Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease, Cognition, SB-742457
Brief summary
The study is designed to investigate the efficacy, safety and tolerability of SB-742457 versus placebo in subjects with mild-to-moderate Alzheimer's disease. SB-742457 is an experimental treatment which increases the levels of certain chemicals in the brain that are often decreased in patients with Alzheimer's disease.
Interventions
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects and their caregivers must provide informed consent prior to study entry. * Subjects must have a clinical diagnosis of probable mild-to-moderate Alzheimer's disease with a documented 6-month history of AD symptoms * Subjects must have a regular caregiver who is willing to attend visits, oversee the subject's compliance with the study and report on the subject's status. * Female subjects of child-bearing potential must agree to pregnancy testing and approved form of birth control.
Exclusion criteria
* Diagnosis of possible, probable or definite vascular dementia. * History/evidence of any other CNS disorder that could be interpreted as a cause of dementia * History of known or suspected seizures, loss of consciousness or significant head trauma * Subjects with ECG, blood pressure and laboratory values outside of protocol criteria are excluded. * Subjects with known photosensitivity * Subjects with a history of previous exposure to SB-742457, taking agents for which there is a theoretical risk of interaction with SB-742457, or taking medication for Alzheimer's disease or centrally acting agents which might impact study outcomes may not participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | Baseline (Week 0) and Week 24 | 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 Week 0. Change from Baseline was obtained by subtracting the Baseline value from the post-randomization value at Week 24. |
| Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline (Week 0) and 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. |
| Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24 | Baseline (Week 0) and 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. |
| Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in ADAS-Cog Total Score at Week 12 | Baseline (Week 0) and 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. |
| CIBIC+ Score at Week 12 | 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). |
| Change From Baseline in RBANS Total Score at Week 12 | Baseline (Week 0) and 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. |
| 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 | Baseline (Week 0) and 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. |
| 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 | Baseline (Week 0) and 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. |
| Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12 | 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. |
| Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12 | 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. |
| Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in MMSE Total Score at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Baseline (Week 0) and 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. |
| Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Upto Week 24 | 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. |
| Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Upto Week 24 | 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. |
| Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | Baseline (Week 0) and Week 24 | 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 24. |
| Number of Participants With Hematology Data of PCC ATOT | Upto Week 24 | 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. |
| Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss) | One sample at Day 28±5, 56±5, 84±5, 126±5 and 168±5 post 24 hours of last dose | 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. |
| Number of Participants With Chemistry Data of PCC ATOT | Upto Week 24 | 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. |
| 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 | Baseline (Week 0) and 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. |
| Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24 | Baseline (Week 0) and 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. |
| 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 | Baseline (Week 0) and 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. |
| Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Hematology Parameter Hematocrit | Baseline (Week 0) and Week 24 | 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. |
| Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Baseline (Week 0) and 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. |
| Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24 | Baseline (Week 0) and 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. |
| Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss) | One sample at Day 28±5, 56±5, 84±5, 126±5 and 168±5 post 24 hours of last dose | 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. |
| Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss) | Weeks 4, 8,12,18 and Week 24 | 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. |
| Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Upto Week 24 | 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%). |
| 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 | Baseline (Week 0) and 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. |
Countries
Bulgaria, Chile, Czechia, Estonia, Germany, Greece, Mexico, Poland, Russia, South Africa, South Korea
Participant flow
Recruitment details
This study was conducted at 68 centers in the following 11 countries: Bulgaria, Chile, Czech Republic, Estonia, Germany, Greece, Korea, Mexico, Poland, Russia, and South Africa from 04 July 2008 to 09 Mar 2010 and a total of 967 participants were screened over the recruitment period of 55 weeks.
Pre-assignment details
Of 967 participants screened, 618 (349 screen failures) entered into the placebo run-in period and a total of 576 (42 placebo run-in failures) were randomized of which 2 participants did not take study medication, formed Safety population (574) comprising of randomized participants who took atleast one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received one tablet of matching placebo to SB-742457 (Week 1 to 4) and one capsule of matching placebo orally each evening just prior to going to bed (Week 4 to 24). | 135 |
| SB-742457-15mg Participants received one tablet of SB-742457-15 mg and one capsule of matching placebo to Donepezil orally each evening just prior to going to bed in the two treatment period (Week 1 to 4 and Week 4 to 24). | 142 |
| SB-742457-35mg Participants received one tablet of SB-742457-35 mg and one capsule of matching placebo to Donepezil orally each evening just prior to going to bed in the two treatment period (Week 1 to 4 and Week 4 to 24). | 130 |
| Donepezil Participants received Donepezil capsule by one-step titration 5mg Donepezil once daily (Week 1 to Week 4) before up-titrating at Visit 4 (Week 4) to 10 mg once daily dose for the remaining 20 weeks of the treatment period (Week 4 to 24) along with matching placebo to SB-747457. | 147 |
| Total | 554 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 3 | 4 | 6 |
| Overall Study | Lack of Efficacy | 0 | 4 | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 2 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 | 4 |
| Overall Study | Withdrawal by Subject | 12 | 7 | 8 | 10 |
Baseline characteristics
| Characteristic | Placebo | Total | Donepezil | SB-742457-35mg | SB-742457-15mg |
|---|---|---|---|---|---|
| Age, Continuous | 73.3 Years STANDARD_DEVIATION 6.8 | 72.3 Years STANDARD_DEVIATION 7.49 | 71.1 Years STANDARD_DEVIATION 7.49 | 72.5 Years STANDARD_DEVIATION 7.38 | 72.4 Years STANDARD_DEVIATION 8.12 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 26 Participants | 9 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 23 Participants | 6 Participants | 6 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 128 Participants | 502 Participants | 130 Participants | 118 Participants | 126 Participants |
| Sex: Female, Male Female | 87 Participants | 353 Participants | 95 Participants | 75 Participants | 96 Participants |
| Sex: Female, Male Male | 48 Participants | 201 Participants | 52 Participants | 55 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 145 | 0 / 145 | 1 / 133 | 1 / 151 |
| other Total, other adverse events | 42 / 145 | 39 / 145 | 38 / 133 | 62 / 151 |
| serious Total, serious adverse events | 7 / 145 | 7 / 145 | 3 / 133 | 10 / 151 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24
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 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
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | -0.3 Score on scale | Standard Error 0.56 |
| SB-742457-15mg | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | 0.8 Score on scale | Standard Error 0.58 |
| SB-742457-35mg | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | 0.4 Score on scale | Standard Error 0.62 |
| Donepezil | Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | -0.5 Score on scale | Standard Error 0.45 |
Comparison: ADAS-Cog Total Score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.15995% CI: [-0.4, 2.7]Mixed model repeated measures
Comparison: ADAS-Cog Total Score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.4195% CI: [-0.9, 2.3]Mixed model repeated measures
Comparison: ADAS-Cog Total Score, Placebo Vs Donepezil at Week 24p-value: 0.82195% CI: [-1.6, 1.2]Mixed model repeated measures
Primary
Clinician's Interview-Based Impression of Change - Plus (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).
