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Gamma-Amino Butyric Acid (GABA)-A Alpha2/3 Study

This study has been completed.
Sponsor:
Collaborator:
Merck
Information provided by (Responsible Party):
University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT00129441
First received: August 10, 2005
Last updated: October 14, 2011
Last verified: October 2011
History of Changes
Results First Received: May 25, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Condition: Schizophrenia
Interventions: Drug: Merck L-830982
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
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.
Placebo Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.

Participant Flow:   Overall Study
    L-830982     Placebo  
STARTED     9     6  
Baseline, Visit 1     9 [1]   6  
Week 1, Visit 2     9     6  
Week 2, Visit 3     9     6  
Week 3, Visit 4     9     6  
Week 4, Visit 5     9     6  
Week 5, Visit 6     9     6  
Week 26, Visit 7     9     6  
Year 1, Visit 8     9     6  
COMPLETED     9     6  
NOT COMPLETED     0     0  
[1] Baseline # only includes those who completed 4-week trial (one L-830982 subject did not complete).



  Baseline Characteristics
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Reporting Groups
  Description
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.
Placebo Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Total Total of all reporting groups

Baseline Measures
    L-830982     Placebo     Total  
Number of Participants  
[units: participants]
 		  9     6     15  
Age  
[units: participants]
 		     
<=18 years     0     0     0  
Between 18 and 65 years     9     6     15  
>=65 years     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation 		  39.3  ± 10.6     35.7  ± 6.8     37.9  ± 9.2  
Gender  
[units: participants]
 		     
Female     0     0     0  
Male     9     6     15  
Region of Enrollment  
[units: Participants]
 		     
United States     9     6     15  
N-back Task Reaction Time [1]
[units: msec]
Mean ± Standard Deviation 		  874  ± 238     669  ± 158     801  ± 230  
N-back Task Error Rate [1]
[units: proportion of errors]
Mean ± Standard Deviation 		  0.247  ± 0.102     0.250  ± 0.028     0.248  ± 0.081  
AX Continuous Performance Test Task d-prime [2]
[units: d-prime]
Mean ± Standard Deviation 		  0.9  ± 0.7     0.7  ± 0.9     0.8  ± 0.7  
Preparing to Overcome Prepotency (POP) Task - Reaction Time [3]
[units: msec]
Mean ± Standard Deviation 		  66  ± 48     36  ± 61     54  ± 53  
Preparing to Overcome Prepotency (POP) Task - Error Rate [3]
[units: proportion of errors]
Mean ± Standard Deviation 		  0.034  ± 0.050     0.064  ± 0.068     0.046  ± 0.058  
Brief Psychiatric Rating Scale (BPRS) Total Score [4]
[units: Scores on a scale]
Mean ± Standard Deviation 		  24.3  ± 2.6     34.2  ± 7.1     28.3  ± 6.9  
Repeatable Battery for the Assessment of Neuropsychological Status: RBANS Total Score [5]
[units: Standard Score]
Mean ± Standard Deviation 		  71.8  ± 10.6     63.5  ± 7.1     68.5  ± 10.0  
Repeatable Battery for the Assessment of Neuropsychological Status: RBANS Delayed Memory Subindex [6]
[units: Standard Score]
Mean ± Standard Deviation 		  76.8  ± 15.5     60.8  ± 16.1     70.4  ± 17.2  
[1] 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. Those with schizophrenia exhibit substantially impaired performance and decreased functional activation of the dorsolateral prefrontal cortex (DLPFC) relative to matched comparison subjects for the 2-back load condition. 2-back condition was used as the dependent measure, as it provides the best index of performance and DLPFC disturbances in subjects with schizophrenia.
[2] For the AX Continuous Performance Test (AXCPT), 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.
[3] 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.
[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).
[5] 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).
[6] 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).



  Outcome Measures
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1.  Primary:   N-back Task - Reaction Time   [ Time Frame: Week 4 ]
  Show Outcome Measure 1

2.  Primary:   N-back Task - Error Rate   [ Time Frame: Week 4 ]
  Show Outcome Measure 2

3.  Primary:   AX Continuous Performance Test Task D-prime   [ Time Frame: Week 4 ]
  Hide Outcome Measure 3

Measure Type Primary
Measure Title AX Continuous Performance Test Task D-prime
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
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.
Placebo Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.

Measured Values
    L-830982     Placebo  
Number of Participants Analyzed  
[units: participants]
 		  7     4  
AX Continuous Performance Test Task D-prime  
[units: d-prime]
Mean ± Standard Deviation 		  1.9  ± 0.9     0.7  ± 0.9  


Statistical Analysis 1 for AX Continuous Performance Test Task D-prime
Groups [1] All groups
Method [2] ANOVA
P Value [3] 0.12
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



4.  Primary:   Preparing to Overcome Prepotency (POP) Task - Reaction Time   [ Time Frame: Week 4 ]
  Show Outcome Measure 4

5.  Primary:   Preparing to Overcome Prepotency Task - Error Rate   [ Time Frame: Week 4 ]
  Show Outcome Measure 5

6.  Secondary:   Brief Psychiatric Rating Scale Total Score   [ Time Frame: Week 4 ]
  Show Outcome Measure 6

7.  Secondary:   Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score   [ Time Frame: Week 4 ]
  Show Outcome Measure 7

8.  Secondary:   Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex   [ Time Frame: Week 4 ]
  Show Outcome Measure 8


  Serious Adverse Events
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  Other Adverse Events
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  More Information
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Certain Agreements:  
Principal Investigators are NOT 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.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Small sample size; RBANS may lack appropriate sensitivity for short-term study; between-group differences in baseline clinical symptoms & neuropsychological function; excluding those with more modest cognitive impairments (RBANS standard score >90).  


Results Point of Contact:  
Name/Title: David A. Lewis, MD
Organization: University of Pittsburgh
phone: (412) 246-6010
e-mail: lewisda@upmc.edu


Publications of Results:

Other Publications:


Responsible Party: University of Pittsburgh
ClinicalTrials.gov Identifier: NCT00129441     History of Changes
Other Study ID Numbers: 0502027
Study First Received: August 10, 2005
Results First Received: May 25, 2011
Last Updated: October 14, 2011
Health Authority: United States: Food and Drug Administration