Abstract
Objective: To explore treatment effects of once-daily 28-mg extended-release memantine (MemER) over the entire course of a randomized placebo-controlled trial (RCT) in moderate-to-severe Alzheimer’s disease (AD) using an area under the curve (AUC) analysis. Background: Efficacy and safety of MemER were demonstrated in a 24-week RCT (N=677) in patients with moderate-to-severe AD concurrently receiving cholinesterase inhibitor (ChEI) therapy. Protocol-specified analyses revealed significant MemER benefits on baseline-to-endpoint changes in cognition (SIB), global clinical status (CIBIC-Plus), behavior (NPI), and semantic processing (VFT), but not on a measure of daily function (ADCS-ADL19). Methods: ANCOVA analysis was performed for each efficacy parameter and a composite Z-score of patient-level AUCs for changes from baseline across all study visits (n=540). Results: Over the entire 24-week study, MemER-ChEI AUCs for SIB, CIBIC-Plus, and NPI showed mean improvements of 88% (P=0.014), 133% (P=0.019), and 109% (P<0.001), relative to placebo-ChEI. Mean VFT AUC cumulative worsening in the placebo-ChEI group was 139% greater than the AUC improvement in the Mem-ChEI group (P=0.014). Mean ADCS-ADL19 AUC improvement in the MemER-ChEI group was 117% greater than the AUC worsening in the placebo-ChEI group (P=0.528). Other time intervals yielded similar results. In composite Z-score analysis a significant cumulative improvement of 56% across all clinical domains for MemER-ChEI vs placebo-ChEI was observed in Weeks 0-12 (P=0.053), which increased to 198% over the entire 24-week study period (P<0.001). Conclusions: In this post-hoc AUC analysis of an AD RCT, mean cumulative treatment benefits of 198% were observed across five clinical domains for memantine ER added to background ChEI therapy. This approach provides a more complete, ecologically valid, robust and dynamic representation of longitudinal efficacy than the usual baseline-to-endpoint change-score trial analyses. These results support that memantine ER add-on therapy yielded consistent, cumulative and meaningful therapeutic benefits across 24 weeks in patients with moderate-to-severe AD.