Post Hoc Evidence for an Additive Effect of Memantine and Donepezil: Consistent Findings from DOMINO-AD Study and Memantine Clinical Trial Program.

Abstract

Several randomized trials have demonstrated superiority of memantine-cholinesterase inhibitor combination therapy in patients with moderate to severe Alzheimer's disease, yet a recent publication reported no additional benefit of add-on memantine therapy compared to donepezil alone. In this post hoc analysis, we sought to re-evaluate the results from the DOMINO study using common statistical tools and to apply the statistical models used in the DOMINO study to a pooled data set of 24- to 28-week randomized trials of memantine in patients with moderate to severe AD in order to explore the robustness of the primary findings from the DOMINO study. DOMINO study: Randomized, double-blind, placebo-controlled trial (Current Controlled Trial number, ISRCTN49545035); Memantine Clinical Trial Program: Pooled analysis from four randomized, double-blind, placebo-controlled trials. DOMINO study: United Kingdom; Memantine Clinical Trial Program: Multinational. DOMINO study: 295 participants enrolled during the period of February 2008 to March 2010; Memantine Clinical Trial Program: 1417 participants enrolled between August 1998 and January 2008. In the DOMINO study, the co-primary outcome measures were scores on the Standardized Mini-Mental State Examination and the Bristol Activities of Daily Living Scale; Neuropsychiatric Inventory was a secondary measure. In the Memantine Clinical Trial Program, outcome measures included the Severe Impairment Battery, the 19-item Alzheimer's Disease Cooperative Study - Activities of Daily Living scale, Neuropsychiatric Inventory, and a 4-Domain Composite Index (Z-score; a post hoc assessment). Both the pooled analysis of the Memantine Clinical Trial Program and the re-assessment of the DOMINO study with common statistical tools showed that adding memantine to donepezil therapy is associated with benefits across multiple clinical domains. The current analyses suggest that the results of the DOMINO study do not contradict previous studies which investigated the combined effects of memantine-cholinesterase inhibitor treatment.