Schizophrenia
Conditions
Keywords
H3 Antagonist, Schizophrenia, double blind, Histamine, randomised, placebo controlled, Cognition
Brief summary
This study aims to evaluate the cognitive enhancing effects and tolerability of GSK239512 compared to placebo in patients with schizophrenia
Detailed description
This is a 7-week, Phase II, multi-centre, randomised, double-blind, placebo-controlled, parallel group design study in male and female subjects with schizophrenia who are stabilised on antipsychotic medication. Subjects will be randomised to receive either GSK239512 or placebo for 7 weeks. They will undergo weekly review of safety, tolerability and cognitive performance measures.
Interventions
DRUGGSK239512
Histamine H3 Antagonist
DRUGPlacebo
Placebo to match GSK239512
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Clinical diagnosis of Schizophrenia 2. No acute exacerbation of symptoms requiring hospital admission or step up care in the previous six months. 3. Not on any symptomatic treatment for cognition
Exclusion criteria
1. Poses a significant homicidal or suicidal risk or evidence of previous homicidal or suicidal risk. 2. Co-morbid psychiatric or significant physical illness 3. Alcohol or drug abuse or dependence.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Baseline and up to Week 7 | The CSSB is a computerized battery with following domains (score range): Verbal memory (0-75), working memory (0-28), motor speed (0-100), verbal fluency, attention and speed of information processing (0-110) and executive functions with higher score representing better performance. Two Baseline CSSB testing were conducted; the first on the day prior to commencing dosing (Day -1) and the other test pre-dose on Day 1: the average of the two tests was used as Baseline. Change from Baseline was calculated as score at a given time minus score at Baseline. For each individual task from the CSSB, the Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. A composite score was calculated by averaging all the measures, and then calculating a z-score of the composite. Higher the composite score, better is the performance. Z-score is the measure of standard deviation away from the mean score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Baseline and Week 7 | The CSSB is a computerized battery with following domains (score range): Verbal memory (0-75), working memory (0-28), motor speed (0-100), verbal fluency, attention and speed of information processing (0-110) and executive functions with higher score representing better performance. Two Baseline CSSB testing were conducted; the first on the day prior to commencing dosing (Day -1) and the other test pre-dose on Day 1: the average of the two tests was used as Baseline. Change from Baseline was calculated as score at a given time minus score at Baseline. For each individual task from the CSSB, the Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. A composite score was calculated by averaging all the measures, and then calculating a z-score of the composite. Higher the composite score, better is the performance. Z-score is the measure of standard deviation away from the mean score. |
| Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Baseline and Week 7 | MCCB measures functioning across various cognitive domains and is comprised of ten tests that assess seven cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) Its measurements are based on timed paper-and-pencil, computerized, and orally-administered tests, as well as spatial tests using geometric cubes. MCCB composite T scores are between 40 and 60 (normal range) and \< 40 (below normal range). Higher scores indicate better performance. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline. |
| Change From Baseline in Brief Psychiatric Rating Scale (BPRS) at Week 7 | Baseline and Week 7 | BPRS is the clinician rating of psychiatric symptoms; higher score indicates higher severity; 18-items scored 1-7; lower score is 18 and highest score is 126. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline. |
| Change From Baseline in Schedule for Assessment of Negative Symptoms (SANS) at Week 7 | Baseline and Week 7 | The SANS was a tool used to assess five symptom complexes to obtain clinical ratings of negative symptoms in par. with schizophrenia. Complexes include: affective blunting; alogia (impoverished thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention. Assessment was conducted on six-point scale (0=not at all to 5=severe) for a total scoring range of 0-120. Lower scores represent better performance. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline. |
