The primary study hypothesis is that compared with placebo, alpha-tocopherol or memantine (Namenda), will significantly delay clinical progression in mild to moderately demented patients with Alzheimer''''s disease who are currently taking donepezil (Aricept) and that combination treatment with alpha-tocopherol and memantine will add further incremental benefit.

Condition	Intervention	Phase
Alzheimer''''s Disease	Drug: Vitamin E  Drug: Memantine  Drug: Vitamin E and Memantine	Phase III

Further study details as provided by Department of Veterans Affairs:

Expected Total Enrollment:  840

Primary Hypothesis:

The primary study hypothesis is that compared with placebo, alpha-tocopherol or memantine (Namenda), will significantly delay clinical progression in mild to moderately demented patients with Alzheimer''''s disease who are currently taking donepezil (Aricept) and that combination treatment with alpha-tocopherol and memantine will add further incremental benefit.

Secondary Hypotheses:

The secondary study hypotheses are that compared to placebo alpha-tocopherol, memantine or the combination will: slow cognitive decline (ADAS-cog and MMSE); slow functional decline (The Dependence Scale); improve behavioral symptoms (NPI); and reduce caregiver burden (CAS) in mild to moderately demented patients with Alzheimer''''s disease who are currently taking donepezil.

Primary Outcome:

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 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.

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, CSP#546 was designed as a double-blind, placebo-controlled, randomized, clinical trial to assess the efficacy of adding alpha-tocopherol (a fat-soluble vitamin that has been shown to slow the rate of progression of AD), memantine (a moderate-affinity NMDA antagonist that blocks excessive stimulation of NMDA receptors by glutamate), and the combination for the treatment of functional decline in mild to moderately demented patients with Alzheimer''''s disease (MMSE 12-24) who are currently taking donepezil (a cholinesterase inhibitor that facilitates central acetylcholine neurotransmission). 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 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 ADCS/ADL 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.

CSEC Review was conducted on 12/15/03. The study was approved, however, its score was not in a fundable range. The planning committee will review the minutes from CSEC and the principal proponent will meet with NIH to determine if the study will be revised and resubmitted.

A third planning meeting was held on June 8-9 to revise the trial for resubmission to CSEC in the fall 2004.

CCSMRB review was conducted on 10/6/04. The study was approved with a fundable priority score. Once a date for the release of funding is determined, the kick-off date for the trial will be established.

Collaborator: Forest Laboratories, Inc. ($2,800,000 drugs); DSM National Products, Inc. ($75,362 drugs); Pfizer, Inc ($3,648,000 drugs).

Genders Eligible for Study:  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 mg/d or 10 mg/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 institutionalization (skilled nursing or assisted living facility)
3. Current major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by DSM-IV
4. Presence of any uncontrolled systemic illness that would interfere with participation in the study or a life expectancy of less than one year
5. Pregnant or intention to become pregnant
6. Enrollment in another interventional clinical trial
7. Current prescription with more than one AChE inhibitor
8. Current prescription for warfarin
9. Use of vitamin E supplements in the past 2 weeks
10. Use of memantine in the past 4 weeks or known intolerance
11. Estimated creatinine clearance less than 30 ml/min (Cockcroft-Gault formula)
12. Use of amantadine in the past 2 weeks

Please refer to this study by ClinicalTrials.gov identifier  NCT00235716

Study ID Numbers:  546
Last Updated:  January 5, 2006
Record first received:  October 6, 2005
ClinicalTrials.gov Identifier:  NCT00235716
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2006-01-10