Time frame: Week 24
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24 | 4.0 Score on scale | Standard Error 0.11 |
| SB-742457-15mg | Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24 | 4.2 Score on scale | Standard Error 0.1 |
| SB-742457-35mg | Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24 | 3.9 Score on scale | Standard Error 0.1 |
| Donepezil | Clinician's Interview-Based Impression of Change - Plus (CIBIC+) Score at Week 24 | 3.7 Score on scale | Standard Error 0.1 |
Comparison: CIBIC+ Score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.25495% CI: [-0.1, 0.5]Mixed model repeated measures
Comparison: CIBIC+ Score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.39495% CI: [-0.4, 0.2]Mixed model repeated measures
Comparison: CIBIC+ Score, Placebo Vs Donepezil at Week 24p-value: 0.04995% CI: [-0.6, 0]Mixed model repeated measures
Secondary
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
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in ADAS-Cog Total Score at Week 12 | -0.1 Score on scale | Standard Error 0.45 |
| SB-742457-15mg | Change From Baseline in ADAS-Cog Total Score at Week 12 | 0.0 Score on scale | Standard Error 0.46 |
| SB-742457-35mg | Change From Baseline in ADAS-Cog Total Score at Week 12 | -0.2 Score on scale | Standard Error 0.45 |
| Donepezil | Change From Baseline in ADAS-Cog Total Score at Week 12 | -0.6 Score on scale | Standard Error 0.4 |
Comparison: ADAS-Cog Total Score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.84795% CI: [-1.1, 1.4]Mixed model repeated measures
Comparison: ADAS-Cog Total Score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.83395% CI: [-1.4, 1.1]Mixed Models Analysis
Comparison: ADAS-Cog Total Score, Placebo Vs Donepzil at Week 12p-value: 0.44395% CI: [-1.6, 0.7]Mixed model repeated measures
Secondary
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
Population: ITT population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 at Week 24 | -0.7 Score on scale | Standard Error 0.2 |
| Placebo | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 12 | -0.1 Score on scale | Standard Error 0.23 |
| Placebo | 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 at Week 12 | -0.6 Score on scale | Standard Error 0.17 |
| Placebo | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 24 | -0.3 Score on scale | Standard Error 0.27 |
| Placebo | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 12 | 0.2 Score on scale | Standard Error 0.5 |
| Placebo | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 24 | -0.3 Score on scale | Standard Error 0.6 |
| SB-742457-15mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 12 | -0.6 Score on scale | Standard Error 0.55 |
| SB-742457-15mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 12 | -0.1 Score on scale | Standard Error 0.23 |
| SB-742457-15mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 24 | -0.7 Score on scale | Standard Error 0.61 |
| SB-742457-15mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 24 | -0.2 Score on scale | Standard Error 0.26 |
| SB-742457-15mg | 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 at Week 24 | -0.7 Score on scale | Standard Error 0.19 |
| SB-742457-15mg | 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 at Week 12 | -0.5 Score on scale | Standard Error 0.19 |
| SB-742457-35mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 24 | -0.1 Score on scale | Standard Error 0.29 |
| SB-742457-35mg | 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 at Week 12 | -0.4 Score on scale | Standard Error 0.24 |
| SB-742457-35mg | 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 at Week 24 | -0.6 Score on scale | Standard Error 0.24 |
| SB-742457-35mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 12 | 0.3 Score on scale | Standard Error 0.52 |
| SB-742457-35mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 24 | -0.5 Score on scale | Standard Error 0.68 |
| SB-742457-35mg | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 12 | 0.2 Score on scale | Standard Error 0.24 |
| Donepezil | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 12 | 0.4 Score on scale | Standard Error 0.55 |
| Donepezil | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 24 | -0.1 Score on scale | Standard Error 0.3 |
| Donepezil | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Total Independence Score at Week 12 | 0.2 Score on scale | Standard Error 0.23 |
| Donepezil | 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 at Week 24 | -0.8 Score on scale | Standard Error 0.23 |
| Donepezil | 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 at Week 12 | -0.2 Score on scale | Standard Error 0.17 |
| Donepezil | Change From Baseline in ADCS-ADL-Basic Score; ADCS-ADL: Instrumental Score and ADCS-ADL: Total Independence Score at Weeks 12 and 24 | Instrumental score at Week 24 | -0.4 Score on scale | Standard Error 0.7 |
Comparison: Basic Score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.86995% CI: [-0.5, 0.5]Mixed model repeated measures
Comparison: Basic Score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.595% CI: [-0.4, 0.8]Mixed model repeated measures
Comparison: Basic Score, Placebo Vs Donepezil at Week 12p-value: 0.1495% CI: [-0.1, 0.8]Mixed model repeated measures
Comparison: Basic Score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.9195% CI: [-0.6, 0.5]Mixed model repeated measures
Comparison: Basic Score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.77495% CI: [-0.5, 0.7]Mixed model repeated measures
Comparison: Basic Score, Placebo Vs Donepezil at Week 24p-value: 0.72695% CI: [-0.7, 0.5]Mixed model repeated measures
Comparison: Instrumental Score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.29295% CI: [-2.2, 0.7]Mixed model repeated measures
Comparison: Instrumental Score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.94695% CI: [-1.3, 1.4]Mixed model repeated measures
Comparison: Instrumental Score, Placebo Vs Donepezil at Week 12p-value: 0.80295% CI: [-1.3, 1.6]Mixed model repeated measures
Comparison: Instrumental Score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.63695% CI: [-2.1, 1.3]Mixed model repeated measures
Comparison: Instrumental Score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.75295% CI: [-2, 1.5]Mixed model repeated measures
Comparison: Instrumental Score, Placebo Vs Donepezil at Week 24p-value: 0.9295% CI: [-1.9, 1.7]Mixed model repeated measures
Comparison: Total Independence Score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.97295% CI: [-0.7, 0.6]Mixed model repeated measures
Comparison: Total Independence Score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.37895% CI: [-0.4, 0.9]Mixed model repeated measures
Comparison: Total Independence Score, Placebo Vs Donepezil at Week 12p-value: 0.34695% CI: [-0.3, 0.9]Mixed model repeated measures
Comparison: Total Independence Score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.7295% CI: [-0.6, 0.9]Mixed model repeated measures
Comparison: Total Independence Score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.59895% CI: [-0.6, 1]Mixed model repeated measures
Comparison: Total Independence Score, Placebo Vs Donepezil at Week 24p-value: 0.4895% CI: [-0.5, 1.1]Mixed model repeated measures
Secondary
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
Population: ITT population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 12 | -0.4 Score on scale | Standard Error 0.59 |
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 24 | -1.0 Score on scale | Standard Error 0.71 |
| SB-742457-15mg | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 24 | -1.4 Score on scale | Standard Error 0.68 |
| SB-742457-15mg | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 12 | -1.1 Score on scale | Standard Error 0.65 |
| SB-742457-35mg | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 12 | -0.1 Score on scale | Standard Error 0.64 |
| SB-742457-35mg | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 24 | -1.1 Score on scale | Standard Error 0.81 |
| Donepezil | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 12 | 0.2 Score on scale | Standard Error 0.62 |
| Donepezil | Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Total Score at Weeks 12 and 24 | ADCS-ADL Total score at Week 24 | -1.2 Score on scale | Standard Error 0.82 |
Comparison: ADCS-ADL Total score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.41795% CI: [-2.4, 1]Mixed model repeated measures
Comparison: ADCS-ADL Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.72595% CI: [-1.4, 2]Mixed model repeated measures
