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Clinical Trial Results:
A randomized, double-blind, placebo-controlled, parallel group, dose ranging study to assess the effect of repeat doses of GSK962040 on the pharmacokinetics of levodopa in subjects with Parkinson’s disease exhibiting delayed gastric emptying

Summary
EudraCT number	2011-004438-32
Trial protocol	GB SE DE
Global end of trial date	01 May 2014

Results information
Results version number	v1(current)
This version publication date	29 Feb 2016
First version publication date	27 Dec 2014
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MOT115816

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 May 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 May 2014

Was the trial ended prematurely?

Main objective of the trial

To measure the effect of co-administration of GSK962040 on levodopa pharmacokinetic exposure in subjects with Parkinson’s disease with delayed gastric emptying

Protection of trial subjects

Not applicable.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Jul 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 10

Country: Number of subjects enrolled

United Kingdom: 25

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Australia: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

The study consisted of a Screening/Baseline Period, a Treatment Period, and a 14-day post-treatment safety Follow-up Visit. Participants were randomized to receive GSK962040 50 milligrams or placebo in a 2:1 ratio; one participant was randomized to receive GSK962040 125 mg.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received placebo administered orally once daily for 7 to 9 days.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2x25 mg placebo tablets, once daily, 8 days; 1x125 mg placebo tablet, once daily, 8 days (2 subjects only)

GSK962040 Total

Arm description

Participants received GSK962040 50 milligrams (mg) (except for one participant who received GSK962040 125 mg) administered orally once daily for 7 to 9 days.

Arm type

Experimental

Investigational medicinal product name

GSK962040 (camicinal) 50 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2x25 mg tablets, once daily, 8 days; 1x125 mg tablet, once daily, 8 days (1 subject only)

Number of subjects in period 1 ^[1]	Placebo	GSK962040 Total
Started	19	38
Completed	18	37
Not completed	1	1
Consent withdrawn by subject	1	-
Protocol deviation	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristic data are reported for members of the All Subjects Population, which is defined as all participants who received at least one dose of study medication. Not all enrolled participants were members of the All Subjects Population.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received placebo administered orally once daily for 7 to 9 days.

Reporting group title

GSK962040 Total

Reporting group description

Participants received GSK962040 50 milligrams (mg) (except for one participant who received GSK962040 125 mg) administered orally once daily for 7 to 9 days.

Reporting group values	Placebo	GSK962040 Total	Total
Number of subjects	19	38	57
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	66.7 ( 8.04 )	67.4 ( 7.97 )	-
Gender categorical
Units: Subjects
Female	11	9	20
Male	8	29	37
Race, customized
Units: Subjects
White - White/Caucasian/European Heritage	19	38	57

End points

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Reporting group title

Placebo

Reporting group description

Participants received placebo administered orally once daily for 7 to 9 days.

Reporting group title

GSK962040 Total

Reporting group description

Participants received GSK962040 50 milligrams (mg) (except for one participant who received GSK962040 125 mg) administered orally once daily for 7 to 9 days.

Subject analysis set title

Placebo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received placebo administered orally once daily for 7 to 9 days.

Subject analysis set title

GSK962040 50 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received GSK962040 50 milligrams (mg) administered orally once daily for 7 to 9 days.

Subject analysis set title

GSK962040 Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received GSK962040 50 milligrams (mg) (except for one participant who received GSK962040 125 mg) administered orally once daily for 7 to 9 days.

Primary: Dose-normalized levodopa (L-DOPA) area under the plasma concentration-time curve from zero to 4 hours AUC(0-4) at Baseline

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End point title

Dose-normalized levodopa (L-DOPA) area under the plasma concentration-time curve from zero to 4 hours AUC(0-4) at Baseline ^[1]

End point description

Dose-normalized L-DOPA AUC(0-4) was derived from L-DOPA plasma concentration-time data. AUC is a measure of levodopa exposure.

End point type

Primary

End point timeframe

Baseline

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this endpoint at Baseline.

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	17 ^[2]	33 ^[3]
Units: Nanograms*hour/milliliter/milligram
geometric mean (geometric coefficient of variation)	24.13 ( 37.5 )	24.81 ( 36.1 )

Notes
[2] - Pharmacodynamic (PD)/Efficacy Population: participants receiving >=1 dose placebo/GSK962040 50 mg
[3] - Pharmacodynamic (PD)/Efficacy Population: participants receiving >=1 dose placebo/GSK962040 50 mg

No statistical analyses for this end point

Primary: Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8

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End point title

Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8

End point description

Dose-normalized L-DOPA AUC(0-4) was derived from L-DOPA plasma concentration-time data. The adjusted means and ratios (GSK962040 50 mg: Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit, Baseline L-dopa pharmacokinetic (PK) parameter, and Baseline gastric emptying half-time as fixed effects, and participant as a random effect. AUC is a measure of levodopa exposure.

End point type

Primary

End point timeframe

Day 1 and Day 8

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[4]	37 ^[5]
Units: Nanograms*hour/milliliter/milligram
least squares mean (standard error)
Day 1, n=17, 31	26.6 ( 0.058 )	25.7 ( 0.047 )
Day 8, n=17, 32	27.1 ( 0.058 )	24.1 ( 0.047 )

Notes
[4] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[5] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1

Statistical analysis description

Day 1: The adjusted means (AMs) and ratios were estimated using a mixed model (MM) fitting treatment, visit, treatment*visit, Baseline L-dopa PK parameter and Baseline gastric emptying half time as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Ratio of adjusted geometric means

Point estimate

0.965

Confidence interval

level

95%

sides

2-sided

lower limit

0.831

upper limit

1.12

Day 8

Statistical analysis description

Day 8: The AMs and ratios were estimated using a mixed model fitting treatment, visit, treatment*visit, Baseline L-dopa PK parameter and Baseline gastric emptying half time as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Ratio of adjusted geometric means

Point estimate

0.886

Confidence interval

level

95%

sides

2-sided

lower limit

0.763

upper limit

1.029

Primary: Dose-normalized L-DOPA maximum observed concentration (Cmax) at Baseline

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End point title

Dose-normalized L-DOPA maximum observed concentration (Cmax) at Baseline ^[6]

End point description

Dose-normalized L-DOPA Cmax was derived from L-DOPA plasma concentration-time data.

End point type

Primary

End point timeframe

Baseline

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this endpoint at Baseline.

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	17 ^[7]	35 ^[8]
Units: Nanograms/milliliter/milligram
geometric mean (geometric coefficient of variation)	12.77 ( 28 )	12.89 ( 42.6 )

Notes
[7] - PD/Efficacy Population. Only those participants available at the specified time point were analyzed.
[8] - PD/Efficacy Population. Only those participants available at the specified time point were analyzed.

No statistical analyses for this end point

Primary: Dose-normalized L-DOPA Cmax at Day 1 and Day 8

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End point title

Dose-normalized L-DOPA Cmax at Day 1 and Day 8

End point description

Dose-normalized L-DOPA Cmax was derived from L-DOPA plasma concentration-time data. The adjusted means and ratios were estimated using a mixed model fitting treatment, visit, treatment*visit, Baseline L-dopa PK parameter, and Baseline gastric emptying half-time as fixed effects, and participant as a random effect.

End point type

Primary

End point timeframe

Day 1 and Day 8

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[9]	37 ^[10]
Units: Nanograms/milliliter/milligram
least squares mean (standard error)
Day 1, n=18, 35	13.4 ( 0.081 )	11.6 ( 0.065 )
Day 8, n=17, 35	11.6 ( 0.083 )	11.8 ( 0.065 )

Notes
[9] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[10] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1

Statistical analysis description

Day 1: The AMs and ratios were estimated using a mixed model fitting treatment, visit, treatment*visit, Baseline L-dopa PK parameter and Baseline gastric emptying half time as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Ratio of adjusted geometric means

Point estimate

0.864

Confidence interval

level

95%

sides

2-sided

lower limit

0.702

upper limit

1.064

Day 8

Statistical analysis description

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Ratio of adjusted geometric means

Point estimate

1.018

Confidence interval

level

95%

sides

2-sided

lower limit

0.824

upper limit

1.257

Primary: L-DOPA time of occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8

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End point title

L-DOPA time of occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8

End point description

L-DOPA Tmax was derived from L-DOPA plasma concentration-time data.

