Aaron Vederman, PhD, Cogstate Senior Central Rater
Alzheimer’s disease (AD) research has gained momentum in recent years and months with an enormous scope of advancement being seen in clinical trials. As a neuropsychologist working on clinical trials in this space, I’ve observed these changes both in terms of basic science as well as evolving methodologies in research and operational efficiencies.
These trends were highlighted across the recent CTAD 2022 event, with two themes particularly standing out to me—the increase in treatment possibilities for AD and the use of decentralized methodologies to enhance trial efficiencies. The following summary is just a taste of the feast of information shared about these topics at the event.
Broadening Scope of Treatment Possibilities for AD
A clear highlight from the event was the presentation of the Clarity AD trial, a Phase 3 placebo-controlled, double-blind, parallel-group, 18-Month Study evaluating lecanemab in Early Alzheimer’s Disease. In addition to demonstrating a significant reduction of fibrillar amyloid burden beginning at three months (and continuing over the 18-month trial period) in the treatment group, the Clarity AD trial demonstrated impressive group differences in clinical measures of cognitive and behavioral functioning.
In another fascinating presentation, Dr. Suzanne Craft from Wake Forest University discussed the potential for therapeutic opportunities beyond simply removing amyloid deposits in the brain (because this approach may primarily slow but not reverse the illness) by also targeting immune-metabolic pathways. She noted research demonstrates that protein pathways involving metabolism and glial immune function have the strongest relationships with AD, and the most strongly related genes are those which are implicated in inflammation and which are regulated by insulin. As such, she highlighted dysfunction in immune-metabolic pathways which occur early in AD and which appear to be the upstream predecessors to amyloid dysregulation and tau hyperphosphorylation.
Decentralized Methodologies
On the theme of decentralized trials, Dr. Jessica Langbaum from the Banner Alzheimer’s Institute presented on the validation of remote neuropsychological assessment. Prior comparisons of semi-remote and in-person clinical interviews have shown comparability, however there is more limited data comparing fully remote cognitive assessments. Dr. Langbaum presented data from Trailblazer-EXT, a donanemab follow-on study in symptomatic AD. Part A of the study consisted of a multicenter, randomized, multi crossover study to validate the remote assessment of cognitive and functional scales. The primary endpoint was the intraclass correlation coefficient (ICC) between at-home and on-site assessment for the ADAS-Cog, ADCS-ADL, iADRS, MMSE, and CDR-SB. 95 individuals were randomized and 85 completed Part A. ICCs in the 0.8 range were found across scales, leading to the conclusion that there is strong equivalence between on-site and fully remote assessment.
Prof. Paul Maruff of Cogstate presented an overview of technological assessment methodologies adapted to decentralized clinical trials (see a 4-min YouTube summary here). He highlighted the results of a feasibility study which used the CDR, International Shopping List Test (ISLT), Visual Paired Associate Learning Test (CPAL), and Digit-Symbol Substitution Test-Meds (DSST-m). He described how innovations in technology have been driven by those aspects of assessment which require the participant to physically draw, write, or otherwise manipulate test stimuli in a fully remote setting. For instance, “shaping procedures” have been built into the computerized tests which are used to gradually acclimate the participant to the manner of touching and interacting with the device to capture their responses. These gradual shaping procedures are necessary to ensure that—in the absence of a psychometrician sitting directly in the room observing and correcting the participant—once the actual test begins the participant will be prepared to respond appropriately without confusion. In short, the technology itself is required to take on some of the functions previously controlled by the psychometrician.
In terms of results of the feasibility study, there was a correlation of 0.86 between remote and in-person scores on the CDR-SB. Strong equivalency was also seen on ISLT, CPAL, and DSST-m. In sum, the CDR is valid for tele-administration in both preclinical and prodromal AD. Cognitive tests which require rater-controlled presentation of visual stimuli and require motor responses can be adapted for remote administration. With appropriate methods, construct and criterion validity of remote clinical and cognitive assessment is high.
Final Thoughts
With my own hands-on experience as a remote clinical rater, and from observing findings in the presentations given at the event, it is clear that raters working in decentralized model will be responsible for conducting assessments across very broad demographic groups. I believe decentralized clinician-raters will require skills not only in basic clinical assessment, but they will also need to be especially sensitive to factors of cross-cultural assessment.
Given our expertise in neuroscience research, Cogstate is among those playing a visible and leading role in this evolving industry. I invite you to reach out to our team to discuss how we can support your clinical trials.
