The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors

Abstract

Introduction: Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors.

Methods: In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations.

Results: A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %).

Conclusion: Extended-release memantine was efficacious, safe, and well tolerated in this population.

Fig. 1

Study flow. *One patient with a protocol violation was excluded prior to receiving study medication and was not included in the safety population. ChEI cholinesterase inhibitor, ER extended-release formulation (28 mg), ITT intent-to-treat population

Fig. 2

Efficacy outcomes. In ChEI-treated patients with moderate to severe AD, treatment with memantine ER provided significant benefits on primary measures of cognition [(a) SIB] and global status [(b) CIBIC-Plus], as well as secondary measures of behavior [(d) NPI] and verbal fluency (e). No statistically significant differences were observed on the measure of function [(c) ADCS–ADL₁₉]. AD Alzheimer’s disease, ADCS–ADL ₁₉ 19-item Alzheimer’s Disease Cooperative Study–Activities of Daily Living, ChEI cholinesterase inhibitor, CIBIC-Plus Clinician’s Interview-Based Impression of Change Plus Caregiver Input, ER extended-release formulation (28 mg), LOCF last observation carried forward, LS least squares, MMRM mixed-effects model for repeated measures, NPI Neuropsychiatric Inventory, OC observed cases, SEM standard error of the mean, SIB Severe Impairment Battery. *p < 0.05; **p < 0.01; ***p < 0.001; p-values indicating statistically significant differences between groups are shown in bold type