Over 200 publications, including the composite endpoints regulators now recognize. We publish our methodology in the open so reviewers meet it before your submission does.
Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
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2019 · Neurology
Objective: To assess the effect of memantine (MEM) and a cholinesterase inhibitor (ChEI) vs ChEI alone on four syndrome domains of the Neuropsychiatric Inventory (NPI). Background: Neuropsychiatric symptoms negatively impact daily function and quality of life, hasten time to institutionalization, and increase overall healthcare costs. MEM significantly improved multiple domain scores of the NPI in patients with Alzheimer’s disease (AD) compared with placebo (PBO). Design/Methods: Data were pooled for participants with moderate to severe AD (baseline MMSE<20) from three, phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Porsteinsson et al. Alzheimer Research, 2008; Grossberg et al. CNS Drugs, 2013). The NPI has 12 items that were grouped into four syndrome domains: psychosis (agitation/aggression, hallucinations, delusions, irritability/lability), neurovegetative (aberrant motor behavior, nighttime behavior, appetite/eating change), frontal (disinhibition, euphoria/elation), and mood (anxiety, depression/dysphoria, apathy), based on previous analyses (Frisoni et al. Dement Geriatr Cogn Disord, 10:130–138, 1999). MEM/ChEI- and PBO/ChEI-treated participants were compared using an ANCOVA model estimating change from baseline at each time point. Results: Of 1262 patients, 637 were treated with MEM/ChEIs and 625 with PBO/ChEIs (age [mean±SD]: 75.7±8.3 years; baseline MMSE: 11.5±3.5; baseline NPI total score: 14.9±14.6). For all syndrome domains, mean treatment differences favored MEM/ChEIs over PBO/ChEIs. For psychosis symptoms, MEM/ChEI-treated patients improved significantly compared with PBO/ChEI-treated patients at 12 (LSMD −1.167, P<0.0001) and 24 (LSMD −1.238, P<0.0001) weeks. Similarly, neurovegetative scores were significantly improved for MEM/ChEI vs PBO/ChEI-treated patients at 12 (LSMD −0.621, P=0.0103) and 24 (LSMD −0.583, P=0.0441) weeks. For frontal and mood symptoms, no significant LSMDs were observed at 12 or 24 weeks. No analyses showed PBO/ChEI to be superior to MEM/ChEI. Conclusions: In patients with moderate to severe AD taking ChEIs, treatment with the combination of memantine and a ChEI was associated with significant benefit for psychosis and neurovegetative behavioral syndromes compared with ChEI alone.
2019 · Neurology
Objective: To assess maintenance of response on the Severe Impairment Battery (SIB) in participants treated with memantine (MEM) in combination with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI. Background: Rigorous phase 3 studies have demonstrated the efficacy of memantine (MEM) on cognitive and behavioral symptoms of Alzheimer’s disease (AD) when added to ongoing ChEI treatment. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) evaluating MEM for patients with moderate to severe AD (baseline MMSE score<20) receiving stable ongoing ChEI treatment. SIB scores were categorized by level of improvement (≥0-, ≥5-, ≥10-point improvement from baseline) at each timepoint (weeks 4, 8, 12, 18) and were considered maintained if the patient remained in the same improvement category at all following tests through endpoint (week 24). The percentages of patients who maintained response were compared between MEM/ChEI and PBO/ChEI. Results: A significantly greater proportion of MEM/ChEI-treated patients maintained ≥5-point improvements vs PBO/ChEI from weeks 4 to 24 (P=0.0182). From weeks 8 to 24 and 12 to 24, a significantly greater proportion of MEM/ChEItreated patients maintained ≥5- and ≥10-point improvements compared with PBO/ChEI-treated patients (Pvalues< 0.01). From week 18 to 24, a significantly higher proportion of patients treated with MEM/ChEI vs PBO/ChEI maintained score improvements of ≥0 (P=0.0478), ≥5 (P=0.0137), and ≥10 (P=0.0003) points. Conclusions: The combination of MEM with a ChEI resulted in greater percentages of patients who achieved and maintained cognitive improvements over 24 weeks vs PBO/ChEI. This treatment response was particularly pronounced among patients who experienced a 5-point or greater improvement on the SIB. Treatment effects continued to emerge at week 18 and were maintained through week 24, further demonstrating SIB sensitivity and the benefit of MEM when added to ongoing ChEI treatment.
2019 · Neurology
Objective: To evaluate the effect of the combination of memantine (MEM) with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI on total Severe Impairment Battery (SIB) and three higher-order cognitive domains (memory, language, and praxis). Background: The SIB is used to assess cognitive changes in patients with Alzheimer’s disease (AD), allowing for reliable, valid, and sensitive detection of treatment effects when floor effects may be present on other cognitive tests. MEM results in significant improvements on the SIB compared with PBO in moderate to severe AD patients treated concurrently with a ChEI. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) in patients with moderate to severe AD (baseline MMSE score<20). The SIB was administered at baseline and weeks 4, 8, 12, 18, and 24. Based on Schmitt et al. Alzheimer Dis Assoc Disord, 2006, SIB domains were aggregated to create higher-order subscales of memory (memory, attention, orientation, orienting to name), language (language, social interaction), and praxis (praxis, visuospatial ability, construction). Results: Compared with PBO/ChEI, MEM/ChEI significantly improved total SIB scores at weeks 8, 12, 18, and 24 (all, P<0.05). An analysis of higher-order domains demonstrated that MEM/ChEI treatment conferred significant effects on memory and language vs PBO/ChEI at weeks 12, 18, and 24 (all, P<0.05). On the higher-order domain of praxis, MEM/ChEI showed significant effects vs PBO/ChEI at all timepoints (weeks 4, 8, 12, 18, and 24, all P<0.05). Conclusions: The combination of MEM with a ChEI produced early and consistent improvements in cognition for patients with moderate to severe AD. Analysis of higher-order domains on the SIB further supported the efficacy of MEM in maintaining key cognitive functions (memory, language, and praxis), even when these patients are receiving the standard of ongoing ChEI treatment.
2018 · Alzheimer Disease & Associated Disorders
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 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.
2018 · Neurology
Objective: To evaluate Neuropsychiatric Index (NPI) maintenance of response from weeks 12–24 between patients receiving memantine/ChEI vs placebo/ChEI. Background: Neuropsychiatric symptoms, as measured by the NPI, impact daily function and quality of life, hasten time to institutionalization, and increase healthcare costs in patients with AD. Memantine significantly improves NPI scores vs placebo in moderate-to-severe AD. Maintenance of response represents a meaningful treatment benefit and symptom stabilization. Design/Methods: Post hoc analyses used pooled data from moderate to severe (baseline MMSE ≤19)patients (N=1121) in 3 randomized, double-blind, placebo-controlled studies (MEM-MD-02 [Tariot et al, JAMA 2004], MEM-MD-50 [Grossberg et al, CNS Drugs 2013], and MEM-MD-12 [Porsteinsson et al, Curr Alzheimer Res 2008]). To characterize NPI responder rates, evenly spaced change from baseline score groups (≤0, ≤−3, ≤−6, ≤−9, ≤−12) were identified. Maintenance of response was defined as total NPI score change at week 12 (earliest pooled timepoint) that was maintained through week 24 (endpoint). The percentages of patients who maintained response were compared between patients receiving memantine/ChEI or placebo/ChEI using Fisher’s exact test with observed case. Results: Pooled data showed that greater proportions of moderate-to-severe patients treated with memantine/ChEI maintained improvements on total NPI from weeks 12–24 compared with placebo/ChEI patients. For memantine/ChEI-treated vs PBO/ChEI-treated patients, 23.4% vs 18.2% maintained improvements of 6 points or more (P=0.0332); 17.0% vs 11.5% maintained improvements of 9 points or more (P=0.0103); 13.3% vs 7.7% maintained improvements of 12 points or more (P=0.0024). Conclusions: The combination of memantine added to ChEI resulted in improvements on total NPI that were sustained over weeks 12–24 of treatment in this OC analysis, which may represent clinically meaningful improvements for patients with moderate-to-severe AD with neuropsychiatric symptoms. For clinicians, the ability to characterize treatment effects of combination therapy over time may be useful in identifying treatment options and setting patient and caregiver expectations.
