Pregnenolone for Cognitive and Negative Symptoms in Schizophrenia

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00728728
• Collaborator: (none)
• Enrollment: 88
• Location: 1
• Arms: 2
• Duration (Months): 72
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This study will investigate adjunctive pregnenolone for patients with schizophrenia and schizoaffective disorder.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Schizoaffective Disorder	Drug: Dietary Supplement: Pregnenolone; Dietary Supplement: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Pregnenolone for Cognitive and Negative Symptoms in Schizophrenia
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1: Pregnenolone Pregnenolone	Drug: Dietary Supplement: Pregnenolone; Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.
Placebo Comparator: Arm 2: Placebo Placebo	Dietary Supplement: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. MATRICS Consensus Cognitive Battery (MCCB) [Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)]

   The MATRICS Consensus Cognitive Battery (MCCB) is a standardized battery for use with adults with schizophrenia and related disorders to measure cognition in these individuals. The MCCB consists of ten individually administered test which measure speed of processing, attention/vigilance, nonverbal working memory, verbal working memory, verbal learning, visual learning, reasoning and problem solving and social cognition. The primary raw scores are entered into the MCCB Computer Scoring Program which then generates the corresponding T-scores and percentiles, along with a graphic profile of the scores for each of the seven cognitive domains. Higher scores indicate better performance.

2. University of California Performance-based Skills Assessment (UPSA) [Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)]

   The UCSD Performance-based Skills Assessment (UPSA) is a measure of Functional Capacity and assesses skills involved in community tasks. It is composed of five subdomains (comprehension and planning, finance, communication, mobility and house management) when combined, measures functional capacity. The comprehension and planning subdomain ranges from 0 to 14, the finance subdomain ranges from 0 to 11, the communication subdomain ranges from 0 to 12, the mobility subdomain ranges from 0 to 9, and the house management subdomain ranges from 0 to 4. Then a medication management score of 0 to 37 is added. In total, the Assessment is thus scored on a 0 to 87 scale, with higher scores indicating better performance.

3. Brief Assessment of Cognition in Schizophrenia (BACS) [Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)]

   The Brief Assessment of Cognition in Schizophrenia (BACS) captures those domains of cognition that are the most severely affected in patients with schizophrenia and the most strongly correlated with functional outcome. The domains of cognitive function assessed and the associated tests include: Verbal Memory & Learning (Verbal Memory), Working Memory (Digit Sequencing), Motor Function (Token Motor Task), Verbal Fluency (Semantic and Letter Fluency), Speed of Processing (Symbol Coding), and Executive Function (Tower of London). These domains are then converted to Z scores compared to standardized scoring scales, with higher scores representing better performance.

4. Scale for the Assessment of Negative Symptoms(SANS) [Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)]

   The Scale for the Assessment of Negative Symptoms (SANS) is an assessment used to obtain clinical ratings of negative symptoms in patients with schizophrenia. The SANS assesses five symptom complexes. They are: affective blunting; alogia (impoverished thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention. 24 assessments are conducted on a six-point scale (0=not at all to 5=severe) each, for a total scoring range of 0-120. Lower scores represent better performance.

Secondary Outcome Measures

1. The Calgary Depression Scale for Schizophrenia (CDSS) [Prospective, outcome measures collected over 10 week trial period.]

   The CDSS assesses the level of depression in schizophrenia by measuring nine items on a 0 (absent) to 3 (severe) scale each. Thus, the total score range is 0 to 27. Lower scores represent better outcomes.

2. Positive and Negative Syndrome Scale (PANSS) [Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)]

   The PANSS measures positive and negative symptoms of schizophrenia through administering a structured interview. After the interview, 25 PANSS items are each rated 1 (absent) to 7 (extreme). These items are organized into five scales: Negative, Positive, Dysphoric Mood, Activation, and Autistic Preoccupation. The combination of the 25 items produces a total score range of 25-175, and lower scores represent better outcomes.

3. Clinical Global Impressions (CGI) Scale [Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)]

   The CGI scale provides a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. The CGI comprises two companion one-item measures evaluating the severity of psychopathology from 1 to 7 and change from the initiation of treatment on a similar seven-point scale. Thus, scores range from 2 to 14, with lower scores representing better outcomes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis: DSM-IV/DSM-IV TR schizophrenia or schizoaffective disorder;

• Gender: Males and Females;

• Age: 21-65;

• Caucasian or Non Caucasian;

• Capable of providing informed consent;

• Duration of illness equal to or greater than one year;

• No change in antipsychotic medication in the previous eight weeks, no change in antipsychotic dose in the previous four weeks;

• No benzodiazepine use in the past twelve hours prior to cognitive testing;

• The patient cohort will be enriched for cognitive symptoms (Composite BACS scores = 0-3 standard deviations below the mean, assessed at the screening visit).

