Neuroactive Steroids and Traumatic Brain Injury (TBI) in OEF/OIF Veterans

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01336413
First received: April 13, 2011
Last updated: September 9, 2014
Last verified: September 2014
  Purpose

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.

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.


Condition Intervention Phase
Brain Injuries, Traumatic
Drug: Pregnenolone
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Neuroactive Steroids and TBI in OEF/OIF Veterans

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Tower of London (Subscale test of BAC-A) [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Measure of executive functioning


Secondary Outcome Measures:
  • CAPS (Cluster D symptoms) [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Measure of hypervigilence

  • Beck Depression Inventory-II (BDI-II) [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Rating scale for depression symptoms

  • BACS Composite Score [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Assessment of cognitive symptoms

  • CAPS Total Scores [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Rating scale for PTSD symptoms

  • Connor-Davidson Resilience Scale (CD-RISC) [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Rating scale for assessing resilience


Estimated Enrollment: 140
Study Start Date: October 2013
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1
Pregnenolone
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 Comparator: Arm 2
Placebo
Drug: Placebo
Same as active comparator, except placebo dispensed.

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.

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.

  Eligibility

Ages Eligible for Study:   21 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 21-55 years of age, any ethnic group, either sex
  • History of mild TBI since 2001
  • We will adhere to the operational definition of mild TBI suggested by the World Health Organization Task Force (Holm et al 2005), with the exception of Glasgow Coma Scale score criteria (not available for these subjects): a.) One or more of the following: confusion or disorientation, loss of consciousness for 30 minutes or less, post-traumatic amnesia for less than 24 hours, and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; Glasgow Coma Scale (GCS) score of 13-15 after 30 minutes post-injury or later upon presentation for health care (GCS unavailable). This WHO diagnostic definition of mild TBI is also consistent with the CDC Report to Congress on Mild TBI in the United States, September 2003 (specifically, altered consciousness attributable to the head injury [=transient confusion, disorientation or impaired consciousness] or self reported loss of consciousness lasting 30 minutes or less).
  • Ability to participate fully in the informed consent process.
  • No anticipated need to alter psychiatric medications for the 10-week duration of the study. Since this study is adjunctive to treatment-as-usual, patients will not be tapered from any psychiatric medications they may be receiving at enrollment.
  • No changes in psychotropic or behavioral interventions during the study or in the 4 weeks prior to study enrollment.

Exclusion Criteria:

  • For this pilot study, we will diverge slightly from the above WHO definition of mild TBI and exclude patients who report a history of seizures for this investigation. Although no seizures have been reported to the FDA in relationship to pregnenolone use, pregnenolone could theoretically influence seizure threshold if metabolized to its sulfated derivative, which demonstrates negative modulatory actions at GABAA receptors. Since our preliminary data suggest that pregnenolone administration increases the GABAergic neuroactive steroid allopregnanolone five-fold, however, and since allopregnanolone demonstrates marked anticonvulsant activity in a number of animal seizure models, this theoretical risk may be small or non-existent.
  • Subjects with current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern.
  • Concomitant medications for medical conditions will be addressed on a case-by-case base and determined if exclusionary.
  • Current DSM-IV diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than TBI.
  • Female patients who are pregnant or breast-feeding.
  • Known allergy to study medication.
  • Substance dependence or abuse (other than nicotine dependence), as determined by MINI assessment.
  • Serious unstable medical illness. History of cerebrovascular accident, prostate, uterine or breast cancer.
  • Use of oral contraceptives or other hormonal supplementation such as estrogen [although early studies suggested no effects on menstrual cycle, alterations in downstream metabolites of pregnenolone could theoretically impact efficacy of oral contraceptives and estrogen replacement].
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01336413

Contacts
Contact: Jennifer C Naylor, PhD (919) 286-0411 ext 7722 naylorjc@duke.edu
Contact: Susan O'Loughlin, BA (919) 286-0411 ext 7510 susan.oloughlin@va.gov

Locations
United States, North Carolina
Durham VA Medical Center, Durham, NC Recruiting
Durham, North Carolina, United States, 27705
Contact: Christine Marx, MD MA    919-286-0411 ext 5112    christine.marx@va.gov   
Principal Investigator: Christine Marx, MD MA         
Sponsors and Collaborators
Investigators
Principal Investigator: Christine Marx, MD MA Durham VA Medical Center, Durham, NC
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01336413     History of Changes
Obsolete Identifiers: NCT01327131
Other Study ID Numbers: B4603-I
Study First Received: April 13, 2011
Last Updated: September 9, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
brain injuries, traumatic
pregnenolone
Veteran
OEF/OIF
neurosteroid

Additional relevant MeSH terms:
Brain Injuries
Brain Diseases
Central Nervous System Diseases
Craniocerebral Trauma
Nervous System Diseases
Trauma, Nervous System
Wounds and Injuries

ClinicalTrials.gov processed this record on October 23, 2014