A Study of SB-742457, Added to Donepezil for the Treatment of Mild-to-moderate Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT00710684
• Recruitment Status: Completed
• First Posted: July 4, 2008
• Results First Posted: December 7, 2017
• Last Update Posted: December 7, 2017
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Alzheimer's Disease
• Interventions: Drug: SB-742457 15mg; Drug: SB-742457 35mg; Drug: Placebo; Drug: donepezil 5-10mg
• Enrollment: 682

Participant Flow

Recruitment Details	A total of 684 participants were randomized from 100 centers i.e. Australia, Argentina, Chile, Canada, United States of America, Czech Republic, Spain, Italy, Germany between 01 July 2008 and 16 November 2010.
Pre-assignment Details	Out of 1132 participants screened, 725 entered into 4-week placebo run-in period out of which 41 participants were placebo run-in failures. Out of 684 participants randomized, 682 were included in safety population (1 participant each from Donepezil+Placebo and Donepezil+SB742457 35 milligram [mg] group failed to take a dose of study medication).

Arm/Group Title	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Period Title: Overall Study
Started	225	221	236
Completed	151	147	172
Not Completed	74	74	64
Reason Not Completed
Adverse Event	11	19	16
Lack of Efficacy	4	3	5
Protocol Violation	5	5	5
Lost to Follow-up	4	6	7
Physician Decision	0	2	4
Withdrawal by Subject	24	18	11
Missing	1	0	0
Did not continue after week 24	25	21	16

Baseline Characteristics

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg	Total
Arm/Group Description		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		223	218	236	677
Baseline Analysis Population Description		Out of 682 participants, 5 participants did not have at least one post-Baseline or health outcomes assessment. Hence a total of 677 participants were included in intent-to-treat (ITT) population and they were used to assess Baseline characteristics.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	223 participants	218 participants	236 participants	677 participants
		73.1 (7.49)	74.2 (6.82)	73.8 (6.92)	73.7 (7.09)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	223 participants	218 participants	236 participants	677 participants
	Female	129 57.8%	118 54.1%	148 62.7%	395 58.3%
	Male	94 42.2%	100 45.9%	88 37.3%	282 41.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	223 participants	218 participants	236 participants	677 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	3 1.4%	2 0.8%	5 0.7%
	White	223 100.0%	215 98.6%	233 98.7%	671 99.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	1 0.4%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24
Description	ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the case report form (CRF) for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean is presented.
Time Frame	Baseline(Week 0) and Week 24

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed	193	184	200
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
	1.2 (0.45)	0.5 (0.44)	-0.4 (0.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.279
	Comments	[Not Specified]
	Method	mixed model for repeated measures (MMRM)
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -1.9 to 0.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.012
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -2.7 to -0.3
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24
Description	The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time Frame	Baseline(Week 0) and Week 24

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed	191	184	200
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
	0.9 (0.13)	0.8 (0.13)	0.7 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.711
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.3
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.462
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.2
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24
Description	RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the indicated time points were analyzed.

Arm/Group Title	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed	190	176	193
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
	-3.6 (1.18)	-5.9 (1.29)	-4.0 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.174
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -5.8 to 1.1
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.776
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -3.6 to 2.7
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48
Description	ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the CRF for questions 3 to 6 and 8 to 11. In cases where more than one question was missing, a total score was not be imputed. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been present
Time Frame	Baseline (Week 0) and Week 12, 36 and 48

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		223	218	236
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
Week 12	Number Analyzed	206 participants	202 participants	219 participants
		0.4 (0.33)	0.1 (0.37)	-0.9 (0.34)
Week 36	Number Analyzed	164 participants	156 participants	181 participants
		2.1 (0.45)	2.1 (0.48)	0.9 (0.45)
Week 48	Number Analyzed	145 participants	142 participants	170 participants
		3.4 (0.52)	3.4 (0.60)	1.8 (0.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.631
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -1.2 to 0.7
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.006
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -2.2 to -0.4
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.947
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.2
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.057
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -2.5 to 0.0
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.925
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.6 to 1.5
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.024
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -3.1 to -0.2
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Baseline in CDR-SB Score at Week 12, 36 and 48
Description	The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time Frame	Baseline (Week 0) and Week 12, 36, 48

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		223	218	236
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
Week 12	Number Analyzed	203 participants	199 participants	221 participants
		0.5 (0.10)	0.4 (0.09)	0.2 (0.08)
Week 36	Number Analyzed	163 participants	154 participants	179 participants
		1.2 (0.15)	1.4 (0.18)	1.0 (0.13)
Week 48	Number Analyzed	146 participants	142 participants	170 participants
		1.6 (0.16)	1.9 (0.20)	1.5 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.387
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.1
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.018
	Comments	[Not Specified]
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.5 to -0.1
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.439
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.6
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.336
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.2
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.190
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.8
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.787
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.4
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Change From Baseline in RBANS Score at Week 12, 36 and 48
Description	RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time Frame	Baseline (Week 0) and Week 12, 36 and 48

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		223	218	236
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
Week 12	Number Analyzed	200 participants	194 participants	214 participants
		-7.2 (0.94)	-8.5 (1.02)	-6.5 (0.79)
Week 36	Number Analyzed	161 participants	153 participants	174 participants
		-3.9 (1.32)	-4.8 (1.21)	-1.8 (1.19)
Week 48	Number Analyzed	143 participants	136 participants	164 participants
		-7.3 (1.36)	-9.4 (1.45)	-4.7 (1.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.337
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -4.0 to 1.4
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.596
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; -1.7 to 3.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.634
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -4.4 to 2.7
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.238
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.1
	Confidence Interval	(2-Sided) 95%; -1.4 to 5.6
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg, Donepezil + SB-742457 35 mg
	Comments	SB-742457 15 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.292
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -6.0 to 1.8
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.161
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 95%; -1.0 to 6.2
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48
Description	The ADCS-ADL is an interviewer-administered informant-based scale where the informant (caregiver) responds to 23 activities of daily living questions about the participant. The questions ranged from basic to instrumental activities of daily living and take approximately 20 minutes to complete. The Total score ranges from 0-78 and a higher score signified greater functional ability. The questionnaire was split into two types of questions, an initial question relating to whether a participant had completed a particular activity and then a follow on question which scored how much assistance the participant had required if they had performed that particular activity. The total score was calculated by adding up the responses for each of the individual activities. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time Frame	Baseline (Week 0) and Week 12, 24, 36 and 48

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		223	218	236
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
Week 12	Number Analyzed	202 participants	200 participants	222 participants
		-1.4 (0.57)	-0.8 (0.49)	0.3 (0.47)
Week 24	Number Analyzed	192 participants	185 participants	209 participants
		-3.4 (0.66)	-1.9 (0.61)	-1.4 (0.60)
Week 36	Number Analyzed	164 participants	159 participants	183 participants
		-3.7 (0.67)	-3.8 (0.80)	-1.8 (0.65)
Week 48	Number Analyzed	147 participants	144 participants	171 participants
		-5.5 (0.85)	-5.0 (0.87)	-3.5 (0.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.396
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; -0.8 to 2.1
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 12
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.019
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.7
	Confidence Interval	(2-Sided) 95%; 0.3 to 3.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.110
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -0.3 to 3.2
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.024
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; 0.3 to 3.7
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo ate Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.944
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -2.1 to 2.0
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 36
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.037
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; 0.1 to 3.8
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.705
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -1.9 to 2.9
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.088
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -0.3 to 4.2
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48
Description	The MMSE consisted of 11 items covering orientation, memory (recent and immediate), concentration, language and praxis. Scores ranged from 0 to 30, with lower scores indicating greater cognitive impairment. Scores for each of the 11 individual tests were not recorded on the CRF, therefore if any item was missing then the total score was be set to missing. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented.
Time Frame	Baseline (Week 0) and Week 24 and 48

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		223	218	236
Least Squares Mean (Standard Error); Unit of Measure: Score on scale
Week 24	Number Analyzed	196 participants	188 participants	209 participants
		-0.4 (0.21)	-0.3 (0.23)	0.1 (0.21)
Week 48	Number Analyzed	149 participants	145 participants	172 participants
		-1.1 (0.28)	-1.3 (0.33)	-0.7 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.962
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 24
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.134
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -0.1 to 1.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 15 mg
	Comments	SB-742457 15 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.782
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.7
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Donepezil + Placebo, Donepezil + SB-742457 35 mg
	Comments	SB-742457 35 mg versus placebo at Week 48
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.268
	Comments	[Not Specified]
	Method	MMRM
	Comments	The MMRM model included fixed categorical terms for treatment, visit, treatment by visit interaction and country.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -0.3 to 1.2
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase
Description	An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.
Time Frame	Up to follow-up i.e. 2 weeks post end of treatment (Week 24, Week 48 or Early Withdrawal)

Outcome Measure Data

Analysis Population Description

Safety population consisted of all participants randomized to treatment who had received at least one dose of study medication.

Arm/Group Title	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed	225	221	236
Measure Type: Count of Participants; Unit of Measure: Participants
Any AE	125 55.6%	137 62.0%	146 61.9%
Any SAE	17 7.6%	26 11.8%	27 11.4%

10. Secondary Outcome

Title	Number of Participants With Parameters of Clinical Concern - Hematology
Description	Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Eosinophils (high-2), Hematocrit (low- 0.8, high-1.2), Lymphocytes (low-0.75, high-1.5), Mean Corpuscle Hemoglobin (MCH) (low-0.8, high-1.2), Monocytes(low-0.75, high-2), Neutrophil bands (high-10), Platelet count (low-100, high-500), Segmented Neutrophils (low-0.75, high-1.3), Total Neutrophils (low-0.75, high-1.5), and white blood cells (WBC) (low-3, high-15).
Time Frame	Up to Week 48

Outcome Measure Data

Analysis Population Description

Safety population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		225	221	236
Measure Type: Count of Participants; Unit of Measure: Participants
Eosinophils, high	Number Analyzed	222 participants	217 participants	235 participants
		1 0.5%	0 0.0%	4 1.7%
Hematocrit, low	Number Analyzed	222 participants	217 participants	235 participants
		2 0.9%	2 0.9%	1 0.4%
Hematocrit, high	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	1 0.5%	0 0.0%
Hemoglobin, low	Number Analyzed	222 participants	217 participants	235 participants
		5 2.3%	3 1.4%	8 3.4%
Hemoglobin, high	Number Analyzed	222 participants	217 participants	235 participants
		3 1.4%	1 0.5%	0 0.0%
Lymphocytes, low	Number Analyzed	222 participants	217 participants	235 participants
		6 2.7%	5 2.3%	7 3.0%
Lymphocytes, high	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	2 0.9%	1 0.4%
MCH, low	Number Analyzed	204 participants	198 participants	216 participants
		0 0.0%	1 0.5%	0 0.0%
MCV, low	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	1 0.5%	0 0.0%
Monocytes, low	Number Analyzed	222 participants	217 participants	235 participants
		35 15.8%	32 14.7%	32 13.6%
Monocytes, high	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	1 0.5%	0 0.0%
Neutrophil bands, high	Number Analyzed	1 participants	3 participants	3 participants
		0 0.0%	1 33.3%	1 33.3%
Platelet count, low	Number Analyzed	222 participants	216 participants	235 participants
		1 0.5%	4 1.9%	3 1.3%
Platelet count, high	Number Analyzed	222 participants	216 participants	235 participants
		2 0.9%	3 1.4%	5 2.1%
Segmented Neutrophils, low	Number Analyzed	222 participants	217 participants	235 participants
		7 3.2%	3 1.4%	7 3.0%
Segmented Neutrophils, high	Number Analyzed	222 participants	217 participants	235 participants
		3 1.4%	4 1.8%	5 2.1%
Total Neutrophils, low	Number Analyzed	222 participants	217 participants	235 participants
		7 3.2%	3 1.4%	7 3.0%
Total Neutrophils, high	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	3 1.4%	2 0.9%
WBC, low	Number Analyzed	222 participants	217 participants	235 participants
		4 1.8%	1 0.5%	5 2.1%
WBC, high	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	3 1.4%	2 0.9%

11. Secondary Outcome

Title	Number of Participants With Parameters of Clinical Concern - Clinical Chemistry
Description	Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Alanine Amino Transferase (ALT) (high-1.5), Alkaline Phosphatase (high-1.5), Aspartate Amino Transferase (ASAT) (high-1.5), BUN/Creatinine ratio (high-1.5), Calcium (low- 0.75, high-1.25), Carbon dioxide content/Bicarbonate (low-15, high- 40), Cholesterol (high-1.25), Creatine Kinase ((low- 0.5, high-1.25), Creatinine (low- 0.5, high-1.25), Direct Bilirubin (high-1.5), Gamma Glutamyl Transferase (GGT) (high-2), Glucose (low- 3.6, high-7.8), HDL Cholesterol (low-0.65), LDL Cholesterol (hig-1.25), Magnesium (low-0.5, high-2), Phosphorus inorganic (low- 0.5, high-1.5), Potassium (low- 3, high-5.5), Sodium (low- 130, high-150), Total Bilirubin (high-1.5), Triglycerides (high -4) and Urea/BUN (high-11).
Time Frame	Up to Week 48

Outcome Measure Data

Analysis Population Description

Safety population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		225	221	236
Measure Type: Count of Participants; Unit of Measure: Participants
ALT, high	Number Analyzed	222 participants	217 participants	235 participants
		2 0.9%	4 1.8%	4 1.7%
Alkaline Phosphatase, high	Number Analyzed	222 participants	217 participants	235 participants
		5 2.3%	6 2.8%	4 1.7%
ASAT, high	Number Analyzed	222 participants	217 participants	235 participants
		2 0.9%	7 3.2%	4 1.7%
BUN/Creatinine ratio, high	Number Analyzed	222 participants	217 participants	235 participants
		11 5.0%	7 3.2%	5 2.1%
Calcium, low	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	0 0.0%	1 0.4%
Carbon dioxide content/Bicarbonate, low	Number Analyzed	222 participants	217 participants	235 participants
		3 1.4%	2 0.9%	2 0.9%
Cholesterol, high	Number Analyzed	204 participants	196 participants	215 participants
		11 5.4%	4 2.0%	7 3.3%
Creatine Kinase, high	Number Analyzed	204 participants	196 participants	215 participants
		5 2.5%	2 1.0%	6 2.8%
Creatinine, high	Number Analyzed	222 participants	217 participants	235 participants
		3 1.4%	3 1.4%	5 2.1%
Direct Bilirubin, high	Number Analyzed	222 participants	217 participants	235 participants
		2 0.9%	1 0.5%	1 0.4%
GGT, high	Number Analyzed	222 participants	217 participants	235 participants
		5 2.3%	7 3.2%	7 3.0%
Glucose, low	Number Analyzed	222 participants	217 participants	235 participants
		17 7.7%	24 11.1%	13 5.5%
Glucose, high	Number Analyzed	222 participants	217 participants	235 participants
		54 24.3%	42 19.4%	54 23.0%
HDL Cholesterol, direct, low	Number Analyzed	204 participants	195 participants	215 participants
		3 1.5%	0 0.0%	2 0.9%
LDL Cholesterol, high	Number Analyzed	201 participants	195 participants	214 participants
		35 17.4%	29 14.9%	40 18.7%
Magnesium, low	Number Analyzed	204 participants	195 participants	215 participants
		0 0.0%	1 0.5%	0 0.0%
Phosphorus, inorganic, high	Number Analyzed	204 participants	196 participants	215 participants
		0 0.0%	0 0.0%	1 0.5%
Potassium, high	Number Analyzed	222 participants	217 participants	235 participants
		2 0.9%	10 4.6%	9 3.8%
Sodium, high	Number Analyzed	222 participants	217 participants	235 participants
		0 0.0%	1 0.5%	1 0.4%
Total Bilirubin, high	Number Analyzed	222 participants	217 participants	235 participants
		2 0.9%	1 0.5%	1 0.4%
Triglycerides, high	Number Analyzed	204 participants	196 participants	215 participants
		1 0.5%	0 0.0%	0 0.0%
Urea/BUN, high	Number Analyzed	222 participants	217 participants	235 participants
		17 7.7%	12 5.5%	25 10.6%

12. Secondary Outcome

Title	Exposure Estimates for SB-742457 : Area Under the Concentration Time Curve Over the Dosing Interval at Steady State (AUCτss)
Description	AUCτss of SB-742457 was estimated via nonlinear mixed effect analysis. This pharmacokinetic(PK) model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution.
Time Frame	Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48

Outcome Measure Data

Analysis Population Description

PK population included all participants for whom a pharmacokinetic sample was obtained and analyzed.

Arm/Group Title	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed	215	233
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram hour per milliliter (ng*h/mL)
	1640.76; (35.96%)	4160.29; (31.67%)

13. Secondary Outcome

Title	Exposure Estimates for SB-742457 : Minimum Concentrations at Steady State (Cmin-ss)
Description	Cmin-ss was estimated via nonlinear mixed effect analysis. This PK model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution.
Time Frame	Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48

Outcome Measure Data

Analysis Population Description

PK population.

Arm/Group Title	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed	215	233
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	53.42; (38.58%)	135.05; (33.08%)

14. Secondary Outcome

Title	Exposure Estimates for Donepezil (Cavgss)
Description	Participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) were allowed to participate in this study. Cavgss for donepezil approximately 12 to 20 hours after dosing were summarized by donepezil dose level 5 mg/7.5 mg/10 mg/15 mg.
Time Frame	Post-dose at 12 to 20 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48

Outcome Measure Data

Analysis Population Description

Donepezil PK population comprised of participants who received a stable dose of donepezil 5 mg/7.5 mg/10 mg/15 mg. Analysis is exclusively for Cavgss of donepezil therefore the two arms SB-742457 15 mg and SB-742457 35 mg have not been presented.

Arm/Group Title	Donepezil 5 mg	Donepezil 7.5 mg	Donepezil 10 mg	Donepezil 15 mg
Arm/Group Description:	Participants received a stable dose of donepezil 5 mg at least for 6 months and a stable regimen for at least 2 months. The participants received SB742457 15 mg or 35 mg or placebo matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy.	Participants received a stable dose of donepezil 7.5 mg at least for 6 months and a stable regimen for at least 2 months. The participants received SB742457 15 mg or 35 mg or placebo matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy.	Participants received a stable dose of donepezil 10 mg at least for 6 months and a stable regimen for at least 2 months. The participants received SB742457 15 mg or 35 mg or placebo matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy.	Participants received a stable dose of donepezil 15 mg at least for 6 months and a stable regimen for at least 2 months. The participants received SB742457 15 mg or 35 mg or placebo matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy.
Overall Number of Participants Analyzed	179	1	484	1
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	20.72; (45.07%)	17.68 [1]; (NA%)	39.79; (46.62%)	36.60 [2]; (NA%)

[1]

Only one participant was analyzed, hence, dispersion value could not be generated.

[2]

Only one participant was analyzed.

15. Secondary Outcome

Title	Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene
Description	Genetic analyses was conducted to assess the effect of APOE4 carriage. ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five-point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicating greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores were recorded on the CRF for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value.
Time Frame	Baseline (Week 0) to Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

PGx ITT Population consisted of all participants in the ITT population who had evaluable PGx data. Only those participants with APOE gene and available at the specified time point were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		206	202	219
Mean (Standard Deviation); Unit of Measure: Score on scale
Week 24	Number Analyzed	98 participants	94 participants	114 participants
		1.9 (5.58)	1.0 (6.63)	-0.1 (5.40)
Week 48	Number Analyzed	74 participants	72 participants	90 participants
		4.7 (6.52)	4.2 (7.46)	1.8 (5.72)

16. Secondary Outcome

Title	Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene
Description	Genetic analyses was conducted to assess the effect of APOE4 carriage. The CDR-SB is an interviewer administered scale and impairment is scored in following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment was scored on a scale in which none =0, questionable =0.5, mild =1, moderate =2 and severe =3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher score indicating severe impairment. If there were any missing items then CDR-SB was set to missing and was not imputed. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value.
Time Frame	Baseline (Week 0) to Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

PGx ITT Population. Only those participants with APOE gene and available at the specified time point were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		206	202	219
Mean (Standard Deviation); Unit of Measure: Score on scale
Week 24	Number Analyzed	95 participants	94 participants	113 participants
		1.1 (2.02)	0.6 (1.59)	0.8 (1.47)
Week 48	Number Analyzed	75 participants	71 participants	91 participants
		1.8 (1.98)	1.5 (2.11)	1.4 (1.92)

17. Secondary Outcome

Title	Change From Baseline in RBANS Scale in Participants With APOE4 Gene
Description	Genetic analyses was conducted to assess the effect of APOE4 carriage. RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value.
Time Frame	Baseline (Week 0) to Week 24 and Week 48

Outcome Measure Data

Analysis Population Description

PGx ITT Population. Only those participants with APOE gene and available at the specified time point were analyzed.

Arm/Group Title		Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description:		Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
Overall Number of Participants Analyzed		206	202	219
Mean (Standard Deviation); Unit of Measure: Score on scale
Week 24	Number Analyzed	96 participants	94 participants	110 participants
		-5.2 (14.30)	-6.0 (20.07)	-6.0 (14.84)
Week 48	Number Analyzed	74 participants	72 participants	87 participants
		-7.7 (16.46)	-11.3 (16.13)	-5.9 (14.04)

Adverse Events

Time Frame	AE data was collected up to follow-up i.e. 2 weeks post end of treatment Up to follow-up i.e. 2 weeks post end of treatment (Week 24, Week 48 or Early Withdrawal).
Adverse Event Reporting Description	Safety population consisted of all participants randomized to treatment who had received at least one dose of study medication. Safety population was used for the analysis of SAE and nSAE.
Arm/Group Title	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
Arm/Group Description	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received placebo tablets matching with SB742457 orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 15 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.	Eligible participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) received SB742457 35 mg orally once daily for a treatment period of 48 weeks as an adjunct treatment to stable donepezil therapy. At the end of 24 weeks treatment participants were asked to consent/assent to continue their randomized treatment for a further 24 weeks.
All-Cause Mortality
	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/225 (0.44%)	5/221 (2.26%)	4/236 (1.69%)
Serious Adverse Events
	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	17/225 (7.56%)	26/221 (11.76%)	27/236 (11.44%)
Cardiac disorders
Bradycardia † 1	0/225 (0.00%)	1/221 (0.45%)	1/236 (0.42%)
Adams-Stokes syndrome † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Angina pectoris † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Arteriosclerosis coronary artery † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Cardiac failure † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Cardio-respiratory arrest † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Sick sinus syndrome † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Ear and labyrinth disorders
Vertigo † 1	0/225 (0.00%)	0/221 (0.00%)	2/236 (0.85%)
Gastrointestinal disorders
Abdominal pain upper † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Colonic polyp † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Diarrhoea † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Diverticulum † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Dyspepsia † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Oesophageal obstruction † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Vomiting † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
General disorders
Death † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Fatigue † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Pyrexia † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Hepatobiliary disorders
Biliary colic † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Infections and infestations
Pneumonia † 1	3/225 (1.33%)	1/221 (0.45%)	3/236 (1.27%)
Urinary tract infection † 1	1/225 (0.44%)	1/221 (0.45%)	0/236 (0.00%)
Abdominal abscess † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Bronchopneumonia † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Diverticulitis † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Erysipelas † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Influenza † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Respiratory tract infection † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Skin infection † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Injury, poisoning and procedural complications
Fall † 1	2/225 (0.89%)	0/221 (0.00%)	0/236 (0.00%)
Humerus fracture † 1	1/225 (0.44%)	0/221 (0.00%)	1/236 (0.42%)
Femur fracture † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Hand fracture † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Hip fracture † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Joint dislocation † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Lower limb fracture † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Post procedural haemorrhage † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Radius fracture † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Skin laceration † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Skull fracture † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Splenic injury † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Subdural haematoma † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	1/225 (0.44%)	1/221 (0.45%)	0/236 (0.00%)
Decreased appetite † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Musculoskeletal and connective tissue disorders
Neck pain † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Glioblastoma † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Malignant melanoma † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Oesophageal carcinoma † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Penile neoplasm † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Squamous cell carcinoma † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Nervous system disorders
Cerebrovascular accident † 1	1/225 (0.44%)	3/221 (1.36%)	1/236 (0.42%)
Syncope † 1	1/225 (0.44%)	1/221 (0.45%)	2/236 (0.85%)
Cerebral haemorrhage † 1	0/225 (0.00%)	2/221 (0.90%)	0/236 (0.00%)
Aphasia † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Dementia Alzheimer's type † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Dizziness † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Epilepsy † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Loss of consciousness † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Psychomotor hyperactivity † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Sciatica † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Transient ischaemic attack † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Psychiatric disorders
Confusional state † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Disorientation † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Renal and urinary disorders
Urethral stenosis † 1	0/225 (0.00%)	1/221 (0.45%)	0/236 (0.00%)
Reproductive system and breast disorders
Metrorrhagia † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Dyspnoea † 1	1/225 (0.44%)	0/221 (0.00%)	0/236 (0.00%)
Epistaxis † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Vascular disorders
Circulatory collapse † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Deep vein thrombosis † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
Haematoma † 1	0/225 (0.00%)	0/221 (0.00%)	1/236 (0.42%)
1 Term from vocabulary, MedDRA; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Donepezil + Placebo	Donepezil + SB-742457 15 mg	Donepezil + SB-742457 35 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	41/225 (18.22%)	32/221 (14.48%)	33/236 (13.98%)
Infections and infestations
Nasopharyngitis † 1	17/225 (7.56%)	19/221 (8.60%)	18/236 (7.63%)
Urinary tract infection † 1	15/225 (6.67%)	10/221 (4.52%)	13/236 (5.51%)
Injury, poisoning and procedural complications
Fall † 1	12/225 (5.33%)	4/221 (1.81%)	5/236 (2.12%)
1 Term from vocabulary, MedDRA; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

Results Point of Contact

• Name/Title: GSK Response Center
• Organization: GlaxoSmithKline
• Phone: 866-435-7343

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Maher-Edwards G, Watson C, Ascher J, Barnett C, Boswell D, Davies J, Fernandez M, Kurz A, Zanetti O, Safirstein B, Schronen JP, Zvartau-Hind M, Gold M. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease. Alzheimers Dement (N Y). 2015 May 7;1(1):23-36. doi: 10.1016/j.trci.2015.04.001. eCollection 2015 Jun.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00710684
• Other Study ID Numbers: AZ3110866
• First Submitted: June 30, 2008
• First Posted: July 4, 2008
• Results First Submitted: August 18, 2017
• Results First Posted: December 7, 2017
• Last Update Posted: December 7, 2017