By Chris Berrie
BRUSSELS, BELGIUM -- August 29, 2007 -- Memantine, a moderate affinity, noncompetitive, N-methyl-D-aspartic acid (NMDA)-receptor antagonist, shows good safety and tolerability and is associated with better cognitive and functional performance when compared with projected placebo data for patients with moderate to severe Alzheimer's disease (AD), indicate study findings.
This 134-week extension study following two 24-week, double-blind, placebo-controlled clinical studies, comprised an initial 4-week, double-blind titration period, followed by a total of 130 weeks as open-label memantine maintenance. The aim was to evaluate the long-term safety and efficacy of memantine, while also monitoring the tolerability toward a shorter titration period and a once-daily dosing. The study findings were presented on behalf of the Memantine MEM-MD-03 Study Group by Stephen H. Graham, PhD, Trial Director and Senior Director, Clinical Development, Forest Research Institute, Jersey City, New Jersey, United States, here on August 26 at the 11th Congress of the European Federation of Neurological Societies (EFNS).
The two lead-in studies (MEM-MD-01, MEM-MD-02) involved a total of 1,136 outpatients aged 50 years or older who were diagnosed with probable AD. Exclusions were made for various clinically relevant abnormalities, diseases, and cancers, along with psychiatric/neurological disorders.
The extension study started with two main arms for the 4-week titration period: the previously placebo-treated patients (n = 264; mean age, 76.9 years; male, 30.3%) who were randomised to one of four titration schemes for memantine; and the previous memantine-treated patients (n = 296; mean age, 76.3 years; male, 82.4%) who were randomised to one of two memantine-dosing regimens. The clinical characteristics of these patients on entering this phase were similar for mean patient weight (66.2 vs 68.2 kg), Mini Mental State Examination (MMSE) score (10.3 vs 10.1), and duration of dementia (48.8 vs 47.3 months).
All patients completed the remaining 130 weeks of the maintenance study with memantine 10 mg BID, with long-term efficacy assessed by the Severe Impairment Battery (SIB) and the 19-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL19) scale. These were compared with projected placebo data, which were based upon the placebo-treated patients entering the extension study and were calculated according to models of cognitive (SIB) and functional (ADCS-ADL19) decline in untreated patients; these models did not allow for yearly attrition.
For the initial dose-titration phase with the previously placebo-treated patients, there were more instances of dizziness and diarrhoea associated with the more rapid (8-day) titration, as compared with the traditional 22-day titration. Also, once- and twice-daily dosing of memantine appeared to be essentially comparable.
In the final 130-week memantine maintenance phase, the data were compared with the projected placebo scores for both SIB and ADCS-ADL19. For the former, the memantine-treated patients showed significantly better SIB scores at weeks 28, 80, and 134 (P <.001 for all). For the ADCS-ADL19, the memantine-treated patients again saw benefits that showed significance at weeks 80 and 134. Dr. Graham said, "This is suggestive that not only do you have benefits on cognition out to the 3 years, but also benefits on functionality as well."
The safety data over the memantine maintenance phase indicated there were no unexpected safety risks associated with this 3-year exposure to memantine, 10 mg BID. The occurrence and types of adverse events (AEs) experienced were similar throughout the full combined trial periods, with those most frequent being falls (~30%), agitation (~10%), accidental injuries (~10%), and urinary tract infections (~10%).
Dr. Graham pointed out, while noting the shortcomings of this analysis due to the projected nature of the placebo group, that it indeed appears that long-term memantine treatment is not only safe and shows a favourable tolerability profile, but is also associated with better cognitive and functional performances than would be expected from nontreatment of these patients with moderate to severe Alzheimer's disease.
This study was sponsored by Forest Laboratories Inc.
[Presentation title: Long-Term Safety and Efficacy of Memantine Treatment in Moderate-to-Severe Alzheimer's Disease: Results From a Three-Year Trial. Abstract P1097]
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