Title: A randomized clinical trial to compare early versus delayed treatment of superficial venous reflux in patients with chronic venous ulceration. Early Venous Reflux Ablation (EVRA) ulcer trial
Funder: Department of Health and Social Care

Abstract: STUDY DESIGN: Multicentre randomized clinical trial RESEARCH QUESTION: What is 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? HEALTH TECHNOLOGIES BEING ASSESSED: 1) Multilayer elastic compression bandaging (control group); 2) Multilayer elastic compression bandaging plus early treatment of superficial venous reflux using endovenous interventions (ultrasound guided foam sclerotherapy, endovenous laser or radiofrequency ablation). The choice of endovenous modality will be left to the discretion of the responsible clinician, in the patient’s best interests. However, the only stipulation will be that the first stage of the endovenous treatment strategy should be planned within 2 weeks of randomisation, if possible. SETTING: Hospital and community run leg ulcer clinics within Vascular Surgery Departments from across the UK. A total of 20 NHS Trusts have randomised participants in the trial. 1. Imperial College Healthcare NHS Trust 2. Cambridge University Hospitals NHS Foundation Trust 3. Worcestershire Acute Hospitals NHS Trust 4. North West London Hospitals NHS Trust 5. Gloucestershire Hospitals NHS Foundation Trust 6. Heart of England NHS Trust 7. University Hospital Birmingham NHS Trust 8. City and Sandwell NHS Trust 9. The Dudley Group NHS Trust 10. The Royal Wolverhampton Hospitals NHS Trust 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 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 TARGET POPULATION: Patients with open chronic leg ulceration (>6 weeks duration) will be targeted in hospital and community settings. In patients with bilateral venous ulceration, the worst leg (as assessed by the patient) will be designated the ‘reference’ leg. Adults over 18 years of age with superficial venous reflux (in great, small or non-saphenous veins) of >1s duration, will be assessed for eligibility. Exclusion criteria will include current deep vein thrombosis (DVT) or obstruction, arterial disease (ABPI<0.8), pregnancy, non-compliance with multilayer elastic compression and inability to perform prompt endovenous intervention. OUTCOME MEASURES: The primary outcome measure will be time to ulcer healing. Secondary outcomes will be ulcer healing rate, ulcer free time (to 1 year), Quality of life (generic and disease specific), health economic assessments (using in trial analysis and modelling techniques) and other markers of clinical success (including VCSS and incidence of complications). The economic evaluation will be based on both a modeling exercise and a patient level in-trial analysis, developed from the model used for another HTA funded project (REACTIV trial). SAMPLE SIZE: Participants will be randomized to two groups: multilayer elastic compression bandaging alone (standard therapy) or multilayer elastic compression plus early endovenous treatment of superficial reflux. 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. RANDOMISATION: Consenting participants will be registered on the InForm ITM (Integrated Trial Management) System, managed by Imperial Clinical Trials Unit (ICTU). 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. Participants will be assigned the next available entry in the appropriate randomization list. BASELINE ASSESSMENTS: Eligible patients that have given signed informed consent to participate in the study will undergo a general baseline assessment (Demographic information, clinical details, ulcer details and anatomy of venous disease). Additional baseline assessments will include Clinical, Etiologic, Anatomic, Pathophysiological (CEAP) grade, venous clinical severity score (VCSS) and evaluation of disease specific (Aberdeen varicose vein questionnaire – AVVQ) and generic (EuroQuol 5D – EQ5D & short form (SF) 36) quality of life. ADDITIONAL ASSESSMENTS: At A 6-week clinic visit, colour duplex scanning will be performed and complications will be recorded. Patients will be assessed by the patient self-completed questionnaire (EQ-5D, SF36, AVVQ, return to normal activities/work). At 6 and 12-months, patients will be assessed by the self-completed questionnaire. Assessments of the status of the reference leg will be performed at least monthly (clinical and telephone assessments involving using hospital staff, community professionals and patients). Once notified that the reference leg has healed, an urgent verification assessment will be arranged and photographs will be taken for blinded independent assessment. 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 allowing a median follow-up period of up to 5 years (median approximately 3.7 years) to be obtained. RECRUITMENT RATE: The trial recruitment period was extended by 8 months, and therefore the total recruitment period was 36 months. Recruitment was closed in September 2016 with 450 participants randomised into the study.

Lay abstract: A large number of patients (around 1% of the adult population) suffer from an ulcer (break in the skin surface) near the ankle. In most people, such a wound should heal up within a week or two. However, when there is an underlying problem with the skin, ulcers do not heal and may result in longstanding (chronic), painful, smelly and embarrassing wounds. The ulcers are often due to “varicose veins” in the legs, which can cause skin breakdown and ulcer formation. Blood flow in the veins is normally towards the heart. However, damaged valves within the veins of the leg result in blood flow down the leg (with gravity) which is called ‘reflux’. Venous reflux commonly occurs in superficial veins in the leg and results in prolonged high pressure in the leg, which causes inflammation / damage to the skin and eventual ulceration. To get the ulcer to heal, the current best treatment is to wear a tight compression bandage with multiple layers, with which about 60% of these ulcers will heal within 24 weeks. The bandaging helps to reduce the high venous pressure in the leg, but can be uncomfortable and requires specialist trained staff to apply. The majority of patients with venous ulcers have varicose veins that may be amenable to treatment. There is evidence that treatment of the varicose veins by surgery will prevent the ulcer from returning after it has healed. In recent years, varicose vein surgery has been replaced by less invasive, local anaesthetic treatments. Recent studies have suggested that these newer techniques of treating varicose veins, such as injecting a medicine into the varicose vein (sclerotherapy) or treating the vein with heat ablation to seal it (using laser or radiofrequency), in an outpatient setting may help the ulcers to heal more quickly and (like surgery) reduce the chance of the ulcer coming back. These techniques can be done in the outpatient setting and are probably much better tolerated by patients in comparison to surgery. To see if early treatment of the varicose veins using sclerotherapy or heat ablation helps with healing, we would like to do a trial in which patients with a leg ulcer and varicose veins are treated either by compression bandaging with treatment of varicose veins after the ulcer has healed (the current best treatment) or by compression bandaging and early treatment of the veins. Patients would be randomly allocated to each group (effectively by the toss of a coin). In the trial we would be looking at the number of ulcers healed in both patient groups and the speed at which the ulcers heal. We would also be asking the patients to comment on any changes in their quality of life following treatment, using specially designed questionnaires. Furthermore we would be looking at the costs of the two treatment groups. If early treatment of varicose veins of these patients improves healing rates in patients with leg ulcers, there will be significant cost savings for the NHS as well as great benefit for the patient group. The extension data will help clarify the short, medium and long-term impact of early intervention and will help define the role of these interventions in the patient pathway and help inform guidelines and protocols.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR;SKIN