Alzheimer Disease
Conditions
Keywords
antibody, immunotherapy
Brief summary
This is a study to evaluate the efficacy and safety of multiple doses of bapineuzumab in patients with mild to moderate Alzheimer Disease. Patients will receive either bapineuzumab or placebo. Each patient's participation will last approximately 1.5 years.
Interventions
DRUGbapineuzumab
Bapineuzumab 0.5 mg/kg administered by IV infusion approximately every 13 weeks through week 65.
DRUGplacebo
Placebo will be administered by IV infusion approximately every 13 weeks through week 65.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of probable Alzheimer Disease (AD), with Mini Mental State Examination (MMSE) score of 16-26, and brain magnetic resonance imaging (MRI) consistent with the diagnosis of AD * Concurrent use of cholinesterase inhibitor or memantine allowed, if stable * Caregiver will participate and be able to attend clinic visits with patient
Exclusion criteria
* Significant neurological disease other than AD * Major psychiatric disorder * Contraindication to undergo brain MRI \[e.g., pacemaker, cerebrospinal fluid (CSF) shunt, or foreign metal objects in the body\] * Women of childbearing potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)/11 Total Score at Week 78 | 78 weeks | The ADAS-Cog is a multi-item, objective measure of cognitive function. The scale evaluates memory, language, and praxis with items such as orientation, word recall, word recognition, object identification, comprehension, and the completion of simple tasks. Analysis of the ADAS-Cog for this study was based upon an 11 item score from the following items 1) word recall task, 2) naming objects and fingers, 3) following commands, 4) constructional praxis, 5) ideational praxis, 6) orientation, 7) word recognition, 8) remembering test instructions, 9) spoken language ability, 10) word finding difficulty in spontaneous speech, and 11) comprehension. This scale had to be administered by a trained and certified psychometric rater who did not have access to any information regarding adverse events experienced. The ADAS-Cog/11 ranged from 0 to 70 points, with higher scores indicating a greater degree of impairment. A negative change from baseline indicates a decrease in cognitive impairment. |
| The Change From Baseline in the Disability Assessment for Demential (DAD) Total Score at Week 78 | 78 weeks | The DAD measures instrumental and basic activities of daily living in participants with Alzheimer's Disease (AD). The DAD is administered to the participants'caregiver in the form of an interview. This scale had to be administered by a trained and certified global rater who did not have access to any information regarding adverse events experienced by the participant. This scale assesses a participants' ability to initiate, plan, and perform activities related to hygiene, dressing, continence, eating, meal preparation, telephoning, going on an outing, finance and correspondence, medications, leisure, and housework. Each item can be scored as 1 = yes, 0 = no, non applicable = NA. A total score is obtained by adding the rating for each question and converting this total score out of 100. Higher scores indicate better function; a positive change from baseline indicates an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline in Brain Volume at Week 71 | 71 Weeks | Brain volume was examined in a subset of participants by Magnetic Resonance Imaging Brain Boundary Shift Integral (MRI BBSI). Cerebral atrophy correlates closely with the gradual cognitive decline in AD and can be visualized by MRI. The BBSI technique involves positional matching of serial 3-dimensional MRI brain images, such that brain MRI-image volumes were first registered and then subtracted from each other. Atrophy rates would generally be expected to be lower if the underlying disease was attenuated by effective treatment. |
| Divergence of Effect on the ADAS-Cog/11 Total Scores From Week 39 to Week 78 | 39 Weeks | The MMRM estimated slope (based on linear contrasts) of the differences between bapineuzumab and placebo for the ADAS-Cog/11 total scores from Week 39 to Week 78 was presented. |
| Divergence of Effect on the DAD Total Scores From Week 39 to Week 78 | 39 weeks | The MMRM estimated slope (based on linear contrasts)of the differences between bapineuzumab and placebo for the DAD total scores from Week 39 to Week 78 was presented. |
| Time to Median Placebo Deterioration on ADAS-Cog/11 Total Score (European Union [EU] Analysis Plan) | 78 Weeks | The time to first median placebo deterioration (for the EU) was defined as the first time a subject experienced an increase from baseline (worsening) in ADAS Cog/11 total score greater than or equal to the median worsening observed at Week 78 in the placebo group. The Kaplan Meier estimate of the median time to first median placebo deterioration in ADAS Cog/11 total score was presented. |