| Change From Baseline in University of California and San Diego (UCSD) Performance Based Skills Assessment (UPSA) at Week 7 | Baseline and Week 7 | The 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 ranges from 0 to 14, the finance ranges from 0 to 11, the communication ranges from 0 to 12, the mobility ranges from 0 to 9, and the house management 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. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was score at a given time post Baseline minus Baseline score |
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to Day 59 | AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. |
| Change From Baseline in Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at Week 7 | Baseline and Week 7 | MCCB measures functioning across various cognitive domains and is comprised of ten tests that assess seven cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition). Its measurements are based on timed paper-and-pencil, computerized, and orally-administered tests, as well as spatial tests using geometric cubes. MCCB composite T scores are between 40 and 60 (normal range) and \< 40 (below normal range). Higher scores indicate better performance. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline. |
| Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | Up to Day 59 | Blood pressure readings both systolic and diastolic were collected at pre-dose and then hourly post-dose until 6 hours post-dose or until the par. got discharged. Blood pressure was measured in both standing (Std) and supine (Sup) position. Data with only abnormal values were presented. For SBP the data of concern was \<90 or \>140 and increase from Baseline (IFB) \>=40; \<90 or \>140 and decrease from Baseline (DFB) \>=30. For DBP the data of concern was \<50 or \>90 and IFB \>=30; \<50 or \>90 and DFB \>=20. |
| Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range | Up to Day 59 | Heart rate readings were collected at pre-dose and then hourly post-dose until 6 hours post-dose or until the participant got discharged. It was measured in both supine and standing position. For both Std and Sup positions, heart rate data of concern was \<50 or \>100 and IFB \>=30; \<50 or \>100 and DFB \>=30. Data with only abnormal values were presented. |
| Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Up to Day 59 | Hematology parameters: Basophils, Eosinophils, Hematocrit, Hemoglobin, Lymphocytes, Mean Corpuscle Hemoglobin (MCH), Mean Corpuscle Hemoglobin concentration (MCHC), Mean Corpuscle Volume (MCV), Monocytes, Platelet count, Red blood cell count (RBC), Reticulocytes, Neutrophils count and White blood cell (WBC) count were presented as values of potential clinical concern at any time on treatment. Only those parameters with any abnormal value are presented. |
| Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | Up to Day 59 | Clinical chemistry parameters: Alanine Amino Transferase (ALT), Albumin, Alkaline Phosphatase, Aspartate Amino Transferase (AST), Calcium, Creatinine, Direct Bilirubin, Gamma Glutamyl Transferase (GGT), Glucose, Potassium, Sodium, Total Bilirubin, Total protein, Urea/ Blood urea nitrogen (BUN) were presented as values of potential clinical concern at any time on treatment. Only those parameters with any abnormal value are presented. |
| Number of Par. With Abnormal Urinalysis Parameters Values of Potential Clinical Concern | Up to Day 59 | Samples for urinalysis were collected on Days 1, 7, 14, 21, 28, 35, 42, 49 and up to Day 59 (follow-up) to assess specific gravity, pH, glucose, protein, blood and ketone by dipstick and microscopic examination (if blood or protein is abnormal). |
| Plasma Concentrations of GSK239512 (Cmax) at Steady State After Repeat Dosing on Dose Review Visit at Any Time On-treatment | 15 minutes prior to start and 15 minutes after completion of CSSB at Week 1,2,3,4,5,6 and 7 | One Pharmacokinetic (PK) sample was collected within 15 minutes prior to the start of the CSSB and one PK sample was collected within 15 minutes after completion of the CSSB. 'n' was the number of samples available for analysis. |
| Number of Par. With Most Severe On-treatment Abnormal Electrocardiogram (ECG) Findings | Up to Day 59 | Triplicate 12-lead ECGs were obtained at Baseline (screening visit). Single 12-lead ECGs were obtained at each subsequent time point during the study. Abnormal ECG findings were presented for the most severe on-treatment result. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 14 centers in the United States from 1 December 2009 to 10 August 2011. Study included d-amphetamine therapeutic challenge (dropped in amendment 2), treatment period of 7 weeks (4 weeks titration and 3 weeks of maintenance) and follow up visit approximately 7-10 days following their last dose of study medication.
