- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03491007
Neurosteroids in PTSD - Biomarkers to Therapeutics
Study Overview
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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North Carolina
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Durham, North Carolina, United States, 27705
- Durham VA Medical Center, Durham, NC
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / 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.
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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.
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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).
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Functional Connectivity Between Amygdala-hippocampus Assessed Using fMRI Based Shifted-attention Emotion Appraisal (SEAT) Paradigm.
Time Frame: 6 weeks
|
The Shifted-Attention Emotion Appraisal (SEAT) Paradigm will present compound stimuli that include both emotional faces (e.g.
sad, happy, angry) and neutral scenes.
In three different conditions, participants are asked to respond to three different questions: (1) 'Gender'; (2) 'Inside/Outside'; or (3) 'Like/Dislike'.
This allows multiple components of cognition to be probed including (1) implicit emotional processing, (2) attentional modulation, and (3) cognitive modulation of emotion.
Item-specific memory will be tested first using yes/no recognition judgments.
The conjunctive memory test will require participants to make "match" (previously viewed faces and buildings presented in a combinations seen during encoding) or "mismatch" (items in combinations not previously seen together) judgments.
Change in SEAT paradigm (Z score) from baseline to 6 weeks
|
6 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
Time Frame: Baseline and 6 weeks
|
The CAPS is the gold standard in PTSD assessment.
The CAPS-5 is a 30-item structured interview that can be used to make a diagnosis of PTSD and assess PTSD symptoms.
It assesses the intensity and frequency of PTSD symptoms.
Change in total CAPS-5 score from baseline to 6 weeks.
Scores range from 0-80; higher score indicates greater severity.
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Baseline and 6 weeks
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Beck-Depression Inventory-II (BDI-II)
Time Frame: Baseline and 6 weeks
|
The BDI-II is a 21-item self-report inventory of depression symptoms.
The minimum and maximum values for the BDI-II are (0-63).
Change in total BDI-II score from baseline to 6 weeks.
Higher score indicates greater severity.
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Baseline and 6 weeks
|
Hamilton Anxiety Rating Scale (HAM-A)
Time Frame: Baseline and 6 weeks
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The HAM-A is clinician-rated interview that measures presence of anxiety-related symptoms in 14 areas.
Total score ranges from 0 to 56.
Higher score indicates greater anxiety.
Change in total HAM-A score from baseline to 6 weeks
|
Baseline and 6 weeks
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Symptom Checklist-90-Revised (SCL-90-R)
Time Frame: Baseline and 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.
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Baseline and 6 weeks
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Patient-Reported Outcomes Measurement Information System (PROMIS) - Pain Intensity Scale
Time Frame: Baseline and 6 weeks
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PROMIS Pain Intensity is a three item scale measuring the severity of pain using a five-point Likert-type scale (i.e., no pain=1, mild=2, moderate=3, severe=4, very severe=5).Change in total PROMIS Pain Intensity Scale score (range: 3 to 15) from baseline to 6 weeks.
Higher score indicates greater severity.
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Baseline and 6 weeks
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Patient-Reported Outcomes Measurement Information System (PROMIS) - Sleep Disturbance Scale
Time Frame: Baseline and 6 weeks
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The 8-item PROMIS Sleep Disturbance measures sleep disturbance with each item on the measure rated on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 5=always) with a range in score from 8-40.
Change in total PROMIS-Sleep Disturbance score from baseline to 6 weeks.
Higher score indicates greater severity.
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Baseline and 6 weeks
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PROMIS-Anger Scale
Time Frame: Baseline and 6 weeks
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The PROMIS-Anger Scale is an 8-item scale that assesses anger.
Scores range from 5 to 25, with higher scores indicating greater anger severity.
Change in total PROMIS-Anger score from baseline to 6 weeks.
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Baseline and 6 weeks
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Barrat Impulsivity Scale (BIS-11)
Time Frame: Baseline and 6 weeks
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The BIS-11 is a 30 item questionnaire to measure impulsiveness.
Items are answered on a 4-point scale.
Total scores range from 30-120 with a higher summed score indicating higher impulsivity.
Change in total BIS-11 score from baseline to 6 weeks.
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Baseline and 6 weeks
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Connor-Davidson Resilience Scale (CD-RISC)
Time Frame: Baseline and 6 weeks
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The CD-RISC scale assesses resiliency in individuals.
There are 25 items in the survey, each item is scored from 0-4, and the total ranges from 0-100.
Higher scores indicate greater resilience.
Change in total CD-RISC score from baseline to 6 weeks.
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Baseline and 6 weeks
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Hamilton Depression Ratings Scale (HAM-D)
Time Frame: Baseline and 6 weeks
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The HAM-D is a standardized, clinician-administered rating scale; assesses 17 items characteristically associated with major depression.
Total scores range from 0-50.
Higher score indicates greater severity.
Change in total HAM-D score from baseline to 6 weeks.
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Baseline and 6 weeks
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Patient-Reported Outcomes Measurement Information System (PROMIS) - Depression Scale
Time Frame: Baseline and 6 weeks
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PROMIS-Depression Scale is a self-reported scale of depressive symptoms Each item is scored 1-5 (1 = Never; 5 = Always).
Total ranges are 8 to 40.
Higher score indicates greater severity.
Change in total PROMIS Depression score from baseline to 6 weeks.
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Baseline and 6 weeks
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Patient-Reported Outcomes Measurement Information System (PROMIS) - Anxiety Scale
Time Frame: Baseline and 6 weeks
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The PROMIS-Anxiety Scale is a self-report of anxiety symptoms.
Each item is scored 1-5 (1 = Never; 5 = Always).
Total score ranges from 8 to 40.
Higher score indicates greater severity.
Change in total PROMIS Anxiety score from baseline to 6 weeks.
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Baseline and 6 weeks
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Clinician Global Impression Scale (CGI)
Time Frame: Baseline and 6 weeks
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The CGI scale will be used to rate improvement in the subject's condition.
Total score range of 0-30.
Higher scores indicates greater severity.
Change in total CGI score from baseline to 6 weeks.
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Baseline and 6 weeks
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Brief Pain Inventory (BPI)
Time Frame: Baseline and 6 weeks
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The Brief Pain Inventory (BPI) assesses the severity of pain and its impact on functioning.
Total range of 0-110.
Higher score indicates greater severity.
Change in total BPI score from baseline to 6 weeks.
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Baseline and 6 weeks
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Serum DHEA
Time Frame: 6 weeks
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Change in serum levels of DHEA from baseline to 6 weeks
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6 weeks
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Myelin Integrity Susceptibility Tensor Imaging (STI)
Time Frame: 6 weeks
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Change in STI (Z score) from baseline to 6 weeks
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6 weeks
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Serum DHEAS
Time Frame: 6 weeks
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Change in serum DHEAS levels from baseline to 6 weeks
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6 weeks
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Serum Androsterone
Time Frame: 6 weeks
|
Change in serum androsterone levels from baseline to 6 weeks
|
6 weeks
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Collaborators and Investigators
Investigators
- Principal Investigator: Steven Szabo, MD PhD, Durham VA Medical Center, Durham, NC
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- MHBB-021-17S
- 1IK2CX001397-01A2 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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