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

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: 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, 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.