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

Condition(s) targeted: Alzheimer's Disease

Intervention: dl-alpha-tocopherol (Drug); Memantine (Drug); dl-alpha-tocopherol (Drug); Memantine (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Department of Veterans Affairs

Official(s) and/or principal investigator(s):
Maurice Dysken, Study Chair, Affiliation: Minneapolis Veterans Affairs Medical Center

Overall contact:
Susan Love, MA, Phone: (612) 467-3342, Email: lovex008@tc.umn.edu

The primary study hypothesis is that compared with placebo, alpha-tocopherol, memantine (Namenda), or the combination will significantly delay clinical progression in mild to moderately demented patients with Alzheimer's disease.

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

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Factorial Assignment, Efficacy Study

Primary outcome: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS/ADL) Inventory

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 patients 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: ADAS-cog (cognition), MMSE (cognition), The Dependence Scale (function), NPI (behavior), and 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 840 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, subjects 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 sites will be established to enroll an average of one patient 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.

Minimum age: 40 Years. Maximum age: N/A. Gender(s): Both.

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 (9 mg or 18 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

Susan Love, MA, Phone: (612) 467-3342, Email: lovex008@tc.umn.edu

VA Medical Center, San Juan, San Juan 00921, Puerto Rico; Recruiting
Annette Melendez, MS, Phone: 787-641-7582, Ext: 10161, Email: annette.melendez@med.va.gov

VA Medical Center, Bay Pines, Bay Pines, Florida 33708, United States; Recruiting
Charlene McCarthy, MPH, Phone: 727-398-6661, Ext: 7630, Email: wilma.mccarthy@va.gov

VA Medical Center, Miami, Miami, Florida 33125, United States; Recruiting
Evangelia Sevdalis, MS, Phone: 305-575-7000, Ext: 6962, Email: evangelia.sevdalis@va.gov

VA Medical Center, Iowa City, Iowa City, Iowa 52246-2208, United States; Recruiting
Annette Ray, RN, Phone: 319-338-0581, Ext: 7518, Email: annette.ray@va.gov

VA Maryland Health Care System, Baltimore, Baltimore, Maryland 21201, United States; Recruiting
Sara Carney, MS, Phone: 410-605-7000, Ext: 4858, Email: sara.carney@va.gov

VA Medical Center, Jamaica Plain Campus, Boston, Massachusetts 02130, United States; Recruiting
Kyle Kolbe, MA, Phone: 857-364-4812, Email: kyle.kolbe@va.gov

VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48113, United States; Recruiting
Karen Belanger, MS, Phone: 734-845-5685, Email: karen.belanger@va.gov

VA Medical Center, Minneapolis, Minneapolis, Minnesota 55417, United States; Recruiting
Cindy Seidel, LPN, Phone: 612-467-4343, Email: cynthia.seidel@va.gov
Maurice Dysken, Study Chair

VA Medical Center, Cleveland, Cleveland, Ohio 44106, United States; Recruiting
Arlette Coulter, BA, Phone: 216-791-3800, Ext: 4763, Email: arlette.coulter@va.gov

Ralph H Johnson VA Medical Center, Charleston, Charleston, South Carolina 29401-5799, United States; Recruiting
Marilyn Stuckey, RN, Phone: 843-740-1592, Ext: 36, Email: stuckeym@musc.edu

VA North Texas Health Care System, Dallas, Dallas, Texas 75216, United States; Recruiting
Nona D Flye, RN, Phone: 214-857-1051, Email: nonad.flye@va.gov

VA Puget Sound Health Care System, Seattle, Seattle, Washington 98108, United States; Recruiting
Karen Enstrom, RN, Phone: 253-583-2010, Email: karen.enstrom@va.gov

Wlliam S. Middleton Memorial Veterans Hospital, Madison, Madison, Wisconsin 53705, United States; Recruiting
Peggy Sivesind, BS, Phone: 608-256-1901, Ext: 12919, Email: pasivesind@medicine.wisc.edu

Starting date: August 2007
Ending date: July 2012
Last updated: October 15, 2009