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Sponsors and Collaborators: |
Department of Veterans Affairs Forest Laboratories DSM Nutritional Products, Inc. |
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Information provided by: | Department of Veterans Affairs |
ClinicalTrials.gov Identifier: | NCT00235716 |
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.
Condition | Intervention | Phase |
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Alzheimer's Disease |
Drug: dl-alpha-tocopherol Drug: Memantine Drug: Placebo |
Phase III |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Factorial Assignment, Efficacy Study |
Official Title: | CSP#546 - A Randomized, Clinical Trial of Vitamin E and Memantine in Alzheimer's Disease (TEAM-AD) |
Estimated Enrollment: | 840 |
Study Start Date: | August 2007 |
Estimated Study Completion Date: | July 2011 |
Estimated Primary Completion Date: | July 2011 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
2,000 IU per day of dl-alpha-tocopherol plus placebo for memantine
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Drug: dl-alpha-tocopherol
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.
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2: Experimental
20 mg per day of memantine plus placebo for dl-alpha-tocopherol
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Drug: Memantine
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.
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3: Experimental
Combination of 2,000 IU per day of dl-alpha-tocopherol and 20 mg per day of memantine
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Drug: dl-alpha-tocopherol
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.
Drug: Memantine
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.
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4: Placebo Comparator
Matching placebos for dl-alpha-tocopherol and memantine
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Drug: Placebo
Matching placebos for dl-alpha-tocopherol and memantine.
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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 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.
Ages Eligible for Study: | 40 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Susan Love, MA | (612) 467-3342 | lovex008@tc.umn.edu |
Contact: Julie Tomaska, MSPH | (612) 467-1563 | julie.tomaska@va.gov |
United States, Florida | |
VA Medical Center, Bay Pines | Recruiting |
Bay Pines, Florida, United States, 33708 | |
Contact: Charlene McCarthy, MPH 727-398-6661 ext 7630 wilma.mccarthy@va.gov | |
VA Medical Center, Miami | Recruiting |
Miami, Florida, United States, 33125 | |
Contact: Evangelia Sevdalis, MS 305-575-7000 ext 6962 evangelia.sevdalis@va.gov | |
United States, Iowa | |
VA Medical Center, Iowa City | Recruiting |
Iowa City, Iowa, United States, 52246-2208 | |
Contact: Annette Ray, RN 319-338-0581 ext 7518 annette.ray@va.gov | |
United States, Maryland | |
VA Maryland Health Care System, Baltimore | Recruiting |
Baltimore, Maryland, United States, 21201 | |
Contact: Sara Carney, MS 410-605-7000 ext 4858 sara.carney@va.gov | |
United States, Massachusetts | |
VA Medical Center, Jamaica Plain Campus | Recruiting |
Boston, Massachusetts, United States, 02130 | |
Contact: Kyle Kolbe, MA 857-364-4812 kyle.kolbe@va.gov | |
United States, Michigan | |
VA Ann Arbor Healthcare System | Recruiting |
Ann Arbor, Michigan, United States, 48113 | |
Contact: Karen Belanger, MS 734-845-5685 karen.belanger@va.gov | |
United States, Minnesota | |
VA Medical Center, Minneapolis | Recruiting |
Minneapolis, Minnesota, United States, 55417 | |
Contact: Cindy Seidel, LPN 612-467-4343 cynthia.seidel@va.gov | |
Study Chair: Maurice Dysken | |
United States, Ohio | |
VA Medical Center, Cleveland | Recruiting |
Cleveland, Ohio, United States, 44106 | |
Contact: Arlette Coulter, BA 216-791-3800 ext 4763 arlette.coulter@va.gov | |
United States, South Carolina | |
Ralph H Johnson VA Medical Center, Charleston | Recruiting |
Charleston, South Carolina, United States, 29401-5799 | |
Contact: Marilyn Stuckey, RN 843-740-1592 ext 36 stuckeym@musc.edu | |
United States, Texas | |
VA North Texas Health Care System, Dallas | Recruiting |
Dallas, Texas, United States, 75216 | |
Contact: Nona D Flye, RN 214-857-1051 nonad.flye@va.gov | |
United States, Wisconsin | |
Wlliam S. Middleton Memorial Veterans Hospital, Madison | Recruiting |
Madison, Wisconsin, United States, 53705 | |
Contact: Michele Gassman, MA 608-256-1901 ext 12919 mcg@medicine.wisc.edu | |
Puerto Rico | |
VA Medical Center, San Juan | Recruiting |
San Juan, Puerto Rico, 00921 | |
Contact: Annette Melendez, MS 787-641-7582 ext 10161 annette.melendez@med.va.gov |
Study Chair: | Maurice Dysken | Minneapolis Veterans Affairs Medical Center |
Responsible Party: | Department of Veterans Affairs ( Dysken, Maurice - Study Chair ) |
Study ID Numbers: | 546 |
Study First Received: | October 6, 2005 |
Last Updated: | December 4, 2008 |
ClinicalTrials.gov Identifier: | NCT00235716 |
Health Authority: | United States: Federal Government; United States: Food and Drug Administration |
Alzheimer's Disease double-blind clinical trial randomized controlled trial |
alpha-tocopherol vitamins Namenda memantine |
Excitatory Amino Acids Tocopherol acetate Alzheimer Disease Central Nervous System Diseases Brain Diseases Neurodegenerative Diseases Cognition Disorders Alpha-Tocopherol |
Tocopherols Vitamin E Dopamine Delirium, Dementia, Amnestic, Cognitive Disorders Mental Disorders Memantine Dementia Delirium |
Neurotransmitter Agents Antioxidants Molecular Mechanisms of Pharmacological Action Anti-Dyskinesia Agents Growth Substances Nervous System Diseases Physiological Effects of Drugs Antiparkinson Agents Excitatory Amino Acid Agents |
Protective Agents Pharmacologic Actions Vitamins Therapeutic Uses Dopamine Agents Micronutrients Tauopathies Central Nervous System Agents Excitatory Amino Acid Antagonists |