Schizophrenia
Conditions
Keywords
schizophrenia
Brief summary
The purpose of this research study is to determine whether a short-term administration of an investigational study drug may provide evidence of improvement in cognitive functioning in a group of stable male subjects with schizophrenia.
Detailed description
The goal of this study is to determine whether the short-term (4 week), double-blind administration of Merck L-830982 provides evidence of improvement in cognitive functioning in stable male subjects with schizophrenia. This initial, small sample size study (n=9 on L-830982 and n=6 on placebo) is restricted to males in order to reduce the variance that might be attributable to the well-documented sex differences in the clinical features of schizophrenia.
Interventions
DRUGMerck L-830982
The initial dose of L-830982 was 3.0 mg twice daily (b.i.d.) the dosage increased to 5.0 mg b.i.d. at the end of week 1 and 8.0 mg b.i.d. at the end of week 2, which was continued for the remaining 2 weeks of the trial. Medications were dispensed weekly in blister packs by the hospital pharmacy.
DRUGPlacebo
Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Sponsors
Merck Sharp & Dohme LLC
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Male participants * Between the ages of 18 and 50 * Meet diagnostic criteria for schizophrenia or schizoaffective disorder * Are clinically stable for a minimum of 3 months on current dose of medication * Are unemployed (i.e., work less than 20 hours per week at competitive employment)
Exclusion criteria
* Psychoactive substance dependence within the past 6 months or substance abuse within the past month * History of head trauma or other neurological disorder * Medical illness or medications, such as benzodiazepine treatment or HIV medications, that may be affected by study participation (the study doctor will discuss this with potential subjects) * Mental retardation * Seizure disorder * History of a heart attack, arrhythmia, or other heart disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Preparing to Overcome Prepotency Task - Error Rate | Week 4 | The POP task is a cued stimulus-response reversal paradigm that, similar to the AX Continuous Performance Test, requires increases in cognitive control through the maintenance and use of context information to overcome prepotent response tendencies. |
| N-back Task - Error Rate | Week 4 | The N-back task is a sequential-letter memory task for which working memory load is varied, as the respondent must indicate when the current stimulus matches the one from 'n' steps earlier in the sequence. The dependent measure for the N-back task was performance in the 2-back condition, which provides the best index of performance and dorsolateral prefrontal cortex disturbances in subjects with schizophrenia. |
| AX Continuous Performance Test Task D-prime | Week 4 | For the AX Continuous Performance Test, subjects are required to maintain an attentional set across a delay interval in order to overcome a prepotent response tendency (target responses are required when an X is presented but only in the context of a preceding A; non-target conditions are AY, BX and BY). The dependent measure was d-prime at the long delay (calculated as AX hits minus BX false alarms, which is particularly sensitive to context processing impairments in individuals with schizophrenia. |
| Preparing to Overcome Prepotency (POP) Task - Reaction Time | Week 4 | The POP task is a cued stimulus-response reversal paradigm that, similar to the AX Continuous Performance Test, requires increases in cognitive control through the maintenance and use of context information to overcome prepotent response tendencies. |
| N-back Task - Reaction Time | Week 4 | The N-back task is a sequential-letter memory task for which working memory load is varied, as the respondent must indicate when the current stimulus matches the one from 'n' steps earlier in the sequence. The dependent measure for the N-back task was performance in the 2-back condition, which provides the best index of performance and dorsolateral prefrontal cortex disturbances in subjects with schizophrenia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score | Week 4 | Five index scores are computed from the RBANS (immediate memory, language, visuospatial, attention, delayed memory) that are combined to provide the Total Score. The Total Score is expressed as a standardized score normalized to a population mean of 100, with a standard deviation of 15 (possible scores 40-135). Higher scores reflect better performance. All subjects received the A form at baseline and the wk-4 visit and the B form at the wk-2 visit (the A/B forms are equivalent alternate forms, which allow for retesting patients without the confound of practice effects). |
| Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex | Week 4 | The Delayed Memory Index consists of verbal and nonverbal recall tasks (words, drawings) that the subject views early in the evaluation and without warning, is asked to recall \ 1/2 hr later. Scores are expressed as standardized scores normalized to a population mean of 100, with a standard deviation of 15 (possible scores between 40-135). Higher scores reflect better performance. Subjects received the A form at baseline and wk-4 visit and the B form at the wk-2 visit (A/B forms are equivalent alternate forms, which allow for retesting patients without the confound of practice effects). |
| Brief Psychiatric Rating Scale Total Score | Week 4 | The Brief Psychiatric Rating Scale-anchored (BPRS; Overall and Gorham, 1962; Woerner, Mannuzza, Kane, 1988) is an 18-item scale that is among the most widely used measure of psychopathology. Scores range from 1-7, with higher scores reflecting greater pathology. A total score is derived from the sum of all 18 items (possible scores range from 18-126). It relies on clinical judgment in the assessment of key areas of psychopathology (depression, anxiety, psychosis). |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through referrals from clinicians in the outpatient clinical services at Western Psychiatric Institute & Clinic and through a Psychosis Registry. 29 males signed consent and 16 were eligible-one subject did not complete the study and is not included in any summary statistics. Recruitment period: 4/05 through 1/07.
