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

NCT01336413 | Completed Phase 2 Results DMC

• 1 other identifier: B4603-I
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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.

Conditions

Brain Injuries, Traumatic

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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.

  Baseline, 4 Weeks, and 8 Weeks

• Tower of London (Subscale Test of BAC) - PRIMARY COGNITIVE OUTCOME MEASURE

  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.

  Baseline, 4 Weeks, and 8 Weeks

Secondary Outcomes (4)

• Beck Depression Inventory-II (BDI-II)

  Baseline, 4 Weeks, and 8 Weeks

• BAC Composite

  Baseline, 4 Weeks, and 8 Weeks

• CAPS Total Scores

  Baseline, 4 Weeks, and 8 Weeks

• Connor-Davidson Resilience Scale (CD-RISC)

  Baseline, 4 Weeks, and 8 Weeks

Other Outcomes (3)

• Functional Magnetic Resonance Imaging (Exploratory Neuroimaging Outcome)

  10 weeks

• Diffusion Tensor Imaging (Exploratory Neuroimaging Outcome)

  10 weeks

• Quantitative Susceptibility Mapping/Susceptibility Tensor Imaging (Exploratory Neuroimaging Outcome)

  10 weeks

Study Arms (2)

Arm 1

ACTIVE COMPARATOR

Pregnenolone

Drug: Pregnenolone

Arm 2

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Pregnenolone DRUG

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

Arm 1

Placebo DRUG

Same as active comparator, except placebo dispensed.

Arm 2

Eligibility Criteria

• Age: 21 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705, United States

Location

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Pregnenolone

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones

Results Point of Contact

• Title: Christine E. Marx, MD MA
• Organization: VHA Durham

christine.marx@va.gov

9192860411

Study Officials

• Christine Marx, MD MA

  Durham VA Medical Center, Durham, NC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 13, 2011
• First Posted: April 15, 2011
• Study Start: October 1, 2013
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: July 12, 2019
• Results First Posted: October 20, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)