A Randomised Clinical Trial to Compare Early Versus Delayed Endovenous Treatment of Superficial Venous Reflux in Patients With Chronic Venous Ulceration
Phase: NA
Conditions: Venous Leg Ulcer
Sponsor: Imperial College London

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
1 
 
  
 
 
 
EVRA (Early Venous Reflux Ablation) ulcer trial 
 
A randomised clinical trial to compare early versus 
delayed endovenous treatment of superficial venous 
reflux in patients with chronic venous ulceration.  
 
Version 5.0, 06/04/2017 
MAIN SPONSOR: Imperial College London (Sponsor Number 13HH0722) 
ISRCTN02335796 
STUDY COORDINATION CENTRE: Imperial College Trials Unit 
NRES reference: 13/SW/0199 
IRAS Ref: 131153.   UK CRN Study ID: 15078 
 
 
 
Authorised by:          Name: 
Professor Alun H Davies 
 
 
 
 
 
 
 
 
 
 
Date  
 
11/05/2017 
Signature  

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
2 
 
Revision History 
 
Protocol Version 
Date  
Amendments 
V5.0 
06/04/2017 
To incorporate the HTA funding extension to the trial to allow 
for the collection of longer term follow-up during October 2018 
and March 2019 
Amendments to the health economics section to clarify some 
items which were unclear in the previous version, and update 
the protocol to reflect new NIHR guidelines. 
V4.0 
16/03/2016 
To correct sample size from 500 participants to 450 participants 
which was originally calculated erroneously 
To allow for a reduction in the number of photo verification 
visits performed if the core lab confirms the ulcer is healed. 
V3.0 
10/03/2014 
Amended in order to display posters, leaflets and disseminate 
patient information sheets in primary care sites 
V2.0 
06/01/2014 
A clearer definition of ulcer healing is required to clarify that 
healing cannot be assume if a scab is present. 
Statistics and Data Analysis’ section amended for clarity of per-
protocol analyses. 
Serious adverse event (section 8.2) amended for clarity. 
Section 5.4 amended to clarify that patients can be offered 
intervention in the standard care (compression arm) if their 
ulcer has not healed at 6 months. 
V1.0 
19/06/2013 
 
N/A – Original Protocol 
 
Study Management Group  
Chief Investigator: Professor Alun H Davies 
Co-investigators: Mr Manjit S Gohel, Mr Richard Bulbulia, Mr Keith R Poskitt, Professor 
Andrew Bradbury, Professor Nicky Cullum, Miss Sophie R Renton, Mr I Nyamekye 
Statistician: Dr Jane Warwick 
Health economist: Dr David Epstein 
Study Management: Miss Francine M Heatley 
Study Coordination Centre  
For general queries, supply of study documentation, and collection of data, please contact:  
Study Coordinator: Miss Francine M Heatley 
Address: Vascular Surgery Research Group, Room 4E3, 4th Floor East Wing 
Charing Cross Hospital, Fulham Palace Road, London W6 8RF 
Tel: 020 3311 7371 
E-mail: f.heatley@imperial.ac.uk 
Web address: www.evrastudy.org 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
3 
 
 
Clinical Queries  
Clinical queries should be directed to either the Local PI or the Study Coordinator who will 
direct the query to the appropriate person  
 
Sponsor  
Imperial College London is the main research Sponsor for this study. For further information 
regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at:  
Joint Research Compliance Office  
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 1872  
 
This protocol describes the EVRA study and provides information about procedures 
for entering participants. Every care was taken in its drafting, but corrections or 
amendments may be necessary. These will be circulated to investigators in the study. 
Problems relating to this study should be referred, in the first instance, to the Chief 
Investigator.  
This study will adhere to the principles outlined in the NHS Research Governance 
Framework for Health and Social Care (2nd edition). It will be conducted in compliance 
with the protocol, UK Clinical Trials Regulations, the Data Protection Act and other 
regulatory requirements as appropriate.  
 
 
This project is funded by the National Institute for Health Research HTA (project 
number 11/129/197). The views and opinions expressed therein are those of the 
authors and do not necessarily reflect those of the HTA, NIHR, NHS or the 
Department of Health. 
 
 
 
 
 
 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
4 
 
 
 
 
 
 
ABBREVIATIONS 
 
AE 
Adverse Event 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
ICTU 
Imperial Clinical Trials Unit 
REC 
Research Ethics Committee 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSC 
Trial Steering Committee 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
5 
 
1. INTRODUCTION  
1.1 BACKGROUND  
Chronic leg ulcers are open “sores” on the lower limbs situated between the ankles 
and knees, which fail to heal within 6 weeks. These ulcers represent a source of 
great discomfort and social isolation to patients who often complain of associated 
pain, odour and wound discharge. The time taken for the ulcers to heal means that 
the condition is also particularly frustrating to health carers involved in their 
management in hospital and community settings. The underlying cause of leg 
ulceration in over 70% of cases is lower limb venous dysfunction, sometimes evident 
as varicose veins but often undetectable by visual examination alone1. The 
estimated overall prevalence of active venous ulceration is as high as 1.5 to 1.8 per 
1000 population, increasing to 3.8 per 1000 population in those over 40 years of 
age23. As patients with venous ulceration usually suffer episodes of recurrence 
between periods when the ulcer remains healed, the number of patients with a high 
risk of ulceration may actually be 4-5 fold higher4. It should also be noted that with an 
aging and increasingly obese population5, the incidence and prevalence of venous 
ulceration are both likely to increase. Treatment of the condition in the UK produces 
a substantial cost burden estimated at £400-600 million per annum6. 
Venous ulcers are characterised by protracted healing times. Despite some recent 
advances in the management of patients with venous ulcers, 24 week healing rates 
in published randomised trials are around 60-65%78, and the true population healing 
rates are likely to be significantly lower. Some patients may never heal and those 
that do heal are at high risk of recurrent ulceration. These poor outcomes are likely 
to be a reflection of the severe underlying venous dysfunction in this patient group, 
although inadequate assessment and suboptimal treatment are also likely to be 
important contributing factors. 
1.1.1 Pathophysiology of venous ulceration 
The venous circulation of the lower limb has two components, the deep and 
superficial systems. Blood normally flows from the superficial to the deep veins and 
is prevented from flowing back down the leg under the influence of gravity by ‘one-
way’ valves along the veins. When these valves become incompetent (leaky), the 
superficial veins usually become dilated and tortuous (varicose) and the resulting 
sustained high venous and capillary pressures lead to skin inflammation and 
ulceration (breakdown of skin). The deep veins also have valves, which may also 
become incompetent, but are not visible on the skin. Duplex ultrasound studies91011 
on patients in leg ulcer clinics suggest that: 
 Around 50% of patients with venous leg ulcers have diseased superficial veins 
alone, with a further 30-40% having a mixture of superficial and deep venous 
disease. Both of these groups of patients benefit from correction of their 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
6 
 
superficial venous reflux, which has been shown to reduce the risk of ulcer 
recurrence12. 
 A minority (5-10%) of patients with venous ulcers have diseased deep venous 
systems only, and are not amenable to surgical correction. These patients are 
usually treated with compression bandaging alone 
Ulcer healing strategies are based on efforts to reduce this leakage (reflux) of blood 
back down the leg and into the skin, as this is considered the most significant cause 
of high venous pressure in most patients. Longstanding venous hypertension has 
been shown to cause a number of changes to the microcirculation in the lower leg, 
which can contribute to the chronic skin changes or eventual ulceration associated 
with chronic venous disease13. Compression bandaging to the leg (which may need 
to be re-applied 1-4 times per week) counteracts the gravitational force on the blood, 
in effect temporarily replacing the incompetent valves14. Diseased superficial veins 
can be surgically removed (open varicose vein surgery) or ablated using 
endovenous interventions (see below) without harming the overall venous function of 
the leg, theoretically removing a causative factor for recurrence of the ulcer after the 
compression bandaging has ceased. The deep vein defects are not generally 
amenable to surgery. 
1.1.2 Treatment options for superficial venous reflux 
For over a century, the treatment of superficial venous reflux has involved operative 
ligation and surgical stripping of the vein and avulsion of bulging varicose veins15. 
Until recent years, open surgery has been considered the definitive treatment option 
for superficial venous reflux. However, the operation usually requires general 
anaesthesia and patients often suffer discomfort, bruising and significant time off 
work in the post-operative period. Long-term studies have also identified significant 
complications of open surgery including nerve damage and recurrence of varicose 
veins, seen in over 60% of patients at 11 years in one randomised study16.  
In response to this high complication rate and a growing patient desire for less 
invasive treatments, a range of novel, minimally invasive endovenous treatment 
options have been developed and have gained in popularity over the last decade. 
Interventions such as ultrasound guided foam sclerotherapy (UGFS)17, endovenous 
laser (EVLA)18 or radiofrequency ablation (RFA)19 can be performed using local 
anaesthesia in an outpatient setting. These treatments involve cannulation of the 
vein to be treated (usually under ultrasound guidance) and obliteration of the venous 
channel by either chemical ablation (using foam sclerosant), or thermal ablation 
(using a laser or radiofrequency fibre). Numerous randomised studies have 
demonstrated that endovenous modalities are, at worst, comparable to open surgery 
in terms of recurrence (and likely to be better), but clearly superior in terms of pain, 
bruising and other early complications20-22. Each of the different endovenous 
modalities has advantages and potential disadvantages, although all are less 
invasive than traditional open surgery. This is of particular relevance to patients with 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
7 
 
chronic venous ulceration, who are often elderly, have extensive co-morbidities and 
may be reluctant to undergo surgical procedures involving general anaesthesia. 
Endovenous techniques can also be performed without discontinuing anti-
coagulation therapy, which is increasingly prescribed in this patient population. 
1.1.3 Summary of current research 
The most significant study of superficial venous intervention in patients with venous 
ulceration is the ESCHAR study (Barwell, Poskitt; Lancet 2004 & Gohel, Poskitt; 
BMJ 2007)712. The study aimed to evaluate the role of traditional superficial venous 
surgery in reducing ulcer recurrence in patients with open or recently healed venous 
ulcers. Following prospective observational studies to inform power calculations, a 
total of 500 patients were randomised to compression therapy alone or compression 
with open surgery for superficial venous reflux. The group randomised to surgical 
treatment had significantly lower venous ulcer recurrence rates at 4 years (Figure 1).  
Analysis stratified by pattern of venous reflux demonstrated that this clinical benefit 
was present for patients with isolated superficial venous reflux and patients with 
superficial and segmental deep reflux. This clearly indicated that the majority of 
patients with chronic venous ulceration could benefit from superficial venous 
intervention. As a result, the current optimal management of patients with venous 
ulceration includes the treatment of refluxing superficial veins to reduce the risk of 
ulcer recurrence23.  
Analysis of ulcer healing within the ESCHAR trial demonstrated that there was no 
significant improvement in ulcer healing rates for the group randomised to 
compression plus surgery (Figure 2). This finding has led many to conclude that 
treatment of venous reflux does not have a role in patients with open ulcers.  
 
 
 
 
 
 
 
 
 
However, the ESCHAR study was designed and powered to assess ulcer recurrence 
rather than healing, and the statistical power of this trial was further weakened by a 
high cross-over rate, as around a quarter of patients randomised to surgery 
subsequently refused to have an operation. This highlights the need for a minimally 
invasive superficial venous treatment modality in this patient group. In addition, the 
Figure 1. ESCHAR trial – ulcer 
recurrence 
Figure 2. ESCHAR trial – ulcer 
healing 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
8 
 
median time to treatment within the study was around 2 months, by which time 
smaller ulcers may have already healed with compression bandaging, and, in many 
cases, the surgical procedures used were suboptimal when judged by current 
standards. Consequently, it is plausible that the benefits of treating superficial 
venous reflux were underestimated in this study, particularly for the assessment of 
ulcer healing.  
In a smaller Dutch randomised trial, 170 patients (200 legs) were randomised to 
compression alone or compression with surgical treatment of superficial reflux 
(including subfascial endoscopic perforator surgery – SEPS)8. Although results did 
not reach statistical significance, there was a clear trend towards improved ulcer 
healing rates and greater ulcer free time in the group randomised to surgery.  
Despite the widespread acceptance of endovenous modalities, few prospective 
studies have been published reporting outcomes after endovenous treatment in 
patients with leg ulcers. In a prospective study of 186 patients with leg ulceration 
treated with UGFS, the ulcer healing rate was over 70% and the patient acceptability 
of treatment was excellent (Poskitt et al)24. In a further study of foam sclerotherapy in 
130 patients, a healing rate of 82% was achieved (Bradbury et al)25. Whilst these 
small non-randomised studies lend support to our hypothesis that early intervention 
to correct superficial venous reflux will promote ulcer healing, a large randomised 
trial is required to provide reliable evidence and thus change practice. 
 
1.2 RATIONALE FOR CURRENT STUDY 
Whilst the management of patients with venous ulcers has evolved in recent years 
and ulcer healing and recurrence rates have shown some improvement, we believe 
that there is a strong argument in favour of this study at this time for the following 
reasons: 
 The prevalence of venous ulceration is likely to increase, particularly with an 
aging and increasingly obese population. In view of the significant financial and 
psychosocial costs of venous ulceration, it is imperative that the optimal 
treatment strategies are identified.  
 Despite numerous studies of topical ulcer treatments, the only treatment shown 
to improve venous ulcer healing is compression bandaging. Compression 
supports the venous circulation, but is poorly tolerated by some patients and 
does not address the underlying problem of venous reflux. The intervention in this 
proposal involves treating the underlying anatomical venous disorder using 
effective, minimally invasive endovenous interventions and offers a logical, 
deliverable and long-term approach to reducing venous hypertension.   
 The treatment of superficial venous reflux has been transformed in recent years 
through the widespread use of minimally invasive, endovenous interventions, 
which patients find more acceptable than traditional open surgery. 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
9 
 
 Ablation of superficial reflux should be considered in all patients with leg ulcers 
and superficial venous reflux, but if early intervention is associated with moderate 
improvements in ulcer healing compared to deferred intervention (i.e. post-
healing), significant cost savings could be realised.  
 Patients find venous leg ulcers painful, distressing and a significant inhibition to 
normal, independent life. Interventions to reduce the time to healing could reduce 
patient distress and significantly improve quality of life.  
Therefore, we believe that there is a cogent argument for conducting this trial at this 
time. Non-randomised studies suggest that outcomes may be improved by treating 
underlying superficial reflux using the latest technologies, but there is no robust 
evidence to support early intervention. The research team has a strong track record 
in relevant research areas and includes clinicians and researchers who successfully 
completed the landmark clinical trial on which this proposal is based (ESCHAR trial), 
and numerous other high impact clinical trials evaluating treatments in venous 
ulceration. 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
10 
 
2. OBJECTIVES 
2.1 PRIMARY OBJECTIVE 
To determine the clinical and cost effectiveness of early endovenous treatment of 
superficial venous reflux in addition to standard care compared to standard care 
alone in patients with chronic venous ulceration. 
 