Pre-assignment details
A total of 118 participants (par.) were screened. Out of these 50 participants were randomized. Out of these, safety population consisted of 50 participants and intent-to-treat (ITT) population consisted of 46 participants.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks. | 24 |
| GSK239512 Par. received oral GSK239512 once daily for a period of 7 weeks (4 weeks titration and 3 weeks at maintenance). Par. started at a daily dose of 10 micrograms (μg) GSK239512 and titrated up weekly through successive dose levels of 20 μg, 40 μg up to a maximum dose of 80 μg according to the titration regimen. | 22 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | GSK239512 | Total |
|---|---|---|---|
| Age, Continuous | 40.1 Years STANDARD_DEVIATION 9.54 | 38.2 Years STANDARD_DEVIATION 13.1 | 39.2 Years STANDARD_DEVIATION 11.3 |
| Race/Ethnicity, Customized African American/African Heritage | 11 Number | 11 Number | 22 Number |
| Race/Ethnicity, Customized Mixed Race | 0 Number | 2 Number | 2 Number |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Number | 1 Number | 1 Number |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 13 Number | 8 Number | 21 Number |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 19 Participants | 17 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 11 / 25 | 15 / 25 |
| serious Total, serious adverse events | 1 / 25 | 0 / 25 |
Outcome results
Primary
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512
The CSSB is a computerized battery with following domains (score range): Verbal memory (0-75), working memory (0-28), motor speed (0-100), verbal fluency, attention and speed of information processing (0-110) and executive functions with higher score representing better performance. Two Baseline CSSB testing were conducted; the first on the day prior to commencing dosing (Day -1) and the other test pre-dose on Day 1: the average of the two tests was used as Baseline. Change from Baseline was calculated as score at a given time minus score at Baseline. For each individual task from the CSSB, the Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. A composite score was calculated by averaging all the measures, and then calculating a z-score of the composite. Higher the composite score, better is the performance. Z-score is the measure of standard deviation away from the mean score.
Time frame: Baseline and up to Week 7
Population: ITT Population. Only those participants available at the specified time points were analyzed. Par. recruited under protocol amendment 2 were not assessed at Weeks 1, 3, 5 or 6 and hence the number of par. at these visits are lower.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 3 | 0.076 Scores on a scale | Standard Error 0.0816 |
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 5 | 0.099 Scores on a scale | Standard Error 0.0675 |
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 2 | 0.086 Scores on a scale | Standard Error 0.0814 |
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 6 | -0.001 Scores on a scale | Standard Error 0.1234 |
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 4 | 0.157 Scores on a scale | Standard Error 0.0859 |
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 7 | 0.004 Scores on a scale | Standard Error 0.1106 |
| Placebo | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 1 | 0.065 Scores on a scale | Standard Error 0.0606 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 7 | 0.107 Scores on a scale | Standard Error 0.1105 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 1 | 0.016 Scores on a scale | Standard Error 0.1342 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 2 | 0.104 Scores on a scale | Standard Error 0.0682 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 3 | -0.012 Scores on a scale | Standard Error 0.1139 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 4 | 0.068 Scores on a scale | Standard Error 0.0901 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 5 | 0.184 Scores on a scale | Standard Error 0.1057 |
| GSK239512 | Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 | Week 6 | 0.194 Scores on a scale | Standard Error 0.1539 |
Comparison: Week 1p-value: 0.723990% CI: [-0.288, 0.19]Mixed Model Repeated Measure
Comparison: Week 2p-value: 0.835190% CI: [-0.127, 0.163]Mixed Model Repeated Measure
Comparison: Week 3p-value: 0.454190% CI: [-0.287, 0.11]Mixed Model Repeated Measure
Comparison: Week 4p-value: 0.414890% CI: [-0.272, 0.093]Mixed Model Repeated Measure
Comparison: Week 5p-value: 0.388790% CI: [-0.082, 0.254]Mixed Model Repeated Measure
Comparison: Week 6p-value: 0.259490% CI: [-0.093, 0.484]Mixed Model Repeated Measure
Comparison: Week 7p-value: 0.477890% CI: [-0.139, 0.344]Mixed Model Repeated Measure
Secondary
Change From Baseline in Brief Psychiatric Rating Scale (BPRS) at Week 7
BPRS is the clinician rating of psychiatric symptoms; higher score indicates higher severity; 18-items scored 1-7; lower score is 18 and highest score is 126. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline.
Time frame: Baseline and Week 7
Population: ITT Population. Only those participants available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Brief Psychiatric Rating Scale (BPRS) at Week 7 | -2.795 Scores on a scale | Standard Error 1.241 |
| GSK239512 | Change From Baseline in Brief Psychiatric Rating Scale (BPRS) at Week 7 | -3.819 Scores on a scale | Standard Error 1.1512 |
p-value: 0.440690% CI: [-3.237, 1.19]Mixed Model Repeated Measure
Secondary
Change From Baseline in Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at Week 7
MCCB measures functioning across various cognitive domains and is comprised of ten tests that assess seven cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition). Its measurements are based on timed paper-and-pencil, computerized, and orally-administered tests, as well as spatial tests using geometric cubes. MCCB composite T scores are between 40 and 60 (normal range) and \< 40 (below normal range). Higher scores indicate better performance. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline.
Time frame: Baseline and Week 7
Population: ITT Population. Only those participants available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at Week 7 | 1.108 Scores on a scale | Standard Error 1.8759 |
| GSK239512 | Change From Baseline in Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at Week 7 | 0.371 Scores on a scale | Standard Error 1.7801 |
p-value: 0.694790% CI: [-3.884, 2.409]ANCOVA
Secondary
Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7
The CSSB is a computerized battery with following domains (score range): Verbal memory (0-75), working memory (0-28), motor speed (0-100), verbal fluency, attention and speed of information processing (0-110) and executive functions with higher score representing better performance. Two Baseline CSSB testing were conducted; the first on the day prior to commencing dosing (Day -1) and the other test pre-dose on Day 1: the average of the two tests was used as Baseline. Change from Baseline was calculated as score at a given time minus score at Baseline. For each individual task from the CSSB, the Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. A composite score was calculated by averaging all the measures, and then calculating a z-score of the composite. Higher the composite score, better is the performance. Z-score is the measure of standard deviation away from the mean score.
Time frame: Baseline and Week 7
Population: ITT Population. Only those participants available at the specified time points were analyzed. Par. recruited under protocol amendment 2 were not assessed at Weeks 1, 3, 5 or 6 and hence the number of par. at these visits are lower.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Speed of Processing/Simple Reaction Time | 0.541 Scores on a scale | Standard Error 0.1628 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Attention/Vigilance | 0.067 Scores on a scale | Standard Error 0.1756 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Working Memory | 0.021 Scores on a scale | Standard Error 0.203 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Visual Learning | -0.198 Scores on a scale | Standard Error 0.2414 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Verbal Learning | -0.558 Scores on a scale | Standard Error 0.2853 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Reasoning/Problem Solving | 0.016 Scores on a scale | Standard Error 0.1168 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Social Cognition | -0.431 Scores on a scale | Standard Error 0.1544 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Working Memory (Two-Back Memory) | 0.247 Scores on a scale | Standard Error 0.1862 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Working Memory (Two-Back Memory) | 0.316 Scores on a scale | Standard Error 0.2374 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Speed of Processing/Simple Reaction Time | 0.289 Scores on a scale | Standard Error 0.1391 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Verbal Learning | -0.160 Scores on a scale | Standard Error 0.2339 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Attention/Vigilance | 0.246 Scores on a scale | Standard Error 0.1932 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Social Cognition | -0.401 Scores on a scale | Standard Error 0.1339 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Working Memory | 0.412 Scores on a scale | Standard Error 0.2164 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Reasoning/Problem Solving | 0.192 Scores on a scale | Standard Error 0.1085 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 | Visual Learning | 0.081 Scores on a scale | Standard Error 0.1699 |
p-value: 0.139990% CI: [-0.535, 0.03]Mixed Model Repeated Measure
p-value: 0.399290% CI: [-0.176, 0.534]Mixed Model Repeated Measure
p-value: 0.154790% CI: [-0.063, 0.845]Mixed Model Repeated Measure
p-value: 0.253190% CI: [-0.127, 0.685]Mixed Model Repeated Measure
p-value: 0.241790% CI: [-0.167, 0.963]Mixed Model Repeated Measure
p-value: 0.206990% CI: [-0.055, 0.409]Mixed Model Repeated Measure
p-value: 0.864590% CI: [-0.262, 0.322]Mixed Model Repeated Measure
p-value: 0.787390% CI: [-0.364, 0.503]Mixed Model Repeated Measure
Secondary
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7
MCCB measures functioning across various cognitive domains and is comprised of ten tests that assess seven cognitive domains (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) Its measurements are based on timed paper-and-pencil, computerized, and orally-administered tests, as well as spatial tests using geometric cubes. MCCB composite T scores are between 40 and 60 (normal range) and \< 40 (below normal range). Higher scores indicate better performance. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline.