| Time to First Clinically Meaningful Deterioration on ADAS-Cog/11 Total Score (United States [US] Analysis Plan) | 78 weeks | The time to first clinically meaningful deterioration (for the US) was defined as the first time a participant experienced an increase (worsening) from baseline in ADAS-Cog/11 total score of \>=7. |
| Time to Median Placebo Deterioration on DAD Total Score | 78 Weeks | The time to first median placebo deterioration (for the EU) was defined as the first time a participant experienced a decrease (worsening) in DAD total score greater than or equal to the median worsening at Week 78 in the placebo group. |
| The Change From Baseline in Brain Amyloid Burden at Week 71. | 71 Weeks | Brain amyloid burden as imaged by 11C-Pittsburgh compound B (PiB) positron emission tomography (PET). The latter is a semiquantitative measure of the extent of fibrillar amyloid in the brain. PIB PET measurements were made in cortical regions found to have the highest burden of fibrillar amyloid at autopsy in participants diagnosed as having Alzheimer's pathology, and also regions reported to have the highest average retention of PIB signal in previous PET studies enrolling participants with probable AD. This parameter reflects overall brain amyloid deposition as indexed by imaging. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified regions of interest (ROI) assessed by PIB PET imaging in a subset of participants. |
| Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | 78 Weeks | Percentage of participants whose increase (worsening) in ADAS-Cog/11 total score from baseline to Week 78 was at most 0, 3, 7 points. |
| Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (US Analysis Plan) | 78 Weeks | Percentage of participants whose increase (worsening) from baseline to Week 78 in ADAS-Cog/11 total score is \<7. |
| Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | 78 Weeks | Percentage of participants whose decrease (worsening) from baseline to Week 78 in DAD total score was at most 0, 6, 12 points. |
| Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (US Analysis Plan) | 78 weeks | Percentage of participants whose decrease (worsening) from baseline to Week 78 in DAD total score was \<12. |
| Change From Baseline in Dependence Scale Total Score at Week 78 | 78 Weeks | The Dependence Scale (DS) is a 13-item, caregiver-rated instrument for determining the amount of support required by a participant with AD. The DS total score ranges from 0 to 15, with higher scores indicating more need for assistance. The DS was administered as an interview to the caregiver at scheduled study visits. |
| Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SOB) Total Score at Week 78 | 78 Weeks | The CDR-SOB is a global clinical staging instrument that sums 6 clinical ratings: 1) memory, 2) orientation, 3) judgment and problem solving, 4) involvement in community affairs, 5) home and hobbies, and 6) personal care based on the Clinical Dementia Rating Scale (CDR) interview. The CDR includes discussions with the participant and caregiver using a structured format. This scale had to be administered by a trained and certified global rater who did not have access to any information regarding adverse events experienced by the participant. CDR-SOB total score range is 0 (least impairment) to 18 (most impairment); a negative change from baseline indicates an improvement. |
| Time to First Clinically Meaningful Deterioration on DAD Total Score (US Analysis Plan) | 78 Weeks | The time to first clinically meaningful deterioration was defined as the first time a participant experienced a decrease (worsening)from baseline in DAD total score of \>=12. |
| The Change From Baseline in Phospho-tau Levels in the Cerebrospinal Fluid (CSF) at Week 71. | 71 Weeks | Biomarkers CSF phospho-tau (p-tau) is an indicator of neuronal injury and neurodegeneration. An elevation in levels of tau, as well as specific p-tau species, is thought to be a marker for progressive cellular degeneration in AD. Accordingly, a reduction from baseline in levels of CSF tau in participants who received bapineuzumab compared with participants who received placebo may be indicative of a reduction in neuronal loss in participants treated with bapineuzumab. |
Countries
Argentina, Australia, Belgium, Canada, Chile, Croatia, Finland, France, Germany, Italy, Japan, Mexico, Netherlands, New Zealand, Poland, Portugal, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was terminated on 06 August 2012 due to lack of clinical efficacy observed in completed studies ELN115727-301 (ApoE4 non-carriers) and ELN115727-302. A total of 329 participants had completed the study up to and including Week 78 before the decision was taken to terminate the study.
