Clinical trial NCT02158806
Conditions: Venous Leg Ulcer
Keywords: Venous ulcer, varicose ulcer, gravitational ulcer, aspirin
Sponsor: University of Auckland, New Zealand
Start date: 2015-03-01; Completion date: 2017-03-31
Enrollment: 251 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Venous leg ulcers (VLU) are the most common leg ulcer, can be painful, and limit work, lifestyles and activity, especially in older patients. There are few effective treatments - compression therapy (tight bandaging or stockings) helps healing, but about half the people with a VLU remain unhealed even after 12 weeks of treatment. Research suggests taking aspirin as well as using compression may speed up healing for VLU, but the current evidence is not enough to change clinical practice. We will conduct a randomised controlled trial to test whether using low dose aspirin (150 mg daily or placebo) really does speed up healing.

Detailed description:
A pragmatic, community based, double-blind, placebo-controlled, randomised trial to determine whether low dose aspirin accelerates venous leg ulcer healing at 24 weeks when used in addition to compression. Participants in have compression therapy (system of choice guided by patient and/or clinical preference) as delivered through district nursing services at the study centres as a background treatment. Low dose aspirin (150 mg) or placebo will be taken once daily as an oral capsule.

Participants will be district nursing service patients in five study centres in New Zealand with prevalent or incident venous leg ulcers. A venous leg ulcer will be defined as a wound on the lower leg that has remained unhealed for 4 or more weeks, appears to be primarily venous in aetiology with other causative diseases ruled out. If the participant has two or more venous leg ulcers, the largest ulcer will be the reference ulcer.

Participants will receive three visits from the research nurse - visit 1 to screen for eligibility, visit 2 to consent and randomise the participant, visit 3 to collect outcome data. District nurses will continue to visit the participant (about weekly or more frequently if required) to provide routine care between research nurse visits.

Block randomisation will be used, stratified by study centre and prognostic index (ulcer size greater than 5cm2 and ulcer duration greater than 6 months) to ensure a balance of participants within study centres and for participants likely to be slow healers. Research nurses in the study centres will contact a central telephone answering service, provide information on inclusion criteria, exclusion criteria, and relevant clinical history on consented participants. Randomised participants will receive a bottle of 168 capsules of study medication identified only by unique code and will take the capsule until the reference ulcer heals or up to 24 weeks, whichever occurs sooner.

Participants will take the study medication for up to 24 weeks or until the reference ulcer heals. If the participant has a serious adverse event, needs to start taking aspirin, or must stop taking aspirin to use other medications, they will be withdrawn from treatment, although they will still be followed up at 24 weeks.

Arms: arm 1: 150 mg capsule once daily for up to 24 weeks arm 2: Matching capsule once daily for up to 24 weeks
Interventions: intervention 1: Aspirin intervention 2: Placebo
Intervention descriptions: intervention 1: 150 mg aspirin in capsule form once daily for up to 24 weeks intervention 2: Matching placebo capsule containing inert bulking agent

Protocol documents:
ICF_002.pdf: 
Lay study title: Aspirin4VLU 
 
Page 1 of 6 
PIS/CF version no.1  
 
   
 Dated: 22 August  2014 
 
PRINT ON LETTERHEAD AND ADD LOCAL DETAILS  
 
 
 
 
 
Participant Information Sheet 
 
Trial title: 
Aspirin4VLU: A randomised trial of low dose aspirin for venous leg 
ulcers 
 
Ethics committee ref: 
 
 
Local Investigator 
[Specific site details inserted] 
 
 
 
Lead investigator: 
 
Associate Professor Andrew Jull  
National Institute for Health Innovation,  University of Auckland 
09 923 4259 
 
Project Manager: 
Angela Wadham 
National Institute for Health Innovation,  University of Auckland 
09 923 2337 
 
 
You are invited to take part in a trial of aspirin for treating venous leg ulcers.   
 
Whether or not you take part is your choice.  If you don’t want to take part, you don’t have to 
give a reason, and it won’t affect the care you receive.   
 
This Participant Information Sheet will help you decide if you would like to take part.  It tells 
you why we are doing the trial, what it would involve for you, what the benefits and risks 
might be, and what would happen after the trial ends. The research nurse will go through 
this information with you to answer any questions. You do not have to decide today whether 
or not you will participate in this trial. Before you decide you may want to talk about the trial 
with other people, such as family, whanau, friends, or healthcare providers. Feel free to do 
this.  
 
If you agree to take part in this trial, you will be asked to sign the Consent Form on the last 
page of this document. You will be given a copy of this document to keep. 
What is the purpose of the trial? 
This clinical trial is funded by the Health Research Council of New Zealand. It is co-
ordinated by researchers at the University of Auckland. The aim is to find out whether using 
low-dose aspirin capsules (150mg - half the strength of usual aspirin) as well as 
compression bandaging speeds up venous leg ulcer healing. Some studies suggest aspirin 
might help venous ulcer healing, but they have been too small to provide an answer.  
 
In this trial half of the participants will get low-dose aspirin capsules to take every day and 
the other half will get placebo capsules to take every day. A placebo capsule looks like the 
aspirin capsule but contains no aspirin. Who gets which capsule will be random (50:50 
chance) and nobody will know until after the trial which capsule they were taking. Creating 


 
Lay study title: Aspirin4VLU 
 
Page 2 of 6 
PIS/CF version no.1 
 
   
 Dated: 22 August  2014 
 
 
groups this way will mean the two groups are alike except for taking aspirin or not. 
Comparing ulcer healing in the two groups will then show whether there is any difference in 
ulcer healing caused by taking aspirin. 
What will my participation in the trial involve? 
We are inviting 354 people with venous leg ulcers to take part in the clinical trial. You have 
been invited because you have a venous leg ulcer. If you decide to take part, a research 
nurse will visit you three times. The visits will be where you would normally receive a district 
nurse visit (i.e. your home or a clinic). Each visit will take about 30-60 minutes. The research 
nurse is a qualified district nurse with experience in leg ulcer care.  
 
