Clinical trial NCT00235716
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease clinical trial randomized controlled trial alpha-tocopherol vitamin E Namenda memantine
Sponsor: US Department of Veterans Affairs
Start date: 2007-08-01; Completion date: 2012-10-01
Enrollment: 613 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

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.

Arms: arm 1: 2,000 IU per day of dl-alpha-tocopherol plus placebo for memantine arm 2: 20 mg per day of memantine plus placebo for dl-alpha-tocopherol arm 3: Combination of 2,000 IU per day of dl-alpha-tocopherol and 20 mg per day of memantine arm 4: Matching placebos for dl-alpha-tocopherol and memantine
Interventions: intervention 1: dl-alpha-tocopherol intervention 2: Memantine intervention 3: dl-alpha-tocopherol intervention 4: Memantine intervention 5: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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. intervention 4: 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. intervention 5: Matching placebos for dl-alpha-tocopherol and memantine.

Protocol documents: