Estimating attrition in mild‐to‐moderate Alzheimer’s disease and mild cognitive impairment clinical trials

Abstract

AbstractBackgroundParticipant retention directly affects the validity and generalizability of clinical trial results. Investigators need information about expected attrition when planning trials of varying durations.MethodUsing the Alzforum and clinicaltrials.gov databases we reviewed 351 phase 2 and 3 placebo‐controlled trials conducted since 1998. Eighty‐six mild‐to‐moderate Alzheimer’s disease (AD) and eleven Mild Cognitive Impairment (MCI) trials met criteria for inclusion in this study. We first assessed the frequency with which trial arms differed in overall retention. When trials included more than one active arm, we combined those arms into a single group. To model associations between trial duration and retention, we used binomial regression.ResultFigure 1 illustrates differences in the observed proportion of participants completing in each trial between active and placebo arms for mild‐to‐moderate AD (Figure 1A) and MCI trials (Figure 1B). For each trial, a 95% confidence interval for the true difference between arms is provided. Since there was no consistent difference between arms, subsequent analyses combined active and placebo arms. Figure 2 illustrates the completion rate by trial duration for mild‐to‐moderate AD (Figure 2A) and MCI trials (Figure 2B). A local smoother along with uncertainty regions is added for visual aid. In general, trials with longer study duration had lower retention rates. Using binomial regression with robust variance estimates to account for within‐trial correlation, we estimated that a 6‐month increase in trial duration is associated with a 34% decrease in the odds of trial completion (OR=0.66; 95% CI: 0.58, 0.75; p<0.001) among mild‐to‐moderate AD trials and a 20% decrease (OR=0.80; 95% CI: 0.68, 0.93; p=0.004) among MCI trials. From the binomial regression model, the proportion of participants completing 6, 12, and 18‐month trials were estimated to be 82.9%, 76.3%, and 68.0% for mild‐to‐moderate AD trials and 82.6%, 79.1%, and 75.2% for MCI trials, respectively.ConclusionWhile decisions related to expected trial attrition are guided by several factors, these estimates may assist investigators designing trials and suggest that trial attrition is frequent and related to trial duration.