At the first visit the research nurse will explain the trial and check that you can enter the trial. 
The research nurse will also look after your leg ulcer at this visit instead of the district nurse. 
You will be asked if you want to take part in this trial and asked to sign a consent form if you 
do.  
 
If you sign the consent the research nurse will ask you some questions about your medical 
history, about your leg ulcer and may need to measure your blood pressure at your arm and 
at your ankle. Consent also includes permission to contact your GP to ensure you are able 
to take aspirin. If your GP tells the research nurse you are not able to take aspirin (or that 
you should be taking aspirin), the research nurse will phone you with this information and 
you cannot take part in the trial.  
 
If you still meet all the entry criteria the research nurse will arrange another visit (visit 2).   
They will ask you some more questions, measure your ulcer and ask you to complete a 
questionnaire about your health. The research nurse will look after your leg ulcer at this visit 
and give you the trial capsules. 
 
At the third visit (6 months after the second visit) the research nurse will visit again to check 
whether your ulcer has healed. If your leg ulcer has healed, the research nurse will need to 
look at your district nursing records to see what date your leg ulcer healed. The research 
nurse will ask you to complete a questionnaire about your health. You will also be asked to 
complete a survey about participating in the trial. The research nurse will look after your leg 
ulcer at this visit. 
 
In between the second and third trial visits, your usual district nurse will continue to look 
after your leg ulcer and check if it has healed. If your ulcer heals between the second and 
third research nurse visits, you will need to stop taking the trial capsules. If you want to 
contact the research nurse in between these visits, you can do so.  
What are the possible benefits and risks of this trial? 
Possible benefits 
Your participation in this clinical trial will improve our understanding of the effect of low dose 
aspirin (150 mg) on venous leg ulcers and may improve the treatment of leg ulcers for 
others in the future.  
 
Possible risks 
Aspirin is a drug that has side effects. The common side effect is upset stomach. 
Uncommon side effects include any gastric bleeding, bleeding that requires going to hospital 
for transfusion (major bleeding), and stroke caused by bleeding.  
 
In people without diseases that need to be treated with aspirin, the rate of major bleeding 
that requires transfusion or causes death is 10 per 10,000 people per year when taking 
aspirin and 7 per 10,000 people per year when not taking aspirin. The rate of stroke caused 


 
Lay study title: Aspirin4VLU 
 
Page 3 of 6 
PIS/CF version no.1 
 
   
 Dated: 22 August  2014 
 
 
by bleeding is 4 per 10,000 people per year when taking aspirin and 3 per 10,000 per year 
when not taking aspirin.  
 
The risk of bleeding increases with age or if you have diabetes or if you smoke tobacco. The 
risk of bleeding is not affected by the type of aspirin or the dose of aspirin.  
 
You will be issued a card to confirm your participation in a clinical trial. Please show this 
card to health professionals at the time of any treatment (including going to the dentist or 
chemist). 
 
You may need to stop taking the trial capsules: 
 
If you are admitted to hospital. 
 
If you start having side effects of aspirin. 
 
If you start taking new medications that should not be taken with aspirin. 
 
If your GP or other doctor thinks you should stop taking aspirin. 
 
If your GP or other doctor thinks you should definitely start taking aspirin. 
 
Nobody knows whether you will be on the aspirin or placebo capsules. If you need to stop 
taking aspirin, or you need to start taking aspirin, you will need to stop taking the trial 
capsules.  
Who pays for the trial? 
Taking part in this clinical trial will not cost you any more than you pay now for receiving care 
from district nurses for your leg ulcer.  
What if something goes wrong? 
If you were injured in this trial, which is unlikely, you would be eligible for compensation from 
ACC just as you would be if you were injured in an accident at work or at home. You will 
have to lodge a claim with ACC, which may take some time to assess. If your claim is 
accepted, you will receive funding to assist in your recovery.   
 
If you have private health or life insurance, you may wish to check with your insurer that 
taking part in this trial won’t affect your cover. 
What are my rights? 
You do not have to take part in this trial. If you do not take part, your care will not be 
affected. If you agree to take part in the trial, you can stop taking the trial capsules at any 
time, or withdraw from the trial at any time. If you stop taking the trial capsules, we would still 
like to contact you at 6 months to see if your leg ulcer has healed. If you withdraw from the 
trial we would like to use your information up to the point you withdraw. 
 
The trial files and all information that you provide will be strictly confidential.  No material that 
could identify you will be used in any reports on this trial. The information will be kept at the 
National Institute for Health Innovation, the University of Auckland.  All computer records will 
be password protected and paper records stored in a secure storage facility. All future use of 
the information collected will be strictly controlled in accordance with the Privacy Act, 1994. 
 
During the trial only the Aspirin4VLU researchers and the trial monitor will have direct 
access to your information. Representatives of Medsafe or the ethics committee may also 
require access. This access will only be to check the accuracy of the information collected 
for the trial and the information will remain confidential. 
 
As a participant you have the right to access your information and to correct your information 
in the trial documents. Ask the research nurse how to do this. You also have the right to 


 
Lay study title: Aspirin4VLU 
 
Page 4 of 6 
PIS/CF version no.1 
 
   
 Dated: 22 August  2014 
 
 
services of an appropriate standard. This means that if we learn of any new information 
about aspirin that will have a positive or negative effect on your health, we will inform you as 
soon as possible. 
What happens after the trial? 
You will remain on the trial capsules for 6 months at the most. If your leg ulcer heals before 
6 months are completed you will need to stop taking the trial capsules then. At the 6 month 
visit, the research nurse will ask for any remaining trial capsules to be returned. If your leg 
ulcer is still not healed, we recommend you do not take aspirin until the trial results are 
known. You should discuss with your GP whether taking aspirin for other reasons is needed.   
 
When all participants have completed the trial, the data will be analysed and published. At 
the earliest, this will be about 2 ½ years after the first person started on the trial. We will then 
notify you of the results by email or post. We will tell you which capsule you were on (aspirin 
or placebo). We may be asked to submit individual participant data to a clinical trials register 
in order to have the results published in a well-known journal. If we are required to submit 
data to such a register, you would not be able to be identified. 
 
