Extended-release Memantine Research Articles

An evaluation of memantine ER + donepezil for the treatment of Alzheimer’s disease

ABSTRACTIntroduction: Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and carries an immense societal burden. Unfortunately, no curative or disease-modifying treatment has yet been discovered. The currently approved medications are symptomatic. They include two classes: the cholinesterase inhibitors, such as donepezil, and the NMDA receptor antagonist memantine. Most evidence has shown that combining both classes is superior to monotherapy but may complicate the treatment regimen for patients and families. Namzaric®, a fixed dose combination of donepezil and memantine extended-release (ER) (FDC memantine ER/donepezil), was recently approved by the U.S. Food and Drug Administration (FDA) for patients with moderate to severe AD and warrants further consideration as a clinically useful and advantageous pharmacotherapy in AD.Areas covered: This review discusses the pharmacological properties, efficacy, and safety/tolerability data of this FDC memantine ER/donepezil as well as its benefits and disadvantages for patients and families. A literature search using PubMed was conducted using Namzaric, donepezil, memantine, AD, and medication adherence as keywords.Expert opinion: Aside from its cost, FDC memantine ER/donepezil improves adherence to medication and reduces caregiver burden. It allows patients to benefit from combination therapy as the disease progresses, especially in those with dysphagia, poor adherence and limited caregiver support.

Memantine ER Maintains Patient Response in Moderate to Severe Alzheimer's Disease: Post Hoc Analyses From a Randomized, Controlled, Clinical Trial of Patients Treated With Cholinesterase Inhibitors.

Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline to endpoint changes on the Severe Impairment Battery (SIB) in a 24-week, randomized trial (NCT00322153) in patients with moderate to severe Alzheimer's disease taking a cholinesterase inhibitor (ChEI). A post hoc analysis compared patients receiving memantine ER/ChEI to placebo/ChEI for time to onset of response and if the response was maintained (achieving improvement at weeks 8, 12, or 18 and maintaining through endpoint/week 24) on the SIB, the Neuropsychiatric Inventory (NPI), CIBIC-Plus, and Activities of Daily Living (ADL) using Fisher exact test. A second post hoc analysis compared percentages of patients for all possible combinations of 2 to 4 assessments with either no decline or clinically notable response using Wald χ. Significantly greater percentages of memantine ER/ChEI patients achieved an early response that was maintained on SIB, NPI, and CIBIC-Plus (P<0.05) versus placebo/ChEI. Significantly greater percentages of memantine ER/ChEI-treated patients achieved and maintained a clinically notable response on ADL/NPI, SIB/ADL/NPI, and SIB/ADL/CIBIC-Plus, compared with placebo/ChEI (P<0.05). Memantine ER results in early, maintained improvement in patients with moderate to severe Alzheimer's disease concurrently taking ChEIs, compared with cholinesterase treatment alone.

Response Across Multiple Outcome Measures in a Randomized Trial of Extended-release Memantine (28 mg, once daily) in Patients with Moderate to Severe Alzheimer’s Disease Receiving Donepezil (P3.086)

Response Across Multiple Outcome Measures in a Randomized Trial of Extended-release Memantine (28 mg, once daily) in Patients with Moderate to Severe Alzheimer’s Disease Receiving Donepezil (P3.086)

A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer&amp;rsquo;s disease

Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

Caregiver Distress Related to Neuropsychiatric Symptoms is Reduced with Extended-Release Memantine - Cholinesterase Inhibitor Combination in Patients with Moderate to Severe Alzheimer’s Disease (P2.219)

Caregiver Distress Related to Neuropsychiatric Symptoms is Reduced with Extended-Release Memantine - Cholinesterase Inhibitor Combination in Patients with Moderate to Severe Alzheimer’s Disease (P2.219)

Memantine and donepezil: a fixed drug combination for the treatment of moderate to severe Alzheimer's dementia.

