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Trial registered on ANZCTR


Trial ID
ACTRN12613000755730
Ethics application status
Approved
Date submitted
2/07/2013
Date registered
5/07/2013
Date last updated
6/06/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Low dose aspirin and age-related macular degeneration: randomized controlled trial
Scientific title
In people 70 years or older, does low dose of aspirin, compared to placebo, influence the incidence and/or progression of age-related macular degeneration (AMD)?
Secondary ID [1] 282759 0
None
Universal Trial Number (UTN)
Trial acronym
ASPREE-AMD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Age-related macular degeneration 289499 0
Condition category
Condition code
Eye 289825 289825 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Acetylsalicylic acid (ASA) 100 mg once daily: enteric-coated un-scored white oral tablets versus placebo.

Duration of administration: 5 years.

Compliance is monitored annually by pill count.
Inclusion compliance must be more than 80 percent, assessed over a 4 week period of daily pill taking prior to randomisation.
Intervention code [1] 287424 0
Prevention
Intervention code [2] 287466 0
Treatment: Drugs
Comparator / control treatment
Enteric-coated un-scored white oral tablet of identical appearance to the Acetylsalicylic acid (ASA) tablets.
Control group
Placebo

Outcomes
Primary outcome [1] 289891 0
Incidence of AMD,
detected on non-mydriatic 45 degree colour digital retinal images centered on fovea.

The Beckman categories of AMD development will be used:
1. No apparent ageing change: no drusen and no AMD pigmentation abnormalities,
2. Normal ageing changes: only small drusen (<63 microns) and no AMD pigmentation abnormalities,
3. Early AMD: Medium drusen (from 63 to 124 microns) with no AMD pigmentation abnormalities,
4. Intermediate AMD: Medium drusen (from 63 to 124 microns) with AMD pigmentation abnormalities Or Large drusen (equal or greater than 125 microns),
5. Advanced AMD : Neovascular AMD or any geographic atrophy.

Note: Increase of the Beckman AMD Classification Category in at least one eye from Categories 1 or 2 to any higher category (3, 4 or 5) would be considered as AMD incidence.
Timepoint [1] 289891 0
3-year follow up and 5-year follow up
Primary outcome [2] 289940 0
Progression in severity of non advanced AMD,
detected on non-mydriatic 45 degree colour digital retinal images centered on fovea.

Increase of the Beckman AMD Classification Category in at least one eye from Categories 3 or 4 by at least one level would be considered as AMD progression.
Timepoint [2] 289940 0
3-year follow up and 5-year follow up
Primary outcome [3] 289941 0
Progression of advanced AMD:

Development of fresh retinal haemorrhage in eyes with choroidal neovascularisation (CNV) or geographic atrophy (GA), either detected on colour retinal images (confirmed by the participant's ophthalmologist when necessary) or reported by the participant/medical practitioner if the event occured and was detected/treated earlier during the follow up period.
Timepoint [3] 289941 0
3-year follow up and 5-year follow up
Secondary outcome [1] 303620 0
The prevalence and severity of AMD in a large cohort of older Australians.
Timepoint [1] 303620 0
3-year follow up and 5-year follow up

Eligibility
Key inclusion criteria
Inclusion criteria for the main ASPREE study will apply to this sub-study. Eligible participants in ASPREE-AMD should be consecutive participants who enter the ASPREE study to maintain balance in treatment groups, according to the block randomisation procedures for the main study.

ASPREE Inclusion Criteria:

1. Men and women
2. Any person aged 70 years or older
3. Willing and able to provide informed consent, and willing to accept the study requirements

Minimum age
70 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
In addition to the ASPREE exclusion criteria, the exclusion criteria for ASPREE-AMD study include Geographic atrophy or Choroidal neovascular AMD in both eyes, or if baseline images are unavailable/non-existent.


ASPREE Exclusion Criteria:

1. A history of a diagnosed cardiovascular event
2. A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer or obstructive airways disease
3. A current or recurrent condition with a high risk of major bleeding, e.g.: cerebral aneurysm
4. Anemia
5. Absolute contraindication or allergy to aspirin
6. Current participation in a clinical trial
7. Current continuous use of aspirin or other anti-platelet drug or anticoagulant for secondary prevention. People with previous use of aspirin for primary prevention may enter the trial, provided they agree to cease existing use of aspirin and understand that they may be subsequently randomly allocated to low dose aspirin or placebo.
8. A systolic blood pressure >/=180 mmHg and / or a diastolic blood pressure >/=105 mmHg
9. A history of dementia
10. Severe difficulty or an inability to perform any one of the 6 Katz Basic Activities of Daily Living (ADL)
11. Non-compliance to taking pill


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)
Treatment allocation and concealment procedures are conducted at the parent ASPREE study. Here is the extract from the ASPREE study Protocol:

The computer-generated randomization list is prepared by an independent statistician. This arrangement ensures that the randomization code remains inaccessible to all study staff and senior investigators. Following the completion of the randomization process by the research assistant/nurse, a study medication number is provided. All staff, participants and general practitioners remain blinded to treatment allocation through the randomization procedure.

Participants in the study are allocated to one of two treatments: a) Acetylsalicylic acid (ASA) 100 mg: enteric-coated un-scored white tablet or b) placebo: enteric-coated un-scored white tablet with identical appearance. Study medications are provided by Bayer Schering Pharma (Germany). A 100mg dosage was selected as this is the common international dose. The enteric coating ensures that both active and placebo medication have an identical taste.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization list is generated using the STATA “ralloc” procedure. Randomization is stratified for age ('less than 80 yrs' and 'greater or equal to 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 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Of the participants being enrolled into the ASPREE study in Australia, approximately 50% are aged 70-74, 30% are 75-79 and 20% are 80 years of age and over. We have estimated the prevalence of non-advanced and advanced AMD from data provided in a 2011 report by Deloitte Access Economics for the Macular Degeneration Foundation, entitled ‘Eyes on the Future’, which was based on the Blue Mountains Eye Study data (similar to data from other international studies) stratified by age. For the purposes of sample size calculation, we have assumed a prevalence of early AMD (correspondent to ‘Intermediate AMD’ definition in the new classification adopted for this study) at entry to the study as 22% (averaged amongst males and females). The corresponding figure for neovascular AMD is 3%, and geographic atrophy 1.5% (total for advanced AMD is 4.5%).

During the period of follow-up, some ASPREE participants will develop new AMD, and some will progress in AMD severity.
To estimate likely progression rates in the ASPREE population, we have taken 50% of the 10-year rates of individuals aged 70-79 (noting that after 5 years, 50% will be aged 75-80, and 50% over 80). On this basis, we estimate after 5 years of follow up, 18% of ASPREE participants will develop intermediate AMD, 4% will develop advanced AMD and 8% will progress from intermediate to advanced AMD. Corresponding estimates for 3-year follow up are 11%, 2.4% and 4.8%.
Using these data, the 5-year follow-up of 6000 individuals with 1:1 allocation of active treatment and placebo has 80% power or greater, with alpha of 0.05, to detect a 15% reduction in incidence of early AMD incidence and 25% change in risk of progression from early AMD to advanced AMD. With this sample-size we could detect a 50% increase or decrease in the risk of development of advanced AMD.


*In addition, we will account for the progression rates from early to intermediate AMD, obtained from Ferris et al (Ferris et al. Clinical classification of age-related macular degeneration. Ophthalmology. 2013) those with early AMD (medium sized drusen from 63 to124 microns) would progress to large drusen equal to or larger than 125 microns (the main component of Intermediate AMD) at the 3-year rate from 10% (for drusen in one eye only) to 40% (for drusen in both eyes). This additional component will further substantially increase the study power and allow to reduce the requirements for sample size. *

**The number of participants required to enter ASPREE-AMD study needs to account for cross-over treatment of 5% per annum and 1.5% annual attrition due to deaths, therefore it needs to be about 20% to 25% greater at baseline than the sample size required at the end of the study. **

Group descriptive statistics will be used to define the baseline characteristics of participants randomised to aspirin and placebo groups. Continuous variable changes will be normalised prior to analysis. Non-parametric methods will be used where required. Chi-square and logistic regression analysis will be used to assess changes in categorical variables over the study period. Logistic regression analysis, separately for each binary outcome, will be used to determine the association between aspirin treatment and 1) AMD incidence, 2) advanced AMD incidence (for the total advanced AMD, and also separately for GA and CNV), and 3) progression of AMD towards advanced AMD, over the study period.