We will keep your information for 10 years after the trial is completed.  
 
Your data may be used in a study called a meta-analysis. This type of trial collects individual 
participant information from all trials of aspirin for venous leg ulcers. If we do share your data 
for such a study, you would not be able to be identified.  
Who do I contact for more information or if I have concerns? 
If you want to talk to someone who isn’t working on the trial, you can contact a health and 
disability advocate on: 
 
Phone: 0800 555 050 
Fax: 0800 2 SUPPORT (0800 2787 7678) 
Email:  advocacy@hdc.org.nz 
 
For Maori health support please contact : 
[Insert locality details - Name, position 
 
Telephone number 
 
Email] 
 
You can also contact the Health and Disability Ethics Committee (HDEC) that approved this 
trial on: 
 
 
Phone: 
0800 4 ETHICS 
 
Email:  
hdecs@moh.govt.nz 
 
This clinical trial is registered on the website ClinicalTrials.gov [NCT02158806].


 
Lay study title: Aspirin4VLU 
 
Page 5 of 6 
PIS/CF version no.1 
 
   
 Dated: 22 August  2014 
 
 
Consent Form 
 
Aspirin4VLU: A randomised trial of low dose aspirin for venous leg ulcers 
 
 
Please tick to indicate your agreement to the following 
 
I have read, and I understand the Participant Information Sheet.   
Yes  
No  
I have been given sufficient time to consider whether or not to participate in 
this trial. 
Yes  
No  
I have had the opportunity to use a legal representative, whanau/ family 
support or a friend to help me ask questions and understand the trial. 
Yes  
No  
I am satisfied with the answers I have been given regarding the trial. 
Yes  
No  
I understand that taking part in this trial is voluntary (my choice) and that I may 
withdraw from the trial at any time without this affecting my clinical care. 
Yes  
No  
If I decide to withdraw from using the trial tablets, I agree to be contacted at 6 
months for a follow-up visit. 
Yes  
No  
If I decide to withdraw from the trial, I agree that the information collected 
about me up to the point when I withdraw may continue to be used. 
Yes  
No  
I consent to the research staff collecting and processing my information, 
including information about my health. 
Yes  
No  
I consent to my GP or current provider being contacted about my participation 
in the trial and being asked about my qualifying to be part of the trial. 
Yes  
No  
I understand that there may be risks associated with the treatment. 
Yes  
No  
I agree to an approved auditor appointed by the New Zealand Health and 
Disability Ethic Committees, or any relevant regulatory authority or their 
approved representative reviewing my relevant clinical records for the sole 
purpose of checking the accuracy of the information recorded for the trial. 
Yes  
No  
I understand that my participation in this trial is confidential and that no 
material, which could identify me personally, will be used in any reports on this 
trial. 
Yes  
No  
I understand the compensation provisions in case of injury during the trial. 
Yes  
No  
I know who to contact if I have any questions about the trial in general. 
Yes  
No  
I understand my responsibilities as a trial participant. 
Yes  
No  
I understand that information may be shared with other studies or registers but 
that no information that identifies me personally will be used. 
Yes  
No  
I wish to receive a summary of the results from the trial. 
Yes  
No  
 
 


 
Lay study title: Aspirin4VLU 
 
Page 6 of 6 
PIS/CF version no.1 
 
   
 Dated: 22 August  2014 
 
 
Declaration by participant: 
 
I hereby consent to take part in this trial. 
 
Participant’s name: 
Signature: 
Date: 
 
 
 
Declaration by member of research team: 
 
I have given a verbal explanation of the research project to the participant, and have 
answered the participant’s questions about it.   
 
I believe that the participant understands the trial and has given informed consent to 
participate. 
 
I will ensure a copy of the Participant Information Sheet and Informed Consent Form is 
provided to the participant.  
 
Researcher’s name: 
Role in Project: 
Researcher’s contact phone number: 
 
Signature: 
Date: 
 
 
 
 

Prot_000.pdf: 
Protocol	  –	  Version	  1.1	  
Date:	  6	  May	  2015	  
1	  
- 
CONFIDENTIAL	  -­‐	  
- 
Not	  for	  public	  circulation	  or	  reproduction	  -­‐	  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A randomized, blinded, placebo controlled trial 
of adjuvant low dose aspirin  
for venous leg ulcers 
(ClinicalTrials.gov NCT02158806) 
 
 
 
 
Principal investigator 
 
Associate Professor Andrew Jull 
National Institute for Health Innovation, University of Auckland 
 
 
 
   















































































SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Final 
Arandomised,blinded,placebocontrolledtrial
ofadjuvantlowdoseaspirin
forvenouslegulcers
National Institute for Health Innovation: Aspirin4VLU Statistical Analysis Plan, Final.doc 
© NIHI, The University of Auckland, 2015 
Page 1 of 15 


NIHI 
STATISTICAL ANALYSIS PLAN APPROVAL SHEET 
Study: Aspirin4VLU 
Trial registration number: NCT02158806 
Title: Low dose adjuvant aspirin for venous leg ulcers: a randomised trial 
Authors: Varsha Parag 
Version: Final 
Version date: 10th February 2015 
Who else was involved in the discussion of the analysis: 
Andrew Jull and Angela Wadham 
The undersigned have reviewed this document and find it to be consistent with 
the requirements of the protocol as it applies to their respective areas. The 
author/reviewer also finds this document to be in compliance with ICH-E9 as 
well as NIHI SOP BS-0004. 
Varsh1g 
Study Statistician 
igator 
Date 
(2. z_. 201 !, 
Date 
National Institute for Health Innovation: Aspirin4VLU Statistical Analysis Plan, Final.doc 
© NIHI, The University of Auckland, 2015 
Page 2 of 15 