Comparison: ADCS-ADL Total score, Placebo Vs Donepezil at Week 12p-value: 0.50695% CI: [-1.1, 2.2]Mixed model repeated measures
Comparison: ADCS-ADL Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.72395% CI: [-2.3, 1.6]Mixed model repeated measures
Comparison: ADCS-ADL Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.91995% CI: [-2.2, 2]Mixed model repeated measures
Comparison: ADCS-ADL Total score, Placebo Vs Donepezil at Week 24p-value: 0.89695% CI: [-2.3, 2]Mixed model repeated measures
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24 | 0.8 Ratio | Standard Deviation 19.99 |
| SB-742457-15mg | Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24 | 2.3 Ratio | Standard Deviation 19.32 |
| SB-742457-35mg | Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24 | -3.7 Ratio | Standard Deviation 17.44 |
| Donepezil | Change From Baseline in Clinical Chemistry Parameter Blood Urea Nitrogen /Creatinine Ratio at Week 24 | -0.3 Ratio | Standard Deviation 17.76 |
Secondary
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
Population: Safety population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | Lactate dehydrogenase at Week 24 | 0.8 IU/L | Standard Deviation 25.09 |
| Placebo | 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 | Aspartate amino transferase at Week 24 | -0.3 IU/L | Standard Deviation 6.15 |
| Placebo | 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 | Alkaline phosphatase at Week 24 | -3.4 IU/L | Standard Deviation 15.71 |
| Placebo | 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 | Creatine kinase at Week 24 | -16.8 IU/L | Standard Deviation 242.93 |
| Placebo | 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 | Gamma glutamyl transferase at Week 24 | -1.5 IU/L | Standard Deviation 13.06 |
| Placebo | 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 | Alanine amino transferase at Week 24 | -0.3 IU/L | Standard Deviation 8.76 |
| SB-742457-15mg | 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 | Gamma glutamyl transferase at Week 24 | -0.2 IU/L | Standard Deviation 11.23 |
| SB-742457-15mg | 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 | Lactate dehydrogenase at Week 24 | -2.9 IU/L | Standard Deviation 28.88 |
| SB-742457-15mg | 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 | Alanine amino transferase at Week 24 | 0.0 IU/L | Standard Deviation 4.88 |
| SB-742457-15mg | 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 | Alkaline phosphatase at Week 24 | -0.1 IU/L | Standard Deviation 10.91 |
| SB-742457-15mg | 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 | Creatine kinase at Week 24 | -5.4 IU/L | Standard Deviation 47.97 |
| SB-742457-15mg | 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 | Aspartate amino transferase at Week 24 | 0.0 IU/L | Standard Deviation 3.8 |
| SB-742457-35mg | 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 | Alanine amino transferase at Week 24 | -0.1 IU/L | Standard Deviation 6.77 |
| SB-742457-35mg | 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 | Gamma glutamyl transferase at Week 24 | -1.3 IU/L | Standard Deviation 15.08 |
| SB-742457-35mg | 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 | Aspartate amino transferase at Week 24 | -0.1 IU/L | Standard Deviation 6.88 |
| SB-742457-35mg | 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 | Creatine kinase at Week 24 | 16.2 IU/L | Standard Deviation 157.67 |
| SB-742457-35mg | 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 | Alkaline phosphatase at Week 24 | 0.8 IU/L | Standard Deviation 14.63 |
| SB-742457-35mg | 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 | Lactate dehydrogenase at Week 24 | -0.4 IU/L | Standard Deviation 22.65 |
| Donepezil | 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 | Lactate dehydrogenase at Week 24 | -1.2 IU/L | Standard Deviation 25.99 |
| Donepezil | 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 | Creatine kinase at Week 24 | 0.6 IU/L | Standard Deviation 82.86 |
| Donepezil | 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 | Alkaline phosphatase at Week 24 | 2.0 IU/L | Standard Deviation 17.81 |
| Donepezil | 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 | Aspartate amino transferase at Week 24 | 0.5 IU/L | Standard Deviation 12.88 |
| Donepezil | 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 | Gamma glutamyl transferase at Week 24 | 3.6 IU/L | Standard Deviation 32.97 |
| Donepezil | 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 | Alanine amino transferase at Week 24 | 1.6 IU/L | Standard Deviation 29.47 |
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Albumin at Week 24 | -0.5 grams per liter | Standard Deviation 2.37 |
| Placebo | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Total protein at Week 24 | -0.8 grams per liter | Standard Deviation 3.52 |
| SB-742457-15mg | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Albumin at Week 24 | -0.5 grams per liter | Standard Deviation 2.44 |
| SB-742457-15mg | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Total protein at Week 24 | -0.9 grams per liter | Standard Deviation 4 |
| SB-742457-35mg | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Total protein at Week 24 | -1.3 grams per liter | Standard Deviation 3.5 |
| SB-742457-35mg | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Albumin at Week 24 | -0.6 grams per liter | Standard Deviation 2.54 |
| Donepezil | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Total protein at Week 24 | -1.2 grams per liter | Standard Deviation 3.62 |
| Donepezil | Change From Baseline in Clinical Chemistry Parameters Albumin and Total Protein at Week 24 | Albumin at Week 24 | -0.8 grams per liter | Standard Deviation 2.62 |
Secondary
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
Population: Safety population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | Glucose at Week 24 | 0.02 mmol/L | Standard Deviation 1.108 |
| Placebo | 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 | Sodium at Week 24 | 0.1 mmol/L | Standard Deviation 2.24 |
| Placebo | 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 | HDL cholesterol at Week 24 | -0.023 mmol/L | Standard Deviation 0.2272 |
| Placebo | 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 | Phosphorus at Week 24 | 0.010 mmol/L | Standard Deviation 0.1435 |
| Placebo | 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 | Calcium at Week 24 | -0.008 mmol/L | Standard Deviation 0.091 |
| Placebo | 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 | Magnesium at Week 24 | -0.001 mmol/L | Standard Deviation 0.0606 |
| Placebo | 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 | Potassium at Week 24 | -0.00 mmol/L | Standard Deviation 0.45 |
| Placebo | 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 | CO2 content/bicarbonate at Week 24 | 0.5 mmol/L | Standard Deviation 2.91 |
| Placebo | 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 | Urea/blood urea nitrogen at Week 24 | 0.06 mmol/L | Standard Deviation 1.642 |
| Placebo | 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 | Triglycerides at Week 24 | -0.040 mmol/L | Standard Deviation 0.875 |
| Placebo | 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 | Chloride at Week 24 | 0.2 mmol/L | Standard Deviation 2.54 |
| Placebo | 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 | LDL cholesterol at Week 24 | 0.149 mmol/L | Standard Deviation 0.8387 |
| SB-742457-15mg | 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 | Sodium at Week 24 | 0.0 mmol/L | Standard Deviation 2.57 |
| SB-742457-15mg | 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 | Glucose at Week 24 | 0.03 mmol/L | Standard Deviation 1.327 |
| SB-742457-15mg | 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 | LDL cholesterol at Week 24 | -0.032 mmol/L | Standard Deviation 0.6176 |
| SB-742457-15mg | 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 | Potassium at Week 24 | 0.09 mmol/L | Standard Deviation 0.458 |
| SB-742457-15mg | 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 | Urea/blood urea nitrogen at Week 24 | 0.29 mmol/L | Standard Deviation 1.51 |
| SB-742457-15mg | 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 | Calcium at Week 24 | -0.012 mmol/L | Standard Deviation 0.0956 |
| SB-742457-15mg | 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 | Chloride at Week 24 | 0.3 mmol/L | Standard Deviation 2.97 |