2018 · Neurology
Objective: To assess cognitive performance via the Severe Impairment Battery (SIB) and maintenance of improvement for memantine-ER/donepezil versus placebo/donepezil during 24-week treatment in moderate-to-severe Alzheimer’s disease (AD). Background: Memantine ER produced a significantly better outcome than placebo on co-primary endpoints of Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline-to-endpoint change on SIB in a 24-week, randomized, double-blind, placebo-controlled trial (RCT) in patients with moderate-to-severe AD concurrently taking a cholinesterase inhibitor. Design/Methods: This was a post-hoc analysis of NCT00322153 RCT observed data. Baseline-to-endpoint changes were used to classify patients based on equal scoring intervals (score changes of ≥0, ≥5, ≥10, ≥15, and ≥20). Proportions of memantine/donepezil- and placebo/donepezil-treated patients who were responders and who attained score changes at weeks 8, 12, and 18 and maintained those score changes through week 24 were compared using Fisher’s exact test. Results: 370 patients were included (187 memantine/donepezil, 183 placebo/donepezil), with baseline mean age 76.18 (SD=7.54), mean MMSE 10.92 (SD=2.73), and mean SIB total score 75.64 (SD=18.23). Compared with the placebo/donepezil group, a significantly higher percentage of patients in the memantine/donepezil-treated group achieved a score change of ≥10 (15.3% vs 27.3%, P=0.0053) or ≥15 (7.7% vs 16.6%, P=0.0105) on the SIB. The proportion of memantine/donepezil-treated patients numerically exceeded that of placebo/donepezil-treated patients at each cut-off for maintenance of response, with a significantly greater proportion maintaining a change of ≥5 (P=0.0391) and ≥10 (P=0.0283) from weeks 8–24, and a change of ≥10 and ≥15 from weeks 12–24 (P=0.0107 and 0.0349, respectively) and weeks 18–24 (P=0.0051 and 0.0100, respectively). Conclusions: Concomitant treatment with memantine ER/donepezil was associated with significant, maintained improvements over 24 weeks on the SIB than treatment with placebo/donepezil in this observed cases (OC) analysis; this favorable treatment response was particularly pronounced among patients who experienced the highest level of cognitive improvements.
2018 · Neurology
Objective: To examine Severe Impairment Battery (SIB) score changes (improvement or worsening) of ≥5, ≥10, and ≥15 points for patients with moderate to severe Alzheimer’s disease (AD) receiving memantine ER (MemER)/cholinesterase inhibitors (ChEI) vs placebo (PBO)/ChEI. Background: Rigorous phase 3 studies demonstrated memantine efficacy, in combination with ChEI, on cognition, function, and global outcomes in patients with moderate-to-severe AD. In a randomized, double-blind, PBO-controlled study (NCT00322153, MemER/ChEI treatment significantly improved SIB scores vs PBO/ChEI, with a PBO-adjusted mean difference of 2.6 points at week 24. Design/Methods: Post hoc analyses examined SIB baseline-to-endpoint (week 24) score changes in patients receiving an ChEI randomized to MemER (28 mg/day) or PBO. SIB score changes were examined in 5-point increments (eg, absolute changes of 1–5, 6–10, 11–15). “Improvement/decline” was noted at 5-point changes; “notable improvement/decline” at 10-point changes; and “remarkable improvement/decline” at 15-point changes. Results: Of 676 patients (safety population), 541 had SIB scores at baseline and week 24 (n=270 MemER/ChEI; n=271 PBO/ChEI). At week 24, 40% of MemER/ChEI patients experienced a ≥5-point SIB improvement vs 31% of PBO/ChEI patients. More MemER/ChEI patients had notable improvements of ≥10 points vs PBO/ChEI patients (23% vs 13%); twice as many had remarkable improvements (≥15 points) with MemER/ChEI vs PBO/ChEI (14% vs 7%). Fewer MemER/ChEI patients declined by ≥5 points vs PBO/ChEI (19% vs 24%), with similar results at declines of ≥10 (10% vs 13%) and ≥15 (6% vs 7%). Conclusions: Compared with PBO/ChEI, more MemER/ChEI-treated patients experienced improvements of ≥5, ≥10 and ≥15 points on the SIB, all greater than the PBO-adjusted mean of 2.6 points; fewer MemER/ChEI-patients experienced a decline in cognition. As no disease-modifying AD treatments are available, these data reaffirm the efficacy of combination therapy with MemER/ChEI on cognition and support its use in patients with moderate to severe AD.
2017 · Alzheimer's & Dementia
Background: Edonerpic (T-817; 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate, Toyama Chemical, Ltd) protects against Aβ42-induced neurotoxicity and memory deficits, promotes cortical and hippocampal neuron outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice, possibly via sigma receptor activation. The primary objective was to assess the efficacy and safety of T-817 in Alzheimer's disease (NCT 02079909). Methods: Outpatients, ages 55 to 85, meeting criteria for probable AD, MMSE 12–22, taking stable doses of donepezil or rivastigmine, taking or not memantine, were randomly assigned (1:1:1) to placebo, 224mg, or 448mg of T-817 once/day for 52 weeks. The primary outcomes were the ADAScog and ADCS-CGIC (CIBIC+) at week 52. Secondary outcomes were the MMSE, ADCS-ADL, FAQ, and NPI at week 52; and the outcomes at weeks 12, 24, 36, and 44. Biomarkers were MRI whole brain, lateral ventricular, and hippocampal volumes; and CSF Aβ40, 42, t-tau, and p-tau; and population pharmacokinetics. Results: 140 of 158 (88.6%) participants assigned to placebo, 117 of 166 (70.5%) to 224mg, and 120 of 158 (75.9%) to 448mg completed the trial, conducted from June 2014 to December 2016 at 52 US sites. LS mean ADAScog change was 7.9, 7.5, and 7.1 for the placebo, 224mg, and 448mg groups, respectively; difference, placebo vs. 448mg, -0.8 (95% CI: -2.8, 1.1; P=0.3919). Mean ADCS-CGIC scores were 5.2, 5.2, and 5.3; difference, 0.04 (95% CI: -0.19, 0.26; P=0.7588). There were no significant differences for the secondary outcomes. P-tau was nominally significantly lower in the 448mg group vs. placebo (n=24 and N=18, P=0.0338). Hippocampal volumes decreased less in the 224mg group than placebo (n=79 and N=89; -0.27 vs. -0.39 mL, P=0.0106) but not in the 448mg group (n=76; -0.31 vs. -0.39 mL, P=0.0996). 4.4%, 13.9% and 14.6% discontinued because of AEs, placebo, 224mg, and 448mg groups, respectively. Most frequent AEs ≥ 5%: diarrhea (12.7%, 20.5%, 31.0%), nausea (3.8%, 7.8%, 5.7%); infections, injuries, falls, agitation and anxiety were more common with placebo. Conclusions: T-817 appeared safe, tolerable, with expected GI symptoms occurring early, but without evidence for clinical effect in the protocol-specified primary and secondary outcomes. Decreased CSF p-tau and hippocampal volumes require confirmation.