End point type

Primary

End point timeframe

Baseline, Day 1, and Day 8

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[11]	37 ^[12]
Units: Hours
median (full range (min-max))
Baseline, n=17, 35	1.5 (0.3 to 3.6)	2 (0.3 to 4)
Day 1, n=18, 35	1.61 (0.5 to 3.4)	1.5 (0.3 to 3.5)
Day 8, n=17, 35	2 (0.5 to 3.5)	1.55 (0.3 to 4)

Notes
[11] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[12] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.157

Method

Wilcoxon rank-sum test

Confidence interval

Day 8

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.186

Method

Wilcoxon rank-sum test

Confidence interval

Primary: L-DOPA terminal phase half-life (t1/2) at Baseline, Day 1, and Day 8

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End point title

L-DOPA terminal phase half-life (t1/2) at Baseline, Day 1, and Day 8 ^[13]

End point description

L-DOPA t1/2 was derived from L-DOPA plasma concentration-time data. This endpoint was not assessed because there were insufficient L-DOPA data/profiles to calculate this parameter.

End point type

Primary

End point timeframe

Baseline, Day 1, and Day 8

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this endpoint.

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	0 ^[14]	0 ^[15]
Units: Hours
median (full range (min-max))	( to )	( to )

Notes
[14] - PD/Efficacy Population
[15] - PD/Efficacy Population

No statistical analyses for this end point

Secondary: Gastric half emptying time (GE t1/2) at Baseline (BL), Day 1, and Day 8

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End point title

Gastric half emptying time (GE t1/2) at Baseline (BL), Day 1, and Day 8

End point description

Gastric half emptying time is the time taken for half the contents of the stomach to empty. Gastric emptying was measured using the 13C-oral breath test, which is a tracer method that utilizes 13C, a non-radioactive isotope. Basal breath samples were obtained after an overnight fast or otherwise after 4 hours of fasting following a light meal. On Day 1 and Day 8, participants were then dosed with GSK962040 and additional breath test samples were taken prior to administration of a 13C-labelled test meal. The test meal was consumed approximately 80 minutes later. After consumption of the test meal, breath samples were collected at pre-specified time points over an approximately 4 hour period following the test meal. For the duration of the breath test, no food or drink were allowed. The 13C breath content was determined by isotope ratio mass spectrometry. GE t1/2 was determined by using the cumulative percentage of the administered dose of 13C excreted in breath over 4 hours.

End point type

Secondary

End point timeframe

Baseline, Day 1, and Day 8

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[16]	37 ^[17]
Units: Minutes
arithmetic mean (standard deviation)
Baseline, n=19, 37	99.6 ( 21.26 )	96.9 ( 21.67 )
Day 1, n=19, 37	97.5 ( 15.81 )	91.9 ( 21.47 )
Day 8, n=17, 36	98.7 ( 25.03 )	90.6 ( 26.75 )

Notes
[16] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[17] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1

Statistical analysis description

Day 1: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit, and Baseline gastric half emptying time as fixed effects, and participant as a random effect.

Comparison groups

GSK962040 50 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-4.239

Confidence interval

level

95%

sides

2-sided

lower limit

-16.015

upper limit

7.537

Day 8

Statistical analysis description

Day 8: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit, and Baseline gastric half emptying time as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-5.327

Confidence interval

level

95%

sides

2-sided

lower limit

-17.567

upper limit

6.914

Secondary: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores at Baseline, Day 1, and Day 8 (pre-levodopa dose)

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End point title

Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores at Baseline, Day 1, and Day 8 (pre-levodopa dose)

End point description

The MDS-UPDRS is used to assess the status of Parkinson's Disease. It has four parts: Part I (non-motor experiences of daily living), Part II (motor experiences of daily living), Part III (motor examination), and Part IV (motor complications). Each part is made up of several questions, with each question given a score ranging from 0 (normal) to 4 (severe). Part I and Part II consist of 13 items each, and have a score ranging between 0 (normal) and 52 (severe). Part III consists of 33 items, and has a score ranging between 0 (normal) and 132 (severe). Part IV consists of 6 items, and has a score ranging between 0 (normal) and 24 (severe). The total score is the summed score of all four parts and ranges between 0 (normal) and 260 (severe). A higher score indicates more severe symptoms.

End point type

Secondary

End point timeframe

Baseline, Day 1, and Day 8 at pre-levodopa dose

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[18]	37 ^[19]
Units: Scores on a scale
arithmetic mean (standard deviation)
Part I: Baseline, n=19, 37	9.1 ( 4.56 )	10.1 ( 6.17 )
Part I: Day 1, n=19, 37	10.1 ( 4.98 )	8.6 ( 5.12 )
Part I: Day 8, n=18, 36	10 ( 5.25 )	7.1 ( 4.67 )
Part II: Baseline, n=19, 37	14.9 ( 7.09 )	12.5 ( 6.33 )
Part II: Day 1, n=19, 37	16.1 ( 9.09 )	11.5 ( 6.54 )
Part II: Day 8, n=18, 36	15.3 ( 9.29 )	10.3 ( 6.37 )
Part III: Baseline, n=19, 37	42.2 ( 14.63 )	38 ( 18.95 )
Part III: Day 1, n=19, 37	40.4 ( 17.56 )	34.9 ( 17.97 )
Part III: Day 8, n=18, 36	44.2 ( 19.25 )	34 ( 17.46 )
Part IV: Baseline, n=19, 37	5.5 ( 2.7 )	5.3 ( 3.63 )
Part IV: Day 1, n=19, 37	5.9 ( 3.07 )	5.2 ( 3.61 )
Part IV: Day 8, n=18, 36	5.7 ( 3.79 )	4.5 ( 3.41 )
Total: Baseline, n=19, 37	71.7 ( 23.53 )	65.8 ( 27.02 )
Total: Day 1, n=19, 37	72.5 ( 29.01 )	60.2 ( 25.9 )
Total: Day 8, n=18, 36	75.2 ( 34.27 )	55.9 ( 25.34 )

Notes
[18] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[19] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1; Part I

Statistical analysis description

Day 1; Part I: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-2.16

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

-0.41

Day 8; Part I

Statistical analysis description

Day 8; Part I: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.63

Confidence interval

level

95%

sides

2-sided

lower limit

-5.41

upper limit

-1.85

Day 1; Part II

Statistical analysis description

Day 1; Part II: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-2.29

Confidence interval

level

95%

sides

2-sided

lower limit

-4.65

upper limit

0.07

Day 8; Part II

Statistical analysis description

Day 8; Part II: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-2.46

Confidence interval

level

95%

sides

2-sided

lower limit

-4.85

upper limit

-0.07

Day 1; Part III

Statistical analysis description

Day 1; Part III: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-6.53

upper limit

3.13

Day 8; Part III

Statistical analysis description

Day 8; Part III: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-5.38

Confidence interval

level

95%

sides

2-sided

lower limit

-10.28

upper limit

-0.49

Day 1; Part IV

Statistical analysis description

Day 1; Part IV: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-1.65

upper limit

0.54

Day 8; Part IV

Statistical analysis description

Day 8; Part IV: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.02

upper limit

0.22

Day 1; Total

Statistical analysis description

Day 1; Total: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-6.69

Confidence interval

level

95%

sides

2-sided

lower limit

-13.77

upper limit

0.39

Day 8; Total

Statistical analysis description

Day 8; Total: The AMs and differences (GSK 962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit interaction, and Baseline MDS-UPDR score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-12.5

Confidence interval

level

95%

sides

2-sided

lower limit

-19.67

upper limit

-5.29

Secondary: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores at Baseline, Day 1, and Day 8 (pre-dose; 120, 180, and 240 minutes post-dose)

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End point title

Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores at Baseline, Day 1, and Day 8 (pre-dose; 120, 180, and 240 minutes post-dose)

End point description

End point type

Secondary

End point timeframe

Baseline, Day 1, and Day 8 at pre-dose and 120, 180, and 240 minutes (min) post-dose (PD); Follow-up visit (up to Day 25)