| SB-742457-15mg | 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 | CO2 content/bicarbonate at Week 24 | 0.3 mmol/L | Standard Deviation 2.46 |
| SB-742457-15mg | 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 | Magnesium at Week 24 | -0.007 mmol/L | Standard Deviation 0.0538 |
| SB-742457-15mg | 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 | Phosphorus at Week 24 | -0.018 mmol/L | Standard Deviation 0.1529 |
| SB-742457-15mg | 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 | HDL cholesterol at Week 24 | -0.060 mmol/L | Standard Deviation 0.2402 |
| SB-742457-15mg | 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 | Triglycerides at Week 24 | -0.071 mmol/L | Standard Deviation 0.7146 |
| SB-742457-35mg | 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 | Potassium at Week 24 | 0.04 mmol/L | Standard Deviation 0.44 |
| SB-742457-35mg | 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 | Calcium at Week 24 | -0.025 mmol/L | Standard Deviation 0.1215 |
| SB-742457-35mg | 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 | HDL cholesterol at Week 24 | -0.060 mmol/L | Standard Deviation 0.305 |
| SB-742457-35mg | 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 | Phosphorus at Week 24 | 0.043 mmol/L | Standard Deviation 0.1728 |
| SB-742457-35mg | 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 | Triglycerides at Week 24 | -0.024 mmol/L | Standard Deviation 0.7678 |
| SB-742457-35mg | 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 | CO2 content/bicarbonate at Week 24 | -0.5 mmol/L | Standard Deviation 3.01 |
| SB-742457-35mg | 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 | Chloride at Week 24 | 0.1 mmol/L | Standard Deviation 2.87 |
| SB-742457-35mg | 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 | Glucose at Week 24 | 0.14 mmol/L | Standard Deviation 1.808 |
| SB-742457-35mg | 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 | LDL cholesterol at Week 24 | -0.115 mmol/L | Standard Deviation 0.5971 |
| SB-742457-35mg | 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 | Magnesium at Week 24 | -0.002 mmol/L | Standard Deviation 0.0569 |
| SB-742457-35mg | 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 | Sodium at Week 24 | -0.2 mmol/L | Standard Deviation 2.43 |
| SB-742457-35mg | 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 | Urea/blood urea nitrogen at Week 24 | 0.14 mmol/L | Standard Deviation 1.467 |
| Donepezil | 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 | Potassium at Week 24 | 0.05 mmol/L | Standard Deviation 0.45 |
| Donepezil | 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 | Glucose at Week 24 | 0.07 mmol/L | Standard Deviation 1.605 |
| Donepezil | 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 | Chloride at Week 24 | -0.0 mmol/L | Standard Deviation 2.7 |
| Donepezil | 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 | Urea/blood urea nitrogen at Week 24 | 0.10 mmol/L | Standard Deviation 1.453 |
| Donepezil | 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 | Sodium at Week 24 | 0.4 mmol/L | Standard Deviation 2.31 |
| Donepezil | 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 | CO2 content/bicarbonate at Week 24 | 0.5 mmol/L | Standard Deviation 2.84 |
| Donepezil | 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 | Phosphorus at Week 24 | 0.026 mmol/L | Standard Deviation 0.1752 |
| Donepezil | 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 | Triglycerides at Week 24 | 0.082 mmol/L | Standard Deviation 1.0874 |
| Donepezil | 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 | HDL cholesterol at Week 24 | -0.035 mmol/L | Standard Deviation 0.2477 |
| Donepezil | 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 | Calcium at Week 24 | -0.013 mmol/L | Standard Deviation 0.0932 |
| Donepezil | 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 | Magnesium at Week 24 | -0.001 mmol/L | Standard Deviation 0.0591 |
| Donepezil | 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 | LDL cholesterol at Week 24 | -0.032 mmol/L | Standard Deviation 0.7417 |
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Total bilirubin at Week 24 | -0.1 umol/L | Standard Deviation 3.33 |
| Placebo | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Direct bilirubin at Week 24 | -0.1 umol/L | Standard Deviation 0.79 |
| Placebo | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Creatinine at Week 24 | -0.3 umol/L | Standard Deviation 20.4 |
| SB-742457-15mg | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Total bilirubin at Week 24 | -0.1 umol/L | Standard Deviation 2.82 |
| SB-742457-15mg | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Creatinine at Week 24 | 1.2 umol/L | Standard Deviation 10.83 |
| SB-742457-15mg | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Direct bilirubin at Week 24 | 0.1 umol/L | Standard Deviation 0.84 |
| SB-742457-35mg | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Direct bilirubin at Week 24 | -0.1 umol/L | Standard Deviation 1.17 |
| SB-742457-35mg | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Creatinine at Week 24 | 5.7 umol/L | Standard Deviation 10.64 |
| SB-742457-35mg | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Total bilirubin at Week 24 | 0.0 umol/L | Standard Deviation 3.66 |
| Donepezil | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Total bilirubin at Week 24 | -0.8 umol/L | Standard Deviation 3.89 |
| Donepezil | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Direct bilirubin at Week 24 | -0.1 umol/L | Standard Deviation 1.01 |
| Donepezil | Change From Baseline in Clinical Chemistry Parameters Creatinine, Direct Bilirubin and Total Bilirubin at Week 24 | Creatinine at Week 24 | 1.4 umol/L | Standard Deviation 8.53 |
Secondary
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
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24 | 0.0 Score on scale | Standard Error 0.26 |
| SB-742457-15mg | Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24 | -0.1 Score on scale | Standard Error 0.25 |
| SB-742457-35mg | Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24 | 0.3 Score on scale | Standard Error 0.26 |
| Donepezil | Change From Baseline in Cornell Scale for Depression in Dementia (CSDD) Total Score at Week 24 | 0.3 Score on scale | Standard Error 0.25 |
Comparison: CSDD Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.59495% CI: [-0.9, 0.5]ANCOVA
Comparison: CSDD Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.52395% CI: [-0.5, 0.9]ANCOVA
Comparison: CSDD Total score, Placebo Vs Donepezil at Week 24p-value: 0.42995% CI: [-0.4, 1]ANCOVA
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter Hematocrit | 0.0038 Ratio | Standard Deviation 0.02264 |
| SB-742457-15mg | Change From Baseline in Hematology Parameter Hematocrit | 0.0037 Ratio | Standard Deviation 0.02242 |
| SB-742457-35mg | Change From Baseline in Hematology Parameter Hematocrit | -0.0003 Ratio | Standard Deviation 0.02509 |
| Donepezil | Change From Baseline in Hematology Parameter Hematocrit | 0.0002 Ratio | Standard Deviation 0.02351 |
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24 | -0.21 picograms | Standard Deviation 0.949 |
| SB-742457-15mg | Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24 | -0.19 picograms | Standard Deviation 1.173 |
| SB-742457-35mg | Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24 | -0.10 picograms | Standard Deviation 1.023 |
| Donepezil | Change From Baseline in Hematology Parameter Mean Corpuscle Hemoglobin at Week 24 | -0.08 picograms | Standard Deviation 0.83 |
Secondary
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
Population: Safety population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean platelet volume at Week 24 | -0.01 femtoliters | Standard Deviation 0.711 |
| Placebo | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean corpuscle volume at Week 24 | 0.8 femtoliters | Standard Deviation 2.84 |
| SB-742457-15mg | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean corpuscle volume at Week 24 | 1.4 femtoliters | Standard Deviation 2.45 |
| SB-742457-15mg | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean platelet volume at Week 24 | -0.04 femtoliters | Standard Deviation 0.626 |
| SB-742457-35mg | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean corpuscle volume at Week 24 | 0.6 femtoliters | Standard Deviation 2.35 |
| SB-742457-35mg | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean platelet volume at Week 24 | 0.13 femtoliters | Standard Deviation 0.715 |