Exclusion Criteria:

• Subjects with a DSM-IV/DSM-IV TR diagnosis of alcohol or substance dependence (other than nicotine) within the last month;

• Subjects with a history of significant head injury/trauma, as defined by one or more of the following:

• Loss of consciousness (LOC) for more than 1 hour,

• Recurring seizures resulting from the head injury,

• Clear cognitive sequelae of the injury,

• Cognitive rehabilitation following the injury;

• Subjects with unstable medical illness or neurological illness (seizures, CVA);

• Patients with hormone-sensitive tumors (such as breast, uterine, or prostate cancer);

• Clinically significant abnormalities in physical examination , ECG, or laboratory assessments;

• Pregnant women or women of child-bearing potential, who are either not surgically-sterile or not using appropriate methods of birth control (serum beta-human chorionic gonadotropin [HCG] will be performed at baseline, 4 weeks, and 8 weeks to exclude pregnancy);

• Women who are breast-feeding;

• Electroconvulsive therapy (ECT) treatment within the last 3 months;

• 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 (such as estradiol) could theoretically impact the efficacy of oral contraceptives and/or estrogen replacement. Similarly, it is theoretically possible that pregnenolone could be metabolized to other steroids, resulting in hair, skin, or other steroid-related changes. Since we have determined in our prior study that pregnenolone administration does not result in downstream elevations in DHEA, DHEAS, estradiol, or testosterone, these possibilities may be unlikely;

• Current active suicidal and/or homicidal ideation, intent, or plan;

• Known allergy to study medication.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Christine Marx, MD MA, Durham VA Medical Center, Durham, NC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00728728
• Other Study ID Numbers: MHBB-012-07F; NCT00639886
• First Posted: Aug 6, 2008
• Last Update Posted: Feb 10, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by VA Office of Research and Development: pregnenolone; schizophrenia; cognitive; positive symptom; negative symptom; placebo control
• Additional relevant MeSH terms: Schizophrenia; Psychotic Disorders

Study Results

Participant Flow

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Period Title: Overall Study
STARTED	42	46
COMPLETED	38	34
NOT COMPLETED	4	12

Baseline Characteristics

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo	Total
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group	Total of all reporting groups
Overall Participants	42	46	88
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.9 (8.5)	51.6 (8.4)	51.7 (8.4)
Gender (Count of Participants)
Female	6 14.3%	7 15.2%	13 14.8%
Male	36 85.7%	39 84.8%	75 85.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	27 64.3%	36 78.3%	63 71.6%
White	12 28.6%	9 19.6%	21 23.9%
More than one race	3 7.1%	1 2.2%	4 4.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	42 100%	46 100%	88 100%

Outcome Measures

1. Primary Outcome

Title	MATRICS Consensus Cognitive Battery (MCCB)
Description	The MATRICS Consensus Cognitive Battery (MCCB) is a standardized battery for use with adults with schizophrenia and related disorders to measure cognition in these individuals. The MCCB consists of ten individually administered test which measure speed of processing, attention/vigilance, nonverbal working memory, verbal working memory, verbal learning, visual learning, reasoning and problem solving and social cognition. The primary raw scores are entered into the MCCB Computer Scoring Program which then generates the corresponding T-scores and percentiles, along with a graphic profile of the scores for each of the seven cognitive domains. Higher scores indicate better performance.
Time Frame	Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Measure Participants	38	34
Baseline	30.92 (1.83)	30.32 (1.40)
Week 4	33.43 (1.75)	32.76 (1.72)
Week 8	36.97 (1.90)	34.25 (2.11)