Preface 
The<purpose<of<this<Statistical<Analysis<Plan<(SAP)<is<to<provide<a<detailed<statement<of<
the<intended<statistical<analyses<that<will<be<performed<in<the<analysis<of<data<from<the<
Aspirin4VLU.< This<document<is<intended<to<be<stand-alone<from<the<protocol<and<
adhere<to<the<main<points<in<the<analysis<summary<specified<in<the<protocol.< However<it<
is<envisaged<that<the<SAP<can<undergo<revision<outside<of<the<protocol.<
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protocol<analysis<would<require<review<by<an<ethics<committee.<
It<is<assumed<that<the<study<documentation<provided<by<Data<Management<follows<
standard<operating<procedures.< These<procedures<describe<the<process<for<setting<up<
and<maintaining<study<documentation,<recording<decisions<affecting<data<handling,<as<
well<as<methods<of<data<capture<and<the<algorithms<to<ensure<accurate<data<are<
collected<and<maintained.< It<is<assumed<that<the<SAP<will<use<data<from<a<locked<
database<that<has<been<verified<against<the<clinical<record<and<is<a<true<record<of<the<
data<collected<from<the<patient.< Any<data<that<are<missing<will<be<flagged<and<assumed<
to<be<undiscoverable.<
The<SAP<will<also<outline<the<proposed<layout<of<tables/figures<that<will<be<presented.<
Scope 
Please<note<that<the<scope<of<this<SAP<is<intended<to<cover<ONLY<those<main<analyses<
described<in<the<protocol.< For<additional<research<questions<not<detailed<within<this<
SAP<and/or<questions<requiring<further<exploratory<analyses<please<refer<to<other<
separate<SAPs.<
To<keep<within<timeframe<of<issue<of<Biostatistics<report,<input<into<required<analysis<
needs<to<be<pre-specified<in<this<analysis<plan.<Requests<for<additional<analyses<must<
be<minimal<after<sign-off<of<this<document.< This<enables<all<pre-programming<programs<
to<be<performed<ahead<of<database<lock.<
National Institute for Health Innovation: Aspirin4VLU Statistical Analysis Plan, Final.doc 
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TABLE OF CONTENTS 
1.
Introduction ......................................................................................................... 5 
2.
Study objectives .................................................................................................. 5 
3.
Study design ........................................................................................................ 5 
3.1. Eligibility criteria ........................................................................................... 6 
3.2. Randomisation ............................................................................................. 6 
3.3. Sample size .................................................................................................. 6 
4.
Study outcomes .................................................................................................. 7 
4.1. Primary outcome .......................................................................................... 7 
4.2. Secondary outcomes ................................................................................... 7 
5.
Data sources ........................................................................................................ 7 
6.
Variable definitions ............................................................................................. 7 
7.
Biostatistics quality assurance .......................................................................... 9 
8.
Analysis populations .......................................................................................... 9 
8.1. Intention to Treat .......................................................................................... 9 
8.2. Per Protocol ................................................................................................. 9 
9.
Statistical analysis ............................................................................................ 10 
9.1. CONSORT statement ................................................................................ 10 
9.2. Participant accountability ........................................................................... 10 
9.3. Baseline characteristics ............................................................................. 10 
9.4. Concomitant medications ........................................................................... 10 
9.5. Primary outcomes analysis ........................................................................ 11 
9.5.1. Sensitivity analyses .................................................................................... 11 
9.5.2. Subgroup analyses .................................................................................... 11 
9.6. Secondary outcomes analysis ................................................................... 11 
9.6.1. Proportion healed ....................................................................................... 11 
9.6.2.Change in ulcer area .................................................................................. 12 
9.6.3.Change in quality of life .............................................................................. 12 
9.6.4.Treatment adherence ................................................................................. 12 
9.6.5. Efficacy of blinding ..................................................................................... 12 
9.6.6.Adverse events .......................................................................................... 12 
10.
Data safety and monitoring board ................................................................... 12 
11.
Peer review ........................................................................................................ 13 
12.
Budget ................................................................................................................ 13 
13.
Dissemination .................................................................................................... 14 
Appendix I: List of table templates ........................................................................... 15 
National Institute for Health Innovation: Aspirin4VLU Statistical Analysis Plan, Final.doc 
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1. 
INTRODUCTION
Leg ulcers are chronic, recurrent and have a major impact of the lives of elders. The 
vast majority of health care for leg ulcers is undertaken in the community, where 
district nurses alone have been estimated to spend up to a quarter of their time in 
leg ulcer care. Venous leg ulcers are the most common type of leg ulcer accounting 
for up to 8 out of every 10 people with leg ulcers. 
There is limited but suggestive evidence for aspirin as an adjuvant for treating venous 
