Alzheimer's DiseasePhase 3TEAM-ADNCT00235716

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

A Phase 3 study testing dl-alpha-tocopherol and Memantine in people with Alzheimer's Disease, run by US Department of Veterans Affairs at 14 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 40 years and older
Conditions the study is for: Alzheimer's Disease
What is being tested?: dl-alpha-tocopherol and Memantine
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 613 participants
Where: 14 sitesin 2 countries
Study dates: Aug 2007to Oct 2012
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 40 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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)

Who cannot join

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

Show all 11Show fewer

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

Trial locations and contacts

14 sites in 2 countries.

Country

City, postcode or hospital

14 sites in 2 countries

United States13 sites

VA Ann Arbor Healthcare System
Ann Arbor, Michigan, 48113
VA Maryland Health Care System, Baltimore
Baltimore, Maryland, 21201
VA Medical Center, Bay Pines
Bay Pines, Florida, 33708
VA Medical Center, Jamaica Plain Campus
Boston, Massachusetts, 02130
Ralph H Johnson VA Medical Center, Charleston
Charleston, South Carolina, 29401-5799
VA Medical Center, Cleveland
Cleveland, Ohio, 44106
VA North Texas Health Care System, Dallas
Dallas, Texas, 75216
VA Medical Center, Iowa City
Iowa City, Iowa, 52246-2208
Wlliam S. Middleton Memorial Veterans Hospital, Madison
Madison, Wisconsin, 53705
VA Medical Center, Miami
Miami, Florida, 33125
VA Medical Center, Minneapolis
Minneapolis, Minnesota, 55417
Salisbury VAMC
Salisbury, North Carolina, 28144
VA Puget Sound Health Care System, Seattle
Seattle, Washington, 98108

Other trials in United States

Puerto Rico1 site

VA Medical Center, San Juan
San Juan, 00921

Other trials in Puerto Rico

About this study

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

Read the 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

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.

Conditions: Alzheimer's Disease
Being tested: dl-alpha-tocopherol, Memantine, Placebo
Keywords: Alzheimer's Disease, clinical trial, randomized controlled trial, alpha-tocopherol, vitamin E, Namenda, memantine
Medical subject headings: Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

dl-alpha-tocopherolDrug
Also called Vitamin E
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.
MemantineDrug
Also called Namenda (R)
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.
dl-alpha-tocopherolDrug
Also called Vitamin E
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.
MemantineDrug
Also called Namenda (R)
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.
PlaceboDrug
Matching placebos for dl-alpha-tocopherol and memantine.

Study groups in NCT00235716
Study group	Role	What they receive
Arm 1	Experimental	2,000 IU per day of dl-alpha-tocopherol plus placebo for memantine Receives: Drug: dl-alpha-tocopherol
Arm 2	Experimental	20 mg per day of memantine plus placebo for dl-alpha-tocopherol Receives: Drug: Memantine
Arm 3	Experimental	Combination of 2,000 IU per day of dl-alpha-tocopherol and 20 mg per day of memantine Receives: Drug: dl-alpha-tocopherol; Drug: Memantine
Arm 4	Placebo comparator	Matching placebos for dl-alpha-tocopherol and memantine Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline

Secondary outcomes (1)

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).
Measured: Every 6 months to a maximum of 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Aug 2007Oct 2012

First posted10 Oct 2005 (estimated)
Study startAug 2007
Primary completionSep 2012
Study completionOct 2012

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Alzheimer's DiseaseStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Factorial
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 613 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00235716
Sponsor's protocol ID: 546
Acronym: TEAM-AD
Status last verified: Jul 2014
First submitted: 6 Oct 2005
Last updated: 23 Jul 2014
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Dysken MW, Guarino PD, Vertrees JE, Asthana S, Sano M, Llorente M, Pallaki M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Carney S, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Vatassery G. Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data. Alzheimers Dement. 2014 Jan;10(1):36-44. doi: 10.1016/j.jalz.2013.01.014. Epub 2013 Apr 11.
PubMed 23583234
Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PD. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44. doi: 10.1001/jama.2013.282834.
PubMed 24381967

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 23 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: CSP #546 - A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD)
ClinicalTrials.gov ID: NCT00235716
Acronym / sponsor ID: TEAM-AD / 546
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease, clinical trial, randomized controlled trial, alpha-tocopherol, vitamin E, Namenda, memantine
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 613 participants (actual)
Lead sponsor: US Department of Veterans AffairsUS federal agency
Collaborators: Forest Laboratories, dsm-firmenich Switzerland AG
Study start: Aug 2007
Primary completion: Sep 2012 (actual)
Study completion: Oct 2012 (actual)
First posted: 10 Oct 2005 (estimated)
Results: Posted 29 Jan 2014

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Factorial
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
Arm 1	Experimental	Drug: dl-alpha-tocopherol2,000 IU per day of dl-alpha-tocopherol plus placebo for memantine
Arm 2	Experimental	Drug: Memantine20 mg per day of memantine plus placebo for dl-alpha-tocopherol
Arm 3	Experimental	Drug: dl-alpha-tocopherol, Drug: MemantineCombination of 2,000 IU per day of dl-alpha-tocopherol and 20 mg per day of memantine
Arm 4	Placebo comparator	Drug: PlaceboMatching placebos for dl-alpha-tocopherol and memantine

Who may qualify

Ages: 40 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

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

Key exclusion criteria (11 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
dl-alpha-tocopherolAlso: Vitamin EAlpha-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.	Drug	Arm 1
MemantineAlso: Namenda (R)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.	Drug	Arm 2
dl-alpha-tocopherolAlso: Vitamin EAlpha-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.	Drug	Arm 3
MemantineAlso: Namenda (R)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.	Drug	Arm 3
PlaceboMatching placebos for dl-alpha-tocopherol and memantine.	Drug	Arm 4

Primary outcome

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
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.
Mini-Mental State Examination Change From Baseline
Time frame: 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.
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
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.
Neuropsychiatric Inventory Change From Baseline
Time frame: 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
Time frame: 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.