Donepezil (and other cholinesterase inhibitors [ChEIs]) and memantine are the mainstays of treatment in Alzheimer's dementia, addressing respectively, the cholinergic and glutamatergic dysregulation which underlies or results from its pathophysiology. To alleviate the pill burden and swallowing difficulties associated with the condition, a fixed drug combination of extended-release memantine and donepezil was developed. This combination was shown to be both bioequivalent to the components administered separately and could be administered sprinkled over soft food. The mode of action, pharmacokinetics, clinical efficacy and safety and tolerability of the combination are discussed together with the wider, often conflicting trial literature of combination versus monotherapy with memantine and ChEIs, their meta-analyses and treatment guidelines.

Memantine ER/Donepezil: A Review in Alzheimer's Disease.

A once-daily, fixed-dose combination of memantine extended-release (ER)/donepezil 28/10mg (Namzaric™) is available in the USA for patients with moderate to severe Alzheimer's disease (AD) on stable memantine and donepezil therapy. The fixed-dose formulation is bioequivalent to coadministration of the individual drugs. In a 24-week, phase III trial in patients with moderate to severe AD, addition of memantine ER 28mg once daily to stable cholinesterase inhibitor (ChEI) therapy was more effective than add-on placebo on measures of cognition, global clinical status, dementia behaviour and semantic processing ability, although between-group differences on a measure of daily function did not significantly differ. In subgroup analyses in donepezil-treated patients, add-on memantine ER was more effective than add-on placebo on measures of cognition, dementia behaviour and semantic processing, although there were no significant between-group differences on measures of global clinical status and daily function. Memantine ER plus ChEI combination therapy was generally well tolerated in the phase III trial, with diarrhoea, dizziness and influenza occurring at least twice as often with add-on memantine ER as add-on placebo in donepezil-treated patients. Thus, memantine ER plus donepezil combination therapy is an effective and well tolerated treatment option for patients with moderate to severe AD. The fixed-dose combination is potentially more convenient than coadministration of the individual agents.

Cost-utility analysis of memantine extended release added to cholinesterase inhibitors compared to cholinesterase inhibitor monotherapy for the treatment of moderate-to-severe dementia of the Alzheimer’s type in the US

Objective:This study evaluates the cost-effectiveness of memantine extended release (ER) as an add-on therapy to acetylcholinesterase inhibitor (AChEI) [combination therapy] for treatment of patients with moderate-to-severe Alzheimer’s disease (AD) from both a healthcare payer and a societal perspective over 3 years when compared to AChEI monotherapy in the US.Methods:A phase III trial evaluated the efficacy and safety of memantine ER for treatment of AD patients taking an AChEI. The analysis assessed the long-term costs and health outcomes using an individual patient simulation in which AD progression is modeled in terms of cognition, behavior, and functioning changes. Input parameters are based on patient-level trial data, published literature, and publicly available data sources. Changes in anti-psychotic medication use are incorporated based on a published retrospective cohort study. Costs include drug acquisition and monitoring, total AD-related medical care, and informal care associated with caregiver time. Incremental cost-utility ratio (ICUR), life years, care time for caregiver, time in community and institution, time on anti-psychotics, time by disease severity, and time without severe symptoms are reported. Costs and health outcomes are discounted at 3% per annum.Results:Considering a societal perspective over 3 years, this analysis shows that memantine ER combined with an AChEI provides better clinical outcomes and lower costs than AChEI monotherapy. Discounted average savings were estimated at $18,355 and $20,947 per patient and quality-adjusted life-years (QALYs) increased by an average of 0.12 and 0.13 from a societal and healthcare payer perspective, respectively. Patients on combination therapy spent an average of 4 months longer living at home and spend less time in moderate–severe and severe stages of the disease.Conclusion:Combination therapy for patients with moderate-to-severe AD is a cost-effective treatment compared to AChEI monotherapy in the US.

Memantine extended release (28 mg once daily): a review of its use in Alzheimer's disease.

