Traumatic Brain Injury
Conditions
Keywords
TBI, Pregnenolone, Cognition
Brief summary
Mild traumatic brain injury (TBI) is common among veterans who have served in OEF/OIF (Operation Enduring Freedom in Afghanistan/Operation Iraqi Freedom) and other theatres. Delayed symptoms may occur following TBI, including cognitive symptoms (impaired attention, processing speed, executive functioning), as well as behavioral symptoms such as anxiety, depression, and irritability (Fann et al. 2004; Holsinger et al. 2002). Neuroactive steroids have neuroprotective effects in rodent models of TBI (Djebaili et al. 2005; Djebaili et al. 2004; He et al. 2004; Pettus et al. 2005; Roof et al. 1997) and the neuroactive steroid pregnenolone and its sulfated derivative also markedly enhance learning and memory in rats (Akwa et al. 2001; Flood et al. 1992; Flood et al. 1995; Vallee et al. 1997; Vallee et al. 2003). In humans, reductions in pregnenolone (George et al. 1994) and its GABAergic metabolite allopregnanolone (Uzunova et al. 1998) have been associated with depressive symptoms. Pharmacological intervention with the neuroactive steroid pregnenolone could therefore result in a multi-targeted treatment approach, potentially improving cognitive deficits as well as anxiety and depression symptoms following TBI.
Detailed description
See brief summary
Interventions
DRUGPregnenolone
Placebo for two weeks (during placebo lead-in), then: Pregnenolone 100 mg in divided doses (50 mg, PO, BID) Pregnenolone 300 mg in divided doses (150 mg, PO, BID) Pregnenolone 500 mg in divided doses (250 mg, PO, BID)
DRUGPlacebo
Placebo for two weeks (placebo lead in), then: Placebo equivalent to Pregnenolone arm: 100 mg in divided doses (50 mg, PO, BID) Placebo equivalent to Pregnenolone arm: 300 mg in divided doses (150 mg, PO, BID) Placebo equivalent to Pregnenolone arm: 500 mg in divided doses (250 mg, PO, BID)
Sponsors
Durham VA Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. 18-55 years of age, any ethnic group, either sex 2. History of mild TBI since September 2001. TBI occurring at age 18 or older. 3. 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 the Glasgow Coma Scale Score criteria (not available for these participants). 4. Ability to participate fully in the informed consent process. 5. No anticipated need to alter medications for the 10-week duration of the study.
Exclusion criteria
1. For this pilot study, we will exclude patients who report a history of seizures. 2. Serious unstable medical illness. History of cerebrovascular accident, prostate, uterine, or breast cancer. Use of oral contraceptives or other hormonal supplementation such as estrogen. 3. Current active suicidal and/or homicidal ideation, intent or plan. 4. Concomitant medications for medical conditions will be addressed on a case-by-case base and determined if exclusionary. 5. Current DSM-IV (Diagnostic and Statistical Manual, Fourth Edition) diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than TBI. 6. Female patients who are pregnant or breast-feeding. 7. Known allergy to study medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brief Assessment of Cognition in Affective Disorders (BAC-A) | Week 2, Week 10 | Mean change scores (Week 2 minus Week 10) to assess cognitive changes. The BAC-A 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. Mean change scores from week 2 and week 10 (Week 2 minus Week 10). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinician Administered PTSD Scale (CAPS) | Week 2, Week 10 | Mean change scores (Week 2 minus Week 10) 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 an increase in CAPS score indicates an increase (worsening) in PTSD symptoms. |
| Quick Inventory of Depressive Symptomatology (QIDS) | Week 2, Week 10 | The QIDS total scores range from 0 to 27. Total score is obtained by adding the scores for each of the nine symptom domains of the DSM-IV Major Depressive Disorder (MDD) criteria: depressed mood,loss of interest or pleasure,concentration/decision making,self-outlook,suicidal ideation, energy/fatigability,sleep,weight/appetite change,and psychomotor changes. Each item is rated 0-3 (0=least or no severity, 3=greatest severity). |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Durham Medical Center, Durham, NC.
Pre-assignment details
Each subject received a two week placebo-lead in following enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Pregnenolone Pregnenolone
Pregnenolone : Pregnenolone 100 mg in divided doses (50 mg, PO, BID) Pregnenolone 300 mg in divided doses (150 mg, PO, BID) Pregnenolone 500 mg in divided doses (250 mg, PO, BID) | 11 |
| Placebo Placebo
Subjects received placebo study medication; dispensed exactly as active study medication was dispensed. | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Placebo | Pregnenolone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Age Continuous | 36.38 years STANDARD_DEVIATION 9.74 | 34.27 years STANDARD_DEVIATION 10.51 | 35.76 years STANDARD_DEVIATION 9.97 |
| Region of Enrollment United States | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 11 | 6 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Brief Assessment of Cognition in Affective Disorders (BAC-A)
Mean change scores (Week 2 minus Week 10) to assess cognitive changes. The BAC-A 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. Mean change scores from week 2 and week 10 (Week 2 minus Week 10).
Time frame: Week 2, Week 10
Population: 22 out of 30 patients randomized completed 4 or more weeks of the study and were retained for data analysis. Statistics were completed using Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Brief Assessment of Cognition in Affective Disorders (BAC-A) | 0.61 units on a scale | Standard Error 0.14 |
| Placebo | Brief Assessment of Cognition in Affective Disorders (BAC-A) | 0.80 units on a scale | Standard Error 0.17 |
Secondary
Clinician Administered PTSD Scale (CAPS)
Mean change scores (Week 2 minus Week 10) 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 an increase in CAPS score indicates an increase (worsening) in PTSD symptoms.
Time frame: Week 2, Week 10
Population: 22 out of 30 patients randomized completed 4 or more weeks of the study and were retained for data analysis. Statistics were completed using LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Clinician Administered PTSD Scale (CAPS) | -8.5 units on a scale | Standard Error 3.22 |
| Placebo | Clinician Administered PTSD Scale (CAPS) | -7.3 units on a scale | Standard Error 4.74 |
Secondary
Quick Inventory of Depressive Symptomatology (QIDS)
The QIDS total scores range from 0 to 27. Total score is obtained by adding the scores for each of the nine symptom domains of the DSM-IV Major Depressive Disorder (MDD) criteria: depressed mood,loss of interest or pleasure,concentration/decision making,self-outlook,suicidal ideation, energy/fatigability,sleep,weight/appetite change,and psychomotor changes. Each item is rated 0-3 (0=least or no severity, 3=greatest severity).
Time frame: Week 2, Week 10
Population: 22 out of 30 patients randomized completed 4 or more weeks of the study and were retained for data analysis. Statistics were completed using LOCF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Quick Inventory of Depressive Symptomatology (QIDS) | -1.09 units on a scale | Standard Error 0.73 |
| Placebo | Quick Inventory of Depressive Symptomatology (QIDS) | -0.54 units on a scale | Standard Error 0.71 |