Trial registered on ANZCTR


Trial ID
ACTRN12615000347561
Ethics application status
Approved
Date submitted
31/03/2015
Date registered
16/04/2015
Date last updated
16/04/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A randomised controlled trial of low-dose aspirin for the prevention of fractures in healthy older people: the ASPREE-Fracture sub-study
Scientific title
A double-blind, randomised, placebo-controlled trial to determine the effects of daily low-dose aspirin (100mg) versus placebo on the risk of fractures and fall-related hospital presentations in healthy older adults aged 70 years and over
Secondary ID [1] 286458 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fractures 294641 0
Fall-related hospital presentations 294642 0
Condition category
Condition code
Injuries and Accidents 294940 294940 0 0
Fractures
Injuries and Accidents 294941 294941 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a double-blind, randomised placebo-controlled trial and a sub-study of the ASPirin in Reducing Events in the Elderly trial (ASPREE, ClinicalTrials.gov identifier NCT01038583, website www.aspree.org).
ASPREE is a double-blind, randomised, placebo-controlled primary prevention trial that is examining the benefits and risks of low-dose aspirin in 19,000 healthy people (16,500 aged 70 years and over from Australia and 2,500 people aged 65 years and over from the US) without overt cardiovascular disease or dementia. The primary aim of ASPREE is to determine whether low-dose aspirin (100mg enteric coated, daily) will prolong disability and dementia free survival; and provides a net benefit for older people in a primary prevention setting.
The ASPREE-Fracture sub-study will mirror the design of the ASPREE principal trial and extends current ASPREE data collection to include fracture events and fall-related hospital presentation events from all participants from the beginning of the study. The ASPREE-Fracture sub-study aims to determine the effect of daily low-dose aspirin on fracture risk (primary outcome) and falls resulting in a hospital presentation (secondary outcome) in the 16,500 ASPREE participants recruited in Australia.
Participants in the ASPREE principal trial are allocated to one of two treatments (intervention and placebo). The intervention group participants will receive a once daily dose of 100mg enteric-coated aspirin for an average of 5 years post randomisation (range 3-7 years). Compliance and retention of the intervention is maintained through research staff direct phone contact every 3 months, interspersed with annual face-to-face visits.
Intervention code [1] 291541 0
Prevention
Intervention code [2] 291542 0
Treatment: Drugs
Comparator / control treatment
The control group will receive a once daily dose of a placebo enteric-coated un-scored white tablet with identical appearance to aspirin. The enteric coating will
ensure that both active and placebo medication have an identical taste.
Control group
Placebo

Outcomes
Primary outcome [1] 294696 0
Occurrence of any fracture in the average of 5 years post randomisation (range 3-7 years).

A fracture event will be defined as any type of vertebral, hip and non-vert-non-hip fracture (including traumatic and pathological) confirmed by medical imaging (e.g. x-ray). Data on fracture events will be collected via annual face-to-face visits with study participants; 6-monthly interviewer administered questionnaires (designed specifically for this study) through telephone contact; and audit of hospital, general practice and specialist medical records—including hospital admission notes, hospital discharge summaries, medical imaging reports (x-rays, MRI, CT and bone scan reports), ED progress notes and death certificates.
Timepoint [1] 294696 0
5 years post randomisation
Secondary outcome [1] 313884 0
Fall-related hospital presentations in the average of 5 years post randomisation (range 3-7 years).

A fall-related hospital presentation event will be defined as ‘any event which results in a person coming to rest inadvertently on the ground or floor or lower level’ that results in a hospital presentation (including emergency department presentations and hospital admissions). Data on fall-related hospital presentation events will be collected via annual face-to-face visits with study participants; 6-monthly interviewer administered questionnaires (designed specifically for this study) through telephone contact; and audit of hospital, general practice and specialist medical records—including hospital admission notes, hospital discharge summaries, ED progress notes and death certificates.
Timepoint [1] 313884 0
5 years post randomisation