Pre-assignment details
The study originally included bapineuzumab 2.0 mg/kg dose level, which was discontinued on 02 April 2009 based on input from independent safety monitoring committee. It was estimated at the time that about 10 participants received 2.0mg/kg. These participants are not included in the efficacy analyses.
Participants by arm
| Arm | Count |
|---|---|
| Bapineuzumab 0.5 mg/kg Participants received 0.5 mg/kg bapineuzumab by IV infusion every 13 weeks, for a total of 6 infusions over the course of the study. A final follow-up visit was performed at Week 78, 13 weeks after the last infusion. | 267 |
| Bapineuzumab 1.0 mg/kg Participants received 1.0 mg/kg bapineuzumab by IV infusion every 13 weeks, for a total of 6 infusions over the course of the study. A final follow-up visit was performed at Week 78, 13 weeks after the last infusion. | 263 |
| Placebo Participants received placebo by IV infusion every 13 weeks, for a total of 6 infusions over the course of the study. A final follow-up visit was performed at Week 78, 13 weeks after the last infusion. | 344 |
| Bapineuzumab 2.0 mg/kg Participants received 2.0 mg/kg bapineuzumab by IV infusion every 13 weeks, for a total of 6 infusions over the course of the study. A final follow-up visit was performed at Week 78, 13 weeks after the last infusion. | 11 |
| Total | 885 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 14 | 19 | 1 |
| Overall Study | Death | 1 | 1 | 3 | 0 |
| Overall Study | Discontinuation of Study by Sponsor | 130 | 118 | 155 | 0 |
| Overall Study | Failed to Return | 0 | 0 | 2 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 2 | 0 |
| Overall Study | Loss of Caregiver | 0 | 1 | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 4 | 2 | 0 |
| Overall Study | Other | 6 | 6 | 5 | 0 |
| Overall Study | Physician Decision | 1 | 1 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 2 | 0 | 0 |
| Overall Study | Vasogenic Edema Recurrence | 0 | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 14 | 20 | 29 | 1 |
Baseline characteristics
| Characteristic | Bapineuzumab 0.5 mg/kg | Bapineuzumab 1.0 mg/kg | Placebo | Bapineuzumab 2.0 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 71.4 Years STANDARD_DEVIATION 9.38 | 70.8 Years STANDARD_DEVIATION 9.73 | 69.9 Years STANDARD_DEVIATION 9.76 | 66.5 Years STANDARD_DEVIATION 7.94 | 70.6 Years STANDARD_DEVIATION 9.63 |
| Age, Customized <65 years | 73 Years | 81 Years | 115 Years | 6 Years | 275 Years |
| Age, Customized ≥65 years | 194 Years | 182 Years | 229 Years | 5 Years | 610 Years |
| Sex: Female, Male Female | 151 Participants | 150 Participants | 199 Participants | 4 Participants | 504 Participants |
| Sex: Female, Male Male | 116 Participants | 113 Participants | 145 Participants | 7 Participants | 381 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 109 / 267 | 123 / 263 | 124 / 344 | 9 / 11 |
| serious Total, serious adverse events | 32 / 267 | 34 / 263 | 53 / 344 | 2 / 11 |
Outcome results
Primary
The Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)/11 Total Score at Week 78
The ADAS-Cog is a multi-item, objective measure of cognitive function. The scale evaluates memory, language, and praxis with items such as orientation, word recall, word recognition, object identification, comprehension, and the completion of simple tasks. Analysis of the ADAS-Cog for this study was based upon an 11 item score from the following items 1) word recall task, 2) naming objects and fingers, 3) following commands, 4) constructional praxis, 5) ideational praxis, 6) orientation, 7) word recognition, 8) remembering test instructions, 9) spoken language ability, 10) word finding difficulty in spontaneous speech, and 11) comprehension. This scale had to be administered by a trained and certified psychometric rater who did not have access to any information regarding adverse events experienced. The ADAS-Cog/11 ranged from 0 to 70 points, with higher scores indicating a greater degree of impairment. A negative change from baseline indicates a decrease in cognitive impairment.
