Efficacy and Tolerability of Memantine Extended Release Added to Stable Donepezil Regimen in Individuals with Moderate to Severe Alzheimer’s Disease: Subset Analysis of a Randomized Clinical Trial (P7.101)

OBJECTIVE: This subset analysis assessed the efficacy and tolerability of extended-release memantine (MemER; 28 mg/day) in patients with moderate to severe Alzheimer’s disease (AD) receiving donepezil, the most commonly used cholinesterase inhibitor (ChEI). BACKGROUND: In a 24-week randomized trial (N=677) of patients with moderate to severe AD receiving stable ChEI therapy (donepezil, galantamine, or rivastigmine), MemER-treated group significantly outperformed the placebo-treated group on measures of cognition (SIB), global clinical status (CIBIC-Plus), behavior (NPI), and semantic processing ability (VFT), but not on the measure of daily functioning (ADCS-ADL19). DESIGN/METHODS: Prospectively defined assessments in the donepezil subset (MemER/Don, 232; Placebo/Don, 224) utilized the last observation carried forward (LOCF) approach and an ANCOVA model (SIB, NPI, VFT, ADCS-ADL19: baseline-to-endpoint changes) or Cochran-Mantel-Haenszel test (CIBIC-Plus; endpoint scores). Post hoc sensitivity analyses, based on the observed cases (OC), assessed (a) changes from baseline across all visits (mixed-effects model with repeated measures [MMRM]), and (b) areas under the curve (AUC, Week0-Week24; ANCOVA). Tolerability was assessed by examining treatment-emergent adverse events (TEAEs) in the safety population (MemER/Don, 236; Placebo/Don, 227). RESULTS: The prospectively defined analyses revealed a significant endpoint advantage of MemER/Don over Placebo/Don on SIB (P=0.001), NPI (P=0.009), and VFT (P<0.001), but not on CIBIC Plus (P=0.165) or ADCS-ADL19 (P=0.894). The MMRM analysis demonstrated a significant advantage of MemER/Don over Placebo/Don across all visits for SIB (P<0.001), CIBIC-Plus (P=0.008), NPI (P=0.013), and VFT (P<0.001), but not for ADCS-ADL19 (P=0.606), which was corroborated by the AUC analysis (SIB, P=0.028; CIBIC-Plus, P=0.019; NPI, P=0.012; VFT, P=0.008; ADCS-ADL19, P=0.758). Overall TEAE rates were 61.9[percnt] (MemER/Don) and 59.9[percnt] (Placebo/Don). CONCLUSIONS: These analyses suggest that addition of memantine extended release to donepezil in patients with moderate to severe AD is associated with benefits across several clinical domains, with good tolerability. Study Supported by: Forest Laboratories, LLC, a subsidiary of Actavis, Inc. Disclosure: Dr. Grossberg has received personal compensation for activities with Forest, Lundbeck, Novartis, Otsuka, and Takeda. Dr. Grossberg has received personal compensation in an editorial capacity for Current Psychiatry. Dr. Grossberg9s institution has received Dr. Alva has received personal compensation for activities with Novartis, Forest Laboratories, Janssen Pharmaceutica, Wyeth/Pfizer, AstraZeneca, Bristol-Myers Squibb Co., and Jazz Pharmaceuticals as a speaker. Dr. Hendrix has received personal compensation for activities with Pentara Corporation as an owner/employee. Dr. Hofbauer has received personal compensation for activities with Forest Laboratories as an employee. Dr. Pejovic has received personal compensation for activities with Prescott Medical Communications Group as an employee. Dr. Graham has received personal compensation for activities with Forest Laboratories Inc., as an employee.