| Donepezil | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean platelet volume at Week 24 | 0.03 femtoliters | Standard Deviation 0.627 |
| Donepezil | Change From Baseline in Hematology Parameter Mean Corpuscle Volume and Mean Platelet Volume at Week 24 | Mean corpuscle volume at Week 24 | 0.9 femtoliters | Standard Deviation 2.43 |
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24 | -0.03 trillion cells per liter | Standard Deviation 0.276 |
| SB-742457-15mg | Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24 | 0.01 trillion cells per liter | Standard Deviation 0.256 |
| SB-742457-35mg | Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24 | -0.08 trillion cells per liter | Standard Deviation 0.329 |
| Donepezil | Change From Baseline in Hematology Parameter Red Blood Cell Count at Week 24 | -0.07 trillion cells per liter | Standard Deviation 0.262 |
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Total neutrophils at Week 24 | 0.002 giga cells per liter | Standard Deviation 1.2619 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Platelet count at Week 24 | -4.8 giga cells per liter | Standard Deviation 33.13 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Segmented neutrophils at Week 24 | 0.002 giga cells per liter | Standard Deviation 1.2619 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Eosinophils at Week 24 | -0.011 giga cells per liter | Standard Deviation 0.0923 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | White blood cell count at Week 24 | -0.05 giga cells per liter | Standard Deviation 1.357 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Lymphocytes at Week 24 | -0.037 giga cells per liter | Standard Deviation 0.4182 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Monocytes at Week 24 | -0.002 giga cells per liter | Standard Deviation 0.1415 |
| Placebo | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Basophils at Week 24 | 0.001 giga cells per liter | Standard Deviation 0.0168 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Eosinophils at Week 24 | -0.006 giga cells per liter | Standard Deviation 0.0858 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Total neutrophils at Week 24 | 0.015 giga cells per liter | Standard Deviation 1.3909 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | White blood cell count at Week 24 | -0.08 giga cells per liter | Standard Deviation 1.551 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Basophils at Week 24 | 0.002 giga cells per liter | Standard Deviation 0.0189 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Monocytes at Week 24 | -0.007 giga cells per liter | Standard Deviation 0.1403 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Segmented neutrophils at Week 24 | 0.015 giga cells per liter | Standard Deviation 1.3909 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Lymphocytes at Week 24 | -0.075 giga cells per liter | Standard Deviation 0.4373 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Platelet count at Week 24 | -8.7 giga cells per liter | Standard Deviation 32.33 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | White blood cell count at Week 24 | 0.01 giga cells per liter | Standard Deviation 1.295 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Lymphocytes at Week 24 | -0.151 giga cells per liter | Standard Deviation 0.3949 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Total neutrophils at Week 24 | 0.163 giga cells per liter | Standard Deviation 1.2329 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Basophils at Week 24 | 0.003 giga cells per liter | Standard Deviation 0.0183 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Segmented neutrophils at Week 24 | 0.163 giga cells per liter | Standard Deviation 1.2329 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Platelet count at Week 24 | -5.3 giga cells per liter | Standard Deviation 36.83 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Monocytes at Week 24 | 0.000 giga cells per liter | Standard Deviation 0.1643 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Eosinophils at Week 24 | -0.004 giga cells per liter | Standard Deviation 0.1272 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | White blood cell count at Week 24 | -0.17 giga cells per liter | Standard Deviation 1.288 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Total neutrophils at Week 24 | -0.110 giga cells per liter | Standard Deviation 1.155 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Basophils at Week 24 | -0.001 giga cells per liter | Standard Deviation 0.0173 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Eosinophils at Week 24 | -0.004 giga cells per liter | Standard Deviation 0.0997 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Monocytes at Week 24 | -0.008 giga cells per liter | Standard Deviation 0.1306 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Platelet count at Week 24 | -9.4 giga cells per liter | Standard Deviation 36.13 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Segmented neutrophils at Week 24 | -0.109 giga cells per liter | Standard Deviation 1.1543 |
| Donepezil | Change From Baseline in Hematology Parameters Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Segmented Neutrophils, Total Neutrophils, White Blood Cell Count at Week 24 | Lymphocytes at Week 24 | -0.047 giga cells per liter | Standard Deviation 0.5084 |
Secondary
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
Population: Safety population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Hemoglobin at Week 24 | -1.1 grams per liter | Standard Deviation 7.24 |
| Placebo | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Mean corpuscle hemoglobin concentration at Week 24 | -5.3 grams per liter | Standard Deviation 8.99 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Mean corpuscle hemoglobin concentration at Week 24 | -5.9 grams per liter | Standard Deviation 9.74 |
| SB-742457-15mg | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Hemoglobin at Week 24 | -1.6 grams per liter | Standard Deviation 7.4 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Hemoglobin at Week 24 | -1.8 grams per liter | Standard Deviation 8.06 |
| SB-742457-35mg | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Mean corpuscle hemoglobin concentration at Week 24 | -3.9 grams per liter | Standard Deviation 9.73 |
| Donepezil | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Hemoglobin at Week 24 | -1.6 grams per liter | Standard Deviation 7.55 |
| Donepezil | Change From Baseline in Hematology Parameters Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Week 24 | Mean corpuscle hemoglobin concentration at Week 24 | -4.2 grams per liter | Standard Deviation 9.64 |
Secondary
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
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MMSE Total Score at Week 24 | -0.3 Score on scale | Standard Error 0.29 |
| SB-742457-15mg | Change From Baseline in MMSE Total Score at Week 24 | -0.3 Score on scale | Standard Error 0.28 |
| SB-742457-35mg | Change From Baseline in MMSE Total Score at Week 24 | -0.1 Score on scale | Standard Error 0.29 |
| Donepezil | Change From Baseline in MMSE Total Score at Week 24 | 0.5 Score on scale | Standard Error 0.27 |
Comparison: MMSE Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.96695% CI: [-0.8, 0.8]ANCOVA
Comparison: MMSE Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.50595% CI: [-0.5, 1.1]ANCOVA
Comparison: MMSE Total score, Placebo Vs Donepezil at Week 24p-value: 0.04495% CI: [0, 1.6]ANCOVA
Secondary
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
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in RBANS Total Score at Week 12 | -6.7 Score on scale | Standard Error 1.16 |
| SB-742457-15mg | Change From Baseline in RBANS Total Score at Week 12 | -8.7 Score on scale | Standard Error 1.24 |
| SB-742457-35mg | Change From Baseline in RBANS Total Score at Week 12 | -5.9 Score on scale | Standard Error 1.11 |
| Donepezil | Change From Baseline in RBANS Total Score at Week 12 | -3.4 Score on scale | Standard Error 1.06 |
Comparison: RBANS total score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.25795% CI: [-5.2, 1.4]Mixed model repeated measures
Comparison: RBANS total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.5795% CI: [-2.2, 4]Mixed model repeated measures
Comparison: RBANS total score, Placebo Vs Donepzil at Week 12p-value: 0.03195% CI: [0.3, 6.4]Mixed model repeated measures
Secondary
Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24
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 24.