Time frame: 78 weeks
Population: The modified intent-to-treat (mITT) included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and Disability Assessment for Dementia (DAD) total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | The Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)/11 Total Score at Week 78 | 6.05 Units on a scale | Standard Error 0.71 |
| Bapineuzumab 1.0 mg/kg | The Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)/11 Total Score at Week 78 | 8.07 Units on a scale | Standard Error 0.73 |
| Placebo | The Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)/11 Total Score at Week 78 | 7.88 Units on a scale | Standard Error 0.64 |
Comparison: Change from baseline in ADAS-Cog/11 total score was analyzed using a restricted maximum likelihood (REML) based mixed model for repeated-measures (MMRM). The number of participants in each group provided approximately 90% power to detect a 2.65 point advantage at Week 78. This calculation was based on a 2-sided test with alpha set at 0.05, the use of the Hochberg procedure to control for multiplicity.p-value: 0.05795% CI: [-3.71, 0.05]Mixed Models Analysis
Comparison: Change from baseline in ADAS-Cog/11 total score was analyzed using a REML based MMRM. The number of participants in each group provided approximately 90% power to detect a 2.65 point advantage at Week 78. This calculation was based on a 2-sided test with alpha set at 0.05, the use of the Hochberg procedure to control for multiplicity.p-value: 0.84895% CI: [-1.73, 2.1]Mixed Models Analysis
Primary
The Change From Baseline in the Disability Assessment for Demential (DAD) Total Score at Week 78
The DAD measures instrumental and basic activities of daily living in participants with Alzheimer's Disease (AD). The DAD is administered to the participants'caregiver in the form of an interview. This scale had to be administered by a trained and certified global rater who did not have access to any information regarding adverse events experienced by the participant. This scale assesses a participants' ability to initiate, plan, and perform activities related to hygiene, dressing, continence, eating, meal preparation, telephoning, going on an outing, finance and correspondence, medications, leisure, and housework. Each item can be scored as 1 = yes, 0 = no, non applicable = NA. A total score is obtained by adding the rating for each question and converting this total score out of 100. Higher scores indicate better function; a positive change from baseline indicates an improvement.
Time frame: 78 weeks
Population: The Modified Intent-to-Treat (mITT) population included as all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | The Change From Baseline in the Disability Assessment for Demential (DAD) Total Score at Week 78 | -14.58 Units on a scale | Standard Error 1.5 |
| Bapineuzumab 1.0 mg/kg | The Change From Baseline in the Disability Assessment for Demential (DAD) Total Score at Week 78 | -15.07 Units on a scale | Standard Error 1.55 |
| Placebo | The Change From Baseline in the Disability Assessment for Demential (DAD) Total Score at Week 78 | -16.08 Units on a scale | Standard Error 1.36 |
Comparison: Change from baseline in DAD total score was analyzed using a REML based MMRM. The number of participants in each group provided approximately 90% power to detect a 6.56 point advantage at Week 78. This calculation was based on a 2-sided test with alpha set at 0.05, the use of the Hochberg procedure to control for multiplicity.p-value: 0.45995% CI: [-2.48, 5.49]Mixed Models Analysis