Pre-assignment details
To ensure eligibility before randomization, the following were administered: a urine drug screen; diagnostic, medical history and adverse events ratings; Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); electrocardiogram; blood tests (for kidney and liver function); and a complete eye exam, including a slit-lamp exam.
Participants by arm
| Arm | Count |
|---|---|
| L-830982 The initial dose of L-830982 was 3.0 mg twice daily (b.i.d.) the dosage increased to 5.0 mg b.i.d. at the end of week 1 and 8.0 mg b.i.d. at the end of week 2, which was continued for the remaining 2 weeks of the trial. Medications were dispensed weekly in blister packs by the hospital pharmacy. | 9 |
| Placebo Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug. | 6 |
| Total | 15 |
Baseline characteristics
| Characteristic | L-830982 | Placebo | 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 | 9 Participants | 6 Participants | 15 Participants |
| Age Continuous | 39.3 years STANDARD_DEVIATION 10.6 | 35.7 years STANDARD_DEVIATION 6.8 | 37.9 years STANDARD_DEVIATION 9.2 |
| AX Continuous Performance Test Task d-prime | 0.9 d-prime STANDARD_DEVIATION 0.7 | 0.7 d-prime STANDARD_DEVIATION 0.9 | 0.8 d-prime STANDARD_DEVIATION 0.7 |
| Brief Psychiatric Rating Scale (BPRS) Total Score | 24.3 Scores on a scale STANDARD_DEVIATION 2.6 | 34.2 Scores on a scale STANDARD_DEVIATION 7.1 | 28.3 Scores on a scale STANDARD_DEVIATION 6.9 |
| N-back Task Error Rate | 0.247 proportion of errors STANDARD_DEVIATION 0.102 | 0.250 proportion of errors STANDARD_DEVIATION 0.028 | 0.248 proportion of errors STANDARD_DEVIATION 0.081 |
| N-back Task Reaction Time | 874 msec STANDARD_DEVIATION 238 | 669 msec STANDARD_DEVIATION 158 | 801 msec STANDARD_DEVIATION 230 |
| Preparing to Overcome Prepotency (POP) Task - Error Rate | 0.034 proportion of errors STANDARD_DEVIATION 0.05 | 0.064 proportion of errors STANDARD_DEVIATION 0.068 | 0.046 proportion of errors STANDARD_DEVIATION 0.058 |
| Preparing to Overcome Prepotency (POP) Task - Reaction Time | 66 msec STANDARD_DEVIATION 48 | 36 msec STANDARD_DEVIATION 61 | 54 msec STANDARD_DEVIATION 53 |
| Region of Enrollment United States | 9 Participants | 6 Participants | 15 Participants |
| Repeatable Battery for the Assessment of Neuropsychological Status: RBANS Delayed Memory Subindex | 76.8 Standard Score STANDARD_DEVIATION 15.5 | 60.8 Standard Score STANDARD_DEVIATION 16.1 | 70.4 Standard Score STANDARD_DEVIATION 17.2 |
| Repeatable Battery for the Assessment of Neuropsychological Status: RBANS Total Score | 71.8 Standard Score STANDARD_DEVIATION 10.6 | 63.5 Standard Score STANDARD_DEVIATION 7.1 | 68.5 Standard Score STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 0 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 |
Outcome results
Primary
AX Continuous Performance Test Task D-prime
For the AX Continuous Performance Test, subjects are required to maintain an attentional set across a delay interval in order to overcome a prepotent response tendency (target responses are required when an X is presented but only in the context of a preceding A; non-target conditions are AY, BX and BY). The dependent measure was d-prime at the long delay (calculated as AX hits minus BX false alarms, which is particularly sensitive to context processing impairments in individuals with schizophrenia.
Time frame: Week 4
Population: Four subjects did not complete a sufficient number of trials for the AXCPT task at both testing periods, therefore 7 L-830982 and 4 placebo subjects data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | AX Continuous Performance Test Task D-prime | 1.9 d-prime | Standard Deviation 0.9 |
| Placebo | AX Continuous Performance Test Task D-prime | 0.7 d-prime | Standard Deviation 0.9 |
p-value: 0.12ANOVA
Primary
N-back Task - Error Rate
The N-back task is a sequential-letter memory task for which working memory load is varied, as the respondent must indicate when the current stimulus matches the one from 'n' steps earlier in the sequence. The dependent measure for the N-back task was performance in the 2-back condition, which provides the best index of performance and dorsolateral prefrontal cortex disturbances in subjects with schizophrenia.