Time frame: Baseline and Week 7
Population: ITT Population. Only those participants at indicated time point were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Working Memory | 3.368 T-scores | Standard Error 2.0677 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Verbal Learning | -1.174 T-scores | Standard Error 2.1772 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Attention/Vigilance | -0.111 T-scores | Standard Error 2.3028 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Reasoning and Problem Solving | 0.488 T-scores | Standard Error 2.0863 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Visual Learning | -0.718 T-scores | Standard Error 2.3868 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Social Cognition | -0.411 T-scores | Standard Error 3.0119 |
| Placebo | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Speed of Processing | 2.045 T-scores | Standard Error 1.7359 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Social Cognition | -0.750 T-scores | Standard Error 2.779 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Speed of Processing | -1.979 T-scores | Standard Error 1.603 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Attention/Vigilance | -2.351 T-scores | Standard Error 2.1303 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Working Memory | 1.330 T-scores | Standard Error 1.9086 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Visual Learning | -1.464 T-scores | Standard Error 2.206 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Verbal Learning | 1.938 T-scores | Standard Error 2.1123 |
| GSK239512 | Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 | Reasoning and Problem Solving | 1.460 T-scores | Standard Error 1.9621 |
p-value: 0.022590% CI: [-6.872, -1.175]ANCOVA
p-value: 0.331795% CI: [-6.085, 1.605]ANCOVA
p-value: 0.324390% CI: [-5.482, 1.406]ANCOVA
p-value: 0.749790% CI: [-4.667, 3.175]ANCOVA
p-value: 0.158590% CI: [-0.537, 6.761]ANCOVA
p-value: 0.658290% CI: [-2.709, 4.654]ANCOVA
p-value: 0.909290% CI: [-5.316, 4.639]ANCOVA
Secondary
Change From Baseline in Schedule for Assessment of Negative Symptoms (SANS) at Week 7
The SANS was a tool used to assess five symptom complexes to obtain clinical ratings of negative symptoms in par. with schizophrenia. Complexes include: affective blunting; alogia (impoverished thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention. Assessment was conducted on six-point scale (0=not at all to 5=severe) for a total scoring range of 0-120. Lower scores represent better performance. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either measurement meant to be used in the mean was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was calculated as score at a given time post Baseline minus score at Baseline.
Time frame: Baseline and Week 7
Population: ITT Population. Only those participants available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Schedule for Assessment of Negative Symptoms (SANS) at Week 7 | -3.206 Scores on a scale | Standard Error 2.4684 |
| GSK239512 | Change From Baseline in Schedule for Assessment of Negative Symptoms (SANS) at Week 7 | -5.082 Scores on a scale | Standard Error 2.4087 |
p-value: 0.519790% CI: [-6.743, 2.99]Mixed Model Repeated Measure
Secondary
Change From Baseline in University of California and San Diego (UCSD) Performance Based Skills Assessment (UPSA) at Week 7
The 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 ranges from 0 to 14, the finance ranges from 0 to 11, the communication ranges from 0 to 12, the mobility ranges from 0 to 9, and the house management 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. The Baseline was calculated as the mean of the second screening assessment and the Day 1 pre-dose assessment. If either was missing, then the Baseline value was the non-missing assessment. If both were missing, then Baseline was considered missing and the task was excluded from the analysis. Change from Baseline was score at a given time post Baseline minus Baseline score
Time frame: Baseline and Week 7
Population: ITT Population. Only those participants available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in University of California and San Diego (UCSD) Performance Based Skills Assessment (UPSA) at Week 7 | 2.926 Scores on a scale | Standard Error 2.6007 |
| GSK239512 | Change From Baseline in University of California and San Diego (UCSD) Performance Based Skills Assessment (UPSA) at Week 7 | 4.750 Scores on a scale | Standard Error 2.3332 |
p-value: 0.463790% CI: [-2.334, 5.982]Mixed Model Repeated Measure
Secondary
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
Time frame: Up to Day 59
Population: Safety Population consisted of all randomized par. who took at least one dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 16 Participants |
| Placebo | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 1 Participants |
| GSK239512 | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 17 Participants |
| GSK239512 | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
Secondary
Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment
Clinical chemistry parameters: Alanine Amino Transferase (ALT), Albumin, Alkaline Phosphatase, Aspartate Amino Transferase (AST), Calcium, Creatinine, Direct Bilirubin, Gamma Glutamyl Transferase (GGT), Glucose, Potassium, Sodium, Total Bilirubin, Total protein, Urea/ Blood urea nitrogen (BUN) were presented as values of potential clinical concern at any time on treatment. Only those parameters with any abnormal value are presented.