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that is a well-established treatment option for moderate to severe dementia of the Alzheimer's type, either alone or in combination with cholinesterase inhibitors. The immediate-release (IR) formulations of memantine (tablets and oral solution) have been available in numerous countries, including the USA, for more than a decade and are administered orally twice daily at a maximum recommended total daily dosage of 20mg/day. The memantine extended-release (ER) (Namenda XR(®)) 28mg once-daily capsule formulation was approved in the USA in 2010 and became available more recently. The potential advantages of memantine ER over the IR formulation include a more convenient dosage regimen and lower pill burden that may improve adherence to therapy; also, memantine ER capsules may be opened and the contents sprinkled on applesauce for patients who have difficulty swallowing. Memantine ER provides a higher total daily dosage than the recommended memantine IR regimen and pharmacokinetic data indicate greater exposure with the ER formulation, but the clinical implications of this are unclear, as the two formulations have not been assessed in a comparative clinical trial. The efficacy of memantine ER 28mg once daily was demonstrated in a large, multinational, phase III trial, which showed that the addition of memantine ER to ongoing oral cholinesterase inhibitors improved key outcomes compared with cholinesterase inhibitor monotherapy, including measures of cognition and global status, which were the co-primary endpoints of the study. The most common adverse events were headache, diarrhoea and dizziness.

PHARMACOKINETICS OF MEMANTINE AND DONEPEZIL AFTER A SINGLE DOSE OF A ONCE-DAILY FIXED-DOSE COMBINATION CAPSULE OF MEMANTINE EXTENDED RELEASE AND DONEPEZIL IN TWO PHASE I TRIALS

Combining two standard-of-care therapeutics into a single dosage unit may increase compliance and adherence to treatment, leading to an improved therapeutic outcome. A fixed-dose combination (FDC) capsule containing 28-mg memantine extended release (ER) and 10-mg donepezil was developed and tested for (1) bioequivalence with co-administered commercially available memantine ER (Namenda XR, 28 mg) and donepezil (Aricept, 10 mg), (2) bioavailability following food intake, and (3) bioavailability following sprinkling of the capsule contents on applesauce. Both studies were single-dose, randomized, open-label, and crossover (with 21-day washout periods between treatments), conducted in 18-45-year-old healthy individuals. In Study 1, fasting participants (N=38) received Treatment A (co-administration of Namenda XR and Aricept) or Treatment B (FDC). In Study 2, participants (N=36) received three treatments: Treatment A (intact FDC capsule, while fasting), Treatment B (intact FDC capsule, following a high-fat meal), and Treatment C (FDC contents sprinkled on applesauce, while fasting). In both studies, C max and AUC 0- ˇž for memantine and donepezil were compared using a linear mixed-effects model. Bioequivalence or no effect in the comparison of treatments was declared if the 90% confidence intervals (CI) of the least-squares geometric mean ratios of C max and AUC 0- ˇž were within the range of 80.00%-125.00%. T max values were compared using a Wilcoxon signed-rank test. Safety parameters were also evaluated. CIs of all the comparisons were within 80.00%-125.00% window. The FDC capsule containing memantine ER and donepezil was bioequivalent to co-administered Namenda XR and Aricept. There was no significant food effect on the bioavailability of the FDC capsule. The intact FDC capsule and capsule contents sprinkled on applesauce were bioequivalent. There were no clinically relevant differences in T max across treatments. Safety profiles were also similar across treatments. A FDC capsule containing 28-mg memantine ER and 10-mg donepezil is bioequivalent to co-administered commercially available memantine ER and donepezil. In addition to ingestion by swallowing with or without food, the formulation allows for sprinkling of the capsule contents on applesauce, making ingestion and administration easier for patients and caregivers, respectively. Sponsorship: Forest Research Institute.

COST-EFFECTIVENESS OF MEMANTINE EXTENDED RELEASE FOR TREATMENT OF MODERATE-TO-SEVERE ALZHEIMER'S DISEASE IN THE UNITED STATES

A double-blind, placebo-controlled, phase III trial (Grossberg et al. 2013) evaluated the efficacy and safety of memantine extended release (ER) for the treatment of patients with moderate-to-severe Alzheimer's disease (AD) taking a cholinesterase inhibitor (AChEI). This economic study evaluated the cost-effectiveness of memantine ER as an add-on therapy to AChEI (combination therapy) over a time horizon of 3 years when compared to AChEI monotherapy. The analysis was done from payer and societal perspectives in the United States (US). Long-term costs and health outcomes were assessed using a modified version of the AHEAD II model, an individual patient simulation in which AD progression is modeled in terms of changes in cognition, behavior and function. Treatment efficacy was based on cumulative probabilities of mean changes in scores at week 24 in the MEM-MD-50 trial. Thereafter, disease progression was modeled using equations derived directly from trial data. Changes in antipsychotic medications use upon initiation of AD treatment and following treatment discontinuation were incorporated using data from a published retrospective cohort study. Costs included drug acquisition and monitoring costs, total medical costs and informal care costs associated with caregiver time. Costs were reported in 2013 US dollars. Costs and health outcomes were discounted at 3% per annum. Over 3 years, combination therapy was less costly and more effective when compared with AChEI monotherapy. Combination therapy was associated with a discounted quality-adjusted life-year (QALY) gain of 0.13 per patient. Over 3 years, direct medical and societal discounted costs were reduced by $20,947 and $18,355 per patient, respectively. Reductions in costs were mostly attributable to reductions in the need for institutional care. With combination therapy, patient time at home was increased by an average of 3.99 months, with a reduction of time spent in the most severe stages of the AAIC 2014 Cost-Effectiveness of Memantine ER in the US disease of 2.29 months. One-way sensitivity analyses and probabilistic sensitivity analyses found that combination therapy was less costly and more effective than AChEI monotherapy in almost all scenarios. Memantine ER and AChEI for patients with moderate-to-severe AD is a cost-effective treatment compared to AChEI monotherapy in the US.

Cumulative Benefits of Extended-Release Memantine (28 mg, Once Daily) Across Clinical Domains in Patients With Moderate to Severe Alzheimer's Disease: An Area Under the Curve Analysis

The efficacy and safety of the extended-release formulation of memantine (MemER; 28 mg, once daily) in patients with moderate to severe Alzheimer's disease (AD) have been demonstrated in a 24-week, randomized, double-blinded, placebo-controlled trial of 677 patients (placebo, n=335; MemER, n=342) concurrently receiving background therapy with a cholinesterase inhibitor (ChEI) (Grossberg et al, 2013). The protocol-specified analyses in Grossberg et al. focused on changes from baseline (Week 0) to endpoint (Week 24), and revealed significant benefits of adding MemER to the ongoing ChEI therapy in the domains of cognition (Severe Impairment Battery [SIB]), global clinical status (Clinician's Impression of Change Plus Caregiver Input [CIBIC-Plus]), behavior (Neuropsychiatric Inventory [NPI]), and semantic processing ability (Verbal Fluency Test [VFT]); no significant benefits were observed in the domain of daily function (the 19-item Alzheimer Disease Cooperative Study - Activities of Daily Living scale [ADCS-ADL19]). Instead of limiting analysis of treatment benefits to score changes between baseline (Week 0) and the Week-24 endpoint, which provides little information about variation among trial participants in their cumulative responses over time, this study aimed to explore treatment effects during the entire course of the trial. For each patient (observed cases; N=540), the area under the curve (AUC) for changes from baseline on the SIB, CIBIC-Plus, NPI, VFT, and ADCS-ADL19 was calculated for all available time intervals (Weeks 0-24, 4-24, etc), using the trapezoidal rule. For each treatment interval, patient-level data were combined and treatment groups were compared by means of an analysis of covariance (ANCOVA) model with treatment group, center, and baseline value in the model (α=0.05, two-sided). Over the entire study period (Weeks 0-24), the group treated with add-on MemER (MemER-ChEI) displayed AUCs for the SIB, CIBIC-Plus, and NPI that reflected mean improvements of 88% (71.2 ± 11.1 vs 37.9 ± 10.8, P=0.014), 133% (-5.3 ± 1.1 vs -2.3 ± 1.0, P=0.019), and 109% (-91.1 ± 11.9 vs -42.9 ± 11.5, P<0.001), respectively, over the AUC improvements observed in the placebo-ChEI group. (For CIBIC-Plus and NPI, negative score changes indicate improvement.) For the VFT, an AUC indicating cumulative improvement in the MemER-ChEI group was significantly different than the AUC for the placebo-ChEI group that indicated cumulative worsening (P=0.014); the cumulative worsening in the placebo-ChEI group was 139% greater in magnitude than the improvement observed in the MemER-ChEI group (2.5 ± 2.9 vs -6.0 ± 2.8). For the ADCS-ADL19, the mean AUC improvement in the MemER-ChEI group was 117% greater in magnitude than the AUC worsening observed in the placebo-ChEI group, but the difference was not statistically significant (3.9 ± 7.4 vs -1.8 ± 7.2, P=0.528). Other time intervals yielded similar results, i.e., significant AUC improvements for the MemER-ChEI group for the SIB, CIBIC-Plus, NPI, and VFT. In this post-hoc AUC analysis of a randomized placebo-controlled trial, cumulative benefits were observed across multiple clinical domains for the treatment of patients with moderate to severe AD with memantine ER added to background ChEI therapy. The AUC approach provides a more complete representation of longitudinal therapeutic effect than the change score analyses often used in clinical trials: it is more ecologically valid, robust, and dynamic; does not rely on simple two-point change scores; and is not limited by an assumption of linear changes with time in making inferences and interpreting results. The significant cumulative improvements in cognition, global clinical status, behavior, and semantic processing abilities provide support to the view that add-on therapy with memantine ER yielded meaningful therapeutic benefits across the 24-week trial period.

Clinical benefits of extended-release memantine (28 mg, once daily) as a function of disease severity in people with moderate to severe Alzheimer's disease: Post hoc analysis from a randomized trial

Clinical benefits of extended-release memantine (28 mg, once daily) as a function of disease severity in people with moderate to severe Alzheimer's disease: Post hoc analysis from a randomized trial

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.

IntroductionImmediate-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.MethodsIn 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.ResultsA 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 %).ConclusionExtended-release memantine was efficacious, safe, and well tolerated in this population.Electronic supplementary materialThe online version of this article (doi:10.1007/s40263-013-0077-7) contains supplementary material, which is available to authorized users.

Extended-Release Memantine (28 mg, Once Daily) Provides Behavioral Benefits Across a Wide Range of Disease Severity in Patients With Moderate to Severe Alzheimer's Disease: Post Hoc Analysis From a Randomized Trial

Extended-Release Memantine (28 mg, Once Daily) Provides Behavioral Benefits Across a Wide Range of Disease Severity in Patients With Moderate to Severe Alzheimer's Disease: Post Hoc Analysis From a Randomized Trial

Behavioral Effects of Extended-Release Memantine (28 mg, Once Daily) across a Wide Range of Disease Severity in Patients with Moderate to Severe Alzheimer's Disease: Post Hoc Analysis from a Randomized Trial (P01.012)

Behavioral Effects of Extended-Release Memantine (28 mg, Once Daily) across a Wide Range of Disease Severity in Patients with Moderate to Severe Alzheimer's Disease: Post Hoc Analysis from a Randomized Trial (P01.012)

Safety and Efficacy of Memantine Extended-Release in the Management of Alzheimer's Disease

Alzheimer's disease (AD) affects the majority of the 35 million people with dementia worldwide. Four pharmacological treatment options are available for this patient group, of which memantine is licensed for treatment of people with moderate to severe stages of the condition. Memantine acts through its function as an NMDA-glutamate receptor blocker and has an established safety profile. The evidence supporting its efficacy in people with AD includes a number of large randomized clinical trials showing benefit to cognition, function, and overall clinical outcome. Additional favorable health economics analyses have confirmed the clinical and cost-effectiveness of this drug. More recently an extended-release formulation has been developed. This review outlines the key evidence base supporting memantine as a treatment for moderate to severe AD, in addition to discussing the conditions under which it may provide additional value in combination with other drugs. The review also discusses the use of memantine to address behavioral and psychological symptoms of dementia (BPSD) arising in people with AD and the limited evidence around its use in AD in people with Down's syndrome. Finally the review considers the potential value of the extended release formulation in AD.

A new measure of caregiver burden in Alzheimer's disease: the caregiver-perceived burden questionnaire.

To validate the Caregiver-Perceived Burden Questionnaire (CPBQ) and report its psychometric properties. The CPBQ was administered to caregivers of patients with moderate-to-severe AD in a double-blind randomized trial comparing extended-release memantine to placebo (n = 676). Measurement properties were analyzed using factor analysis, classical test theory, and Rasch analysis. Two subscales were identified: the Caregivers' Assessment of the Patient (CAP) and the Caregivers' Assessment of Themselves (CAT). The reliability was .89 (CAP) and .83 (CAT). The CAP scores were significantly correlated (r > .3) with scores from the Severe Impairment Battery (SIB) and the Neuropsychiatric Inventory (NPI). The CAT scores were significantly correlated with NPI scores. The CAT discriminated among patients by clinician-rated severity and significantly differentiated between responders and nonresponders. The CPBQ appears to be a reliable, valid, and responsive measure that enables linking caregiver's perceptions about burden and patient function in patients with moderate-to-severe AD.

P3‐380: Effects of extended‐release memantine (28 mg, once daily) on language and communication abilities in a randomized trial of patients with moderate‐to‐severe Alzheimer's disease

The efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) has been demonstrated previously in a 24-week, multinational, randomized, double-blind, placebo-controlled, parallel-group trial (MEM-MD-50, NCT00322153; placebo, n=335; memantine, n=342) in patients with moderate to severe AD concurrently taking a cholinesterase inhibitor (ChEI). The current study is a post hoc analysis, designed to explore the effects of memantine ER on face-valid groupings of language- and communication-related items from multiple outcome measures in that trial. Language items from the Severe Impairment Battery (SIB) were grouped into subscales of naming, reading/writing, and comprehension/repetition/discourse. In addition, a functional communication score was constructed using communication-related items from 2 scales administered to caregivers: the 19-item Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-ADL 19) and the caregiver perceived burden questionnaire (CPBQ). These items were designed to assess patients' verbal and non-verbal communication abilities, for example: “Did the subject pay attention to conversation or small talk?” (ADCS-ADL 19), or “How talkative has he/she been over the past month?” (CPBQ). For each post hoc measure, the change from baseline at week 24 was compared between groups. Analyses using observed cases (OC) and the last observation carried forward (LOCF) approach were based on an analysis of covariance (ANCOVA) model using treatment group and study center as factors and baseline value as a covariate. Analysis using the mixed-effects model with repeated measures (MMRM) utilized an unstructured covariance matrix with treatment, time, treatment by time interaction, and center as factors and baseline value as a covariate. At week 24, patients receiving memantine ER performed significantly better than patients taking placebo on the SIB subscales of Reading/Writing (OC: P=0.002; LOCF: P<0.001; MMRM: P<0.001), and Comprehension/Repetition/Discourse (OC: P=0.048; LOCF: P=0.004; MMRM: P=0.006). There was no significant difference between treatment groups on the SIB subscale of Naming (OC: P=0.093; LOCF: P=0.073; MMRM: P=0.057), or on the Functional Communication Score (OC: P=0.257; LOCF: P=0.131; MMRM: P=0.116). This post hoc analysis suggests that, in patients with moderate to severe AD receiving stable ChEI treatment, the addition of memantine ER may be associated with benefits in language abilities.

Extended-Release Memantine (28 mg, Once Daily) and Sustained Behavioral Improvement: Post Hoc Responder Analysis from a Randomized Trial in Patients with Moderate to Severe Alzheimer's Disease (P04.197)

Objective: To assess the efficacy of extended-release (ER) memantine on sustained behavioral improvements in patients with moderate to severe Alzheimer9s disease (AD). Background An ER formulation of memantine (28 mg, once daily) was recently approved in the US based on a 24-week, randomized, placebo-controlled trial (MEM-MD-50; NCT00322153) in patients with moderate to severe AD concurrently taking a cholinesterase inhibitor. Memantine ER-treated patients significantly outperformed placebo-treated patients on several outcome measures, including the Neuropsychiatric Inventory (NPI), an instrument for assessing behavior patients with dementia. Design/Methods: In this post hoc analysis of that trial, an NPI responder was defined as a patient who demonstrated an improvement over baseline of at least 3 points. Percentages of patients in each group who achieved this response (or greater) at Week 12 and maintained it at Weeks 18 and 24 were compared by means of Fisher9s exact test. Data were analyzed using observed cases (OC) and the last observation carried forward (LOCF) approach; corrections for multiple comparisons were not performed. Results: A total of 531 patients (261 memantine ER, 270 placebo; OC) had available NPI data at all 3 visits (Weeks 12, 18, and 24). At Week 12, a 3-point or greater improvement was experienced by 131 (50.2%) memantine-treated and 127 (47.0%) placebo-treated patients, respectively. Of participants with available NPI data at all 3 visits, a total of 39.5% (103/261) of memantine ER-treated patients and 28.9% (78/270) of placebo-treated patients maintained the response across Weeks 12, 18 and 24 ( P =0.011). An LOCF analysis yielded similar results (37.4% [119/318] memantine ER vs. 27.4% [88/321] placebo; P =0.007). Conclusions: In this post hoc analysis, memantine ER treatment of patients with moderate to severe AD was associated with a significantly higher rate of sustained behavioral improvement, compared with placebo. Supported by: Forest Laboratories, Inc. Disclosure: Dr. Cummings has received personal compensation for activities with Abbott Laboratories, Inc., Acadia, Acerra, ADAMAS, Anavex, Astellas, Avanir Pharmaceuticals, Baxter, Bristol-Myers Squibb Company, Eisai Inc., Elan Corporation, EnVivo, Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Inc., Janssen Pharmaceutica, Eli Lilly & Company, Lundbeck Research USA, Inc, Medivation, Medtronic, Inc., Merck & Co., Inc., Neurokos, Novartis, Pfizer Inc, Prana, QR, Sonexa, Takeda Pharmaceutical, Toyama, Bayer Pharmaceuticals, Avid, GE Healthcare, MedAvante, Neurotrax, UCB Pharma, and QR Pharma. Dr. Cummings has received (royalty or license fee or contractual rights) payments from Neuropsychiatric Inventory. Dr. Cummings holds stock and/or stock options in ADAMAS, Prana, Sonexa, MedAvante, Neurotrax, Neurokos, and QR pharma, which sponsored research in which Dr. Cummings was involved as an investigator. Dr. Hendrix holds stock and/or stock options in Pentara Corporation. Dr. Miller has received personal compensation for activities with Prescott Medical Communications Group and Forest Laboratories. 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. Dr. Tocco has received personal compensation for activities with Forest Laboratories as an employee.