Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment

被引:40
作者
Lorenzi, M. [1 ]
Donohue, M. [2 ]
Paternico, D. [1 ]
Scarpazza, C. [1 ]
Ostrowitzki, S. [3 ]
Blin, O. [4 ,5 ]
Irving, E. [6 ]
Frisoni, G. B. [1 ,7 ]
机构
[1] IRCCS San Giovanni Dio FBF, LENITEM Lab Epidemiol Neuroimaging & Telemed, Brescia, Italy
[2] Univ Calif San Diego, Div Biostat & Bioinformat, San Diego, CA 92103 USA
[3] F Hoffmann La Roche Ltd, Neurosci, Translat Med, Basel, Switzerland
[4] CHU Timone, CNRS, UMR 6193, Inst Cognit Neurosci,Clin Invest Ctr CIC UPCET, Marseille, France
[5] CHU Timone, CNRS, UMR 6193, Inst Cognit Neurosci,Dept Clin Pharmacol, Marseille, France
[6] GlawSmithKline, Neurosci CEDD, Harlow, Essex, England
[7] AFaR Assoc Fatebenefratelli Ric, Rome, Italy
关键词
Mild cognitive impairment; Conversion; Marker disease; Clinical trials; Enrichment; DISEASE; DIAGNOSIS; DEMENTIA; PROGRESSION; DONEPEZIL; CRITERIA; MCI;
D O I
10.1016/j.neurobiolaging.2010.04.036
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C-FIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:1443 / 1451
页数:9
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