Schizophrenia
Conditions
Keywords
Schizophrenia, Pregnenolone, Cognition, Negative Symptoms
Brief summary
This is a pilot study of pregnenolone as an augmentation treatment for schizophrenia. The goal of this placebo-controlled study is to provide preliminary efficacy data for potential pregnenolone effects on cognitive symptoms and negative symptoms in patients with schizophrenia. Depressive symptoms and positive symptoms will also be assessed.
Detailed description
See brief summary
Interventions
DRUGPregnenolone
Pregnenolone 50 mg twice a day (BID) x 2 weeks, Pregnenolone 150 mg BID x 2 weeks, Pregnenolone 250 mg BID x 4 weeks
DRUGPlacebo
Placebo (similar to active comparator) 50 mg BID x 2 weeks, Placebo (similar to active comparator) 150 mg BID x 2 weeks, Placebo (similar to active comparator) 250 mg BID x 4 weeks
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 65 Years
Healthy volunteers
No
Inclusion criteria
1. 18-65 years of age, any ethnic group, either sex 2. Diagnostic and Statistical Manual, 4th edition (DSM IV) diagnosis of schizophrenia or schizoaffective disorder 3. Ability to participate fully in the informed consent process, or have a legal guardian able to participate in the informed consent process. 4. Patient cohort enriched for moderate to severe cognitive symptoms (composite Brief Assessment of Cognition in Schizophrenia (BACS) score 0-3 SD below the mean). 5. No change in antipsychotic for 8 weeks or longer. No change in antipsychotic dose for 4 weeks or longer. 6. No change in anticholinergic, benzodiazepine, or mood stabilizer medications for 4 weeks or longer. 7. No anticipated need to alter any of the above medications (antipsychotics, anticholinergics, benzodiazepines, or mood stabilizers) for the 10-week duration of the study.
Exclusion criteria
1. Unstable medical illness or neurologic illness (seizures, cerebrovascular accident); history of prostate, breast, uterine, or ovarian cancer. 2. Use of oral contraceptives or other hormonal supplementation such as estrogen. 3. Other concomitant medications for medical conditions will be addressed on a case-by-case base to determine if exclusionary. 4. Active expression of suicidal or homicidal ideation. 5. Comorbid substance dependence (other than nicotine dependence), or presenting symptoms likely substance-induced, as judged by a study physician. 6. Female patients who are pregnant or breast-feeding. 7. Known allergy to study medication. 8. Drugs with a narrow therapeutic index (e.g. thioridazine, mesoridazine, ziprasidone, clozapine, etc) will be excluded as suggested by the Federal Drug Administration (FDA); patients taking these agents will not be eligible for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Score on the Scale for the Assessment of Negative Symptoms (SANS), p=0.048 | SANS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward) | The SANS assesses negative symptoms in schizophrenia. The SANS consists of 21 clinical interview questions assessing negative symptoms of schizophrenia. Each question is rated on a scale of 0 (no symptoms) to 7 (severe symptoms). |
| Mean Change of Z-scores on the Brief Assessment of Cognition in Schizophrenia (BACS) | Change in composite BACS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward) | The BACS 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. |
| Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) | Change in composite MATRICS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward) | The MATRICS is a battery for the assessment of cognitive symptoms in patients with schizophrenia. Composite T-scores are calculated (T-score ranges are -20 to +80, and are normed on gender and age). Higher scores are indicative of better cognitive performance, lower scores are indicative of poorer cognitive performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Score Change in Calgary Depression Scale for Schizophrenia (CDSS) | Change in CDSS scores at baseline and 8 weeks (at least 4 weeks; last observation carried forward) | The CDSS is used measure to investigate depressive symptoms in schizophrenia. The measure includes 9 questions ranked from 0 (no symptoms) to 3 (severe symptoms). Range of possible scores: 0-27. |
| Clinical Global Impression Scale (CGI-I) | CGI-I scores at 8 weeks post-randomization (at least 4 weeks; last observation carried forward) | The CGI-I is a commonly used psychiatric scale to assess overall general improvement. The CGI-I consists of one interviewer-rated question on a scale of 1-7. Lower scores are indicative of fewer symptoms; while higher scores are indicative of more symptoms. |
| Mean Score on the Positive and Negative Symptom Scale (PANSS) | Change in PANSS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward) | The PANSS is a widely used measure with several subdomains, including positive symptoms, negative symptoms, and general psychopathology of schizophrenia. Lower scores are indicative of fewer symptoms; higher scores are indicative of more symptoms. Total PANSS scores range from 0-20. |
Countries
United States
Participant flow
Recruitment details
Patient recruitment occurred between 8-05 and 4-06 for this single-site study at the Durham VAMC, Durham, NC.
