BENEFITS OF EARLY VERSUS DELAYED MEMANTINE ADDITION TO DONEPEZIL MONOTHERAPY IN PATIENTS WITH MODERATE TO SEVERE ALZHEIMER'S DISEASE: A POOLED ANALYSIS OF TWO RANDOMIZED TRIALS

Abstract

For patients with moderate to severe Alzheimer's disease (AD), treatment guidelines recommend adding memantine when symptoms of the disease are not well controlled with cholinesterase inhibitor (ChEI) monotherapy. Two large 24-week, randomized (1:1), placebo-controlled trials (RCTs) have been conducted in which memantine was added to stable treatment with donepezil or any ChEI in individuals with moderate to severe AD. In order to assess whether timing of mematine addition relative to the initiation of background donepezil monotherapy influenced clinical outcomes, we performed a pooled analysis of those two trials. Data were pooled from all participants (observed cases) in trial MEM-MD-02 (n=384) and the donepezil subset of trial MEM-MD-50 (n=444). The analysis evaluated measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global clinical status (CIBIC-Plus). Placebo/donepezil and memantine/donepezil groups were compared based on the covariate duration of donepezil monotherapy, using a mixed model (main effects: α=0.05, two-sided; interaction effects: α=0.10, two-sided). Duration of donepezil pretreatment (mean ± SD) for the entire pooled sample was 20.8 ± 17.7 months. On the SIB, NPI, and CIBIC-Plus, memantine/donepezil was associated with a significant advantage over placebo/donepezil at week 24, with no significant differences in the treatment effect for different durations of donepezil pretreatment (range: 0-36 months). On the ADCS-ADL 19, duration of donepezil pretreatment did affect the advantage of memantine addition: memantine/donepezil was statistically superior to placebo/donepezil at week 24 in patients pretreated with donepezil for at least 24 months. This analysis suggests that, in patients with moderate to severe AD, delaying the addition of memantine to stable donepezil treatment offers no therapeutic advantage over earlier point of initiation, as the benefits of dual therapy over monotherapy continuation remain consistent across major clinical domains. The design and interpretation of future add-on studies need to consider the role of duration of stable prior treatment, since significant treatment-by-duration interactions may occur.