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

Cooper SA, Caslake M, Evans J, Hassiotis A, Jahoda A, McConnachie A, Morrison J, Ring H, Starr J, Stiles C, Sullivan F - Trials (2014)

Bottom Line: 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.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.Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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. Sally-Ann.Cooper@glasgow.ac.uk.

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 40 mg 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).

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Related in: MedlinePlus

Flowchart of the study protocol. AE, Adverse event; APO E, apolipoprotein E; AR, Adverse reaction; CYP3A4, Cytochrome P450 3A4; GG&C, NHS Greater Glasgow & Clyde; OD, Once daily; RCT, Randomized controlled trial; SAR, Serious adverse reaction.
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Figure 1: Flowchart of the study protocol. AE, Adverse event; APO E, apolipoprotein E; AR, Adverse reaction; CYP3A4, Cytochrome P450 3A4; GG&C, NHS Greater Glasgow & Clyde; OD, Once daily; RCT, Randomized controlled trial; SAR, Serious adverse reaction.

Mentions: The study is a double-blind RCT of 12 months of simvastatin 40 mg OD by mouth versus placebo. It includes a nested qualitative study. The flowchart shown in Figure 1 summarizes the study protocol.


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

Cooper SA, Caslake M, Evans J, Hassiotis A, Jahoda A, McConnachie A, Morrison J, Ring H, Starr J, Stiles C, Sullivan F - Trials (2014)

Flowchart of the study protocol. AE, Adverse event; APO E, apolipoprotein E; AR, Adverse reaction; CYP3A4, Cytochrome P450 3A4; GG&C, NHS Greater Glasgow & Clyde; OD, Once daily; RCT, Randomized controlled trial; SAR, Serious adverse reaction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061534&req=5

Figure 1: Flowchart of the study protocol. AE, Adverse event; APO E, apolipoprotein E; AR, Adverse reaction; CYP3A4, Cytochrome P450 3A4; GG&C, NHS Greater Glasgow & Clyde; OD, Once daily; RCT, Randomized controlled trial; SAR, Serious adverse reaction.
Mentions: The study is a double-blind RCT of 12 months of simvastatin 40 mg OD by mouth versus placebo. It includes a nested qualitative study. The flowchart shown in Figure 1 summarizes the study protocol.

Bottom Line: 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.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.Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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. Sally-Ann.Cooper@glasgow.ac.uk.

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 40 mg 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).

Show MeSH
Related in: MedlinePlus