Time frame: Baseline (Week 0) and Week 24
Population: ITT population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -2.3 Score on scale | Standard Error 1.44 |
| SB-742457-15mg | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -4.0 Score on scale | Standard Error 1.42 |
| SB-742457-35mg | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -4.4 Score on scale | Standard Error 1.49 |
| Donepezil | Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | -0.3 Score on scale | Standard Error 1.21 |
Comparison: RBANS Total Score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.42395% CI: [-5.6, 2.3]Mixed model repeated measures
Comparison: RBANS Total Score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.30595% CI: [-6.1, 1.9]Mixed model repeated measures
Comparison: RBANS Total Score, Placebo Vs Donepezil at Week 24p-value: 0.28295% CI: [-1.7, 5.7]Mixed model repeated measures
Secondary
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
Population: ITT population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CIBIC+ Score at Week 12 | 3.9 Score on scale | Standard Error 0.08 |
| SB-742457-15mg | CIBIC+ Score at Week 12 | 4.0 Score on scale | Standard Error 0.08 |
| SB-742457-35mg | CIBIC+ Score at Week 12 | 3.9 Score on scale | Standard Error 0.09 |
| Donepezil | CIBIC+ Score at Week 12 | 3.7 Score on scale | Standard Error 0.08 |
Comparison: CIBIC+ Score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.3295% CI: [-0.1, 0.3]Mixed model repeated measures
Comparison: CIBIC+ Score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.92795% CI: [-0.2, 0.2]Mixed model repeated measures
Comparison: CIBIC+ Score, Placebo Vs Donepzil at Week 12p-value: 0.05995% CI: [-0.4, 0]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 16-26) which comprised of participants who had a baseline MMSE score of 16-26. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | MMSE Score 16-26 on ADAS-Cog total score | -1.3 Score on scale | Standard Error 0.55 |
| Placebo | 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 | MMSE Score 16-26 on RBANS total score | -1.3 Score on scale | Standard Error 1.61 |
| SB-742457-15mg | 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 | MMSE Score 16-26 on RBANS total score | -2.4 Score on scale | Standard Error 1.74 |
| SB-742457-15mg | 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 | MMSE Score 16-26 on ADAS-Cog total score | 0.1 Score on scale | Standard Error 0.66 |
| SB-742457-35mg | 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 | MMSE Score 16-26 on RBANS total score | -2.8 Score on scale | Standard Error 1.82 |
| SB-742457-35mg | 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 | MMSE Score 16-26 on ADAS-Cog total score | -0.4 Score on scale | Standard Error 0.73 |
| Donepezil | 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 | MMSE Score 16-26 on RBANS total score | 1.1 Score on scale | Standard Error 1.52 |
| Donepezil | 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 | MMSE Score 16-26 on ADAS-Cog total score | -1.0 Score on scale | Standard Error 0.53 |
Comparison: Baseline MMSE score of 16-26 on ADAS-Cog Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.09695% CI: [-0.3, 3.1]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on ADAS-Cog Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.28195% CI: [-0.8, 2.8]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on ADAS-Cog Total score, Placebo Vs Donepezil at Week 24p-value: 0.6395% CI: [-1.1, 1.9]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on RBANS Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.65595% CI: [-5.7, 3.6]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on RBANS Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.54595% CI: [-6.2, 3.3]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on RBANS Total score, Placebo Vs Donepezil at Week 24p-value: 0.2795% CI: [-1.9, 6.8]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 10-20). Only those participants available at the specified time-points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | MMSE Score 10-20 on ADAS-Cog total score | 0.4 Score on scale | Standard Error 0.51 |
| Placebo | 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 | MMSE Score 10-20 on RBANS total score | -6.4 Score on scale | Standard Error 1.36 |
| SB-742457-15mg | 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 | MMSE Score 10-20 on RBANS total score | -10.0 Score on scale | Standard Error 1.29 |
| SB-742457-15mg | 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 | MMSE Score 10-20 on ADAS-Cog total score | 0.4 Score on scale | Standard Error 0.61 |
| SB-742457-35mg | 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 | MMSE Score 10-20 on ADAS-Cog total score | 0.2 Score on scale | Standard Error 0.6 |
| SB-742457-35mg | 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 | MMSE Score 10-20 on RBANS total score | -6.8 Score on scale | Standard Error 1.26 |
| Donepezil | 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 | MMSE Score 10-20 on ADAS-Cog total score | -0.9 Score on scale | Standard Error 0.51 |
| Donepezil | 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 | MMSE Score 10-20 on RBANS total score | -1.7 Score on scale | Standard Error 1.2 |
Comparison: Baseline MMSE score of 10-20 on ADAS-Cog Total score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.90895% CI: [-1.5, 1.7]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on ADAS-Cog Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.82695% CI: [-1.7, 1.4]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on ADAS-Cog Total score, Placebo Vs Donepezil at Week 12p-value: 0.08895% CI: [-2.7, 0.2]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on RBANS Total score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.05395% CI: [-7.3, 0]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on RBANS Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.84895% CI: [-4, 3.3]Mixed Models Analysis
Comparison: Baseline MMSE score of 10-20 on RBANS Total score, Placebo Vs Donepezil at Week 12p-value: 0.01195% CI: [1.1, 8.2]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 10-20) which comprised of participants who had a baseline MMSE score of 16-26. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | MMSE Score 10-20 on ADAS-Cog total score | 0.0 Score on scale | Standard Error 0.71 |
| Placebo | 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 | MMSE Score 10-20 on RBANS total score | -3.7 Score on scale | Standard Error 1.79 |
| SB-742457-15mg | 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 | MMSE Score 10-20 on ADAS-Cog total score | 1.6 Score on scale | Standard Error 0.76 |
| SB-742457-15mg | 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 | MMSE Score 10-20 on RBANS total score | -5.8 Score on scale | Standard Error 1.73 |
| SB-742457-35mg | 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 | MMSE Score 10-20 on ADAS-Cog total score | 1.3 Score on scale | Standard Error 0.73 |
| SB-742457-35mg | 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 | MMSE Score 10-20 on RBANS total score | -4.8 Score on scale | Standard Error 1.68 |
| Donepezil | 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 | MMSE Score 10-20 on RBANS total score | -1.0 Score on scale | Standard Error 1.44 |
| Donepezil | 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 | MMSE Score 10-20 on ADAS-Cog total score | -0.1 Score on scale | Standard Error 0.58 |
Comparison: Baseline MMSE score of 10-20 on ADAS-Cog Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.13895% CI: [-0.5, 3.6]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on ADAS-Cog Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.21695% CI: [-0.7, 3.2]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on ADAS-Cog Total score, Placebo Vs Donepezil at Week 24p-value: 0.92195% CI: [-1.9, 1.7]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on RBANS Total score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.4195% CI: [-7, 2.9]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on RBANS Total score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.66795% CI: [-5.9, 3.8]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on RBANS Total score, Placebo Vs Donepezil at Week 24p-value: 0.24695% CI: [-1.9, 7.2]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 10-20). Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12 | 4.0 Score on scale | Standard Error 0.1 |
| SB-742457-15mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12 | 4.1 Score on scale | Standard Error 0.1 |
| SB-742457-35mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12 | 4.1 Score on scale | Standard Error 0.11 |
| Donepezil | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 12 | 3.7 Score on scale | Standard Error 0.11 |
Comparison: Baseline MMSE score of 10-20 on CIBIC+ score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.36995% CI: [-0.2, 0.4]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on CIBIC+ Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.5595% CI: [-0.2, 0.4]Mixed model repeated measures
Comparison: Baseline MMSE score of 10-20 on CIBIC+ Total score, Placebo Vs Donepezil at Week 12p-value: 0.08295% CI: [-0.5, 0]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 10-20). Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24 | 4.2 Score on scale | Standard Error 0.15 |
| SB-742457-15mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24 | 4.4 Score on scale | Standard Error 0.13 |
| SB-742457-35mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24 | 4.1 Score on scale | Standard Error 0.12 |
| Donepezil | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 10-20) on the CIBIC+ Score at Week 24 | 3.9 Score on scale | Standard Error 0.12 |
Comparison: Baseline MMSE score of 16-26 on CBIC+, Placebo Vs SB-742457-15mg at Week 24p-value: 0.29595% CI: [-0.2, 0.6]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on CBIC+, Placebo Vs SB-742457-35mg at Week 24p-value: 0.49595% CI: [-0.5, 0.2]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on CBIC+, Placebo Vs Donepezil at Week 24p-value: 0.16695% CI: [-0.6, 0.1]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 16-26). Only those participants available at the specified time-points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | MMSE Score 16-26 on ADAS-Cog total score | -0.6 Score on scale | Standard Error 0.48 |
| Placebo | 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 | MMSE Score 16-26 on RBANS total score | -7.5 Score on scale | Standard Error 1.28 |
| SB-742457-15mg | 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 | MMSE Score 16-26 on ADAS-Cog total score | -0.4 Score on scale | Standard Error 0.47 |
| SB-742457-15mg | 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 | MMSE Score 16-26 on RBANS total score | -8.3 Score on scale | Standard Error 1.51 |
| SB-742457-35mg | 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 | MMSE Score 16-26 on ADAS-Cog total score | -0.5 Score on scale | Standard Error 0.52 |
