Abstract
Background: No well-established, validated endpoints exist that are sensitive to change in MCI populations in clinical trials. Our goal was to develop a tool based on standard clinical items that would demonstrate maximum responsiveness to progression and to treatment in an MCI population and would also perform well in a mild AD population (collectively referred to as Early AD). This analysis uses a novel approach by utilizing data from multiple studies to investigate responsiveness to progression and treatment effects rather than sensitivity to baseline deficits. Methods: This tool was built empirically with no a priori assumptions. A partial least squares (PLS) regression model used placebo data from 4 MCI studies over 12 months to select the combination of cognitive and functional items which is most sensitive to change over time, using items from a variety of well-established and validated scales. The PLS regression coefficients from the model were used to form a weighted composite score. The resulting composite score is comprised of ADAS-Cog, MMSE and CDR items. Performance of the composite score was assessed against the original scales in an MCI population, in enriched (CSF Aβ positive) MCI subgroups, with split sample validation, in the presence of a treatment effect and in a mild AD patient population combining data from 3 studies. Results: A composite clinical score was devised from 12 items from the ADAS-Cog, MMSE, and CDR-SB that assess both cognition and global function. This score demonstrates improved sensitivity to decline, as well as reduced heterogeneity, as compared with original scales, and is responsive to treatment effect in MCI, enriched MCI and mild AD populations. The composite score allows for substantial sample sizes reductions in non-enriched and enriched MCI populations for a 12-month study (see Figure). Conclusions: A new composite clinical score that utilizes relevant items from validated and well-established clinical tools provides a tool that can be used as a single clinical outcome in studies that target MCI, enriched MCI and mild AD populations. This tool will enable the use of substantially smaller sample sizes due to improved sensitivity to disease progression and treatment effects.