2.2 SECONDARY OBJECTIVES 
To investigate: 
 The ulcer free time to 1 year and with the extension, up to 5 years (median of 
approximately 3.7 years) 
 The technical success of endovenous interventions 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
11 
 
3. PARTICIPANT ENTRY  
3.1 PRE-REGISTRATION EVALUATIONS  
Prior to commencing, information will be disseminated to GP practices in each 
recruiting region and meetings will be arranged with key community nursing staff and 
at leg ulcer clinics to promote the trial. Patients will be referred to secondary care as 
part of the standard care pathway as per the July 2013 NICE Guidelines. To aid 
recruitment, selected Primary Care trusts not currently involved in the trial will be set-
up as Patient Identification Centres (PIC sites) displaying posters, leaflets and 
disseminating patient information sheets to patients.  Selected Primary Care trusts 
involved in follow-up of the trial (research sites) will also aid recruitment by displaying 
posters, leaflets and disseminating patient information sheets to patients. Patients 
will still need to be referred to the secondary care recruiting sites to be consented 
and randomised into the trial.   
At the referral visit patients will be given an appropriate time period to consider 
participation (at least 24 hours). Written consent will be obtained from those patients 
who agree to participate and randomization will be performed using the online 
service. For patients randomised to endovenous ablation of superficial venous reflux, 
a date for intervention will be booked as soon as possible (i.e. within 2 weeks). At 
each recruiting centre, an online log of all screened patients will be kept using the 
InForm system. Basic demographic data and reasons for non-eligibility will be 
recorded. Whilst participant baseline characteristics may vary slightly across 
recruiting sites, randomised treatment allocation will allow reliable assessment of the 
effects of early versus delayed endovenous ablation in ulcer healing. 
3.2 INCLUSION CRITERIA  
 Current leg ulceration of greater than 6 weeks, but less than 6 months duration 
 Able to give informed consent to participate in the study after reading the patient 
information documentation 
 Patient age > 18 years 
 Ankle Brachial Pressure Index (ABPI) ≥ 0.8 
 Superficial venous disease on colour duplex assessment deemed to be 
significant enough to warrant ablation by the treating clinician (either primary or 
recurrent venous reflux) 
Patients who cannot speak / understand English will be eligible for inclusion and 
informed consent will be obtained with assistance from translation services as per 
standard clinical practice. In view of the lack of cross-cultural validation for quality of 
life tools, only healing outcome data will be collected. 
3.3 EXCLUSION CRITERIA  
 Presence of deep venous occlusive disease or other conditions precluding 
superficial venous intervention (at the discretion of local research team) 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
12 
 
 Patients who are unable to tolerate any multilayer compression bandaging / 
stockings will be excluded. However, concordance with compression therapy can 
be variable for patients at different times. Patients who are generally compliant 
with compression, but unable to tolerate the bandages for short periods will still 
be eligible to inclusion. A period of non-compliance with compression bandages 
will not be considered a protocol violation, but a normal variation within the 
spectrum of ‘standard therapy’.  
 Inability of the patient to receive prompt endovenous intervention by recruiting 
centre 
 Pregnancy (female participants of reproductive age will be eligible for inclusion in 
the study, subject to a negative pregnancy test prior to randomisation) 
 Leg ulcer of non-venous aetiology (as assessed by responsible clinician) 
 If patient is deemed to require skin grafting they cannot be included 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
13 
 
4. STUDY DESIGN  
The EVRA ulcer trial is a pragmatic; multicentre randomised clinical trial with 
participants randomised1:1 to either: 
1. ‘Standard’ therapy consisting of multilayer elastic compression bandaging/ 
stockings with deferred treatment of superficial reflux (usually once the ulcer has 
healed) 
2. Early endovenous treatment of superficial venous reflux(within 2 weeks) in 
addition to standard therapy 
The study design is summarised in Figure 3 below.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
14 
 
4.1 PATIENT RANDOMIZATION 
The normal clinical team will make initial contact with potentially eligible patients at 
the referral visit.  
Those who consent will be registered on the InForm ITM (Integrated Trial 
Management) System, a web-based data entry system, which is maintained by ICTU, 
and their eligibility for the study confirmed.  A randomization list will be loaded onto 
the InForm system for each centre (as stratification will be by centre) before 
recruitment commences, having been prepared in advance by a statistician who is 
independent of the study. Each potential participant, if confirmed to be eligible, will 
be assigned the next available entry in the appropriate randomization list (i.e. without 
foreknowledge). Thereafter, treatment allocation will not be blinded (with the 
exception of assessment of ulcer healing – see 4.3.1). For patients with bilateral 
venous ulceration, the worst leg (according to the patient) will be designated the 
‘reference leg’. Interventions may be performed on both legs, if deemed appropriate 
by the responsible clinician. 
4.2 STUDY SETTING 
Eligible patients with chronic venous ulcers will initially be recruited from the 
following centres: 
1. Imperial College Healthcare NHS Trust (PI: Professor AH Davies) 
2. Cambridge University Hospitals NHS Foundation Trust (PI: Mr MS Gohel) 
3. Worcestershire Acute Hospitals NHS Trust (PI: Mr I Nyamekye) 
4. North West London Hospitals NHS Trust (PI: Miss SR Renton) 
5. Gloucestershire Hospitals NHS Foundation Trust (PI: Mr KR Poskitt) 
6. Heart of England NHS Trust (PI: Professor A Bradbury) 
7. University Hospital Birmingham NHS Trust (PI: Mr Rajiv Vohra) 
8. City and Sandwell NHS Trust (PI: Miss Rachel Sam) 
9. The Dudley Group NHS Trust (PI: Mr Andrew Garnham) 
10. The Royal Wolverhampton Hospitals NHS Trust (PI: Mr Andrew Garnham) 
11. York Hospitals NHS Foundation Trust 
12. Hull & East Yorkshire Hospitals NHS Trust 
13. The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust 
14. Frimley Park Hospital NHS Foundation Trust 
15. Plymouth Hospitals NHS Trust 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
15 
 
16. Bradford Teaching Hospitals NHS Foundation Trust 
17. Salisbury NHS Foundation Trust 
18. Leeds Teaching Hospitals NHS Trust 
19. Sheffield Teaching Hospitals NHS Foundation Trust 
20. Taunton and Somerset NHS Foundation Trust  
As per section 3.1 Primary Care Trusts will be set-up as either PIC sites or research sites 
aiding recruitment by displaying posters, leaflets and disseminating patient information 
sheets. Patients will still need to be referred to the secondary care recruiting sites to be 
randomised into the trial.   
4.3STUDY OUTCOME MEASURES 
4.3.1 Primary outcome measure 
The primary outcome measure will be time to ulcer healing (from date of 
randomization to date of healing). For the purposes of this study, ulcer healing is 
defined as complete re-epithelialisation of all ulceration on the randomised 
(reference) leg in the absence of a scab (eschar) with no dressing required. 
Community or hospital healthcare staff, depending on the local model of care, will 
perform assessment of ulcer healing.  
Data on the status of the reference leg will be collected throughout the study by 
research staff scrutinising community medical / nursing records and contacting the 
patient / community nursing teams by telephone(on a monthly basis at least). 
If either the community nursing / medical staff or the patient believe that ulcer healing 
has been achieved, they will be asked to contact the local research centre 
immediately. This notification of possible ulcer healing will constitute a ‘trigger’ forth 
research staff at the recruiting centre to arrange an urgent verification assessment 
by a member of the healthcare team (within 1 week). 
Verification will be by clinical assessment and digital photography, to be repeated 
weekly for 4 weeks, unless otherwise agreed by the trial manager. The digital 
images will be evaluated by two blinded expert assessors in order to ascertain the 
date of healing, which will be considered the primary healing end-point. For the 
purposes of the trial healing will be defined as the complete re-epithelialisation of the 
ulcerated (reference) leg in the absence of a scab (eschar) with no dressing required. 
Healing cannot be assumed if a scab present.  
Disagreements will be resolved through discussion with involvement of a third 
blinded expert reviewer if necessary. This approach will be applied to patients in both 
treatment arms and is consistent with the methods utilized in other large HTA funded 
leg ulcer trials (e.g. VenUS IV). Legs deemed to have an open ulcer on clinical 
assessment would continue within the study. If healing is confirmed by clinical and 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
16 
 
