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

ABSTRACT

BACKGROUND: 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. OBJECTIVES: 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. DESIGN: 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. SETTING: DOMINO study United Kingdom; Memantine Clinical Trial Program Multinational. PARTICIPANTS: 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. MEASUREMENTS 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). RESULTS: 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. CONCLUSIONS: 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.