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A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD)

This study has been completed.
Sponsor:
Collaborators:
Forest Laboratories
DSM Nutritional Products, Inc.
Information provided by (Responsible Party):
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT00235716
First received: October 6, 2005
Last updated: July 14, 2014
Last verified: July 2014
Results First Received: December 6, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Factorial Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Alzheimer's Disease
Interventions: Drug: dl-alpha-tocopherol
Drug: Memantine
Drug: Placebo

  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
Recruitment initiated in August, 2007 and concluded in March, 2012. Enrollment took place at 14 VA medical centers.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine (Namenda) Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Participant Flow:   Overall Study
    Vitamin E   Memantine (Namenda)   Vitamin E + Memantine   Placebo
STARTED   152   155   154   152 
COMPLETED   90   88   89   90 
NOT COMPLETED   62   67   65   62 
Death                26                39                32                31 
Withdrawal by Subject                23                19                17                18 
Lost to Follow-up                12                7                14                10 
Adverse Event                1                1                1                0 
Physician Decision                0                1                1                3 



  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
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine (Namenda) Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine
Total Total of all reporting groups

Baseline Measures
   Vitamin E   Memantine (Namenda)   Vitamin E + Memantine   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 152   155   154   152   613 
Age 
[Units: Years]
Mean (Standard Deviation)
 78.6  (7.2)   78.8  (7.2)   78.3  (7.0)   79.4  (7.0)   78.8  (7.1) 
Gender 
[Units: Participants]
         
Female   6   6   4   3   19 
Male   146   149   150   149   594 
Ethnicity (NIH/OMB) 
[Units: Participants]
         
Hispanic or Latino   17   15   15   19   66 
Not Hispanic or Latino   135   140   139   133   547 
Unknown or Not Reported   0   0   0   0   0 
Race (NIH/OMB) 
[Units: Participants]
         
American Indian or Alaska Native   0   0   0   1   1 
Asian   0   1   0   0   1 
Native Hawaiian or Other Pacific Islander   0   1   0   0   1 
Black or African American   21   21   18   20   80 
White   130   132   136   131   529 
More than one race   1   0   0   0   1 
Unknown or Not Reported   0   0   0   0   0 
Region of Enrollment 
[Units: Participants]
         
United States   152   155   154   152   613 
Education 
[Units: Participants]
         
<High School Graduation   41   41   26   29   137 
High School Graduation   46   48   57   56   207 
Some College   27   38   37   33   135 
College Graduation or Advanced Degree   38   28   34   34   134 
Apolipoprotein E ε4 status [1] 
[Units: Participants]
         
Non-carriers   47   48   59   55   209 
One ε4 allele   39   44   44   38   165 
Two ε4 alleles   10   13   8   10   41 
Not Tested   56   50   43   49   198 
[1] Data collected through genetic sub-study with separate informed consent.
Concomitant Medications Acetylcholinesterase Inhibitors (AChEI) 
[Units: Participants]
         
Donepezil   104   100   100   96   400 
Galantamine   43   47   49   55   194 
Rivastigmine   5   8   4   1   18 
None   0   0   1   0   1 
Weeks from AChEI Initiation to Randomization 
[Units: Participants]
         
≤ 12 weeks   46   36   49   37   168 
> 12 weeks   105   119   104   115   443 
Missing   1   0   1   0   2 
Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory 
[Units: Units on a scale]
Mean (Standard Deviation)
 56.6  (14.9)   57.3  (14.2)   56.4  (14.0)   56.8  (13.7)   56.8  (14.2) 
Mini-Mental State Examination 
[Units: Units on a scale]
Mean (Standard Deviation)
 21.3  (3.3)   20.8  (3.8)   21.3  (3.4)   20.8  (3.8)   21.0  (3.6) 
Alzheimer's Disease Assessment Scale - Cognitive portion 
[Units: Units on a scale]
Mean (Standard Deviation)
 18.5  (8.8)   19.5  (7.9)   18.0  (8.4)   19.1  (8.4)   18.8  (8.4) 
Neuropsychiatric Inventory 
[Units: Units on a scale]
Mean (Standard Deviation)
 12.2  (13.3)   12.1  (13.1)   12.3  (13.3)   13.5  (14.2)   12.5  (13.4) 
Caregiver Activity Survey 
[Units: Hours per day]
Mean (Standard Deviation)
 7.3  (14.3)   6.7  (9.0)   6.6  (10.5)   6.5  (9.2)   6.8  (10.9) 
Dependence Scale [1] 
[Units: Participants]
         
