Effects of informant replacement in Alzheimer's disease clinical trials

Abstract INTRODUCTION Alzheimer's disease (AD) trials require enrollment with an informant. METHODS We assessed relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS‐ADL between successive visits. We used analysis of covariance to estimate the association between replacement and 18‐month change from baseline, and an F‐test to compare the variance of this change. RESULTS Among 1336 participants, 63 (≈5%) experienced replacement. Between‐visit mean change in ADCS‐ADL was 2.44 points lower comparing replacement to stable informants (95% confidence interval [CI]: –3.91, –0.98). The difference in between‐visit mean absolute change was 2.38 points (95% CI: 1.24, 3.52). Replacement was not significantly associated with an 18‐month change from baseline. The ratio of variances (replacement/stable) was 1.80 (95% CI: 1.19, 2.99). DISCUSSION Informant replacement is associated with bias and increased variability between visits and increased variance for overall ADCS‐ADL.