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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.
8 publications
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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 · Alzheimer's Research & Therapy
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.
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