Eligibility
Key inclusion criteria
Participants will be included in the ASPREE-Fracture sub-study if they are enrolled in the Australian arm of the ASPREE principal trial. The inclusion criteria for the ASPREE principal trial are: (1) aged 70 years and over; and (2) able and willing to provide informed consent.
Minimum age
70 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants will be excluded from the ASPREE trial, and therefore this sub-study, if they have: (1) a history of a diagnosed cardiovascular disease event or stroke; (2) a clinical diagnosis of arterial fibrillation; (3) a serious inter-current illness likely to cause death within the next 5 years; (4) a current or recurrent condition with a high risk of major bleeding; (5) anaemia; (6) current continuous use of aspirin or other anti-platelet drug or anticoagulant; (7) an absolute contraindication to or allergy to aspirin; (8) a systolic blood pressure greater than or equal to 180 mmHg or diastolic blood pressure greater than or equal to 105 mmHg; (9) a history of dementia or a Modified Mini-Mental State Examination score less than or equal to 77; (10) an inability to perform any one of the six Katz ADL’s [26]; (11) a pill-taking compliance outside the range of 80- 100% during placebo run-in phase; or (12) are currently participating in another clinical trial.

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)
Enrolment
The majority of participants are recruited through general medical practices (approximately 2,000) and a small number through community advertising. At the general practice, limited key terms are used to derive a list of potentially eligible patients on the basis of age, pre-existing cardiovascular disease or anti-platelet therapy, although not all criteria are available from each clinic database. Each potentially eligible patient is sent a letter from their usual GP inviting them to consider participation in the trial. The letter advises those who are interested to call a toll-free ASPREE number to discuss their participation in the study. On calling the number, interested participants are checked for self-reported eligibility, and suitable persons are invited to attend a screening visit (week 0) where baseline examination and testing is organized and run-in medication (placebo) is provided for four weeks. If entry testing and compliance with run-in medication is deemed satisfactory at a second visit (week 4) and the GP has authorized participation, each participant who meets the inclusion criteria is randomized and enters the study. Participants enrolled into the ASPREE principal trial in Australia will automatically be included in the ASPREE-Fracture sub-study.
Treatment allocation
Enrolled participants will be randomly assigned into one of the two groups: intervention (daily dose of 100 mg enteric-coated aspirin) or control (daily dose of a placebo enteric-coated un-scored white tablet with identical appearance to aspirin), using a computer-generated randomisation schedule via the ASPREE web portal.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomisation schedule via the ASPREE web portal will be generated by an independent statistician, in a ratio of 1:1 to active or placebo therapy. Permuted block randomization stratified by recruitment site and age (less than 80 years or greater than or equal to 80 years) to ensure equal number across groups.
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)
Safety/efficacy
Statistical methods / analysis
Outcome analyses will be undertaken on an intention to treat basis by a statistician blinded to group allocation.

Fracture end-points will be analysed without Bonferroni correction using a survival time method and the proportional hazards assumption (which will be tested). This analysis will compare time to first fracture between aspirin and placebo groups. Primary analysis will be unadjusted. Secondary analysis will adjust for a number of covariates including: osteoarthritis, rheumatoid arthritis, use of medications that affect BMD, cognitive impairment, age, malignancy, alcohol intake and smoking. This will increase the efficiency of the analysis and allow for any imbalance between groups in these baseline variables. We will also perform an unadjusted log-rank test on final results. Secondary analysis, using recurrent events survival models will also be conducted including all fracture events (not just the first fracture) to compare the overall fracture risk between aspirin and placebo groups over the 5 year follow-up.

Fall events will be analysed using negative binomial regression models, where the dependent variable will be the total number of fall-related hospital presentations for each participant during the trial, and group allocation will be the independent variable. The rate of fall-related hospital presentations in the aspirin compared with those in the placebo group and will be expressed as an incidence rate ratio (IRR). Using a negative binomial regression model will allow for the fact that fall-related hospitalisations can be recurrent events with a non-normal distribution; individual participants may have different follow-up times; and allow the investigation of the treatment effect adjusted for known confounding variables. Secondary analysis that adjusts for covariates (cognitive impairment and age) will be undertaken if found to be significant when added to the model. This will increase the efficiency of the analysis.

Data from the Geelong Osteoporosis Study and a national report on fall-related hospital presentations were applied to the expected age distribution of Australian participants on recruitment to the ASPREE principal trial of 50%, 30%, 15%, 5% in the age groups 70-74 years, 75-79 years, 80-84 years, 85 years and over, respectively to estimate outcome event rates in the placebo group. Based on the an average follow-up of 4.25 years per participant, and that 14% of participants in the placebo group will sustain a fracture in the follow-up period, a sample size of 16,500 provides 80% power to detect a Hazard Ratio (HR) of 0.88 comparing the intervention group to placebo in an intention to treat analysis (P=0.05; two tailed). The underlying true effect for all fractures is assumed to be a HR of 0.85 on the basis that we expect 5% per annum of placebo-group participants to initiate aspirin use or vice versa.
Based on the an average follow-up of 4.25 years per participant and an expected event rate of 53 fall-related hospital presentations per 1,000 person-years in the placebo group, a sample size of 16,500 provides 80% power to detect an IRR of 0.88 comparing the intervention group to placebo in an intention to treat analysis (over-dispersion parameter=1.3; P=0.05; two tailed). The underlying true effect for fall-related hospital presentations is assumed to be an IRR of 0.85 on the basis that we expect 5% per annum of placebo-group participants to initiate aspirin use or vice versa.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Actual
Recruitment in Australia
Recruitment state(s)
ACT,NSW,SA,TAS,VIC

Funding & Sponsors
Funding source category [1] 291026 0
Government body
Name [1] 291026 0
National Health and Medical Research Council (NHMRC)
Address [1] 291026 0
16 Marcus Clarke Street, Canberra, ACT 2601
Country [1] 291026 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Department of Epidemiology and Preventive Medicine, The Alfred Centre, Level 6, 99 Commercial Rd, Melbourne, VIC 3004
Country
Australia
Secondary sponsor category [1] 289707 0
None
Name [1] 289707 0
Address [1] 289707 0
Country [1] 289707 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292609 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 292609 0
Monash Research Office Building 3d, Monash University, VIC 3800
Ethics committee country [1] 292609 0
Australia
Date submitted for ethics approval [1] 292609 0
Approval date [1] 292609 0
23/06/2014
Ethics approval number [1] 292609 0
CF14/1740 - 2014000872

Summary
Brief summary
Disability, mortality and healthcare burden from fractures in older people is a growing problem worldwide. During 2007, there were an average 262 fracture-related hospitalisations per day in Australia with the financial burden associated with direct treatment cost for fractures in Australia estimated at $1.9billion per year. A small number of low-quality observational studies examining the effect of aspirin on fracture risk in older people have demonstrated conflicting results. A large-scale controlled trial is required to provide more accurate information on this effect.
The ASPREE-Fracture sub-study aims to investigate whether daily low-dose aspirin (100mg) is associated with decreased incidence of vertebral, hip and non-vert-non-hip fractures in healthy men and women aged 70 years and over; and whether the reduced fracture risk is explained, in part, by reducing risk of fall-related hospital presentations.
The ASPREE-Fracture sub-study has the potential to change current fracture prevention practice and policies for older people by offering a population intervention. Even if small impacts are observed on fracture incidence, the net benefits of aspirin in terms of reduced fracture risk at a population level may be substantial.
Trial website
Trial related presentations / publications
Barker AL, McNeil JJ, Ward SA, Sanders KM, Kholsa S, Cumming RG, Seeman E, Pasco JA, Bohensky MA, Ebeling PR, Woods RL, Lockery J, Wolfe R, Talevski J and the ASPREE Investigator Group. A randomised controlled trial of low-dose aspirin for the prevention of fractures in healthy older people: protocol for the ASPREE-Fracture sub-study. Injury Prevention (under review).
Public notes

Contacts
Principal investigator
Name 56218 0
A/Prof Anna Barker
Address 56218 0
Monash University, DEPM,
The Alfred Centre, Level 6,
99 Commercial Road,
Melbourne, VIC Australia 3004
Country 56218 0
Australia
Phone 56218 0
+61 3 9903 0556
Fax 56218 0
+61 3 9903 0556
Email 56218 0
anna.barker@monash.edu
Contact person for public queries
Name 56219 0
Mr Jason Talevski
Address 56219 0
Monash University, DEPM,
The Alfred Centre, Level 6,
99 Commercial Road,
Melbourne, VIC Australia 3004
Country 56219 0
Australia
Phone 56219 0
+61 3 9903 0377
Fax 56219 0
+61 3 9903 0556
Email 56219 0
jason.talevski@monash.edu
Contact person for scientific queries
Name 56220 0
A/Prof Anna Barker
Address 56220 0
Monash University, DEPM,
The Alfred Centre, Level 6,
99 Commercial Road,
Melbourne, VIC Australia 3004
Country 56220 0
Australia
Phone 56220 0
+61 3 9903 0556
Fax 56220 0
+61 3 9903 0556
Email 56220 0
anna.barker@monash.edu