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Neurosteroids for PTSD in Veterans

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03799562
Recruitment Status : Recruiting
First Posted : January 10, 2019
Last Update Posted : May 7, 2019
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
This study seeks to determine if pregnenolone can improve symptoms of PTSD and other symptoms that commonly occur with PTSD in Iraq/Afghanistan-era Veterans. The total study duration is 10 weeks. Eligible Veterans with PTSD will receive either pregnenolone or placebo throughout the study duration and will complete mental and physical health assessments at each study visit. Eligible participants will attend 6 in-person study visits and receive several short "check-in" phone calls.

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

Detailed Description:

BACKGROUND: There is an acute and urgent need to develop new and effective posttraumatic stress disorder (PTSD) pharmacotherapies, as there are currently only two FDA-approved medications for the treatment of PTSD (both of which are from the same drug class and have shown only moderate effect sizes in FDA registration trials). Many Veterans with PTSD thus remain symptomatic despite the availability of these treatments, increasing the likelihood of receiving pharmacological treatment interventions for which there is little or no empirical evidence. Multiple national and VA working groups focusing on PTSD have identified the critical need to address the paucity of PTSD pharmacotherapies, and have strongly recommended more randomized clinical trials to evaluate possible effective pharmacological treatments. Both preclinical and clinical data suggest that reductions in neurosteroids are involved in the pathophysiology of PTSD, and that ameliorating these deficits could potentially be clinically therapeutic - the proposed investigation targeting a neurosteroid intervention for the treatment of PTSD could thus be a promising research avenue. The investigators therefore propose to conduct a randomized clinical trial (RCT) to determine the efficacy of a neurosteroid intervention (pregnenolone) for PTSD and commonly co-occurring disorders in Iraq/Afghanistan-era Veterans, an understudied cohort that may be less treatment-refractory.

METHODS: This study will be a 10-week randomized, placebo-controlled, double-blind clinical trial of pregnenolone or matching placebo in Veterans with PTSD. The trial will include a 2-week single-blind placebo lead-in phase followed by 8 weeks of study medication (placebo or pregnenolone). Forty-five subjects meeting DSM-5 criteria for PTSD (as measured by a CAPS-5 score of 30) will be randomized to receive pregnenolone, and 45 subjects meeting DSM-5 criteria for PTSD will be randomized to receive placebo. The primary outcome for this RCT will be changes in total CAPS-5 score at Visit 6 for this modified intent-to-treat sample. Secondary clinical outcomes for this RCT include changes in pain intensity and functional interference, as measured by the Brief Pain Inventory, Short Form (BPI-SF) and depression symptoms by the Hamilton-Depression Rating Scale (HAM-D). Blood samples will be collected for serum analysis at all study visits and frozen in a -80 degree freezer. Upon completion of the study, samples will be thawed and analyzed using Gas Chromatography/Mass Spectrometry for neurosteroid analyses and inflammatory markers will be quantified. Genetic analyses will be conducted to determine therapeutic response.

PREDICTED RESULTS: The investigators hypothesize that treatment with pregnenolone will be efficacious in Iraq/Afghanistan-era Veterans with PTSD, and will significantly reduce PTSD symptoms as assessed by the CAPS-5 (primary endpoint) compared to placebo. Secondary endpoints will include the assessment of conditions that frequently co-occur with PTSD; specifically, the investigators hypothesize that pregnenolone will also demonstrate efficacy for co-occurring chronic pain symptoms and depression symptoms. The investigators hypothesize that increases in pregnenolone and other neurosteroids (and decreases in inflammatory markers) will predict improvements in PTSD, depression, and chronic pain symptoms. The investigators also hypothesize that neurosteroids are dysregulated in PTSD, and that specific SNPs of genes coding for neurosteroidogenic enzymes will be associated with therapeutic response.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will be randomized to receive the active study medication (pregnenolone) or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This is a randomized, double-blind, placebo-controlled trial. All roles will be masked with the exception of the research pharmacist.
Primary Purpose: Treatment
Official Title: Neurosteroid Intervention for PTSD in Iraq/Afghanistan-era Veterans
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 1, 2024
Estimated Study Completion Date : December 1, 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Pregnenolone
Placebo lead in 14 DAYS, followed by Pregnenolone 50 mg BID x 14 DAYS, followed by Pregnenolone 150 mg BID x 14 DAYS, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial
Drug: Pregnenolone
Pregnenolone 50 mg BID x 14 DAYS, followed by Pregnenolone 150 mg BID x 14 DAYS, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial. Placebo will be identical to the pregnenolone arm, except placebo will be dispensed.

