Clinical Trial Endpoints and Their Clinical Meaningfulness in Early Stages of Alzheimer's Disease

Abstract

As the focus of Alzheimer's disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.

Keywords: Early Alzheimer’s disease; assessment tools; clinical meaningfulness; clinical trials; endpoints.

Figure 1.

Cognitive, functional, and behavioral impairment across the AD continuum A. There is progressive cognitive and functional decline, initially observed in Stages 2 and 3 of AD, as classified by the FDA in 2018 (U.S. Food and Drug Administration 2018). Behavioral impairment differs across the continuum, with variable appearance and resolution of behavioral symptoms. B. Different ADL are impaired differentially across the AD continuum, with each ADL being initially affected during different stages of AD. Adapted from Galasko 1998 with permission (Galasko 1998). Abbreviations: AD = Alzheimer’s disease; ADL = activities of daily living; FDA = Food and Drug Administration; MCI = mild cognitive impairment; MMSE, Mini-Mental State Examination; NIA-AA= National Institute of Aging–Alzheimer’s Association

Figure 2.

Selection of clinical endpoints depends on the stage of Alzheimer’s disease Clinical trials for AD vary in length based on the population of patients they involve, as classified here by the FDA staging (U.S. Food and Drug Administration 2018). Selection of clinical endpoints for clinical trials differs dependent upon the clinical stage of AD, with measurement of clinically meaningful changes also having varying challenges across the AD continuum. Abbreviations: AD = Alzheimer’s disease; FDA = Food and Drug Administration; MCI = mild cognitive impairment; NIA-AA = National Institute of Aging–Alzheimer’s Association