Drug Development

Background: In Alzheimer's disease (AD) clinical trials, participants must enroll with a study partner informant who accompanies them to visits and completes validated instruments. Mid-trial informant replacement (IR) has been found to impact academic trial results. We hypothesized that a similar impact would be observed in industry-sponsored trials.

Method: We conducted a retrospective analysis of two industry-sponsored AD clinical trials testing semagacestat in mild-to-moderate AD. We assessed the relationship between IR and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score between visits using generalized estimating equations (GEE). The outcomes of interest were mean change in ADCS-ADL between successive visits and the mean absolute change in ADCS-ADL between successive visits, which was used to assess variability. Both models were adjusted for a priori-specified potential confounding variables including participant sex, age, informant type, trial, time, and previous ADCS-ADL measurement. To analyze impacts on a primary outcome measure, we used an ANCOVA model to estimate the association between IR and 76-week change from baseline in ADCS-ADL, where we adjusted for participant sex, age, informant type, trial, and baseline ADCS-ADL measurement. We conducted an F-test to compare the variances of this change.

Result: Among N = 2642 randomized participants, 72 (∼3%) of participants experienced IR at least once with a total of 81 occurrences. For visits standardized to be three months apart, we estimated that the difference in the mean between-visit change in ADCS-ADL was approximately -1.41 points (95% CI: -3.52, 0.72; P = 0.194) and the difference in the mean between-visit absolute change was approximately 1.85 points (95% CI: 0.22, 3.49; P = 0.026), comparing participants who experienced IR to similar participants who had stable informants. We did not estimate a statistically significant difference in week-76 change from baseline ADCS-ADL (Est. = -0.98, 95% CI: -6.02, 4.06; P = 0.702) or a significant ratio of variances (Est. = 1.09, 95% CI: 0.65, 2.17; P = 0.700) comparing this measure for participants with IR to those with stable informants.

Conclusion: IR is associated with increased variability in ADCS-ADL measurements between successive visits and should be considered when planning AD clinical trials.