blinded photograph assessments at the first verification visit, the date of healing 
notification (by patient or community nurse) will be taken as the date of ulcer healing. 
4.3.2 Secondary outcome measures 
A number of secondary outcome measures will be evaluated in the EVRA study: 
1. Ulcer Healing Rate: Healing rate will be reported at 24 weeks in addition to time 
to ulcer healing to allow comparison with other published studies.  
2. Ulcer recurrence / Ulcer Free Time: Will be calculated up to 1 year for each study 
arm and with the extension, up to 5 years (median approximately 3.7 years). This 
will allow a very practical and easily understood assessment of the clinical 
difference between the 2 arms of the study. This will also allow comparison with 
other studies that have reported this outcome. In order to facilitate accurate 
calculation of reoccurrence / ulcer free time, clinical follow up will be continued 
after ulcer healing up to 1 year after randomisation. 
3. Quality Of Life (QoL): Disease specific (AVVQ) and generic (EQ5D & SF36) 
quality of life assessments will be compared at 6 weeks post randomisation, 6 
months, 12 months and at one time point between October 2018 and March 2019. 
The 6-week questionnaire will be given to the patient at the follow-up 
appointment, whereas other QoL questionnaires will be sent to the patient or 
completed by the patient via telephone. AVVQ is the most widely utilised disease 
specific QoL tool in venous disease and has been extensively validated. A score 
out of 100 points is calculated, with a higher score indicating more severe QoL 
impairment. Changes in QoL scores will offer a comparison with other studies 
and, in the standard treatment arm, will allow an assessment of the natural 
history of venous ulceration treated with compression.  
4. Health Economic Assessment: A within-RCT cost effectiveness analysis will be 
carried out based on the data collected in the trial, Resource use items in hospital 
and community care related to the treatment of venous ulceration or 
complications will be recorded for each patient at each follow-up. Resource use 
will be multiplied by UK unit costs obtained from published literature, HRG costs, 
and manufacturers’ list prices to calculate overall costs. A standard tariff will be 
applied for each bandage change. Utilities (QALYs) will be calculated from the 
EQ-5D questionnaire administered to patients at baseline, 6 weeks, 6 months, 12 
months and at one time point between October 2018 and March 2019. The extent 
of missing data will be assessed and appropriate methods to handle missing data 
will be applied if necessary.  The incremental cost-effectiveness ratio will be 
calculated and compared to current UK decision making thresholds. Discounting 
will be applied at the standard rate. Sensitivity analysis will be carried out to test 
the robustness of results to alternative assumptions (for example, about missing 
data, or using per-protocol estimates of treatment effect) or alternative data (for 
example, about unit costs). Probabilistic sensitivity analysis will be carried out 
using bootstrapping. A decision model will also be constructed to take account of 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
17 
 
outcomes (such as recurrence or healing) that might occur beyond time horizon 
of the RCT, or to take account of other relevant comparators in this patient group.    
5. Other Markers of Clinical Success: The Venous Clinical Severity Score (VCSS) 
will be assessed at 6 weeks. In addition, the incidence of complications related to 
the endovenous intervention as well as the presence of residual / recurrent 
varicose veins will also be assessed at 6 weeks in the early arm.  
 
 
 
 
4.4 DURATION OF FOLLOW-UP 
In the original study, participants were to be followed-up until either: 
1. 1 year post-randomization 
2. Patient choice to withdraw from the study. Patients who no longer wish to 
complete quality of life questionnaires will be asked if they would object to the 
use of healing status data (to contribute to the primary outcome) 
3. Death 
In order to allow assessment of ulcer free time to 1 year, patients with healed ulcers 
were to be evaluated using telephone follow-up (performed by staff at the recruiting 
centre) on a monthly basis until 1 year. The aim of the telephone follow-up was to 
confirm that the ulcer remains healed, or in cases of ulcer recurrence, to ascertain 
the date of recurrence and of subsequent healing.  
In December 2016 The HTA approved an extension to the trial follow-up allowing the 
collection of follow-up data for all patients who have not withdrawn consent to the 
trial. Data collection will commence in October 2018, allowing a median follow-up 
period of up to 5 years (median approximately 3.7 years) to be obtained (further 
details given in section 6.6). 
 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
18 
 
 
4.5 STUDY DURATION 
The EVRA study will take 70 months to complete. The revised study timetable is summarised in Figure 4. 
 
 
 
 
 
 
 
 
 
 
Figure 4. EVRA Study timeline

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
19 
 
5. DETAILS OF INTERVENTIONS 
5.1 VARIATIONS IN ENDOVENOUS INTERVENTIONS 
A wide range of endovenous treatment modalities are now available and in 
widespread use for the ablation of superficial venous reflux. These include: 
 Endovenous thermal ablation using laser or radiofrequency 
 Ultrasound guided foam sclerotherapy (UGFS) 
 Other endovenous interventions such as mechanochemical ablation, steam 
ablation and glue 
 Any combination of the above treatments 
In addition to the different modalities in use, the treatment strategy may also vary 
between institutions and between individual clinicians within the same department. 
Variations may occur in: 
 Site of vein cannulation (and therefore the length of vein ablated) 
 Location of treatment (‘office’ or clinic based versus operating theatre) 
 Treatment strategy for sub-ulcer venous plexus (to ablate or not) 
 The treatment of visible varicose veins (no treatment, UGFS or surgical 
avulsion) and the timing of any intervention 
5.2 STANDARDISATION OF INTERVENTIONS IN EVRA STUDY 
With the lack of consensus on a single, optimal endovenous treatment strategy for 
superficial reflux in patients with leg ulceration, perfect standardisation of 
interventions will be impossible. All endovenous interventions should be performed 
as deemed to be ‘optimal’ by the treating clinician for each individual patient, with the 
following stipulations: 
1. The endovenous strategy must include ablation of the main truncal venous 
reflux 
2. Truncal venous reflux should be treated to the lowest point of incompetence, 
where possible 
3. Significant (as deemed by the treating clinician) residual / recurrent superficial 
reflux on the 6 week duplex scan, should be ablated 
4. Patients should continue with multilayer compression / stockings immediately 
after treatment 
5.3 
STANDARDISATION OF COMPRESSION 
Patients will receive the standard compression used in the individual centres prior to 
ulcer healing following randomisation (this will include four layer bandaging, three 
layer bandaging, European short stretch, stockings). Post healing the patients will be 
given compression hosiery in line with local policy.   

