Robin Wolz1, Adam J Schwarz2, Katherine R Gray2, Peng Yu2, Derek L G Hill2. 1. From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis. rwolz@ixico.com. 2. From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
Abstract
OBJECTIVE: To investigate the effect of enriching mild cognitive impairment (MCI) clinical trials using combined markers of amyloid pathology and neurodegeneration. METHODS: We evaluate an implementation of the recent National Institute for Aging-Alzheimer's Association (NIA-AA) diagnostic criteria for MCI due to Alzheimer disease (AD) as inclusion criteria in clinical trials and assess the effect of enrichment with amyloid (A+), neurodegeneration (N+), and their combination (A+N+) on the rate of clinical progression, required sample sizes, and estimates of trial time and cost. RESULTS: Enrichment based on an individual marker (A+ or N+) substantially improves all assessed trial characteristics. Combined enrichment (A+N+) further improves these results with a reduction in required sample sizes by 45% to 60%, depending on the endpoint. CONCLUSIONS: Operationalizing the NIA-AA diagnostic criteria for clinical trial screening has the potential to substantially improve the statistical power of trials in MCI due to AD by identifying a more rapidly progressing patient population.
OBJECTIVE: To investigate the effect of enriching mild cognitive impairment (MCI) clinical trials using combined markers of amyloid pathology and neurodegeneration. METHODS: We evaluate an implementation of the recent National Institute for Aging-Alzheimer's Association (NIA-AA) diagnostic criteria for MCI due to Alzheimer disease (AD) as inclusion criteria in clinical trials and assess the effect of enrichment with amyloid (A+), neurodegeneration (N+), and their combination (A+N+) on the rate of clinical progression, required sample sizes, and estimates of trial time and cost. RESULTS: Enrichment based on an individual marker (A+ or N+) substantially improves all assessed trial characteristics. Combined enrichment (A+N+) further improves these results with a reduction in required sample sizes by 45% to 60%, depending on the endpoint. CONCLUSIONS: Operationalizing the NIA-AA diagnostic criteria for clinical trial screening has the potential to substantially improve the statistical power of trials in MCI due to AD by identifying a more rapidly progressing patient population.
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