1 secondary outcome

Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)
Time frame: Every 6 months to a maximum of 4 years

Results and safety

Results posted to the registry on 29 Jan 2014, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Vitamin E	152	90
Memantine (Namenda)	155	88
Vitamin E + Memantine	154	89
Placebo	152	90

Primary outcome: 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. Least squares mean (Standard Error). Unit: units on a scale

Measure	Vitamin E n = 140	Memantine n = 142	Vitamin E + Memantine n = 139	Placebo n = 140
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)

Vitamin E vs Placebo: Mean Difference (Net): 3.15 (95% CI 0.92 to 5.39), p = 0.03, Mixed Models Analysis
Memantine vs Placebo: Mean Difference (Net): 1.98 (95% CI -0.24 to 4.20), p = 0.40, Mixed Models Analysis
Vitamin E + Memantine vs Placebo: Mean Difference (Net): 1.76 (95% CI -0.48 to 4.00), p = 0.49, Mixed Models Analysis

Population analysed: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Primary outcome: Mini-Mental State Examination Change From Baseline

Time frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline. Least squares mean (Standard Error). Unit: units on a scale

Measure	Vitamin E n = 136	Memantine n = 140	Vitamin E + Memantine n = 136	Placebo n = 137
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)

Vitamin E vs Placebo: Mean Difference (Net): 0.19 (95% CI -0.54 to 0.92), p = 0.84, Mixed Models Analysis
Memantine vs Placebo: Mean Difference (Net): 0.12 (95% CI -0.61 to 0.84), p = 0.84, Mixed Models Analysis
Vitamin E + Memantine vs Placebo: Mean Difference (Net): 0.37 (95% CI -0.36 to 1.10), p = 0.84, Mixed Models Analysis

Population analysed: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Primary outcome: 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. Least squares mean (Standard Error). Unit: units on a scale

Measure	Vitamin E n = 135	Memantine n = 140	Vitamin E + Memantine n = 136	Placebo n = 137
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)

Vitamin E vs Placebo: Mean Difference (Net): -1.80 (95% CI -3.28 to -0.33), p = 0.10, Mixed Models Analysis
Memantine vs Placebo: Mean Difference (Net): -1.39 (95% CI -2.85 to 0.07), p = 0.25, Mixed Models Analysis
Vitamin E + Memantine vs Placebo: Mean Difference (Net): -1.65 (95% CI -3.12 to -0.17), p = 0.14, Mixed Models Analysis

Population analysed: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

Primary outcome: Neuropsychiatric Inventory Change From Baseline

Time frame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline. Least squares mean (Standard Error). Unit: units on a scale

Measure	Vitamin E n = 140	Memantine n = 142	Vitamin E + Memantine n = 139	Placebo n = 140
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)

Vitamin E vs Placebo: Mean Difference (Net): -1.46 (95% CI -3.55 to 0.63), p = 0.94, Mixed Models Analysis
Memantine vs Placebo: Mean Difference (Net): -0.39 (95% CI -2.47 to 1.70), p = 0.94, Mixed Models Analysis
Vitamin E + Memantine vs Placebo: Mean Difference (Net): -0.47 (95% CI -2.57 to 1.63), p = 0.94, Mixed Models Analysis

Population analysed: Intention-to-treat analysis that includes all participants with baseline and at least one follow-up measurement.

1 secondary outcome is reported in the full results.

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Vitamin E	82 of 152 (53.9%)	91 of 152 (59.9%)	Not reported
Memantine	84 of 155 (54.2%)	97 of 155 (62.6%)	Not reported
Vitamin E + Memantine	83 of 154 (53.9%)	90 of 154 (58.4%)	Not reported
Placebo	95 of 152 (62.5%)	89 of 152 (58.6%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2014.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 23583234Dysken MW, Guarino PD, Vertrees JE, Asthana S, Sano M, Llorente M, Pallaki M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Carney S, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Vatassery G. Vitamin E and memantine in Alzheimer's disease: clinical trial methods and baseline data. Alzheimers Dement. 2014 Jan;10(1):36-44. doi: 10.1016/j.jalz.2013.01.014. Epub 2013 Apr 11.
Results publication: PubMed 24381967Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PD. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44. doi: 10.1001/jama.2013.282834.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Maurice Dysken study chair

Minneapolis Veterans Affairs Medical Center

14 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing dl-alpha-tocopherol and Memantine in people with Alzheimer's Disease, run by US Department of Veterans Affairs at 14 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Jan 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00235716, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2014.