A Long-Term Safety And Tolerability Study 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:
NCT00996918
First received: October 14, 2009
Last updated: November 12, 2013
Last verified: November 2013
Results First Received: November 12, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Alzheimer Disease
Interventions: Drug: Bapineuzumab 0.5 mg/kg
Drug: Bapineuzumab 1.0 m/kg

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This extension study was conducted at 91 centers in 17 countries. The study was terminated early by the sponsor on 06 August 2012. Participants who had not completed the final follow-up visit prior to 06 August 2012 were asked to complete an early termination visit.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants who had completed the base study protocol 3133K1-3000 were allowed to participate in this extension study. Participants who developed vasogenic edema during study 3133K1-3000 were considered for study 3133K1-3002 participation if the abnormality was resolved and the participant met criteria to resume the investigational product.

Reporting Groups
  Description
Placebo/Bapineuzumab 0.5 Milligram/Kilogram(mg/kg) Participants received placebo in the base study and 0.5 mg/kg bapineuzumab in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg Participants received 0.5 mg/kg bapineuzumab in both the base and extension studies. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Placebo/Bapineuzumab 1.0 mg/kg Participants received placebo in the base study and 1.0 mg/kg bapineuzumab in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg Participants received 1.0 mg/kg bapineuzumab in both the base and extension studies. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 2.0 mg/kg/ Bapineuzumab 1.0 mg/kg Participants originally randomized to 2.0 mg/kg bapineuzumab were reassigned to the 1.0 mg/kg dose level after discontinuation of 2.0 mg/kg dose level in the base study and continued the 1.0 mg/kg dose in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.

Participant Flow:   Overall Study
    Placebo/Bapineuzumab 0.5 Milligram/Kilogram(mg/kg)     Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg     Placebo/Bapineuzumab 1.0 mg/kg     Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg     Bapineuzumab 2.0 mg/kg/ Bapineuzumab 1.0 mg/kg  
STARTED     39     66     37     56     4  
Treated     39     66     37     56     4  
COMPLETED     0     0     0     0     0  
NOT COMPLETED     39     66     37     56     4  
Lack of Efficacy                 1                 1                 2                 2                 0  
Adverse Event                 2                 5                 2                 6                 0  
Withdrawal by Subject                 1                 4                 3                 3                 2  
Physician Decision                 1                 0                 0                 0                 0  
Discontinuation of Study by Sponsor                 31                 54                 30                 45                 2  
Loss of Caregiver                 0                 1                 0                 0                 0  
Not Specified                 3                 1                 0                 0                 0  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Placebo/Bapineuzumab 0.5 mg/kg Participants received placebo in the base study and 0.5 mg/kg bapineuzumab in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg Participants received 0.5 mg/kg bapineuzumab in both the base and extension studies. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Placebo/Bapineuzumab 1.0 mg/kg Participants received placebo in the base study and 1.0 mg/kg bapineuzumab in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg Participants received 1.0 mg/kg bapineuzumab in both the base and extension studies. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 2.0 mg/kg/Bapineuzumab 1.0 mg/kg Participants originally randomized to 2.0 mg/kg bapineuzumab were reassigned to the 1.0 mg/kg dose level after discontinuation of 2.0 mg/kg dose level in the base study and continued the 1.0 mg/kg dose in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Total Total of all reporting groups

Baseline Measures
    Placebo/Bapineuzumab 0.5 mg/kg     Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg     Placebo/Bapineuzumab 1.0 mg/kg     Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg     Bapineuzumab 2.0 mg/kg/Bapineuzumab 1.0 mg/kg     Total  
Number of Participants  
[units: participants]
  38     62     33     53     4     190  
Age  
[units: Years]
Mean ± Standard Deviation
  68.9  ± 9.70     71.9  ± 8.83     68.8  ± 8.59     70.6  ± 9.13     71.3  ± 10.63     70.4  ± 9.08  
Age, Customized  
[units: Number of participants]
           
< 65     17     15     12     17     1     62  
>= 65     21     47     21     36     3     128  
Gender  
[units: Number of participants]
           
Female     13     28     14     19     3     77  
Male     25     34     19     34     1     113  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants Reporting a Serious Adverse Event.   [ Time Frame: Up to Week 195 ]

2.  Secondary:   Change From Base Study Baseline in Alzheimer's Disease Assesment Scale-Cognitive Subscale (ADAS-Cog/11) at Weeks 13, 26, 39, 52 and 78.   [ Time Frame: Weeks 13, 26, 39, 52 and 78 ]

3.  Secondary:   Change From Extension Study Baseline in ADAS-Cog/11 at Weeks 13, 26, 39, 52 and 78.   [ Time Frame: Weeks 13, 26, 39, 52 and 78 ]

4.  Secondary:   Change From Base Study Baseline in Disability Assessment for Dementia (DAD) Score at Weeks 13, 26, 39, 52 and 78.   [ Time Frame: Weeks 13, 26, 39, 52 and 78 ]

5.  Secondary:   Change From Extension Study Baseline in DAD Score at Weeks 13, 26, 39, 52 and 78   [ Time Frame: Weeks 13, 26, 39, 52 and 78 ]

6.  Secondary:   Change From Base Study Baseline in Neuropsychiatric Inventory (NPI) Score at Weeks 26, 52 and 78.   [ Time Frame: Weeks 26, 52 and 78 ]

7.  Secondary:   Change From Extension Study Baseline in NPI Score at Weeks 26, 52 and 78.   [ Time Frame: Weeks 26, 52 and 78 ]

8.  Secondary:   Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.   [ Time Frame: Weeks 6, 19, 32, 45 and 78 ]
  Hide Outcome Measure 8

Measure Type Secondary
Measure Title Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Measure Description MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Time Frame Weeks 6, 19, 32, 45 and 78  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Extension mITT Population was defined as all randomly assigned participants who received at least one dose of investigational product in the extension study and who had a baseline for the extension study and at least one valid post-baseline assessment of the ADAS-Cog total score and DAD total score in the extension study.