Level 0   5   6   8   3   22 
Level 1   8   6   8   5   27 
Level 2   85   91   80   79   335 
Level 3   31   35   31   37   134 
Level 4   4   7   10   8   29 
Level 5   19   10   17   20   66 
[1] Higher the level the more dependence / less independence.


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

Measure Type Primary
Measure Title Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Measure Description The primary outcome of the study was the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory. The ADCS/ADL Inventory is designed to assess functional abilities to perform activities of daily living in Alzheimer patients with a broad range of dementia severity. The total score ranges from 0 to 78 with higher scores indicating greater abilities. Outcome analysis is average least square means change from baseline.
Time Frame 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline  
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.
Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 140   142   139   140 
Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline 
[Units: Units on a scale]
Least Squares Mean (Standard Error)
       
6 months minus baseline   -1.72  (0.95)   -2.40  (0.94)   -2.78  (0.96)   -4.52  (0.95) 
12 months minus baseline   -4.29  (1.20)   -6.99  (1.21)   -6.60  (1.21)   -8.11  (1.23) 
18 months minus baseline   -8.01  (1.40)   -9.32  (1.42)   -7.98  (1.41)   -10.21  (1.43) 
24 months minus baseline   -11.88  (1.66)   -14.06  (1.70)   -12.82  (1.68)   -16.18  (1.74) 
30 months minus baseline   -15.84  (1.94)   -18.30  (1.97)   -15.66  (1.97)   -19.67  (2.06) 
36 months minus baseline   -19.71  (2.34)   -18.78  (2.43)   -18.89  (2.32)   -24.82  (2.51) 
42 months minus baseline   -25.30  (2.57)   -23.48  (2.65)   -23.44  (2.52)   -28.13  (2.76) 
48 months minus baseline   -26.55  (3.11)   -24.60  (3.18)   -29.25  (3.08)   -27.55  (3.38) 
Average change from baseline   -13.81  (1.11)   -14.98  (1.10)   -15.20  (1.11)   -16.96  (1.11) 


Statistical Analysis 1 for Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Groups [1] Vitamin E vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.03
Mean Difference (Net) [4] 3.15
95% Confidence Interval 0.92 to 5.39
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value adjusted for 6 treatment group comparisons.
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the placebo group.

Statistical Analysis 2 for Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Groups [1] Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.40
Mean Difference (Net) [4] 1.98
95% Confidence Interval -0.24 to 4.20
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the memantine group minus the placebo group.

Statistical Analysis 3 for Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Groups [1] Vitamin E + Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.49
Mean Difference (Net) [4] 1.76
95% Confidence Interval -0.48 to 4.00
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the placebo group.

Statistical Analysis 4 for Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Groups [1] Vitamin E vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.60
Mean Difference (Net) [4] -1.39
95% Confidence Interval -3.63 to 0.85
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the vitamin E group.

Statistical Analysis 5 for Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Groups [1] Memantine vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.85
Mean Difference (Net) [4] -0.22
95% Confidence Interval -2.44 to 2.01
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the memantine group.

Statistical Analysis 6 for Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
Groups [1] Vitamin E vs. Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.60
Mean Difference (Net) [4] 1.18
95% Confidence Interval -1.04 to 3.39
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the memantine group.



2.  Primary:   Mini-Mental State Examination Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

Measure Type Primary
Measure Title Mini-Mental State Examination Change From Baseline
Measure Description The Mini-Mental State Examination (MMSE) briefly and objectively assess cognitive status in psychiatric patients with cognitive impairment. The MMSE questions are grouped into seven categories, each representing a different cognitive domain. The MMSE yields a total score that ranges from 0 for a patient who gives no correct response to a score of 30 for a patient who makes no errors. Outcome analysis is average least square means change from baseline.
Time Frame 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline  
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.
Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 136   140   136   137 
Mini-Mental State Examination Change From Baseline 
[Units: Units on a scale]
Least Squares Mean (Standard Error)
       
6 months minus baseline   -0.35  (0.29)   -0.24  (0.28)   -0.20  (0.29)   -0.34  (0.29) 
12 months minus baseline   -0.95  (0.34)   -1.09  (0.34)   -0.65  (0.34)   -1.39  (0.35) 
18 months minus baseline   -2.00  (0.44)   -2.62  (0.45)   -1.22  (0.44)   -2.21  (0.45) 
24 months minus baseline   -2.62  (0.52)   -3.44  (0.54)   -2.29  (0.53)   -2.90  (0.55) 
30 months minus baseline   -3.67  (0.61)   -3.79  (0.63)   -3.16  (0.61)   -3.26  (0.65) 
36 months minus baseline   -4.97  (0.74)   -4.26  (0.78)   -3.69  (0.73)   -3.87  (0.79) 
42 months minus baseline   -4.84  (0.79)   -4.59  (0.80)   -3.80  (0.74)   -4.68  (0.83) 
48 months minus baseline   -5.26  (0.94)   -5.98  (0.98)   -5.70  (0.91)   -5.42  (1.02) 
Average change from baseline   -2.97  (0.33)   -3.05  (0.33)   -2.80  (0.33)   -3.16  (0.33) 


Statistical Analysis 1 for Mini-Mental State Examination Change From Baseline
Groups [1] Vitamin E vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.19
95% Confidence Interval -0.54 to 0.92
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the placebo group.

Statistical Analysis 2 for Mini-Mental State Examination Change From Baseline
Groups [1] Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.12
95% Confidence Interval -0.61 to 0.84
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the memantine group minus the placebo group.

Statistical Analysis 3 for Mini-Mental State Examination Change From Baseline
Groups [1] Vitamin E + Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.37
95% Confidence Interval -0.36 to 1.10
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the placebo group.

Statistical Analysis 4 for Mini-Mental State Examination Change From Baseline
Groups [1] Vitamin E vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.17
95% Confidence Interval -0.56 to 0.90
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the vitamin E group.

Statistical Analysis 5 for Mini-Mental State Examination Change From Baseline
Groups [1] Memantine vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.25
95% Confidence Interval -0.47 to 0.98
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the memantine group.

Statistical Analysis 6 for Mini-Mental State Examination Change From Baseline
Groups [1] Vitamin E vs. Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.08
95% Confidence Interval -0.65 to 0.80
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the memantine group.



3.  Primary:   Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

Measure Type Primary
Measure Title Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Measure Description The Alzheimer's Disease Assessment Scale (ADAS) is a 21-item scale designed to assess the severity of cognitive and non-cognitive behavioral impairments in patients with Alzheimer's disease. The cognitive portion of the scale (ADAS-cog) consists of 11 items to assess memory, language, and praxis functions. The ADAS-cog total score ranges from 0 (no errors) to 70 (severe cognitive impairment). Outcome analysis is average least square means change from baseline.
Time Frame 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline  
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.
Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 135   140   136   137 
Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline 
[Units: Units on a scale]
Least Squares Mean (Standard Error)
       
6 months minus baseline   1.38  (0.63)   1.11  (0.62)   1.53  (0.63)   3.04  (0.63) 
12 months minus baseline   2.40  (0.72)   3.32  (0.72)   2.48  (0.72)   4.26  (0.74) 
18 months minus baseline   4.34  (0.91)   5.69  (0.91)   3.46  (0.90)   6.04  (0.92) 
24 months minus baseline   4.32  (1.10)   6.73  (1.12)   5.76  (1.11)   6.71  (1.15) 
30 months minus baseline   7.87  (1.31)   7.64  (1.34)   5.85  (1.30)   8.90  (1.38) 
36 months minus baseline   9.00  (1.53)   8.31  (1.60)   8.26  (1.50)   10.77  (1.63) 
42 months minus baseline   10.35  (1.60)   8.24  (1.64)   7.97  (1.51)   10.61  (1.69) 
48 months minus baseline   10.73  (1.87)   11.74  (1.97)   9.70  (1.82)   10.85  (2.04) 
Average change from baseline   5.97  (0.70)   6.38  (0.70)   6.13  (0.71)   7.78  (0.70) 


Statistical Analysis 1 for Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Groups [1] Vitamin E vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.10
Mean Difference (Net) [4] -1.80
95% Confidence Interval -3.28 to -0.33
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the placebo group.

Statistical Analysis 2 for Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Groups [1] Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.25
Mean Difference (Net) [4] -1.39
95% Confidence Interval -2.85 to 0.07
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the memantine group minus the placebo group.

Statistical Analysis 3 for Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Groups [1] Vitamin E + Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.14
Mean Difference (Net) [4] -1.65
95% Confidence Interval -3.12 to -0.17
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the placebo group.

Statistical Analysis 4 for Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Groups [1] Vitamin E vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] 0.15
95% Confidence Interval -1.32 to 1.63
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the vitamin E group.

Statistical Analysis 5 for Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Groups [1] Memantine vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] -0.26
95% Confidence Interval -1.72 to 1.21
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the memantine group.

Statistical Analysis 6 for Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
Groups [1] Vitamin E vs. Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.84
Mean Difference (Net) [4] -0.41
95% Confidence Interval -1.88 to 1.06
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the memantine group.



4.  Primary:   Neuropsychiatric Inventory Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

Measure Type Primary
Measure Title Neuropsychiatric Inventory Change From Baseline
Measure Description The Neuropsychiatric Inventory (NPI) assesses psychological and behavioral problems in patients with dementia. For each of twelve domains, there are four scores: frequency, severity, total frequency x severity, and caregiver distress. The frequency x severity total scores from each domain are summed for an overall total score that ranges from 0 to 144. The total caregiver distress scores are also summed for an overall total caregiver distress score that ranges from 0 to 60. The secondary endpoint for the trial will be the overall frequency times severity total score. Outcome analysis is average least square means change from baseline.
Time Frame 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline  
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.
Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 140   142   139   140 
Neuropsychiatric Inventory Change From Baseline 
[Units: Units on a scale]
Least Squares Mean (Standard Error)
       
6 months minus baseline   -1.24  (1.07)   -0.20  (1.06)   -0.47  (1.08)   0.46  (1.07) 
12 months minus baseline   -1.04  (1.21)   0.31  (1.22)   -0.17  (1.22)   1.08  (1.24) 
18 months minus baseline   0.93  (1.40)   1.18  (1.43)   0.41  (1.41)   4.06  (1.44) 
24 months minus baseline   2.16  (1.74)   4.29  (1.79)   1.98  (1.77)   3.59  (1.84) 
30 months minus baseline   3.21  (1.70)   2.62  (1.71)   2.16  (1.71)   1.66  (1.81) 
36 months minus baseline   2.15  (1.97)   3.24  (2.07)   2.79  (1.95)   0.60  (2.16) 
42 months minus baseline   0.81  (2.64)   3.63  (2.75)   1.85  (2.54)   3.64  (2.89) 
48 months minus baseline   -0.60  (2.53)   2.79  (2.60)   5.14  (2.54)   0.30  (2.79) 
Average change from baseline   0.79  (1.00)   1.87  (1.00)   1.79  (1.00)   2.26  (1.01) 


Statistical Analysis 1 for Neuropsychiatric Inventory Change From Baseline
Groups [1] Vitamin E vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.94
Mean Difference (Net) [4] -1.46
95% Confidence Interval -3.55 to 0.63
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the placebo group.

Statistical Analysis 2 for Neuropsychiatric Inventory Change From Baseline
Groups [1] Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.94
Mean Difference (Net) [4] -0.39
95% Confidence Interval -2.47 to 1.70
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the memantine group minus the placebo group.

Statistical Analysis 3 for Neuropsychiatric Inventory Change From Baseline
Groups [1] Vitamin E + Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.94
Mean Difference (Net) [4] -0.47
95% Confidence Interval -2.57 to 1.63
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the placebo group.

Statistical Analysis 4 for Neuropsychiatric Inventory Change From Baseline
Groups [1] Vitamin E vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.94
Mean Difference (Net) [4] 0.99
95% Confidence Interval -1.09 to 3.07
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the vitamin E group.

Statistical Analysis 5 for Neuropsychiatric Inventory Change From Baseline
Groups [1] Memantine vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.94
Mean Difference (Net) [4] -0.08
95% Confidence Interval -2.16 to 1.99
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the memantine group.

Statistical Analysis 6 for Neuropsychiatric Inventory Change From Baseline
Groups [1] Vitamin E vs. Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.94
Mean Difference (Net) [4] -1.08
95% Confidence Interval -3.14 to 0.99
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the memantine group.



5.  Primary:   Caregiver Activity Survey Change From Baseline   [ Time Frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline ]

Measure Type Primary
Measure Title Caregiver Activity Survey Change From Baseline
Measure Description The Caregiver Activity Survey (CAS) was developed to measure the time caregivers spend aiding Alzheimer patients with their day-to-day activities. The CAS consists of six items that ask for an estimate in hours and minutes of the time that the caregiver spent during the previous 24 hours performing these particular activities. The six CAS items are as follows: 1) communication with the person, 2) using transportation, 3) dressing, 4) eating, 5) looking after one's appearance, and 6) supervising the person. The more caregiving hours the worse the patient's functioning level. Outcome analysis is average least square means change from baseline.
Time Frame 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline  
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.
Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 140   142   139   140 
Caregiver Activity Survey Change From Baseline 
[Units: Hours per day]
Least Squares Mean (Standard Error)
       
6 months minus baseline   -0.93  (0.82)   0.99  (0.81)   1.08  (0.83)   1.20  (0.82) 
12 months minus baseline   -0.18  (1.00)   2.72  (1.01)   1.39  (1.01)   1.89  (1.04) 
18 months minus baseline   2.12  (1.20)   3.77  (1.22)   2.69  (1.20)   3.16  (1.23) 
24 months minus baseline   1.60  (1.09)   3.06  (1.13)   2.82  (1.11)   3.45  (1.16) 
30 months minus baseline   4.14  (1.22)   5.22  (1.25)   3.41  (1.24)   4.36  (1.32) 
36 months minus baseline   7.69  (2.30)   5.72  (2.43)   4.90  (2.24)   10.68  (2.51) 
42 months minus baseline   4.95  (1.81)   9.46  (1.89)   5.48  (1.73)   10.62  (1.99) 
48 months minus baseline   10.17  (2.74)   9.27  (2.80)   13.80  (2.74)   12.17  (3.03) 
Average change from baseline   3.35  (0.78)   5.52  (0.78)   5.00  (0.78)   5.14  (0.79) 


Statistical Analysis 1 for Caregiver Activity Survey Change From Baseline
Groups [1] Vitamin E vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.12
Mean Difference (Net) [4] -1.79
95% Confidence Interval -3.35 to -0.23
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the placebo group.

Statistical Analysis 2 for Caregiver Activity Survey Change From Baseline
Groups [1] Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.86
Mean Difference (Net) [4] 0.38
95% Confidence Interval -1.18 to 1.94
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the memantine group minus the placebo group.

Statistical Analysis 3 for Caregiver Activity Survey Change From Baseline
Groups [1] Vitamin E + Memantine vs. Placebo
Method [2] Mixed Models Analysis
P Value [3] 0.86
Mean Difference (Net) [4] -0.14
95% Confidence Interval -1.70 to 1.42
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the placebo group.

Statistical Analysis 4 for Caregiver Activity Survey Change From Baseline
Groups [1] Vitamin E vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.14
Mean Difference (Net) [4] 1.65
95% Confidence Interval 0.11 to 3.19
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the vitamin E group.

Statistical Analysis 5 for Caregiver Activity Survey Change From Baseline
Groups [1] Memantine vs. Vitamin E + Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.86
Mean Difference (Net) [4] -0.52
95% Confidence Interval -2.07 to 1.02
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E + memantine group minus the memantine group.