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[20]	37 ^[21]
Units: Scores on a scale
arithmetic mean (standard deviation)
Baseline, pre-dose, n=19, 37	42.2 ( 14.63 )	38 ( 18.95 )
Baseline, 120 minutes post-dose, n=19, 37	33.1 ( 16.61 )	27.7 ( 16.04 )
Baseline, 180 minutes post-dose, n=19, 36	30.3 ( 14.55 )	27.5 ( 14.21 )
Baseline, 240 minutes post-dose, n=19, 37	31.6 ( 16.27 )	29.2 ( 16.62 )
Day 1, pre-dose, n=19, 37	40.4 ( 17.56 )	34.9 ( 17.97 )
Day 1,120 minutes post-dose, n=19, 37	32.3 ( 15.01 )	26.2 ( 16.25 )
Day 1, 180 minutes post-dose, n=19, 37	31 ( 17.1 )	25.5 ( 18.04 )
Day 1, 240 minutes post-dose, n=19, 37	32.7 ( 20.5 )	27.2 ( 17.68 )
Day 8, pre-dose n=18, 36	44.2 ( 19.25 )	34 ( 17.46 )
Day 8, 120 minutes post-dose, n=18, 36	32.3 ( 14.9 )	24.2 ( 14.24 )
Day 8, 180 minutes post-dose, n=18, 36	33.3 ( 16.17 )	25.1 ( 14.27 )
Day 8, 240 minutes post-dose, n=18, 36	37.1 ( 20.19 )	25.4 ( 15.27 )
Follow-up, n=19, 37	30.3 ( 13.45 )	24.9 ( 11.79 )

Notes
[20] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[21] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1; Pre-dose

Statistical analysis description

Day 1; Pre-dose: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.14

Confidence interval

level

95%

sides

2-sided

lower limit

-9.07

upper limit

2.78

Day 1; 120 min PD

Statistical analysis description

Day 1; 120 min PD: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.18

Confidence interval

level

95%

sides

2-sided

lower limit

-9.11

upper limit

2.75

Day 1; 180 min PD

Statistical analysis description

Day 1; 180 min PD: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.66

Confidence interval

level

95%

sides

2-sided

lower limit

-9.59

upper limit

2.27

Day 1; 240 min PD

Statistical analysis description

Day 1; 240 min PD: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-4.15

Confidence interval

level

95%

sides

2-sided

lower limit

-10.07

upper limit

1.76

Day 8; Pre-dose

Statistical analysis description

Day 8; Pre-dose: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-12.79

upper limit

-0.81

Day 8; 120 min PD

Statistical analysis description

Day 8; 120 min PD: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.97

Confidence interval

level

95%

sides

2-sided

lower limit

-9.96

upper limit

2.03

Day 8; 180 min PD

Statistical analysis description

Day 8; 180 min PD: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-5.29

Confidence interval

level

95%

sides

2-sided

lower limit

-11.29

upper limit

0.71

Day 8; 240 min PD

Statistical analysis description

Day 8; 240 min PD: The AMs and differences (GSK962040 minus Placebo) were estimated using a mixed model fitting treatment, visit, treatment*visit*time point interaction, and Baseline UPDRS-3 score as fixed effects, and participant as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-8.9

Confidence interval

level

95%

sides

2-sided

lower limit

-14.88

upper limit

-2.91

Secondary: Period mean amount of hours spent “ON,” “ON” without dyskinesia, "ON" with non-troublesome dyskinesia, "ON" with troublesome dyskinesia, and “OFF” at Baseline and during the treatment period (Days 1-8), Week 1 of Follow-up, and Week 2 of Follow-up

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End point title

Period mean amount of hours spent “ON,” “ON” without dyskinesia, "ON" with non-troublesome dyskinesia, "ON" with troublesome dyskinesia, and “OFF” at Baseline and during the treatment period (Days 1-8), Week 1 of Follow-up, and Week 2 of Follow-up

End point description

Participants were provided with the "ON/OFF" diary to capture details of the amount of awake time spent on/off of PD symptoms, and were asked to complete the diary daily. Participants checked the box most appropriate for their dominant motor state in the preceding 30-minute period. The catergories included: "ON" (including “ON without dyskinesia” and “ON with non-troublesome dyskinesia"), "ON" with troublesome dyskinesia (TD), and "OFF." For Baseline, data were collected for 2 days prior to Day 1, and the mean value of the 2 days was used.

End point type

Secondary

End point timeframe

Baseline, Days 1-8, Week 1 of Follow-up (Days 6 and 7 of Follow-up; up to Day 16), and Week 2 of Follow-up (Days 13 and 14 of Follow-up; up to Day 23)

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[22]	37 ^[23]
Units: hours
arithmetic mean (standard deviation)
Baseline: "ON," n=18, 37	11.21 ( 3.602 )	11.31 ( 3.021 )
Baseline: "ON" without dyskinesia, n=18, 37	10.11 ( 4.069 )	9.65 ( 3.787 )
Baseline: "ON" with non-TD, n=18, 37	1.1 ( 1.787 )	1.66 ( 2.956 )
Baseline: "ON" with TD, n=18, 37	0.54 ( 1.24 )	0.4 ( 1.292 )
Baseline: "OFF," n=18, 37	4.92 ( 3.417 )	4.23 ( 2.484 )
Treatment period: "ON," n=18, 36	10.61 ( 3.927 )	12.44 ( 3.375 )
Treatment period: "ON" without dyskinesia, n=18, 3	9.82 ( 4.042 )	10.47 ( 4.479 )
Treatment period: "ON" with non-TD, n=18, 36	0.79 ( 1.875 )	1.98 ( 2.987 )
Treatment period: "ON" with TD, n=18, 36	0.47 ( 1.548 )	0.59 ( 1.985 )
Treatment period: "OFF," n=18, 36	5.57 ( 4.364 )	2.94 ( 2.954 )
Week 1 of FU: "ON," n=18, 36	11 ( 3.309 )	12.13 ( 3.134 )
Week 1 of FU: "ON" without dyskinesia, n=18, 36	10.17 ( 4.232 )	10.63 ( 3.948 )
Week 1 of FU: "ON" with non-TD, n=18, 36	0.83 ( 1.933 )	1.5 ( 2.369 )
Week 1 of FU: "ON" with TD, n=18, 36	0.71 ( 2.083 )	0.52 ( 1.986 )
Week 1 of FU: "OFF," n=18, 36	4.83 ( 3.7 )	3.31 ( 2.642 )
Week 2 of FU: "ON," n=16, 32	11.34 ( 3.58 )	11.69 ( 3.562 )
Week 2 of FU: "ON" without dyskinesia, n=16, 32	11.13 ( 4.138 )	9.98 ( 4.872 )
Week 2 of FU: "ON" with non-TD, n=16, 32	0.22 ( 0.875 )	1.7 ( 2.838 )
Week 2 of FU: "ON" with TD, n=16, 32	0.38 ( 1.5 )	0.8 ( 2.362 )
Week 2 of FU: "OFF," n=16, 32	4.47 ( 3.601 )	3.36 ( 2.857 )

Notes
[22] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[23] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

OFF

Statistical analysis description

OFF: Treatment Period: The AMs and differences (GSK962040 minus Placebo) were estimated using an analysis of covariance (ANCOVA) model fitting treatment and Baseline amount of hours spent ON/OFF as main effects.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-2.31

Confidence interval

level

95%

sides

2-sided

lower limit

-3.71

upper limit

-0.9

Statistical analysis description

ON: Treatment Period: The AMs and differences (GSK962040 minus Placebo) were estimated using an analysis of covariance (ANCOVA) model fitting treatment and Baseline amount of hours spent ON/OFF as main effects.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

1.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

3.48

Secondary: Number of times a participant could alternatively tap two counter keys 30 centimeters apart in 1 minute (min) at Baseline, Day1, Day 8, and Follow-up

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End point title

Number of times a participant could alternatively tap two counter keys 30 centimeters apart in 1 minute (min) at Baseline, Day1, Day 8, and Follow-up

End point description

Participants were asked to alternatively tap two keys 30 centimeters apart in 1 minute in two trials with the most affected hand or the dominant hand in symmetric disease. The finger tapping was scored manually by the study staff. The finger-tapping assessment was repeated at eight separate time points (pre-dose, 0 min, 30 min, 60 min, 90 min, 120 min, 180 min, and 240 min post-dose) at each visit (Baseline, Day 1, and Day 8). At each time point, the mean of the two assessments was calculated.

