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

Study Overview
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Brief Summary
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The study is designed to investigate the safety and efficacy of SB-742457 when added to stable donepezil treatment in subjects with mild-to-moderate Alzheimer's disease.

Official Title
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Study AZ3110866, a Fixed Dose Study of SB-742457 Versus Placebo When Added to Existing Donepezil Treatment in Subjects With Mild-to-moderate Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: SB-742457 15mg
* Drug: SB-742457 35mg
* Drug: Placebo
* Drug: donepezil 5-10mg


Participation Criteria
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Eligibility Criteria
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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 no evidence of disorders that are thought to be the cause of, or contributing to the severity of the subject's dementia and a documented history of at least 6 months of ongoing donepezil therapy with stable dosing for at least the last 2 months. 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 abstinence or an approved form of birth control. Subjects must have adequate blood pressure and laboratory values. Exclusion Criteria: Subjects with a diagnosis of possible, probable or definite vascular dementia may not participate. Subjects with known hypersensitivity to sunlight or a history of seizures, 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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DONEPEZIL + SB-742457 15 MG<br>SB-742457 - 15mg added to existing donepezil treatment | Drug: SB-742457 15mg<br>* SB-742457 - 15mg added to existing donepezil treatment<br>Drug: donepezil 5-10mg<br>* existing donepezil treatment<br>|
| Placebo Comparator: DONEPEZIL + PLACEBO<br>Placebo added to existing donepezil | Drug: Placebo<br>* Placebo added to existing donepezil<br>Drug: donepezil 5-10mg<br>* existing donepezil treatment<br>|
| Experimental: DONEPEZIL + SB-742457 35 MG<br>SB-742457 - 35mg added to existing donepezil | Drug: SB-742457 35mg<br>* SB-742457 - 35mg added to existing donepezil<br>Drug: donepezil 5-10mg<br>* existing donepezil treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score at Week 24 | ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the case report form (CRF) for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean is presented. | Baseline(Week 0) and Week 24 | 
| Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score at Week 24 | The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. | Baseline(Week 0) and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Score at Week 24 | RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. | Baseline (Week 0) and Week 24 | 
| Change From Baseline in ADAS-Cog Total Score at Week 12, 36 and 48 | ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicated greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores recorded on the CRF for questions 3 to 6 and 8 to 11. In cases where more than one question was missing, a total score was not be imputed. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been present | Baseline (Week 0) and Week 12, 36 and 48 | 
| Change From Baseline in CDR-SB Score at Week 12, 36 and 48 | The CDR-SB is an interviewer administered scale and impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18 (severe impairment). If there were any missing items then CDR-SB was set to missing and was not imputed. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. | Baseline (Week 0) and Week 12, 36, 48 | 
| Change From Baseline in RBANS Score at Week 12, 36 and 48 | RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. | Baseline (Week 0) and Week 12, 36 and 48 | 
| Change From Baseline in Alzheimer's Disease Co-operative Study Group - Activities of Daily Living Inventory (ADCS- ADL) Total Score at Weeks 12, 24, 36 and 48 | The ADCS-ADL is an interviewer-administered informant-based scale where the informant (caregiver) responds to 23 activities of daily living questions about the participant. The questions ranged from basic to instrumental activities of daily living and take approximately 20 minutes to complete. The Total score ranges from 0-78 and a higher score signified greater functional ability. The questionnaire was split into two types of questions, an initial question relating to whether a participant had completed a particular activity and then a follow on question which scored how much assistance the participant had required if they had performed that particular activity. The total score was calculated by adding up the responses for each of the individual activities. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. | Baseline (Week 0) and Week 12, 24, 36 and 48 | 
| Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 24 and 48 | The MMSE consisted of 11 items covering orientation, memory (recent and immediate), concentration, language and praxis. Scores ranged from 0 to 30, with lower scores indicating greater cognitive impairment. Scores for each of the 11 individual tests were not recorded on the CRF, therefore if any item was missing then the total score was be set to missing. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. Baseline was Week 0 value. Data for adjusted mean has been presented. | Baseline (Week 0) and Week 24 and 48 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During Treatment Phase | An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to follow-up i.e. 2 weeks post end of treatment (Week 24, Week 48 or Early Withdrawal) | 
| Number of Participants With Parameters of Clinical Concern - Hematology | Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Eosinophils (high-2), Hematocrit (low- 0.8, high-1.2), Lymphocytes (low-0.75, high-1.5), Mean Corpuscle Hemoglobin (MCH) (low-0.8, high-1.2), Monocytes(low-0.75, high-2), Neutrophil bands (high-10), Platelet count (low-100, high-500), Segmented Neutrophils (low-0.75, high-1.3), Total Neutrophils (low-0.75, high-1.5), and white blood cells (WBC) (low-3, high-15). | Up to Week 48 | 
| Number of Participants With Parameters of Clinical Concern - Clinical Chemistry | Only parameters with values have been presented. Data has been reported for number of participants with high and/ or low values for Alanine Amino Transferase (ALT) (high-1.5), Alkaline Phosphatase (high-1.5), Aspartate Amino Transferase (ASAT) (high-1.5), BUN/Creatinine ratio (high-1.5), Calcium (low- 0.75, high-1.25), Carbon dioxide content/Bicarbonate (low-15, high- 40), Cholesterol (high-1.25), Creatine Kinase ((low- 0.5, high-1.25), Creatinine (low- 0.5, high-1.25), Direct Bilirubin (high-1.5), Gamma Glutamyl Transferase (GGT) (high-2), Glucose (low- 3.6, high-7.8), HDL Cholesterol (low-0.65), LDL Cholesterol (hig-1.25), Magnesium (low-0.5, high-2), Phosphorus inorganic (low- 0.5, high-1.5), Potassium (low- 3, high-5.5), Sodium (low- 130, high-150), Total Bilirubin (high-1.5), Triglycerides (high -4) and Urea/BUN (high-11). | Up to Week 48 | 
| Exposure Estimates for SB-742457 : Area Under the Concentration Time Curve Over the Dosing Interval at Steady State (AUCτss) | AUCτss of SB-742457 was estimated via nonlinear mixed effect analysis. This pharmacokinetic(PK) model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution. | Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48 | 
| Exposure Estimates for SB-742457 : Minimum Concentrations at Steady State (Cmin-ss) | Cmin-ss was estimated via nonlinear mixed effect analysis. This PK model was a steady state one compartment model with first-order absorption, with between participant variability on clearance and volume of distribution. | Post-dose at 3, 8 and 24 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48 | 
| Exposure Estimates for Donepezil (Cavgss) | Participants who were on donepezil (at least 6 months and a stable regimen for at least 2 months) were allowed to participate in this study. Cavgss for donepezil approximately 12 to 20 hours after dosing were summarized by donepezil dose level 5 mg/7.5 mg/10 mg/15 mg. | Post-dose at 12 to 20 hours on Week 0, 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48 | 
| Change From Baseline in ADAS-Cog Scale in Participants With APOE4 Gene | Genetic analyses was conducted to assess the effect of APOE4 carriage. ADAS-cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a five-point scale. There were in all 11 questions. Total scores were calculated as the sum of the individual components. Scores ranged from 0 to 70 with higher scores indicating greater dysfunction. The ADAS-Cog total score was the sum of the calculated scores for questions 1, 2, and 7, and the scores were recorded on the CRF for questions 3 to 6 and 8 to 11. When a score was missing for one of the questions, the total score was calculated as a weighted average of the scores provided for the remaining ten questions. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. | Baseline (Week 0) to Week 24 and Week 48 | 
| Change From Baseline in CDR-SB Scale in Participants With APOE4 Gene | Genetic analyses was conducted to assess the effect of APOE4 carriage. The CDR-SB is an interviewer administered scale and impairment is scored in following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment was scored on a scale in which none =0, questionable =0.5, mild =1, moderate =2 and severe =3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher score indicating severe impairment. If there were any missing items then CDR-SB was set to missing and was not imputed. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. | Baseline (Week 0) to Week 24 and Week 48 | 
| Change From Baseline in RBANS Scale in Participants With APOE4 Gene | Genetic analyses was conducted to assess the effect of APOE4 carriage. RBANS is an individually administered cognitive battery comprising 12 subtests across five domains (Attention, Language, Visuospatial/Constructional Abilities, and Immediate and Delayed memory). Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges between 0 and 311, where a low score indicates greater impairment. Baseline was Week 0 value. The change from Baseline was obtained by subtracting the Baseline value from the post-randomization value. | Baseline (Week 0) to Week 24 and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease cognition SB-742457