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Neurosteroids in PTSD - Biomarkers to Therapeutics

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ClinicalTrials.gov Identifier: NCT03491007
Recruitment Status : Recruiting
First Posted : April 6, 2018
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
The purpose of this research is to determine if a study medication called Dehydroepiandrosterone (DHEA) helps to reduce PTSD symptoms in OEF/OIF/OND Veterans. In addition to finding out if DHEA is effective for treating PTSD symptoms, this research seeks to determine if DHEA is effective in treating other symptoms, such as depression and anxiety. Depression and anxiety are symptoms that are frequently present in Veterans who are experiencing PTSD. Another purpose of this research is to takes pictures of the brain using magnetic resonance imaging (MRI) and blood levels of various small molecules including neurosteroids and also proteins, which may be affected by the study drug and/or related to symptoms in Veterans with PTSD. This study seeks to determine if DHEA is changed to other compounds after it is taken by mouth and the safety and effectiveness of DHEA in Veterans with PTSD. This is an "add-on" study and Veterans enrolled in the study will continue to take all of their current medications without any changes (also called "usual care"), and DHEA or a sugar pill (also called a "placebo") will then be added to their current medication regimen.

Condition or disease Intervention/treatment Phase
Posttraumatic Stress Disorder Drug: DHEA Phase 2

Detailed Description:

This is a parallel-group, double-blind, placebo (PBO)-controlled, randomized Phase 2 pilot study using adjunctive dehydroxyepiandrosterone [DHEA (400 mg)] to establish Proof of Concept (POC) for use of this agent in Veterans with PTSD.

The investigators' first objective is POC target engagement to evaluate a one-time adjunctive oral dose of DHEA (400 mg) relative to PBO on the neuronal circuity of fear-anxiety-emotion connectivity. This will be achieved by comparing pre- to post-treatment changes in amygdala-hippocampal functional connectivity to DHEA and PBO during fMRI activation. The investigators hypothesize that compared with PBO, DHEA will increase task-associated fMRI functional connectivity between the amygdala and hippocampus (primary outcome).

The second objective is to determine if an 8-week treatment with adjunctive DHEA is superior to PBO in reducing symptoms of PTSD (CAPS-5) and depression (BDI) in OEF/OIF/OND Veterans, and enhancing resilience (CD-RISC). The investigators hypothesize that 400mg DHEA will result in reduced PTSD and depression symptom severity relative to PBO, as determined by a pre- to post-treatment decrease in CAPS-5 and BDI scores, respectively, with enhancement in resilience scores using the CD-RISC at 6-weeks.

The third objective is to evaluate the impact of DHEA relative to PBO on serum neurosteroid levels in OEF/OIF/OND Veterans with PTSD. The investigators hypothesize that DHEA will result in a statistically-significant increase in serum neurosteroid levels (DHEA, DHEAS, androsterone) relative to PBO, as determined by pre- to post-treatment reductions in PTSD symptoms severity. This association will be evaluated by correlating neurosteroid levels with PTSD, depression, and resilience scores over 6 weeks of treatment.

The exploratory objective is to determine preliminary evidence for an association of fMRI and myelin integrity measures of fear-anxiety-emotion circuits with serum neurosteroid levels and treatment response to DHEA. Changes in myelin integrity following DHEA treatment will be evaluated using novel susceptibility diffusion imaging [STI]), as DHEA impacts myelination in preclinical rodent models. The investigators will also determine if serum neurosteroid levels are correlated with myelin integrity on STI. The investigators hypothesize that fMRI and myelin integrity of fear-anxiety circuits will correlate with serum neurosteroids and treatment response.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a parallel-group, double-blind, placebo (PBO)-controlled, randomized Phase 2 pilot study using adjunctive dehydroxyepiandrosterone [DHEA (400 mg)] will be evaluated to establish Proof of Concept (POC) for this agent in Veterans with PTSD.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind, placebo (PBO)-controlled, randomized Phase 2 pilot study
Primary Purpose: Treatment
Official Title: Neurosteroids in PTSD - Biomarkers to Therapeutics
Actual Study Start Date : July 8, 2019
Estimated Primary Completion Date : January 2, 2023
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Coal Tar