End point type

Secondary

End point timeframe

Baseline, Day 1, and Day 8 at pre-dose and 0, 30, 60, 90, 120, 180, and 240 minutes post-dose; Follow-up visit (up to Day 25)

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[24]	37 ^[25]
Units: Finger taps per minute
arithmetic mean (standard deviation)
Baseline: pre-dose, n=19, 37	92.4 ( 47.53 )	77.8 ( 38 )
Baseline: 0 min, n=19, 35	91.2 ( 49.84 )	80.1 ( 35.28 )
Baseline: 30 min, n=19, 34	89.3 ( 42.91 )	85.2 ( 41.45 )
Baseline: 60 min, n=19, 36	88.6 ( 42.32 )	89.3 ( 45.32 )
Baseline: 90 min, n=19, 36	91.2 ( 44.14 )	90.8 ( 45.18 )
Baseline: 120 min, n=19, 37	92.6 ( 40.99 )	92 ( 43.37 )
Baseline: 180 min, n=19, 37	94.1 ( 47.19 )	92.8 ( 44.86 )
Baseline: 240 min, n=19, 37	95.2 ( 44.6 )	93.2 ( 46.17 )
Day 1: pre-dose, n=19, 36	92.3 ( 43.44 )	85.1 ( 40.05 )
Day 1: 0 min, n=19, 364	90.7 ( 40.78 )	86.8 ( 44.65 )
Day 1: 30 min, n=18, 35	93.4 ( 43.95 )	92.4 ( 49.92 )
Day 1: 60 min, n=18, 35	93.8 ( 44.8 )	94.6 ( 44.06 )
Day 1: 90 min, n=19, 34	97.7 ( 50.46 )	91.4 ( 42.09 )
Day 1: 120 min, n=19, 35	99.9 ( 50.51 )	96.4 ( 42.06 )
Day 1: 180 min, n=18, 36	99 ( 49.44 )	92.3 ( 41.01 )
Day 1: 240 min, n=18, 36	98.2 ( 51.97 )	97.6 ( 48.4 )
Day 8: pre-dose, n=18, 35	95.7 ( 40.9 )	92.8 ( 43.92 )
Day 8: 0 min, n=18, 35	92 ( 44.3 )	91.1 ( 42.9 )
Day 8: 30 min, n=18, 34	95.8 ( 45.07 )	92.2 ( 41.14 )
Day 8: 60 min, n=18, 35	94.6 ( 46.8 )	93.2 ( 39.01 )
Day 8: 90 min, n=18, 34	95 ( 48.82 )	95.5 ( 42.6 )
Day 8: 120 min, n=18, 35	97.2 ( 47.67 )	97.4 ( 42.34 )
Day 8: 180 min, n=18, 34	96.8 ( 52.5 )	101.2 ( 49.86 )
Day 8: 240 min, n=18, 35	98.3 ( 53.3 )	102.8 ( 51.84 )
Follow-up: n=18, 35	104.4 ( 48.13 )	105.7 ( 56.59 )

Notes
[24] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[25] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

Day 1, pre-dose

Statistical analysis description

Day 1, pre-dose: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-2.83

Confidence interval

level

95%

sides

2-sided

lower limit

-21.79

upper limit

16.13

Day 1, 0 min PD

Statistical analysis description

Day 1, 0 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-18.39

upper limit

19.56

Day 1, 30 min PD

Statistical analysis description

Day 1, 30 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

1.84

Confidence interval

level

95%

sides

2-sided

lower limit

-17.18

upper limit

20.86

Day 1, 60 min PD

Statistical analysis description

Day 1, 60 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-18.72

upper limit

19.28

Day 1, 90 min

Statistical analysis description

Day 1, 90 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.38

Confidence interval

level

95%

sides

2-sided

lower limit

-22.35

upper limit

15.58

Day 1, 120 min PD

Statistical analysis description

Day 1, 120 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-4.18

Confidence interval

level

95%

sides

2-sided

lower limit

-23.13

upper limit

14.76

Day 1, 180 min PD

Statistical analysis description

Day 1, 180 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-6.39

Confidence interval

level

95%

sides

2-sided

lower limit

-25.36

upper limit

12.58

Day 1, 240 min PD

Statistical analysis description

Day 1, 240 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

-18.2

upper limit

19.75

Day 8, pre-dose

Statistical analysis description

Day 8, pre-dose: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-18.51

upper limit

19.52

Day 8, 0 min PD

Statistical analysis description

Day 8, 0 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

3.32

Confidence interval

level

95%

sides

2-sided

lower limit

-15.7

upper limit

22.33

Day 8, 30 min PD

Statistical analysis description

Day 8, 30 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-2.94

Confidence interval

level

95%

sides

2-sided

lower limit

-21.97

upper limit

16.08

Day 8, 60 min PD

Statistical analysis description

Day 8, 60 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-3.12

Confidence interval

level

95%

sides

2-sided

lower limit

-22.13

upper limit

15.88

Day 8, 90 min PD

Statistical analysis description

Day 8, 90 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-1.38

Confidence interval

level

95%

sides

2-sided

lower limit

-20.4

upper limit

17.63

Day 8, 120 min PD

Statistical analysis description

Day 8, 120 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-19.7

upper limit

18.28

Day 8, 180 min PD

Statistical analysis description

Day 8, 180 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

3.02

Confidence interval

level

95%

sides

2-sided

lower limit

-15.98

upper limit

22.02

Day 8, 240 min PD

Statistical analysis description

Day 8, 240 min PD: The AMs/differences (GSK962040 minus Placebo) were estimated using a MM fitting treatment, visit, time point (TP), treatment*visit*TP interaction, and BL score as fixed effects, TP as a repeated effect, and par. as a random effect.

Comparison groups

Placebo v GSK962040 50 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in AMs of change from BL

Point estimate

4.08

Confidence interval

level

95%

sides

2-sided

lower limit

-14.91

upper limit

23.07

Secondary: Total daily L-DOPA equivalent dose at Baseline and on Days 1, 2, 3, 4, 5, 6, 7, 8, and 9

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End point title

Total daily L-DOPA equivalent dose at Baseline and on Days 1, 2, 3, 4, 5, 6, 7, 8, and 9

End point description

Various formulations of L-DOPA were utilized by participants for the treatment of Parkinson’s Disease. The total daily L-DOPA equivalent dose was calculated as the sum of all L-DOPA equivalent doses for each L-DOPA-containing drug taken on the same day.

End point type

Secondary

End point timeframe

Baseline and Days 1, 2, 3, 4, 5, 6, 7, 8, and 9

End point values	Placebo	GSK962040 50 mg
Number of subjects analysed	19 ^[26]	37 ^[27]
Units: Milligrams
arithmetic mean (standard deviation)
Baseline, n=19, 37	113.2 ( 41.14 )	164.5 ( 119.66 )
Day 1, n=19, 37	353.9 ( 174.85 )	368.6 ( 216.54 )
Day 2, n=19, 36	465.8 ( 229.61 )	514.5 ( 300.44 )
Day 3, n=19, 36	481.6 ( 243.79 )	516.9 ( 299.98 )
Day 4, n=19, 36	481.6 ( 241.5 )	518.3 ( 313.07 )
Day 5, n=19, 36	484.2 ( 243.13 )	503 ( 293.48 )
Day 6, n=17, 36	516.2 ( 249.21 )	511.3 ( 307.31 )
Day 7, n=17, 35	486.8 ( 247.51 )	499.6 ( 310.57 )
Day 8, n=17, 34	191.2 ( 175.43 )	281.3 ( 234 )
Day 9, n=0, 5	0 ( 0 )	235 ( 121.96 )

Notes
[26] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.
[27] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 8

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End point title

Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 8

End point description

Blood pressure measurements were taken at pre-dose and at 0 min (completion of meal) on Day 1 and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 1, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[28]	37 ^[29]	38 ^[30]
Units: Millimeters of mercury
arithmetic mean (standard deviation)
SBP, Day 1: 0 min, n=19, 37, 38	-4 ( 12.05 )	-2.5 ( 18.66 )	-2.1 ( 18.58 )
SBP, Day 8: pre-dose, n=18, 36, 37	-2.8 ( 13.24 )	-3.9 ( 13.19 )	-3.7 ( 13.06 )
SBP, Day 8: 0 min, n=18, 36, 37	-3.4 ( 11.55 )	-1 ( 15.04 )	-1.1 ( 14.84 )
DBP, Day 1: 0 min, n=19, 37, 38	-5.4 ( 7.67 )	-0.9 ( 7.51 )	-0.7 ( 7.55 )
DBP, Day 8: pre-dose, n=18, 36, 37	-4.2 ( 6.88 )	-0.9 ( 8.54 )	-0.8 ( 8.48 )
DBP, Day 8: 0 min, n=18, 36, 37	-3.7 ( 5.81 )	0.9 ( 8.32 )	0.9 ( 8.21 )

Notes
[28] - All Subjects Population (ASP): all participants who received >=1 dose of study medication
[29] - All Subjects Population (ASP): all participants who received >=1 dose of study medication
[30] - All Subjects Population (ASP): all participants who received >=1 dose of study medication

No statistical analyses for this end point

Secondary: Change from Baseline in heart rate at Day 1 and Day 8

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End point title

Change from Baseline in heart rate at Day 1 and Day 8

End point description

Heart rate measurements were taken at pre-dose and 0 min (completion of meal) on Day 1 and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 1, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[31]	37 ^[32]	38 ^[33]
Units: Beats per minute
arithmetic mean (standard deviation)
Day 1: 0 min, n=19, 37, 38	-2.2 ( 7.3 )	0.8 ( 9.19 )	0.5 ( 9.26 )
Day 8: pre-dose, n=18, 36, 37	-2.9 ( 7.67 )	0.6 ( 6.12 )	0 ( 6.84 )
Day 8: 0 min, n=18, 36, 37	-2.5 ( 7.64 )	-0.5 ( 6.8 )	-0.5 ( 6.71 )

Notes
[31] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[32] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[33] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with the indicated electrocardiogram (ECG) findings at Day 1 and Day 8

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End point title

Number of participants with the indicated electrocardiogram (ECG) findings at Day 1 and Day 8

End point description

ECG measurements were taken at pre-dose and 0 min (completion of meal) on Day 1 and Day 8. The Baseline value was the Day 1 pre-dose value. ECG findings were categorized as normal, abnormal - not clinically significant, and abnormal - clinically significant (CS), based on interpretation by the site.

End point type

Secondary

End point timeframe

Day 1 and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[34]	37 ^[35]	38 ^[36]
Units: participants
Day 1: pre-dose, Normal, n=19, 37, 38	14	17	18
Day 1: pre-dose, Abnormal - Not CS, n=19, 37, 38	5	19	19
Day 1: pre-dose, Abnormal - CS, n=19, 37, 38	0	1	1
Day 1: 0 min, Normal, n=19, 37, 38	12	16	16
Day 1: 0 min, Abnormal - Not CS, n=19, 37, 38	7	20	21
Day 1: 0 min, Abnormal - CS, n=19, 37, 38	0	1	1
Day 8: pre-dose, Normal, n=18, 36, 37	14	18	19
Day 8: pre-dose, Abnormal - Not CS, n=18, 36, 37	4	17	17
Day 8: pre-dose, Abnormal - CS, n=18, 36, 37	0	1	1
Day 8: 0 min, Normal, n=18, 36, 37	12	19	20
Day 8: 0 min, Abnormal - Not CS, n=18, 36, 37	6	16	16
Day 8: 0 min, Abnormal - CS, n=18, 36, 37	0	1	1

Notes
[34] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[35] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[36] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in albumin (ALB) and total protein (TP) at Day 4 and Day 8

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End point title

Change from Baseline in albumin (ALB) and total protein (TP) at Day 4 and Day 8

End point description

ALB and TP measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[37]	37 ^[38]	38 ^[39]
Units: Grams per liter
arithmetic mean (standard deviation)
ALB, Day 4, n=18, 34, 35	0.06 ( 2.313 )	-0.38 ( 2.155 )	-0.37 ( 2.124 )
ALB, Day 8, n=18, 34, 35	0.11 ( 2.22 )	-0.33 ( 2.084 )	-0.29 ( 2.065 )
TP, Day 4, n=18, 30, 31	-0.3 ( 3.28 )	-0.9 ( 3.93 )	-1 ( 3.97 )
TP, Day 8, n=15, 31, 32	0 ( 3.24 )	-0.3 ( 3.72 )	-0.3 ( 3.66 )

Notes
[37] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[38] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[39] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) at Day 4 and Day 8

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End point title

Change from Baseline in alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) at Day 4 and Day 8

End point description

ALP, ALT, AST, and GGT measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[40]	37 ^[41]	38 ^[42]
Units: International units per liter
arithmetic mean (standard deviation)
ALP, Day 4, n=19, 33, 34	-0.8 ( 5.26 )	2.4 ( 14.14 )	2.2 ( 13.98 )
ALP, Day 8, n=18, 34, 35	-0.1 ( 7.66 )	1.4 ( 13.35 )	1.2 ( 13.21 )
ALT, Day 4, n=19, 33, 34	-6.4 ( 10.45 )	-5.9 ( 9.77 )	-7.1 ( 11.72 )
ALT, Day 8, n=18, 34, 35	-1.6 ( 6.88 )	-0.4 ( 5.46 )	-0.6 ( 5.57 )
AST, Day 4, n=19, 32, 33	0.2 ( 3.16 )	-1.2 ( 2.89 )	-1.3 ( 2.96 )
AST, Day 8, n=16, 31, 32	0.6 ( 4.55 )	1 ( 3.65 )	0.9 ( 3.63 )
GGT, Day 4, n=19, 33, 34	-0.8 ( 3.2 )	-0.8 ( 3.06 )	-0.9 ( 3.04 )
GGT, Day 4, n=18, 33, 34	-0.1 ( 5.22 )	-1 ( 5.02 )	-1 ( 4.95 )

Notes
[40] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[41] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[42] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in direct bilirubin (D-Bil), total bilirubin (T-Bil), and creatinine (CRT) at Day 4 and Day 8

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End point title

Change from Baseline in direct bilirubin (D-Bil), total bilirubin (T-Bil), and creatinine (CRT) at Day 4 and Day 8

End point description

D-Bil, T-Bil, and CRT measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[43]	37 ^[44]	38 ^[45]
Units: Micromoles per liter
arithmetic mean (standard deviation)
D-Bil, Day 4, n=9, 14, 14	-0.5 ( 1.98 )	-0.6 ( 0.76 )	-0.6 ( 0.76 )
D-Bil, Day 8, n=9, 16, 16	0.2 ( 0.97 )	-0.1 ( 0.61 )	-0.1 ( 0.61 )
T-Bil, Day 4, n=19, 34, 35	0.1 ( 5.45 )	-1.5 ( 2.53 )	-1.5 ( 2.53 )
T-Bil, Day 8, n=18, 34, 35	0.1 ( 3.38 )	-0.6 ( 3.82 )	-0.6 ( 3.76 )
CRT, Day 4, n=19, 34, 35	1.29 ( 8.628 )	3.85 ( 7.126 )	4.22 ( 7.364 )
CRT, Day 8, n=18, 34, 35	2.84 ( 7.679 )	7.31 ( 9.219 )	7.04 ( 9.217 )

Notes
[43] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[44] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[45] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in calcium, chloride, carbon dioxide content (CO2)/bicarbonate (BC), glucose, potassium, sodium, urea/blood urea nitrogen (BUN), and uric acid (UA) at Day 4 and Day 8

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End point title

Change from Baseline in calcium, chloride, carbon dioxide content (CO2)/bicarbonate (BC), glucose, potassium, sodium, urea/blood urea nitrogen (BUN), and uric acid (UA) at Day 4 and Day 8

End point description

Calcium, chloride, CO2/BC, glucose, potassium, sodium, urea/BUN, and UA measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[46]	37 ^[47]	38 ^[48]
Units: Millimoles per liter
arithmetic mean (standard deviation)
Calcium, Day 4, n=19, 34, 35	0.01 ( 0.0746 )	-0.009 ( 0.0659 )	-0.011 ( 0.0667 )
Calcium, Day 8, n=18, 35, 36	0.026 ( 0.0756 )	-0.018 ( 0.0662 )	-0.017 ( 0.0652 )
Chloride, Day 4, n=19, 33, 34	-1.37 ( 1.832 )	-0.42 ( 2.346 )	-0.41 ( 2.311 )
Chloride, Day 8, n=18, 33, 34	0.39 ( 2.57 )	0.52 ( 1.734 )	0.53 ( 1.71 )
CO2/BC, Day 4, n=9, 21, 22	-0.06 ( 2.833 )	0.16 ( 2.602 )	0.2 ( 2.546 )
CO2/BC, Day 8, n=8, 22, 23	0.51 ( 2.053 )	0.23 ( 2.139 )	0.13 ( 2.141 )
Glucose, Day 4, n=19, 35, 36	1.14 ( 2.944 )	0.14 ( 1.198 )	0.15 ( 1.185 )
Glucose, Day 8, n=18, 36, 36	-0.03 ( 0.865 )	0.09 ( 0.594 )	-0.09 ( 0.594 )
Potassium, Day 4, n=19, 32, 33	0.008 ( 0.3393 )	0.168 ( 0.3408 )	0.151 ( 0.3497 )
Potassium, Day 8, n=16, 31, 32	0.055 ( 0.3405 )	0.048 ( 0.2897 )	0.043 ( 0.2862 )
Sodium, Day 4, n=19, 34, 35	-0.89 ( 2.787 )	-0.56 ( 1.779 )	-0.51 ( 1.772 )
Sodium, Day 8, n=18, 34, 35	1.39 ( 3.202 )	0.21 ( 1.647 )	0.29 ( 1.69 )
Urea/BUN, Day 4, n=17, 32, 33	-0.27 ( 1.757 )	0 ( 1.496 )	-0.02 ( 1.477 )
Urea/BUN, Day 8, n=17, 34, 35	-0.63 ( 1.318 )	0.13 ( 1.308 )	0.14 ( 1.289 )
UA, Day 4, n=16, 30, 31	-14.22 ( 23.416 )	0.53 ( 29.735 )	-0.78 ( 30.127 )
UA, Day 8, n=14, 29, 30	-1.56 ( 22.601 )	6.39 ( 30.819 )	6.17 ( 30.306 )

Notes
[46] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[47] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[48] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, total absolute neutrophil count (ANC), and platelet count (PC) at Day 4 and Day 8

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End point title

Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, total absolute neutrophil count (ANC), and platelet count (PC) at Day 4 and Day 8

End point description

Basophils, eosinophils, lymphocytes, monocytes, total ANC, and PC measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[49]	37 ^[50]	38 ^[51]
Units: Giga (10^9) cells per liter
arithmetic mean (standard deviation)
Basophils, Day 4, n=19, 34, 35	-0.003 ( 0.02 )	-0.006 ( 0.0247 )	-0.006 ( 0.0244 )
Basophils, Day 8, n=17, 35, 36	-0.006 ( 0.0153 )	-0.001 ( 0.0195 )	-0.001 ( 0.0192 )
Eosinophils, Day 4, n=19, 34, 35	0.003 ( 0.1219 )	-0.031 ( 0.0584 )	-0.034 ( 0.0599 )
Eosinophils, Day 8, n=17, 35, 36	-0.016 ( 0.0519 )	-0.001 ( 0.0466 )	0 ( 0.0467 )
Lymphocytes, Day 4, n=19, 34, 35	0.093 ( 0.4326 )	0.044 ( 0.3592 )	0.033 ( 0.3592 )
Lymphocytes, Day 8, n=17, 35, 36	-0.049 ( 0.3258 )	0.076 ( 0.5874 )	0.073 ( 0.5793 )
Monocytes, Day 4, n=19, 34, 35	0.006 ( 0.1313 )	0.002 ( 0.0923 )	0.004 ( 0.0913 )
Monocytes, Day 8, n=17, 35, 36	-0.004 ( 0.086 )	-0.013 ( 0.0928 )	-0.013 ( 0.0916 )
Total ANC , Day 4, n=19, 34, 35	0.021 ( 0.8866 )	0.392 ( 0.948 )	0.406 ( 0.9377 )
Total ANC , Day 8, n=17, 35, 36	0.007 ( 0.8586 )	-0.114 ( 0.85 )	-0.122 ( 0.8392 )
PC, Day 4, n=19, 34, 35	4.5 ( 18.45 )	3.6 ( 18.76 )	3.3 ( 18.53 )
PC, Day 8, n=17, 35, 36	1.8 ( 24.42 )	1.4 ( 22.97 )	0.7 ( 22.97 )

Notes
[49] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[50] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[51] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 4 and Day 8

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End point title

Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 4 and Day 8

End point description

Hemoglobin and MCHC measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[52]	37 ^[53]	38 ^[54]
Units: Grams per liter
arithmetic mean (standard deviation)
Hemoglobin, Day 4, n=19, 34, 35	-2.3 ( 6.53 )	-2 ( 6.35 )	-2.3 ( 6.44 )
Hemoglobin, Day 8, n=17, 35, 36	-2.4 ( 4.27 )	-2.3 ( 4.71 )	-2.2 ( 4.64 )
MCHC, Day 4, n=13, 24, 24	0 ( 8.85 )	0.6 ( 8.83 )	0.6 ( 8.83 )
MCHC, Day 8, n=12, 25, 25	0.4 ( 8.3 )	-2.3 ( 8.47 )	-2.3 ( 8.47 )

Notes
[52] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[53] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[54] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in hematocrit at Day 4 and Day 8

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End point title

Change from Baseline in hematocrit at Day 4 and Day 8

End point description

Hematocrit measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[55]	37 ^[56]	38 ^[57]
Units: proportion of 1
arithmetic mean (standard deviation)
Day 4, n=19, 34, 35	-0.0059 ( 0.02331 )	-0.0059 ( 0.02029 )	-0.0067 ( 0.02051 )
Day 8, n=17, 35, 36	-0.0044 ( 0.01383 )	-0.0037 ( 0.01702 )	-0.0039 ( 0.01682 )

Notes
[55] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[56] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[57] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in mean corpuscle hemoglobin (MCH) at Day 4 and Day 8

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End point title

Change from Baseline in mean corpuscle hemoglobin (MCH) at Day 4 and Day 8

End point description

MCH measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[58]	37 ^[59]	38 ^[60]
Units: Picograms
arithmetic mean (standard deviation)
Day 4, n=19, 34, 35	-0.12 ( 0.464 )	-0.06 ( 0.744 )	0.07 ( 0.737 )
Day 8, n=17, 35, 36	0.03 ( 0.718 )	-0.2 ( 0.832 )	0.19 ( 0.826 )

Notes
[58] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[59] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[60] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in mean corpuscle volume (MCV) at Day 4 and Day 8

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End point title

Change from Baseline in mean corpuscle volume (MCV) at Day 4 and Day 8

End point description

MCV measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[61]	37 ^[62]	38 ^[63]
Units: Femtoliters
arithmetic mean (standard deviation)
Day 4, n=19, 34, 35	-0.13 ( 1.945 )	-0.14 ( 1.339 )	-0.17 ( 1.334 )
Day 8, n=17, 35, 36	0.72 ( 1.322 )	-0.05 ( 1.401 )	-0.06 ( 1.381 )

Notes
[61] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[62] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[63] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Change from Baseline in red blood cell count (RBC), reticulocytes (RET), and white blood cell count (WBC) at Day 4 and Day 8

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End point title

Change from Baseline in red blood cell count (RBC), reticulocytes (RET), and white blood cell count (WBC) at Day 4 and Day 8

End point description

RBC, RET, and WBC measurements were taken at pre-dose on Day 1 (Baseline), Day 4, and Day 8. The Baseline value was the Day 1 pre-dose value. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline value.

End point type

Secondary

End point timeframe

Baseline, Day 4, and Day 8

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[64]	37 ^[65]	38 ^[66]
Units: Tera (10^12) cells per liter
arithmetic mean (standard deviation)
RBC, Day 4, n=19, 34, 35	-0.055 ( 0.2345 )	0.068 ( 0.2138 )	-0.074 ( 0.214 )
RBC, Day 8, n=17, 35, 36	-0.073 ( 0.127 )	0.041 ( 0.1752 )	-0.043 ( 0.173 )
RET, Day 4, n=16, 28, 29	0 ( 0.0075 )	0.002 ( 0.0093 )	0.001 ( 0.0098 )
RET, Day 8, n=13, 28, 29	0.004 ( 0.008 )	0.001 ( 0.0093 )	0.001 ( 0.0095 )
WBC, Day 4, n=19, 34, 35	0.14 ( 0.9284 )	0.39 ( 1.0592 )	0.392 ( 1.0437 )
WBC, Day 8, n=17, 35, 36	-0.036 ( 0.8961 )	-0.154 ( 0.9006 )	-0.161 ( 0.8886 )

Notes
[64] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[65] - ASP. Participants with available data (n=X, X in category titles) were analyzed.
[66] - ASP. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: Number of participants with any adverse event (AE) or serious adverse event (SAE)

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End point title

Number of participants with any adverse event (AE) or serious adverse event (SAE)

End point description

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, is a congenital anomaly or birth defect, is associated with liver injury and impaired liver function, or are serious events as per the medical or scientific judgment.

End point type

Secondary

End point timeframe

From the start of study medication until Follow-up (up to Day 25)

End point values	Placebo	GSK962040 50 mg	GSK962040 Total
Number of subjects analysed	19 ^[67]	37 ^[68]	38 ^[69]
Units: participants
Any AE	17	23	24
Any SAE	2	2	2

Notes
[67] - All Subjects Population
[68] - All Subjects Population
[69] - All Subjects Population

No statistical analyses for this end point

Secondary: GSK962040 area under the plasma concentration-time curve from zero to 5.5 hours (AUC[0-5.5] and area under the plasma concentration-time curve from zero to infinity (AUC[0-inf]) at Days 1 and 8

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End point title

GSK962040 area under the plasma concentration-time curve from zero to 5.5 hours (AUC[0-5.5] and area under the plasma concentration-time curve from zero to infinity (AUC[0-inf]) at Days 1 and 8

End point description

GSK AUC(0-5.5) and AUC(0-inf) were derived from GSK962040 plasma concentration-time data. Only participants who received GSK962040 50 mg were analyzed. AUC is a measure of levodopa exposure.

End point type

Secondary

End point timeframe

Day 1 and Day 8

End point values	GSK962040 50 mg
Number of subjects analysed	36 ^[70]
Units: Nanograms.hour/milliliter
geometric mean (geometric coefficient of variation)
AUC(0-5.5): Day 1	1632.5 ( 38.1 )
AUC(0-5.5): Day 8	3036.9 ( 45.8 )
AUC(0-inf): Day 1	2972.8 ( 49.2 )

Notes
[70] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: GSK962040 percentage of AUC(0-inf) obtained by extrapolation (%AUCex) at Day 1

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End point title

GSK962040 percentage of AUC(0-inf) obtained by extrapolation (%AUCex) at Day 1

End point description

GSK962040 %AUCex was derived from GSK962040 plasma concentration-time data. %AUCex is the percentage of the AUC(0-inf) extrapolated from the last PK sample drawn to infinity. This parameter is only reported in conjunction with single-dose AUC(0-inf). Only participants who received GSK962040 50 mg were analyzed. AUC is a measure of levodopa exposure.

End point type

Secondary

End point timeframe

Day 1

End point values	GSK962040 50 mg
Number of subjects analysed	36 ^[71]
Units: Percentage
geometric mean (geometric coefficient of variation)	41.64 ( 28.9 )

Notes
[71] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: GSK962040 Cmax at Day1 and Day 8

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End point title

GSK962040 Cmax at Day1 and Day 8

End point description

GSK962040 Cmax was derived from GSK962040 plasma concentration-time data. Only participants who received GSK962040 50 mg were analyzed.

End point type

Secondary

End point timeframe

Day 1 and Day 8

End point values	GSK962040 50 mg
Number of subjects analysed	36 ^[72]
Units: Nanograms/milliliter
geometric mean (geometric coefficient of variation)
Day 1	501 ( 45.4 )
Day 8	788.3 ( 46 )

Notes
[72] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Secondary: GSK962040 tmax at Day1 and Day 8

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End point title

GSK962040 tmax at Day1 and Day 8

End point description

GSK962040 tmax was derived from GSK962040 plasma concentration-time data. Only participants who received GSK962040 50 mg were analyzed.

End point type

Secondary

End point timeframe

Day 1 and Day 8

End point values	GSK962040 50 mg
Number of subjects analysed	36 ^[73]
Units: Hours
median (full range (min-max))
Day 1	0.75 (0.25 to 3.5)
Day 8	1 (0.25 to 3.72)

Notes
[73] - PD/Efficacy Population. Participants with available data (n=X, X in category titles) were analyzed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Post-randomization adverse events include those that occured on or after the randomization date.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo

Reporting group description

Participants received placebo administered orally once daily for 7 to 9 days.

Reporting group title

GSK962040 50 mg

Reporting group description

Participants received GSK962040 50 milligrams (mg) administered orally once daily for 7 to 9 days.

Reporting group title

GSK962040 125 mg

Reporting group description

Participants received GSK962040 125 milligrams (mg) administered orally once daily for 7 to 9 days.

Serious adverse events	Placebo	GSK962040 50 mg	GSK962040 125 mg
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 19 (10.53%)	2 / 37 (5.41%)	0 / 1 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Parkinson’s disease
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Placebo	GSK962040 50 mg	GSK962040 125 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	17 / 19 (89.47%)	21 / 37 (56.76%)	1 / 1 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Hypertensive crisis
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 19 (10.53%)	5 / 37 (13.51%)	0 / 1 (0.00%)
occurrences all number	2	12	0
Chills
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Malaise
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Medical device complication
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Mucosal inflammation
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Non-cardiac chest pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	3	0
Pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Nervousness
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Nightmare
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Sleep disorder
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Blood creatinine increased
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 19 (5.26%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	1	1	0
Excoriation
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Fall
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Procedural pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	7 / 19 (36.84%)	9 / 37 (24.32%)	0 / 1 (0.00%)
occurrences all number	9	16	0
Dizziness
subjects affected / exposed	4 / 19 (21.05%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	6	1	0
Dyskinesia
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	1 / 1 (100.00%)
occurrences all number	0	1	1
Somnolence
subjects affected / exposed	0 / 19 (0.00%)	2 / 37 (5.41%)	0 / 1 (0.00%)
occurrences all number	0	5	0
Clumsiness
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Dysgeusia
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Hypoaesthesia
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Migraine
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Paraesthesia
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Parkinson's disease
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0
Sensory disturbance
subjects affected / exposed	0 / 19 (0.00%)	0 / 37 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 19 (10.53%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0
Microcytic anaemia
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Eye disorders
Eye pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Metamorphopsia
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	4 / 19 (21.05%)	3 / 37 (8.11%)	0 / 1 (0.00%)
occurrences all number	8	4	0
Constipation
subjects affected / exposed	3 / 19 (15.79%)	1 / 37 (2.70%)	1 / 1 (100.00%)
occurrences all number	3	1	1
Abdominal pain upper
subjects affected / exposed	2 / 19 (10.53%)	2 / 37 (5.41%)	0 / 1 (0.00%)
occurrences all number	2	2	0
Diarrhoea
subjects affected / exposed	2 / 19 (10.53%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	2	1	0
Toothache
subjects affected / exposed	2 / 19 (10.53%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	2	1	0
Dyspepsia
subjects affected / exposed	1 / 19 (5.26%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	2	2	0
Abdominal pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	3	0
Abdominal pain lower
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Flatulence
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Frequent bowel movements
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Gastritis
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Gingival pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Pruritus
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Micturition disorder
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Pollakiuria
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 19 (5.26%)	3 / 37 (8.11%)	0 / 1 (0.00%)
occurrences all number	1	3	0
Muscle spasms
subjects affected / exposed	3 / 19 (15.79%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	0	0
Arthralgia
subjects affected / exposed	2 / 19 (10.53%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	4	0	0
Muscle twitching
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Musculoskeletal pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Pain in extremity
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	4	0
Spinal pain
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Infections and infestations
Cystitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Escherichia urinary tract infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Influenza
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Rhinitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Staphylococcal infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 37 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0
Urinary tract infection
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Hyperkalaemia
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 19 (0.00%)	1 / 37 (2.70%)	0 / 1 (0.00%)
occurrences all number	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

15 Mar 2012

MHRA requested addition of GFR limits as exclusion criteria and change to dose stopping criteria.

28 Aug 2012

Screening experience indicates that finger tapping trials must be reduced in number. Permitted medications have been updated to aid in recruitment.

