The Safe, Tolerability, and Efficacy of Once-Daily Memantine (28mg): A multinational, randomized, placebo-controlled trial in patients with moderate to severe Alzheimer?s disease taking cholinesterase inhibitor.

GROSSBERG GT, MANES F, ALLEGRI RF, GUTIERREZ ROBLEDO LM, GLOGER S, XIE L, MILLER ÑL, PERHACH JL, GRAHAM SM

CNS DRUGS

ADIS INT LTD

Año: 2013 vol. 27 p. 469 - 478

1172-7047

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-tosevere AD concurrently taking cholinesterase inhibitors.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 baselineto-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?ADL); 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. A total of 677 patients were randomized to receive extended-release memantine (>342) or placebo(>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]; , CIBIC-Plus (>0.008), NPI (>0.005), and verbal fluency test (>0.004); the effect did not achieve significance on ADCS?ADL5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). Extended-release memantine was efficacious, safe, and well tolerated in this population. 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-tosevere AD concurrently taking cholinesterase inhibitors.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 baselineto-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?ADL); 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 (>342) or placebo(>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]; >0.001), CIBIC-Plus (>0.008), NPI (>0.005), and verbal fluency test (>0.004); the effect did not achieve significance on ADCS?ADL>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 %). Extended-release memantine was efficacious, safe, and well tolerated in this population.