Arm Intervention/treatment
No Intervention: Placebo
Subjects will receive a one-time oral dose of PBO prior to initial brain imaging followed by sustained administration of PBO for 6 weeks.
Placebo Comparator: DHEA
Subjects will receive a one-time oral dose of DHEA prior to initial brain imaging followed by sustained administration of DHEA for 6 weeks.
Drug: DHEA
Subjects will be randomized to receive a one-time oral dose of DHEA (400mg) or PBO and sustained administration of the study drug for 6 weeks. There will be a 2 week placebo lead-in period [all participants], followed by subjects continuing in the randomization block of DHEA or placebo for 6 weeks following acute administration).




Primary Outcome Measures :
  1. Functional connectivity between amygdala-hippocampus assessed using fMRI based shifted-attention emotion appraisal (SEAT) paradigm. [ Time Frame: 6 weeks ]
    Change in SEAT paradigm (Z score) from baseline to 6 weeks


Secondary Outcome Measures :
  1. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) [ Time Frame: 6 weeks ]
    Change in total CAPS-5 score (range: 0 to 80; higher score indicates greater severity) from baseline to 6 weeks.

  2. Beck-Depression Inventory-II (BDI-II) [ Time Frame: 6 weeks ]
    Change in total BDI-II score (range: 0 to 63; higher score indicates greater severity) from baseline to 6 weeks

  3. Hamilton Anxiety Rating Scale (HAM-A) [ Time Frame: 6 weeks ]
    Change in total HAM-A score (range: 0 to 56; higher score indicates greater severity) from baseline to 6 weeks

  4. Symptom Checklist-90-Revised (SCL-90-R) [ Time Frame: 6 weeks ]
    Change in total SCL-90-R score (range: 90 to 450; higher score indicates greater severity) from baseline to 6 weeks. This scale assesses somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism.

  5. Patient-Reported Outcomes Measurement Information System (PROMIS) - Pain Intensity Scale [ Time Frame: 6 weeks ]
    Change in total PROMIS Pain Intensity Scale score (range: 3 to 15; higher score indicates greater severity) from baseline to 6 weeks

  6. Patient-Reported Outcomes Measurement Information System (PROMIS) - Sleep Disturbance Scale [ Time Frame: 6 weeks ]
    Change in total PROMIS-Sleep Disturbance score (range: 8 to 40; higher score indicates greater severity) from baseline to 6 weeks

  7. PROMIS-Anger Scale [ Time Frame: 6 weeks ]
    Change in total PROMIS-Anger score (range: 5 to 25; higher score indicates greater severity) from baseline to 6 weeks

  8. Barrat Impulsivity Scale (BIS-11) [ Time Frame: 6 weeks ]
    Change in total BIS-11 score (range: 30 to 120; higher score indicates greater severity) from baseline to 6 weeks

  9. Connor-Davidson Resilience Scale (CD-RISC) [ Time Frame: 6 weeks ]
    Change in total CD-RISC score (range: 0 to 40; higher score indicates greater severity) from baseline to 6 weeks

  10. Hamilton Depression Ratings Scale (HAM-D) [ Time Frame: 6 weeks ]
    Change in total HAM-D score (range: 0 to 50; higher score indicates greater severity) from baseline to 6 weeks.

  11. Patient-Reported Outcomes Measurement Information System (PROMIS) - Depression Scale [ Time Frame: 6 weeks ]
    Change in total PROMIS Depression score (range: 8 to 40; higher score indicates greater severity) from baseline to 6 weeks

  12. Patient-Reported Outcomes Measurement Information System (PROMIS) - Anxiety Scale [ Time Frame: 6 weeks ]
    Change in total PROMIS Anxiety score (range: 8 to 40; higher score indicates greater severity) from baseline to 6 weeks

  13. Clinician Global Impression Scale (CGI) [ Time Frame: 6 weeks ]
    Change in total CGI score (range: 0 to 30; higher score indicates greater severity) from baseline to 6 weeks

  14. Brief Pain Inventory (BPI) [ Time Frame: 6 weeks ]
    Change in total BPI score (range: 0 to 110; higher score indicates greater severity) from baseline to 6 weeks