Reporting Groups
  Description
Placebo/Bapineuzumab 0.5 mg/kg Participants received placebo in the base study and 0.5 mg/kg bapineuzumab in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg Participants received 0.5 mg/kg bapineuzumab in both the base and extension studies. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Placebo/Bapineuzumab 1.0 mg/kg Participants received placebo in the base study and 1.0 mg/kg bapineuzumab in this extension study. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.
Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg Participants received 1.0 mg/kg bapineuzumab in both the base and extension studies. In this extension study bapineuzumab was administered by IV infusion approximately every 13 weeks up to Week 195.

Measured Values
    Placebo/Bapineuzumab 0.5 mg/kg     Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg     Placebo/Bapineuzumab 1.0 mg/kg     Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg  
Number of Participants Analyzed  
[units: participants]
  38     62     33     53  
Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.  
[units: Units on a scale]
Least Squares Mean ± Standard Error
       
Week 6 (N = 38, 61, 33, 53)     -2.89  ± 0.46     -2.85  ± 0.37     -2.02  ± 0.49     -2.22  ± 0.39  
Week 19 (N = 36, 59, 28, 50)     -2.80  ± 0.47     -2.66  ± 0.38     -2.76  ± 0.51     -3.29  ± 0.39  
Week 32 (N = 32, 51, 26, 41)     -3.82  ± 0.49     -3.43  ± 0.40     -4.40  ± 0.53     -3.88  ± 0.42  
Week 45 (N = 23, 41, 21, 35)     -4.86  ± 0.56     -4.13  ± 0.44     -4.63  ± 0.58     -4.51  ± 0.46  
Week 78 (N = 13, 27, 11, 21)     -7.62  ± 0.70     -5.10  ± 0.54     -6.97  ± 0.75     -4.89  ± 0.56  


Statistical Analysis 1 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 0.5 mg/kg vs. Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.938
Mean Difference (Final Values) [4] 0.05
95% Confidence Interval ( -1.12 to 1.21 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 6.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
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[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4] Other relevant estimation information:
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Statistical Analysis 2 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 1.0 mg/kg vs. Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.753
Mean Difference (Final Values) [4] -0.20
95% Confidence Interval ( -1.43 to 1.04 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 6.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 0.5 mg/kg vs. Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.809
Mean Difference (Final Values) [4] 0.15
95% Confidence Interval ( -1.04 to 1.33 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 19.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4] Other relevant estimation information:
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Statistical Analysis 4 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 1.0 mg/kg vs. Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.421
Mean Difference (Final Values) [4] -0.52
95% Confidence Interval ( -1.80 to 0.75 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 19.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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Statistical Analysis 5 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 0.5 mg/kg vs. Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.535
Mean Difference (Final Values) [4] 0.39
95% Confidence Interval ( -0.85 to 1.63 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 32.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4] Other relevant estimation information:
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Statistical Analysis 6 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 1.0 mg/kg vs. Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.445
Mean Difference (Final Values) [4] 0.52
95% Confidence Interval ( -0.82 to 1.86 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 32.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 7 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 0.5 mg/kg vs. Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.309
Mean Difference (Final Values) [4] 0.73
95% Confidence Interval ( -0.67 to 2.12 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 45.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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Statistical Analysis 8 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 1.0 mg/kg vs. Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.872
Mean Difference (Final Values) [4] 0.12
95% Confidence Interval ( -1.34 to 1.57 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 45.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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Statistical Analysis 9 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 0.5 mg/kg vs. Bapineuzumab 0.5 mg/kg/ Bapineuzumab 0.5 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.004
Mean Difference (Final Values) [4] 2.52
95% Confidence Interval ( 0.79 to 4.26 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 78.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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Statistical Analysis 10 for Change From Base Study Baseline in Mini-mental State Examination (MMSE) Score at Weeks 6, 19, 32, 45 and 78.
Groups [1] Placebo/Bapineuzumab 1.0 mg/kg vs. Bapineuzumab 1.0 mg/kg/Bapineuzumab 1.0 mg/kg
Method [2] Mixed Models Analysis
P Value [3] 0.026
Mean Difference (Final Values) [4] 2.09
95% Confidence Interval ( 0.25 to 3.93 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
 

Change from base study baseline in MMSE score at Week 78.

Results are from a REML-based MMRM with change from base study baseline as the response and the following fixed effect model terms: treatment, visit (scheduled week), treatment-by-visit interaction, baseline value of the response variable, baseline MMSE total score stratum and cholinesterase inhibitor or memantine use stratum.

[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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9.  Secondary:   Change From Extension Study Baseline in MMSE Score at Weeks 6, 19, 32, 45 and 78.   [ Time Frame: Weeks 6, 19, 32, 45 and 78 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Bapineuzumab program was discontinued prematurely. Efficacy results obtained after Week 78 are not presented due to the very small number of participants after this time point.


  More Information