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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.

ABSTRACT: 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 ?. 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.

SUBMITTER: Grossberg GT

PROVIDER: S-EPMC6110375 | biostudies-literature | 2018 Jul-Sep

REPOSITORIES: biostudies-literature

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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.

Grossberg George T GT Alva Gustavo G Hendrix Suzanne S Ellison Noel N Kane Mary C MC Edwards John J

Alzheimer disease and associated disorders 20180701 3

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 respo ...[more]

PMID: 29771687

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Project description:BackgroundPharmacological treatment of Alzheimer's disease (AD) involves symptomatic improvement of cognition using cholinesterase inhibitors (ChEIs) and memantine. The cost-effectiveness of these medications will guide decision-makers in making judicious use of scarce healthcare resources, particularly during the advanced disease stages.ObjectiveTo evaluate the cost-effectiveness of ChEIs, memantine, and ChEI-memantine combinations in persons with moderate-to-severe AD from the US healthcare perspective.MethodsThis pharmacoeconomic evaluation study used a state-transition Markov cohort model to simulate the costs and effectiveness of ChEI-memantine combinations compared with monotherapies of ChEI (donepezil, galantamine and rivastigmine) and memantine in persons with moderate-to-severe AD over a lifetime horizon with a 1-year cycle length. We estimated expected quality-adjusted life-years (QALYs), costs (in 2020 $US), net monetary benefits, and incremental cost-effectiveness ratios (ICERs). We discounted future costs and QALYs at the rate of 3%.ResultsIn this study, donepezil monotherapy, galantamine-memantine combination, and rivastigmine transdermal patch formed the cost-effectiveness frontier. Findings suggests that rivastigmine transdermal patch is the optimal treatment strategy at a willingness-to-pay (WTP) threshold of $150,000/QALY (ICER = $93,307/QALY [versus donepezil monotherapy]). Results across subgroups by age and sex also suggest that the rivastigmine transdermal patch is the optimal treatment strategy with the highest net benefit.ConclusionFrom the US healthcare perspective, we found that, for persons with moderate-to-severe AD at a WTP threshold of $150,000/QALY, the rivastigmine transdermal patch is the most cost-effective pharmacological treatment option. Given that the transdermal patch is a preferred route of administration for persons with AD and their caregivers due to its convenience, our findings provide additional incentives for its use.

Project description:Memantine is licensed for moderate-to-severe Alzheimer's disease (AD). National Institute for Clinical Excellence (NICE) guidance does not recommend the use of memantine in combination with cholinesterase inhibitors (acetylcholinesterase inhibitor (AChEI)). The underpinning meta-analysis was disputed by the manufacturer.To compare the efficacy of AChEI monotherapy with combination memantine and AChEI therapy in patients with moderate-to-severe AD and to examine the impact of including unpublished data on the results.Systematic review and meta-analysis of randomised controlled trials.The Cochrane Dementia Group trial register, ALOIS, searched for the last time on 3 May 2011.Data from four domains (clinical global, cognition, function, behaviour and mood) were pooled. Sensitivity analyses examined the impact on the NICE-commissioned meta-analysis of restricting data to patients with moderate-to-severe AD and of including an unpublished trial of an extended release preparation of memantine.Pooled data from the trials, which were included in the NICE-commissioned meta-analysis but which were restricted to moderate-to-severe AD only, showed a small effect of combination therapy on cognition (standardised mean difference (SMD)=-0.29, 95% CI -0.45 to -0.14). Adding data from an unpublished trial of an extended release memantine (total three trials, 1317 participants) showed a small benefit of combination therapy on global scores (SMD=-0.20, 95% CI -0.31 to -0.09), cognition (SMD=-0.25, 95% CI -0.36 to -0.14) and behaviour and mood (SMD=-0.17, 95% CI -0.32 to -0.03) but not on function (SMD=-0.04, 95% CI -0.21 to 0.13) at 6 months. No clinical data have been reported from a 1-year trial, although this found 'no significant benefit' on any clinical measures at 1 year.These results suggest that there may be a small benefit at 6 months of adding memantine to AChEIs. However, the impact on clinical global impression depends on exactly which studies are included, and there is no benefit on function, so its clinical relevance is not robustly demonstrated. Currently available information from randomised controlled trails indicates no benefit of combination therapy over monotherapy at 1 year. Legislation on the form and content of registry posted results is needed in Europe.

