Jasmin A. Duehring, Diane M. Jacobs, Michael L. Thomas, Hiroko H. Dodge, Howard H. Feldman, Steven D. Edland
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We have also described how the performance of composite outcome measures depends on parameters that may be influenced by PEs.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>To investigate this, we used the cognitive battery within the National Alzheimer's Coordinating Center (NACC) Uniform Data Set to characterize the potential impact of PEs on clinical trial design and outcome measures. The analysis restricted to <i>N</i> = 1094 amnestic mild cognitively impaired participants with 3 years of follow-up data. Linear mixed effects models estimate the magnitude of PEs observed in aMCI participants. Power calculations informed by the pattern of progression in the NACC sample were used to describe the net impact of PEs on trials with and without a run-in phase. Weighting parameters of optimal composite measures constructed from the NACC battery were also compared.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>PEs were large, often exceeding the magnitude of annual rate of change observed in later assessments. Annualized rate of change, and therefore target treatment effect sufficient to achieve a specified percentage reduction in rate of decline, was larger after run-in. Sample size projections for the run-in design were a fraction of those required for trials without run-in. Weighting parameters that optimize composite outcome performance were also different for the two designs, underscoring the importance of considering design in the construction of composite outcomes.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Clinical trials randomizing after a run-in period measure treatment efficacy relative to decline unbiased by PEs, and require smaller sample size.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>In the National Alzheimer's Coordinating Center (NACC), amnestic mild cognitive impairment (aMCI) cohort practice effects often exceed annualized rate of change.</li>\n \n <li>Run-in clinical trial designs can be used to extinguish practice effects.</li>\n \n <li>Rate of decline after run-in is faster and unbiased by practice effects.</li>\n \n <li>Run-in designs correctly target the most clinically relevant outcome signal.</li>\n \n <li>Practice effects also impact weighting of optimal composite measures.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70154","citationCount":"0","resultStr":"{\"title\":\"Implications of practice effects for the design of Alzheimer clinical trials\",\"authors\":\"Jasmin A. 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Implications of practice effects for the design of Alzheimer clinical trials
INTRODUCTION
Practice effects (PEs) are a well-known potential confound in natural history studies of longitudinal cognitive decline in aging and early-stage Alzheimer's disease. The implication of PEs on Alzheimer's disease clinical trials is less well understood, although we have previously speculated that a “run-in” period of repeated cognitive assessments prior to randomization may improve the efficiency of clinical trials [Jacobs et al. Alzheimer's & Dementia 2017;3(4):531-535]. We have also described how the performance of composite outcome measures depends on parameters that may be influenced by PEs.
METHODS
To investigate this, we used the cognitive battery within the National Alzheimer's Coordinating Center (NACC) Uniform Data Set to characterize the potential impact of PEs on clinical trial design and outcome measures. The analysis restricted to N = 1094 amnestic mild cognitively impaired participants with 3 years of follow-up data. Linear mixed effects models estimate the magnitude of PEs observed in aMCI participants. Power calculations informed by the pattern of progression in the NACC sample were used to describe the net impact of PEs on trials with and without a run-in phase. Weighting parameters of optimal composite measures constructed from the NACC battery were also compared.
RESULTS
PEs were large, often exceeding the magnitude of annual rate of change observed in later assessments. Annualized rate of change, and therefore target treatment effect sufficient to achieve a specified percentage reduction in rate of decline, was larger after run-in. Sample size projections for the run-in design were a fraction of those required for trials without run-in. Weighting parameters that optimize composite outcome performance were also different for the two designs, underscoring the importance of considering design in the construction of composite outcomes.
DISCUSSION
Clinical trials randomizing after a run-in period measure treatment efficacy relative to decline unbiased by PEs, and require smaller sample size.
Highlights
In the National Alzheimer's Coordinating Center (NACC), amnestic mild cognitive impairment (aMCI) cohort practice effects often exceed annualized rate of change.
Run-in clinical trial designs can be used to extinguish practice effects.
Rate of decline after run-in is faster and unbiased by practice effects.
Run-in designs correctly target the most clinically relevant outcome signal.
Practice effects also impact weighting of optimal composite measures.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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