ulceration. Two small randomised controlled trials (n=71) evaluated 300 mg daily oral 
aspirin in addition to compression bandaging in patients with venous ulcers, with more 
people in the aspirin group healing in both trials (RR 1.91 and 1.41). However, this 
evidence is not sufficient to change practice. 
The main barrier to further testing of aspirin is the belief that many older adults are 
already being treated with aspirin. However, two New Zealand venous ulcer trials 
showed aspirin use in such patients was low (similar to a trial in the UK). Only 30% of 
participants in the HALT trial (recruitment 2003-2005, n=368) and 17% in the 
PREPARE Pilot trial (recruitment 2007, n=41) were taking aspirin at baseline. Analysis 
of the HALT trial data found the 89 participants who were on low dose aspirin healed 
about 30% faster than those not on aspirin; the 150 mg dose was most effective (HR 
1.77, 95%CI 1.13 to 2.75, n=33). 
A definitive trial is required to provide more evidence of the effect aspirin when used 
with compression. 
2. 
STUDY OBJECTIVES
The main aim of this trial is to evaluate the effectiveness of low dose aspirin compared 
to placebo when used in addition to compression therapy for VLU time-to-healing over 
24 weeks follow up. 
Other aims include estimating the effect of aspirin on proportion of patients healed, 
adverse events, adherence and health-related quality of life (HRQoL). 
3. 
STUDY DESIGN
Please refer to the study protocol for a full description of the study design. This is a 
prospective community-based, double-blind, placebo-controlled, randomised trial with 
participants receiving either 150 mg aspirin daily for up to 24 weeks or matching 
placebo. Participants in both arms will also receive compression therapy (with system of 
choice guided by patient and/or clinical preference) as delivered through district nursing 
services at the trial centres. Patients with venous leg ulcers who present for treatment to 
or already receiving treatment from the community-based district nursing services at the 
following trial centres will be recruited: Auckland, Counties Manukau, Waikato, and 
Southern District Health Boards, and Nurse Maude community nursing services in 
Christchurch. Baseline and 24 week assessments will be conducted by the research 
nurse. The patient will continue to receive district nursing care as per normal protocol. 
National Institute for Health Innovation: Aspirin4VLU Statistical Analysis Plan, Final.doc 
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3.1. Eligibility criteria 
Participants will be eligible for inclusion if they: 
•
aged 18 years or older
•
determined to have a venous leg ulcer (clinical indications of venous ulceration,
ABI .:: 0.8, and other causative aetiologies ruled out)
•
able to tolerate compression therapy
•
able to provide written informed consent
•
confirmation with participant's general practitioner that the participant can take
low dose aspirin or placebo
Participants will be excluded if they: 
•
pregnant or breast-feeding women
•
history of myocardial infarction, stroke, transient ischaemic attack, angina or
significant peripheral arterial disease
•
history of adverse effects related to aspirin use
•
currently using aspirin, or other anti-platelet or anticoagulant therapy
•
participant has any other existing condition or treatment that is a
contraindication to use of aspirin or to participation in the trial
•
participant has any other existing condition where treatment with aspirin is
indicated
3.2. Randomisation 
Immediately after baseline data have been recorded, consented patients who fulfil 
entry criteria will be randomised by computer to one of the two trial groups using 
stratified blocked randomisation with varying block sizes of 2 and 4. The 
randomisation sequence will be prepared by the trial statistician and loaded into a 
secure website. Randomisation will be stratified by trial centre and prognostic index 
(based on ulcer and duration) which will isolate any centre effect in clinical 
management and ensure a balance on key prognostic variables known to influence 
healing at 24 weeks. Each participant will receive a randomly assigned unique 
double-blind trial treatment number. 
3.3. Sample size 
A sample size of 354 (177 in each group) would be sufficient to show a four week 
difference in time-to-healing at 90% power with an alpha of 0.05, and assuming 
10% loss to follow up and the median time-to-healing in the control group over a six 
month follow up is 92 days (the median time to healing suggested by a previous 
bandaging trial for VLU patients over 24 weeks). These data equate to a hazard 
ratio for VLU healing of 1.45, which is smaller than that suggested by our re­
analysis of data from a cohort in a previous VLU trial (hazard ratio for VLU healing 
1.77 for 150 mg dose). A four week difference was the minimal important difference 
that would most frequently persuade people to use aspirin in a small commissioned 
survey of older people in Auckland, was the time interval used in a Canadian 
venous ulcer trial and is lower than clinically significant differences used to 
calculate the sample sizes in two large venous ulcer trials conducted in the United 
Kingdom (the Venus II and Ill trials). 
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Even if recruitment were lower than anticipated, using the same assumptions as 
above, a sample of 238 inflated to 264 (132 in each group) to allow for 10% loss to 
follow up would be sufficient to show a four week difference in time to healing with 
80% power with an alpha of 0.05. 
4.
STUDY OUTCOMES
4.1. Primary outcome
The primary outcome is time to healing over 24 weeks follow up period.
4.2. Secondary outcomes
The secondary outcomes are:
•
Proportion of participants with a healed reference VLU at 24 weeks
•
Change in estimated ulcer area between baseline and 24 weeks
•
Change between baseline and 24 weeks in health related quality of life
(HRQoL) using SF-36, CXVUQ and EQ5D
•
Treatment adherence at 24 weeks
•
Efficacy of blinding at 24 weeks
•
Adverse events during 24 week trial period
5.
DATA SOURCES
Data collected from the following Aspirin4VLU case report forms and questionnaires 
which will be extracted from the NIHI Oracle database into SAS for the analyses: 
•
Screening log
•
Form A: Registration
•
Form B: Baseline
•
Form C: 24-week endpoint assessment
•
Form Q: Participant questionnaire booklet
•
Form M: Concomitant medications
•
Form X: Adverse events
6.
VARIABLE DEFINITIONS
The following definitions relate more specifically to the derived variables and non­
standard definitions required for analysis of the data that are specific to the analyses 
referred to throughout this SAP. Please refer to the study protocol for a complete list of 
