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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
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
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
Hide 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
Arm/Group Title Donepezil + Placebo Donepezil + SB-742457 15 mg Donepezil + SB-742457 35 mg Total
Hide 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
Hide 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%
1.Primary Outcome
Title Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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]
Hide 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]
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
PK population.
Arm/Group Title Donepezil + SB-742457 15 mg Donepezil + SB-742457 35 mg
Hide 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)
Hide 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
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Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
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
Hide 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%) 
Hide 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
Hide 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
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
Layout table for Results Point of Contact information
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
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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