| SB-742457-35mg | 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 | MMSE Score 16-26 on RBANS total score | -4.4 Score on scale | Standard Error 1.35 |
| Donepezil | 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 | MMSE Score 16-26 on RBANS total score | -3.3 Score on scale | Standard Error 1.31 |
| Donepezil | 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 | MMSE Score 16-26 on ADAS-Cog total score | -0.5 Score on scale | Standard Error 0.42 |
Comparison: Baseline MMSE score of 16-26 on ADAS-Cog Total score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.79895% CI: [-1.1, 1.5]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on ADAS-Cog Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.91895% CI: [-1.3, 1.4]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on ADAS-Cog Total score, Placebo Vs Donepezil at Week 12p-value: 0.92495% CI: [-1.2, 1.3]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on RBANS Total score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.67695% CI: [-4.7, 3]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on RBANS Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.08695% CI: [-0.4, 6.7]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on RBANS Total score, Placebo Vs Donepezil at Week 12p-value: 0.02195% CI: [0.6, 7.7]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 16-26). Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12 | 3.8 Score on scale | Standard Error 0.08 |
| SB-742457-15mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12 | 3.8 Score on scale | Standard Error 0.09 |
| SB-742457-35mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12 | 3.7 Score on scale | Standard Error 0.1 |
| Donepezil | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 12 | 3.6 Score on scale | Standard Error 0.08 |
Comparison: Baseline MMSE score of 16-26 on CIBIC+ score, Placebo Vs SB-742457-15mg at Week 12p-value: 0.67195% CI: [-0.2, 0.3]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on CIBIC+ Total score, Placebo Vs SB-742457-35mg at Week 12p-value: 0.41395% CI: [-0.4, 0.2]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on CIBIC+ Total score, Placebo Vs Donepezil at Week 12p-value: 0.24595% CI: [-0.4, 0.1]Mixed model repeated measures
Secondary
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
Population: Intent-to-Treat (Baseline MMSE 16-26). Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24 | 3.8 Score on scale | Standard Error 0.12 |
| SB-742457-15mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24 | 4.0 Score on scale | Standard Error 0.12 |
| SB-742457-35mg | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24 | 3.7 Score on scale | Standard Error 0.11 |
| Donepezil | Effect of Baseline Severity (Including Subgroup Analyses Based on Baseline MMSE Scores 16-26) on the CIBIC+ Score at Week 24 | 3.5 Score on scale | Standard Error 0.11 |
Comparison: Baseline MMSE score of 16-26 on CBIC+ score, Placebo Vs SB-742457-15mg at Week 24p-value: 0.14695% CI: [-0.1, 0.6]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on CBIC+ score, Placebo Vs SB-742457-35mg at Week 24p-value: 0.73395% CI: [-0.4, 0.3]Mixed model repeated measures
Comparison: Baseline MMSE score of 16-26 on CBIC+ score, Placebo Vs Donepezil at Week 24p-value: 0.14595% CI: [-0.5, 0.1]Mixed model repeated measures
Secondary
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
Population: Pharmacokinetic concentration population. Only those participants with data available at the time of analysis were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss) | 17.53 nanograms per milliliter | Geometric Coefficient of Variation 50.51 |
| SB-742457-15mg | Exposure Estimates for Donepezil Average Concentration at Steady State (Cavgss) | 31.80 nanograms per milliliter | Geometric Coefficient of Variation 60.14 |
Secondary
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
Population: Pharmacokinetic concentration population comprised of all participants for whom a pharmacokinetic sample was obtained and analyzed. Only those participants with data available at the time of analysis were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss) | 1434.89 nanograms hour per milliliter | Geometric Coefficient of Variation 36.04 |
| SB-742457-15mg | Exposure Estimates for SB-742457 Area Under Curve Over the Dosing Interval at Steady State (AUCτss) | 3424.91 nanograms hour per milliliter | Geometric Coefficient of Variation 38.04 |
Secondary
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
Population: Pharmacokinetic concentration population. Only those participants with data available at the time of analysis were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss) | 46.03 nanograms per milliliter | Geometric Coefficient of Variation 109.69 |
| SB-742457-15mg | Exposure Estimates for SB-742457 Minimum Concentration at Steady State (Cmin-ss) | 37.47 nanograms per milliliter | Geometric Coefficient of Variation 39.47 |
Secondary
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
Population: Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any SAE | 7 Participants |
| Placebo | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any AE | 45 Participants |
| SB-742457-15mg | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any AE | 42 Participants |
| SB-742457-15mg | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any SAE | 7 Participants |
| SB-742457-35mg | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any AE | 39 Participants |
| SB-742457-35mg | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any SAE | 3 Participants |
| Donepezil | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any SAE | 10 Participants |
| Donepezil | Number of Participants With Any Adverse Event (Serious and Non-serious) and Serious Adverse Events (SAEs) | Any AE | 65 Participants |
Secondary
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
Population: Safety population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Potassium, ATOT, high | 5 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Low Density Lipoprotein Cholesterol, ATOT, high | 21 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Cholesterol, ATOT, high | 5 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Total Bilirubin, ATOT, high | 1 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Carbon dioxide content/Bicarbonate, ATOT, low | 1 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Creatinine, ATOT, high | 3 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Gamma Glutamyl Transferase, ATOT, high | 3 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Triglycerides, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Aspartate Amino Transferase, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Blood urea nitrogen/Creatinine ratio, ATOT, high | 1 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, high | 27 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Urea/Blood urea nitrogen, ATOT, high | 7 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Creatine Kinase, ATOT, high | 3 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, low | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Direct Bilirubin, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Calcium, ATOT, low | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Lactate Dehydrogenase, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Alanine Amino Transferase, ATOT, high | 2 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Alkaline Phosphatase, ATOT, high | 1 Participants |
| Placebo | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, low | 7 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Total Bilirubin, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Aspartate Amino Transferase, ATOT, high | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Calcium, ATOT, low | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Creatine Kinase, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Blood urea nitrogen/Creatinine ratio, ATOT, high | 4 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Carbon dioxide content/Bicarbonate, ATOT, low | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Potassium, ATOT, high | 5 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Cholesterol, ATOT, high | 5 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, low | 5 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, low | 2 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, high | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Gamma Glutamyl Transferase, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Lactate Dehydrogenase, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Low Density Lipoprotein Cholesterol, ATOT, high | 26 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Triglycerides, ATOT, high | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Direct Bilirubin, ATOT, high | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Urea/Blood urea nitrogen, ATOT, high | 6 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, high | 16 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Alanine Amino Transferase, ATOT, high | 0 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Creatinine, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Chemistry Data of PCC ATOT | Alkaline Phosphatase, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, high | 23 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Low Density Lipoprotein Cholesterol, ATOT, high | 12 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Lactate Dehydrogenase, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Potassium, ATOT, high | 2 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, low | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Total Bilirubin, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Triglycerides, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Urea/Blood urea nitrogen, ATOT, high | 8 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Alanine Amino Transferase, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Alkaline Phosphatase, ATOT, high | 2 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Aspartate Amino Transferase, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Blood urea nitrogen/Creatinine ratio, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Calcium, ATOT, low | 1 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Carbon dioxide content/Bicarbonate, ATOT, low | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Cholesterol, ATOT, high | 2 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Creatine Kinase, ATOT, high | 5 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Creatinine, ATOT, high | 4 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Direct Bilirubin, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Gamma Glutamyl Transferase, ATOT, high | 4 Participants |