The main analysis will be conducted on an intention-to-treat basis. To ensure the robustness of the study results, we will also analyse the effect of intervention on a sample of ‘on protocol only’ participants and we will also perform a cross-over analysis, accounting for those who crossed over to the other treatment arm during the study.

Note: * and ** these two considerations mutually compensate the effect of each other.

Recruitment
Recruitment status
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
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 1184 0
The Alfred - Prahran
Recruitment postcode(s) [1] 7043 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 287530 0
Government body
Name [1] 287530 0
National Health and Medical Research Council
Address [1] 287530 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 287530 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Monash University, Wellington Rd, Melbourne, Victoria, Australia, 3168
Country
Australia
Secondary sponsor category [1] 286281 0
Other Collaborative groups
Name [1] 286281 0
Centre for Eye Research Australia
Address [1] 286281 0
32 Gisborne Street, East Melbourne, VIC, 3002,
Country [1] 286281 0
Australia
Other collaborator category [1] 277520 0
University
Name [1] 277520 0
University of Iowa
Address [1] 277520 0
PFP 11205
200 Hawkins Drive
Iowa City, IA 52242
Country [1] 277520 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289512 0
Monash University HREC
Ethics committee address [1] 289512 0
Level 1, Building 3e, Clayton campus, Wellington Rd, Clayton, VIC, 3800
Ethics committee country [1] 289512 0
Australia
Date submitted for ethics approval [1] 289512 0
31/01/2013
Approval date [1] 289512 0
04/02/2013
Ethics approval number [1] 289512 0
CF13/282 – 2013000121

Summary
Brief summary
Age-related macular degeneration (AMD) is a major cause of visual impairment in advanced countries, responsible for nearly half of all legal blindness in Australia. Due to increased life expectancy, the number of people with this progressive late onset disease will double by 2025. Aspirin could prevent or delay the onset of AMD in older persons but its bleeding risk also needs to be considered. This ASPREE-AMD project will determine whether treatment with low dose aspirin reduces incidence or progression of AMD.

ASPREE-AMD study is a sub-study of the large-scale randomised controlled trial ASPREE, which is registered with the International Standardised Randomised Controlled Trials Register. Title: Aspirin in Reducing Events in the Elderly (ASPREE). Number: ISRCTN83772183.
Trial website
www.aspree.org
Trial related presentations / publications
NIL
Public notes

Contacts
Principal investigator
Name 40562 0
Prof John McNeil, AM , MSc, PhD, FRACP, FAFPHM
Address 40562 0
John McNeil,
Professor and Head of School

School of Public Health & Preventive Medicine
Department of Epidemiology & Preventive Medicine
Faculty of Medicine, Nursing and Health Sciences
The Alfred Centre
99 Commercial Road,
Melbourne, VIC, 3004



Country 40562 0
Australia
Phone 40562 0
+613 9903 0565
Fax 40562 0
+613 9903 0047
Email 40562 0
john.mcneil@monash.edu
Contact person for public queries
Name 40563 0
A/Prof Robyn Woods, PhD
Address 40563 0
Executive Officer, ASPREE
Director, ASPREE Healthy Ageing Biobank
ASPREE Co-ordinating Centre, Ground floor, Burnet Building
89 Commercial Road, Melbourne, VIC, 3004
Country 40563 0
Australia
Phone 40563 0
+613 9903 0345
Fax 40563 0
+613 9903 0047
Email 40563 0
robyn.woods@monash.edu
Contact person for scientific queries
Name 40564 0
Dr Luba Robman, MBBS (equiv), PhD
Address 40564 0
ASPREE Trial
Department of Epidemiology and Preventive Medicine
Monash University
89 Commercial Road, Prahran, VIC 3181
Country 40564 0
Australia
Phone 40564 0
+61 3 99030903
Fax 40564 0
+613 9903 0047
Email 40564 0
liubov.robman@monash.edu