Clinical trial NCT00235716: A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease
Official title: CSP #546 - A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease
clinical trial
randomized controlled trial
alpha-tocopherol
vitamin E
Namenda
memantine
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Forest Laboratories
name: DSM Nutritional Products, Inc.
First posted: 2005-10-10
Enrollment: 613
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory Change From Baseline
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline
measure: Mini-Mental State Examination Change From Baseline
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline
measure: Alzheimer's Disease Assessment Scale - Cognitive (ADAS-cog) Change From Baseline
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline
measure: Neuropsychiatric Inventory Change From Baseline
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline
measure: Caregiver Activity Survey Change From Baseline
timeFrame: 6, 12, 18, 24, 30, 36, 42 and 48 months minus baseline
Secondary outcomes:
measure: Dependence Scale: Time to Event Analysis (Increase of of One Dependence Level)
timeFrame: Every 6 months to a maximum of 4 years
Other outcomes:
measure: All-cause Mortality
timeFrame: up to 4 years
Locations:
city: Bay Pines
country: United States
facility: VA Medical Center, Bay Pines
state: Florida
city: Miami
country: United States
facility: VA Medical Center, Miami
state: Florida
city: Iowa City
country: United States
facility: VA Medical Center, Iowa City
state: Iowa
city: Baltimore
country: United States
facility: VA Maryland Health Care System, Baltimore
state: Maryland
city: Boston
country: United States
facility: VA Medical Center, Jamaica Plain Campus
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System
state: Michigan
city: Minneapolis
country: United States
facility: VA Medical Center, Minneapolis
state: Minnesota
city: Salisbury
country: United States
facility: Salisbury VAMC
state: North Carolina
city: Cleveland
country: United States
facility: VA Medical Center, Cleveland
state: Ohio
city: Charleston
country: United States
facility: Ralph H Johnson VA Medical Center, Charleston
state: South Carolina
city: Dallas
country: United States
facility: VA North Texas Health Care System, Dallas
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System, Seattle
state: Washington
city: Madison
country: United States
facility: Wlliam S. Middleton Memorial Veterans Hospital, Madison
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: VA Medical Center, San Juan
Study officials:
affiliation: Minneapolis Veterans Affairs Medical Center
name: Maurice Dysken
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.