| SB-742457-35mg | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, low | 8 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, high | 22 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Creatine Kinase, ATOT, high | 7 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Alkaline Phosphatase, ATOT, high | 6 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Alanine Amino Transferase, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Glucose, ATOT, low | 6 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Creatinine, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Urea/Blood urea nitrogen, ATOT, high | 4 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Triglycerides, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Lactate Dehydrogenase, ATOT, high | 0 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Direct Bilirubin, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Total Bilirubin, ATOT, high | 2 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Low Density Lipoprotein Cholesterol, ATOT, high | 25 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Gamma Glutamyl Transferase, ATOT, high | 4 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Sodium, ATOT, low | 0 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Carbon dioxide content/Bicarbonate, ATOT, low | 0 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Calcium, ATOT, low | 0 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Potassium, ATOT, high | 7 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Cholesterol, ATOT, high | 7 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Blood urea nitrogen/Creatinine ratio, ATOT, high | 3 Participants |
| Donepezil | Number of Participants With Chemistry Data of PCC ATOT | Aspartate Amino Transferase, ATOT, high | 1 Participants |
Secondary
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
Population: Safety population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ANCS | 58 Participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Central cardiologist interpretation abnormal | 49 Participants |
| Placebo | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ACS | 0 Participants |
| SB-742457-15mg | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ANCS | 60 Participants |
| SB-742457-15mg | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Central cardiologist interpretation abnormal | 51 Participants |
| SB-742457-15mg | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ACS | 1 Participants |
| SB-742457-35mg | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ACS | 0 Participants |
| SB-742457-35mg | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ANCS | 59 Participants |
| SB-742457-35mg | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Central cardiologist interpretation abnormal | 51 Participants |
| Donepezil | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ANCS | 67 Participants |
| Donepezil | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Central cardiologist interpretation abnormal | 59 Participants |
| Donepezil | Number of Participants With Electrocardiogram (ECG) Findings as Assessed by Investigator and Central Cardiologist | Investigator interpretion ACS | 2 Participants |
Secondary
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
Population: Safety population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Hematocrit, ATOT, low | 1 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, low | 4 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, high | 0 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, low | 2 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, high | 1 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Monocytes, ATOT, low | 17 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Hemoglobin, ATOT. low | 2 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, low | 2 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, low | 2 Participants |
| Placebo | Number of Participants With Hematology Data of PCC ATOT | Platelet count, ATOT, low | 3 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Hemoglobin, ATOT. low | 1 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, low | 1 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, high | 3 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Hematocrit, ATOT, low | 0 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, low | 0 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, high | 1 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Platelet count, ATOT, low | 2 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, low | 5 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, high | 2 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, low | 1 Participants |
| SB-742457-15mg | Number of Participants With Hematology Data of PCC ATOT | Monocytes, ATOT, low | 10 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, high | 1 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Hematocrit, ATOT, low | 0 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Hemoglobin, ATOT. low | 2 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, high | 0 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Monocytes, ATOT, low | 9 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Platelet count, ATOT, low | 2 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, low | 0 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, high | 1 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, low | 0 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, low | 3 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, low | 1 Participants |
| SB-742457-35mg | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, high | 0 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Lymphocytes, ATOT, low | 2 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, low | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Hemoglobin, ATOT. low | 6 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Hematocrit, ATOT, low | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Total neutrophils, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, low | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Platelet count, ATOT, low | 2 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | White blood cell count, ATOT, low | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Segmented neutrophils, ATOT, high | 1 Participants |
| Donepezil | Number of Participants With Hematology Data of PCC ATOT | Monocytes, ATOT, low | 24 Participants |
Secondary
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
Population: Safety population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, IFB>=7% | 4 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and DFB >=20 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP orthostatic, fall in SBP >30 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP orthostatic, fall in SBP >20 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR standing ATOT <50 or >100 and IFB >=30 | 1 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, DFB>=7% | 6 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and IFB >=30 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and DFB >=20 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP sitting ATOT <90 or > 140 and IFB >=40 | 1 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and DFB >=30 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR orthostatic, increase in HR>= >20 | 5 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and IFB >=40 | 0 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and IFB >=30 | 2 Participants |
| Placebo | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR sitting ATOT <50 or >100 and DFB >=30 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, IFB>=7% | 4 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and DFB >=30 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and IFB >=30 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and DFB >=20 | 1 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and DFB >=20 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, DFB>=7% | 8 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP orthostatic, fall in SBP >30 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP orthostatic, fall in SBP >20 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR sitting ATOT <50 or >100 and DFB >=30 | 1 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and IFB >=30 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR standing ATOT <50 or >100 and IFB >=30 | 0 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR orthostatic, increase in HR>= >20 | 2 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and IFB >=40 | 3 Participants |
| SB-742457-15mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP sitting ATOT <90 or > 140 and IFB >=40 | 2 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR orthostatic, increase in HR>= >20 | 2 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and IFB >=40 | 3 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and DFB >=30 | 0 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and IFB >=30 | 1 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and DFB >=20 | 0 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and IFB >=30 | 2 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and DFB >=20 | 0 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP orthostatic, fall in SBP >20 | 1 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR sitting ATOT <50 or >100 and DFB >=30 | 0 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, IFB>=7% | 6 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, DFB>=7% | 5 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP sitting ATOT <90 or > 140 and IFB >=40 | 2 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP orthostatic, fall in SBP >30 | 3 Participants |
| SB-742457-35mg | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR standing ATOT <50 or >100 and IFB >=30 | 0 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and DFB >=20 | 1 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP orthostatic, fall in SBP >20 | 1 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and DFB >=30 | 4 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP standing ATOT <90 or > 140 and IFB >=40 | 1 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR standing ATOT <50 or >100 and IFB >=30 | 0 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, DFB>=7% | 10 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR sitting ATOT <50 or >100 and DFB >=30 | 0 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | HR orthostatic, increase in HR>= >20 | 6 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP standing ATOT <50 or > 90 and IFB >=30 | 0 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and IFB >=30 | 1 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | Weight, IFB>=7% | 6 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP orthostatic, fall in SBP >30 | 1 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | SBP sitting ATOT <90 or > 140 and IFB >=40 | 0 Participants |
| Donepezil | Number of Participants With Vital Signs Data of Potential Clinical Concern (PCC) Any Time on Treatment (ATOT) | DBP sitting ATOT <50 or > 90 and DFB >=20 | 0 Participants |