Clinical trial NCT01336413: Neuroactive Steroids and Traumatic Brain Injury (TBI) in OEF/OIF Veterans
Official title: Neuroactive Steroids and TBI in OEF/OIF Veterans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Brain Injuries, Traumatic
Keywords: brain injuries, traumatic
pregnenolone
Veteran
OEF/OIF
neurosteroid
allopregnanolone
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2011-04-15
Enrollment: 53
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* 21-55 years of age, any ethnic group, either sex
* History of mild TBI since 2001
* The investigators 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, the investigators 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 the 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 \[although early studies suggested no effects on menstrual cycle, alterations in downstream metabolites of pregnenolone could theoretically impact efficacy of oral contraceptives and estrogen replacement\].

Primary outcomes:
measure: CAPS (Cluster D Symptoms) - PRIMARY BEHAVIORAL OUTCOME MEASURE
timeFrame: Baseline, 4 Weeks, and 8 Weeks
measure: Tower of London (Subscale Test of BAC) - PRIMARY COGNITIVE OUTCOME MEASURE
timeFrame: Baseline, 4 Weeks, and 8 Weeks
Secondary outcomes:
measure: Beck Depression Inventory-II (BDI-II)
timeFrame: Baseline, 4 Weeks, and 8 Weeks
measure: BAC Composite
timeFrame: Baseline, 4 Weeks, and 8 Weeks
measure: CAPS Total Scores
timeFrame: Baseline, 4 Weeks, and 8 Weeks
measure: Connor-Davidson Resilience Scale (CD-RISC)
timeFrame: Baseline, 4 Weeks, and 8 Weeks
Other outcomes:
measure: Functional Magnetic Resonance Imaging (Exploratory Neuroimaging Outcome)
timeFrame: 10 weeks
measure: Diffusion Tensor Imaging (Exploratory Neuroimaging Outcome)
timeFrame: 10 weeks
measure: Quantitative Susceptibility Mapping/Susceptibility Tensor Imaging (Exploratory Neuroimaging Outcome)
timeFrame: 10 weeks
Locations:
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
Study officials:
affiliation: Durham VA Medical Center, Durham, NC
name: Christine Marx, MD MA
role: PRINCIPAL_INVESTIGATOR
References: