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Trial registered on ANZCTR


Registration number
ACTRN12613001313729
Ethics application status
Approved
Date submitted
22/11/2013
Date registered
25/11/2013
Date last updated
6/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The ASPREE NEURO study: Does daily, low dose aspirin in adults aged 70 years and over affect age related changes in brain small blood vessels seen on MRI over time, and do these changes improve prediction of stroke risk or cognitive decline?
Scientific title
The ASPREE NEURO study: Does daily, low dose aspirin in adults aged 70 years and over affect age related changes in brain small blood vessels seen on MRI over time, and do these changes improve prediction of stroke risk or cognitive decline?
Secondary ID [1] 283626 0
Nil
Universal Trial Number (UTN)
U1111-1150-6183
Trial acronym
ASPREE NEURO Sub-study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cerebral Microhaemorrhage (CMH) 290557 0
White matter Hyperintensity 290558 0
Cognitive Decline 290559 0
Stroke 290560 0
Condition category
Condition code
Neurological 290956 290956 0 0
Dementias
Stroke 290957 290957 0 0
Haemorrhagic
Stroke 290960 290960 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a sub-study of the Aspirin in Reducing Events in the Elderly study (ASPREE, ClinicalTrials.gov identifier NCT01038583, website www.aspree.org). ASPREE is a double blinded, randomised controlled trial of low dose aspirin, 100mg oral tablets versus placebo, taken daily for a mean of five years in healthy participants aged 70 and over, followed over a mean of five years for the primary outcomes of dementia-free survival and disability-free survival. It is a primary prevention study.

The ASPREE NEURO substudy will involve a subset of newly enrolling participants in the parent ASPREE study based in Melbourne. At the ASPREE randomisation visit ASPREE participants will be given information on the ASPREE NEURO substudy and will later be screened for any contraindication to MRI.

Participants will undergo a non contrast 3 Tesla brain MRI early after entry into the ASPREE study, and again at year 3. The MRI study will include T1 and T2 weighted images, diffusion weighted imaging and SWI.

Participants will now also be invited to undergo an additional non contrast 3 Tesla Brain MRI, utilising the same MRI protocol, 1 year after their baseline image.
Intervention code [1] 288320 0
Prevention
Comparator / control treatment
The constituents of the placebo tablets are: calcium hydrogen phosphate dehydrate, cellulose (microcrystalline), citric acid anhydrous, lactose monohydrate, magnesium stearate, maize starch and silica (colloidal anhydrous).
Control group
Placebo

Outcomes
Primary outcome [1] 290936 0
Number of Cerebral microhaemorrhage on brain MRI
Timepoint [1] 290936 0
Three years
Secondary outcome [1] 305626 0
Haemorrhagic and ischaemic stroke. This is an outcome measured through the parent ASPREE study. The diagnosis of stroke is confirmed by review of medical records and adjudicated by a stroke endpoint adjudication committee.
Timepoint [1] 305626 0
Three years
Secondary outcome [2] 305630 0
Volume of white matter hyperintensity on brain MRI
Timepoint [2] 305630 0
Three years
Secondary outcome [3] 305631 0
Cognitive Function as measured through the parent ASPREE study. This outcome is assessed using the Modified Minimental State Test (3MS), Hopkins Verbal Learning Test (HVLT), Symbol Digit Modalities Test (SDMT), Controlled Oral Word Association Test (COWAT), Stroop and Colour Trails
Timepoint [3] 305631 0
Three years
Secondary outcome [4] 312001 0
Number of cerebral microhaemorrhages on brain MRI
Timepoint [4] 312001 0
1 year

Eligibility
Key inclusion criteria
Enrolling into the ASPREE study in Melbourne
Aged 70 and over
Able and willing to provide informed consent
Minimum age
70 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for ASPREE: History of diagnosed cardiovascular event, including MI and stroke, atrial fibrillation, serious intercurrent illness likely to cause death within 5 years, cognitive impairment or dementia, disability, anaemia, a current or recurrent condition with a high risk of major bleeding, absolute contradindication or allergy to aspirin.

Additional exclusion criteria for this study: Any contraindication to MRI scanning (e.g. implanted pacemaker, presence of metal in eye, claustrophobia, cerebral aneurysm clip).

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Enrollment into the parent study ASPREE is through general practitioner co-investigators. Informed consent for participation in ASPREE is obtained by ASPREE research staff. Enrollment into the ASPREE NEURO study takes place at the second baseline ASPREE visit, after randomisation but prior to initiation of study medication of either aspirin or placebo in ASPREE.

Randomisation takes place through the parent ASPREE study. All staff remain blinded to treatment allocation through the randomisation procedure.

The randomisation list is generated by an independent statistician using the STATA "ralloc" procedure with randomisation stratified for site and age (<80 yrs and >80yrs).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation list is generated by an independent statistician using the STATA "ralloc" procedure with randomsiation stratified for site and age (<80 yrs and >80 yrs).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power calculations for the ASPREE NEURO study have been based on ensuring a sufficient number of subjects to test the primary hypothesis that the number of cerebral microhaemorrhage (CMH) in the aspirin treated group at 3 year follow-up will be greater than the number of CMH in the placebo treated group.

Sample size calculations are based on our pilot study data in which the standard deviation for the number of CMH was found to be approximately 1.5 units. Therefore, 235 subjects per group will enable a 95% power to detect a difference equal to one third of a standard deviation with a two sided p-value of 0.05. While the standard deviation in the number of CMH at 3 years is unknown, it is anticipated to be higher than at 12 months. Based on an estimated standard deviation of 2, a total of 504 subjects (252 per group) will enable an 80% power to detect a difference equal to one quarter of a standard deviation with a two sided p-value of 0.05. In anticipation that the distribution for the number of CMH will not follow a normal distribution, these numbers have been inflated by 15% in accordance with Lehmann and further inflated by 5% to account for dropout, loss to follow-up or cross-over.

