Abstract
AbstractINTRODUCTIONIn Alzheimer's disease (AD) clinical trials, participants must enroll with a study partner informant who completes validated study instruments. We hypothesized that mid‐trial informant replacement impacts study data in industry‐sponsored trials.METHODSWe conducted a retrospective analysis of two industry‐sponsored AD clinical trials testing semagacestat in mild‐to‐moderate AD dementia. We assessed the relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) scores. Using generalized estimating equations, we assessed bias and variability using mean (bias) and mean absolute (variance) change in ADCS‐ADL between successive visits as outcomes. Both models adjusted for a priori–specified potential confounding variables including participant sex, age, informant type, trial, time, previous ADCS‐ADL score, and region. To analyze the impact on end‐of‐study change‐from‐baseline results, we used an analysis of covariance model to estimate the association between replacement and end‐of‐study change‐from‐baseline in ADCS‐ADL, in which we adjusted for participant sex, age, informant type, trial, baseline measurement, and region. We conducted an F‐test to compare the variances of this change.RESULTSAmong N = 2637 randomized participants, 69 participants (2.6%) experienced 78 occurrences of replacement. For visits standardized to be 3 months apart, the difference in mean between‐visit change in ADCS‐ADL was approximately −1.61 points (95% confidence interval [CI]: −3.79, 0.57; P = 0.147), comparing participants who experienced replacement to similar participants who had stable informants. The difference in the mean between‐visit absolute change was approximately 2.02 points (95% CI: 0.34, 3.70; P = 0.019). We did not estimate a statistically significant difference in end‐of‐study change‐from‐baseline (Est. = −0.70 points; 95% CI: −5.88, 4.48; P = 0.790) or a significant ratio of variances (Est. = 1.13; 95% CI: 0.67, 2.28; P = 0.600) for participants with replacement compared to those with stable informants.DISCUSSIONInformant replacement was associated with increased between‐visit variability but had limited impact on overall trial outcomes.Highlights Informant replacement occurred in 2.6% of participants in these industry trials. Informant replacement was associated with increased variance in acute Alzheimer's Disease Cooperative Study Activities of Daily Living reporting. Informant replacement had a limited impact on overall change‐from‐baseline outcomes.
Published Version
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