Memantine and Cholinesterase Inhibitor Use in Alzheimer Disease Trials: Potential for Confounding by Indication

Objective: To evaluate the impact of acetylcholinesterase inhibitors (AChEIs) and memantine in cognitive and functional trajectories when use along novel therapies in trials for Alzheimer’s disease (AD). Background: AChEIs and memantine are commonly prescribed medications for AD. Their concurrent use in AD RCTs with novel therapies is generally allowed without full appreciation of the potential for treatment interaction or confounding by indication. Recently failed AD trials have increased attention to such treatment interactions. We seek to evaluate whether use of AChEIs and/or memantine in AD trials are associated with different rates of cognitive and functional decline. Design/Methods: We pooled data from five Alzheimer’s Disease Cooperative Study (ADCS) RCTs of mild to moderate AD (2003–2013). Subjects were included with an initial MMSE of 14–26 and with completion of 12 months of RCTs. Four groups were defined: AChEI use only (27%), memantine use only (16%), AChEIs+memantine (46%) and non-use (11%). Outcome measures were ADAS-cog, ADCS-ADL and MMSE change from baseline to 12 months. We used Fisher’s exact test, Wilcoxon signed rank test and Spearman’s tests to identify potential confounding variables. Mixed effect repeated measures models were used for adjustments and pairwise tests for comparing change score between subject groups. Results: There were 1423 subjects analyzed. Age, apolipoprotein E and initial MMSE were identified as significant covariates. On the ADAS-Cog there was a larger decline from baseline to 12 months in the memantine (p=0.0001) and AChEIs+memantine groups (p Conclusions: Memantine use, either as monotherapy or in combination with AChEIs, was associated with more rapid cognitive and functional decline over the course of 1 year. Further research will clarify whether biological differences could explain this apparent confounding by indication. Disclosure: Dr. Huisa-Garate has nothing to disclose. Dr. Thomas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Toyama, InTelGenx. Dr. Thomas has received research support from Toyama. Dr. Jin has nothing to disclose. Dr. Oltersdorf has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neuropore Therapies, Oncternal Therapeutics, Intercept Pharmaceuticals, Crinetics Pharmaceuticals. Dr. Taylor has nothing to disclose. Dr. Feldman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Medscape. Dr. Feldman has received research support from consulting service agreements with UCSD for Tau Rx, Merck, Eisai, Genentech, and Probiodrug (unpaid). Funding to the ADCS for clinical trials with Lilly, Toyama, and Biohaven.