With 606 subjects, this study will have >95% power to detect a difference between low dose aspirin and placebo in the average number of CMH at 12 months equal to one half of one unit of CMH, with a two sided p-value of 0.05 and >80% power to detect the same difference after 3 years. A difference of this magnitude is perceived to be of clinical importance.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
26/11/2013
Actual
26/11/2013
Date of last participant enrolment
Anticipated
6/01/2015
Actual
6/01/2015
Date of last data collection
Anticipated
5/01/2018
Actual
22/01/2018
Sample size
Target
600
Accrual to date
Final
559
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 7568 0
3800 - Monash University

Funding & Sponsors
Funding source category [1] 288308 0
University
Name [1] 288308 0
Monash University
Country [1] 288308 0
Australia
Funding source category [2] 290426 0
Government body
Name [2] 290426 0
National Health and Medical Research Council (NHMRC)
Country [2] 290426 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Road,
Clayton,
Victoria, 3800
Country
Australia
Secondary sponsor category [1] 287025 0
None
Name [1] 287025 0
None
Address [1] 287025 0
None
Country [1] 287025 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290201 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 290201 0
Monash University
Level 1, Building 3e, Clayton Campus
Wellington Rd
Clayton VIC 3800
Ethics committee country [1] 290201 0
Australia
Date submitted for ethics approval [1] 290201 0
Approval date [1] 290201 0
06/08/2012
Ethics approval number [1] 290201 0
CF12/2271 – 2012001223

Summary
Brief summary
Changes to the small cerebral blood vessels are commonly obeserved on brain MRIs of the elderly. Two common changes observed are cerebral microhaemorrhages (CMH), which have been reported in 10-60% of healthy elderly subjects, and areas of white matter hyperintensity (WHI). The clinical significance of CMH remains uncertain, though there is a possibility they could predipose to later, clinically overt, haemorrhages.

There have been mixed reports, derived from cross-sectional and longitudinal studies, on whether long-term low-dose aspirin increases the risk of CMH but this has not been evaluated in the context of a clinical trial.

This study will investigate whether daily low dose aspirin increases the number of CMH after one and three years, as measured on brain MRI, as well as determine whether daily low dose aspirin changes the volume of WHI over the same time period, whether the presence of CMH on MRI at baseline is associated with subsequent incidence of ischaemic and haemorrhagic stroke and cognitive decline, and will also correlate imaging biomarkers measured with MRI with cognitive and clinical outcomes over three years.
Trial website
http://www.aspree.org/AUS/aspree-content/aspree-sub-studies/ASPREE-NEURO.aspx
Trial related presentations / publications
Ward SA, Raniga P, Ferris NJ, Woods RL, Storey E, Bailey MJ, Brodtmann A,
Yates PA, Donnan GA, Trevaks RE, Wolfe R, Egan GF, McNeil JJ; (Joint Senior
authorship); on behalf of the ASPREE investigator group.. ASPREE-NEURO study
protocol: A randomized controlled trial to determine the effect of low-dose
aspirin on cerebral microbleeds, white matter hyperintensities, cognition, and
stroke in the healthy elderly. Int J Stroke. 2016 Sep 15. pii: 1747493016669848.
[Epub ahead of print] PubMed PMID: 27634976.
Public notes

Contacts
Principal investigator
Name 44454 0
Prof John McNeil
Address 44454 0
Department of Epidemiology and Preventive Medicine
School of Public Health
Monash University
Level 6, The Alfred Centre
Commercial Road
Melbourne, Victoria, 3000
Country 44454 0
Australia
Phone 44454 0
+61 03 99030565
Fax 44454 0
Email 44454 0
[email protected]
Contact person for public queries
Name 44455 0
Robyn Woods
Address 44455 0
ASPREE National Coordinating Centre
Ground Floor
Burnet Building
89 Commercial Rd
Melbourne, Victoria 3000
Country 44455 0
Australia
Phone 44455 0
+61 03 99030345
Fax 44455 0
Email 44455 0
[email protected]
Contact person for scientific queries
Name 44456 0
Robyn Woods
Address 44456 0
ASPREE National Coordinating Centre
Ground Floor
Burnet Building
89 Commercial Rd
Melbourne, Victoria 3000
Country 44456 0
Australia
Phone 44456 0
+61 03 99030345
Fax 44456 0
Email 44456 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseASPREE-NEURO study protocol: A randomized controlled trial to determine the effect of low-dose aspirin on cerebral microbleeds, white matter hyperintensities, cognition, and stroke in the healthy elderly.2017https://dx.doi.org/10.1177/1747493016669848
EmbaseIndividual differences in haemoglobin concentration influence bold fMRI functional connectivity and its correlation with cognition.2020https://dx.doi.org/10.1016/j.neuroimage.2020.117196
EmbaseIntracerebral haemorrhage, microbleeds and antithrombotic drugs.2021https://dx.doi.org/10.1016/j.neurol.2020.05.008
EmbaseBrain-predicted age difference is associated with cognitive processing in later-life.2022https://dx.doi.org/10.1016/j.neurobiolaging.2021.10.007
EmbaseThe association between sex hormones and the change in brain-predicted age difference in older women.2023https://dx.doi.org/10.1111/cen.14898
N.B. These documents automatically identified may not have been verified by the study sponsor.