Journal
ALZHEIMERS & DEMENTIA
Volume 6, Issue 5, Pages 367-377Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2010.07.004
Keywords
Alzheimer disease; Mild cognitive impairment; Biomarkers; Clinical trials; Simulations; Amyloid-beta protein; Alzheimer's disease neuroimaging initiative (ADNI); Alzheimer's disease assessment scale; Clinical dementia rating
Categories
Funding
- Alzheimer's Disease Neuroimaging Initiative (ADNI) [NIH U01 AG024904]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- NIH [P30 AG010129, K01 AG030514]
- The Dana Foundation
- USC Alzheimer's Disease Research Center [NIH P50 AG05142, NIH T32 HL072757]
- Alexion
- Accentia
- Bayer
- Barofold
- Biogen-Idec
- CibaVision
- Enzo
- Eisai
- Genentech
- Millenium
- Novartis
- Consortium of Multiple Sclerosis Centers
- Peptimmune
- Klein-Buendel Incorporated
- Incyte
- Somnus
- Teva
- Visioneering Technologies
- Alzheimer's Association for a registry for dementia and cognitive impairment trials
- Baxter
- Elan Pharmaceuticals
- Johnson Johnson
- Eli Lilly
- Myriad
- Pfizer
- Abbott Laboratories
- AC Immune
- Allergan
- Allon
- Alzheimer Drug Discovery Foundation
- AstraZeneca
- Bristol-Myers Squibb
- Elan
- Exonhit
- Forest
- GlaxoSmithKline
- Ipsen
- Lundbeck
- Medavante
- Medivation
- Merck
- Roche
- Sanofi-Aventis
- Schering-Plough
- Servier
- Toyama
- Transition Therapeutics
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Background: Low cerebrospinal fluid (CSF) amyloid-beta(1-42) concentration and high total-tau/A beta(1-42) ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403-13; Dubois et al, Lancet Neurol 2007;6:734-46). Methods: We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF A beta(1-42) <= 192 mg/mL, (3) and aMCI with total-tau/A beta(1-47) > 0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power. Findings: Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low A beta(1-42) or high tau/A beta(1-42) requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups. Interpretations: Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF A beta(1-41) marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug. (c) 2010 The Alzheimer's Association. All rights reserved.
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