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.
Showing publications 101–150
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2015 · The Journal of Prevention of Alzheimer's Disease
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 · Alzheimer's & Dementia
Background: There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Methods: Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. Results: The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. Conclusions: We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention Initiative's preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD.
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
An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.
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 · Alzheimer's Research & Therapy
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 · The American Society of Human Genetics
To date, the widely used genome-wide association studies (GWASs) of the human genome have reported thousands of variants that are significantly associated with various human traits. However, in the vast majority of these cases, the causal variants responsible for the observed associations remain unknown. In order to facilitate the identification of causal variants, we designed a simple computational method called the “preferential linkage disequilibrium (LD)” approach, which follows the variants discovered by GWASs to pinpoint the causal variants, even if they are rare compared with the discovery variants. The approach is based on the hypothesis that the GWAS-discovered variant is better at tagging the causal variants than are most other variants evaluated in the original GWAS. Applying the preferential LD approach to the GWAS signals of five human traits for which the causal variants are already known, we successfully placed the known causal variants among the top ten candidates in the majority of these cases. Application of this method to additional GWASs, including those of hepatitis C virus treatment response, plasma levels of clotting factors, and late-onset Alzheimer disease, has led to the identification of a number of promising candidate causal variants. This method represents a useful tool for delineating causal variants by bringing together GWAS signals and the rapidly accumulating variant data from next-generation sequencing.
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 · Alzheimer's & Dementia
Background: No well-established, validated endpoints exist that are sensitive to change in MCI populations in clinical trials. Our goal was to develop a tool based on standard clinical items that would demonstrate maximum responsiveness to progression and to treatment in an MCI population and would also perform well in a mild AD population (collectively referred to as Early AD). This analysis uses a novel approach by utilizing data from multiple studies to investigate responsiveness to progression and treatment effects rather than sensitivity to baseline deficits. Methods: This tool was built empirically with no a priori assumptions. A partial least squares (PLS) regression model used placebo data from 4 MCI studies over 12 months to select the combination of cognitive and functional items which is most sensitive to change over time, using items from a variety of well-established and validated scales. The PLS regression coefficients from the model were used to form a weighted composite score. The resulting composite score is comprised of ADAS-Cog, MMSE and CDR items. Performance of the composite score was assessed against the original scales in an MCI population, in enriched (CSF Aβ positive) MCI subgroups, with split sample validation, in the presence of a treatment effect and in a mild AD patient population combining data from 3 studies. Results: A composite clinical score was devised from 12 items from the ADAS-Cog, MMSE, and CDR-SB that assess both cognition and global function. This score demonstrates improved sensitivity to decline, as well as reduced heterogeneity, as compared with original scales, and is responsive to treatment effect in MCI, enriched MCI and mild AD populations. The composite score allows for substantial sample sizes reductions in non-enriched and enriched MCI populations for a 12-month study (see Figure). Conclusions: A new composite clinical score that utilizes relevant items from validated and well-established clinical tools provides a tool that can be used as a single clinical outcome in studies that target MCI, enriched MCI and mild AD populations. This tool will enable the use of substantially smaller sample sizes due to improved sensitivity to disease progression and treatment effects.
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 · Progress in neurobiology
Abstract: Despite enormous financial and scientific efforts, still no approved disease-modifying therapies exist for Alzheimer's disease (AD). During the last decade all Phase III clinical trials on disease modifiers in AD have failed. The dementia stage of AD being probably too late in order to allow for successful disease modification has been identified as a possible culprit that could explain the failure of so many clinical trials. In parallel, a major development in the diagnostic research field of AD was achieved by the recent proposal of new diagnostic criteria for AD, which also specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD, thus extending the traditional definition of disease to very early stages that may be a more feasible target for various disease modifying therapeutic interventions. This ongoing paradigm shift in AD definition and diagnosis represents a fundamental basis for redefinition of interventional trials in AD, allowing to specifically focus on preventative measures during very early pathophysiologically confirmed stages of disease. This consensus paper reflects the outcome from a European Union and North American Task Force meeting comprised of experts from academia, industry, private foundations, and regulatory agencies that was convened in Toulouse, France on November 5, 2010 and that focused on prevention trials in AD. This position paper thoroughly analyzes prerequisites for successful preventative trials in AD and concludes with concrete recommendations on biomarkers, statistical tools and other variables important for improved study designs suitable for preventative as well as for early therapeutic interventional trials in AD.