Comparison: Change from baseline in DAD total score was analyzed using a REML based MMRM. The number of participants in each group provided approximately 90% power to detect a 6.56 point advantage at Week 78. This calculation was based on a 2-sided test with alpha set at 0.05, the use of the Hochberg procedure to control for multiplicity.p-value: 0.62395% CI: [-3.04, 5.07]Mixed Models Analysis
Secondary
Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SOB) Total Score at Week 78
The CDR-SOB is a global clinical staging instrument that sums 6 clinical ratings: 1) memory, 2) orientation, 3) judgment and problem solving, 4) involvement in community affairs, 5) home and hobbies, and 6) personal care based on the Clinical Dementia Rating Scale (CDR) interview. The CDR includes discussions with the participant and caregiver using a structured format. This scale had to be administered by a trained and certified global rater who did not have access to any information regarding adverse events experienced by the participant. CDR-SOB total score range is 0 (least impairment) to 18 (most impairment); a negative change from baseline indicates an improvement.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SOB) Total Score at Week 78 | 2.23 Units on a scale | Standard Error 0.23 |
| Bapineuzumab 1.0 mg/kg | Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SOB) Total Score at Week 78 | 2.41 Units on a scale | Standard Error 0.23 |
| Placebo | Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SOB) Total Score at Week 78 | 2.59 Units on a scale | Standard Error 0.2 |
Comparison: Change in CDR-SOB total score was analyzed using a REML based MMRM.p-value: 0.23895% CI: [-0.96, 0.24]Mixed Models Analysis
Comparison: Change in CDR-SOB total score was analyzed using a REML based MMRM.p-value: 0.56495% CI: [-0.78, 0.43]Mixed Models Analysis
Secondary
Change From Baseline in Dependence Scale Total Score at Week 78
The Dependence Scale (DS) is a 13-item, caregiver-rated instrument for determining the amount of support required by a participant with AD. The DS total score ranges from 0 to 15, with higher scores indicating more need for assistance. The DS was administered as an interview to the caregiver at scheduled study visits.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | Change From Baseline in Dependence Scale Total Score at Week 78 | 1.29 Units on a scale | Standard Error 0.19 |
| Bapineuzumab 1.0 mg/kg | Change From Baseline in Dependence Scale Total Score at Week 78 | 1.16 Units on a scale | Standard Error 0.19 |
| Placebo | Change From Baseline in Dependence Scale Total Score at Week 78 | 1.45 Units on a scale | Standard Error 0.17 |
Comparison: Change in DS score was analyzed using a REML based MMRM.p-value: 0.51695% CI: [-0.65, 0.33]Mixed Models Analysis
Comparison: Change in DS score was analyzed using a REML based MMRM.p-value: 0.25795% CI: [-0.79, 0.21]Mixed Models Analysis
Secondary
Divergence of Effect on the ADAS-Cog/11 Total Scores From Week 39 to Week 78
The MMRM estimated slope (based on linear contrasts) of the differences between bapineuzumab and placebo for the ADAS-Cog/11 total scores from Week 39 to Week 78 was presented.
Time frame: 39 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | Divergence of Effect on the ADAS-Cog/11 Total Scores From Week 39 to Week 78 | -1.32 Units/Year | Standard Error 1.06 |
| Bapineuzumab 1.0 mg/kg | Divergence of Effect on the ADAS-Cog/11 Total Scores From Week 39 to Week 78 | 0.38 Units/Year | Standard Error 1.09 |
p-value: 0.21295% CI: [-3.4, 0.76]Mixed Models Analysis
p-value: 0.72595% CI: [-1.76, 2.52]Mixed Models Analysis
Secondary
Divergence of Effect on the DAD Total Scores From Week 39 to Week 78
The MMRM estimated slope (based on linear contrasts)of the differences between bapineuzumab and placebo for the DAD total scores from Week 39 to Week 78 was presented.