abbreviations set out for this study. 
•
Ankle Brachia! Index (ABI): The ABI is an index of arterial insufficiency in the
lower leg. An ABI < 0.8 indicates that there is a high probability that some arterial
insufficiency is present. An ABI will be obtained from the clinical records for each
participant. Where a potential participant already in treatment has an ABI obtained
more than three months prior to the eligibility screen, a new ABI will be obtained
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prior to inclusion to ensure no development or progression of arterial disease. ABI 
will be collected in form A question 5.01. 
•
Healing: Defined as intact skin without a scab and without the ulcer re-opening.
Healing data will be obtained from clinical records. District nurses will visit patients
on a weekly basis as part of normal care and record healing. At 24 weeks, the
research nurse will visit the participant and determine if the reference ulcer is
healed. If the ulcer is healed, the research nurses will access the participant's
clinical records to determine the week within the 24 week visit that date of healing
was first recorded. This data will be entered in form C questions 2.01 and 2.09.
•
Estimated ulcer area: Obtained from measuring the maximum width(mm) and
length(mm) of the reference ulcer (form B questions 2.02 and 2.03, and form C
questions 2.02 and 2.03), and the ulcer area is calculated using the area of an
ellipse formula:
Ulcer area = (Length/10) x (Width/10) x (TT=3.1416 / 4) 
E.g. if length=30mm and width=15mm
then estimated ulcer area=3 x 1.5 x 3.1416 / 4 = 3.53 cm2 
•
Prognostic index: calculated using following Margolis index formula from form B
questions 2.01 to 2.03:
if (duration>6mths = N) and (ulcer areas 5cm2) then prognostic index = 0, 
if (duration>6mths = Y) or (ulcer area > 5cm2) then prognostic index = 1, 
if (duration>6mths = Y) and (ulcer area > 5cm2) then prognostic index = 2 
•
RAND-36 questionnaire: The RAND-36 is a 36-item self-administered instrument
to measure generic health-related quality of life. Participants' perceived health is
measured across 8 domains (physical functioning, role limitations due to physical
functioning, bodily pain, general health, vitality, social functioning, role limitations
due to emotional functioning and mental health). Additionally, two summary
component scores (physical and mental) will be obtained. RAND-36 domain and
summary scores will be calculated at baseline and 24 weeks from form Q
questions 1 to 11.04.
•
Charing Cross Venous Ulcer Questionnaire (CCVUQ): The CCVUQ is a 21-
item self-administered disease-specific instrument to measure health-related
quality of life across four domains (social function, domestic activities, cosmesis
and emotional status). CCVUQ domains will be calculated at baseline and 24
weeks from form Q question 12 to 19.
•
EuroQol 5D {EQ50): The EQ5D is a 6-item self-administered generic instrument
to measure health-related quality of life across 5 domains (mobility, self-care, usual
activities, pain/discomfort and anxiety/depression). A utility score associated with a
health state is also generated. Measured at baseline and 24 weeks from form Q
questions 20 to 25.
•
Treatment adherence: Measured at 24 weeks using count of remaining capsules
by the research nurse in form C question 5.04. Note participants are to take one
capsule per day so a full course of study treatment is 168 capsules (if ulcer has not
healed). A leeway of 10% either way has been allowed.
Treatment adherence will be coded as:
-
If the ulcer is not healed at 24 weeks (form C question 2.01=No):
o And if question 5.04 is between O and 17 then treatment adherence = 
Yes
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o And if question 5.04 is P 18 then treatment adherence = No
-
If the ulcer is healed at 24 weeks (form C question 2.01=Yes):
o First work out number of days participant should have taken the
capsules: date healed (form C question 2.09) minus randomisation date
o
Subtract this number from 168 to get number of capsules that should be
remaining. Work out the 10% leeway range around this, and:
11 If question 5.04 is included in this range then treatment 
adherence = Yes 
11 If question 5.04 is not included in this range then treatment 
adherence = No 
o
E.g. If participant is randomised on 1 Feb and healed on 1 May then the
difference is 89 days, and they should have 168-89=79 capsules
remaining (and with a 10% leeway either way this gives between 71 to
87 capsules remaining). So if question 5.01 is between 71 and 87 then
participant is coded as treatment adherence = Yes. Otherwise they are
coded as treatment adherence = No.
•
Efficacy of blinding: Measured at 24 weeks, the efficacy of blinding will be tested
by asking patients which treatment they believed they received, and asking the
same question of the research nurses. From form C questions 5.05 and 5.06.
7.
BIOSTATISTICS QUALITY ASSURANCE
Well in advance of study data-lock, programming across all analyses will commence 
with dummy data. This will allow sufficient time to turn around the 'real' analyses as 
quickly as possible. Early programming will also allow for a preliminary run at merging· 
of the various datasets into the correct data structure required for analysis. Specifically, 
the datasets in section 5 will be taken before data-lock and passed through the 
necessary biostatistical processes (which will include checking that all the datasets 
have been imported correctly into SAS and are all able to be correctly merged 
together). 
8.
ANALYSIS POPULATIONS
8.1. Intention to Treat 
All treatment evaluations will be performed on the principle of 'Intention To Treat' 
(ITT) unless otherwise specified. The ITT population will consist of all randomised 
participants regardless of whether they actually satisfied the entry criteria, the 
treatment actually received and subsequent withdrawal or deviation from the 
protocol. 
8.2. Per Protocol 
A per protocol analysis will also be performed on the primary and main secondary 
outcomes in order to check the robustness of the results. A per protocol analysis 
involves looking at the major protocol violations such as treatment adherence, 
withdrawals and lost to follow-up. Criteria for defining the per protocol population 
will include consideration of the following: those who have complied with the 
treatment allocated, were exposed to the intervention as planned (i.e. used only 
assigned intervention), were not lost to follow-up, and who do not have major 
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protocol deviations pertaining to eligibility or the assessment of the treatment 
difference. 
9.
STATISTICAL ANALYSIS
