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- W2897721799 abstract "Hippocampal atrophy is associated with progression in Alzheimer disease (AD). The Critical Path for Alzheimer's Disease (CPAD) consortium is pursuing FDA qualification of baseline intracranial volume-adjusted hippocampal volume (ICV-HV) as an enrichment biomarker in clinical trials targeting mild cognitive impairment (MCI). Hence, the association between ICV-HV and disease progression was assessed using the Clinical Dementia Rating Scale Sum-of-Boxes (CDR-SB). Data: Subject-level data from three sources – the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2 observational studies, and the Investigation Into Delay to Diagnosis of Alzheimer's Disease With Exelon (InDDEx) trial placebo arm – yielded a total of 1,051 aMCI subjects with 7,860 CDR-SB time points in the screening-to-48 months interval. The statistical model used ADNI-1/-2 (N=702), and InDDEx was reserved for external validation. Statistical Modeling: The time course of CDR-SB was described by a non-linear mixed-effects repeated measures model. Covariates were: baseline ICV-HV, sex, baseline mini-mental-state-examination (MMSE), baseline age, and apolipoprotein-E-encoding gene (APOE4) genotype. ICV-HV enrichment was compared between two image analysis algorithms (LEAP™ and FreeSurfer™). Monte Carlo clinical trial simulations were performed to compare the statistical power by sample size in trials with(out) ICV-HV enrichment. Non-enriched trials included subjects sampled from the whole distribution of ICV-HV in the analysis dataset. Enriched trials sampled subjects from truncated ICV-HV distributions based on different cut-off values. A hypothetical drug effect of 50% reduction in progression rate was assumed. In a generalized logistic model, accounting for all covariate effects, a 1 cm3 decrease in baseline ICV-HV was associated with a more than 50% increase in CDR-SB progression rate. In a simulated 24-month placebo-controlled parallel group clinical trial, ICV-HV enrichment yielded meaningful reduction in trial size, ∼63%, ∼35%, and ∼25%, respectively, when including only subjects with baseline ICV-HV lower than the 50th (median), 84.1th (+1 standard deviation, SD), and 97.7th (+2 SD) percentile of the ICV-HV distribution. The sample size savings between LEAP™ and FreeSurfer™ were similar (within 6-to-8% of each other). External validation with InDDEx is ongoing. ICV-HV serves as a prognostic indicator of MCI clinical progression, with utility to optimize the sample size to demonstrate the drug effects in clinical trials." @default.
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- W2897721799 date "2018-07-01" @default.
- W2897721799 modified "2023-10-16" @default.
- W2897721799 title "P3‐031: THE CRITICAL PATH FOR ALZHEIMER'S DISEASE: HIPPOCAMPAL VOLUME AS AN ENRICHMENT BIOMARKER IN TRIALS OF PATIENTS WITH MILD COGNITIVE IMPAIRMENT" @default.
- W2897721799 doi "https://doi.org/10.1016/j.jalz.2018.06.1386" @default.
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