Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease, clinical trial, randomized controlled trial, alpha-tocopherol, vitamin E, Namenda, memantine
Brief summary
The purpose of this study is to determine whether alpha-tocopherol, memantine (Namenda), or the combination will significantly delay clinical progression in mild to moderately demented patients with Alzheimer's disease compared to placebo.
Detailed description
Abstract: Alzheimer's disease (AD), a neurodegenerative disorder resulting in cognitive loss, behavioral problems, and functional decline, is characterized by well-established and well-known neuropathological changes in the brain. Cognitive deficits and behavioral symptoms are thought to be due to cholinergic neuronal degeneration and loss associated with oxidative stress and inflammatory responses. Current therapeutic strategies include efforts to 1. enhance cholinergic neuronal function, 2. promote neuroprotective effects, and 3. block pathologic activity of excessive glutamate with a moderate-affinity NMDA antagonist. A combination of pharmacological therapies directed at simultaneously improving neuronal function and neuroprotection would presumably be more effective than either treatment alone. To test this hypothesis, this study will examine the efficacy of drug treatment with a combination of 1. any of three FDA approved cholinesterase inhibitors that facilitates central acetylcholine neurotransmission (donepezil, rivastigmine, galantamine); 2. alpha-tocopherol, a fat soluble vitamin that has been shown to slow the rate of progression of AD, presumably through neuroprotective mechanism that reduces oxidative stress; and 3. memantine, a moderate-affinity NMDA antagonist that blocks excessive stimulation of NMDA receptors by glutamate. CSP#546 will be a double-blind, placebo-controlled, randomized, clinical trial to assess the efficacy of adding alpha-tocopherol, memantine, and the combination for the treatment of functional decline in mild-to-moderately demented patients with Alzheimer's disease (MMSE 12-26) who are currently taking an acetylcholinesterase inhibitor (AchEI). Eligible Veterans will be randomly assigned to either 1. 2,000 IU/d of alpha-tocopherol plus memantine placebo, 2. 20 mg/d of memantine (Namenda) plus alpha-tocopherol placebo, 3. 2,000 IU/d of alpha-tocopherol plus 20 mg/d of memantine, or 4. alpha-tocopherol placebo plus memantine placebo. The primary outcome for the study will be progression of AD as measured by the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) inventory. The ADCS/ADL inventory is an established outcome measure that was designed to assess functional capacity over a broad range of dementia severity and to be sensitive in measuring dementia progression. Secondary outcome measures will include the following five instruments: Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) (cognition), MMSE (cognition), The Dependence Scale (function), Neuropsychiatric Inventory (NPI) (behavior), and Caregiver Activity Survey (CAS) (caregiver time). Outcomes and safety assessments will be obtained at baseline and every six months. The target sample size for the trial will be 620 patients (210 per treatment arm). This sample size will provide 90% power to detect a 4-point mean treatment difference in the ADCS/ADL inventory by the end of the average follow-up period, adjusted for losses. The effects to be detected are modest and translate into a 17.7% reduction in the annual rate of decline with each therapy given alone, and if the effects are additive, an approximate 35% reduction for combined therapy. These effects are equivalent to slowing the rate of progression of the disease by nearly 6 months for monotherapy and 12 months for combined therapy. To achieve the target sample size, Veterans will be recruited over a 3-year period with an estimated minimum follow-up of 1 year and a maximum of 4 years. A total of 10 to 15 VA sites will be established to enroll an average of one Veteran every 2 weeks. CSP#546 is designed to assess both a clinically and economically important treatment effect. If the study definitely determined that alpha-tocopherol, memantine, or the combination delays the progression of AD, the study would be tremendously valuable in reducing the financial and emotional costs of the disease in the VA and U.S. as a whole.
Interventions
Alpha-tocopherol will be given as an oral dose of 1000 IU twice a day (morning and evening). The form of vitamin E that will be used in this study will be hard gel capsules of dl-alpha-tocopheryl acetate (synthetic) vitamin E.
DRUGMemantine
A moderate-affinity NMDA antagonist. Memantine will be titrated over four weeks to a maintenance dose of 10 mg twice a day. During week 1 patients will take one 5-mg memantine tablet in the morning. During week 2 patients will take one 5-mg memantine tablet in the morning and one in the evening. During week 3 patients will take two 5-mg memantine tablets in the morning and one 5-mg tablet in the evening. Beginning with week 4, participants will take four 5-mg tablets daily, two in the morning and two in the evening.