2. Primary Outcome

Title	University of California Performance-based Skills Assessment (UPSA)
Description	The UCSD Performance-based Skills Assessment (UPSA) is a measure of Functional Capacity and assesses skills involved in community tasks. It is composed of five subdomains (comprehension and planning, finance, communication, mobility and house management) when combined, measures functional capacity. The comprehension and planning subdomain ranges from 0 to 14, the finance subdomain ranges from 0 to 11, the communication subdomain ranges from 0 to 12, the mobility subdomain ranges from 0 to 9, and the house management subdomain ranges from 0 to 4. Then a medication management score of 0 to 37 is added. In total, the Assessment is thus scored on a 0 to 87 scale, with higher scores indicating better performance.
Time Frame	Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Measure Participants	38	34
Baseline	77.49 (1.63)	76.68 (1.76)
Week 4	77.29 (2.65)	80.12 (1.63)
Week 8	85.63 (1.31)	82.03 (2.05)

3. Primary Outcome

Title	Brief Assessment of Cognition in Schizophrenia (BACS)
Description	The Brief Assessment of Cognition in Schizophrenia (BACS) captures those domains of cognition that are the most severely affected in patients with schizophrenia and the most strongly correlated with functional outcome. The domains of cognitive function assessed and the associated tests include: Verbal Memory & Learning (Verbal Memory), Working Memory (Digit Sequencing), Motor Function (Token Motor Task), Verbal Fluency (Semantic and Letter Fluency), Speed of Processing (Symbol Coding), and Executive Function (Tower of London). These domains are then converted to Z scores compared to standardized scoring scales, with higher scores representing better performance.
Time Frame	Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Measure Participants	38	34
Baseline	-1.37 (0.13)	-1.53 (0.12)
Week 4	-1.11 (0.14)	-1.17 (0.12)
Week 8	-0.79 (0.13)	-1.09 (0.18)

4. Primary Outcome

Title	Scale for the Assessment of Negative Symptoms(SANS)
Description	The Scale for the Assessment of Negative Symptoms (SANS) is an assessment used to obtain clinical ratings of negative symptoms in patients with schizophrenia. The SANS assesses five symptom complexes. They are: affective blunting; alogia (impoverished thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention. 24 assessments are conducted on a six-point scale (0=not at all to 5=severe) each, for a total scoring range of 0-120. Lower scores represent better performance.
Time Frame	Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo: Placebo
Measure Participants	38	34
Baseline	26.92 (1.75)	25.88 (1.94)
Week 4	23.87 (2.05)	21.74 (1.87)
Week 8	21.00 (2.47)	20.77 (2.40)

5. Secondary Outcome

Title	The Calgary Depression Scale for Schizophrenia (CDSS)
Description	The CDSS assesses the level of depression in schizophrenia by measuring nine items on a 0 (absent) to 3 (severe) scale each. Thus, the total score range is 0 to 27. Lower scores represent better outcomes.
Time Frame	Prospective, outcome measures collected over 10 week trial period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Measure Participants	38	34
Baseline	2.84 (0.64)	3.18 (0.64)
Week 4	2.39 (0.62)	2.79 (0.66)
Week 8	2.68 (0.74)	2.46 (0.90)

6. Secondary Outcome

Title	Positive and Negative Syndrome Scale (PANSS)
Description	The PANSS measures positive and negative symptoms of schizophrenia through administering a structured interview. After the interview, 25 PANSS items are each rated 1 (absent) to 7 (extreme). These items are organized into five scales: Negative, Positive, Dysphoric Mood, Activation, and Autistic Preoccupation. The combination of the 25 items produces a total score range of 25-175, and lower scores represent better outcomes.
Time Frame	Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Measure Participants	38	34
Baseline	65.74 (2.28)	63.68 (2.58)
Week 4	61.47 (2.55)	56.79 (2.03)
Week 8	59.10 (2.95)	57.12 (3.16)

7. Secondary Outcome

Title	Clinical Global Impressions (CGI) Scale
Description	The CGI scale provides a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. The CGI comprises two companion one-item measures evaluating the severity of psychopathology from 1 to 7 and change from the initiation of treatment on a similar seven-point scale. Thus, scores range from 2 to 14, with lower scores representing better outcomes.
Time Frame	Prospective, outcome measures collected over 10 week trial period. (Weeks 2, 6 and 10)

Outcome Measure Data

Analysis Population Description

Missing data for a total of 5 participants for the CGI.

