Appropriate use of meaningful within‐patient change (MWPC) thresholds in Alzheimer's disease
Year: 2024
Type: article
Abstract: Appropriate use of meaningful within-patient change (MWPC) thresholds in Alzheimer's diseaseDetermining whether disease-modifying treatments (DMTs) in early Alzheimer's disease (AD) provide clinically meaningful benefits to people living with AD is critical and has triggered much debate in the field.[1][2][3][4] AD is a slowly progressive, ultimately fatal, neurodegenerative disease, characterized by progressive loss in cognitive ability and daily function.5 Current DMTs aim to slow disease progression, an important treatment-related outcome for people with, or at risk for, AD and their care partners.6 A widely adopted approach to evaluate the clinical relevance of a treatment benefit is to compare the proportion of patients who experience a meaningful improvement or deterioration in their symptoms and/or overall condition over the course of a clinical trial.In progressive diseases where emerging DMTs aim to slow the rate of progression in symptoms and underlying disease (as opposed to the temporary improvements provided by symptomatic therapies), evaluating meaningful deterioration is arguably more appropriate.To conduct such analyses in AD, estimates of meaningful score change on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed to reflect clinically relevant deterioration in an individual patient's cognition and daily function.Lansdall et al. 7 used established methods to generate meaningful within-patient change (MWPC) thresholds to define meaningful deterioration on the CDR-SB, building on existing estimates.8,9 This letter aims to provide clarification on the appropriate application of MWPC thresholds to evaluate clinical trial data.Thresholds to define meaningful individual-level change on a scale are commonly used in neurology trials, both to identify responders and progressors.Examples include confirmed disability progression on the clinician-administered Expanded Disability Status Scale in multiple sclerosis or meaningful reduction of neuropathic pain on a pain intensity numeric rating scale.10,11 Figure 5 of the FDA Aricept (donepezil) label, a symptomatic treatment for AD, also includes an example of how to apply MWPC thresholds to clinical trial data, using 4 and 7 points improvement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) to report the proportion of responders across treatment and placebo arms.Although the intended use of these thresholds is to define and assess MWPC, recent publications in AD have instead applied MWPC thresholds to evaluate whether the magnitude of observed between-group differences in mean changefrom-baseline (commonly the primary endpoint in AD trials) is clinically
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.14436
Institutions: Roche (Switzerland), University of Nevada, Las Vegas
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
OpenAlex ID: W4405512234