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Using cognitive decline in novel trial designs for primary prevention and early disease-modifying therapy trials of Alzheimer's disease

Published online by Cambridge University Press:  11 April 2011

David Darby ,
Amy Brodtmann ,
Michael Woodward ,
Marc Budge  and
Paul Maruff
David Darby*
Affiliation:
CogState Ltd, Melbourne, Victoria, Australia Florey Neuroscience Institutes, Parkville, Victoria, Australia Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia Aged and Residential Care Services, Heidelberg Repatriation Hospital, Austin Health, West Heidelberg, Victoria, Australia
Amy Brodtmann
Affiliation:
Florey Neuroscience Institutes, Parkville, Victoria, Australia Eastern Cognitive Disorders Clinic, Boxhill Hospital, Victoria, Australia
Michael Woodward
Affiliation:
Aged and Residential Care Services, Heidelberg Repatriation Hospital, Austin Health, West Heidelberg, Victoria, Australia
Marc Budge
Affiliation:
Department of Geriatric Medicine, Australian National University Medical School, Canberra, ACT, Australia
Paul Maruff
Affiliation:
CogState Ltd, Melbourne, Victoria, Australia Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia
*
Correspondence should be addressed to: David Darby, Chief Medical Officer, CogState Ltd, Level 2, 255 Bourke St, Melbourne VIC 3000, Australia. Phone: +613-9664-1300; Fax: +613-9664-130. Email: [email protected].
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Abstract

Background: Ideally putative disease-modifying therapies for Alzheimer's disease (AD) should be tested in patients who have minimal morbidity. Current barriers to such trials in early disease include the lack of disease-specific early biomarkers, insensitivity of quantitative cognitive outcome measures, and expensive trial designs requiring large sample sizes and long duration. This paper describes principles and progress towards a novel trial design that overcomes these problems, utilizing wide-scale cognitive performance screening to define pre-trial cognitive decline trajectories which can serve as trial outcome measures to assess AD disease-modifying efficacy.

Methods: Theoretical principles important for the detection of intra-individual cognitive decline and a practical example are described.

Results: Serial evaluations of community-based volunteers demonstrate how a screening tool method to detect subtle cognitive decline can predict in vivo amyloid pathology as a trigger for etiological evaluation. Trajectories of decline appear consistent over at least two years, suggesting they could be used as a trial inclusion criterion and ameliorable outcome measure together with other AD biomarkers. Informative trial durations could be 6–12 months, or extend to incorporate staggered random withdrawal or start designs, with as few as 20 individuals per treatment arm.

Conclusions: This trial methodology offers significant advantages over current AD trial designs, including treatment at earlier stages of disease, shorter trial duration, obviation of informed consent difficulties, smaller sample sizes, reduced cost and – given adequate screening programs – sufficient subjects for multiple simultaneous trials. Importantly, it allows the rapid evaluation of putative treatments that may only be efficacious in pre-dementia states.

Keywords

cognitiondementia screeningAlzheimer diseaseclinical trialspre-clinical diagnosis
Type
Review Article
Information
International Psychogeriatrics , Volume 23 , Issue 9 , November 2011 , pp. 1376 - 1385
Copyright
Copyright © International Psychogeriatric Association 2011

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