Adjunctive Pregnenolone in Veterans With Mild TBI

• Sponsor: Durham VA Medical Center (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00623506
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 58
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Drug: Pregnenolone; Drug: Placebo	N/A

Detailed Description

See brief summary

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Adjunctive Pregnenolone in Veterans With Mild TBI
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Pregnenolone	Drug: Pregnenolone; 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)
Placebo Comparator: 2 Placebo	Drug: Placebo; 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)

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Durham VA Medical Center	Durham	North Carolina	United States	27705

Sponsors and Collaborators

• Durham VA Medical Center

Investigators

• Principal Investigator: Christine E Marx, MD, MA, Durham VAMC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Durham VA Medical Center
• ClinicalTrials.gov Identifier: NCT00623506
• Other Study ID Numbers: VA IRB# 01209; VA IRB# 01209
• First Posted: Feb 26, 2008
• Last Update Posted: Jun 20, 2013
• Last Verified: May 1, 2013

• Keywords provided by Durham VA Medical Center: TBI; Pregnenolone; Cognition
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the Durham Medical Center, Durham, NC.
Pre-assignment Detail	Each subject received a two week placebo-lead in following enrollment.

Arm/Group Title	Pregnenolone	Placebo
Arm/Group Description	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)	Placebo Subjects received placebo study medication; dispensed exactly as active study medication was dispensed.
Period Title: Overall Study
STARTED	15	15
Week 4	11	11
COMPLETED	11	11
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Pregnenolone	Placebo	Total
Arm/Group Description	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)	Placebo Subjects received placebo study medication; dispensed exactly as active study medication was dispensed.	Total of all reporting groups
Overall Participants	11	11	22
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	11 100%	22 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.27 (10.51)	36.38 (9.74)	35.76 (9.97)
Sex: Female, Male (Count of Participants)
Female	2 18.2%	1 9.1%	3 13.6%
Male	9 81.8%	10 90.9%	19 86.4%
Region of Enrollment (participants) [Number]
United States	11 100%	11 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Brief Assessment of Cognition in Affective Disorders (BAC-A)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Pregnenolone	Placebo
Arm/Group Description	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)	Placebo Subjects received placebo study medication; dispensed exactly as active study medication was dispensed.
Measure Participants	11	11
Mean (Standard Error) [units on a scale]	0.61 (0.14)	0.80 (0.17)

2. Secondary Outcome

Title	Clinician Administered PTSD Scale (CAPS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Pregnenolone	Placebo
Arm/Group Description	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)	Placebo Subjects received placebo study medication; dispensed exactly as active study medication was dispensed.
Measure Participants	11	11
Mean (Standard Error) [units on a scale]	-8.5 (3.22)	-7.3 (4.74)

3. Secondary Outcome

Title	Quick Inventory of Depressive Symptomatology (QIDS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Pregnenolone	Placebo
Arm/Group Description	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)	Placebo Subjects received placebo study medication; dispensed exactly as active study medication was dispensed.
Measure Participants	11	11
Mean (Standard Error) [units on a scale]	-1.09 (0.73)	-0.54 (0.71)

Adverse Events

Time Frame	Adverse Events were collected following the one-week placebo-lead phase and at each subsequent study visit and telephone check-in. Adverse events were collected during 11 out of the 12 weeks.
Arm/Group Title	Pregnenolone		Placebo
Arm/Group Description	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)		Placebo Subjects received placebo study medication; dispensed exactly as active study medication was dispensed.
All Cause Mortality
	Pregnenolone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pregnenolone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Pregnenolone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)		6/11 (54.5%)
General disorders
Headache	3/11 (27.3%)	4	1/11 (9.1%)	1
Excitation and Agitation	1/11 (9.1%)	1	0/11 (0%)	0
Restlessness	0/11 (0%)	0	1/11 (9.1%)	1
Increased motor activity	0/11 (0%)	0	1/11 (9.1%)	1
Decreased Motor Activity	0/11 (0%)	0	1/11 (9.1%)	2
Malaise	1/11 (9.1%)	1	1/11 (9.1%)	1
Insomnia	0/11 (0%)	0	1/11 (9.1%)	2
Hypersomnia	1/11 (9.1%)	1	0/11 (0%)	0
Drowsiness	1/11 (9.1%)	1	3/11 (27.3%)	7
Cramps	0/11 (0%)	0	1/11 (9.1%)	1
Akathisia	0/11 (0%)	0	1/11 (9.1%)	1
Dizziness	1/11 (9.1%)	1	1/11 (9.1%)	1
Dry Mouth	1/11 (9.1%)	1	1/11 (9.1%)	1
Blurred Vision	0/11 (0%)	0	1/11 (9.1%)	1
Constipation	0/11 (0%)	0	1/11 (9.1%)	1
Nausea	1/11 (9.1%)	1	1/11 (9.1%)	1
Decreased Interest in Sex	1/11 (9.1%)	2	0/11 (0%)	0
Impaired Sexual Performance	1/11 (9.1%)	1	1/11 (9.1%)	1
Dermatological	2/11 (18.2%)	4	2/11 (18.2%)	4
Muscle pain/stiffness	1/11 (9.1%)	1	0/11 (0%)	0
Decreased Appetite	1/11 (9.1%)	1	0/11 (0%)	0
Increased appetite	1/11 (9.1%)	1	2/11 (18.2%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.