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
20 
 
5.4 
FURTHER TREATMENT FOR STANDARD CARE (COMPRESSION 
ALONE) ARM 
Patients randomised to multilayer compression / stockings alone can be offered 
endovenous treatment of superficial reflux once healing has been confirmed or at 6 
month post randomisation (see 4.3.1). Endovenous ablation should be performed as 
per standard practice in the treating centre and details of this will be recorded. 
Endovenous intervention may also be offered if there is clinical deterioration in the 
active leg ulcer and it is clinically felt that the patient may benefit from early 
intervention. This will be recorded on the electronic case report form. 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
21 
 
6. ASSESSMENT AND FOLLOW-UP  
6.1 PATIENT IDENTIFICATION 
Patients will be referred to secondary care for evaluation of the management of their 
leg ulcer as part of the standard pathway of care. 
6.2 REFERRAL VISIT 
At the initial visit the patient will be evaluated by clinical assessment and colour 
duplex examination, which is part of the normal investigation of a patient with leg 
ulceration. Dependant on the results of these tests, the patient will be asked if they 
would consider taking part in the trial and approached for consent. The patient will be 
given a minimum of 24 hours to consider the trial and if willing to participate will 
return to the leg ulcer clinic to give consent and undergo a baseline visit.  
6.3 BASELINE VISIT 
Patients will undergo detailed clinical assessment by the research nurse as part of 
the baseline evaluation (see Appendix 1). Recorded assessments will include: 
 Demographic details (age, sex, ethnicity) 
 Pregnancy test for woman of child bearing potential 
 General clinical details (body mass index, ankle brachial pressure index – 
performed within previous 4 weeks, comorbidities, medication history) 
 Ulcer details (duration, progression, previous ulcer history, size of current ulcer – 
using photography and planimetry) 
 Details of venous disease (previous deep vein thrombosis, previous venous 
interventions, pattern of venous reflux on duplex) 
Additional assessments will include: 
 Assessment of Clinical, Etiologic, Anatomic, Pathophysiological (CEAP) score 
 Assessment of venous clinical severity score (VCSS) 
 Disease specific (Aberdeen varicose vein questionnaire – AVVQ) and generic 
(EuroQoL 5D – EQ5D & short form (SF) 36) quality of life assessments  
At this visit, eligible and consenting patients will be randomised into the trial. 
6.4 FOLLOW-UP ASSESSMENTS 
Randomised patients will undergo routine leg ulcer care in community or hospital (or 
both) settings, in accordance with the local standard. This will equate to wound 
reviews and dressing changes ranging between once and 4 times per week 
(depending on the ulcer). The exact nature of dressings and date of dressing change 
will be documented by the completion of patient diaries. This will allow an accurate 
record of the dressing types used and will be collected and verified by the research 
nurse. 
In addition, the following assessments will be conducted: 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
22 
 
6.4.1 6-week clinic visit 
 Clinical assessment 
 In the compression plus early venous reflux ablation group, venous duplex 
scanning will be performed at 6 weeks post-randomization to verify anatomical 
treatment success. Depending on the results of the scan, the decision to perform 
further superficial venous interventions will be left to the discretion of the 
responsible clinical staff. Irrespective of the number and timing of venous 
interventions, all analyses will be performed on intention to treat. 
 Wound tracing and photo 
 Assessments of disease specific and generic quality of life (AVVQ, EQ5D & SF36) 
by means of self-completed questionnaire 
 
6.4.2 Further follow-up 
 Assessments of disease specific and generic quality of life (AVVQ, EQ5D & SF36) 
by means of self-completed questionnaire at 6 months and 12 months post-
randomization (sent to the patient). 
 The research team will perform monthly telephone evaluation of the patient and 
access the community notes or telephone the community nurses in order to 
collect and verify the data collected. 
 Once the research team has been informed that the ulcer has healed the patient 
will undergo an urgent verification visit 
 
6.5 URGENT VERIFICATION VISIT 
 A member of the local research team will perform the four verification visits to 
confirm healing. Photographs will be taken and send to the Trials Unit for 
independent verification. In order to minimise inconvenience to the 
participants, once core labs confirms healing it is not necessary for the 
research team to perform further verification visits. Please note all four photos 
should be taken unless the trial manager confirms otherwise. 
 
6.6 LONGER TERM FOLLOW-UP 
For each randomised patient a single telephone assessment will be performed 
between October 2018 and March 2019 to collect: 
 Details of any further ulcer recurrence and healing events 
 Assessment of ulcer related healthcare attendances and costs 
 Details of all further venous interventions performed and any associated 
adverse events 
 Assessments of disease specific and generic quality of life (AVVQ, EQ5D & 
SF36) by means of self-completed questionnaire completed over the 
telephone (or via post) 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
23 
 
 
 
 
The research teams will also evaluate healthcare records to: 
 verify ulcer recurrence and healing events 
 obtain specific details about venous investigations and interventions 
performed including delays to intervention.  
 
No anatomical assessments of long-term treatment success are planned; however, 
additional treatments will be recorded and included in the health-economic 
evaluations. 
 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
24 
 
7. STATISTICS AND DATA ANALYSIS 
Data and all appropriate documentation will be stored for a minimum of 10 years 
after the completion of the study, including the follow-up period in accordance with 
the Imperial College JCRO Archiving Study Documents SOP.  
7.1 SAMPLE SIZE CALCULATION 
The sample size calculation for this study was based on the primary outcome of 
ulcer healing. The ESCHAR trial was a similar randomised study, which published 
the final results in 2007 (see 1.1.3). A total of 500 patients with open or recently 
healed venous ulcers were randomised to standard therapy alone or standard 
therapy plus open surgery for superficial venous reflux. The study was powered and 
designed to evaluate differences in ulcer recurrence (rather than healing). 
Consequently, the median time from randomization to treatment delivery was over 7 
weeks. Nevertheless, the 24-week healing rate in patients randomised to standard 
treatment (compression alone) was approximately 60%. Two recent prospective 
studies evaluating the early treatment of superficial venous reflux suggested that the 
24-week healing rate may be as high as 82%24 25.  
In order to calculate a sample size for this study, a benefit associated with early 
treatment is estimated at around 15%. Assuming the 24-week healing rate in the 
standard arm is 60%, to identify a difference in 24-week healing rates of 15% 
between the two groups (60% vs 75%) with 90% power and allowing for 10% 
dropout the study will therefore require 416 subjects (208 in each arm, 254 healed 
leg ulcers in total). To incorporate further allowances for protocol violations and 
unexpected dropouts, the target sample size will be 450 patients. 
Assuming a 15% drop out rate for the study and that 90% of primary ulcers 
eventually heal, it is estimated that >340 of the recruited 450 patients will be eligible 
for inclusion in the ulcer recurrence analysis. With this number of participants, and 
allowing for the healing rates (of the index ulcer prior to entry into this analysis of 
ulcer recurrence) to differ by up to 20% between the two study arms, the study 
extension will have at least 80% power to detect a difference of 15% or more in ulcer 
recurrence rates between the two arms at the 5% significance level.  
 
7.2 PLANNED ANALYSES 
No formal interim analyses are planned. Informal interim analyses will be performed 
if requested by the Data Monitoring Committee (DMC) but findings will be made 
available to member of the DMC only. Basic descriptive methods will be used to 
present the data on study participants, trial conduct, clinical outcomes and safety (in 
total and for each study group separately). The primary outcome will be time to 
complete healing. We will test the hypothesis that there is no difference in time to 
complete healing between the control and intervention groups using a log-rank test 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
25 
 
(two-tailed, 5% significance level). Kaplan-Meier survival curves will also be 
presented and we will perform a subsidiary analysis investigating the effect of study 
centre, participant age, ulcer size and chronicity on time to complete healing using 
Cox regression. To adjust for potential surgeon and centre effects, surgeon and 
centre will be included in the Cox regression analysis as random effects. All analyses 
will be on an intention-to-treat basis. If there is substantial cross-over, per-protocol 
analyses may be explored for sensitivity analyses. Safety and tolerability data will be 
presented by the two arms on an intention-to-treat basis. The statistical analysis plan 
(SAP) for the original trial (follow up to 1 year) will be finalised prior to the final 
analysis. An additional SAP for the extension follow-up (up to 5 years) will be 
finalised before the analysis of extension data. 
 
7.3 MISSING, UNUSED AND SPURIOUS DATA 
There will be no data imputation for missing data in the primary endpoint (time to 
healing) and the secondary endpoint of ulcer free time. Any imputation methods 
used may be proposed for purposes of sensitivity analysis for other secondary 
outcomes, including ulcer healing rate, QoL and markers of clinical success. 
Imputation methods will be fully documented in the SAP.  
7.4 DEVIATIONS FROM THE STATISTICAL ANALYSIS PLAN 
Any deviation(s) from the final statistical analysis plan in the final analysis will be 
described and justification given in the final report.  
 
7.5 
HEALTH ECONOMIC ANALYSIS 
The economic evaluation will be based on both a modelling exercise and a patient 
level in-trial analysis. The main analyses will be performed from the perspective of 
the NHS and Personal Social Services. Secondary analyses will be performed from 
a societal perspective. The price year will be 2017-18. Discounting will be applied 
according to UK Government guidelines. The study will be reported according to 
current guidelines for economic evaluation (CHEERS).  
The within-trial analysis will compare early versus delayed endovenous treatment of 
superficial venous reflux in patients with chronic venous ulceration, within the time-
horizon of the extended trial. Data will be collected by case note review and 
questionnaires completed at baseline, 6 weeks, 6 months,12 months and at a single 
time point during October 2018 and March 2019. Resource use items in hospital and 
community care related to the treatment of venous ulceration, adverse events or 
complications will be recorded for each patient at each follow-up. Resource use will 
be multiplied by UK unit costs obtained from published literature, Healthcare 
Resource Groups (HRG) costs, and manufacturers’ list prices to calculate overall 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
26 
 
costs. A standard tariff will be applied for each bandage change. Utilities (QALYs) 
will be calculated from the EQ-5D questionnaire administered to patients at each 
follow-up. The extent of missing data will be assessed and appropriate methods to 
handle missing data will be applied. The incremental cost-effectiveness ratio will be 
calculated and compared to current UK decision making thresholds. Sensitivity 
analysis will be carried out to test the robustness of results to alternative 
assumptions (for example, about missing data, or using per-protocol estimates of 
treatment effect) or alternative data (for example, about unit costs). Probabilistic 
sensitivity analysis will be carried out using bootstrapping. 
 
A decision model will also be constructed to take into account outcomes that might 
be expected to occur beyond the timeframe of the RCT (e.g. recurrence, healing), 
the results of other RCTs that have assessed early or delayed endovascular therapy 
for treating venous ulcers, or any relevant comparators that are not considered in the 
RCT (e.g. surgery, bandaging only). The health states used in the model will be 
based on the natural history of chronic venous ulcers, to be obtained from the trial, 
from the literature and from expert opinion. . The inputs for the model will be the 
transition rates for moving from one state to another, the relative risks for each 
treatment compared with usual care, and the costs and HRQOL associated with 
each health state. Use of secondary and primary care patient resource use and EQ-
5D responses associated with health states will be estimated mainly from the trial. 
Sensitivity analyses will be carried out to test the robustness of the model results to 
alternative assumptions and alternative data. Probabilistic sensitivity analysis will be 
carried out using Monte-Carlo simulation. 
 
7.6 
LOSSES TO FOLLOW-UP AND PROTOCOL VIOLATIONS 
The primary assessment involves intention-to-treat analysis. Therefore, strenuous 
efforts will be made to ensure that only patients willing to undergo either immediate 
or delayed superficial venous ablation and compression bandaging are randomised. 
Monthly reports of protocol violations will be provided by local sites to the trial 
coordinators, who reserve the right to suspend or exclude sites in the event of wilful 
protocol violations. Similarly, efforts will be made to obtain complete follow-up for all 
randomised participants (irrespective of whether or not they underwent allocated 
treatment). For those participants unable or unwilling to attend follow-up 
appointments, home-visits or follow-up by community nurses may be considered. 
A high rate of protocol violation was seen in previous trials of venous ulceration 
(including the ESCHAR trial). This is likely to reflect the reluctance and apprehension 
of elderly patients to undergo surgical interventions involving general anaesthesia. 
The modern management of superficial venous disease involves a range of 
minimally invasive, endovenous modalities that can be performed using local or no 
anaesthesia. Procedures are performed on an outpatient basis and can be 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
27 
 
completed in around 30 minutes. Published studies of endovenous interventions 
have demonstrated excellent patient satisfaction and few treatment refusals. Due to 
the published evidence and extensive personal experience among the research 
team, the rate of participation should be higher and rate of protocol violations lower 
than previous studies. 
 
The following will be recorded as protocol deviations: 
1) Patients randomised to multilayer compression / stockings plus early venous 
reflux ablation, who receive endovenous intervention more than two weeks 
from randomization. 
2) Patients who are non-compliant with compression bandaging, defined as use 
<75% of the prescribed duration. 
3) Patients randomised to compression bandaging alone who undergo 
endovenous ablation prior to verified healing. 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
28 
 
8. ADVERSE EVENTS  
8.1 REPORTING PROCEDURES  
During the first 12 months all serious adverse events and all intervention-related 
adverse events should be reported. Any serious adverse events reported at the 
October 2018 to March 2019 follow-up time point should be reviewed the Principal 
Investigator to assess whether they are related to the treatment pathway  and only 
related events should be reported to the sponsor via INFORM. Depending on the 
nature of the event the reporting procedures below should be followed. Any 
questions concerning adverse event reporting should be directed to the Chief 
Investigator in the first instance.  
8.2 RELATED ADVERSE EVENTS 
Patients randomised to early venous intervention have the potential risks of 
treatment. Competent, experienced medical staff will perform all procedures and 
every effort will be made to prevent adverse effects. The adverse events listed below 
are expected to be related to the endovenous interventions used in the trial and 
should be reported. Please note this is not an exhaustive list, if you suspect an 
event is related to treatment please contact the Trials Unit. 
Systemic 
• 
allergic reaction req. local / no treatment  
• 
migraine 
• 
visual disturbance 
• 
fainting 
• 
Cough / chest tightness 
• 
Systemic infection 
• 
PE 
• 
TIA 
• 
Stroke 
Local 
• 
Bleeding requiring intervention 
• 
Blistering of skin 
• 
Pressure damage 
• 
Nerve damage 
• 
DVT 
• 
Hematoma 
• 
Patient reported parathesia 
• 
Pigmentation of skin 
• 
Superficial thrombophlebitis 
• 
New ulcer 
• 
Deterioration of ulcer 
• 
Wound infection 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
29 
 
