Objective: The only treatments for Alzheimer’s disease (AD) approved in the US are cholinesterase inhibitors (ChEIs). The moderate-affinity, uncompetitive NMDA receptor antagonist memantine represents a novel therapy for AD in the US, and is currently approved for this indication in Europe. Memantine monotherapy has been shown in multicenter placebo-controlled trials to be effective and well tolerated in AD patients, but there are no data addressing combination therapy. We conducted a 24-week, double blind, parallel arm, placebo-controlled trial at 37 US centers in patients with moderate to severe AD also treated with stable doses of the ChEI, donepezil.
Design/Methods: Inclusion criteria were diagnosis of probable AD by NINCDS-ADRDA criteria, Mini-Mental State Exam (MMSE) score of 5-14, MRI or CT scan consistent with the diagnosis of probable AD, and daily donepezil therapy for the past 6 months (stable dose for the past 3 months). Primary outcome assessments were the Severe Impairment Battery (SIB), a performance-based measure of cognition, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) inventory, a measure of daily function. A physician’s global assessment, the Clinician’s Interview-Based Impression of Change-Plus (CIBIC-Plus) also was performed. Statistical analyses were performed on the ITT population using an LOCF approach.
Results: Of 403 patients randomized and treated with memantine 10 mg b.i.d. (n=202) or placebo (n=201), 85% of memantine-treated patients and 75% of placebo patients completed the trial. Mean MMSE at entry was 10. At week 24, patients treated with memantine/ donepezil showed a statistically significant improvement (p<0.001) in cognitive function (SIB) compared to patients treated with placebo/donepezil, and showed significantly less decline (p=0.028) in daily function (ADCS-ADL). A significant difference in favor of memantine/donepezil also was seen on the CIBIC-Plus global assessment (p=0.027). Memantine/donepezil treatment was safe and well tolerated.
Conclusion: These results further support the safety and efficacy of memantine therapy for patients with moderate to severe AD and demonstrate that treatment with memantine combined with donepezil is superior to donepezil alone. Importantly, treatment with memantine/donepezil resulted in improved cognitive performance relative to baseline, whereas treatment with donepezil alone was associated with continued cognitive decline.
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