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

Neuroactive Steroids and TBI in OEF/OIF Veterans

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01336413

Enrollment

Registered

2011-04-15

Start date

2013-10-31

Completion date

2016-02-29

Last updated

2019-07-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Brain Injuries, Traumatic

Keywords

brain injuries, traumatic, pregnenolone, Veteran, OEF/OIF, neurosteroid, allopregnanolone

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.

Interventions

DRUGPregnenolone

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

DRUGPlacebo

Same as active comparator, except placebo dispensed.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

21 Years to 55 Years

Healthy volunteers

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 \[although early studies suggested no effects on menstrual cycle, alterations in downstream metabolites of pregnenolone could theoretically impact efficacy of oral contraceptives and estrogen replacement\].

Design outcomes

Primary

Measure	Time frame	Description
CAPS (Cluster D Symptoms) - PRIMARY BEHAVIORAL OUTCOME MEASURE	Baseline, 4 Weeks, and 8 Weeks	The CAPS-IV criterion D is defined by persistent symptoms of increasing arousal (not present before the trauma), indicated by at least two of the following: difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hyper-vigilance, and exaggerated startle response There are two scales, frequency and intensity. Frequency scores range from 0 = none of the time to 4 = most or all of the time and intensity scores range from 0 = none to 4 = extreme. Severity scores are calculated from the sum of frequency and intensity scores. Five items are included in criterion D, thus the range of severity scores is 0-45. Higher scores are indicative of more symptoms.
Tower of London (Subscale Test of BAC) - PRIMARY COGNITIVE OUTCOME MEASURE	Baseline, 4 Weeks, and 8 Weeks	Subscale test asking subjects to determine the minimum number of moves that will be required to make convert one image of colored balls on pegs into a second different image. The test administers 20 items/images, with 2 additional items if all of the first 20 are answered correctly. Thus, scores range from 0-22, with lower scores representing greater impairment. Raw scores are converted to z scores that generally range from -3 to 3, with lower scores again representing greater impairment.

Secondary

Measure	Time frame	Description
BAC Composite	Baseline, 4 Weeks, and 8 Weeks	Composite z scores (allowing comparison from week 2 to week 10) to assess cognitive changes. The BAC includes brief assessments of executive functions, verbal fluency, attention, verbal memory, working memory and motor speed. z scores are calculated from composite scores. Higher z scores are indicative of better cognitive performance, lower z scores are indicative of lower cognitive performance. Range of z scores anticipated to be between -3 and 3.
Beck Depression Inventory-II (BDI-II)	Baseline, 4 Weeks, and 8 Weeks	21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression. Scores range from 0 (no depression) to 63 (severe depression).
CAPS Total Scores	Baseline, 4 Weeks, and 8 Weeks	Mean scores in posttraumatic stress disorder symptoms. Scores may range from 0 (no symptoms) to 136 (severe symptoms; score of 136 is based on the first 17 CAPS items administered). A reduced CAPS score indicates a reduction in (improvement) PTSD symptoms, while and increase in CAPS score indicates an increase (worsening) in PTSD symptoms.
Connor-Davidson Resilience Scale (CD-RISC)	Baseline, 4 Weeks, and 8 Weeks	The CD-RISC was developed and tested as (i) a measure of degree of resilience, (ii) as a predictor of outcome to treatment with medication or psychotherapy, stress management and resilience-building, (iii) as a marker of progress during treatment, and (iv) as a marker of biological changes in the brain. The scale comprises 25 items, each rated on a 5-point scale (0-4) for a total range of 0-100, with higher scores reflecting greater resilience.

Other

Measure	Time frame	Description
Diffusion Tensor Imaging (Exploratory Neuroimaging Outcome)	10 weeks	Diffusion Tensor Imaging (DTI) to assess possible white matter brain changes associated with intervention.
Functional Magnetic Resonance Imaging (Exploratory Neuroimaging Outcome)	10 weeks	Functional Magnetic Resonance Imaging (fMRI) to assess possible functional brain changes related to attention and emotion circuits associated with the intervention. The dependent measure is the BOLD (fMRI) response to images of faces expressing neutral emotions and fearful emotions.
Quantitative Susceptibility Mapping/Susceptibility Tensor Imaging (Exploratory Neuroimaging Outcome)	10 weeks	Quantitative Susceptibility Mapping/Susceptibility Tensor Imaging (QSM/STI) to assess possible myelin brain changes related to the intervention.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Pregnenolone 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	27
Placebo Placebo: Same as active comparator, except placebo dispensed.	26
Total	53

Baseline characteristics

Characteristic	Pregnenolone	Total	Placebo
Age, Continuous	32.74 years STANDARD_DEVIATION 5.4	33.87 years STANDARD_DEVIATION 6.15	35.04 years STANDARD_DEVIATION 6.75
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	3 Participants	9 Participants	6 Participants
Race (NIH/OMB) More than one race	2 Participants	3 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	3 Participants	1 Participants
Race (NIH/OMB) White	19 Participants	37 Participants	18 Participants
Region of Enrollment United States	27 participants	53 participants	26 participants
Sex: Female, Male Female	1 Participants	2 Participants	1 Participants
Sex: Female, Male Male	26 Participants	51 Participants	25 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 27	0 / 26
other Total, other adverse events	22 / 27	13 / 26
serious Total, serious adverse events	0 / 27	0 / 26

Outcome results

Primary

CAPS (Cluster D Symptoms) - PRIMARY BEHAVIORAL OUTCOME MEASURE

The CAPS-IV criterion D is defined by persistent symptoms of increasing arousal (not present before the trauma), indicated by at least two of the following: difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hyper-vigilance, and exaggerated startle response There are two scales, frequency and intensity. Frequency scores range from 0 = none of the time to 4 = most or all of the time and intensity scores range from 0 = none to 4 = extreme. Severity scores are calculated from the sum of frequency and intensity scores. Five items are included in criterion D, thus the range of severity scores is 0-45. Higher scores are indicative of more symptoms.