Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment of Veterans With Posttraumatic Stress Disorder (PTSD)

Study Overview
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Brief Summary
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There is large body of evidence demonstrating that Posttraumatic Stress Disorder (PTSD) is associated with alterations in the stress hormone cortisol. There is also evidence that medications that block cortisol may be beneficial for treating PTSD and depression. The VA recently completed a study of a mifepristone, a medication that blocks cortisol and progesterone hormones, and found some benefit for Veterans who did not have a history of traumatic brain injury. The proposal will test a medication from a new class of cortisol blockers which have no effect on progesterone. The proposed study will test the drug CORT108297 for treatment of PTSD and will establish a safety profile that will inform the design of future studies.

Detailed Description
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Posttraumatic stress disorder (PTSD) is a serious psychiatric disorder associated with significant morbidity and mortality worldwide. There is an urgent unmet need to develop effective pharmacologic treatments for Veterans with PTSD. The pathophysiology of PTSD is associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and represents a potential target for therapy. Glucocorticoid receptor (GR) antagonists have shown promise for treating both PTSD and Major Depression. Glucocorticoid receptor antagonists such as mifepristone are hypothesized to recalibrate the HPA axis through blockade of peripheral and central GR and enhance central glucocorticoid signaling. In PTSD, enhanced central glucocorticoid signaling and normalization of HPA axis regulation could constrain stress responsive systems, such as the sympathetic nervous system, that are disrupted in PTSD leading to clinical improvement. A recently completed trial of mifepristone, a GR antagonist that can modulate dysregulation of the HPA axis, demonstrated clinical benefits at 4 weeks in a sub-group of Veterans with PTSD without history of traumatic brain injury. Mifepristone also antagonizes the progesterone receptor (PR) and has abortifacient effects, limiting its potential for widespread use. CORT108297 is a second-generation glucocorticoid receptor antagonist which has no affinity for the PR and is proposed for a Phase IIa clinical trial in Veterans with PTSD. CORT108297 has been shown to have efficacy in preclinical CNS models, and was well tolerated and safe in Phase I healthy volunteer studies making it a candidate for further development. Thus, the goal will be to complete a Phase IIa proof of concept trial of CORT108297 to focus on safety and tolerability, and obtain pilot efficacy data to inform the design of future clinical trials. The investigators propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297- 180mg daily for 7 days for PTSD symptoms in Veterans. The key outcome measures will be obtained at baseline, day 7, 28, and day 56. Male and female Veterans between the ages of 18-69 who meet criteria for current full syndrome PTSD will be enrolled in a 2 site trial. Each of the two sites will enroll 44 medically healthy male and female Veterans with chronic PTSD who will be randomized (1:1 to either a) CORT108297 or b) placebo (n=22 per condition per site) resulting in a final sample size of 88 participants over a 26-month enrollment window.

Official Title
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Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment of Veterans With Posttraumatic Stress Disorder (PTSD)

Conditions
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PTSD

Intervention / Treatment
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* Drug: CORT108297
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of US military service Capable of reading and understanding English Able to provide written informed consent Criterion A event meets DSM-5 criteria and occurred during military service, including combat and military sexual trauma Chronic full syndromal PTSD diagnosis >3 months duration as indexed by CAPS-5 at screening, and CAPS-5 total score of 23 or greater for the past month at screening Participants (male or pre-menopausal females) agree to use two forms of reliable contraception, one of which is a barrier method Participants may be on a stable dose (8 weeks at minimum) of an SSRI or SNRI for treatment of their PTSD Participants may be on a stable dose of trazodone for sleep maintenance. If pain medications are required (opiates), the dose must be stable for 4 weeks at minimum For participants who are in psychotherapy, treatment must be stable for 6 weeks Exclusion Criteria: DSM-5 alcohol, marijuana, and/or other drug use disorder in the last 3 months Mild alcohol and marijuana use not meeting criteria for use disorder will be allowed Lifetime bipolar disorder I or II, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, or major depressive disorder with psychotic features Exposure to trauma in the last 3 months Use of exclusionary antidepressant (doxepin, tricyclics), mood stabilizers (e.g., lithium), antipsychotic medication Prominent suicidal or homicidal ideation or any suicidal behavior in the past 3 months on the Columbia Suicide Severity Rating Scale (C-SSRS) or increased risk of suicide that necessitates additional therapy or inpatient treatment Pre-existing sleep apnea in the absence of adherence to effective treatment (such as CPAP or oral device) or positive screen for sleep apnea by type III device Veteran has a medical condition that requires the use of corticosteroids (oral or inhaled) Neurologic disorder or systemic illness affecting CNS function Chronic or unstable medical illness including unstable angina, myocardial infarction within the past 6 months, congestive heart failure, preexisting hypotension or orthostatic hypotension heart block or arrhythmia chronic renal or hepatic failure, and pancreatitis severe chronic obstructive pulmonary disease History of hepatobiliary disease or an AST or ALT greater than 2x the upper limit of normal, History of renal disease or an eGFR of less than 60 ml/min A prolonged QTc >450 msec on ECG at screening History of additional risk factors for Torsades de pointes e.g., heart failure, hypokalemia, family history of long QT syndrome Participants who may require the use of concomitant medications that prolong the QT/QTc interval Use of concomitant medications that might increase the plasma concentration of CORT108297 e.g., use of strong inhibitors of CYP3A such as Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir Poorly controlled hypertension Poorly controlled diabetes mellitus History of moderate or severe traumatic brain injury Mild cognitive impairment assessed by the Montreal Cognitive Assessment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The investigators propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297- 180mg daily for 7 days for PTSD symptoms in Veterans.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CORT108297<br>CORT108297- 180mg daily for 7 days | Drug: CORT108297<br>* CORT108297- 180mg daily for 7 days<br>|
| Placebo Comparator: Placebo<br>Placebo- 180mg daily for 7 days | Drug: Placebo<br>* Placebo- 180mg daily for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinician Administered PTSD Scale for DSM-5 (CAPS) | The CAPS is a 30-item interview that is the gold standard assessment for PTSD. The CAPS provides a dimensional and categorical measure of PTSD, and incorporates frequency and intensity of symptoms into a single severity score. | 56 days | 
| Frequency, Intensity, Burden of Side Effects (FIBSER) | The FIBSER is a self-report 0-6 Likert-type scale that measures global frequency, intensity, and overall burden of side effects. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Columbia Suicide Severity Rating Scale | The C-SSRS is FDA approved for assessing severity and change of suicidality in drug studies. | 56 days | 
| PTSD Checklist for DSM-5 | The PCL is a validated self-report scale assessing PTSD symptoms corresponding to DSM-5. | 56 days | 
| World Health Organization Quality of Life (WHOQOL-BREF) | The WHOQOL-BREF instrument comprises 26 items, which measure the following broad domains: physical health, psychological health, social relationships, and environment. The WHOQOL-BREF is a shorter version of the original WHOQOL-100 instrument and is more convenient for use in large research studies or clinical trials. | 56 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucocorticoids, Posttraumatic Stress Disorder, Quality of Life