2017 · Neurology
Objective: To detect treatment effects in severe patients with Alzheimer’s disease (AD) using a composite score of Severe Impairment Battery (SIB) items. Background: While the SIB detects treatment effects in patients with moderate-to-severe AD who perform at floor level on other cognitive scales, traditional total SIB scoring may lack sensitivity in severe AD. Design/Methods: A quantitative-SIB composite score (qSIB-total) and a severe SIB composite score (qSIB-severe) were developed using partial least squares (PLS) regressions and tested in separate datasets (Training-dataset and Test-dataset, respectively) utilizing an MMRM approach. The Training-dataset (N=966) was pooled from three 24-week phase 3 memantine trials in moderate-to-severe AD patients. A composite of weighted SIB items (qSIB-composite) with variable importance projection (VIP) ≥0.80 was derived using PLS regression. The qSIB-composite and qSIB-severe were tested in the Test-dataset (N=661) from an independent study of memantine in moderate-to-severe AD patients using MMRM regression. Results: For all patients, the SIB total score identified significant treatment effects in memantine-vs placebo-treated patients at weeks 18 and 24 (P<0.05). The qSIB-total scores did not improve sensitivity. The qSIB-severe composite included 5 items (language, memory, praxis, attention, and orientation) with weights of 0.009, 0.003, 0.021, 0.020, and 0.044, respectively, and a minimum VIP=0.8101. Compared with SIB total score, the qSIB-severe score improved sensitivity (lower P-values) in severe AD patients (baseline MMSE<9) at weeks 8 (qSIB-composite, P=0.6304; total SIB, P=0.7057), 12 (P=0.6305; P=0.8403), 18 (P=0.0204; P=0.0491), and 24 (P=0.002; P=0.0241). Conclusions: In severe AD patients, qSIB-severe provided additional measurement sensitivity and differentiation between memantine- and placebo-treated versus total SIB score. The qSIB-total did not improve sensitivity, indicating that SIB total score is optimized for combined moderate-to-severe patients. Development and utilization of quantitatively optimized composite scales from established clinical trial measures may improve scale sensitivity in patient subgroups, particularly when floor effects are present.
2017 · Neurology
Objective: To explore the effects of extended-release (ER) memantine (28 mg, once daily) on outcome measure combinations in the subset of Alzheimer’s disease (AD) patients receiving donepezil during the MEM-MD-50 trial (NCT00322153). Background: The efficacy of memantine ER was demonstrated in the 24-week, randomized, double-blind, placebo-controlled, parallel-group trial, MEM-MD-50 (placebo, n=335; memantine, n=342) in patients with moderate to severe AD concurrently taking a cholinesterase inhibitor. Design/Methods: Efficacy outcomes included measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), and global status (CIBIC-Plus). In this post hoc analysis, two levels of response were defined for each measure: improvement or stabilization (“no decline”; baseline-to-endpoint improvement of ≥0 points for the SIB, ADCS-ADL19, and NPI; endpoint score ≤4 for CIBIC-Plus) and clinically notable response (baseline-to-endpoint improvement of ≥3 points for the SIB, ADCS-ADL19, and NPI; endpoint score ≤3 for CIBIC-Plus). Treatment groups were compared by calculating the proportions of patients who achieved no decline or a clinically notable response on any combination of 2, 3, or all 4 efficacy measures. Data were analyzed using observed cases and Wald’s test (α=0.05); numbers needed to treat (NNTs) were also calculated. Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: In patients receiving donepezil, the proportions of responders in the memantine ER group (n=187) exceeded those in the placebo group (n=184) for both response levels and all outcome combinations, except for the ADCS-ADL19 (≥3 points) in which responder proportions were almost identical. The difference between proportions of memantine ER- and placebo-treated patients who experienced no decline was significant for the SIB/CIBIC-Plus combination (62.0% vs 50.8%; P=0.0240, NNT=9). Conclusions: This exploratory post-hoc analysis suggests that, in patients with moderate to severe AD receiving donepezil, memantine ER provides simultaneous benefits on multiple clinical domains, especially stabilization of cognition and global status.
2017 · American Journal of Geriatric Psychiatry
Objective: To evaluate the effect of memantine added to cholinesterase inhibitors (ChEIs) on agitation, other neuropsychiatric symptoms, and related caregiver burden in patients with Alzheimer’s disease (AD) experiencing agitation. Background: Agitation, a common, problematic neuropsychiatric symptom associated with AD, can increase caregiver burden and costs. Memantine and its extended-release formulation are approved for moderate-to-severe AD; ChEIs are additionally approved in mild AD. Previous studies suggest that ChEIs, memantine, and memantine added to ChEIs provide benefits for neuropsychiatric symptoms in AD. Design/Methods: Data were pooled from three phase 3, randomized, double-blind, placebo-controlled 24-week trials evaluating memantine for patients with moderate-to-severe or mild-to-moderate AD receiving concurrent ChEIs. Inclusion for these analyses required Neuropsychiatric Inventory-agitation (NPI-agitation) scores >0 at baseline or end-of-treatment. A mixed-effect repeated-measure model evaluated least squares mean differences (LSMD) between groups on NPI-agitation and NPI Caregiver Distress-agitation (NPI-D-agitation), as well as total and subdomain scores, from baseline to weeks 12 and 24, with alpha 0.05. Effect sizes were estimated with Cohen’s d. Results: Of 1140 patients, 532 had symptomatic agitation and were analyzed (mean age±SEM 76.10±0.349 years; mean baseline MMSE±SEM 10.83±0.137): 269 placebo/ChEIs, 263 memantine/ChEIs. Memantine/ChEIs significantly improved NPI-agitation at weeks 12 (P=0.0003; d,−0.3193) and 24 (P=0.0001; d, −0.3554) compared with placebo/ChEIs. Similar between-group effects were observed for NPI-D-agitation at week 12 (P=0.0067; d, −0.3346) and week 24 (P=0.0147; d,−0.3126). Congruent benefits of memantine were observed for NPI total score (week 12: P=0.0003; d,−0.3174; week 24: P=0.0004; d,−0.3213), NPI-delusion (week 12: P=0.0217; d,−0.2016; week 24: P=0.0365; d,−0.1913), NPI-D-delusion (week 12: P=0.0191; d,−0.2894), NPI-irritability/lability (week 12: P=0.0001; d,−0.3400; week 24: P=0.0013; d,−0.2933), NPI-D-irritability/lability (week 12: P=0.0109; d,−0.3152), and NPI-anxiety and NPI-apathy/indifference (week 24: P=0.0400; d,−0.1875; P=0.0127; d,−0.2287). Conclusions: Memantine added to ChEIs may substantially reduce agitation and other behavioral disturbances in AD patients who experience agitation, and also may reduce caregiver burden related to these symptoms.
2017 · Neurology
Objective: To examine the effects of memantine extended-release (ER) on Activities of Daily Living (ADLs) in patients with moderate-to-severe Alzheimer’s disease (AD). Background: In a 24-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT00322153), the efficacy of memantine ER (28 mg, once daily) on co-primary measures of cognition and global change was demonstrated in patients with moderate-to-severe AD (MMSE 3–14) concurrently taking a cholinesterase inhibitor (ChEI); treatment with adjunctive memantine ER did not achieve significance on the secondary measure of function, the 19-item Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL19). The lack of observed benefit of memantine on ADLs is in contrast to results from two pivotal memantine trials conducted in a similar patient population (MMSE 3–14 and MMSE 5–14). In those trials, monotherapy treatment with the immediate-release memantine conferred significant therapeutic benefits vs placebo on the ADCS-ADL. Design/Methods: In this post hoc analysis, the percentage of responders with ADCS-ADL19 change scores of ≤0, −2, −4, −6 and −8 were compared between treatment groups (memantine- and placebo-treated patients concurrently receiving a ChEI) using Fisher’s exact test. Results: While functional abilities declined in all patients, a greater percentage of patients treated with placebo (ChEI only) declined compared with those treated with memantine and ChEIs, with significant between-group differences observed among those with a change score of ≤-4 (20.0% placebo vs 12.1% memantine; P=0.0137), ≤-6 (13.3% vs 8.0%; P=0.0499), and ≤-8 (9.6% vs 4.9%; P=0.0453) by study end (weeks 18–24). Conclusions: This post hoc analysis suggests that the inevitable decline in function in moderate-to-severe AD patients may be ameliorated with memantine treatment compared with treatment with ChEIs alone.
2016 · Alzheimer's & Dementia
Background: Agitation is a common neuropsychiatric comorbidity associated with Alzheimer’s disease (AD) that can increase caregiver burden. The MEM-MD-50 trial demonstrated the behavioral benefits of treatment with extended-release memantine (MemER) in moderate to severe AD patients receiving a cholinesterase inhibitor (ChEI). This post hoc analysis aimed to examine the effects of treatment with MemER+ChEI vs placebo+ChEI on agitation among trial participants with agitation at either baseline or end of treatment. Methods: Patients with moderate to severe AD were randomized to MemER+ChEI or placebo+ChEI treatment in the double-blind MEM-MD-50 study (NCT00322153) for 24 weeks. Least squares mean differences (LSMD) between groups in change from baseline to Weeks 12 and 24 for the Neuropsychiatric Inventory (NPI) total score, Caregiver Distress (NPI-D) total score, and individual item scores were analyzed among participants with a score at either baseline or endpoint >0 for each respective variable, using an analysis of covariance (ANCOVA; α=0.05). Results: A total of 593 participants were included in the analysis, 291 treated with MemER+ChEI and 302 treated with placebo+ChEI. A total of 280 (96.2%) and 291 (96.4%) of those subjects had NPI total scores >0 at baseline or endpoint; 151 (51.9%) and 148 (49.0%) participants, respectively, had NPI-agitation item scores >0 at baseline or endpoint. At Week 12, the LSMD were significant in favor of MemER+ChEI for the NPI total score (-1.89, P<0.05), NPI-Agitation (-0.72, P<0.05), NPI-D total (-0.92, P=0.07), and for NPI-D-Agitation (-0.50, P<0.05). At Week 24, the LSMD for NPI total score was -3.21 (P<0.01), -1.29 for NPI-Agitation (P<0.01), -1.12 for NPI-D total score (P=0.07), and -0.63 for NPI-D-Agitation (P<0.05). Other items with significant between-group differences in LSMD at Week 12 included NPI-Aberrant Motor Behavior, NPI-Delusion, and NPI-D-Delusion; at Week 24, significant between-group differences were also observed for NPI-Delusion, and NPI-Nighttime Behavior (all in favor of MemER+ChEI treatment). Conclusions: This post hoc analysis suggests that the addition of MemER to ChEI treatment may reduce agitation in moderate to severe AD patients, and may also reduce the caregiver burden associated with agitation.
2016 · Neurology
Objective: A pooled post hoc analysis of ADCS-ADL19 scores from two, 24-week, placebo-controlled trials was performed to evaluate the impact of combining memantine with ChEI treatment on daily functioning and assess potential clusters of functional tasks that improved together. Background: Moderate to severe Alzheimers disease is frequently treated with a cholinesterase inhibitor (ChEI) in combination with memantine. Methods: Data were pooled from trials MEM-MD-02 and MEM-MD-50 (placebo+ChEI, n=525; memantine+ChEI, n=531). Factors were derived using a principal components analysis based on change-from-baseline item values (placebo and memantine groups combined), varimax rotation, maximum loading for each item, and eigenvalues of ≥1 for each factor with a designated maximum of 4 factors. Between-group comparisons of item and factor score changes used a mixed-effects model with repeated measures (MMRM; OC and LOCF) analysis. Results:At Week 24, there were significant advantages of memantine+ChEI treatment over placebo+ChEI for grooming (P<0.001), conversing (P=0.010), and finding belongings (P=0.002). The 4 subscales identified were: basic ADLs (eating, walking, toileting, bathing, grooming, dressing; loading value range [LVR]: 0.41-0.71), higher-level ADLs requiring communication/comprehension skills (using telephone, watching television, conversing, finding belongings, traveling, left alone; LVR: 0.37-0.58), simple praxis (faucet on, faucet off, light on; LVR: 0.53-0.80), and praxis items requiring visuo-spatial and memory skills (clearing table, obtaining beverage, disposing of litter, light off; LVR: 0.35-0.63). At Week 24, the memantine+ChEI group declined less than placebo+ChEI on each subscale: basic ADLs (least squares difference [LSDiff]=0.376; P=0.017), higher level ADLs (LSDiff=0.265; P=0.156), simple praxis (LSDiff=0.077; P=0.043), and praxis items requiring visuo-spatial and memory skills (LSDiff=0.300; P=0.017). Conclusions:The addition of memantine to stable ChEI treatment was associated with significant improvements in grooming, conversing, and finding belongings. The factor analysis identified 4 subscales, and significant advantages of memantine+ChEI treatment over placebo+ChEI for basic ADLs, simple praxis, and praxis items requiring visuo-spatial and memory skills.
2015 · Alzheimer's & Dementia
Background: In patients with Alzheimer's disease (AD) either with or without stable cholinesterase inhibitor (ChEI) treatment, clinical trials have shown significant and beneficial Baseline-to-Endpoint effects following memantine (MEM) treatment in comparison with placebo. Time to meaningful levels of change on outcome measures can also provide clinically relevant information for physicians. This new post hoc analysis used a time-to-event Kaplan-Meier methodology to evaluate clinically meaningful changes in four 6-7 month studies of memantine alone or in combination with a ChEI. Methods: The populations of 4 trials were pooled (N=1,628): 3 randomized, double-blind, placebo-controlled trials of MEM IR (10 mg BID; 2 monotherapy; 1 of patients on stable donepezil) and 1 trial of MEM ER (28 mg QD; patients on stable ChEI regimen) in moderate to severe AD. Efficacy outcomes included cognition (SIB), function (ADCS-ADL19), behavior (NPI), and global status (CIBIC-Plus), and clinically meaningful events were defined as the median decline at Endpoint for placebo-only treated patients; the K-M method was used to compare median time to reach this point in the treatment groups and an unadjusted log-rank test was performed on the intent-to-treat population. Results: Meaningful events were defined as declines of ≥4 points on SIB, ≥3 points on ADCS-ADL19, NPI total score increase ≥0, and final score ≥5 for CIBIC-Plus. The median times-to-events (days) were: SIB (PBO-only: 85; PBO+ChEI: 176 [P<0.0001 vs PBO-only]; MEM-only: 188 [P=0.0001 vs PBO-only]; MEM+ChEI: >196 [P<0.0001 vs PBO-only]; all-PBO groups: 168; all-MEM groups: 193 [P=0.0037 vs all-PBO]), ADCS-ADL19 (PBO-only: 125; PBO+ChEI: 127 [P=0.9854 vs PBO-only]; MEM-only: 172 [P=0.0445 vs PBO-only]; MEM+ChEI: 168 [P=0.2390 vs PBO-only]; all-PBO: 127; all-MEM: 168 [P=0.0127 vs all-PBO]), NPI (PBO-only: 85; PBO+ChEI: 84 [P<0.0001 vs PBO-only]; MEM-only: 101 [P=0.3518 vs PBO-only]; MEM+ChEI: 87 [P=0.0333 vs PBO-only]; all-PBO: 85; all-MEM: 88 [P=0.0027 vs all-PBO]), and CIBIC-Plus (PBO-only: 126; PBO+ChEI: 126 [P=0.4567 vs PBO-only]; MEM-only: 168 [P=0.1429 vs PBO-only]; MEM+ChEI: 168 [P=0.4011 vs PBO-only]; all-PBO: 126; all-MEM: 168 [P=0.0205 vs all-PBO]). Conclusions: Time-to-event analyses support the conclusion that memantine alone or in combination with a ChEI is efficacious in delaying cognitive, functional, and behavioral declines in patients with moderate to severe AD.
2015 · Neurology
OBJECTIVE: This subset analysis assessed the efficacy and tolerability of extended-release memantine (MemER; 28 mg/day) in patients with moderate to severe Alzheimer’s disease (AD) receiving donepezil, the most commonly used cholinesterase inhibitor (ChEI). BACKGROUND: In a 24-week randomized trial (N=677) of patients with moderate to severe AD receiving stable ChEI therapy (donepezil, galantamine, or rivastigmine), MemER-treated group significantly outperformed the placebo-treated group on measures of cognition (SIB), global clinical status (CIBIC-Plus), behavior (NPI), and semantic processing ability (VFT), but not on the measure of daily functioning (ADCS-ADL19). DESIGN/METHODS: Prospectively defined assessments in the donepezil subset (MemER/Don, 232; Placebo/Don, 224) utilized the last observation carried forward (LOCF) approach and an ANCOVA model (SIB, NPI, VFT, ADCS-ADL19: baseline-to-endpoint changes) or Cochran-Mantel-Haenszel test (CIBIC-Plus; endpoint scores). Post hoc sensitivity analyses, based on the observed cases (OC), assessed (a) changes from baseline across all visits (mixed-effects model with repeated measures [MMRM]), and (b) areas under the curve (AUC, Week0-Week24; ANCOVA). Tolerability was assessed by examining treatment-emergent adverse events (TEAEs) in the safety population (MemER/Don, 236; Placebo/Don, 227). RESULTS: The prospectively defined analyses revealed a significant endpoint advantage of MemER/Don over Placebo/Don on SIB (P=0.001), NPI (P=0.009), and VFT (P<0.001), but not on CIBIC Plus (P=0.165) or ADCS-ADL19 (P=0.894). The MMRM analysis demonstrated a significant advantage of MemER/Don over Placebo/Don across all visits for SIB (P<0.001), CIBIC-Plus (P=0.008), NPI (P=0.013), and VFT (P<0.001), but not for ADCS-ADL19 (P=0.606), which was corroborated by the AUC analysis (SIB, P=0.028; CIBIC-Plus, P=0.019; NPI, P=0.012; VFT, P=0.008; ADCS-ADL19, P=0.758). Overall TEAE rates were 61.9[percnt] (MemER/Don) and 59.9[percnt] (Placebo/Don). CONCLUSIONS: These analyses suggest that addition of memantine extended release to donepezil in patients with moderate to severe AD is associated with benefits across several clinical domains, with good tolerability. Study Supported by: Forest Laboratories, LLC, a subsidiary of Actavis, Inc.
2015 · Neurology
OBJECTIVE: We assessed the effects of adding memantine to stable cholinesterase inhibitor (ChEI) therapy on neuropsychiatric symptoms in moderate to severe Alzheimer’s disease (AD). BACKGROUND: Neuropsychiatric symptoms are common in moderate to severe AD and associated with caregiving burden; most patients experience several of them at any point in time. Antipsychotics, often used to manage individual symptoms, carry safety risks. Clinical-trial evidence indicates that memantine/ChEI combinations are superior to monotherapy with either drug. DESIGN/METHODS: Data from patients with moderate to severe AD (N=1,140) were pooled from three 24-week, randomized, placebo-controlled trials of memantine added to stable ChEI therapy. Neuropsychiatric symptoms were assessed using the 12-item Neuropsychiatric Inventory (NPI). Total and single-item score changes from baseline at week 24 in all patients and those symptomatic at baseline (total NPI score 蠅1; n=939) were analyzed via ANCOVA (intent-to-treat population, observed cases; α=0.05). Percentages of patients asymptomatic at baseline and at week 24 (total/item NPI score =0) were compared using Fisher’s exact test (α=0.05). RESULTS: At week 24, memantine/ChEI-treated patients significantly outperformed placebo/ChEI-treated patients on the NPI total score (all patients: P=0.001; symptomatic subset: P=0.003) and on the items of agitation (all: P<0.001; symptomatic: P=0.019), appetite/eating change (symptomatic: P=0.037), delusion (all: P=0.038; symptomatic: P=0.039), disinhibition (all: P=0.057; symptomatic: P=0.0497), irritability/lability (all: P=0.009; symptomatic: P=0.055), and nighttime behavior (all: P=0.0495). The percentages of patients who were asymptomatic at both baseline and week 24 on total NPI were not significantly different between groups (memantine/ChEI: 5.6[percnt]; placebo/ChEI: 3.5[percnt], P=0.119). CONCLUSIONS: These results suggest that adding memantine to stable ChEI therapy in individuals with moderate to severe AD may confer benefits in various neuropsychiatric symptoms. Study Supported by: Forest Laboratories, LLC, a subsidiary of Actavis, Inc.
2014 · Neurology
Objective: To explore treatment effects of once-daily 28-mg extended-release memantine (MemER) over the entire course of a randomized placebo-controlled trial (RCT) in moderate-to-severe Alzheimer’s disease (AD) using an area under the curve (AUC) analysis. Background: Efficacy and safety of MemER were demonstrated in a 24-week RCT (N=677) in patients with moderate-to-severe AD concurrently receiving cholinesterase inhibitor (ChEI) therapy. Protocol-specified analyses revealed significant MemER benefits on baseline-to-endpoint changes in cognition (SIB), global clinical status (CIBIC-Plus), behavior (NPI), and semantic processing (VFT), but not on a measure of daily function (ADCS-ADL19). Methods: ANCOVA analysis was performed for each efficacy parameter and a composite Z-score of patient-level AUCs for changes from baseline across all study visits (n=540). Results: Over the entire 24-week study, MemER-ChEI AUCs for SIB, CIBIC-Plus, and NPI showed mean improvements of 88% (P=0.014), 133% (P=0.019), and 109% (P<0.001), relative to placebo-ChEI. Mean VFT AUC cumulative worsening in the placebo-ChEI group was 139% greater than the AUC improvement in the Mem-ChEI group (P=0.014). Mean ADCS-ADL19 AUC improvement in the MemER-ChEI group was 117% greater than the AUC worsening in the placebo-ChEI group (P=0.528). Other time intervals yielded similar results. In composite Z-score analysis a significant cumulative improvement of 56% across all clinical domains for MemER-ChEI vs placebo-ChEI was observed in Weeks 0-12 (P=0.053), which increased to 198% over the entire 24-week study period (P<0.001). Conclusions: In this post-hoc AUC analysis of an AD RCT, mean cumulative treatment benefits of 198% were observed across five clinical domains for memantine ER added to background ChEI therapy. This approach provides a more complete, ecologically valid, robust and dynamic representation of longitudinal efficacy than the usual baseline-to-endpoint change-score trial analyses. These results support that memantine ER add-on therapy yielded consistent, cumulative and meaningful therapeutic benefits across 24 weeks in patients with moderate-to-severe AD.
2013 · The American Journal of Geriatric Psychiatry
Introduction: In Alzheimer’s disease (AD), significant behavioral symptoms are associated with patient distress, caregiver burden, admission to long-term care facilities, and use of psychotropic medications. Because of safety risks involved with antipsychotic use in this patient population, evaluating the efficacy of antidementia drugs on behavioral symptoms is of great interest. A new, extended-release (ER) formulation of memantine (28 mg, once daily) has been approved in the US, based upon the results of a 24-week, multinational, randomized, placebo-controlled trial (MEM-MD-50, NCT00322153) in patients with moderate to severe AD concurrently taking a cholinesterase inhibitor (placebo, n¼335; memantine, n¼342). In that trial, memantine ER treatment was associated with significant benefits compared with placebo on multiple outcome measures, including the Neuropsychiatric Inventory (NPI), a scale designed to assess behavioral symptoms in AD. Here we report results from a post hoc analysis of that trial, in which we assessed the behavioral effects memantine ER as a function of patients’ disease severity at Baseline, as determined using the Mini Mental State Examination (MMSE). Methods: Patients (observed cases; N¼540) were divided into 14 subgroups, corresponding to Baseline MMSE scores (range: 4-17). Baseline-to-Endpoint (Week 24) changes for memantine ER and placebo groups were assessed for each subgroup using a mixed-effects model with repeated measures, with the Baseline MMSE score as a linear covariate; sensitivity analyses were conducted using a quadratic model and a separate means model. Due to the exploratory nature of this analysis, no corrections for multiple hypothesis testing were performed. Results: At Week 24, memantine ER was associated with mean improvement on the NPI over placebo for patients with Baseline MMSE values across the full range of 4-17, with mean between-group differences ranging from 2.7 to 3.0 points. The mean differences reached significance (p<0.05) in the range of 7-14, with the analysis of the outlying score ranges being limited by small n values and low statistical power. Sensitivity analyses yielded similar results. Conclusions: In this post hoc analysis, 6 months of treatment with memantine ER in patients with moderate to severe AD was associated with a significant mean improvement in behavioral symptoms across a wide range of Baseline severities.
2013 · Alzheimer's & Dementia
Background: Memantine is an NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer’s disease (AD); donepezil is a cholinesterase inhibitor (ChEI), approved for mild to severe AD in the US. Treatment of AD typically involves initiation of donepezil therapy in early stages, with memantine added as the disease progresses to moderate and severe stages. Two large 24-week randomized trials and several observational studies suggest that this combined treatment is superior to monotherapy with either drug; while results of one small 52-week randomized trial generated debate. To further investigate the effects of combination therapy vs monotherapy, we pooled four similarly designed randomized, placebo-controlled trials of memantine inpatients with moderate to severe AD and compared Baseline-to-Endpoint changes in measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global clinical status (CIBIC-Plus), stratified by treatment/concur-rent therapy regimen (placebo, memantine, placebo/donepezil, or memantine/donepezil). Methods: All patients from two memantine monotherapy trials (MRZ-9001-9605 and MEM-MD-01; N¼567) and donepezil-treated patients from two memantine add-on trials (MEM-MD-02 and MEM-MD-50; N¼841) were pooled and Endpoint changes from Baseline for the SIB, ADCS-ADL 19, NPI, and CIBIC-Plus were assessed using a mixed-effects model with repeated measures (observed cases). Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: At study Endpoint, the memantine/donepezil treatment group was significantly superior to placebo (P<0.001) and both memantine and placebo/donepezil monotherapy groups (P<0.05) on all four efficacy measures. There were no statistically significant differences between memantine and placebo/donepezil monotherapy groups on the CIBIC-plus, ADCS-ADL 19, and NPI; however, the placebo/donepezil group performed significantly better than the memantine group on the SIB (P<0.001). Both memantine and placebo/donepezil treatment groups were significantly better than placebo on the SIB, ADCS-ADL 19, and CIBIC-plus (P<0.01), but no significant treatment differences were observed among these three treatment groups on the NPI. Conclusions: This pooled analysis is in agreement with evidence suggesting that adding memantine to stable donepezil treatment in patients with moderate to severe AD is associated with improvements across several clinical domains, compared with monotherapy using either drug. Appropriately powered, long-term, prospective studies of add-on therapy in AD are warranted.
2013 · Neurology
OBJECTIVE: In this post hoc analysis of a 24-week, randomized, placebo-controlled trial (MEM-MD-50, NCT00322153) of extended-release (ER) memantine (28 mg, once daily) in patients with moderate to severe Alzheimer's disease (AD) concurrently taking a cholinesterase inhibitor (placebo, n=335; memantine, n=342), we assessed the behavioral effects memantine ER as a function of patients' disease severity at Baseline, as determined using the Mini-Mental State Examination (MMSE). BACKGROUND: Because of safety risks involved with antipsychotic use in patients with AD, the use of antidementia drugs to help manage behavioral symptoms is of great interest. A new memantine ER formulation has demonstrated significant benefits compared with placebo on multiple outcome measures, including the Neuropsychiatric Inventory (NPI), a scale designed to assess behavioral symptoms in AD. DESIGN/METHODS: Patients (observed cases; N=540) were divided into 14 subgroups, corresponding to Baseline MMSE scores (range: 4-17). Baseline-to-Endpoint (Week 24) changes for memantine ER and placebo groups were assessed for each subgroup using a mixed-effects model with repeated measures, with the Baseline MMSE score as a linear covariate; sensitivity analyses were conducted using a quadratic model and a separate means model. Due to the exploratory nature of this analysis, no corrections for multiple hypothesis testing were performed. RESULTS: At Week 24, memantine ER was associated with mean improvement on the NPI over placebo across the full Baseline MMSE range of 4-17, with statistically significant (p<0.05) differences observed in the range of 7-14; outlying score ranges were limited by small n values and low statistical power. Mean between-group differences ranged from 2.7 to 3.0 points. Sensitivity analyses yielded similar results. CONCLUSIONS: In this post hoc analysis, 6 months of treatment with memantine ER in patients with moderate to severe AD was associated with significant improvement in behavioral symptoms across a wide range of Baseline severities.
2012 · Alzheimer's & Dementia
Background 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 Alzheimer's disease (AD) concurrently taking a cholinesterase inhibitor. The current study is a post hoc analysis, designed to explore the effects of memantine ER on combinations of outcome measures utilized in that trial. Methods Efficacy outcomes included measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global status (CIBIC-Plus). For each measure, two levels of response were defined: improvement or stabilization (“no decline”; baseline-to-endpoint improvement of ≥0 points for the SIB, ADCS-ADL 19, and NPI; endpoint score ≤4 for the CIBIC-Plus) and clinically notable response (baseline-to-endpoint improvement of ≥3 points for the SIB, ADCS-ADL 19, and NPI; endpoint score ≤3 for the CIBIC-Plus). The treatment groups were compared by calculating the proportions of patients who achieved no decline or a clinically notable response on any combination of 2, 3, or all 4 efficacy measures. Data were analyzed using observed cases and Wald's test (±=0.05); numbers needed to treat (NNTs) were also calculated. Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results For both response levels and all outcome combinations, proportions of responders in the memantine ER group (n=266-269) exceeded those in the placebo group (n= 271-272). The difference between proportions of memantine ER- and placebo-treated patients who experienced no decline approached statistical significance for the SIB/CIBIC-Plus combination (54.6% vs 46.1%; P =0.054, NNT=12). For clinically notable responses, memantine ER was significantly superior to placebo for the 2-measure combination of ADCS-ADL 19/NPI (21.3% vs 15.8%; P =0.042, NNT=18), and the 3-measure combinations of ADCS-ADL 19/NPI/SIB (15.4% vs 9.6%; P =0.027, NNT=17), and ADCS-ADL 19/SIB/CIBIC-Plus (12.4% vs 7.4%; P =0.030, NNT=20). Conclusions This exploratory post hoc analysis suggests that, in patients with moderate to severe AD, memantine ER may provide simultaneous benefits on multiple clinical domains, especially when improvements in cognition and function are observed, and when a response to therapy is relatively strong.
2012 · Journal of the American Geriatrics Society
Objective: To assess the efficacy of extended-release (ER) memantine on sustained behavioral improvements in patients with moderate to severe Alzheimer's 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 Fisher's 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.
2012 · Annals of Neurology
In this post hoc analysis, sustained cognitive improvement was assessed in a 24-week, randomized, placebo-controlled trial of once-daily, extended-release (ER) memantine (28 mg) in ChEI-treated patients with moderate to severe AD. Five positive SIB response levels to double-blind treatment were selected (improvements of ≥0, ≥5, ≥10, ≥15, and ≥20 points), corresponding to 0-2 standard deviations (SDs) of the observed baseline-to-endpoint score change. Numbers of patients in each group who attained such responses at weeks 4, 8, 12, or 18 and maintained them through week 24 were compared using Fisher’s exact test. Significantly more memantine ER-treated than placebo-treated patients maintained week 8 SIB responses of ≥5 points (26.1% vs 17.0%; P = 0.014) and ≥10 points (14.6% vs 7.6%; P = 0.012) through week 24. Similar results were observed for sustained responses obtained at week 12 (≥5 points: 28.5% vs 19.9%, P = 0.025; ≥10 points: 16.3% vs 8.2%, P = 0.005; ≥15 points: 9.5% vs 4.1%, P = 0.015) and week 18 (≥10 points:18.8% vs 10.0%, P = 0.004; ≥15 points: 10.9% vs 4.5%, P = 0.006). In conclusion, memantine ER was associated with cognitive improvement attained after 8-18 weeks and sustained through week 24.
2012 · Neurology
Objective: To assess the efficacy of extended-release (ER) memantine on sustained behavioral improvements in patients with moderate to severe Alzheimer's 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 Fisher's 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.
2011 · Alzheimer's & Dementia
Background: Top-line results of a 24-week, multinational, randomized, placebo-controlled trial in patients with moderate to severe Alzheimer's disease (AD) receiving stable concurrent cholinesterase inhibitor treatment (MEM-MD-50, NCT00322153) demonstrated the efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) on primary outcome measures (SIB and CIBIC-plus), as well as on the NPI and a verbal fluency test. In this post-hoc analysis, we examined the effects of memantine ER on individual SIB domains, as well as on aggregated domains defined previously (Schmitt et al., 2006). Methods: Treatment groups were compared in terms of mean change from Baseline at Endpoint for nine SIB domains (Social Interaction, Memory, Orientation, Language, Attention, Praxis, Visuospatial Ability, Construction, and Orienting to Name) and combinations of domains aggregated using a face-valid approach into three higher-order subscales: MEMORY (memory, attention, orientation, orienting to naming), LANGUAGE (language, social interaction), and PRAXIS (praxis, visuospatial ability, construction). Between-group comparisons were based on the intent-to-treat population (placebo: n = 328; memantine ER: n = 333) and performed by means of an ANCOVA model with treatment group and study center as factors and baseline value as covariate, using observed cases (OC) and the last observation carried forward (LOCF) approach to missing data. In addition, a mixed-effects model with repeated measures (MMRM) that included terms for treatment group, visit, treatment-by-visit interaction, baseline score, baseline-by-treatment interaction, and center was used to compare the groups across the entire trial. No adjustments for multiple comparisons were made. Results: Significant advantage of memantine ER over placebo was observed for the domains of Memory (OC, P = 0.021; LOCF, P = 0.016; MMRM, P = 0.008), Language (OC, P = 0.003; LOCF, P = 0.004; MMRM, P = 0.001), Attention (OC, P = 0.014; LOCF, P = 0.003; MMRM, P = 0.004), Praxis (OC, P = 0.015; LOCF, P = 0.002; MMRM, P = 0.002), Orientation (LOCF, P = 0.043; MMRM, P = 0.028), and Construction (OC, P = 0.042), and for all three higher-order subscales (MEMORY: OC, P = 0.002; LOCF, P = 0.003; MMRM P < 0. 001; LANGUAGE: OC, LOCF, P = 0.003; MMRM, P = 0.001; PRAXIS: OC, P = 0.012; LOCF, P = 0.004; MMRM, P = 0.004). Conclusions: In this post-hoc analysis, memantine ER was associated with significant improvement relative to placebo on several cognitive domains, including memory, language, praxis, and attention.
2011 · Journal of the American Medical Directors Association
2010 · European Neuropsychopharmacology
2010 · Alzheimer's & Dementia
Background: In patients with Alzheimer's disease (AD), it is of interest to determine whether therapy can prevent worsening across multiple clinical domains. In a previously reported, randomized trial in moderate AD (NCT00469456), memantine was superior to placebo at improving functional communication, as recognized by caregivers. Here we focus on patients from that trial who experienced worsening on three possible outcomes: a clinician's assessment of global status (CGI-C), a measure of the patient's language and functional communication (the Functional Linguistic Communication Inventory [FLCI]), and a caregiver's assessment of the patient's functional communication skills (the combined Social Communication and Communication of Basic Needs subscales of the American Speech-Language-Hearing Association - Functional Assessment of Communication Skills of Adults scale [ASHA-FACS]). Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n = 133) versus placebo (ITT n = 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. In this post hoc analysis (LOCF), we selected patients who experienced any decline from baseline on the three outcome measures (CGI-C >4, FLCI <0, or ASHA-FACS <0). We also examined the subsets of patients in the CGI-C >4 subset who evidenced greater-than-mild decline on the FLCI (FLCI <-3) and ASHA-FACS (ASHA-FACS <-10). We then used Generalized Estimating Equations to compare treatment groups in terms of proportions of patients who fulfilled these criteria for double and triple outcome measure combinations at endpoint and overall (i.e., throughout the trial). Results: In the three possible double-outcome measure combinations for patients experiencing any decline, memantine treatment (vs. placebo) significantly prevented worsening at endpoint and overall for the ASHA-FACS/CGI-C combination and overall for the ASHA-FACS/FLCI combination (P < 0.05). No significant differences in prevention of worsening were observed for the FLCI/CGI-C double-outcome combination or for the triple-outcome combination. In the group that experienced greater-than mild decline, all three double-outcome combinations and the triple-outcome combination demonstrated significant prevention of worsening in the memantine group at endpoint and overall (P < 0.05). Conclusions: In patients with moderate AD, memantine is associated with a prevention of worsening in functional communication and global clinical status.
2010 · Alzheimer's & Dementia
Background: In patients with Alzheimer's disease (AD), a declining ability to communicate has been associated with increased caregiver stress. In a previously reported, randomized trial in moderate AD (NCT00469456), memantine was superior to placebo at improving functional communication, as recognized by caregivers. Here we focus on patients from that trial who experienced a worsening on two measures of functional communication: the primary study endpoint, an assessment of patients using the Functional Linguistic Communication Inventory (FLCI), and the secondary study endpoint, an assessment of caregivers using the combined Social Communication and Communication of Basic Needs subscales of the American Speech-Language-Hearing Association - Functional Assessment of Communication Skills of Adults scale (ASHA-FACS). Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n = 133) versus placebo (ITT n = 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. In this post hoc analysis (LOCF), we selected patients whose changes on the FLCI or the ASHA-FACS subscales indicated any worsening (<0, both measures), greater-than-mild worsening (decline of more than 0.5 standard deviations: FLCI, <-3; ASHA-FACS, <-10), or greater-than-moderate worsening (decline of more than 1.0 standard deviation: FLCI, <-6; ASHA-FACS, <-20). We then used Generalized Estimating Equations to compare treatment groups in terms of proportions of patients who experienced each degree of worsening at endpoint and overall (i.e., throughout the trial). Results: On the FLCI, no significant difference was observed between memantine and placebo in the proportion of patients who experienced any decline (endpoint and overall); however, a significantly higher percentage of patients in the placebo group experienced greater-than-mild worsening at endpoint (P = 0.032) and overall (P = 0.013) and greater-than-moderate worsening at endpoint (P = 0.039) but not overall (P = 0.081). On the ASHA-FACS, significantly more caregivers of patients taking placebo relative to memantine reported any worsening overall (P = 0.013) but not at endpoint (P = 0.079); significantly greater-than-mild worsening at endpoint (P = 0.012) and overall (P = 0.018), and significantly greater-than-moderate worsening at endpoint (P = 0.011), though not overall (P = 0.133). Conclusions: Memantine treatment of patients with moderate AD may be associated with a prevention of worsening in functional communication.
2010 · Alzheimer's & Dementia
Background: Patients with Alzheimer's disease (AD) experience a decline in language and communication skills, which contributes significantly to caregiver stress. Memantine is an NMDA receptor antagonist approved for the treatment of moderate to severe AD. We previously reported the results of a randomized trial (MEM-MD-71; NCT00469456), which demonstrated that memantine was superior to placebo in improving functional communication in patients with moderate AD, as recognized by caregivers. This report focuses on global clinical status in patients from that trial. Methods: Native English-speaking outpatients with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized study of memantine (20 mg/day; ITT n = 133) versus placebo (ITT n = 124). Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. The primary and secondary measures were baseline-to-endpoint score changes on the FLCI and the Social Communication/Communication of Basic Needs subscales of the ASHA-FACS, which are, respectively, patient- and caregiver-based instruments designed for the assessment of functional communication abilities. An additional outcome measure was patients' global clinical status, assessed using the 7-point Clinician's Global Impression of Change (CGI-C) scale. The distributions of CGI-C scores (OC and LOCF) were compared between groups using a Cochran-Mantel-Haenszel (CMH) test. Post hoc analyses of the proportions of patients (OC and LOCF) who showed any improvement (CGI-C <4) at Week 12 and overall (i.e., throughout the trial) were performed using Generalized Estimating Equations. Results: CGI-C scores at study endpoint (Week 12; Mean ± SD) indicate a significantly better global clinical status of memantine-treated patients, compared to their placebo-treated counterparts (3.8 ± 1.1 vs. 4.0 ± 1.1, P = 0.03; both OC and LOCF). In addition, memantine treatment was associated with a greater proportion of patients who showed an overall improvement at Week 12 (39.1% vs. 28.6%, P = 0.07; OC and 39.1% vs. 28.2%, P = 0.06; LOCF) and overall (P = 0.045; OC and P = 0.04; LOCF). Conclusions: Memantine treatment of patients with moderate AD is associated with an improvement in patients' global clinical status.
2010 · European Neuropsychopharmacology
2010 · European Neuropsychopharmacology
2008 · Alzheimer's & Dementia
Background: Tarenflurbil is a Selective Aβ42-Lowering Agent (SALA) that modulates γ-secretase activity to preferentially reduce production of Aβ42 in vivo and in vitro. Evidence for potential benefit of tarenflurbil 800 mg bid in subjects with mild AD was recently observed in a randomized, double-blind Phase 2 trial of up to 24 months of treatment. Methods: A target of 1600 subjects with mild AD (MMSE score 20–26) were to be randomized (1:1) to receive tarenflurbil 800 mg bid or placebo for 18 months. Randomization was stratified according to stable use/nonuse of acetylcholinesterase inhibitors (AChEIs) and/or memantine. The co-primary efficacy outcomes are the rate of change (slope) in ADAS-cog and the ADCS-ADL, with assessments conducted every 3 months. The secondary outcome is the CDR-sb, with additional exploratory outcomes including the NPI, Quality of Life-AD, and Caregiver Burden Inventory. ECGs are obtained every 3 months, with adverse events monitored throughout the study. Plasma samples are collected every 3 months for pharmacokinetic and exploratory biomarker analyses. Results: This trial enrolled 1684 subjects at 133 sites in the United States. The last patient visit occured in March 2008, with database lock occuring in June of 2008. At enrollment, 33% of subjects were using AChEIs alone (stable for ≥ 6 months), 6% of subjects were using memantine alone (stable for ≥ 3 months), 41% of subjects were using both AChE is and memantine and 19% of subjects were taking no AD therapy. A second Phase 3 trial of similar design, fully enrolled with 840 subjects, is ongoing in the US, Canada and Europe and is expected to be completed in the clinic in October of 2008. Conclusions: This Phase 3 protocol was developed based on Phase 2 trial results. It is powered to evaluate the efficacy of tarenflurbil with respect to the primary outcomes, and to examine its effect both as monotherapy and as add-on therapy with currently marketed AD medications.
2005 · Alzheimer's & Dementia
Background: Several epidemiological studies have suggested that longer-term use of NSAIDs may reduce the risk of developing Alzheimer's disease (AD). Although there were encouraging results from some earlier studies, more recent longer-term, larger, placebo-controlled clinical trials utilising drugs with an anti-inflammatory action have produced disappointing outcomes. Re-analysis of the epidemiological data has shown that the protective effect is limited to a subgroup of NSAIDs, including flurbiprofen, which have Aβ-42 lowering properties and which were not used in the previous longer-term placebo-controlled trials. Flurizan (MPC-7869 (R)-flurbiprofen) is a single enantiomer of flurbiprofen, which has been shown to lower brain levels of Aβ-42 in a mouse model of AD (Tg2576), with some evidence of an effect on learning and memory. There is little risk of gastric toxicity because of a lack of anti-COX activity, and the compound has been shown to be safe and well tolerated in healthy older volunteers (55-80yrs) at doses of up to 1600mg per day when administered for 21 days in a phase I study. It is therefore an exciting potential disease modifying treatment for AD. Objective(s): This presentation will provide efficacy and safety data from a clinical trial of Flurizan, which to our knowledge will be the first multi-centre, placebo-controlled, double-blind clinical study of a selective Aβ-42 lowering agent in patients with mild to moderate Alzheimer's disease. Methods: This is a one-year trial evaluating both 400mg BID and 800mg BID of (R)-flurbiprofen per day, in 210 patients (50% female) with mild to moderate AD (MMSE 15-26). It employed the ADAS-cog, ADCS-ADL, CDR-sb, CIBIC plus, NPI and MMSE as outcome measures. At baseline the mean age of the subjects was 75 years with an average MMSE score 21 and an average standard ADAS-cog score 23. Of the patients enrolled in the trial, 94 per cent were also taking stable doses of cholinesterase inhibitors. Concomitant treatment with memantine was not allowed. Conclusions: The study completes in March 2005, and the cognitive, functional, global and behavioural outcomes will be presented, together with the safety data.
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