All statistical analyses will be performed using SAS version 9.3 and R version 3.0.1. All 
statistical tests will be two-tailed and at 5% significance level throughout the analyses 
and all treatment evaluations will be performed on the principle of 'intention to treat' 
unless otherwise specified. No adjustments for multiplicity are planned for any of the 
outcomes. 
Summaries of continuous variables which are normally distributed will be presented as 
means and standard deviations or medians and inter-quartiles for skewed data, while 
categorical variables will be presented as frequencies and percentages. Continuous 
variables will be compared with t-tests or Mann-Whitney tests and categorical data with 
chi-squared tests as appropriate. 
The study statistician will conduct all the analyses. Blinded results will be presented to 
the Pl and SC for interpretation. Unblinded results will be revealed to the SC only after 
interpretation of the blinded results has been determined. 
A separate EXCEL file containing the SAP tables specific to this study will be provided 
based on all the analyses stated below (see Appendix I). 
9.1. CONSORT statement 
All participants who were invited to participate in this study should be accounted 
for and a CONSORT statement prepared. The reasons for non-participation will be 
discussed in relation to the external validity of the study and the pattern of protocol 
violations considered as potential sources of bias. Reasons for early withdrawal 
will be listed for all participants that prematurely discontinued intervention or the 
study. The number of participants that were screened but not randomised will also 
be presented from the Screening Log. 
9.2. Participant accountability 
Tables describing patient accountability will be produced. The number of 
participants who were screened, registered, fulfilled eligibility criterion, together with 
reasons for exclusion will be summarised in table 1 a. The status of participants at 
each visit, and the number of major protocol violations will also be summarised in 
table 1a. 
9.3. 
Baseline characteristics 
Baseline demographic variables (age, sex, self-reported ethnicity, education), 
smoking status, history of ulceration, ulcer size, clinical history, current treatments 
(including compression system, use of pentoxifylline and use of statins) and health­
related quality of life variables will be summarised for each intervention group in 
table 1 b. Since any differences between the groups at baseline could only have 
occurred by chance, no formal significance testing will be conducted. 
9.4. Concomitant medications 
Concomitant medications (coded to the Anatomical Therapeutic Chemical, ATC, 
classification system) by number of events and people will be summarised for each 
intervention group in table 2a. Separate tables will be given for general A TC 
categories, and for the detailed A TC codes. 
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9.5. Primary outcomes analysis 
The primary outcome is time to healing over 24 weeks follow up period. All 
analyses for the primary outcome will be ITT unless otherwise stated where 
participants that have not healed by 24 weeks or missing outcomes will be 
censored on the 24 week visit date. Analyses comparing the Aspirin and Placebo 
groups will be presented in table 3a. 
Time to healing will be analysed using Cox regression modelling to take into 
account known covariates and the varying times since randomisation. The 
proportionality assumption will be checked using standard graphical techniques. 
The main analyses will be unadjusted. Kaplan Meier plots and log rank test will also 
be used. 
9.5.1. Sensitivity analyses 
The following sensitivity analyses will be conducted for the unadjusted primary 
outcome: 
• Adjusted analyses including study centre, prognostic index and any
important imbalances in baseline covariates
•
Per Protocol analyses where participants that have any protocol
violations (defined in section 8.2) will be excluded
9.5.2. Subgroup analyses 
If the treatment effect for this outcome is significant (i.e. p<0.05), then subgroup 
analyses will be reported. It is planned that subgroup analyses will be carried 
out on the following baseline variables: sex, age (dichotomised based on the 
median), ethnicity, ulcer size (S 5cm2, > 5cm2), ulcer duration (S6mths, >6mths),
and compression system (2 layer, 3 layer, etc). The model will include the 
subgroup variable along with its interaction with treatment. A test of whether 
the treatment effect differs across the levels of the subgroup will be constructed 
by assessing the significance of the interaction term. The subgroups analyses 
will be presented as a forest plot. 
9.6. Secondary outcomes analysis 
Descriptive summary statistics for each group will be presented for all secondary 
outcomes collected in form C in table 2b. Participants with missing outcome data 
will be excluded from this table. 
The distribution of all continuous endpoints will be assessed for normality and 
skewed data will be subjected to an appropriate transformation before analysis. 
Non-parametric analysis (Mann-Whitney tests) will be used if data is skewed and 
cannot be transformed to be normally distributed. 
9.6.1. Proportion healed 
The proportion of participants with healed ulcers at 24 weeks between the 
groups will be analysed using chi-squared tests. Crude incidence rates, relative 
risks (RR), absolute risk differences, number needed to treat (NNT), and 
corresponding 95% confidence intervals will also be calculated. For the ITT 
analyses participants with missing outcomes will be assumed to be not healed. 
Per protocol analyses will also be conducted where participants that have any 
protocol violations (defined in section 8.2) will be excluded. Results will be 
presented in table 3b. 
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9.6.2. Change in ulcer area 
ChangeEinEulcerEareaEbetweenEbaselineEandE24EweeksEwillEbeEanalysedEusingE
linearEregressionE(ANCOVA).ETheEmodelEwillEincludeEtheEtreatmentEgroupEandE
theEbaselineEulcerEareaEmeasure.EForEtheEITTEanalysesEmissingE24EweekE
outcomesEwillEbeEreplacedEwithEtheEbaselineEulcerEareaE(soEassumingEnoE
change).EResultsEwillEbeEpresentedEinEtableE3c.E
9.6.3. Change in quality of life 
ChangeEbetweenEbaselineEandE24EweeksEinEeachEofEtheEHRQoLEscoresE(SF-36E
domainsEandEsummaryEscores,ECCVUQEdomainsEandEtheEEQ5DEdomains)EwillE
beEanalysedEusingElinearEregressionE(ANCOVA).EEachEmodelEwillEincludeEtheE
treatmentEgroupEandEtheEbaselineEulcerEareaEmeasure.EForEtheEITTEanalysesE
missingE24EweekEoutcomesEwillEbeEreplacedEwithEtheEbaselineEvalueE(soE
assumingEnoEchange).EResultsEwillEbeEpresentedEinEtableE3c.E
9.6.4. Treatment adherence 
