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

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.

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.