DRUGPlacebo
Matching placebos for dl-alpha-tocopherol and memantine.
Sponsors
Forest Laboratories
DSM Nutritional Products, Inc.
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnoses of possible or probable Alzheimer's disease (NINCDS-ADRDA) 2. Presence of a caregiver (friend or relative) who can assume responsibility for medication compliance, can accompany the patient to all visits, and rate patient's condition 3. Written informed consent from both the patient (or surrogate) and caregiver 4. An MMSE score between 12 and 26 inclusive 5. Administration of a maintenance dosage of donepezil (5-10mg/d), rivastigmine (6-12mg/d) or rivastigmine (Exelon) patch (4.6 mg or 9.5 mg), galantamine or galantamine ER (16-24mg/d) for a minimum of 4 weeks prior to randomization 6. Agreement not to take vitamin E supplements and/or memantine outside of the study (daily multivitamin is permitted containing up to 100 IU alpha-tocopherol)
Exclusion criteria
1. A non-Alzheimer primary dementia (e.g., vascular dementia, Lewy body dementia, fronto-temporal dementia, vitamin B-12 deficiency, hypothyroidism) 2. Current major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by DSM-IV 3. Presence of any uncontrolled systemic illness that would interfere with participation in the study or a life expectancy of less than one year 4. Pregnant or intention to become pregnant 5. Enrollment in another interventional clinical trial 6. Current prescription with more than one AChE inhibitor 7. Current prescription for warfarin 8. Use of vitamin E supplements in the past 2 weeks 9. Use of memantine in the past 4 weeks or known intolerance 10. Estimated creatinine clearance less than 5ml/min (Cockcroft-Gault formula) 11. Use of amantadine in the past 2 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mini-Mental State Examination Change From Baseline | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 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. |
| Neuropsychiatric Inventory Change From Baseline | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 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. |
| Caregiver Activity Survey Change From Baseline | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 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. |
| Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 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. |
| Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level) | Every 6 months to a maximum of 4 years | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | up to 4 years | Survival analysis of death from any cause. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Recruitment initiated in August, 2007 and concluded in March, 2012. Enrollment took place at 14 VA medical centers.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 152 |
| 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. | 155 |
| Vitamin E + Memantine 2000 IU of Alpha-tocopherol (vitamin E) per day plus 20 mg memantine per day. | 154 |
| Placebo Matching placebo pills for vitamin E and memantine | 152 |
| Total | 613 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 0 |
| Overall Study | Death | 26 | 39 | 32 | 31 |
| Overall Study | Lost to Follow-up | 12 | 7 | 14 | 10 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 23 | 19 | 17 | 18 |
Baseline characteristics
| Characteristic | Vitamin E | Memantine (Namenda) | Vitamin E + Memantine | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 78.6 years STANDARD_DEVIATION 7.2 | 78.8 years STANDARD_DEVIATION 7.2 | 78.3 years STANDARD_DEVIATION 7 | 79.4 years STANDARD_DEVIATION 7 | 78.8 years STANDARD_DEVIATION 7.1 |
| Alzheimer's Disease Assessment Scale - Cognitive portion | 18.5 units on a scale STANDARD_DEVIATION 8.8 | 19.5 units on a scale STANDARD_DEVIATION 7.9 | 18.0 units on a scale STANDARD_DEVIATION 8.4 | 19.1 units on a scale STANDARD_DEVIATION 8.4 | 18.8 units on a scale STANDARD_DEVIATION 8.4 |
| Alzheimer's Disease Cooperative Study/Activities of Daily Living Inventory | 56.6 units on a scale STANDARD_DEVIATION 14.9 | 57.3 units on a scale STANDARD_DEVIATION 14.2 | 56.4 units on a scale STANDARD_DEVIATION 14 | 56.8 units on a scale STANDARD_DEVIATION 13.7 | 56.8 units on a scale STANDARD_DEVIATION 14.2 |
| Apolipoprotein E ε4 status Non-carriers | 47 participants | 48 participants | 59 participants | 55 participants | 209 participants |
| Apolipoprotein E ε4 status Not Tested | 56 participants | 50 participants | 43 participants | 49 participants | 198 participants |
| Apolipoprotein E ε4 status One ε4 allele | 39 participants | 44 participants | 44 participants | 38 participants | 165 participants |
| Apolipoprotein E ε4 status Two ε4 alleles | 10 participants | 13 participants | 8 participants | 10 participants | 41 participants |
| Caregiver Activity Survey | 7.3 hours per day STANDARD_DEVIATION 14.3 | 6.7 hours per day STANDARD_DEVIATION 9 | 6.6 hours per day STANDARD_DEVIATION 10.5 | 6.5 hours per day STANDARD_DEVIATION 9.2 | 6.8 hours per day STANDARD_DEVIATION 10.9 |
| Concomitant Medications Acetylcholinesterase Inhibitors (AChEI) Donepezil | 104 participants | 100 participants | 100 participants | 96 participants | 400 participants |
| Concomitant Medications Acetylcholinesterase Inhibitors (AChEI) Galantamine | 43 participants | 47 participants | 49 participants | 55 participants | 194 participants |
| Concomitant Medications Acetylcholinesterase Inhibitors (AChEI) None | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Concomitant Medications Acetylcholinesterase Inhibitors (AChEI) Rivastigmine | 5 participants | 8 participants | 4 participants | 1 participants | 18 participants |
| Dependence Scale Level 0 | 5 participants | 6 participants | 8 participants | 3 participants | 22 participants |
| Dependence Scale Level 1 | 8 participants | 6 participants | 8 participants | 5 participants | 27 participants |
| Dependence Scale Level 2 | 85 participants | 91 participants | 80 participants | 79 participants | 335 participants |
| Dependence Scale Level 3 | 31 participants | 35 participants | 31 participants | 37 participants | 134 participants |
| Dependence Scale Level 4 | 4 participants | 7 participants | 10 participants | 8 participants | 29 participants |
| Dependence Scale Level 5 | 19 participants | 10 participants | 17 participants | 20 participants | 66 participants |
| Education College Graduation or Advanced Degree | 38 participants | 28 participants | 34 participants | 34 participants | 134 participants |
| Education <High School Graduation | 41 participants | 41 participants | 26 participants | 29 participants | 137 participants |
| Education High School Graduation | 46 participants | 48 participants | 57 participants | 56 participants | 207 participants |
| Education Some College | 27 participants | 38 participants | 37 participants | 33 participants | 135 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 15 Participants | 15 Participants | 19 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 135 Participants | 140 Participants | 139 Participants | 133 Participants | 547 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mini-Mental State Examination | 21.3 units on a scale STANDARD_DEVIATION 3.3 | 20.8 units on a scale STANDARD_DEVIATION 3.8 | 21.3 units on a scale STANDARD_DEVIATION 3.4 | 20.8 units on a scale STANDARD_DEVIATION 3.8 | 21.0 units on a scale STANDARD_DEVIATION 3.6 |
| Neuropsychiatric Inventory | 12.2 units on a scale STANDARD_DEVIATION 13.3 | 12.1 units on a scale STANDARD_DEVIATION 13.1 | 12.3 units on a scale STANDARD_DEVIATION 13.3 | 13.5 units on a scale STANDARD_DEVIATION 14.2 | 12.5 units on a scale STANDARD_DEVIATION 13.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 21 Participants | 18 Participants | 20 Participants | 80 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 130 Participants | 132 Participants | 136 Participants | 131 Participants | 529 Participants |
| Region of Enrollment United States | 152 participants | 155 participants | 154 participants | 152 participants | 613 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 4 Participants | 3 Participants | 19 Participants |
| Sex: Female, Male Male | 146 Participants | 149 Participants | 150 Participants | 149 Participants | 594 Participants |
| Weeks from AChEI Initiation to Randomization ≤ 12 weeks | 46 participants | 36 participants | 49 participants | 37 participants | 168 participants |
| Weeks from AChEI Initiation to Randomization > 12 weeks | 105 participants | 119 participants | 104 participants | 115 participants | 443 participants |
| Weeks from AChEI Initiation to Randomization Missing | 1 participants | 0 participants | 1 participants | 0 participants | 2 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 91 / 152 | 97 / 155 | 90 / 154 | 89 / 152 |
| serious Total, serious adverse events | 82 / 152 | 84 / 155 | 83 / 154 | 95 / 152 |
Outcome results
Primary
Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
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
Population: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 42 months minus baseline | 10.35 units on a scale | Standard Error 1.6 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 36 months minus baseline | 9.00 units on a scale | Standard Error 1.53 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 48 months minus baseline | 10.73 units on a scale | Standard Error 1.87 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 24 months minus baseline | 4.32 units on a scale | Standard Error 1.1 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 30 months minus baseline | 7.87 units on a scale | Standard Error 1.31 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 18 months minus baseline | 4.34 units on a scale | Standard Error 0.91 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 12 months minus baseline | 2.40 units on a scale | Standard Error 0.72 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 6 months minus baseline | 1.38 units on a scale | Standard Error 0.63 |
| Vitamin E | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | Average change from baseline | 5.97 units on a scale | Standard Error 0.7 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 12 months minus baseline | 3.32 units on a scale | Standard Error 0.72 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 36 months minus baseline | 8.31 units on a scale | Standard Error 1.6 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | Average change from baseline | 6.38 units on a scale | Standard Error 0.7 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 48 months minus baseline | 11.74 units on a scale | Standard Error 1.97 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 42 months minus baseline | 8.24 units on a scale | Standard Error 1.64 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 18 months minus baseline | 5.69 units on a scale | Standard Error 0.91 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 6 months minus baseline | 1.11 units on a scale | Standard Error 0.62 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 24 months minus baseline | 6.73 units on a scale | Standard Error 1.12 |
| Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 30 months minus baseline | 7.64 units on a scale | Standard Error 1.34 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 42 months minus baseline | 7.97 units on a scale | Standard Error 1.51 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 48 months minus baseline | 9.70 units on a scale | Standard Error 1.82 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | Average change from baseline | 6.13 units on a scale | Standard Error 0.71 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 24 months minus baseline | 5.76 units on a scale | Standard Error 1.11 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 30 months minus baseline | 5.85 units on a scale | Standard Error 1.3 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 12 months minus baseline | 2.48 units on a scale | Standard Error 0.72 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 36 months minus baseline | 8.26 units on a scale | Standard Error 1.5 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 6 months minus baseline | 1.53 units on a scale | Standard Error 0.63 |
| Vitamin E + Memantine | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 18 months minus baseline | 3.46 units on a scale | Standard Error 0.9 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | Average change from baseline | 7.78 units on a scale | Standard Error 0.7 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 18 months minus baseline | 6.04 units on a scale | Standard Error 0.92 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 6 months minus baseline | 3.04 units on a scale | Standard Error 0.63 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 24 months minus baseline | 6.71 units on a scale | Standard Error 1.15 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 30 months minus baseline | 8.90 units on a scale | Standard Error 1.38 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 12 months minus baseline | 4.26 units on a scale | Standard Error 0.74 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 36 months minus baseline | 10.77 units on a scale | Standard Error 1.63 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 42 months minus baseline | 10.61 units on a scale | Standard Error 1.69 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline | 48 months minus baseline | 10.85 units on a scale | Standard Error 2.04 |
Comparison: 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.p-value: 0.195% CI: [-3.28, -0.33]Mixed Models Analysis
Comparison: 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.p-value: 0.2595% CI: [-2.85, 0.07]Mixed Models Analysis
Comparison: 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.p-value: 0.1495% CI: [-3.12, -0.17]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-1.32, 1.63]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-1.72, 1.21]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-1.88, 1.06]Mixed Models Analysis
Primary
Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
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
Population: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 42 months minus baseline | -25.30 units on a scale | Standard Error 2.57 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 36 months minus baseline | -19.71 units on a scale | Standard Error 2.34 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | Average change from baseline | -13.81 units on a scale | Standard Error 1.11 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 24 months minus baseline | -11.88 units on a scale | Standard Error 1.66 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 18 months minus baseline | -8.01 units on a scale | Standard Error 1.4 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 12 months minus baseline | -4.29 units on a scale | Standard Error 1.2 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 48 months minus baseline | -26.55 units on a scale | Standard Error 3.11 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 30 months minus baseline | -15.84 units on a scale | Standard Error 1.94 |
| Vitamin E | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 6 months minus baseline | -1.72 units on a scale | Standard Error 0.95 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 30 months minus baseline | -18.30 units on a scale | Standard Error 1.97 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 42 months minus baseline | -23.48 units on a scale | Standard Error 2.65 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 36 months minus baseline | -18.78 units on a scale | Standard Error 2.43 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 12 months minus baseline | -6.99 units on a scale | Standard Error 1.21 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 6 months minus baseline | -2.40 units on a scale | Standard Error 0.94 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 18 months minus baseline | -9.32 units on a scale | Standard Error 1.42 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | Average change from baseline | -14.98 units on a scale | Standard Error 1.1 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 48 months minus baseline | -24.60 units on a scale | Standard Error 3.18 |
| Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 24 months minus baseline | -14.06 units on a scale | Standard Error 1.7 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 30 months minus baseline | -15.66 units on a scale | Standard Error 1.97 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 6 months minus baseline | -2.78 units on a scale | Standard Error 0.96 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 12 months minus baseline | -6.60 units on a scale | Standard Error 1.21 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 18 months minus baseline | -7.98 units on a scale | Standard Error 1.41 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 24 months minus baseline | -12.82 units on a scale | Standard Error 1.68 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 36 months minus baseline | -18.89 units on a scale | Standard Error 2.32 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 42 months minus baseline | -23.44 units on a scale | Standard Error 2.52 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 48 months minus baseline | -29.25 units on a scale | Standard Error 3.08 |
| Vitamin E + Memantine | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | Average change from baseline | -15.20 units on a scale | Standard Error 1.11 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 42 months minus baseline | -28.13 units on a scale | Standard Error 2.76 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 24 months minus baseline | -16.18 units on a scale | Standard Error 1.74 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 18 months minus baseline | -10.21 units on a scale | Standard Error 1.43 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | Average change from baseline | -16.96 units on a scale | Standard Error 1.11 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 48 months minus baseline | -27.55 units on a scale | Standard Error 3.38 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 12 months minus baseline | -8.11 units on a scale | Standard Error 1.23 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 36 months minus baseline | -24.82 units on a scale | Standard Error 2.51 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 30 months minus baseline | -19.67 units on a scale | Standard Error 2.06 |
| Placebo | Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline | 6 months minus baseline | -4.52 units on a scale | Standard Error 0.95 |
Comparison: 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.p-value: 0.0395% CI: [0.92, 5.39]Mixed Models Analysis
Comparison: 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.p-value: 0.495% CI: [-0.24, 4.2]Mixed Models Analysis
Comparison: 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.p-value: 0.4995% CI: [-0.48, 4]Mixed Models Analysis
Comparison: 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.p-value: 0.695% CI: [-3.63, 0.85]Mixed Models Analysis
Comparison: 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.p-value: 0.8595% CI: [-2.44, 2.01]Mixed Models Analysis
Comparison: 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.p-value: 0.695% CI: [-1.04, 3.39]Mixed Models Analysis
Primary
Caregiver Activity Survey Change From Baseline
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
Population: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin E | Caregiver Activity Survey Change From Baseline | 42 months minus baseline | 4.95 hours per day | Standard Error 1.81 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 36 months minus baseline | 7.69 hours per day | Standard Error 2.3 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | Average change from baseline | 3.35 hours per day | Standard Error 0.78 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 24 months minus baseline | 1.60 hours per day | Standard Error 1.09 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 18 months minus baseline | 2.12 hours per day | Standard Error 1.2 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 12 months minus baseline | -0.18 hours per day | Standard Error 1 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 48 months minus baseline | 10.17 hours per day | Standard Error 2.74 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 30 months minus baseline | 4.14 hours per day | Standard Error 1.22 |
| Vitamin E | Caregiver Activity Survey Change From Baseline | 6 months minus baseline | -0.93 hours per day | Standard Error 0.82 |
| Memantine | Caregiver Activity Survey Change From Baseline | 30 months minus baseline | 5.22 hours per day | Standard Error 1.25 |
| Memantine | Caregiver Activity Survey Change From Baseline | 42 months minus baseline | 9.46 hours per day | Standard Error 1.89 |
| Memantine | Caregiver Activity Survey Change From Baseline | 36 months minus baseline | 5.72 hours per day | Standard Error 2.43 |
| Memantine | Caregiver Activity Survey Change From Baseline | 12 months minus baseline | 2.72 hours per day | Standard Error 1.01 |
| Memantine | Caregiver Activity Survey Change From Baseline | 6 months minus baseline | 0.99 hours per day | Standard Error 0.81 |
| Memantine | Caregiver Activity Survey Change From Baseline | 18 months minus baseline | 3.77 hours per day | Standard Error 1.22 |
| Memantine | Caregiver Activity Survey Change From Baseline | Average change from baseline | 5.52 hours per day | Standard Error 0.78 |
| Memantine | Caregiver Activity Survey Change From Baseline | 48 months minus baseline | 9.27 hours per day | Standard Error 2.8 |
| Memantine | Caregiver Activity Survey Change From Baseline | 24 months minus baseline | 3.06 hours per day | Standard Error 1.13 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 30 months minus baseline | 3.41 hours per day | Standard Error 1.24 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 6 months minus baseline | 1.08 hours per day | Standard Error 0.83 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 12 months minus baseline | 1.39 hours per day | Standard Error 1.01 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 18 months minus baseline | 2.69 hours per day | Standard Error 1.2 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 24 months minus baseline | 2.82 hours per day | Standard Error 1.11 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 36 months minus baseline | 4.90 hours per day | Standard Error 2.24 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 42 months minus baseline | 5.48 hours per day | Standard Error 1.73 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | 48 months minus baseline | 13.80 hours per day | Standard Error 2.74 |
| Vitamin E + Memantine | Caregiver Activity Survey Change From Baseline | Average change from baseline | 5.00 hours per day | Standard Error 0.78 |
| Placebo | Caregiver Activity Survey Change From Baseline | 42 months minus baseline | 10.62 hours per day | Standard Error 1.99 |
| Placebo | Caregiver Activity Survey Change From Baseline | 24 months minus baseline | 3.45 hours per day | Standard Error 1.16 |
| Placebo | Caregiver Activity Survey Change From Baseline | 18 months minus baseline | 3.16 hours per day | Standard Error 1.23 |
| Placebo | Caregiver Activity Survey Change From Baseline | Average change from baseline | 5.14 hours per day | Standard Error 0.79 |
| Placebo | Caregiver Activity Survey Change From Baseline | 48 months minus baseline | 12.17 hours per day | Standard Error 3.03 |
| Placebo | Caregiver Activity Survey Change From Baseline | 12 months minus baseline | 1.89 hours per day | Standard Error 1.04 |
| Placebo | Caregiver Activity Survey Change From Baseline | 36 months minus baseline | 10.68 hours per day | Standard Error 2.51 |
| Placebo | Caregiver Activity Survey Change From Baseline | 30 months minus baseline | 4.36 hours per day | Standard Error 1.32 |
| Placebo | Caregiver Activity Survey Change From Baseline | 6 months minus baseline | 1.20 hours per day | Standard Error 0.82 |
Comparison: 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.p-value: 0.1295% CI: [-3.35, -0.23]Mixed Models Analysis
Comparison: 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.p-value: 0.8695% CI: [-1.18, 1.94]Mixed Models Analysis
Comparison: 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.p-value: 0.8695% CI: [-1.7, 1.42]Mixed Models Analysis
Comparison: 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.p-value: 0.1495% CI: [0.11, 3.19]Mixed Models Analysis
Comparison: 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.p-value: 0.8695% CI: [-2.07, 1.02]Mixed Models Analysis
Comparison: 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.p-value: 0.0395% CI: [-3.71, -0.63]Mixed Models Analysis
Primary
Mini-Mental State Examination Change From Baseline
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
Population: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin E | Mini-Mental State Examination Change From Baseline | 42 months minus baseline | -4.84 units on a scale | Standard Error 0.79 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 36 months minus baseline | -4.97 units on a scale | Standard Error 0.74 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | Average change from baseline | -2.97 units on a scale | Standard Error 0.33 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 24 months minus baseline | -2.62 units on a scale | Standard Error 0.52 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 18 months minus baseline | -2.00 units on a scale | Standard Error 0.44 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 12 months minus baseline | -0.95 units on a scale | Standard Error 0.34 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 48 months minus baseline | -5.26 units on a scale | Standard Error 0.94 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 30 months minus baseline | -3.67 units on a scale | Standard Error 0.61 |
| Vitamin E | Mini-Mental State Examination Change From Baseline | 6 months minus baseline | -0.35 units on a scale | Standard Error 0.29 |
| Memantine | Mini-Mental State Examination Change From Baseline | 30 months minus baseline | -3.79 units on a scale | Standard Error 0.63 |
| Memantine | Mini-Mental State Examination Change From Baseline | 42 months minus baseline | -4.59 units on a scale | Standard Error 0.8 |
| Memantine | Mini-Mental State Examination Change From Baseline | 36 months minus baseline | -4.26 units on a scale | Standard Error 0.78 |
| Memantine | Mini-Mental State Examination Change From Baseline | 12 months minus baseline | -1.09 units on a scale | Standard Error 0.34 |
| Memantine | Mini-Mental State Examination Change From Baseline | 6 months minus baseline | -0.24 units on a scale | Standard Error 0.28 |
| Memantine | Mini-Mental State Examination Change From Baseline | 18 months minus baseline | -2.62 units on a scale | Standard Error 0.45 |
| Memantine | Mini-Mental State Examination Change From Baseline | Average change from baseline | -3.05 units on a scale | Standard Error 0.33 |
| Memantine | Mini-Mental State Examination Change From Baseline | 48 months minus baseline | -5.98 units on a scale | Standard Error 0.98 |
| Memantine | Mini-Mental State Examination Change From Baseline | 24 months minus baseline | -3.44 units on a scale | Standard Error 0.54 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 30 months minus baseline | -3.16 units on a scale | Standard Error 0.61 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 6 months minus baseline | -0.20 units on a scale | Standard Error 0.29 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 12 months minus baseline | -0.65 units on a scale | Standard Error 0.34 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 18 months minus baseline | -1.22 units on a scale | Standard Error 0.44 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 24 months minus baseline | -2.29 units on a scale | Standard Error 0.53 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 36 months minus baseline | -3.69 units on a scale | Standard Error 0.73 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 42 months minus baseline | -3.80 units on a scale | Standard Error 0.74 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | 48 months minus baseline | -5.70 units on a scale | Standard Error 0.91 |
| Vitamin E + Memantine | Mini-Mental State Examination Change From Baseline | Average change from baseline | -2.80 units on a scale | Standard Error 0.33 |
| Placebo | Mini-Mental State Examination Change From Baseline | 42 months minus baseline | -4.68 units on a scale | Standard Error 0.83 |
| Placebo | Mini-Mental State Examination Change From Baseline | 24 months minus baseline | -2.90 units on a scale | Standard Error 0.55 |
| Placebo | Mini-Mental State Examination Change From Baseline | 18 months minus baseline | -2.21 units on a scale | Standard Error 0.45 |
| Placebo | Mini-Mental State Examination Change From Baseline | Average change from baseline | -3.16 units on a scale | Standard Error 0.33 |
| Placebo | Mini-Mental State Examination Change From Baseline | 48 months minus baseline | -5.42 units on a scale | Standard Error 1.02 |
| Placebo | Mini-Mental State Examination Change From Baseline | 12 months minus baseline | -1.39 units on a scale | Standard Error 0.35 |
| Placebo | Mini-Mental State Examination Change From Baseline | 36 months minus baseline | -3.87 units on a scale | Standard Error 0.79 |
| Placebo | Mini-Mental State Examination Change From Baseline | 30 months minus baseline | -3.26 units on a scale | Standard Error 0.65 |
| Placebo | Mini-Mental State Examination Change From Baseline | 6 months minus baseline | -0.34 units on a scale | Standard Error 0.29 |
Comparison: 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.p-value: 0.8495% CI: [-0.54, 0.92]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-0.61, 0.84]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-0.36, 1.1]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-0.56, 0.9]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-0.47, 0.98]Mixed Models Analysis
Comparison: 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.p-value: 0.8495% CI: [-0.65, 0.8]Mixed Models Analysis
Primary
Neuropsychiatric Inventory Change From Baseline
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
Population: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | Average change from baseline | 0.79 units on a scale | Standard Error 1 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 30 months minus baseline | 3.21 units on a scale | Standard Error 1.7 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 24 months minus baseline | 2.16 units on a scale | Standard Error 1.74 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 48 months minus baseline | -0.60 units on a scale | Standard Error 2.53 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 12 months minus baseline | -1.04 units on a scale | Standard Error 1.21 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 6 months minus baseline | -1.24 units on a scale | Standard Error 1.07 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 42 months minus baseline | 0.81 units on a scale | Standard Error 2.64 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 36 months minus baseline | 2.15 units on a scale | Standard Error 1.97 |
| Vitamin E | Neuropsychiatric Inventory Change From Baseline | 18 months minus baseline | 0.93 units on a scale | Standard Error 1.4 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 30 months minus baseline | 2.62 units on a scale | Standard Error 1.71 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 12 months minus baseline | 0.31 units on a scale | Standard Error 1.22 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 18 months minus baseline | 1.18 units on a scale | Standard Error 1.43 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 24 months minus baseline | 4.29 units on a scale | Standard Error 1.79 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 36 months minus baseline | 3.24 units on a scale | Standard Error 2.07 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 6 months minus baseline | -0.20 units on a scale | Standard Error 1.06 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 42 months minus baseline | 3.63 units on a scale | Standard Error 2.75 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | 48 months minus baseline | 2.79 units on a scale | Standard Error 2.6 |
| Memantine | Neuropsychiatric Inventory Change From Baseline | Average change from baseline | 1.87 units on a scale | Standard Error 1 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 30 months minus baseline | 2.16 units on a scale | Standard Error 1.71 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 12 months minus baseline | -0.17 units on a scale | Standard Error 1.22 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | Average change from baseline | 1.79 units on a scale | Standard Error 1 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 36 months minus baseline | 2.79 units on a scale | Standard Error 1.95 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 48 months minus baseline | 5.14 units on a scale | Standard Error 2.54 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 24 months minus baseline | 1.98 units on a scale | Standard Error 1.77 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 42 months minus baseline | 1.85 units on a scale | Standard Error 2.54 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 18 months minus baseline | 0.41 units on a scale | Standard Error 1.41 |
| Vitamin E + Memantine | Neuropsychiatric Inventory Change From Baseline | 6 months minus baseline | -0.47 units on a scale | Standard Error 1.08 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 48 months minus baseline | 0.30 units on a scale | Standard Error 2.79 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 30 months minus baseline | 1.66 units on a scale | Standard Error 1.81 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 12 months minus baseline | 1.08 units on a scale | Standard Error 1.24 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 36 months minus baseline | 0.60 units on a scale | Standard Error 2.16 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | Average change from baseline | 2.26 units on a scale | Standard Error 1.01 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 42 months minus baseline | 3.64 units on a scale | Standard Error 2.89 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 6 months minus baseline | 0.46 units on a scale | Standard Error 1.07 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 18 months minus baseline | 4.06 units on a scale | Standard Error 1.44 |
| Placebo | Neuropsychiatric Inventory Change From Baseline | 24 months minus baseline | 3.59 units on a scale | Standard Error 1.84 |
Comparison: 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.p-value: 0.9495% CI: [-3.55, 0.63]Mixed Models Analysis
Comparison: 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.p-value: 0.9495% CI: [-2.47, 1.7]Mixed Models Analysis
Comparison: 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.p-value: 0.9495% CI: [-2.57, 1.63]Mixed Models Analysis
Comparison: 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.p-value: 0.9495% CI: [-1.09, 3.07]Mixed Models Analysis
Comparison: 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.p-value: 0.9495% CI: [-2.16, 1.99]Mixed Models Analysis
Comparison: 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.p-value: 0.9495% CI: [-3.14, 0.99]Mixed Models Analysis
Secondary
Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)
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
Population: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin E | Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level) | 80 participants |
| Memantine | Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level) | 87 participants |
| Vitamin E + Memantine | Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level) | 87 participants |
| Placebo | Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level) | 79 participants |
p-value: 0.69Log Rank
Other Pre-specified
All-cause Mortality
Survival analysis of death from any cause.
Time frame: up to 4 years
Population: Intention-to-treat analysis that includes all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vitamin E | All-cause Mortality | 26 participants |
| Memantine | All-cause Mortality | 39 participants |
| Vitamin E + Memantine | All-cause Mortality | 32 participants |
| Placebo | All-cause Mortality | 31 participants |
p-value: 0.3195% CI: [0.67, 1.13]Log Rank
p-value: 0.4795% CI: [0.91, 1.24]Log Rank
p-value: 0.895% CI: [0.57, 1.54]Log Rank