8.3 NON SERIOUS ADVERSE EVENTS 
All such events, which are judged by the local PI to be related to the interventions, 
whether expected or not, should be recorded in InForm 
8.4 SERIOUS ADVERSE EVENTS 
In addition to clinical assessments, patients will be contacted on a monthly basis by 
telephone for 12 months to identify any additional treatments, admissions or other 
complications related to their leg ulceration. Unrelated serious adverse events will 
also be recorded and reported in accordance with the Good Clinical Practice 
guidance up to 12 months. Serious adverse events (SAE) are defined as those 
adverse events that: result in death; are life-threatening; require in-patient 
hospitalisation or prolongation of existing hospitalisation; result in persistent or 
significant disability or incapacity; result in congenital anomaly or birth defect; are 
cancer; or are other important medical events in the opinion of the responsible 
investigator (i.e. not life threatening or resulting in hospitalisation, but may jeopardise 
the participant or require intervention to prevent one or more of the outcomes 
described previously). 
All SAEs reported by participants at (or between) each follow-up visit will be 
recorded by local researchers and entered into InForm within 24 hours of the 
researcher becoming aware of the event.  
All SAEs will be reported by the trial manager to the Sponsor and Chair of the Data 
Monitoring Committee. Related and unexpected SAEs will also be reported to the 
relevant Ethics Committee. 
In the event that InForm is not accessible notify the Trial Manager, Francine Heatley:  
Tel: 0203 311 7371 (Mon to Fri 09.00 – 17.00) 
Email: EVRAtrial@imperial.ac.uk 
 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
30 
 
9. REGULATORY ISSUES  
9.1 ETHICS APPROVAL  
After approval from the Research Ethics Committee, the study must be submitted for 
Site Specific Assessment (SSA) at each participating NHS Trust. The Chief 
Investigator will require a copy of the Trust R&D approval letter before accepting 
participants into the study. The study will be conducted in accordance with the 
recommendations for physicians involved in research on human subjects adopted by 
the 18th World Medical Assembly, Helsinki 1964 and later revisions.  
 
9.2 CONSENT  
Consent to enter the study must be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration. Signed participant consent should be obtained. The right of the 
participant to refuse to participate without giving reasons must be respected. After 
the participant has entered the study the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the 
participant’s best interest, but the reasons for doing so should be recorded. In these 
cases the participants remain within the study for the purposes of follow-up and data 
analysis. All participants are free to withdraw at any time from the protocol treatment 
without giving reasons and without prejudicing further treatment. Patients will not be 
specifically reconsented for the collection data in October 2018 as they already 
consented for the collection of longer term data at the outset. Patients will be asked, 
however at the telephone contact if they wish to continue in the study.  
 
9.3 CONFIDENTIALITY  
The Chief Investigator will preserve the confidentiality of participants taking part in 
the study and is registered under the Data Protection Act.  
 
9.4 INDEMNITY  
Imperial College London holds negligent harm and non-negligent harm insurance 
policies, which apply to this study. 
 
9.5 SPONSOR  
Imperial College London will act as the main Sponsor for this study. Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.  
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
31 
 
9.6 FUNDING  
This project is funded by the National Institute for Health Research HTA (project 
number 11/129/197).  
9.7 QUALITY ASSURANCE AND CONTROL 
The study may be subject to inspection and audit by Imperial College London under 
their remit as sponsor and other regulatory bodies to ensure adherence to GCP and 
the NHS Research Governance Framework for Health and Social Care (2nd edition). 
Quality Control will be performed according to the requirements of the Risk 
Assessment performed by ICTU. The study may be audited by a Quality Assurance 
representative of the Sponsor. All necessary data and documents will be made 
available for inspection. 
 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
32 
 
10. STUDY MANAGEMENT 
The study will be coordinated by a trial manager based at ICTU reporting to the 
Clinical Coordinators (MG and RB) and the Chief Investigator (AD). The Clinical 
Coordinators will liaise with local principal investigators (L-PI) to ensure that the trial 
is conducted locally according to protocol and in an expeditious manner. The 
organisational structure and responsibilities are outlines below. 
 
10.1 PRINCIPAL INVESTIGATORS 
The chief investigator and clinical coordinators have overall responsibility for: 
 Design and conduct of the study 
 Preparation of the Protocol and subsequent revisions 
 Managing the Trial Coordinating Centre 
 Development of SOPs 
10.2 TRIAL STEERING COMMITTEE 
A Trial Steering Committee (TSC) will be established in line with HTA guidance, 
consisting of the chief Investigator, clinical coordinators, trial manager, trial 
statistician, patient representative, an independent chair and at least 1 other 
independent member will be formed and will meet on a 6-monthly basis to discuss 
trial progress. The TSC is responsible for: 
 Agreement of the final Protocol 
 Agreeing the Data Analysis Plan 
 Reviewing progress of the study and, if necessary, agreeing changes 
to the Protocol 
 Reviewing new studies that may be of relevance 
 Review and approval of study reports 
10.3 DATA MONITORING COMMITTEE 
The independent Data Monitoring Committee (DMC) will be established in line with 
HTA guidance will focus on the rights, safety and wellbeing of study participants. 
DMC responsibilities are: 
 Reviewing unblinded interim data according to the schedule agreed by 
all DMC members. 
 Advising the Steering Committee if, in their view, the randomised data 
provide evidence that may warrant early termination for either safety or 
efficacy. 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
33 
 
10.4 TRIAL COORDINATING CENTRE 
The Trial Coordinating Centre (TCC) is responsible for the overall coordination of the 
Study, including: 
 Study planning and organisation of Steering Committee meetings 
 Agreement of each local recruitment plan 
 Contractual issues with local study sites 
 Ethics Committee applications 
 Design, implementation and maintenance of IT systems for the study 
 Auditing and monitoring of overall progress of the study 
 Clinical safety monitoring (including the reporting of all “related” SAEs 
to the Chair of the DMC and Ethics Committee) 
 Liaison with the Data Monitoring Committee and (where appropriate) 
with regulatory authorities and other outside agencies 
 Responding to technical and administrative queries from local study 
sites 
10.5 LOCAL STUDY SITES 
The local principal investigators (L-PI) and clinical staff at the local study sites are 
responsible for: 
 Obtaining local R&D and management approval (aided by the Trial 
Coordinating Centre) 
 Provision of adequate clinic space and the identification of potentially 
eligible participants 
 Conducting study procedures and follow-up according to study protocol 
 Dealing with routine enquiries from participants and their families 
 Obtaining appropriate information to confirm potential primary and 
secondary study endpoints 
 Attend annual EVRA Study Collaborator Meetings to discuss study 
progress 
 
11. DOCUMENT RETENTION 
Data will be stored for a minimum of 10 years following completion of this trialin 
accordance with the Imperial College JCRO Archiving Study Documents SOP. Data 
generated by this work will be processed in accordance with the Data Protection Act 
1998. 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
34 
 
 
12. PUBLICATION POLICY  
The findings will be disseminated to General Practitioners, nursing staff, surgeons 
and other health care professionals at regular research and educational meetings 
organised at local, regional, national and international levels. All analyses will be 
performed in compliance with a predefined analysis plan. The chief investigator, 
clinical coordinators and trial coordinator will be responsible for drafting the main 
reports from the study. Draft copies of any manuscripts will be provided to local 
principal investigators at each local study site, TSC members and all other 
collaborators for review prior to publication. The results will be put forward for critical 
peer review with a view to publication in relevant medical and nursing journals. 
 
