The ADAS‐Cog revisited: Novel composite scales based on ADAS‐Cog to improve efficiency in MCI and early AD trials

Abstract

Background The 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. Methods Using 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. Results All 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 (Aβ1-42) in a 2-year trial yielded gains in power of 20% to 40% over ADAS-Cog 11, regardless of the novel measure considered. Conclusion An empirical, data-driven approach with e xisting 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 Aβ1-42 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.

Development of a straightforward and sensitive scale for MCI and early AD clinical trials

“…Comparing to the composite scores proposed by other researchers using the ADNI data, all of the composites included some items from the memory domain of ADAS-cog, and all items from the memory domain of CDR. Most of the other composites did not use the functional assessment FAQ whereas ours and "TriAD-G" by Raghavan and colleagues [12] used FAQ to improve sensitivity. None of the studies that examined all available clinical scales in ADNI has identified Executive Function measures (e.g., Trail Making, Digit Symbol, Digit Span, Category Fluency tests) in the development of sensitive composites.…”

“…The selected items were combined using weighting factors to maximize the sensitivity of the composite. Nandini and colleagues [12] proposed two composite scores on the basis of ADNI-1 clinical data. The first one is "TriAD," a cognitive endpoint combining Word Recall, Delayed Word Recall, Orientation, and CDR cognitive components.…”

“…In addition, several pharmaceutical companies have ongoing efforts toward the development of sensitive clinical endpoints for trials in MCI and early AD [8][9][10][11][12][13]. In this report we present our work in developing easyto-use composite endpoints that are sensitive to disease progression and to hypothetical treatment effects of disease-modifying therapies.…”

“…Composite scores were derived based on the most sensitive measures, with a similar hypothesis as in some of the previous work [12] that by combining the most informative scales we could create a composite with stronger signal and reduced variability for the early AD population. In addition to the MCI population, subpopulations enriched by apolipoprotein E (APOE) status, baseline hippocampal volume, and baseline CSF b-amyloid (Ab) were also analyzed.…”

Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology

“…Established instruments to measure cognition lack sensitivity and responsiveness in early stages of the AD process (e.g., Raghavan et al [6]). CAMD's most recent project aims to address this problem by advancing a composite clinical outcome assessment tool built from elements of existing scales through a formal regulatory path for qualification as a primary outcome measure for predementia AD trials.…”