Statistical Analysis 6 for Caregiver Activity Survey Change From Baseline
Groups [1] Vitamin E vs. Memantine
Method [2] Mixed Models Analysis
P Value [3] 0.03
Mean Difference (Net) [4] -2.17
95% Confidence Interval -3.71 to -0.63
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Longitudinal analysis to assess the average treatment effect over 48 months with visits at 6, 12, 18, 24, 30, 36, 42 and 48 months using all available data.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Mixed effects model assuming data missing at random, adjusted for medical center as a random effect and for the baseline outcome score.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p-value is adjusted for 6 treatment group comparisons
[4] Other relevant estimation information:
  Mean difference is the least squares mean changes from baseline for the vitamin E group minus the memantine group.



6.  Secondary:   Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)   [ Time Frame: Every 6 months to a maximum of 4 years ]

Measure Type Secondary
Measure Title Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)
Measure Description The Dependence Scale assesses the level of assistance needed by patients with Alzheimer's disease for activities of daily living. The scale yields six levels of dependence: no assistance required (Level 0); requires occasional reminders (Level 1); requires frequent reminders and/or help with household chores (Level 2); needs daily supervision (Level 3); needs to be dressed, toileted or fed (Level 4); needs to be transferred, diapered or tube fed (Level 5).
Time Frame Every 6 months to a maximum of 4 years  
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.
Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 140   142   139   140 
Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level) 
[Units: Participants]
 80   87   87   79 


Statistical Analysis 1 for Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.69
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  3 degrees of freedom test
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  p- value is unadjusted for multiple comparisons because its a 3 degrees of freedom test for any treatment group differences



7.  Other Pre-specified:   All-cause Mortality   [ Time Frame: up to 4 years ]

Measure Type Other Pre-specified
Measure Title All-cause Mortality
Measure Description Survival analysis of death from any cause.
Time Frame up to 4 years  
Safety Issue Yes  

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.
Intention-to-treat analysis that includes all randomized participants.

Reporting Groups
  Description
Vitamin E Alpha-tocopherol (vitamin E in the form of dl-alpha-tocopheryl acetate), 2000 international units (IU) per day, taken as one 1000 IU hard-gelatin, liquid-filled capsules twice a day plus matching memantine placebos.
Memantine Memantine 20 mg per day, titrated over four weeks to a maintenance dosage of 10 mg pills taken twice a day plus matching vitamin E placebo.
Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day.
Placebo Matching placebo pills for vitamin E and memantine

Measured Values
   Vitamin E   Memantine   Vitamin E + Memantine   Placebo 
Participants Analyzed 
[Units: Participants]
 152   155   154   152 
All-cause Mortality 
[Units: Participants]
 26   39   32   31 


Statistical Analysis 1 for All-cause Mortality
Groups [1] Vitamin E vs. Placebo
Method [2] Log Rank
P Value [3] 0.31
Hazard Ratio (HR) [4] 0.87
95% Confidence Interval 0.67 to 1.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[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:
  p-value is unadjusted for multiple comparisons
[4] Other relevant estimation information:
  Hazard ratio is for vitamin E group relative to the placebo group.

Statistical Analysis 2 for All-cause Mortality
Groups [1] Memantine vs. Placebo
Method [2] Log Rank
P Value [3] 0.47
Hazard Ratio (HR) [4] 1.06
95% Confidence Interval 0.91 to 1.24
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[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:
  p-value is unadjusted for multiple comparisons
[4] Other relevant estimation information:
  Hazard ratio is for the memantine group relative to the placebo group.

Statistical Analysis 3 for All-cause Mortality
Groups [1] Vitamin E + Memantine vs. Placebo
Method [2] Log Rank
P Value [3] 0.80
Hazard Ratio (HR) [4] 0.94
95% Confidence Interval 0.57 to 1.54
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[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:
  p-value is unadjusted for multiple comparisons
[4] Other relevant estimation information:
  Hazard ratio is for the vitamin E + memantine group relative to the placebo group.




  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
No text entered.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Peter Guarino, PhD, Director WH-CSPCC
Organization: Dept. of Veterans Affairs Cooperative Stduies Program
phone: 203-932-5711 ext 3780
e-mail: peter.guarino@va.gov


Publications of Results:
Other Publications:

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT00235716     History of Changes
Other Study ID Numbers: 546
Study First Received: October 6, 2005
Results First Received: December 6, 2013
Last Updated: July 14, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration