A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease

Study Overview
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Brief Summary
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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
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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 enhance cholinergic neuronal function, promote neuroprotective effects, and 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 any of three FDA approved cholinesterase inhibitors that facilitates central acetylcholine neurotransmission (donepezil, rivastigmine, galantamine); 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 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 2,000 IU/d of alpha-tocopherol plus memantine placebo, 20 mg/d of memantine (Namenda) plus alpha-tocopherol placebo, 2,000 IU/d of alpha-tocopherol plus 20 mg/d of memantine, or 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.

Official Title
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CSP #546 - A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD)

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: dl-alpha-tocopherol
* Drug: Memantine
* Drug: dl-alpha-tocopherol
* Drug: Memantine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnoses of possible or probable Alzheimer's disease (NINCDS-ADRDA) 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 Written informed consent from both the patient (or surrogate) and caregiver An MMSE score between 12 and 26 inclusive 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 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: A non-Alzheimer primary dementia (e.g., vascular dementia, Lewy body dementia, fronto-temporal dementia, vitamin B-12 deficiency, hypothyroidism) Current major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by DSM-IV Presence of any uncontrolled systemic illness that would interfere with participation in the study or a life expectancy of less than one year Pregnant or intention to become pregnant Enrollment in another interventional clinical trial Current prescription with more than one AChE inhibitor Current prescription for warfarin Use of vitamin E supplements in the past 2 weeks Use of memantine in the past 4 weeks or known intolerance Estimated creatinine clearance less than 5ml/min (Cockcroft-Gault formula) Use of amantadine in the past 2 weeks

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>2,000 IU per day of dl-alpha-tocopherol plus placebo for memantine | Drug: dl-alpha-tocopherol<br>* 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.<br>* Other names: Vitamin E;|
| Experimental: Arm 2<br>20 mg per day of memantine plus placebo for dl-alpha-tocopherol | Drug: Memantine<br>* 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.<br>* Other names: Namenda (R);|
| Experimental: Arm 3<br>Combination of 2,000 IU per day of dl-alpha-tocopherol and 20 mg per day of memantine | Drug: dl-alpha-tocopherol<br>* 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.<br>* Other names: Vitamin E;Drug: Memantine<br>* 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.<br>* Other names: Namenda (R);|
| Placebo Comparator: Arm 4<br>Matching placebos for dl-alpha-tocopherol and memantine | Drug: Placebo<br>* Matching placebos for dl-alpha-tocopherol and memantine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 
| 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. | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 
| 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. | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 
| 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. | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 
| 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. | 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Every 6 months to a maximum of 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, clinical trial, randomized controlled trial, alpha-tocopherol, vitamin E, Namenda, memantine