Selecting appropriate meaningful change thresholds for trials of early (prodromal‐to‐mild) AD: A caregiver‐rated, anchor‐based analysis based on the Tauriel Study

Abstract

AbstractBackgroundClinically meaningful change thresholds for assessments used in Alzheimer’s disease (AD) trials, including the Clinical Dementia Rating Scale – Sum of Boxes (CDR‐SB), may differ by disease stage and are increasingly important to interpret efficacy. However, anchor‐based estimates for the CDR‐SB have largely used clinician‐ rather than caregiver‐rated anchors. We established meaningful change thresholds for the CDR‐SB using a caregiver‐rated anchor of global change in early (prodromal‐to‐mild) AD patients over an 18‐month clinical trial.MethodAnchor‐based analyses of the Tauriel data (NCT03289143) were conducted to establish CDR‐SB thresholds for biomarker confirmed early AD patients. The Caregiver Global Impression of Change – Alzheimer’s Disease (CaGI‐Alz), a 7‐point caregiver‐rated instrument, provided 2 independent anchors of meaningful decline in memory and activities of daily living (ADLs) (Figure 1). The anchor category of interest for establishing minimal meaningful change thresholds was the ‘Somewhat worse’ category. Average score changes were generated for the ‘No change’ category for comparison. Baseline CDR‐SB and Week 25, 49, and 73 CaGI‐Alz and CDR‐SB data were analyzed; correlations of >0.3 were deemed acceptable for anchor‐based analyses.ResultOur results focus on 49‐ and 73‐week time points based on strength of anchor‐measure correlation and group sample size (Table 1). At 49 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 1.54 (ADL anchor) and 1.08 (memory anchor), mild participants had changes of 2.22 (ADL) and 1.80 (memory), and the combined early AD population had changes of 1.97 (ADL) and 1.51 (memory). At 73 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 2.09 (ADL) and 1.52 (memory), mild participants had changes of 2.25 (ADL) and 2.32 (memory), and the combined early AD population had changes of 2.18 (ADL) and 2.01 (memory).ConclusionAlthough thresholds for meaningful change may differ across disease stages, AD is a continuum and the transition between prodromal to mild is often indistinct. In early (prodromal‐to‐mild) AD populations assessed over longer clinical trials, it may be appropriate to identify meaningful progression on the CDR‐SB using thresholds of 2–2.5 at the individual level.