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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


Grossberg, George T., Manes, Facundo, Allegri, Ricardo F., Gutiérrez-Robledo, Luis Miguel, Gloger, Sergio, Xie, Lei, Jia, X. Daniel, Pejović, Vojislav, Miller, Michael L., Perhach, James L., Graham, Stephen M.


CNS Drugs, Volume: 27, No.: 6, Pages.: 469-478

Year of Publication



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.;

Bibtex Citation

@article{Grossberg_2013, doi = {10.1007/s40263-013-0077-7}, url = {}, year = 2013, month = {jun}, publisher = {Springer Science $mathplus$ Business Media}, volume = {27}, number = {6}, pages = {469--478}, author = {George T. Grossberg and Facundo Manes and Ricardo F. Allegri and Luis Miguel Guti{'{e}}rrez-Robledo and Sergio Gloger and Lei Xie and X. Daniel Jia and Vojislav Pejovi{'{c}} and Michael L. Miller and James L. Perhach and Stephen M. Graham}, title = {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}, journal = {{CNS} Drugs} }


administration & dosage, adverse, adverse effects, aged, alzheimer disease, argentina, cholinesterase inhibitors, delayedaction preparations, diagnosis, double-blind method, drug administration schedule, drug therapy, drug therapy combination, enzymology, events, excitatory amino acid antagonists, female, humans, male, memantine, mexico, pharmacokinetics, psychology, severity of illness index, therapeutic use, treatment outcome, united states

Countries of Study

Argentina, Mexico, USA

Types of Dementia

Alzheimer’s Disease

Types of Study

Randomised Controlled Trial

Type of Outcomes

ADLs/IADLs, Behaviour, Cognition, Other

Type of Interventions

Pharmaceutical Interventions

Pharmaceutical Interventions

Anti-Alzheimer medications, e.g.: donezepil, galantamine, rivastigmine, memantime