Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease
Open accessAbstract
BACKGROUND: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer's disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit. OBJECTIVES: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI). DESIGN: Retrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures. SETTING: Analyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer's Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada. PARTICIPANTS: Analyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada. MEASUREMENTS: The target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI-Clinical Global Impression of Change. RESULTS: Focusing on the 12-month time point, within-patient increases of 1-2.5 points in the CDR-SB and increases of 2-5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively. CONCLUSIONS: These thresholds may be useful to aid the interpretation of Alzheimer's disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.
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Only 8% (19/237) of a community-based Mayo Clinic Study of Aging who had a positive amyloid-PET scan and met criteria for MCI or mild dementia would have met the lecanemab trial eligibility criteria.
“Only 8% (19/237) of a community-based Mayo Clinic Study of Aging who had a positive amyloid-PET scan and met criteria for MCI or mild dementia, would have met the lecanemab trial eligibility criteria. (512)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [512]
The Data source section describes an analysis of the ADC-008 trial, and Participant characteristics reports 769 participants; neither addresses eligibility for the lecanemab trial. Searches for the Mayo Clinic Study of Aging, amyloid-PET, lecanemab, and 19/237 found no passage supporting the claimed 8%. No page numbers were available in our copy. (LLM, conf=0.76)
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Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission
Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., Ames, D., Banerjee, S., Burns, A., Brayne, C., et al. (2024) · The Lancet · doi:10.1016/s0140-6736(24)01296-0 · Cited by 3,860 · see citing works
Expectations and clinical meaningfulness of randomized controlled trials
Petersen, R. C., Aisen, P. S., Andrews, J. S., Atri, A., Matthews, B. R., Rentz, D. M., Siemers, E. R., Weber, C. J., & Carrillo, M. C. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12959 · Cited by 95 · see citing works
Evaluation of clinical benefits of treatments for Alzheimer's disease
Liu, K. Y., Walsh, S., Brayne, C., Merrick, R., Richard, E., & Howard, R. (2023) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(23)00193-9 · Cited by 31 · see citing works
- Authors
- Lansdall, C. J., McDougall, F., Butler, L. M., Delmar, P., Pross, N., Qin, S., McLeod, L., Zhou, X., Kerchner, G. A., & Doody, R. S.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- RTI Health Solutions (US)
- Corresponding author
- Lansdall, Claire J.
- Venue
- The Journal of Prevention of Alzheimer's Disease
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 10
- Issue
- 1
- Pages
- 9-18
- ISSN
- 2274-5807 (ISSN-L)
- OpenAlex
- W4312703859
- Cited by
- 99
- References
- 1
- Citations by year
- 2026: 26 · 2025: 24 · 2024: 29 · 2023: 17 · 2022: 3
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Journal of Prevention of Alzheimer s Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- F. Hoffmann-La Roche
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Health Systems, Economic Evaluations, Quality of Life
- Keywords
- meaningful change thresholds, mild cognitive impairment, Alzheimer's disease, Mini-Mental State Examination, amnestic MCI, anchor-based thresholds, cognitive decline, clinical outcome assessment
- MeSH terms
- Mental Status and Dementia Tests, Alzheimer Disease, Humans, Retrospective Studies, Outcome Assessment, Health Care, Cognitive Dysfunction
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