Time frame: 39 weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | Divergence of Effect on the DAD Total Scores From Week 39 to Week 78 | 3.20 Units/Years | Standard Error 2.22 |
| Bapineuzumab 1.0 mg/kg | Divergence of Effect on the DAD Total Scores From Week 39 to Week 78 | 2.01 Units/Years | Standard Error 2.27 |
p-value: 0.14995% CI: [-1.15, 7.56]Mixed Models Analysis
p-value: 0.37595% CI: [-2.44, 6.46]Mixed Models Analysis
Secondary
Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan)
Percentage of participants whose increase (worsening) in ADAS-Cog/11 total score from baseline to Week 78 was at most 0, 3, 7 points.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 3 points | 16.1 Number of participants |
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 0 points | 10.6 Number of participants |
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 7 points | 23.1 Number of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 3 points | 13.4 Number of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 0 points | 8.7 Number of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 7 points | 19.0 Number of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 0 points | 7.3 Number of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 7 points | 19.2 Number of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (European Union Analysis Plan) | Worsening of 3 points | 10.1 Number of participants |
Secondary
Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (US Analysis Plan)
Percentage of participants whose increase (worsening) from baseline to Week 78 in ADAS-Cog/11 total score is \<7.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (US Analysis Plan) | 22.4 Percentage of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (US Analysis Plan) | 18.6 Percentage of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (US Analysis Plan) | 18.6 Percentage of participants |
p-value: 0.277Cochran-Mantel-Haenszel
p-value: 0.996Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan)
Percentage of participants whose decrease (worsening) from baseline to Week 78 in DAD total score was at most 0, 6, 12 points.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 6 points | 15.7 Percentage of participants |
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 0 points | 10.2 Percentage of participants |
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 12 points | 20.0 Percentage of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 6 points | 16.6 Percentage of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 0 points | 11.9 Percentage of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 12 points | 22.1 Percentage of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 0 points | 9.1 Percentage of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 12 points | 19.5 Percentage of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (European Union Analysis Plan) | Worsening of 6 points | 14.3 Percentage of participants |
Secondary
Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (US Analysis Plan)
Percentage of participants whose decrease (worsening) from baseline to Week 78 in DAD total score was \<12.
Time frame: 78 weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bapineuzumab 0.5 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (US Analysis Plan) | 20.0 Percentage of participants |
| Bapineuzumab 1.0 mg/kg | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (US Analysis Plan) | 22.1 Percentage of participants |
| Placebo | Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (US Analysis Plan) | 19.5 Percentage of participants |
p-value: 0.855Cochran-Mantel-Haenszel
p-value: 0.423Cochran-Mantel-Haenszel
Secondary
The Change From Baseline in Brain Amyloid Burden at Week 71.
Brain amyloid burden as imaged by 11C-Pittsburgh compound B (PiB) positron emission tomography (PET). The latter is a semiquantitative measure of the extent of fibrillar amyloid in the brain. PIB PET measurements were made in cortical regions found to have the highest burden of fibrillar amyloid at autopsy in participants diagnosed as having Alzheimer's pathology, and also regions reported to have the highest average retention of PIB signal in previous PET studies enrolling participants with probable AD. This parameter reflects overall brain amyloid deposition as indexed by imaging. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified regions of interest (ROI) assessed by PIB PET imaging in a subset of participants.
Time frame: 71 Weeks
Population: PiB PET population included all randomized participants who enrolled in the PET substudies and who met the following criteria: a) received at least one infusion or portion of an infusion of study drug, b) had a baseline and at least one post baseline PiB PET assessment, and c) had an SUVr for the global cortical average (GCA) ROI≥1.35 at baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | The Change From Baseline in Brain Amyloid Burden at Week 71. | -0.04 SUVr | Standard Error 0.08 |
| Bapineuzumab 1.0 mg/kg | The Change From Baseline in Brain Amyloid Burden at Week 71. | 0.00 SUVr | Standard Error 0.05 |
| Placebo | The Change From Baseline in Brain Amyloid Burden at Week 71. | 0.02 SUVr | Standard Error 0.04 |
| Pooled Bapineuzumab 0.5/1.0 mg/kg | The Change From Baseline in Brain Amyloid Burden at Week 71. | -0.01 SUVr | Standard Error 0.04 |
Comparison: The analysis is based on the pooled bapineuzumab (with subjects in the bapineuzumab 0.5 and 1.0 mg/kg groups combined) treatment difference estimated at Week 71. The number of participants gave 90% power to detect a 0.186 unit advantage for a bapineuzumab dose group over placebo for PiB PET binding at Week 71. The calculations were based on 2-sided tests with alpha set at 0.05 and the use of the Hochberg procedure to control for multiplicity for 2 individual doses.p-value: 0.65495% CI: [-0.15, 0.09]Mixed Models Analysis
Secondary
The Change From Baseline in Brain Volume at Week 71
Brain volume was examined in a subset of participants by Magnetic Resonance Imaging Brain Boundary Shift Integral (MRI BBSI). Cerebral atrophy correlates closely with the gradual cognitive decline in AD and can be visualized by MRI. The BBSI technique involves positional matching of serial 3-dimensional MRI brain images, such that brain MRI-image volumes were first registered and then subtracted from each other. Atrophy rates would generally be expected to be lower if the underlying disease was attenuated by effective treatment.