Arm/Group Title	Arm 1: Pregnenolone	Arm 2: Placebo
Arm/Group Description	Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.	Placebo control group
Measure Participants	34	33
Baseline	3.56 (0.15)	3.58 (0.13)
Week 4	3.39 (0.12)	3.39 (0.14)
Week 8	3.42 (0.12)	3.24 (0.17)

Adverse Events

Arm/Group Title	Arm 1: Pregnenolone		Arm 2: Placebo
Arm/Group Description	Pregnenolone Dietary Supplement: Pregnenolone: Pregnenolone 50mg BID x 14 days, followed by Pregnenolone 150 x 14 days, followed by Pregnenolone 250 mg BID x thereafter for the remainder of the 8-week trial.		Placebo Placebo: Placebo
All Cause Mortality
	Arm 1: Pregnenolone		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: Pregnenolone		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/42 (7.1%)		4/46 (8.7%)
Endocrine disorders
Hospitalization for Elevated Glucose	1/42 (2.4%)		0/46 (0%)
Gastrointestinal disorders
Medical Admission for Observation	0/42 (0%)		1/46 (2.2%)
Psychiatric disorders
Psychiatric Hopitalization	2/42 (4.8%)		2/46 (4.3%)
Reproductive system and breast disorders
Breast Cancer Diagnosis	0/42 (0%)		1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	Arm 1: Pregnenolone		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/42 (73.8%)		38/46 (82.6%)
Blood and lymphatic system disorders
Cold Extremities	0/42 (0%)		1/46 (2.2%)
Cardiac disorders
Palpitations	4/42 (9.5%)		7/46 (15.2%)
Tachycardia	0/42 (0%)		1/46 (2.2%)
Ear and labyrinth disorders
Tinnitus	3/42 (7.1%)		5/46 (10.9%)
Eye disorders
Blurred Vision	1/42 (2.4%)		4/46 (8.7%)
Gastrointestinal disorders
Diarrhea	8/42 (19%)		7/46 (15.2%)
Constipation	5/42 (11.9%)		12/46 (26.1%)
Nausea	6/42 (14.3%)		2/46 (4.3%)
Vomiting	1/42 (2.4%)		2/46 (4.3%)
General disorders
Restlessness	3/42 (7.1%)		4/46 (8.7%)
Nasal Congestion	1/42 (2.4%)		4/46 (8.7%)
Peripheral Edema	1/42 (2.4%)		1/46 (2.2%)
Malaise	1/42 (2.4%)		1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Cramps	7/42 (16.7%)		6/46 (13%)
Joint pain/ stiffness	5/42 (11.9%)		2/46 (4.3%)
Muscle Pain/Stiffness	3/42 (7.1%)		4/46 (8.7%)
Akathisia	1/42 (2.4%)		0/46 (0%)
Increased Motor Activity	0/42 (0%)		1/46 (2.2%)
Other: "Head/Neck Twitching"	0/42 (0%)		1/46 (2.2%)
Nervous system disorders
Drowsiness	11/42 (26.2%)		10/46 (21.7%)
Hypersomnia	9/42 (21.4%)		8/46 (17.4%)
Insomnia	7/42 (16.7%)		3/46 (6.5%)
Decreased Appetite	8/42 (19%)		6/46 (13%)
Increased appetite	7/42 (16.7%)		9/46 (19.6%)
Dry mouth	5/42 (11.9%)		8/46 (17.4%)
Headache	6/42 (14.3%)		9/46 (19.6%)
Tremor	5/42 (11.9%)		5/46 (10.9%)
Increased Salivation	5/42 (11.9%)		1/46 (2.2%)
Dizziness	4/42 (9.5%)		9/46 (19.6%)
Sweating	2/42 (4.8%)		1/46 (2.2%)
Other: "Lucid Dreams"	1/42 (2.4%)		0/46 (0%)
Decreased Interest in Sex	2/42 (4.8%)		0/46 (0%)
Vertigo	1/42 (2.4%)		0/46 (0%)
Excitement/Agitation	1/42 (2.4%)		1/46 (2.2%)
Confusion	1/42 (2.4%)		2/46 (4.3%)
Paresthesia	0/42 (0%)		2/46 (4.3%)
Renal and urinary disorders
Nocturnal/Enuresis	1/42 (2.4%)		1/46 (2.2%)
Other: "Urinary Retention"	0/42 (0%)		1/46 (2.2%)
Reproductive system and breast disorders
Menstrual Disturbance	1/42 (2.4%)		0/46 (0%)
Skin and subcutaneous tissue disorders
Dermatological	3/42 (7.1%)		4/46 (8.7%)

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.