Cumulative, Additive Benefits of Memantine-Donepezil Combination Over Component Monotherapies in Moderate to Severe Alzheimer’s Dementia: A Pooled Area Under The Curve Analysis (P5.002)

OBJECTIVE: We utilized area-under-the-curve (AUC) analysis to assess the cumulative efficacy of memantine-donepezil combination versus component monotherapies in patients with moderate to severe Alzheimer’s disease (AD) over a 6-month treatment period. BACKGROUND: Clinical studies in moderate to severe AD support the superiority of memantine-cholinesterase inhibitor (ChEI) combination therapy over monotherapy with either agent. DESIGN/METHODS: Data were pooled from four 6-month, randomized trials of memantine monotherapy or add-on therapy in moderate to severe AD (N=1,408). The AUC values (point x week) for cognition (SIB), function (ADCS-ADL19), behavior (NPI), global clinical status (CIBIC-Plus), and composite index (4D-CI: equally weighted composite of the four measures) were calculated using the trapezoidal rule. Placebo-only, memantine-only, placebo-donepezil, and memantine-donepezil groups were compared using ANCOVA (α=0.05, two-sided). Significance of the memantine x donepezil interaction terms (α=0.1) was used to assess whether the combined effect was additive or synergistic. The AUC results were contrasted with visit-by-visit changes from baseline (“snapshot analysis”). RESULTS: Over the 6-month period, placebo-only treatment was associated with cumulative worsening on all outcomes. The memantine-donepezil group showed significantly greater AUC improvements than the placebo-donepezil and memantine-only groups on the SIB, NPI, and CIBIC-Plus, but not on the ADCS-ADL19. The 4D-CI cumulative improvement in the memantine-donepezil group (630.0 point x week) was significantly greater than those in the placebo-donepezil (344.7, P<0.001) and memantine-only (152.1, P<0.001) groups. For all five measures, the effects of combining memantine and donepezil were additive, not synergistic. Compared with the AUC data, snapshot analysis appeared to underestimate the effects of combination therapy, monotherapies, or both. CONCLUSIONS: This large pooled AUC analysis of 6-month randomized-trial data in moderate to severe AD indicates cumulative, additive benefits of combined memantine-donepezil therapy compared with benefits of component monotherapies. Study Supported by: Forest Laboratories, LLC, a subsidiary of Actavis, Inc. Disclosure: Dr. Atri has received personal compensation as a lecturer. Dr. Hendrix has received personal compensation for activities with Pentara Corporation as an owner/employee. Dr. Pejovic has received personal compensation for activities with Prescott Medical Communications Group as an employee. Dr. Hofbauer has received personal compensation for activities with Forest Laboratories as an employee. Dr. Edwards has received personal compensation for activities with Forest Research Institute as an employee. Dr. Molinuevo has nothing to disclose. Dr. Graham has received personal compensation for activities with Forest Laboratories Inc., as an employee.