Project description: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.

Project description:BackgroundAlzheimer's disease (AD) is characterized by progressive cognitive decline, often associated with Behavioral and Psychological Symptoms of Dementia (BPSD). Acetylcholinesterase inhibitors (ChEi) may attenuate cognitive decline and mitigate BPSD. The EVOLUTION group found that the switch from oral ChEi to transdermal rivastigmine patch formulation resulted in improvement/stabilization in the frequency of clinically relevant BPSD, but gender-specific subgroup analyses were not reported.MethodsParticipants underwent Neuropsychiatric Inventory to assess the frequency and severity of neuropsychiatric symptoms at baseline and 3 and 6 months after the switch from oral ChEi to transdermal rivastigmine patch. A descriptive post hoc analysis was conducted to assess whether there were gender-based differences in BPSD profile during the 6 months after the switch.ResultsThe entire sample consisted of 475 patients, 274 women and 201 men. Women were on average slightly older and with poorer cognitive performance (60.6% of the women had moderate-AD, defined as Mini-Mental State Examination [MMSE] score of 10-17, vs. 43.8% of men). In mild-AD patients (MMSE score 18-26), the frequency of BPSD did not change significantly over time and an association was found between gender and depression (odds ratio; OR [95% confidence interval; CI] female vs. male = 3.32 [1.44-7.67]), anxiety (2.42 [1.23-4.79]), apathy (2.25 [1.07-4.70]), nighttime behavior disturbances (3.97 [1.66-9.49]), and appetite/eating abnormalities (2.39 [1.10-5.18]). Moderate-AD female patients had euphoria more frequently than male patients (OR [95% CI] female vs. male = 3.67 [1.25-10.74]). The frequency of delusions, anxiety, and irritability decreased during the first 3 months after the switch, independently of gender.ConclusionMild-AD women tended to suffer more frequently from BPSD than men; in the 3 months after treatment switch, moderate-AD patients showed a decrease in delusions, anxiety, and irritability, with no significant differences between genders. Ad hoc studies to investigate this potential gender effect in AD could be well worthwhile.

Project description:IntroductionAlzheimer's disease (AD) is the most common neurodegenerative form of dementia. Pharmacological therapies for symptomatic treatment, such as acetylcholinesterase inhibitors (AChEIs) and memantine, have been available in the USA since 2000. Over the past decade, few studies have analyzed real-world anti-dementia treatment patterns in the USA. This study evaluated monotherapy AChEIs and memantine treatment patterns among newly diagnosed AD patients.MethodsA retrospective cohort study was conducted using Medicare data and the Minimum Data Set from 2008 to 2012. Patients aged 65-100 years with newly diagnosed AD (ICD-9 code: 331.0) and monotherapy AChEI or memantine treatment initiated after diagnosis were included. Descriptive treatment pattern analyses, including discontinuation and switch, were undertaken. Kaplan-Meier curves were developed to examine the treatment duration.ResultsA total of 9812 newly diagnosed AD patients were identified, with 56.7% (n = 5567) first receiving anti-dementia treatment after the initial AD diagnosis. Among patients initiating monotherapy AChEIs or memantine after AD diagnosis (N = 5200), 51.6% continued index treatment during the entire follow-up period (mean follow-up: 659.7 days) and 21.7% discontinued treatment. Of those who initiated monotherapy treatment with an AChEI, 11.1% received adjunct therapy with memantine. Among patients with ≥1 year of continuous treatment (mean follow-up: 834 days), 75.6% remained on the index drug, 10.2% discontinued during the remaining follow-up period, and 9.5% of the AD patients initiating AChEIs received adjunct memantine therapy during the remaining follow-up period.ConclusionIn the USA Medicare population, about 50% of the patients who initiated treatment with AChEI or memantine after diagnosis continued the index treatment, and more than 20% discontinued and were untreated afterwards over the observation period. AD patients initiating AChEIs or memantine were more likely to remain on their treatment if they were persistently treated for the first year.

Dataset Information

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.

Publications

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.

Similar Datasets

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