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Open Access Study protocol

Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial

Sally-Ann Cooper1*, Muriel Caslake2, Jonathan Evans1, Angela Hassiotis3, Andrew Jahoda1, Alex McConnachie4, Jill Morrison5, Howard Ring6, John Starr7, Ciara Stiles1 and Frank Sullivan8

Author Affiliations

1 Institute of Health and Wellbeing, University of Glasgow, Mental Health and Wellbeing Unit, Gartnavel Royal Hospital, Administrative Building, 1055, Great Western Road, Glasgow G12 0XH, UK

2 Institute of Cardiovascular and Medical Sciences, University of Glasgow, McGregor Building, 2nd floor, Western Infirmary, Glasgow G11 6NT, UK

3 University College London, Bloomsbury Campus, Charles Bell House, 67-73 Riding House Street, London W1W 7EY, UK

4 Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building, Glasgow G12 8QQ, UK

5 Institute of Health and Wellbeing, University of Glasgow, General Practice and Primary Care, 1 Horselethill Road, Glasgow G12 9LX, UK

6 School of Clinical Medicine, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge CB2 2AH, UK

7 Alzheimer Scotland Dementia Research Centre, 7 George Square, Edinburgh EH8 9JZ, UK

8 Gordon F Cheesbrough Research Chair and Director of UTOPIAN, University of Toronto, North York General Hospital, 4001 Leslie Street, Toronto, ON M2K 1E1, Canada

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Trials 2014, 15:202  doi:10.1186/1745-6215-15-202

Published: 3 June 2014

Abstract

Background

Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial.

Methods/Design

TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions.

Discussion

This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies.

Trial registration

Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011)

Keywords:
Alzheimer disease; Dementia; Down syndrome; Neuropsychology; Primary prevention; Simvastatin; Statin