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 · Alzheimer's & Dementia
Background: We have proposed an Alzheimer's Prevention Initiative (API) to relate a presymptomatic Alzheimer's disease (AD) treatment's biomarker effects to clinical outcome in cognitively normal people at the highest imminent risk to develop AD, including the world's largest kindred of early-onset AD (EOAD) causing mutation carriers (mean age at clinical onset=45), from Antioquia, Colombia. Here, we used longitudinal data from cognitively normal E280A Presenilin 1 (PS1) mutation carriers and non-carriers over age 35 to 1) characterize the combination of cognitive tests most sensitive to cognitive decline, 2) estimate the number of mutation carriers needed in randomized clinical trial (RCTs) to detect AD-slowing treatment effect on the composite cognitive endpoint, and 3) estimate the treatment effect that could be detected in 75 PS1 mutation carriers with 80% power and p=0.05. Methods: A battery of 19 cognitive tests, acquired every 2-5 years between 1995 and 2010 by the Neuroscience group at the University of Antioquia, was used to calculate the mean-to-standard-deviation ratios (MSDR) for each combination of one to six measurements. Measurements were adjusted for aging/practice effects using data from no carriers. The best combination was used to estimate statistical power in 24-60 month presymptomatic AD RCTs. Results: After practice/aging correction, the optimal combination to predict cognitive decline included CERAD word list delayed recall, category verbal fluency, MMSE Orientation and Time, Constructional Praxis and Ravens progressive matrices. (A similar pattern was observed in cognitively normal older APOE4 carriers [Langbaum et al, ICAD abstract 2011]). We estimate the need for 215/79 PS1 mutation carriers per group over the age of 35, respectively, to detect a 25% treatment effect in a 24/60-month RCT. We estimate that 75 carriers per group would permit us to detect 43/26% treatment effects, respectively in a 24/60-month RCT. Conclusions: We have identified a combination of cognitive tests to evaluate presymptomatic AD treatments in cognitive normal people at highest imminent risk for EOAD. We have found a similar combination in those at highest risk for late-onset AD. We will continue to develop this approach in preparation for the presymptomatic AD/surrogate marker development trials proposed in the API.
2011 · Journal of the American Medical Directors Association
2011 · Alzheimer's & Dementia
Background: We have proposed an Alzheimer's Prevention Initiative (API) to relate a pre-symptomatic Alzheimer's disease (AD) treatment's biomarker effects to clinical outcome in cognitively normal people who, based on age and genetic background, are at highest imminent risk of symptomatic AD. Here, we used longitudinal data from two cohort studies at the Rush Alzheimer's Disease Center to identify a new cognitive composite score that is sensitive to cognitive decline associated with pre-symptomatic AD to inform on the design of a randomized clinical trial (RCT) in apolipoprotein E (APOE) e4 carriers. Methods: Using a battery of 19-21 cognitive tests, the annualized mean-to-standard-deviation ratios (MSDR) of the change over time were calculated for the un-weighted sum of every combination of two to six tests for those who developed cognitive impairment (MCI or AD) in the five years prior to diagnosis. Measurements were adjusted for aging/practice effects using data from participants who remained cognitively normal. The best combinations were evaluated for construct validity. This optimal test combination was then examined in APOE4 carriers. Results: The optimal combination of measurements that was selected to sensitively measure cognitive decline over time included Logical Memory-delayed recall, CERAD word list-delayed recall, category fluency, Ravens progressive matrices, and MMSE (annual MSDR =0.182847). A similar composite test was independently developed using data from a longitudinal cohort of cognitively normal PS1 E280A mutation carriers (Ayutyanont et al, ICAD abstract 2011). This composite score was also shown to be sensitive to decline in APOE4 carriers relative to non-carriers between the ages of 70 and 85. Using this composite cognitive endpoint, we estimate that 4,360/1,100 APOE4 carriers per group would permit us to detect a 30% treatment effect in a 24/60-month RCT, respectively. Conclusions: In this first phase of the process, we have identified a combination of cognitive tests to evaluate pre-symptomatic AD treatments in cognitive normal people at high imminent risk for late-onset AD, and have shown that a similar combination performs well in individuals at highest risk for early-onset AD. We will continue to develop and refine this approach in preparation for the pre-symptomatic AD/surrogate marker development trials proposed in the API.
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
2009 · Alzheimer's & Dementia
Background: Recently, there has been substantial interest in establishing methods for identifying a disease modifying therapy for Alzheimer's disease. The concept of Disease Modification has been approached in many different ways including cross-over study designs (randomized withdrawal and staggered start), use of biomarkers or imaging outcomes, measuring clinically relevant milestones, comparing slopes of decline and comparing adjusted slopes (Natural History Staggered Start analysis - NHSS). These methods are able to distinguish between different patterns of clinical response. Methods: A definition of Disease Modification is proposed that defines a substantially different pattern of clinical response than that of a symptomatic therapy. Additional definitions are proposed to separate out long term and short term symptomatic responses, and permanent and temporary disease modification effects. Clinical approaches are discussed in the context of supporting these distinct types of mechanisms. Results: The Randomized Withdrawal and Staggered Start designs can separate between disease modifying effects and symptomatic effects. The Natural History Staggered Start analysis can also make this distinction without the difficulties of a two-phase study such as: the potential bias and loss of power associated with a high dropout rate, ethical concerns related to removing a potentially efficacious treatment and the long treatment duration required for these two phase studies. Unadjusted slopes analysis and use of clinically relevant milestones can identify long lasting effects without distinguishing between disease modification and symptomatic effects. Use of biomarkers and imaging outcomes can detect effects on the underlying disease process, but will need additional validation in order to demonstrate that these effects are due to disease modification. Conclusions: The pathological process of Alzheimer's disease is not understood well enough to be directly measurable with biomarkers or imaging outcomes, and is not tied to clinical outcomes except through the symptomatology. In this setting, demonstration of disease modification should rely on clinical evidence with support from several sources including: pre-clinical data supporting a disease modifying mechanism of action, biomarkers connecting that mechanism to the clinical efficacy, and imaging outcomes supporting a structural change consistent with modification of the underlying disease.
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.
2007 · Patent
Abstract: In general, the invention relates to a pharmaceutical dose having R-flurbiprofen as the active ingredient that upon oral administration of a single dose to a fasting subject provides a Cmax of about 30-95 µg per mL. When the dose is administered to an individual having mild-to-moderate Alzheimer's disease (or desiring protection against Alzheimer's disease) twice daily for at least 4 months according to the described guidelines, an improvement or lessening in decline of cognitive function as characterized by cognition tests is observed in the patient. The composition of the invention is formulated with one or more pharmaceutically acceptable excipients, salts or carriers.
2007 · Alzheimer Disease & Associated Disorders
Abstract: To evaluate the safety and tolerability and pharmacokinetic properties of R-flurbiprofen (Tarenflurbil) in normal elderly individuals and to determine the effect of the drug on amyloid beta 42 (Abeta42) levels, we conducted a double-blind, placebo-controlled study of 48 healthy subjects aged 55 to 80. Three successive cohorts were randomized to doses of 400, 800, or 1600 mg/d, or placebo, given as 2 divided doses for 21 days. Blood and cerebrospinal fluid were collected for pharmacokinetic studies and measurement of Abeta levels at baseline and on day 21. R-flurbiprofen was well-tolerated at all 3 doses. The compound penetrated the blood-brain barrier in a dose-dependent manner. From baseline to 21 days, comparisons between study groups revealed no significant differences in changes of cerebrospinal fluid Abeta42 levels and no significant differences in changes of plasma Abeta42 levels at the time of trough drug level at 21 days of treatment. Further analysis of drug concentration-response for plasma samples showed that at the time of peak plasma concentration, higher plasma drug concentration was related to lower Abeta42 plasma levels (P=0.016). R-flurbiprofen had an excellent safety profile and showed dose-dependent central nervous system penetration. Exploratory analyses of plasma Abeta and peak drug levels suggested a short-term effect in plasma that warrants independent verification. The safety, tolerability, and pharmacokinetic profile of R-flurbiprofen in these older individuals support the ongoing studies of this compound in patients with Alzheimer disease.
2007 · European Journal of Neurology
Background: Tarenflurbil is a Selective Ab42-Lowering Agent (SALA) that lowers brain levels of Ab42 in a mouse model of AD and chronic dosing in this model prevents defects in learning and memory. These data and the Phase-2 study indicating sustained benefit in activities of daily living, global function and cognition in mild AD patients, suggest the potential for tarenflurbil to have disease-modifying properties. Methods: This was a placebo-controlled, 1-year study evaluating tarenflurbil in 207 patients with mild-to-moderate AD. At randomization, 94% of subjects were on stable acetylcholinesterase inhibitor therapy. An exploratory post-hoc analysis was performed which compared time to adverse psychiatric events between treatment groups. Results: In subjects with mild AD (MMSE 20–26) was a significant delay in time to clinically significant adverse psychiatric events, 800 mg BID compared to placebo (p=0.011). Among 35% of the placebo group who had an event, the median time was approximately 106 days. In the 800 mg BID group, the median time to event was greater than 333 days with only 14% of this group having an event. The most common psychiatric events reported in the placebo group were agitation, aggression, confusional state and depression.
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