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Trial registered on ANZCTR


Registration number
ACTRN12614000293662
Ethics application status
Approved
Date submitted
12/03/2014
Date registered
20/03/2014
Date last updated
30/04/2019
Date data sharing statement initially provided
30/04/2019
Date results information initially provided
30/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Clinical effectiveness of aspirin as an adjunct to compression therapy in healing chronic venous leg ulcers: a randomised double-blind placebo-controlled trial [the ASPiVLU study]
Scientific title
Clinical effectiveness of Aspirin as an adjunct to compression therapy in healing chronic venous leg ulcers: a randomised double-blind placebo controlled trial
Secondary ID [1] 284157 0
NIL
Universal Trial Number (UTN)
U1111-1153-7794
Trial acronym
The ASPiVLU (ASPirin in Venous Leg Ulcer)study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Venous Leg Ulcer 291244 0
Condition category
Condition code
Cardiovascular 291588 291588 0 0
Diseases of the vasculature and circulation including the lymphatic system
Skin 291756 291756 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Acetylsalicylic acid (ASA) 300 mg: enteric coated un-scored white tablet [ASPIRIN] taken once daily for 24 weeks.

All participants will be treated with compression therapy. The compression system utilised will be selected based on the treating Investigator's clinical judgement for each patient. Participants will be asked not to remove compression between treatments. Compression adherence will be checked from baseline and weekly until healed or to 12 weeks, whichever comes first, and once healed 4-weekly to 24 weeks.
Participants will be asked to self-report trial medication adherence, and to present medication containers for a pill-count at 24 weeks.
As this is a study primarily evaluating the impact of aspirin therapy, the exact mode of compression therapy is secondary and indeed no particular compression system has been proven as universally superior.
Adherence to medication will be checked throughout the study by participant self-report and by medication container return for pill-count at the end of the study period of 24 weeks.
Intervention code [1] 288851 0
Treatment: Drugs
Comparator / control treatment
Placebo: enteric coated un-scored white tablet with identical appearance.

All participants will be treated with compression therapy. The compression system utilised will be selected based on the treating Investigator's clinical judgement for each patient. Participants will be asked not to remove compression between treatments. Compression adherence will be checked from baseline and weekly until healed or to 12 weeks, whichever comes first, and once healed 4-weekly to 24 weeks.
As this is a study primarily evaluating the impact of aspirin therapy, the exact mode of compression therapy is secondary and indeed no particular compression system has been proven as universally superior.
Participants will be asked to self-report trial medication adherence weekly from baseline until healed or to 12 weeks whichever come first, then monthly to 24 weeks from randomisation. Participants will return medication containers for a pill-count at the end of the study period of 24 weeks.
Control group
Placebo

Outcomes
Primary outcome [1] 291539 0
The primary objective is to determine whether aspirin as an adjunct to compression improves time to healing of venous leg ulcers
Timepoint [1] 291539 0
Time to healing will be measured by assessing the size of the ulcer that will be measured at baseline and fortnightly until healed using digital planimetry. Proof of healing: will be measured by independent expert review of digital photos of the ulcer at baseline and fortnightly until healed or to 12 weeks, whichever comes first. The ulcer will be photographed using a digital camera to allow independent verification of ulcer size and proof of healing (100% epithelialisation). A paper ruler with mm/cm markings will be used in each photo next to the ulcer to verify size.
Secondary outcome [1] 307005 0
The rate of ulcer recurrence over 6 months
Timepoint [1] 307005 0
Participants with healed VLU will be phoned to assess target ulcer recurrence and by research nurse at monthly intervals to check if the healed target VLU has recurred (if recurrence noted the participant will be referred to wound clinic). Monthly phone calls will continue for up to 6 months following randomisation and will commence at the 12-week from baseline visit

Eligibility
Key inclusion criteria
Eligible participants will include males and females, aged 18 years and older and have one or more leg ulcers in the presence of venous insufficiency confirmed by clinical assessment and/or duplex ultrasound.

