Neuroactive Steroids and Traumatic Brain Injury (TBI) in OEF/OIF Veterans
Condition: Brain Injuries, Traumatic
MeSH terms: Brain Injuries; Brain Injuries, Traumatic
Study type: Interventional
Phase: Phase 2

Summary: 
      Purpose: Mild traumatic brain injury (TBI) is extremely common among Operation Enduring
      Freedom/Operation Iraqi Freedom (OEF/OIF) era Veterans. Mild TBI is frequently accompanied by
      post-traumatic stress disorder (PTSD) and depression symptoms, co-occurring disorders that
      contribute to increased disability and decreased quality of life. Neuroactive steroids (NS)
      represent promising pharmacological candidates for intervention for these diverse symptom
      domains, since a number of these molecules demonstrate pronounced neuroprotective and
      neurotrophic properties. The NS pregnenolone (PREG) is a logical therapeutic option, since it
      enhances learning and memory and also increases myelination in rodent models. Further,
      decreases in PREG have been associated with depressive symptoms, and PREG is also metabolized
      to allopregnanolone (ALLO), an anxiolytic downstream NS that is decreased in PTSD. ALLO also
      enhances neurogenesis in rodents. The investigators thus propose an randomized controlled
      trial (RCT) in OEF/OIF era Veterans with mild TBI.

      Methodology: The design of this study will be randomized, placebo-controlled, double-blind.
      Trial duration will be 10 weeks, consisting of a 2-week placebo lead-in period for all
      subjects, followed by 8 weeks of treatment with either pregnenolone or placebo. The primary
      cognitive outcome measure will be executive functioning (as assessed by the Tower of London
      test), and the primary behavioral outcome measure will be PTSD Cluster D symptoms (as
      assessed by the Clinician-Administered PTSD Scale, CAPS). The investigators will also
      determine if PREG administration in OEF/OIF Veterans with mild TBI increases downstream ALLO
      and/or other GABAergic NS levels, and the investigators will identify the specific metabolism
      profile of PREG following eight weeks of treatment with this neurosteroid.

      Anticipated Findings: The investigators hypothesize that treatment with PREG in OEF/OIF era
      Veterans with mild TBI will significantly improve executive functioning compared to the
      placebo condition. The investigators also predict that treatment with PREG will decrease
      Cluster D PTSD symptoms compared to treatment with placebo.
    

Detailed description: 
      Purpose: Mild traumatic brain injury (TBI) is extremely common among OEF/OIF (Operation
      Enduring Freedom/Operation Iraqi Freedom) era Veterans. Mild TBI is frequently accompanied by
      post-traumatic stress disorder (PTSD) and depression symptoms, co-occurring disorders that
      contribute to increased disability and decreased quality of life. Neuroactive steroids (NS)
      represent promising pharmacological candidates for intervention for these diverse symptom
      domains, since a number of these molecules demonstrate pronounced neuroprotective and
      neurotrophic properties. The NS pregnenolone (PREG) is a logical therapeutic option, since it
      enhances learning and memory and also increases myelination in rodent models. Further,
      decreases in PREG have been associated with depressive symptoms, and PREG is also metabolized
      to allopregnanolone (ALLO), an anxiolytic downstream NS that is decreased in PTSD. ALLO also
      enhances neurogenesis in rodents. The investigators thus propose an RCT in OEF/OIF era
      Veterans with mild TBI.

      Methodology: The design of this study will be randomized, placebo-controlled, double-blind.
      Trial duration will be 10 weeks, consisting of a 2-week placebo lead-in period for all
      subjects, followed by 8 weeks of treatment with either pregnenolone or placebo. The primary
      cognitive outcome measure will be executive functioning (as assessed by the Tower of London
      test), and the primary behavioral outcome measure will be PTSD Cluster D symptoms (as
      assessed by the Clinician-Administered PTSD Scale, CAPS). The investigators will also
      determine if PREG administration in OEF/OIF Veterans with mild TBI increases downstream ALLO
      and/or other GABAergic NS levels, and the investigators will identify the specific metabolism
      profile of PREG following eight weeks of treatment with this neurosteroid. A subset of
      patients will also receive pre/post neuroimaging (functional magnetic resonance imaging
      [fMRI], diffusion tensor imaging [DTI], and quantitative susceptibility
      mapping/susceptibility tensor imaging [QSM/STI]).

      Anticipated Findings: The investigators hypothesize that treatment with PREG in OEF/OIF era
      Veterans with mild TBI will significantly improve executive functioning compared to the
      placebo condition. The investigators also predict that treatment with PREG will decrease
      Cluster D PTSD symptoms compared to treatment with placebo.
    

Intervention name(s): Pregnenolone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; Same as active comparator, except placebo dispensed.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: brain injuries, traumatic; pregnenolone; Veteran; OEF/OIF; neurosteroid; allopregnanolone