Trial Outcomes & Findings for Study to Evaluate the Efficacy and Safety of GSK239512 in Schizophrenia (NCT NCT01009060)

NCT ID: NCT01009060

Last Updated: 2017-11-08

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 50 participants
• Primary outcome timeframe: Baseline and up to Week 7
• Results posted on: 2017-11-08

Participant Flow

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.

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.

Participant milestones

Measure	Placebo Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	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.
Overall Study STARTED	25	25
Overall Study COMPLETED	21	20
Overall Study NOT COMPLETED	4	5

Reasons for withdrawal

Measure	Placebo Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	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.
Overall Study Adverse Event	1	2
Overall Study Protocol Violation	0	1
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	1	1
Overall Study Withdrawal by Subject	1	1

Baseline Characteristics

Study to Evaluate the Efficacy and Safety of GSK239512 in Schizophrenia

Baseline characteristics by cohort

Measure	Placebo n=24 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=22 Participants 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.	Total n=46 Participants Total of all reporting groups
Age, Continuous	40.1 Years STANDARD_DEVIATION 9.54 • n=5 Participants	38.2 Years STANDARD_DEVIATION 13.10 • n=7 Participants	39.2 Years STANDARD_DEVIATION 11.30 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	11 Number n=5 Participants	11 Number n=7 Participants	22 Number n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 Number n=5 Participants	1 Number n=7 Participants	1 Number n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	13 Number n=5 Participants	8 Number n=7 Participants	21 Number n=5 Participants
Race/Ethnicity, Customized Mixed Race	0 Number n=5 Participants	2 Number n=7 Participants	2 Number n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=24 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=22 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 3	0.076 Scores on a scale Standard Error 0.0816	-0.012 Scores on a scale Standard Error 0.1139	—	—
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 1	0.065 Scores on a scale Standard Error 0.0606	0.016 Scores on a scale Standard Error 0.1342	—	—
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 2	0.086 Scores on a scale Standard Error 0.0814	0.104 Scores on a scale Standard Error 0.0682	—	—
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 4	0.157 Scores on a scale Standard Error 0.0859	0.068 Scores on a scale Standard Error 0.0901	—	—
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 5	0.099 Scores on a scale Standard Error 0.0675	0.184 Scores on a scale Standard Error 0.1057	—	—
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 6	-0.001 Scores on a scale Standard Error 0.1234	0.194 Scores on a scale Standard Error 0.1539	—	—
Change From Baseline in Composite Score of CSSB Following Dosing With GSK239512 Week 7	0.004 Scores on a scale Standard Error 0.1106	0.107 Scores on a scale Standard Error 0.1105	—	—

SECONDARY outcome

Timeframe: Baseline and Week 7

Population: ITT Population. Only those participants available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Placebo n=22 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=19 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
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	0.371 Scores on a scale Standard Error 1.7801	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=24 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=22 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
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	0.246 Scores on a scale Standard Error 0.1932	—	—
Change From Baseline in Individual Cognitive Domain Scores in CSSB at Week 7 Working Memory	0.021 Scores on a scale Standard Error 0.2030	0.412 Scores on a scale Standard Error 0.2164	—	—
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	0.081 Scores on a scale Standard Error 0.1699	—	—
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	-0.160 Scores on a scale Standard Error 0.2339	—	—
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	0.192 Scores on a scale Standard Error 0.1085	—	—
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	0.289 Scores on a scale Standard Error 0.1391	—	—
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	-0.401 Scores on a scale Standard Error 0.1339	—	—
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	0.316 Scores on a scale Standard Error 0.2374	—	—

SECONDARY outcome

Timeframe: Baseline and Week 7

Population: ITT Population. Only those participants at indicated time point were analyzed.

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.

Outcome measures

Measure	Placebo n=22 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=19 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 Visual Learning	-0.718 T-scores Standard Error 2.3868	-1.464 T-scores Standard Error 2.2060	—	—
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 Speed of Processing	2.045 T-scores Standard Error 1.7359	-1.979 T-scores Standard Error 1.6030	—	—
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 Attention/Vigilance	-0.111 T-scores Standard Error 2.3028	-2.351 T-scores Standard Error 2.1303	—	—
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 Working Memory	3.368 T-scores Standard Error 2.0677	1.330 T-scores Standard Error 1.9086	—	—
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 Verbal Learning	-1.174 T-scores Standard Error 2.1772	1.938 T-scores Standard Error 2.1123	—	—
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	1.460 T-scores Standard Error 1.9621	—	—
Change From Baseline in Individual Cognitive Domain Scores in MCCB at Week 7 Social Cognition	-0.411 T-scores Standard Error 3.0119	-0.750 T-scores Standard Error 2.7790	—	—

SECONDARY outcome

Timeframe: Baseline and Week 7

Population: ITT Population. Only those participants available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Placebo n=22 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=20 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Change From Baseline in Brief Psychiatric Rating Scale (BPRS) at Week 7	-2.795 Scores on a scale Standard Error 1.2410	-3.819 Scores on a scale Standard Error 1.1512	—	—

SECONDARY outcome

Timeframe: Baseline and Week 7

Population: ITT Population. Only those participants available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Placebo n=22 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=20 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Change From Baseline in Schedule for Assessment of Negative Symptoms (SANS) at Week 7	-3.206 Scores on a scale Standard Error 2.4684	-5.082 Scores on a scale Standard Error 2.4087	—	—

SECONDARY outcome

Timeframe: Baseline and Week 7

Population: ITT Population. Only those participants available at the indicated time point were analyzed.

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

Outcome measures

Measure	Placebo n=22 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=20 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
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	4.750 Scores on a scale Standard Error 2.3332	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population consisted of all randomized par. who took at least one dose of investigational product.

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.

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=25 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE	16 Participants	17 Participants	—	—
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Any SAE	1 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population. Only those participants who showed most severe on-treatment abnormal ECG findings are presented.

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.

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=22 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Number of Par. With Most Severe On-treatment Abnormal Electrocardiogram (ECG) Findings	8 Participants	10 Participants	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population. Only those par. available at the specified time points were analyzed.

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.

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=25 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—
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	0 Participants	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population. Only those par. available at the specified time points were analyzed.

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.

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=25 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range Std, Week 5, <50 or >100 and IFB >=30	1 Participants	0 Participants	—	—
Number of Par. With Heart Rate Measured Value Outside Clinical Concern Range Std, follow-up, <50 or >100 and IFB >=30	1 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population. Only those par. available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=22 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment Eosinophils, Low	8 Participants	4 Participants	—	—
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment Eosinophils, High	1 Participants	0 Participants	—	—
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment Hemoglobin, Low	1 Participants	0 Participants	—	—
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment Monocytes, Low	3 Participants	1 Participants	—	—
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment RBC count, Low	1 Participants	0 Participants	—	—
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment Reticulocytes, Low	1 Participants	1 Participants	—	—
Number of Par. With Abnormal Hematology Parameters Values at Any Time on Treatment Neutrophils count, Low	1 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population. Only those par. available at the indicated time point were analyzed.

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.

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=22 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment ALT, High	1 Participants	3 Participants	—	—
Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment AST, High	1 Participants	1 Participants	—	—
Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment GGT, High	0 Participants	3 Participants	—	—
Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment Glucose, Low	2 Participants	3 Participants	—	—
Number of Par. With Abnormal Clinical Chemistry Parameters Values at Any Time On-treatment Glucose, High	5 Participants	4 Participants	—	—

SECONDARY outcome

Timeframe: Up to Day 59

Population: Safety Population.

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).

Outcome measures

Measure	Placebo n=25 Participants Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=25 Participants 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.	GSK239512 40 mcg Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
Number of Par. With Abnormal Urinalysis Parameters Values of Potential Clinical Concern	0 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=13 Plasma sample Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=30 Plasma sample 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.	GSK239512 40 mcg n=11 Plasma sample Par. received GSK239512 40 mcg daily as dose level 3 in the third week of study.	GSK239512 80 mcg n=41 Plasma sample Par. received GSK239512 80 mcg daily as dose level 4 in the fourth week of study and continued to receive from fifth to seventh week as maintenance phase.
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	0.0496 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 29.84	0.0790 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 51.85	0.1775 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 42.91

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

GSK239512

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=25 participants at risk Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=25 participants at risk 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 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.
Psychiatric disorders Stress	4.0% 1/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	0.00% 0/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.

Other adverse events

Measure	Placebo n=25 participants at risk Par. received oral placebo tablet matching with GSK239512 once daily for a period of 7 weeks.	GSK239512 n=25 participants at risk 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 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.
Nervous system disorders Headache	16.0% 4/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	24.0% 6/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Nervous system disorders Somnolence	4.0% 1/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	12.0% 3/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Nervous system disorders Dizziness	0.00% 0/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Psychiatric disorders Middle insomnia	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	12.0% 3/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Psychiatric disorders Abnormal dreams	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Psychiatric disorders Insomnia	4.0% 1/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Psychiatric disorders Nightmare	4.0% 1/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Gastrointestinal disorders Diarrhoea	4.0% 1/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Gastrointestinal disorders Nausea	12.0% 3/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	0.00% 0/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
General disorders Fatigue	12.0% 3/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	4.0% 1/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.
Skin and subcutaneous tissue disorders Rash	8.0% 2/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.	0.00% 0/25 • All SAEs and non-SAEs were reported up to Day 59. Safety Population were used to report the AEs and serious AEs.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER