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.
8 publications
Sorted newest first
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 · PLoS One
Identifying safe and effective adjuvants is critical for the advanced development of protein-based vaccines. Pattern recognition receptor (PRR) agonists are increasingly being explored as potential adjuvants, but there is concern that the efficacy of these molecules may be dependent on potentially dangerous levels of non-specific immune activation. The filovirus virus-like particle (VLP) vaccine protects mice, guinea pigs, and nonhuman primates from viral challenge. In this study, we explored the impact of a stabilized dsRNA mimic, polyICLC, on VLP vaccination of C57BL/6 mice and Hartley guinea pigs. We show that at dose levels as low as 100 ng, the adjuvant increased the efficacy of the vaccine in mice. Antigen-specific, polyfunctional CD4 and CD8 T cell responses and antibody responses increased significantly upon inclusion of adjuvant. To determine whether the efficacy of polyICLC correlated with systemic immune activation, we examined serum cytokine levels and cellular activation in the draining lymph node. PolyICLC administration was associated with increases in TNFα, IL6, MCP1, MIP1α, KC, and MIP1β levels in the periphery and with the activation of dendritic cells (DCs), NK cells, and B cells. However, this activation resolved within 24 to 72 hours at efficacious adjuvant dose levels. These studies are the first to examine the polyICLC-induced enhancement of antigen-specific immune responses in the context of non-specific immune activation, and they provide a framework from which to consider adjuvant dose levels.
2014 · Alzheimer's & Dementia
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.
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