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Study Evaluating the Safety and Efficacy of Bapineuzumab in Alzheimer Disease Patients

This study has been terminated.
(The study was terminated on August 6, 2012, because 2 large Phase 3 studies showed no clinical benefit. This decision was not based on any new safety concerns.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00676143
First received: May 2, 2008
Last updated: May 3, 2016
Last verified: May 2016
  Purpose
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.

Condition Intervention Phase
Alzheimer Disease
Drug: bapineuzumab
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase Iii, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Efficacy And Safety Trial Of Bapineuzumab (Aab 001, Eln115727) In Subjects With Mild To Moderate Alzheimer Disease Who Are Apolipoprotein E 4 Carriers

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)/11 Subscale Total Score at Week 78 [ Time Frame: Baseline and 78 weeks ] [ Designated as safety issue: No ]

    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.


  • Change From Baseline in Disability Assessment for Dementia (DAD) Total Score at Week 78 [ Time Frame: Baseline and 78 weeks ] [ Designated as safety issue: No ]

    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 psychometric 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 Outcome Measures:
  • Change From Baseline in Brain Amyloid Burden at Week 71 [ Time Frame: Baseline and 71 weeks ] [ Designated as safety issue: No ]
    Brain amyloid burden as imaged by 11C-Pittsburgh compound B (PIB) positron emission tomography (PET). The latter is a semi-quantitative 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.

  • Change From Baseline in Cerebrospinal Fluid (CSF) Phospho-tau Levels at Week 71 [ Time Frame: Baseline and 71 Weeks ] [ Designated as safety issue: No ]
    Biomarkers CSF phospho-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.

  • Change From Baseline in Brain Volume, as Assessed by Magnetic Resonance Imaging Brain Boundary Shift Integral (MRI BBSI), at Week 71 [ Time Frame: Baseline and 71 Weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 39 to Week 78 ] [ Designated as safety issue: No ]
    Treatment differences are estimated using least-squares (LS) means with factor levels weighted according to overall analysis population proportions. ADAS-Cog/11 total score range is 0 (least impairment) to 70 (most impairment); a negative treatment difference (bapineuzumab minus placebo) favors bapineuzumab. Within the MMRMs for ADAS-Cog/11 described for the primary analyses, linear contrasts were formed to test increasing trend of the differences between bapineuzumab and placebo from Week 39 (the 9-month visit) through Week 78 (the 18 -month visit) for each variable, which is equivalent to testing a positive slope of the differences between each bapineuzumab dose group and placebo from Week 39 through Week 78. Results are from a restricted maximum likelihood (REML)-based mixed model for MMRM.

  • Divergence of Effect on the DAD Total Scores From Week 39 to Week 78 [ Time Frame: Week 39 to Week 78 ] [ Designated as safety issue: No ]
    Treatment differences are estimated using least-squares (LS) means with factor levels weighted according to overall analysis population proportions. DAD total score range is 0 to 100; a positive treatment difference (bapineuzumab minus placebo) favors bapineuzumab. Within the MMRMs for ADAS-Cog/11 described for the primary analyses, linear contrasts were formed to test increasing trend of the differences between bapineuzumab and placebo from Week 39 (the 9-month visit) through Week 78 (the 18 -month visit) for each variable, which is equivalent to testing a positive slope of the differences between each bapineuzumab dose group and placebo from Week 39 through Week 78. Results are from a restricted maximum likelihood (REML)-based mixed model for MMRM.

  • Time to First Median Placebo Deterioration on ADAS-Cog/11 Total Score (European Union [EU] Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    The time to first median placebo deterioration, defined as the first time a participant experienced an increase (worsening) from baseline 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 median time to first median placebo deterioration was presented.

  • Time to First Clinically Meaningful Deterioration on ADAS-Cog/11 Total Score (United States [US] Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    The time to first clinically meaningful deterioration was defined as the first time a participant experienced an increase (worsening) from baseline in ADAS-Cog/11 total score of >=7.

  • Time to First Median Placebo Deterioration on DAD Total Score (EU Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    The time to first median placebo deterioration 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 to First Clinically Meaningful Deterioration on DAD Total Score (US Analysis) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Dependence Scale Total Score at Week 78 [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Worsening From Baseline in ADAS-Cog/11 Total Score at Week 78 (EU Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    Percentage of participants with worsening from baseline to Week 78 in ADAS-Cog/11 total score of ≤0, ≤3, and ≤7 points were reported. In order to calculate time to first median placebo deterioration in ADAS-Cog/11, the median change from baseline to Week 78 among the placebo participants of the mITT analysis population were determined. The median changes were used as the cutpoints for determining "deterioration" for Alzheimer's disease participants in the study. If the median change from baseline to Week 78 in the ADAS-Cog/11 total score among the placebo participants of the mITT Analysis Population is 7 points, then the first median placebo deterioration is the first time where there is a worsening on the ADAS-Cog/11 total score of 7 points or more and the worsening is confirmed by the ADAS-Cog/11 assessment at the next non-missing visit.

  • Percentage of Responders for ADAS-Cog/11 Total Score at Week 78 (US Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    Percentage of participants whose increase (worsening) from baseline to Week 78 in ADAS-Cog/11 total score was <7.

  • Percentage of Participants With Worsening From Baseline in DAD Total Score at Week 78 (EU Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    Percentage of participants whose decrease (worsening) from baseline to Week 78 in DAD total score of ≤ 0, ≤ 6, and ≤ 12 points. In order to calculate time to first median placebo deterioration in DAD, the median change from baseline to Week 78 among the placebo participants of the mITT analysis population were determined. The median changes were used as the cutpoints for determining "deterioration" for Alzheimer's disease participants in the study. If the median change from baseline to Week 78 in the DAD total score among the placebo participants of the mITT Analysis Population is 7 points, then the first median placebo deterioration is the first time where there is a worsening on the DAD total score of 7 points or more and the worsening is confirmed by the DAD assessment at the next non-missing visit.

  • Percentage of Responders for DAD Total Score at Week 78 (US Analysis Plan) [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    Percentage of participants whose decrease (worsening) from baseline to Week 78 in DAD total score was <12.

  • Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SOB) Total Score at Week 78 [ Time Frame: Baseline and 78 Weeks ] [ Designated as safety issue: No ]
    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.


Enrollment: 1100
Study Start Date: January 2008
Study Completion Date: November 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bapineuzumab 0.5 mg/kg Drug: bapineuzumab
Bapineuzumab 0.5 mg/kg administered by IV infusion approximately every 13 weeks through week 65.
Other Name: AAB-001
Placebo Comparator: Placebo Drug: placebo
Placebo will be administered by IV infusion approximately every 13 weeks through week 65.

  Eligibility

Ages Eligible for Study:   50 Years to 88 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of probable AD, with MMSE score of 16-26, and brain 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, or a major psychiatric disorder
  • Contraindication to undergo brain MRI (e.g., pacemaker, CSF shunt, or foreign metal objects in the body)
  • Woman of childbearing potential
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00676143

  Show 287 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00676143     History of Changes
Obsolete Identifiers: NCT00909675
Other Study ID Numbers: 3133K1-3001  B2521002  2007-005995-14 
Study First Received: May 2, 2008
Results First Received: October 14, 2013
Last Updated: May 3, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
antibody
immunotherapy

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders

ClinicalTrials.gov processed this record on September 23, 2016