TreatmentEadherenceEatE24EweeksEwillEbeEpresentedEasEcountsEandE
percentages,EandEtheEdifferenceEbetweenEtheEtreatmentEgroupsEwillEbeEanalysedE
usingEchi-squaredEtest.EMissingEdataEwillEbeEexcluded.EResultsEwillEbeEpresentedE
inEtableE3b.E
9.6.5. Efficacy of blinding 
TheElevelEofEagreementEbetweenEtheEefficacyEofEblindingEreportedEatE24EweeksEbyE
theEparticipantEandEtheEresearchEnursesEwillEbeEcalculatedEusingEaEweightedE
KappaEstatistic.EMissingEdataEwillEbeEexcluded.EResultsEwillEbeEpresentedEinEtableE
3b.E
9.6.6. Adverse events 
AllEadverseEeventEdataEcollectedEonEtheEformEXEwillEbeEreportedEandEcodedEtoE
ICD10-AMEcriteria.EAllEsafetyEdataEwillEbeEsummarizedEinEtheEformEofEfrequencyE
distributions,EdescriptiveEstatistics,EandEtabulations.EThisEincludesEadverseE
eventsE(seriousEandEnon-serious),EforEtheEdurationEofEtheEstudy.E
AdverseEeventEcountsEbyEnumberEofEeventsEandEpeopleEwillEbeEsummarisedEinE
tableE4a.ESeparateEtablesEwillEbeEgivenEforEgeneralEcategories,EandEforEtheE
detailedEcodes.ETableE4bEwillEsummariseEtheEadverseEeventEcountsEbyE
categoriesEcollectedEinEformEXE(typeEandErelationshipEtoEstudyEtreatment),EandE
separateEtablesEwillEalsoEbeEgivenEforEtheEincidenceErateEratiosEandEincidenceE
densityEcomparingEtheEtwoEtreatmentEgroups.ELineElistingsEwillEalsoEbeEproducedE
inEorderEtoEexamineEadverseEeventsEthatEareEseriousEandErelatedEtoEtreatment,E
multipleEadverseEeventsEforEaEparticipantEonEtheEsameEdateEandEbleedingE
adverseEevents,EseeEtablesE4cEtoE4e.E
10. DATA SAFETY AND MONITORING BOARD
TheEDataESafetyEandEMonitoringEBoardE(DSMB)EwillEbeEresponsibleEforEsafeguardingEtheE
interestsEofEtrialEparticipants,E assessingEtheEsafetyEofEtheEinterventionEduringEtheEtrial,E
andEmonitoringEtheEoverallEconductEofEtheEclinicalEtrial.ETheEDSMBEwillEmeetEeveryE6E
monthsEwithEtheEscopeEforEadditionalEmeetingsEshouldEtheEDSMBEdeemEitEnecessary.E
TheEfirstEmeetingEwillEtakeEplaceEbeforeEtheEtrialEtoEconsiderEtheEDSMBEcharterEandEthisE
SAP.ETheEsecondEmeetingEwillEtakeEplaceE6EmonthsEafterEtheEfirstEpersonEhasEbeenE
randomisedEintoEtheEstudy.E
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The purposes of each meeting are: (1) to monitor the safety of the intervention during 
the trial for all adverse events and serious adverse events defined by study protocol; (2) 
to review withdrawals. The DSMB will be advisory to the study SC. The SC will be 
responsible for promptly reviewing the DSMB recommendations, to decide whether to 
continue or terminate the trial, and to determine whether amendments to the protocol or 
changes to the study conduct are required.
Only closed sessions will be held which will involve the DSMB members and the study 
statistician. For each DSMB meeting the study statistician will put together blinded 
closed reports that contain the treatment group ID and send to the DSMB members. 
The key to treatment group ID is kept in an Oracle treatment table and is only 
accessible to the Lead Data Manager or delegate. The Lead Data Manager or delegate 
will access the Oracle treatment table and provide to the DSMB members separately 
the key to the treatment group ID. In this way the study statistician will remain blinded to 
the reports provided to the DSMB and the Lead Data Manager will not have access to 
the DSMB report. The report will contain the following results: participant accountability, 
baseline characteristics, concomitant medications, analysis of proportion ulcers healed 
and ulcer area at 24 weeks (to be included from the third DSMB meeting to allow for 
sufficient data), and all adverse event tables. 
Note analysis of proportion ulcers healed and ulcer area at 24 weeks have been 
included in the DSMB report, even though they are secondary outcomes. It is 
conceivable that aspirin would worsen wound healing enough to be a safety concern, or 
that tolerance of treatment would be poor enough to make the trial results uninformative. 
The report should provide information that is as accurate as possible, however as the 
data will not have been locked there may be outstanding queries. The reports should be 
sent to DSMB members at least one week prior to the date of the meeting. 
For full details of DSMB and content of study reports see following documents: 
•
Aspirin4VLU DSMB charter.doc
•
Aspirin4VLU DSMB table templates.xis
11. PEER REVIEW
The statistical analysis and report for the primary outcome will be peer reviewed by an 
independent member of the NIHI Biostatistics team (not involved in the study). 
12. BUDGET
Level of involvement and engagement of statistical analyses as well as details 
prepared in the statistical report will depend on the study budget for Biostatistics team. 
Please note that for any additional analysis that is not specified in this statistical 
analysis plan or beyond the given budget, additional allowance will be required for 
further analyses in consultation with the principal investigator and/or operations 
manager. 
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13. DISSEMINATION
At-the-end-of-study-(after-data-lock),-all-planned-statistical-analysis-will-be-carried-out.-A-
statistical-analysis-report-will-be-produced-to-summarise-the-main-findings.-ANNEX-
tables-will-be-attached-to-present-all-detailed-results.-
The-study-statistician-will-therefore-take-full-responsibility-on-this-report-(provided-in-
PDF-format)-and-attached-tables-(read-only).- The-study-statistician-does-not-take-any-
responsibility-for-any-modifications-made-in-the-interpretation,-conclusions,-or-
tables/figures-beyond-those-presented-in-statistical-analysis-report.-
Note-that-the-purpose-of-the-statistical-report-(produced-from-the-analyses-specified-in-
this-plan)-is-to-present-the-results-and-assist-the-client-(internal-or-external)-to-interpret-
the-findings.- It-is-not-meant-to-be-used-for-further-dissemination.-
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APPENDIX I: LIST OF TABLE TEMPLATES 
Section 1. Randomisation and baseline information 
Table 1a. Participant accountability 
Table 1 b. Baseline variables 
Section 2. Descriptive summary of follow-up data 
Table 2a. Concomitant medication counts 
Table 2b. 24 week endpoint assessment 
Section 3. Analysis 
Table 3a. Primary outcome analysis 
Table 3b. Secondary outcome analysis (binary) 
Table 3c. Secondary outcome analysis (continuous) 
Section 4. Adverse events 
Table 4a. Adverse event counts 
Table 4b. Adverse events by categories and analysis 
Table 4c. Line listing of adverse events that were related to treatment and serious 
Table 4d. Line listing of multiple adverse events for a participant on the same date 
Table 4e. Line listing of bleeding adverse events 
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