Time frame: Up to Day 59
Population: Safety Population. Only those par. available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | AST, High | 1 Participants |
| Placebo | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | Glucose, Low | 2 Participants |
| Placebo | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | GGT, High | 0 Participants |
| Placebo | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | Glucose, High | 5 Participants |
| Placebo | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | ALT, High | 1 Participants |
| GSK239512 | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | Glucose, High | 4 Participants |
| GSK239512 | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | ALT, High | 3 Participants |
| GSK239512 | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | AST, High | 1 Participants |
| GSK239512 | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | GGT, High | 3 Participants |
| GSK239512 | Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment | Glucose, Low | 3 Participants |
Secondary
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment
Hematology parameters: Basophils, Eosinophils, Hematocrit, Hemoglobin, Lymphocytes, Mean Corpuscle Hemoglobin (MCH), Mean Corpuscle Hemoglobin concentration (MCHC), Mean Corpuscle Volume (MCV), Monocytes, Platelet count, Red blood cell count (RBC), Reticulocytes, Neutrophils count and White blood cell (WBC) count were presented as values of potential clinical concern at any time on treatment. Only those parameters with any abnormal value are presented.
Time frame: Up to Day 59
Population: Safety Population. Only those par. available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Hemoglobin, Low | 1 Participants |
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | RBC count, Low | 1 Participants |
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Eosinophils, High | 1 Participants |
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Reticulocytes, Low | 1 Participants |
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Monocytes, Low | 3 Participants |
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Neutrophils count, Low | 1 Participants |
| Placebo | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Eosinophils, Low | 8 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Neutrophils count, Low | 0 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Eosinophils, Low | 4 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Eosinophils, High | 0 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Hemoglobin, Low | 0 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Monocytes, Low | 1 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | RBC count, Low | 0 Participants |
| GSK239512 | Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment | Reticulocytes, Low | 1 Participants |
Secondary
Number of Par. With Abnormal Urinalysis Parameters Values of Potential Clinical Concern
Samples for urinalysis were collected on Days 1, 7, 14, 21, 28, 35, 42, 49 and up to Day 59 (follow-up) to assess specific gravity, pH, glucose, protein, blood and ketone by dipstick and microscopic examination (if blood or protein is abnormal).
Time frame: Up to Day 59
Population: Safety Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Par. With Abnormal Urinalysis Parameters Values of Potential Clinical Concern | 0 Participants |
| GSK239512 | Number of Par. With Abnormal Urinalysis Parameters Values of Potential Clinical Concern | 0 Participants |
Secondary
Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range
Heart rate readings were collected at pre-dose and then hourly post-dose until 6 hours post-dose or until the participant got discharged. It was measured in both supine and standing position. For both Std and Sup positions, heart rate data of concern was \<50 or \>100 and IFB \>=30; \<50 or \>100 and DFB \>=30. Data with only abnormal values were presented.
