Clinical trial NCT01739335: Novel Therapeutics in Posttraumatic Stress Disorder (PTSD): A Randomized Clinical Trial of Mifepristone
Official title: Novel Therapeutics in PTSD: A Randomized Clinical Trial of Mifepristone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Stress Disorders, Post-Traumatic
Keywords: Stress Disorders, Post-Traumatic
Mifepristone
Veterans
Clinical Trial
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2012-12-03
Enrollment: 81
Sex: MALE
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Primary outcomes:
measure: Percentage of Clinical Responders at 4-week Follow-up
timeFrame: week 4
Secondary outcomes:
measure: Percentage of Clinical Responders at 12-week Follow-up (End of Study)
timeFrame: week 12
measure: Change in CAPS Total Score From Baseline to 4-week and 12-week
timeFrame: baseline to 4-week
Other outcomes:
measure: Change in CAPS Intrusive Symptom Scores From Baseline to 4-Week and 12-Week
timeFrame: baseline to 4-Week and 12-Week
measure: Change in CAPS Avoidance Symptom Scores From Baseline to 4-Week and 12-Week
timeFrame: baseline to 4-Week and 12-Week
measure: Change in CAPS Hyperarousal Symptom Scores From Baseline to 4-Week and 12-Week
timeFrame: baseline to 4-Week and 12-Week
measure: Change in Depression (Measured by the BDI Total Score) From Baseline to 4-Week and 12-Week
timeFrame: baseline to 4-Week and 12-Week
measure: Changes in PTSD Symptom Severity (Measured by the Stressful Life Total Score From the PTSD Checklist) From Baseline to 4-Week and 12-Week
timeFrame: baseline to 4-Week and 12-Week
measure: Change in Sleep Quality (Measured by the PSQI Total Score) From Baseline to 4-Week and 12-Week
timeFrame: baseline to 4-Week and 12-Week
measure: Change in Anger Level (Measured by the STAXI Total Score) From Baseline to 4-Week and 12-Week
timeFrame: Baseline to 4-week and 12-week
measure: Change in Plasma Cortisol From Baseline to 1-Week
timeFrame: Baseline to 1-week
measure: Change in Plasma Cortisol From Baseline to 4-Week
timeFrame: Baseline to 4-week
measure: Change in Adrenocorticotropic Hormone (ACTH) From Baseline to 1-week
timeFrame: baseline to 1-week
measure: Change in Adrenocorticotropic Hormone (ACTH) From Baseline to 4-week
timeFrame: Baseline to 4-week
Locations:
city: San Diego
country: United States
facility: VA San Diego Healthcare System
state: California
city: Albuquerque
country: United States
facility: Albuquerque VA Medical Center
state: New Mexico
city: Bronx
country: United States
facility: James J. Peters VA Medical Center
state: New York
city: Durham
country: United States
facility: Durham VA Medical Center
state: North Carolina
city: Salisbury
country: United States
facility: Salisbury W.G. (Bill) Hefner VA Medical Center
state: North Carolina
Study officials:
affiliation: James J. Peters Veterans Affairs Medical Center
name: Julia A Golier, MD
role: PRINCIPAL_INVESTIGATOR
References: