Study of SB-742457 or Donepezil Versus Placebo in Subjects With Mild-to-moderate Alzheimer's Disease

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline Mini Mental State Examination [MMSE] Scores 16-26) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 24

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 16-26. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline [MMSE Scores 10-20) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 24

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 10-20. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE 16-26. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Higher scores indicate worst outcome. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with baseline MMSE 10-20. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in ADAS-Cog Total Score at Week 12

ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a five point scale. The ADAS-Cog total score is the sum of the calculated scores for Questions 1 (Word recall task), 2 (Naming objects and fingers), and 7 (Word recognition task) and the scores recorded on the CRF for Questions 3 to 6 (Commands, Constructional praxis, Ideational praxis, Orientation) and 8 to 11 (Remembering test instructions, Spoken language ability, Word finding difficulty in spontaneous speech, Comprehension). The total score ranges from 0-70 with higher scores indicating greater dysfunction while lower indicates better cognitive function. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time frame: Baseline (Week 0) and Week 12

CIBIC+ Score at Week 12

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse).

Time frame: Week 12

Change From Baseline in RBANS Total Score at Week 12

RBANS is an individually administered neurocognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). The scale is completed by a trained and experienced neurologist, psychiatrist or neuropsychologist, or another trained and experienced person. It is preferred that this individual is the same person who administers the ADAS-Cog, but he/she must be a separate individual from the person who completes the CIBIC+. The scale is based on the performance of the participant and takes approximately 25-30 minutes to administer. Raw total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where low score= (greater impairment) and high score=(better cognitive function). Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time frame: Baseline (Week 0) and Week 12

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 12

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for Participants with Baseline MMSE score 16-26. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time frame: Baseline (Week 0) and Week 12

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the Change From Baseline in ADAS-Cog Total Score, the Change From Baseline in RBANS Total Score at Week 12

The MMSE was used to measure cognitive impairment. The MMSE consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing and drawing corresponding to 5 domains orientation, memory, attention, and construction. All items were scored as 0 (incorrect response) or 1 (correct response). Total scores ranges from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better function. Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE score 10-20. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 12.

Time frame: Baseline (Week 0) and Week 12

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE score 16-26.

Time frame: Week 12

Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12

The CIBIC+ is a rating scale derived from an interview with the participant and caregiver with an independent rater designed to measure several domains of participant function, such as mental/cognitive state, behavior, and functioning. The scores are rated on a scale of 1 to 7 as follows: 1 (marked improvement), 2 (moderately improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (moderately worse) and 7 (markedly worse). Stratification by Baseline severity, using MMSE score at Baseline, with the strata being MMSE score of 10-15, 16-20 and 21-26. Two subgroups using MMSE score at Baseline were also examined, moderate 10-20 and mild 16-26. Data has been presented for participants with Baseline MMSE score 10-20.

Time frame: Week 12

Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24

The ADCS-ADL measures functional impairment in terms of activities of daily living. The ADCS-ADL is an interviewer-administered informant-based scale where the informant (caregiver) responds to 23 activities of daily living questions (i.e. those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, making judgments and decisions) about the participant. The questions range 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 signifies greater functional ability and lower scores indicating greater impairment. The total score is the sum of all items and sub-questions. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Weeks 12 and 24.

Time frame: Baseline (Week 0) and Weeks 12 and 24

Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24

The CSDD is used to assess signs and symptoms of major depression in demented participants. The CSDD scale contains 19 items on mood-related signs of depression, behavioral disturbance, physical signs of depression, cyclic functions and ideational disturbances, where each item is rated for severity on a scale of 0-2 (0=absent, 1=mild/intermittent, 2=severe). Scores above 10 (probable major depression),scores above 18 (definite major depression), scores below 6 (absence of significant depressive symptoms). The total score was calculated as a weighted average of the scores provided for the remaining 18 questions as follows: Imputed Total= Observed Total Score x 1+ Maximum Score of the missing value/ Sum of the Maximum Score of the non -missing values) and ranges from 0-38. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in MMSE Total Score at Week 24

The MMSE is used to test for cognitive dysfunction. The scale is completed by a trained and experienced neurologist/psychiatrist/neuropsychologist based on the performance of the participants, and takes approximately 5 to 10 minutes to administer. It consists of 11 tests namely orientation to time, orientation to place, registration, attention and calculation, recall, naming, repetition, comprehension, reading, writing, drawing across 5 sections (orientation, registration, attention-calculation, recall, and language). Scoring was done by circling 0 if the response was incorrect, or 1 if the response was correct. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment and higher scores indicating better cognitive function. The total MMSE score was a sum of all item scores. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24

Basic score was calculated as the sum of questions 1-6b and ranges from 0-22 (activities included are: eating, walking, using the toilet, bathing, grooming and dressing) and Instrumental score, sum of questions 7-23, ranges from 0-56 (activities included are: using the telephone, watching television, conversations, clearing dishes, personal belongings, making drinks, making snacks, taking rubbish out, getting out and about, shopping, keeping appointments, being left alone, current events, reading, writing, pastimes/hobbies, household chores). Total independence score is calculated by re-scoring the individual questions for each activity. The total independence score therefore ranges between 0 to 23, where 23 indicates that a participant is independent (based on these 23 ADL). Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Weeks 12 and 24.

Time frame: Baseline (Week 0) and Weeks 12 and 24

Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs)

An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. Number of participants with any adverse event (serious and non-serious) and SAEs were reported.

Time frame: Upto Week 24

Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT)

Vital sign measurements included systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR), Body weight (BW). SBP and DBP and HR were measured once after the participant sat quietly for at least 5 minutes and in addition, upon standing to assess participants for postural hypotension. DBP was measured at the disappearance of Korotkoff sounds (Phase V). The plethysmographic method (preferably with a column sphygmomanometer where available) was used to measure blood pressure throughout the study. Body weight was measured, without shoes and wearing light clothing. The PCC range were as follows: SBP (Reference Range \[RR\] \<90-140\> Increase from Baseline \[IFB\]\>=40 and decrease from baseline \[DFB\] \>=30), DBP (RR \< 50-90\> IFB\>=30 and DFB \>=20), HR (RR \<50-100\> IFB \>=30 and DFB \>=30, BW (IFB \>= 7% and DFB \>=7%).

Time frame: Upto Week 24

Number of Participants With Hematology Data of PCC ATOT

Hematology parameters included hematocrit ratio (reference range males 0.410-0.500, females 0.350-0.460 \[18-64 years\] and males 0.360-0.490, females 0.330-0.460 \[65+ years\]), hemoglobin grams per liter (13.8-17.2), lymphocytes giga per liter (0.85-4.10), monocytes giga per liter (0.20-1.10), platelet count giga per liter (130-400), segmented neutrophils giga per liter (1.80-8.00), total neutrophils (1.80-8.00). Data has been presented in a consolidated format for hematology parameters high and low from the reference range of PCC ATOT.

Time frame: Upto Week 24

Number of Participants With Chemistry Data of PCC ATOT

Clinical chemistry parameters included alanine amino transferase international units per liter (IU/L) RR \[0-48\], alkaline phosphatase IU/L (20-125), aspartate amino transferase international units per liter (0-55), blood urea nitrogen/creatinine ratio (24-101), calcium millimoles per liter (mmol/L) \[2.12-2.56\], carbon dioxide content/bicarbonate mmol/L (20-32), cholesterol mmol/L (0.00-5.15), creatine kinase IU/L (males 0-235 and females 0-190), creatinine micromoles per liter (umol/L) \[44-124\], direct bilirubin umol/L (0-6), gamma glutamyl transferase IU/L (males 0-65 and females 0-45), glucose mmol/L (3.9-6.9), low density lipoprotein cholesterol mmol/L (0.00-3.35), lactate dehydrogenase IU/L (0-270), potassium mmol/L (3.5-5.3), sodium mmol/L (135-146), total bilirubin umol/L (0-22), triglycerides mmol/L (0.00-2.24), urea/blood urea nitrogen mmol/L (2.5-10.5). Data has been presented in a consolidated format for clinical chemistry parameters high and low from the RR of PCC ATOT.

Time frame: Upto Week 24

Change From Baseline in Clinical Chemistry Parameters Alanine Amino Transferase, Alkaline Phosphatase, Aspartate Amino Transferase, Creatine Kinase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Week 24

Clinical chemistry parameters included alanine amino transferase, alkaline phosphatase, aspartate amino transferase, creatine kinase, gamma glutamyl transferase and lactate dehydrogenase. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Weeks 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24

Clinical chemistry parameters included albumin and total protein. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24

Clinical chemistry parameter included blood urea nitrogen /creatinine ratio. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Clinical Chemistry Parameters Calcium, CO2 Content/Bicarbonate, Chloride, Glucose, HDL Cholesterol, LDL Cholesterol, Magnesium, Phosphorus, Potassium, Sodium, Triglycerides, Urea/Blood Urea Nitrogen at Week 24

Clinical chemistry parameters included calcium, CO2 content/bicarbonate, chloride, glucose, HDL cholesterol, LDL cholesterol, magnesium, phosphorus, potassium, sodium, triglycerides, urea/blood urea nitrogen. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24

Clinical chemistry parameters included creatinine, direct bilirubin and total bilirubin. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24

Hematology parameters included basophils, eosinophils, lymphocytes, monocytes, platelet count, segmented neutrophils, total neutrophils, white blood cell count. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Hematology Parameter Hematocrit

Hematology parameter included hematocrit. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24

Hematology parameter included hemoglobin and mean corpuscle hemoglobin concentration. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24

Hematology parameter included mean corpuscle hemoglobin. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24

Hematology parameter included mean corpuscle volume and mean platelet volume. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24

Hematology parameter included red blood cell count. Baseline was defined as the value at Visit 3 (Week 0). Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24.

Time frame: Baseline (Week 0) and Week 24

Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist

The clinical interpretation of the ECG by the investigator was recorded as Normal, Abnormal but not clinically significant (ANCS) and Abnormal clinically significant (ACS). ECG interpretation by the central cardiologist included the most extreme result of the available ECGs where the central cardiologist's interpretation of the ECG was recorded as Normal, Unable to Evaluate and Abnormal. Data has been presented for number of participants with most severe on-treatment abnormal ECG findings.

Time frame: Upto Week 24

Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss)

A total of five pharmacokinetic samples per participant were collected for the purpose of assessing plasma concentrations of SB-742457 and donepezil. At each visit (Day 28±5, 56±5, 84±5, 126±5 and 168±5) one sample was collected post 24 hours of last dose.

Time frame: One sample at Day 28±5, 56±5, 84±5, 126±5 and 168±5 post 24 hours of last dose

Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss)

Blood sample for pharmacokinetic analysis, were obtained within 24 hours of last dose. A total of five pharmacokinetic samples per participants were taken at Weeks 4, 8,12,18 and Week 24. The SB-742457 exposures at steady state Cmin-ss for each participant were estimated via nonlinear mixed effect analysis. Data has been presented in a consolidated format for SB-742457 exposures at steady state Cmin-ss.

Time frame: One sample at Day 28±5, 56±5, 84±5, 126±5 and 168±5 post 24 hours of last dose

Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss)

Blood sample for pharmacokinetic analysis, were obtained within 24 hours of last dose. A total of five pharmacokinetic samples per participants were taken at Weeks 4, 8,12,18 and Week 24. The Donepezil exposures at steady state Cavgss for each participant were estimated via nonlinear mixed effect analysis. Data has been presented in a consolidated format for SB-742457 exposures at steady state Cavgss.

Time frame: Weeks 4, 8,12,18 and Week 24