The ulcer must have been present for at least six weeks.
Participants must have an Ankle Brachial Pressure Index [ABPI] measure of greater than or equal to 0.7 mmHg to exclude significant arterial insufficiency.
The eligible target ulcer will have an area of greater than or equal to 1 cm2 to less than or equal to 20 cm2 as measured by digital planimetry techniques (largest ulcer on limb and separated from other ulcers by at least 1 cm).
Participants must have been off aspirin for 6 weeks before coming into the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Unable to attend scheduled treatment visits and comply with follow-up contact with study staff.
* Current, regular aspirin use.
* Aspirin intolerance.
* Any existing condition or treatment that is a contraindication to aspirin or to participate in the trial (decision made according to medical practitioner’s clinical judgement).
* Concurrent use of any other antiplatelet or anticoagulation therapy.
* Pregnancy or breastfeeding

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Following the completion of screening and assessment participants to ascertain inclusion/exclusion criteria met and wound size in cm2 will then be randomly assigned to receive either aspirin or placebo. The randomization code will be available on a web-based system which will be protected by passwords for study trial staff, who will be required to enter their unique ASPiVLU identification number/password, along with the following key information: study site number, participant identification number, size of wound and confirmation inclusion and exclusion criteria
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation will be stratified by study site and wound size as measured by the Margolis index. The Margolis index (0, 1, 2) is a prognostic score for venous ulcer healing derived from dichotomous categorizations of ulcer area and duration of current ulcer [0 = ulcer size less than or equal to 5 cm2 and less than or equal to 6 months; 1 = ulcer size greater than 5 cm2 or greater than 6 months; 2 = ulcer size greater than 5 cm2 and greater 6 months].
Computer generated medication numbers will be provided to trial sites through the web portal. The randomisation list will be generated by an independent statistician; this arrangement will ensure that the randomisation code remains inaccessible to all study staff and senior investigators. The randomisation list will be generated using STATA “ralloc” procedure with randomisation stratified for site and wound size.
Following randomisation process by the research nurse, a study medication number will be provided. The research nurse is required to immediately confirm the study identification number through the web portal system.
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
All primary and secondary outcomes will be in the form of time to healing data and rates of complete healing that will be calculated using univariate Cox proportional hazards regression to directly compare rates between treatment groups. Given the sample size we anticipate randomisation will adequately balance baseline characteristics of participants in the two treatment groups. If necessary a secondary set of analyses will be performed to adjust for baseline characteristics that are found to be imbalanced between groups to the extent of a 0.25 standard deviation difference in means (quantitative measures) or an odds ratio of 1.5 (binary measures). These analyses will be conducted using multivariate Cox proportional hazards regression methods.
The primary and secondary endpoints will be analysed according to intention-to-treat principles, i.e. according to the group to which participants were randomised and without reference to their actual adherence with assigned treatment.
No statistical adjustments will be made for the multiple secondary endpoints in their analysis but the reporting of all secondary endpoint analyses will make clear whether the primary endpoint was statistically significant and will state the number of secondary endpoints proposed a priori in the study protocol.