Time frame: 71 Weeks
Population: The vMRI population Included all randomized participants who enrolled in the vMRI substudies, received at least one infusion or portion of an infusion of study drug, and had a baseline and at least one postbaseline vMRI that passed quality control and was satisfactory for volumetric analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | The Change From Baseline in Brain Volume at Week 71 | 18.55 mL/year | Standard Error 0.97 |
| Bapineuzumab 1.0 mg/kg | The Change From Baseline in Brain Volume at Week 71 | 18.60 mL/year | Standard Error 1 |
| Placebo | The Change From Baseline in Brain Volume at Week 71 | 17.54 mL/year | Standard Error 0.86 |
Comparison: Change in MRI BBSI was analyzed using a REML based MMRM. The number of participants gave 90% power to detect a 5.05-cm3 advantage for a bapineuzumab dose group over placebo on reduction in brain volume as measured by the BBSI at Week 71. The calculations were based on 2-sided tests with alpha set at 0.05 and the use of the Hochberg procedure to control for multiplicity for 2 individual doses.p-value: 0.43795% CI: [-1.55, 3.57]Mixed Models Analysis
Comparison: Change in MRI BBSI was analyzed using a REML based MMRM. The number of participants gave 90% power to detect a 5.05-cm3 advantage for a bapineuzumab dose group over placebo on reduction in brain volume as measured by the BBSI at Week 71. The calculations were based on 2-sided tests with alpha set at 0.05 and the use of the Hochberg procedure to control for multiplicity for 2 individual doses.p-value: 0.42395% CI: [-1.54, 3.66]Mixed Models Analysis
Secondary
The Change From Baseline in Phospho-tau Levels in the Cerebrospinal Fluid (CSF) at Week 71.
Biomarkers CSF phospho-tau (p-tau) is an indicator of neuronal injury and neurodegeneration. An elevation in levels of tau, as well as specific p-tau species, is thought to be a marker for progressive cellular degeneration in AD. Accordingly, a reduction from baseline in levels of CSF tau in participants who received bapineuzumab compared with participants who received placebo may be indicative of a reduction in neuronal loss in participants treated with bapineuzumab.
Time frame: 71 Weeks
Population: CSF population included all randomized participants who enrolled in the CSF substudies, received at least one infusion or portion of an infusion of study drug, and had a baseline and at least one postbaseline CSF measurement (CSF phospho-tau).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bapineuzumab 0.5 mg/kg | The Change From Baseline in Phospho-tau Levels in the Cerebrospinal Fluid (CSF) at Week 71. | -6.62 pg/mL | Standard Error 3.9 |
| Bapineuzumab 1.0 mg/kg | The Change From Baseline in Phospho-tau Levels in the Cerebrospinal Fluid (CSF) at Week 71. | -6.35 pg/mL | Standard Error 3.73 |
| Placebo | The Change From Baseline in Phospho-tau Levels in the Cerebrospinal Fluid (CSF) at Week 71. | 0.70 pg/mL | Standard Error 3.03 |
| Pooled Bapineuzumab 0.5/1.0 mg/kg | The Change From Baseline in Phospho-tau Levels in the Cerebrospinal Fluid (CSF) at Week 71. | -6.48 pg/mL | Standard Error 2.67 |
Comparison: The analysis is based on the pooled bapineuzumab (with subjects in the bapineuzumab 0.5 and 1.0 mg/kg groups combined) treatment difference estimated at Week 71. The number of participants gave 90% power to detect a 15 ng/L advantage in p-tau for a bapineuzumab dose group over placebo at Week 71. The calculations were based on 2-sided tests with alpha set at 0.05 and the use of the Hochberg procedure to control for multiplicity for 2 individual doses.p-value: 0.08595% CI: [-15.38, 1.02]ANCOVA
Secondary
Time to First Clinically Meaningful Deterioration on ADAS-Cog/11 Total Score (United States [US] Analysis Plan)
The time to first clinically meaningful deterioration (for the US) was defined as the first time a participant experienced an increase (worsening) from baseline in ADAS-Cog/11 total score of \>=7.