Placebo Comparator: Placebo
Same as pregnenolone (active study medication), except placebo dispensed.
Drug: Placebo
Same as pregnenolone (active study medication), except placebo dispensed.

Primary Outcome Measures :
  1. Change in Clinician Administered PTSD Scale for DSM-5 (Visit 6-Baseline) [ Time Frame: Through study completion, an average of 5 years ]
    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. Scores range from 0-80; higher score indicates greater severity.

Secondary Outcome Measures :
  1. Change in Brief Pain Inventory, Short Form (Visit 6-Baseline) [ Time Frame: Through study completion, an average of 5 years ]
    The Brief Pain Inventory, Short Form (BPI-SF) is a self-reported scale that measures the severity of pain and the interference of pain on function. The scores range from 0 (no pain) to 10 (pain as severe as you can imagine). There are 4 questions assessing worst pain, least pain, average pain in the past 24 hours, and the pain right now. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). There are 7 questions assessing the interference of pain in the past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life.

  2. Change in Hamilton-Depression Inventory (Visit 6-Baseline) [ Time Frame: Through study completion, an average of 5 years ]
    The HAM-D measures the severity of depressive symptoms. It is a checklist of 17 items that are ranked on a scale of 0-4 or 0-2. The range for the total score (which is the sum of the scores of all 17 items) is 0-52; a higher score indicates greater severity of symptoms.

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

Inclusion Criteria:

  • DSM-5 diagnosis of PTSD with CAPS-5 Total Score 3
  • Females will be required to use a medically and study approved contraceptive or otherwise not be of child-bearing potential

    • Birth control methods must be non-hormonal
  • No anticipated need to alter psychiatric medications for duration of study involvement
  • Ability to participate fully in the informed consent process

Exclusion Criteria:

  • History of allergy to pregnenolone
  • Medical disorders that may preclude safe administration of pregnenolone or exacerbate PTSD symptoms
  • Current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern

    • Prior suicide attempt history or suicidal ideation that does not require clinical intervention or represent an imminent concern is permitted
  • Serious unstable medical illness, such as:

    • history of cerebrovascular accident
    • prostate
    • uterine or breast cancer
    • others (at the discretion of the PI and medical oversight team)
  • Medical conditions not well controlled will be excluded, at the discretion of the PI and Medical Team
  • Standard pharmacological interventions for PTSD will not be exclusionary, including, but not limited to:

    • antidepressant medications such as SSRIs, SNRIs, tricyclics, bupropion, mirtazapine, venlafaxine, and nefazodone
    • mood stabilizers such as carbamazepine, divalproex, lamotrigine, topiramate
    • atypical antipsychotics, and other agents including prazosin
    • However, there may be no changes in psychotropic medications for PTSD 4 weeks prior to study randomization
  • Benzodiazepine use
  • Current diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than mild TBI (assessed at screening)
  • Initiation or change in psychotherapy within 3 months of randomization

    • i.e., psychotherapy must be stable for 3 months prior to study start
  • Participants on hormonal therapies such as finasteride or hormonal birth control
  • Female participants who are pregnant or breast-feeding
  • As indicated by the DSM-5, moderate or severe Substance Use Disorders (excluding caffeine and tobacco) within 1 month of study entry

    • Mild Alcohol Use Disorder is not exclusionary, at the judgment of the PI and her medical team

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 identifier (NCT number): NCT03799562

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Contact: Jennifer C Naylor, PhD (919) 286-0411 ext 7722
Contact: Christine E Marx, MD MA (919) 286-0411 ext 5112

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United States, North Carolina
Durham VA Medical Center, Durham, NC Recruiting
Durham, North Carolina, United States, 27705
Contact: Bradley J Olson    919-286-6926   
Contact: John D Whited, MD MHS    (919) 286-0411 ext 6926   
Principal Investigator: Jennifer C Naylor, PhD         
Sponsors and Collaborators
VA Office of Research and Development
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Principal Investigator: Jennifer C Naylor, PhD Durham VA Medical Center, Durham, NC

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Responsible Party: VA Office of Research and Development Identifier: NCT03799562     History of Changes
Other Study ID Numbers: MHBB-004-18S
I01CX001784-01 ( U.S. NIH Grant/Contract )
First Posted: January 10, 2019    Key Record Dates
Last Update Posted: May 7, 2019
Last Verified: May 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

Keywords provided by VA Office of Research and Development:
Clinical Trial

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