A randomised clinical trial to compare early versus delayed endovenous treatment of superficial venous reflux in patients with chronic venous ulceration.

Trial Design

Aim:

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

Design:

Multi-centre randomised controlled trial, ISRCTN02335796

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. North Cumbria University Hospitals NHS Trust (PI: Mr Thomas Joseph)
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. Central Manchester University Hospitals NHS Foundation Trust
15. Frimley Park Hospital NHS Foundation Trust
16. Plymouth Hospitals NHS Trust
17. Bradford Teaching Hospitals NHS Foundation Trust
18. Salisbury NHS Foundation Trust
19. Leeds Teaching Hospitals NHS Trust
20. Sheffield Teaching Hospitals NHS Foundation Trust
21. Taunton and Somerset NHS Foundation Trust

Additional centres may join the study at a later date, subject to a feasibility assessment of potentially eligible patients and ability of early intervention.

Methods:

Patients are referred to secondary care as part of the standard care pathway. 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

Outcome measures:

The primary outcome is time to ulcer healing.  Secondary outcome measures include ulcer healing rate, ulcer free time and markers of clinical Success as well as quality of life, costs and cost-effectiveness.

Size of the trial:

The trial plans to recruit 500 patients over a 48 month period, to provide 90% power to detect (as significant at 5%) a difference in time to healing at 24 weeks of 15% (75% in the EVRA arm) assuming the 24-week healing rate in the standard care arm is 60%.

Eligibility

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)

 Exclusions:

• Presence of deep venous occlusive disease or other conditions precluding superficial venous intervention (at the discretion of local research team)
• Patients who are unable to tolerate any multilayer compression bandaging 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

Randomisation (performed through INFORM)

Consenting eligible patients will be randomised through INFORM (Please note this link will only work through internet explorer and is not compatible with google chrome or firefox)

Randomisation will be stratified by the trial centre.

Procedure and follow up (active for 12 months)

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:

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

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
• 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.

Urgent verification visit

• A member of the local research team will perform the four weekly verification visits to confirm healing. Photographs will be taken and send to the Trials Unit for independent verification

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.