Time frame: Up to Day 59
Population: Safety Population. Only those par. available at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range | Std, Week 5, <50 or >100 and IFB >=30 | 1 Participants |
| Placebo | Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range | Std, follow-up, <50 or >100 and IFB >=30 | 1 Participants |
| GSK239512 | Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range | Std, Week 5, <50 or >100 and IFB >=30 | 0 Participants |
| GSK239512 | Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range | Std, follow-up, <50 or >100 and IFB >=30 | 0 Participants |
Secondary
Number of Par. With Most Severe On-treatment Abnormal Electrocardiogram (ECG) Findings
Triplicate 12-lead ECGs were obtained at Baseline (screening visit). Single 12-lead ECGs were obtained at each subsequent time point during the study. Abnormal ECG findings were presented for the most severe on-treatment result.
Time frame: Up to Day 59
Population: Safety Population. Only those participants who showed most severe on-treatment abnormal ECG findings are presented.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Par. With Most Severe On-treatment Abnormal Electrocardiogram (ECG) Findings | 8 Participants |
| GSK239512 | Number of Par. With Most Severe On-treatment Abnormal Electrocardiogram (ECG) Findings | 10 Participants |
Secondary
Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range
Blood pressure readings both systolic and diastolic were collected at pre-dose and then hourly post-dose until 6 hours post-dose or until the par. got discharged. Blood pressure was measured in both standing (Std) and supine (Sup) position. Data with only abnormal values were presented. For SBP the data of concern was \<90 or \>140 and increase from Baseline (IFB) \>=40; \<90 or \>140 and decrease from Baseline (DFB) \>=30. For DBP the data of concern was \<50 or \>90 and IFB \>=30; \<50 or \>90 and DFB \>=20.
Time frame: Up to Day 59
Population: Safety Population. Only those par. available at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 4, <90 or >140 and DFB>=30 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, follow-up, <90 or >140 and DFB>=30 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 5, <90 or >140 and DFB>=30 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Sup, Week 5, <90 or >140 and IFB>=40 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 5, <90 or >140 and IFB>=40 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | DBP, Std, Week 6, <50 or >90 and IBP >=30 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 6, <90 or >140 and DFB>=30 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | DBP, Sup, Week 6, <50 or >90 and IBP >=30 | 1 Participants |
| Placebo | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 3, <90 or >140 and DFB>=30 | 1 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | DBP, Sup, Week 6, <50 or >90 and IBP >=30 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 3, <90 or >140 and DFB>=30 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 4, <90 or >140 and DFB>=30 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 5, <90 or >140 and IFB>=40 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 5, <90 or >140 and DFB>=30 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, Week 6, <90 or >140 and DFB>=30 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Std, follow-up, <90 or >140 and DFB>=30 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | SBP, Sup, Week 5, <90 or >140 and IFB>=40 | 0 Participants |
| GSK239512 | Number of Par. With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Readings Outside Clinical Concern Range | DBP, Std, Week 6, <50 or >90 and IBP >=30 | 0 Participants |
Secondary
Plasma Concentrations of GSK239512 (Cmax) at Steady State After Repeat Dosing on Dose Review Visit at Any Time On-treatment
One Pharmacokinetic (PK) sample was collected within 15 minutes prior to the start of the CSSB and one PK sample was collected within 15 minutes after completion of the CSSB. 'n' was the number of samples available for analysis.
Time frame: 15 minutes prior to start and 15 minutes after completion of CSSB at Week 1,2,3,4,5,6 and 7
Population: PK-concentration population included all par. for whom a PK sample was obtained and analyzed. Number of units analyzed are number of samples available for analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma Concentrations of GSK239512 (Cmax) at Steady State After Repeat Dosing on Dose Review Visit at Any Time On-treatment | 0.0250 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37.44 |
| GSK239512 | Plasma Concentrations of GSK239512 (Cmax) at Steady State After Repeat Dosing on Dose Review Visit at Any Time On-treatment | 0.0496 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29.84 |
| GSK239512 40 mcg | Plasma Concentrations of GSK239512 (Cmax) at Steady State After Repeat Dosing on Dose Review Visit at Any Time On-treatment | 0.0790 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.85 |
| GSK239512 80 mcg | Plasma Concentrations of GSK239512 (Cmax) at Steady State After Repeat Dosing on Dose Review Visit at Any Time On-treatment | 0.1775 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.91 |