Other Outcome Measures:
  1. Serum DHEA [ Time Frame: 6 weeks ]
    Change in serum levels of DHEA from baseline to 6 weeks

  2. Myelin Integrity Susceptibility Tensor Imaging (STI) [ Time Frame: 6 weeks ]
    Change in STI (Z score) from baseline to 6 weeks

  3. Serum DHEAS [ Time Frame: 6 weeks ]
    Change in serum DHEAS levels from baseline to 6 weeks

  4. Serum Androsterone [ Time Frame: 6 weeks ]
    Change in serum androsterone levels from baseline to 6 weeks



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • OEF/OIF/OND era Veterans
  • PTSD diagnosis (CAPS-5 score 33).
  • Negative pregnancy test if female.

    • Sexually active subjects are required to use a medically acceptable form of birth control if they are of childbearing potential and could become pregnant during the study.
    • A medically acceptable form of birth control includes non-hormonal intrauterine devices, surgical sterilization, or double barrier methods (e.g., diaphragm with contraceptive jelly, condom with contraceptive foam, cervical caps with contraceptive jelly).
    • Sexual abstinence with agreement to continue abstinence or to use a medically acceptable method of contraception should sexual activity occur is permissible.
  • Female participants must have had a normal mammogram within the last year (if older than 40)
  • Female participants must have had a normal pelvic exam within the last year
  • No change in medications less than 4 weeks before baseline assessment
  • No anticipated need to alter medications for PTSD for the 6-week study duration (as determined by study physician's review of records and/or discussion with prescribing physician).
  • Ability to fully participate in the informed consent process

Exclusion Criteria:

  • Unstable medical or neurological illness, including seizures, renal impairment or CVA and inability to participate in neuroimaging (fMRI).
  • Use of oral contraceptives or other hormonal supplements, as it is unclear if DHEA metabolism to other neurosteroids such as estradiol may potentially impact contraceptive efficacy.
  • Significant suicidal or homicidal ideation.
  • Current DSM-5 diagnosis of bipolar disorder, schizophrenia, or other psychotic disorder (including major depression with psychotic features), or cognitive disorder due to a general medical condition.
  • Female patients who are pregnant or breast-feeding.
  • Known allergy to study medication.
  • History of moderate or severe TBI.
  • Substance dependence within past three months, per DSM-5 criteria (excluding caffeine and nicotine).
  • Abnormal prostate specific antigen (PSA; >2.5ng/ml in males age 49 or less; >4ng/ml in males age 50 or greater) or history of prostate cancer, breast cancer, or uterine cancer.
  • A family history of prostate, breast or endometrial cancer in a first-degree relative.
  • Presence of any factors/conditions, medical or non-medical, that may interfere with conduction of study assessments in the judgment of the study team.
  • Serious or unstable cardiovascular, hepatic, renal, metabolic, respiratory, or hematologic illness, symptomatic peripheral vascular disease, or other medical condition or psychiatric conditions or behaviors that would compromise participation and/or likely to lead to worsening of symptoms during the course of the study in the opinion of study physician and research team.
  • Are non-ambulatory or require the use of crutches or a walker.
  • Taking Narcotic medications or benzodiazepines for any reason.

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): NCT03491007


Contacts
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Contact: Steven Szabo, MD PhD (919) 286-0411 ext 6146 Steven.Szabo@va.gov

Locations
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United States, North Carolina
Durham VA Medical Center, Durham, NC Recruiting
Durham, North Carolina, United States, 27705
Contact: Jason D Kilts    919-286-0411    Jason.kilts@duke.edu   
Principal Investigator: Steven Szabo, MD PhD         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Steven Szabo, MD PhD Durham VA Medical Center, Durham, NC

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT03491007     History of Changes
Other Study ID Numbers: MHBB-021-17S
1IK2CX001397-01A2 ( U.S. NIH Grant/Contract )
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.: No

Keywords provided by VA Office of Research and Development:
PTSD
DHEA

Additional relevant MeSH terms:
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Stress Disorders, Post-Traumatic
Stress Disorders, Traumatic
Trauma and Stressor Related Disorders
Mental Disorders
Coal Tar
Neurotransmitter Agents
Keratolytic Agents
Dermatologic Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs