Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease

Abstract

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi‐step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much‐needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. Highlights We discuss lessons learned on capturing cognitive changes in predementia stages of AD. We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials. We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials.

Technical Review of Clinical Outcomes Assessments Across the Continuum of Alzheimer's Disease

“…Establishing with patient and care partner input the content validity of concepts being measured in AD trials is a foundational step in understanding how to achieve clinically meaningful advances in treatment [ 31 ]. Our findings complement other efforts to improve COA assessment in AD, including a recently developed framework for outcome assessment in early AD trials [ 3 ].…”

“…In conducting this study, we concur with Jutten et al that “A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer’s disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages” [ 3 ]. Our research is a step in meeting this challenge.…”

Meta-Analysis of Animal Fluency Performance in Amnestic Mild Cognitive Impairment and Cognitively Unimpaired Older Adults

“…Given that there can be significant heterogeneity in the patterns of cognitive decline, 41 Balthazar et al 17 13.9 −0.15 Clark DG et al 18 14.4 −0.90 Clark LJ et al 19 15.4 −0.21 Cooper et al 20 15.0 −0.76 Economu et al 21 12.7 −0.87 Edmonds et al 22 17.5 −0.17 Hall et al 23 16.3 −0.45 Johns et al 24 13.3 −1.17 Kramer et al 4 15.6 −0.62 Kwon et al 25 8.8 −1.65 McDonnell et al 23 15.8 −0.57 McLaughlin et al 27 17.7 −0.12 Mirandez et al 28 12.5 −0.91 Murphy et al 29 15.0 −0.76 Ramanan et al 30 11.6 −1.57 Rinehardt et al 31 14.8 −0.81 Tessaro et al 32 9.3 −1.50 Vaughan et al 33 15.6 NA Wakefield et al 34 13 the inclusion of sensitive nonmemory tests is important, and others have suggested that fluency tests may be helpful in this regard. 42 However, cognitive trajectories in clinical trials are often different from that seen in observational studies, where the effect sizes in rates of cognitive decline between placebo and treatment groups tend to be small and hard to detect. 42 It is important to note that treatment effects for AD prevention trials must be detected within the spectrum of clinically normal cognitive functioning among their participants, which underscores the need to accurately assess significant subclinical cognitive changes.…”

“…The findings of this study and a previous meta-analysis 13 suggest that there are notable changes in nonmemory domains that may be useful in detecting clinically meaningful cognitive changes in individuals with preclinical AD who are at risk for progressing to aMCI. Given that there can be significant heterogeneity in the patterns of cognitive decline, 41 the inclusion of sensitive nonmemory tests is important, and others have suggested that fluency tests may be helpful in this regard 42 . However, cognitive trajectories in clinical trials are often different from that seen in observational studies, where the effect sizes in rates of cognitive decline between placebo and treatment groups tend to be small and hard to detect 42 .…”

Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer’s disease

“…Novel primary endpoints designed to detect early and subtle changes in cognition thus constitute a critical need for any clinical trial targeting the preclinical phase of the disease. (5) Supporting the design of such endpoints, Anderson et al (2017) suggested that clinical trial simulations could be a powerful way to provide insight into the likelihood of a trial succeeding (6, 7)…”