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

NCT01739335 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: MHBA-04-11S
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 5

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.

Conditions

Stress Disorders, Post-Traumatic

Keywords

Stress Disorders, Post-Traumatic; Mifepristone; Veterans; Clinical Trial

Outcome Measures

Primary Outcomes (1)

• Percentage of Clinical Responders at 4-week Follow-up

  A clinical responder at 4-week is defined as a participant who achieves a 30% or greater reduction in CAPS total score (past week symptom status) from baseline to 4-week follow-up. The Clinical Administered PTSD Scale (CAPS) was used to assess the diagnosis of PTSD symptoms. The CAPS total score (ranges 0 - 136) is the sum of 17 PTSD symptoms (each symptom is the sum of the frequency score (ranges 0-4) and the intensity score (ranges 0-4)) in the three different symptom subcategories (intrusive/re-experiencing (0-40), avoidance/numbing (0-56) and hyperarousal (0-40)). The higher is the CAPS total score, the worse is the PTSD symptom. Higher percentage of responders indicate a better drug effect in treating PTSD symptoms.

  week 4

Secondary Outcomes (2)

• Percentage of Clinical Responders at 12-week Follow-up (End of Study)

  week 12

• Change in CAPS Total Score From Baseline to 4-week and 12-week

  baseline to 4-week

Other Outcomes (11)

• Change in CAPS Intrusive Symptom Scores From Baseline to 4-Week and 12-Week

  baseline to 4-Week and 12-Week

• Change in CAPS Avoidance Symptom Scores From Baseline to 4-Week and 12-Week

  baseline to 4-Week and 12-Week

• Change in CAPS Hyperarousal Symptom Scores From Baseline to 4-Week and 12-Week

  baseline to 4-Week and 12-Week

Study Arms (2)

Mifepristone

EXPERIMENTAL

'Mifepristone Oral Tablet \[Korlym\] (2 x 300mg =600 mg total, once daily, at bedtime) for 7 days

Drug: Mifepristone Oral Tablet [Korlym]

Placebo

PLACEBO COMPARATOR

Placebo Oral tablet (2 sugar pills, once daily, at bedtime) for 7 days

Drug: Placebo Oral Tablet

Interventions

Mifepristone Oral Tablet [Korlym] DRUG

2 Mifepristone 300 MG Oral Tablets once daily (600mg total) for 7 days

Also known as: Korlym

Mifepristone

Placebo Oral Tablet DRUG

2 Placebo Oral Tablets once daily for 7 days

Also known as: Sugar pill

Placebo

Eligibility Criteria

• Age: 18 Years - 89 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:
• 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.)
• 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.
• Veteran has diabetes mellitus, an endocrinopathy, or another major medical illness.
• 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.
• Veteran has prolonged QTc interval \>450 msec on ECG at screening.
• Veteran has hypokalemia at screening (defined as potassium level \< 3.5 Milliequivalent Per Liter (mEq/L)).
• 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).
• 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).

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (5)

VA San Diego Healthcare System

San Diego, California, 92161, United States

Location

Albuquerque VA Medical Center

Albuquerque, New Mexico, 87108, United States

Location

James J. Peters VA Medical Center

The Bronx, New York, 10468, United States

Location

Durham VA Medical Center

Durham, North Carolina, 27705, United States

Location

Salisbury W.G. (Bill) Hefner VA Medical Center

Salisbury, North Carolina, 28144, United States

Location

Related Publications (1)

• Golier JA, Li X, Bizien M, Hurley RA, Bechard BW, Kimbrell T, Flory JD, Baker DG, Yehuda R, Reda DJ. Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2310223. doi: 10.1001/jamanetworkopen.2023.10223.

  PMID: 37159200 DERIVED

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic

Interventions

Mifepristone; Sugars

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Carbohydrates

Limitations and Caveats

The study only look at a low dose of mifepristone (600 mg /day) for a short period (7 days). A higher dose of mifepristone (900 mg, 1200mg and etc.) haven't been studied in this trial.

Results Point of Contact

• Title: Dr. Julia Golier; Chief of Psychiatry
• Organization: Bronx VA Medical Center

julia.golier@va.gov

718-584-9000

Study Officials

• Julia A Golier, MD

  James J. Peters Veterans Affairs Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double blinded Placebo-controlled
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2012
• First Posted: December 3, 2012
• Study Start: November 19, 2012
• Primary Completion: September 19, 2016
• Study Completion: November 16, 2016
• Last Updated: January 24, 2018
• Results First Posted: January 24, 2018

Record last verified: 2018-01

Locations

US (5)