Time frame: 78 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bapineuzumab 0.5 mg/kg | Time to First Clinically Meaningful Deterioration on ADAS-Cog/11 Total Score (United States [US] Analysis Plan) | 546.0 Days |
| Bapineuzumab 1.0 mg/kg | Time to First Clinically Meaningful Deterioration on ADAS-Cog/11 Total Score (United States [US] Analysis Plan) | 546.0 Days |
| Placebo | Time to First Clinically Meaningful Deterioration on ADAS-Cog/11 Total Score (United States [US] Analysis Plan) | 546.0 Days |
p-value: 0.079Log Rank
p-value: 0.675Log Rank
Secondary
Time to First Clinically Meaningful Deterioration on DAD Total Score (US Analysis Plan)
The time to first clinically meaningful deterioration was defined as the first time a participant experienced a decrease (worsening)from baseline in DAD total score of \>=12.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bapineuzumab 0.5 mg/kg | Time to First Clinically Meaningful Deterioration on DAD Total Score (US Analysis Plan) | 542.0 Days |
| Bapineuzumab 1.0 mg/kg | Time to First Clinically Meaningful Deterioration on DAD Total Score (US Analysis Plan) | 539.0 Days |
| Placebo | Time to First Clinically Meaningful Deterioration on DAD Total Score (US Analysis Plan) | 540.0 Days |
p-value: 0.933Log Rank
p-value: 0.714Log Rank
Secondary
Time to Median Placebo Deterioration on ADAS-Cog/11 Total Score (European Union [EU] Analysis Plan)
The time to first median placebo deterioration (for the EU) was defined as the first time a subject experienced an increase from baseline (worsening) in ADAS Cog/11 total score greater than or equal to the median worsening observed at Week 78 in the placebo group. The Kaplan Meier estimate of the median time to first median placebo deterioration in ADAS Cog/11 total score was presented.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bapineuzumab 0.5 mg/kg | Time to Median Placebo Deterioration on ADAS-Cog/11 Total Score (European Union [EU] Analysis Plan) | 546.0 Days |
| Bapineuzumab 1.0 mg/kg | Time to Median Placebo Deterioration on ADAS-Cog/11 Total Score (European Union [EU] Analysis Plan) | 462.0 Days |
| Placebo | Time to Median Placebo Deterioration on ADAS-Cog/11 Total Score (European Union [EU] Analysis Plan) | 540.0 Days |
p-value: 0.03Log Rank
p-value: 0.567Log Rank
Secondary
Time to Median Placebo Deterioration on DAD Total Score
The time to first median placebo deterioration (for the EU) was defined as the first time a participant experienced a decrease (worsening) in DAD total score greater than or equal to the median worsening at Week 78 in the placebo group.
Time frame: 78 Weeks
Population: The mITT included all randomized participants who received at least one infusion or portion of an infusion of study drug and who had a baseline and at least one post-baseline assessment of the ADAS-Cog/11 total score and DAD total score.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bapineuzumab 0.5 mg/kg | Time to Median Placebo Deterioration on DAD Total Score | 541.0 Days |
| Bapineuzumab 1.0 mg/kg | Time to Median Placebo Deterioration on DAD Total Score | 534.0 Days |
| Placebo | Time to Median Placebo Deterioration on DAD Total Score | 463.0 Days |
Comparison: Not spsecified.p-value: 0.846Log Rank
p-value: 0.797Log Rank