Trial Outcomes & Findings for Gamma-Amino Butyric Acid (GABA)-A Alpha2/3 Study (NCT NCT00129441)

Last Updated: 2011-10-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

16 participants

Primary outcome timeframe

Week 4

Results posted on

2011-10-17

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	9	6
Overall Study Baseline, Visit 1	9	6
Overall Study Week 1, Visit 2	9	6
Overall Study Week 2, Visit 3	9	6
Overall Study Week 3, Visit 4	9	6
Overall Study Week 4, Visit 5	9	6
Overall Study Week 5, Visit 6	9	6
Overall Study Week 26, Visit 7	9	6
Overall Study Year 1, Visit 8	9	6
Overall Study COMPLETED	9	6
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	L-830982 n=9 Participants 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 n=6 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.	Total n=15 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age Continuous	39.3 years STANDARD_DEVIATION 10.6 • n=5 Participants	35.7 years STANDARD_DEVIATION 6.8 • n=7 Participants	37.9 years STANDARD_DEVIATION 9.2 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Region of Enrollment United States	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
N-back Task Reaction Time	874 msec STANDARD_DEVIATION 238 • n=5 Participants	669 msec STANDARD_DEVIATION 158 • n=7 Participants	801 msec STANDARD_DEVIATION 230 • n=5 Participants
N-back Task Error Rate	0.247 proportion of errors STANDARD_DEVIATION 0.102 • n=5 Participants	0.250 proportion of errors STANDARD_DEVIATION 0.028 • n=7 Participants	0.248 proportion of errors STANDARD_DEVIATION 0.081 • n=5 Participants
AX Continuous Performance Test Task d-prime	0.9 d-prime STANDARD_DEVIATION 0.7 • n=5 Participants	0.7 d-prime STANDARD_DEVIATION 0.9 • n=7 Participants	0.8 d-prime STANDARD_DEVIATION 0.7 • n=5 Participants
Preparing to Overcome Prepotency (POP) Task - Reaction Time	66 msec STANDARD_DEVIATION 48 • n=5 Participants	36 msec STANDARD_DEVIATION 61 • n=7 Participants	54 msec STANDARD_DEVIATION 53 • n=5 Participants
Preparing to Overcome Prepotency (POP) Task - Error Rate	0.034 proportion of errors STANDARD_DEVIATION 0.050 • n=5 Participants	0.064 proportion of errors STANDARD_DEVIATION 0.068 • n=7 Participants	0.046 proportion of errors STANDARD_DEVIATION 0.058 • n=5 Participants
Brief Psychiatric Rating Scale (BPRS) Total Score	24.3 Scores on a scale STANDARD_DEVIATION 2.6 • n=5 Participants	34.2 Scores on a scale STANDARD_DEVIATION 7.1 • n=7 Participants	28.3 Scores on a scale STANDARD_DEVIATION 6.9 • n=5 Participants
Repeatable Battery for the Assessment of Neuropsychological Status: RBANS Total Score	71.8 Standard Score STANDARD_DEVIATION 10.6 • n=5 Participants	63.5 Standard Score STANDARD_DEVIATION 7.1 • n=7 Participants	68.5 Standard Score STANDARD_DEVIATION 10.0 • n=5 Participants
Repeatable Battery for the Assessment of Neuropsychological Status: RBANS Delayed Memory Subindex	76.8 Standard Score STANDARD_DEVIATION 15.5 • n=5 Participants	60.8 Standard Score STANDARD_DEVIATION 16.1 • n=7 Participants	70.4 Standard Score STANDARD_DEVIATION 17.2 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	L-830982 n=9 Participants 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 n=5 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
N-back Task - Reaction Time	786 msec Standard Deviation 231	684 msec Standard Deviation 101

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	L-830982 n=9 Participants 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 n=5 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
N-back Task - Error Rate	0.239 proportion of errors Standard Deviation 0.062	0.297 proportion of errors Standard Deviation 0.075

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	L-830982 n=7 Participants 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 n=4 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
AX Continuous Performance Test Task D-prime	1.9 d-prime Standard Deviation 0.9	0.7 d-prime Standard Deviation 0.9

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	L-830982 n=9 Participants 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 n=6 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Preparing to Overcome Prepotency (POP) Task - Reaction Time	57 msec Standard Deviation 66	66 msec Standard Deviation 55

PRIMARY outcome

Timeframe: Week 4

Outcome measures

Outcome measures
Measure	L-830982 n=9 Participants 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 n=6 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Preparing to Overcome Prepotency Task - Error Rate	0.042 proportion of errors Standard Deviation 0.042	0.031 proportion of errors Standard Deviation 0.074

SECONDARY outcome

Timeframe: Week 4

Population: One subject dropped out prior to completing study

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).

Outcome measures

Outcome measures
Measure	L-830982 n=9 Participants 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 n=6 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Brief Psychiatric Rating Scale Total Score	26.3 Scores on a scale Standard Deviation 5.3	27.0 Scores on a scale Standard Deviation 3.0

SECONDARY outcome

Timeframe: Week 4

Population: One subject dropped out before completing the study.

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).

Outcome measures

Outcome measures
Measure	L-830982 n=9 Participants 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 n=6 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score	76.7 Standard Score Standard Deviation 13.5	70.8 Standard Score Standard Deviation 12.4

SECONDARY outcome

Timeframe: Week 4

Population: One subject dropped out before completing the study.

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

Outcome measures
Measure	L-830982 n=9 Participants 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 n=6 Participants Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Subindex	85.3 Standard Score Standard Deviation 15.7	63.8 Standard Score Standard Deviation 17.6

Adverse Events

L-830982

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	L-830982 n=10 participants at risk 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 n=6 participants at risk Medications were dispensed weekly in blister packs by the hospital pharmacy, using the same number of pills as those on active drug.
General disorders Dizziness	20.0% 2/10 • Number of events 2 • Adverse event data were collected at all timepoints during the 5-week clinical trial. Eye exams were conducted at 6-month and 1-year follow-ups.	0.00% 0/6 • Adverse event data were collected at all timepoints during the 5-week clinical trial. Eye exams were conducted at 6-month and 1-year follow-ups.
General disorders Somnolence	20.0% 2/10 • Number of events 2 • Adverse event data were collected at all timepoints during the 5-week clinical trial. Eye exams were conducted at 6-month and 1-year follow-ups.	0.00% 0/6 • Adverse event data were collected at all timepoints during the 5-week clinical trial. Eye exams were conducted at 6-month and 1-year follow-ups.
General disorders Appetite increase	10.0% 1/10 • Number of events 1 • Adverse event data were collected at all timepoints during the 5-week clinical trial. Eye exams were conducted at 6-month and 1-year follow-ups.	0.00% 0/6 • Adverse event data were collected at all timepoints during the 5-week clinical trial. Eye exams were conducted at 6-month and 1-year follow-ups.

Additional Information

David A. Lewis, MD

University of Pittsburgh

Phone: (412) 246-6010

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place