Data from our previous compression bandaging study shows that in the placebo group we can expect 50% of ulcers to have healed at 12 weeks.15 Aspirin is expected to increase this proportion by another 20% i.e. we expect 70% (odds ratio, OR 2.3) of the aspirin group to be healed at 12 weeks.20 22
For 90% power in a two-sided (alpha=0.05) test for difference in proportions we would require 119 people per group. Allowing for 10% loss to follow-up we will recruit n= 132 participants per group. A sample size of 132 per group will ensure greater than 90% power for the analysis of time to healing assuming a commensurate hazard ratio effect as the odds ratio effect at 12 weeks.
For the secondary endpoint of recurrence, if there is no difference in the proportion remaining recurrence-free of target ulcer at 12 months, then if 53/132 (approx. 40%) in placebo group are healed at 12 weeks and remain recurrence-free at 12 months then we have 80% power to detect a difference of 17%, i.e. a proportion of 57% in placebo group healed at 12 weeks and remain recurrence-free at 12 months.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2014
Actual
9/07/2015
Date of last participant enrolment
Anticipated
30/06/2018
Actual
24/05/2018
Date of last data collection
Anticipated
31/12/2018
Actual
29/11/2018
Sample size
Target
268
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
QLD,TAS,VIC
Recruitment hospital [1] 2133 0
Caulfield Hospital - Caulfield
Recruitment hospital [2] 2134 0
Sunshine Hospital - St Albans
Recruitment hospital [3] 2135 0
Austin Health - Heidelberg Repatriation Hospital - Heidelberg West
Recruitment hospital [4] 2136 0
The Prince Charles Hospital - Chermside
Recruitment hospital [5] 2138 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 7543 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment postcode(s) [1] 15431 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 288783 0
Government body
Name [1] 288783 0
National Health and Medical Research Council
Country [1] 288783 0
Australia
Primary sponsor type
University
Name
Monash University
Address
School of Nursing and Midwifery
Level 3, 35 Rainforest Walk
Monash University
Clayton Campus
Wellington Road
Clayton, VIC 3800
Country
Australia
Secondary sponsor category [1] 287482 0
None
Name [1] 287482 0
Address [1] 287482 0
Country [1] 287482 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290625 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 290625 0
99 Commercial Road
Melbourne Vic 3004
Ethics committee country [1] 290625 0
Australia
Date submitted for ethics approval [1] 290625 0
24/03/2014
Approval date [1] 290625 0
11/06/2014
Ethics approval number [1] 290625 0
EC00315

Summary
Brief summary
We propose a randomised double-blind multicentre placebo-controlled clinical trial to determine the clinical effectiveness of aspirin in addition to compression in healing venous leg ulcers.
All eligible patients who are treated in participating wound clinics and who fulfil selection criteria will be offered study participation. All participants will be treated with best practice compression therapy.
In addition to compression the Aspirin Group: will receive 300 mg of aspirin daily (one tablet each morning) and the Placebo Group: will receive placebo (one tablet in the morning). We will assess wound size/depth, serum samples for inflammatory markers, pain, score, compression adherence, medication adherence, Quality of Life scores, target ulcer recurrence, adverse events and blinding success
Trial website
http://www.med.monash.edu.au/sphpm/aspivlu-study/
Trial related presentations / publications
TBA
Public notes
TBA

Contacts
Principal investigator
Name 46490 0
Prof Carolina Weller
Address 46490 0
School of Nursing and Midwifery
Level 3, 35 Rainforest Walk
Monash University, Clayton Campus
Wellington Road, Clayton, VIC 3800
Country 46490 0
Australia
Phone 46490 0
+61 3 9903 0623
Fax 46490 0
+61 3 9903 0828
Email 46490 0
carolina.weller@monash.edu
Contact person for public queries
Name 46491 0
Prof Carolina Weller
Address 46491 0
School of Nursing and Midwifery
Level 3, 35 Rainforest Walk
Monash University, Clayton Campus
Wellington Road, Clayton, VIC 3800
Country 46491 0
Australia
Phone 46491 0
+61 3 9903 0623
Fax 46491 0
+61 3 9903 0828
Email 46491 0
carolina.weller@monash.edu
Contact person for scientific queries
Name 46492 0
Prof Carolina Weller
Address 46492 0
School of Nursing and Midwifery
Level 3, 35 Rainforest Walk
Monash University, Clayton Campus
Wellington Road, Clayton, VIC 3800
Country 46492 0
Australia
Phone 46492 0
+61 3 9903 0623
Fax 46492 0
Email 46492 0
carolina.weller@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
not completed


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
EmbaseAspirin in venous leg ulcer study (ASPiVLU): Study protocol for a randomised controlled trial.2016https://dx.doi.org/10.1186/s13063-016-1314-4
EmbaseAspirin treatment for chronic wounds: Potential beneficial and inhibitory effects.2017https://dx.doi.org/10.1111/wrr.12502
EmbaseOnce daily 300 mg aspirin with compression versus compression alone in patients with chronic venous leg ulcers (ASPiVLU): A randomised, double-blinded, multicentre, placebo-controlled, clinical trial.2021https://dx.doi.org/10.1016/j.jtv.2021.07.005
N.B. These documents automatically identified may not have been verified by the study sponsor.