Pre-assignment details
Following the screening visit, patients were withdrawn during the placebo lead-in phase and were not randomized for the following reasons: 1. hyponatremia, 2. hospitalization, 3.pneumonia, 4.no show for follow-up study visit, 5.chest pain, 6. elevated prolactin at baseline, 7.prolonged QTc at baseline
Participants by arm
| Arm | Count |
|---|---|
| Pregnenolone * Pregnenolone 100 mg in divided doses (50 mg BID) for 2 weeks, then
* Pregnenolone 300 mg in divided doses (150 mg BID) for 2 weeks, then
* Pregnenolone 500 mg in divided doses (250 mg BID) for 4 weeks. | 10 |
| Placebo Placebo dosing and tablets were identical to Pregnenolone. | 11 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Pregnenolone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 10 Participants | 21.0 Participants |
| Age, Continuous | 49 years STANDARD_DEVIATION 12 | 53 years STANDARD_DEVIATION 6 | 51 years STANDARD_DEVIATION 9 |
| Region of Enrollment United States | 11 participants | 10 participants | 21.0 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2.0 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 9 | 5 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
Mean Change of Z-scores on the Brief Assessment of Cognition in Schizophrenia (BACS)
The BACS 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.
Time frame: Change in composite BACS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Mean Change of Z-scores on the Brief Assessment of Cognition in Schizophrenia (BACS) | 0.60 units on a scale | Standard Deviation 0.78 |
| Placebo | Mean Change of Z-scores on the Brief Assessment of Cognition in Schizophrenia (BACS) | 0.22 units on a scale | Standard Deviation 0.47 |
p-value: 0.22t-test, 2 sided
Primary
Mean Score on the Scale for the Assessment of Negative Symptoms (SANS), p=0.048
The SANS assesses negative symptoms in schizophrenia. The SANS consists of 21 clinical interview questions assessing negative symptoms of schizophrenia. Each question is rated on a scale of 0 (no symptoms) to 7 (severe symptoms).
Time frame: SANS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward)
Population: Pilot proof of concept study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Mean Score on the Scale for the Assessment of Negative Symptoms (SANS), p=0.048 | -10.38 units on a scale | Standard Deviation 10.18 |
| Placebo | Mean Score on the Scale for the Assessment of Negative Symptoms (SANS), p=0.048 | -2.33 units on a scale | Standard Deviation 4.42 |
Comparison: T-test of change scores, pregnenolone vs. placebo post-treatment compared to baseline.p-value: 0.048t-test, 2 sided
Primary
Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)
The MATRICS is a battery for the assessment of cognitive symptoms in patients with schizophrenia. Composite T-scores are calculated (T-score ranges are -20 to +80, and are normed on gender and age). Higher scores are indicative of better cognitive performance, lower scores are indicative of poorer cognitive performance.
Time frame: Change in composite MATRICS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) | 7.00 units on a scale | Standard Deviation 8.87 |
| Placebo | Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) | 7.00 units on a scale | Standard Deviation 4.95 |
Comparison: T-test of change scores, pregnenolone compared to placebo post-treatment vs. pre-randomization.p-value: 1t-test, 2 sided
Secondary
Clinical Global Impression Scale (CGI-I)
The CGI-I is a commonly used psychiatric scale to assess overall general improvement. The CGI-I consists of one interviewer-rated question on a scale of 1-7. Lower scores are indicative of fewer symptoms; while higher scores are indicative of more symptoms.
Time frame: CGI-I scores at 8 weeks post-randomization (at least 4 weeks; last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Clinical Global Impression Scale (CGI-I) | 2.11 units on a scale | Standard Deviation 0.33 |
| Placebo | Clinical Global Impression Scale (CGI-I) | 2.89 units on a scale | Standard Deviation 0.78 |
p-value: 0.014t-test, 2 sided
Secondary
Mean Score Change in Calgary Depression Scale for Schizophrenia (CDSS)
The CDSS is used measure to investigate depressive symptoms in schizophrenia. The measure includes 9 questions ranked from 0 (no symptoms) to 3 (severe symptoms). Range of possible scores: 0-27.
Time frame: Change in CDSS scores at baseline and 8 weeks (at least 4 weeks; last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Mean Score Change in Calgary Depression Scale for Schizophrenia (CDSS) | -1.57 units on a scale | Standard Deviation 2.15 |
| Placebo | Mean Score Change in Calgary Depression Scale for Schizophrenia (CDSS) | -2.00 units on a scale | Standard Deviation 3.66 |
p-value: 0.79t-test, 2 sided
Secondary
Mean Score on the Positive and Negative Symptom Scale (PANSS)
The PANSS is a widely used measure with several subdomains, including positive symptoms, negative symptoms, and general psychopathology of schizophrenia. Lower scores are indicative of fewer symptoms; higher scores are indicative of more symptoms. Total PANSS scores range from 0-20.
Time frame: Change in PANSS scores at baseline and 8 weeks post-randomization (at least 4 weeks; last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregnenolone | Mean Score on the Positive and Negative Symptom Scale (PANSS) | -9.88 units on a scale | Standard Deviation 9.23 |
| Placebo | Mean Score on the Positive and Negative Symptom Scale (PANSS) | -5.44 units on a scale | Standard Deviation 5.27 |