 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
35 
 
13. REFERENCES  
1. Obermayer A, Garzon K. Identifying the source of superficial reflux in venous leg 
ulcers using duplex ultrasound. Journal of vascular surgery 2010;52(5):1255-
61. 
2. Graham ID, Harrison MB, Nelson EA, Lorimer K, Fisher A. Prevalence of lower-
limb ulceration: a systematic review of prevalence studies. Adv Skin Wound 
Care 2003;16(6):305-16. 
3. Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg: extent 
of the problem and provision of care. Br Med J (Clin Res Ed) 
1985;290(6485):1855-6. 
4. Callam MJ, Harper DR, Dale JJ, Ruckley CV. Chronic ulcer of the leg: clinical 
history. Br Med J (Clin Res Ed) 1987;294(6584):1389-91. 
5. Centre THaSCI. Statistics on obesity, physical activity and diet: England, 2012. 
2012. 
6. Laing W. Chronic Venous Diseases of the Leg. In: Economics OoH, editor. 
London, 1992. 
7. Barwell JR, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, et al. 
Comparison of surgery and compression with compression alone in chronic 
venous ulceration (ESCHAR study): randomised controlled trial. Lancet 
2004;363(9424):1854-9. 
8. van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM, Wittens CH. 
Conservative versus surgical treatment of venous leg ulcers: a prospective, 
randomized, multicenter trial. Journal of vascular surgery : official publication, 
the Society for Vascular Surgery [and] International Society for Cardiovascular 
Surgery, North American Chapter 2006;44(3):563-71. 
9. Grabs AJ, Wakely MC, Nyamekye I, Ghauri AS, Poskitt KR. Colour duplex 
ultrasonography in the rational management of chronic venous leg ulcers. The 
British journal of surgery 1996;83(10):1380-2. 
10. Adam DJ, Naik J, Hartshorne T, Bello M, London NJ. The diagnosis and 
management of 689 chronic leg ulcers in a single-visit assessment clinic. Eur 
J Vasc Endovasc Surg 2003;25(5):462-8. 
11. Tassiopoulos AK, Golts E, Oh DS, Labropoulos N. Current concepts in chronic 
venous ulceration. Eur J Vasc Endovasc Surg 2000;20(3):227-32. 
12. Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. Long term 
results of compression therapy alone versus compression plus surgery in 
chronic venous ulceration (ESCHAR): randomised controlled trial. Bmj 
2007;335(7610):83. 
13. Browse NL, Burnand KG. The cause of venous ulceration. Lancet 
1982;2(8292):243-5. 
14. Ibegbuna V, Delis KT, Nicolaides AN, Aina O. Effect of elastic compression 
stockings on venous hemodynamics during walking. Journal of vascular 
surgery : official publication, the Society for Vascular Surgery [and] 
International Society for Cardiovascular Surgery, North American Chapter 
2003;37(2):420-5. 
15. van den Bremer J, Moll FL. Historical overview of varicose vein surgery. Annals 
of vascular surgery 2010;24(3):426-32. 
16. Winterborn RJ, Foy C, Earnshaw JJ. Causes of varicose vein recurrence: late 
results of a randomized controlled trial of stripping the long saphenous vein. 
Journal of vascular surgery : official publication, the Society for Vascular 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
36 
 
Surgery [and] International Society for Cardiovascular Surgery, North 
American Chapter 2004;40(4):634-9. 
17. O'Hare JL, Earnshaw JJ. Randomised clinical trial of foam sclerotherapy for 
patients with a venous leg ulcer. Eur J Vasc Endovasc Surg 2010;39(4):495-9. 
18. Darwood RJ, Gough MJ. Endovenous laser treatment for uncomplicated varicose 
veins. Phlebology 2009;24 Suppl 1:50-61. 
19. Gohel MS, Davies AH. Radiofrequency ablation for uncomplicated varicose veins. 
Phlebology 2009;24 Suppl 1:42-9. 
20. Carradice D, Mekako AI, Mazari FA, Samuel N, Hatfield J, Chetter IC. 
Randomized clinical trial of endovenous laser ablation compared with 
conventional surgery for great saphenous varicose veins. The British journal 
of surgery 2011;98(4):501-10. 
21. Subramonia S, Lees T. Randomized clinical trial of radiofrequency ablation or 
conventional high ligation and stripping for great saphenous varicose veins. 
The British journal of surgery 2010;97(3):328-36. 
22. van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous 
therapies of lower extremity varicosities: a meta-analysis. Journal of vascular 
surgery : official publication, the Society for Vascular Surgery [and] 
International Society for Cardiovascular Surgery, North American Chapter 
2009;49(1):230-9. 
23. (SIGN) SIGN. Management of chronic venous leg ulcers: NHS, 2010. 
24. Kulkarni SR, Slim FJ, Emerson LG, Davies C, Bulbulia RA, Whyman MR, et al. 
Effect of foam sclerotherapy on healing and long-term recurrence in chronic 
venous leg ulcers. Phlebology 2012. 
25. Pang KH, Bate GR, Darvall KA, Adam DJ, Bradbury AW. Healing and recurrence 
rates following ultrasound-guided foam sclerotherapy of superficial venous 
reflux in patients with chronic venous ulceration. Eur J Vasc Endovasc Surg 
2010;40(6):790-5. 
26. Michaels JA, Campbell WB, Brazier JE, Macintyre JB, Palfreyman SJ, Ratcliffe J, 
et al. Randomised clinical trial, observational study and assessment of cost-
effectiveness of the treatment of varicose veins (REACTIV trial). Health 
Technol Assess 2006;10(13):1-196, iii-iv. 

EVRA Protocol Version 5.0, dated:  06/04/2017 
Approved by The NRES Committee South West - Central Bristol REC on 24/05/2017 
37 
 
Appendix 1: Summary of assessments and follow-up visits 
Time point 
Estimated 
duration 
(mins) 
Clinical 
evaluation* 
Telephone 
follow-up** 
Wound 
review/photo 
/tracing*** 
Collection of 
further 
endovenous 
intervention / 
duplex report  
Venous 
duplex 
Randomisation  
Consent  
Health 
Questionnaires 
(EQ-5D, SF-36, 
AVVQ)  
Screening 
Visit 
45 
X 
 
 
 
X 
 
Xa 
 
Baseline 
Visit 
60-90 
X 
 
   X*** 
 
 
X 
Xb 
X 
1 month  
30 
 
X 
 
 
 
 
 
 
6 weeks 
60-90 
X 
 
X?*** 
 
Xc 
 
 
X 
2 months 
30 
 
X 
X? 
 
 
 
 
 
3 months 
30 
 
X 
X? 
 
 
 
 
 
4 months 
30 
 
X 
X? 
 
 
 
 
 
5 months 
30 
 
X 
X? 
 
 
 
 
 
6 months 
30 
 
X 
X? 
 
 
 
 
X 
7 months 
30 
 
X 
X? 
 
 
 
 
 
8 months 
30 
 
X 
X? 
 
 
 
 
 
9 months 
30 
 
X 
X? 
 
 
 
 
 
10 months 
30 
 
X 
X? 
 
 
 
 
 
11 months 
30 
 
X 
X? 
 
 
 
 
 
12 months 
30 
 
X 
X? 
 
 
 
 
X 
Extension 
follow-up 
Oct18 to 
Mar 19 
240 
Xd 
X 
 
X 
 
 
Xe 
X 
*. Demographic details (age, sex, ethnicity), Pregnancy test for woman of child bearing potential. General clinical details (body mass index, ankle brachial pressure index – performed within previous 4 weeks, comorbidities, medication history). Ulcer details 
(duration, progression, previous ulcer history, size of current ulcer – using photography and planimetry). Details of venous disease (previous deep vein thrombosis, previous venous interventions, pattern of venous reflux on duplex) 
**. Ulcer healing assessment, compression type, AE assessment, Concomitant medications, health resource use. ***tracing only performed at baseline & 6 weeks 
a. Approached    b Taken     c. Only for those who have early endovenous treatment  d. review of clinical notes only  e. patients will not be reconsented as already consented for longer term follow-up at outset but will be asked if they wish to continue 
?dependant on whether the ulcer has healed photo will be taken at verification visit and taken weekly for 4 weeks, unless otherwise confirmed by the trial manager. Once the ulcer has healed the patient will still be followed up with monthly phone calls.