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Saving cognitive outcome data in Alzheimer's disease clinical trials during the COVID-19 pandemic: Commentary on the virtual administration of the ADAS-Cog.

ABSTRACT: Elderly participants in Alzheimer's disease (AD) clinical trials are at high risk of morbidity and mortality with interpersonal exposure to COVID-19, a situation that is likely to continue for the foreseeable future. Yet, in-person neuropsychological assessments remain the mainstay primary outcomes for clinical trials seeking prevention and cure for AD. The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) is among the most commonly used cognitive assessment in AD clinical trials, and though currently lacking specific guidelines for virtual administrations, it can be used remotely with appropriate modifications and considerations. Here we propose a novel method of virtual administration of the ADAS-Cog, which considers workarounds for technological and human limitations imposed when the participant is no longer sitting across from the test administrator.

SUBMITTER: Schwab NA

PROVIDER: S-EPMC7744007 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Saving cognitive outcome data in Alzheimer's disease clinical trials during the COVID-19 pandemic: Commentary on the virtual administration of the ADAS-Cog.

Schwab Nadine A NA DesRuisseaux Libby A LA Weinberg Marc S MS Arnold Steven E SE

Alzheimer's & dementia (New York, N. Y.) 20201216 1

Elderly participants in Alzheimer's disease (AD) clinical trials are at high risk of morbidity and mortality with interpersonal exposure to COVID-19, a situation that is likely to continue for the foreseeable future. Yet, in-person neuropsychological assessments remain the mainstay primary outcomes for clinical trials seeking prevention and cure for AD. The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) is among the most commonly used cognitive assessment in AD clinical trials, and th ...[more]

PMID: 33344748

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Project description:BackgroundThe Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) has been used widely as a cognitive end point in Alzheimer's Disease (AD) clinical trials. Efforts to treat AD pathology at earlier stages have also used ADAS-Cog, but failure in these trials can be difficult to interpret because the scale has well-known ceiling effects that limit its use in mild cognitive impairment (MCI) and early AD. A wealth of data exists in ADAS-Cog from both historical trials and contemporary longitudinal natural history studies that can provide insights about parts of the scale that may be better suited for MCI and early AD trials.MethodsUsing Alzheimer's Disease Neuroimaging Initiative study data, we identified the most informative cognitive measures from the ADAS-Cog and other available scales. We used cross-sectional analyses to characterize trajectories of ADAS-Cog and its individual subscales, as well as other cognitive, functional, or global measures across disease stages. Informative measures were identified based on standardized mean of 2-year change from baseline and were combined into novel composite endpoints. We assessed performance of the novel endpoints based on sample size requirements for a 2-year clinical trial. A bootstrap validation procedure was also undertaken to assess the reproducibility of the standardized mean changes of the selected measures and the corresponding composites.ResultsAll proposed novel endpoints have improved standardized mean changes and thus improved statistical power compared with the ADAS-Cog 11. Further improvements were achieved by using cognitive-functional composites. Combining the novel composites with an enrichment strategy based on cerebral spinal fluid beta-amyloid (Aβ(1-42)) in a 2-year trial yielded gains in power of 20% to 40% over ADAS-Cog 11, regardless of the novel measure considered.ConclusionAn empirical, data-driven approach with existing instruments was used to derive novel composite scales based on ADAS-Cog 11 with improved performance characteristics for MCI and early AD clinical trials. Together with patient enrichment based on Aβ(1-42) pathology, these modified endpoints may allow more efficient clinical trials in these populations and can be assessed without modifying current test administration procedures in ongoing trials.

Project description:Introduction:Use of cognitive composites as primary outcome measures is increasingly common in clinical trials of preclinical and prodromal Alzheimer's disease (AD). Composite outcomes can decrease intra-individual variability, resulting in improved sensitivity to detect longitudinal change and increased statistical power. We developed a novel composite outcome, the ADAS-Cog-Exec, for use in the EXERT trial-a Phase 3 randomized, controlled, 12-month exercise intervention in mild cognitive impairment (MCI). Methods:Three combinations of cognitive measures selected from the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13), tests of executive function, and the Clinical Dementia Rating (CDR) were created based on previously documented sensitivity to longitudinal change in MCI and to the effects of exercise. Optimally weighted composites of each combination were modeled using data from the ADNI-1 MCI cohort. Ten-fold cross-validation was performed to obtain a bias-corrected mean to standard deviation ratio (MSDR). The cognitive composites were assessed for their sensitivity to detect 12-month change in MCI. Results:The MSDR of 12-month change for each of the composite outcomes tested exceeded that of the ADAS-Cog13 total score. The composite with the highest MSDR (MSDR = 0.48) and associated statistical power included scores on ADAS-Cog13 Word Recall, Delayed Word Recall, Orientation, and Number Cancellation subtests; Trail-Making Tests A & B, Digit Symbol Substitution and Category Fluency; and cognitive components of the CDR (Memory, Orientation, Judgement & Problem Solving). Discussion:An optimally weighted cognitive composite measure was identified and validated for use in EXERT. This composite contained selected subtests from the ADAS-Cog13, additional measures of executive function, and box scores for cognitive components of the CDR. Because this composite score demonstrated high sensitivity to longitudinal change in MCI it will be used as the primary outcome measure for the EXERT trial.

Dataset Information

Saving cognitive outcome data in Alzheimer's disease clinical trials during the COVID-19 pandemic: Commentary on the virtual administration of the ADAS-Cog.

Publications

Saving cognitive outcome data in Alzheimer's disease clinical trials during the COVID-19 pandemic: Commentary on the virtual administration of the ADAS-Cog.

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