05 Nov 2012

Protocol has been changed from a single-center to a multi-center study to allow for additional sites to aid in recruitment.

06 Feb 2013

Based on the available screening data, the current study design is believed to be not feasible in practice. Therefore, inclusion criteria have been adjusted to allow a greater proportion of screened subjects into the study, without diminishing the scientific validity of the study. The study design has been adjusted from 2 to 1 cohort, and the study will evaluate placebo and a single dose level of 50 milligrams of GSK962040 initially with the option of adding dose levels after an interim analysis. The randomization ratio has been updated to 2:1 for drug:placebo, respectively.

26 Nov 2013

The subject-completed “ON”/”OFF” symptoms diary has been added to the screening visit to allow for baseline comparisons. Additional MDS-UPDRS 3 assessments have been added to allow for evaluation of motor symptoms at the subject defined “ON” time. The overdose definition has been expanded for clarity.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
21 Nov 2012	Interim analysis suggested that 125 milligrams camicinal may be higher in PD patients than anticipated. As a precaution, a substantial amendment was prepared to change the dose levels in study MOT115816. Study recruitment was paused during the amendment preparation. The pause was temporary and not safety related.	06 Feb 2013

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A randomized, double-blind, placebo-controlled, parallel group, dose ranging study to assess the effect of repeat doses of GSK962040 on the pharmacokinetics of levodopa in subjects with Parkinson’s disease exhibiting delayed gastric emptying

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Dose-normalized levodopa (L-DOPA) area under the plasma concentration-time curve from zero to 4 hours AUC(0-4) at Baseline

Primary: Dose-normalized levodopa (L-DOPA) area under the plasma concentration-time curve from zero to 4 hours AUC(0-4) at Baseline

Primary: Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8

Primary: Dose-normalized L-DOPA AUC(0-4) at Day 1 and Day 8

Primary: Dose-normalized L-DOPA maximum observed concentration (Cmax) at Baseline

Primary: Dose-normalized L-DOPA maximum observed concentration (Cmax) at Baseline

Primary: Dose-normalized L-DOPA Cmax at Day 1 and Day 8

Primary: Dose-normalized L-DOPA Cmax at Day 1 and Day 8

Primary: L-DOPA time of occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8

Primary: L-DOPA time of occurrence of Cmax (Tmax) at Baseline, Day 1,and Day 8

Primary: L-DOPA terminal phase half-life (t1/2) at Baseline, Day 1, and Day 8

Primary: L-DOPA terminal phase half-life (t1/2) at Baseline, Day 1, and Day 8

Secondary: Gastric half emptying time (GE t1/2) at Baseline (BL), Day 1, and Day 8

Secondary: Gastric half emptying time (GE t1/2) at Baseline (BL), Day 1, and Day 8

Secondary: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores at Baseline, Day 1, and Day 8 (pre-levodopa dose)

Secondary: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores at Baseline, Day 1, and Day 8 (pre-levodopa dose)

Secondary: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores at Baseline, Day 1, and Day 8 (pre-dose; 120, 180, and 240 minutes post-dose)

Secondary: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores at Baseline, Day 1, and Day 8 (pre-dose; 120, 180, and 240 minutes post-dose)

Secondary: Period mean amount of hours spent “ON,” “ON” without dyskinesia, "ON" with non-troublesome dyskinesia, "ON" with troublesome dyskinesia, and “OFF” at Baseline and during the treatment period (Days 1-8), Week 1 of Follow-up, and Week 2 of Follow-up

Secondary: Period mean amount of hours spent “ON,” “ON” without dyskinesia, "ON" with non-troublesome dyskinesia, "ON" with troublesome dyskinesia, and “OFF” at Baseline and during the treatment period (Days 1-8), Week 1 of Follow-up, and Week 2 of Follow-up

Secondary: Number of times a participant could alternatively tap two counter keys 30 centimeters apart in 1 minute (min) at Baseline, Day1, Day 8, and Follow-up

Secondary: Number of times a participant could alternatively tap two counter keys 30 centimeters apart in 1 minute (min) at Baseline, Day1, Day 8, and Follow-up

Secondary: Total daily L-DOPA equivalent dose at Baseline and on Days 1, 2, 3, 4, 5, 6, 7, 8, and 9

Secondary: Total daily L-DOPA equivalent dose at Baseline and on Days 1, 2, 3, 4, 5, 6, 7, 8, and 9

Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 8

Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 1 and Day 8

Secondary: Change from Baseline in heart rate at Day 1 and Day 8

Secondary: Change from Baseline in heart rate at Day 1 and Day 8

Secondary: Number of participants with the indicated electrocardiogram (ECG) findings at Day 1 and Day 8

Secondary: Number of participants with the indicated electrocardiogram (ECG) findings at Day 1 and Day 8

Secondary: Change from Baseline in albumin (ALB) and total protein (TP) at Day 4 and Day 8

Secondary: Change from Baseline in albumin (ALB) and total protein (TP) at Day 4 and Day 8

Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) at Day 4 and Day 8

Secondary: Change from Baseline in alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), and gamma glutamyl transferase (GGT) at Day 4 and Day 8

Secondary: Change from Baseline in direct bilirubin (D-Bil), total bilirubin (T-Bil), and creatinine (CRT) at Day 4 and Day 8

Secondary: Change from Baseline in direct bilirubin (D-Bil), total bilirubin (T-Bil), and creatinine (CRT) at Day 4 and Day 8

Secondary: Change from Baseline in calcium, chloride, carbon dioxide content (CO2)/bicarbonate (BC), glucose, potassium, sodium, urea/blood urea nitrogen (BUN), and uric acid (UA) at Day 4 and Day 8

Secondary: Change from Baseline in calcium, chloride, carbon dioxide content (CO2)/bicarbonate (BC), glucose, potassium, sodium, urea/blood urea nitrogen (BUN), and uric acid (UA) at Day 4 and Day 8

Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, total absolute neutrophil count (ANC), and platelet count (PC) at Day 4 and Day 8

Secondary: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, total absolute neutrophil count (ANC), and platelet count (PC) at Day 4 and Day 8

Secondary: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 4 and Day 8

Secondary: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 4 and Day 8

Secondary: Change from Baseline in hematocrit at Day 4 and Day 8

Secondary: Change from Baseline in hematocrit at Day 4 and Day 8

Secondary: Change from Baseline in mean corpuscle hemoglobin (MCH) at Day 4 and Day 8

Secondary: Change from Baseline in mean corpuscle hemoglobin (MCH) at Day 4 and Day 8

Secondary: Change from Baseline in mean corpuscle volume (MCV) at Day 4 and Day 8

Secondary: Change from Baseline in mean corpuscle volume (MCV) at Day 4 and Day 8

Secondary: Change from Baseline in red blood cell count (RBC), reticulocytes (RET), and white blood cell count (WBC) at Day 4 and Day 8

Secondary: Change from Baseline in red blood cell count (RBC), reticulocytes (RET), and white blood cell count (WBC) at Day 4 and Day 8

Secondary: Number of participants with any adverse event (AE) or serious adverse event (SAE)

Secondary: Number of participants with any adverse event (AE) or serious adverse event (SAE)

Secondary: GSK962040 area under the plasma concentration-time curve from zero to 5.5 hours (AUC[0-5.5] and area under the plasma concentration-time curve from zero to infinity (AUC[0-inf]) at Days 1 and 8

Secondary: GSK962040 area under the plasma concentration-time curve from zero to 5.5 hours (AUC[0-5.5] and area under the plasma concentration-time curve from zero to infinity (AUC[0-inf]) at Days 1 and 8

Secondary: GSK962040 percentage of AUC(0-inf) obtained by extrapolation (%AUCex) at Day 1

Secondary: GSK962040 percentage of AUC(0-inf) obtained by extrapolation (%AUCex) at Day 1

Secondary: GSK962040 Cmax at Day1 and Day 8

Secondary: GSK962040 Cmax at Day1 and Day 8

Secondary: GSK962040 tmax at Day1 and Day 8

Secondary: GSK962040 tmax at Day1 and Day 8

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A randomized, double-blind, placebo-controlled, parallel group, dose ranging study to assess the effect of repeat doses of GSK962040 on the pharmacokinetics of levodopa in subjects with Parkinson’s disease exhibiting delayed gastric emptying