. This method first establishes all significant
      injuries in one's life and then determines if a TBI may have occurred based on whether the
      participant experienced a loss of consciousness (LOC) and, if so, for how long. A person is
      said to have a mild TBI if LOC does not exceed 30 minutes for any injury, a moderate TBI if
      LOC is between 30 minutes and 24 hours, and a severe TBI if LOC exceeds 24 hours. The OSU TBI
      assessment will be administered by a trained rater during the psychiatric evaluation
      conducted at screening.

      Additionally, Veterans diagnosed with alcohol/substance abuse and dependence will be excluded
      only if they are recently engaged in a maladaptive pattern of use or abuse. More
      specifically, persons who meet diagnostic criteria for alcohol/substance dependence will be
      excluded if they have manifested dependence within the previous three months (i.e., have met
      three or more of the seven criteria for a maladaptive pattern of use in the last three
      months). Persons with alcohol/substance abuse (who, by definition, do not meet criteria for
      alcohol dependence) will be excluded if they have shown a maladaptive pattern of alcohol use
      during the past one month (i.e., have met one or more of the four criteria for a maladaptive
      pattern of abuse).

      Veterans who are currently receiving psychotherapies - individually or in a group setting -
      that are considered to have significant benefit for PTSD, according to the VA and Department
      of Defense (DoD's) Treatment Guidelines, will also be excluded. These therapies are cognitive
      therapy for PTSD (e.g. cognitive processing therapy (CPT)), exposure therapy (e.g., prolonged
      exposure therapy), stress inoculation training, and eye movement desensitization and
      reprocessing (EMDR). Other forms of therapy and case management which do not specifically
      target PTSD symptoms and/or have not been shown to provide significant benefit in PTSD will
      be allowed at entry and throughout the study (e.g. supportive therapy, psychodynamic therapy,
      anger management, cognitive behavioral therapy for symptoms or problems other than PTSD).

      The investigators recognize that PTSD in women is increasingly common and effective
      treatments are needed for this group as well. However, women will be excluded from this
      initial trial for safety reasons, since mifepristone is an abortifacient. Should mifepristone
      prove to be effective in male Veterans with PTSD, this would provide a rationale for future
      studies in women, employing additional safeguards.
    

Intervention name(s): Mifepristone Oral Tablet [Korlym]; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): 2 Mifepristone 300 MG Oral Tablets once daily (600mg total) for 7 days; 2 Placebo Oral Tablets once daily for 7 days
Other intervention name(s): Korlym; Sugar pill
Intervention MeSH terms: Mifepristone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Stress Disorders, Post-Traumatic; Mifepristone; Veterans; Clinical Trial