Time frame: Week 4
Population: Analyses included only those participants who completed the 4-week trial. One participant refused N-back at week-4, so 9 L-830982 and 5 placebo were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | N-back Task - Error Rate | 0.239 proportion of errors | Standard Deviation 0.062 |
| Placebo | N-back Task - Error Rate | 0.297 proportion of errors | Standard Deviation 0.075 |
p-value: 0.162ANOVA
Primary
N-back Task - Reaction Time
The N-back task is a sequential-letter memory task for which working memory load is varied, as the respondent must indicate when the current stimulus matches the one from 'n' steps earlier in the sequence. The dependent measure for the N-back task was performance in the 2-back condition, which provides the best index of performance and dorsolateral prefrontal cortex disturbances in subjects with schizophrenia.
Time frame: Week 4
Population: Analyses included only those participants who completed the 4-week trial. One participant refused N-back at week-4, so 9 L-830982 and 5 placebo were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | N-back Task - Reaction Time | 786 msec | Standard Deviation 231 |
| Placebo | N-back Task - Reaction Time | 684 msec | Standard Deviation 101 |
p-value: 0.16ANOVA
Primary
Preparing to Overcome Prepotency (POP) Task - Reaction Time
The POP task is a cued stimulus-response reversal paradigm that, similar to the AX Continuous Performance Test, requires increases in cognitive control through the maintenance and use of context information to overcome prepotent response tendencies.
Time frame: Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | Preparing to Overcome Prepotency (POP) Task - Reaction Time | 57 msec | Standard Deviation 66 |
| Placebo | Preparing to Overcome Prepotency (POP) Task - Reaction Time | 66 msec | Standard Deviation 55 |
p-value: 0.05ANOVA
Primary
Preparing to Overcome Prepotency Task - Error Rate
The POP task is a cued stimulus-response reversal paradigm that, similar to the AX Continuous Performance Test, requires increases in cognitive control through the maintenance and use of context information to overcome prepotent response tendencies.
Time frame: Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | Preparing to Overcome Prepotency Task - Error Rate | 0.042 proportion of errors | Standard Deviation 0.042 |
| Placebo | Preparing to Overcome Prepotency Task - Error Rate | 0.031 proportion of errors | Standard Deviation 0.074 |
p-value: 0.249ANOVA
Secondary
Brief Psychiatric Rating Scale Total Score
The Brief Psychiatric Rating Scale-anchored (BPRS; Overall and Gorham, 1962; Woerner, Mannuzza, Kane, 1988) is an 18-item scale that is among the most widely used measure of psychopathology. Scores range from 1-7, with higher scores reflecting greater pathology. A total score is derived from the sum of all 18 items (possible scores range from 18-126). It relies on clinical judgment in the assessment of key areas of psychopathology (depression, anxiety, psychosis).
Time frame: Week 4
Population: One subject dropped out prior to completing study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | Brief Psychiatric Rating Scale Total Score | 26.3 Scores on a scale | Standard Deviation 5.3 |
| Placebo | Brief Psychiatric Rating Scale Total Score | 27.0 Scores on a scale | Standard Deviation 3 |
Comparison: At week 4, mean BPRS total scores were nearly the same for the placebo group and L-830982 group as a result of a significant reduction in positive symptoms reported for the placebo group (F=9.12, df=1,13, p=0.01). For the L-830982-treated group, neither total BPRS scores nor any of the factor scores changed over the course of the trial.p-value: 0.01ANOVA
Secondary
Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex
The Delayed Memory Index consists of verbal and nonverbal recall tasks (words, drawings) that the subject views early in the evaluation and without warning, is asked to recall \ 1/2 hr later. Scores are expressed as standardized scores normalized to a population mean of 100, with a standard deviation of 15 (possible scores between 40-135). Higher scores reflect better performance. Subjects received the A form at baseline and wk-4 visit and the B form at the wk-2 visit (A/B forms are equivalent alternate forms, which allow for retesting patients without the confound of practice effects).
Time frame: Week 4
Population: One subject dropped out before completing the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex | 85.3 Standard Score | Standard Deviation 15.7 |
| Placebo | Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex | 63.8 Standard Score | Standard Deviation 17.6 |
p-value: <0.05ANOVA
Secondary
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score
Five index scores are computed from the RBANS (immediate memory, language, visuospatial, attention, delayed memory) that are combined to provide the Total Score. The Total Score is expressed as a standardized score normalized to a population mean of 100, with a standard deviation of 15 (possible scores 40-135). Higher scores reflect better performance. All subjects received the A form at baseline and the wk-4 visit and the B form at the wk-2 visit (the A/B forms are equivalent alternate forms, which allow for retesting patients without the confound of practice effects).
Time frame: Week 4
Population: One subject dropped out before completing the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| L-830982 | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score | 76.7 Standard Score | Standard Deviation 13.5 |
| Placebo | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score | 70.8 Standard Score | Standard Deviation 12.4 |
p-value: <0.05ANOVA