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

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ClinicalTrials.gov Identifier: NCT04452500
Recruitment Status : Not yet recruiting
First Posted : June 30, 2020
Last Update Posted : January 25, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
PTSD Drug: CORT108297 Drug: Placebo Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment of Veterans With Posttraumatic Stress Disorder (PTSD)
Estimated Study Start Date : September 1, 2021
Estimated Primary Completion Date : December 29, 2023
Estimated Study Completion Date : December 29, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CORT108297
CORT108297- 180mg daily for 7 days
Drug: CORT108297
CORT108297- 180mg daily for 7 days

Placebo Comparator: Placebo
Placebo- 180mg daily for 7 days
Drug: Placebo
Placebo- 180mg daily for 7 days




Primary Outcome Measures :
  1. Clinician Administered PTSD Scale for DSM-5 (CAPS) [ Time Frame: 56 days ]
    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.

  2. Frequency, Intensity, Burden of Side Effects (FIBSER) [ Time Frame: 56 days ]
    The FIBSER is a self-report 0-6 Likert-type scale that measures global frequency, intensity, and overall burden of side effects.


Secondary Outcome Measures :
  1. Columbia Suicide Severity Rating Scale [ Time Frame: 56 days ]
    The C-SSRS is FDA approved for assessing severity and change of suicidality in drug studies.

  2. PTSD Checklist for DSM-5 [ Time Frame: 56 days ]
    The PCL is a validated self-report scale assessing PTSD symptoms corresponding to DSM-5.

  3. World Health Organization Quality of Life (WHOQOL-BREF) [ Time Frame: 56 days ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 score > 26 CAPS-5 total score for the past week at baseline
  • 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 (mirtazapine, doxepin, tricyclics), mood stabilizers (e.g., lithium), antipsychotic medication, benzodiazepines
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04452500


Contacts
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Contact: Jennifer A Hlavin, MS (415) 221-4810 ext 6624 jennifer.hlavin@va.gov

Locations
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United States, California
San Francisco VA Medical Center, San Francisco, CA
San Francisco, California, United States, 94121
Contact: Jennifer A Hlavin, MS    415-221-4810 ext 6624    jennifer.hlavin@va.gov   
Principal Investigator: Thomas C. Neylan, MD         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Thomas C. Neylan, MD San Francisco VA Medical Center, San Francisco, CA
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT04452500    
Other Study ID Numbers: MHBB-014-18S
CX001917-01 ( Other Grant/Funding Number: VA CSR&D )
First Posted: June 30, 2020    Key Record Dates
Last Update Posted: January 25, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: For the proposed work final de-identified data from this project will be shared as widely as possible with the scientific community using UCSF DataShare (aka Dash). This self-service tool, available to any UCSF affiliated researcher, is a collaboration between University of California San Francisco's Library, and the UC Curation Center (UC3) at the California Digital Library and the UCSF Clinical and Translational Science Institute (CTSI).
Supporting Materials: Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Within 1 year of the end of the funding period.
Access Criteria: After the raw data is made available on the Dash site, anyone will also be able to view the descriptive metadata used to index the data set. This information is publicly available to allow for maximum discoverability. Individuals wishing to access the data must agree to terms of use for the data set via a Data Use Agreement, and may have to meet additional requirements as set forth by the PI. The data will be permanently archived and available through the California Digital Library.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by VA Office of Research and Development:
Glucocorticoids
Posttraumatic Stress Disorder
Quality of Life
Additional relevant MeSH terms:
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Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Trauma and Stressor Related Disorders
Mental Disorders