Trial protocol for evaluating sub-ulcer foam sclerotherapy as an adjunct to conventional endovenous treatment in patients with venous leg ulcers: The FINNULCER multicenter randomized controlled trial

Abstract

Background

Venous leg ulcers (VLUs) affect approximately 1% of the adult population and incur significant morbidity and healthcare costs. Endovenous interventions, such as endovenous laser ablation (EVLA) and ultrasound-guided foam sclerotherapy (UGFS), have shown benefits in treating venous insufficiency in patients with VLUs. However, the effect of specifically targeting the sub-ulcer venous plexus with foam sclerotherapy remains poorly understood.

Objective

The FINNULCER trial is investigating the addition of sub-ulcer foam sclerotherapy to conventional endovenous treatment (EVLA + UGFS) for managing superficial venous insufficiency in patients with VLUs. The primary aim is to evaluate the effect of sub-ulcer foam sclerotherapy in promoting ulcer healing.

Methods

Patients with VLUs are being screened at four vascular surgery units in Finland. Eligible participants who provide informed consent are randomized into the study group to receive sub-ulcer foam sclerotherapy + EVLA + UGFS or into the control group to receive EVLA + UGFS. The primary outcome is the time to ulcer healing during 1 year of follow-up from randomization. Secondary outcomes include quality of life assessments and procedure-related outcomes.

Trial registration

ClinicalTrials.gov (NCT04737941).

Keywords

Sub-ulcer foam sclerotherapy venous leg ulcer endovenous ablation venous insufficiency

Introduction

Approximately 60% of chronic lower extremity ulcers are venous in origin,¹ with a prevalence of 1% in the adult population.² Venous leg ulcers (VLUs) incur significant patient morbidity, significantly affect quality of life, and place substantial economic burdens on healthcare systems.³ The etiology of VLUs is associated with superficial vein insufficiency,⁴ and the pathophysiology is characterized by chronic inflammation, which is likely triggered by venous hypertension and its effects, such as edema.⁵ VLUs are slow to heal, prone to recurrence, and often resistant to treatment, making their management challenging.⁶

Before the era of superficial venous interventions, the treatment of VLUs primarily relied on compression therapy. Although compression therapy has been shown to promote ulcer healing, it is associated with prolonged healing times and a high risk of recurrence.⁷ In the early 2000s, the ESCHAR trial demonstrated that combining surgical correction of superficial venous insufficiency with compression therapy significantly reduces ulcer recurrence compared to compression therapy alone.⁶ This finding reinforced the importance of actively treating superficial venous reflux in patients with a VLU, especially as the risk of recurrence remained lower in surgically treated patients during long-term follow-up.⁸

The EVRA trial published in 2018 demonstrated that VLUs heal faster when superficial reflux is treated early with endovenous intervention compared to compression therapy. These findings have significantly influenced treatment protocols, shifting the approach towards a more aggressive and timelier treatment of superficial insufficiency in patients with a VLU.^9,10

In addition to conventional endovenous ablation techniques targeting truncal, tributary, and perforating veins, more recent protocols have proposed the sub-ulcer venous plexus as an adjunct target for treatment.¹¹ This plexus may play a key role in transmitting venous hypertension to the soft tissues and skin, thereby contributing to ulcer formation and delayed healing.¹⁰

The European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs include a class IIa recommendation (level of evidence C) that ultrasound-guided foam sclerotherapy (UGFS) of the sub-ulcer venous plexus may be considered as part of the treatment strategy for patients with active VLUs.¹⁰ However, as the current level of evidence is low, the guidelines also emphasize the need for further research to determine its true clinical benefit.¹⁰ Addressing this gap, the FINNULCER trial aims to study the efficacy of sub-ulcer venous plexus ablation with UGFS in VLU management.

Methods

Trial design

The FINNULCER trial is a non-blinded, multicenter, parallel-group, randomized, controlled trial recruiting patients with a VLU in three Finnish university hospitals (Oulu, Helsinki, and Turku) and in Hospital Nova, the central hospital of the Wellbeing Services County of Central Finland in Jyväskylä, Finland. Vascular surgery outpatient clinic patients are being screened for randomization; patients diagnosed with a VLU who meet the inclusion criteria and provide consent to participate are randomized into either the study group to receive sub-ulcer foam sclerotherapy + endovenous laser ablation (EVLA) + UGFS or the control group to receive EVLA + UGFS. The primary outcome of the FINNULCER trial is the time from randomization to ulcer healing. The trial is ongoing and registered at ClinicalTrials.gov under identifier number NCT04737941.

Eligibility criteria

The inclusion and exclusion criteria are presented in Table 1. Patients are being recruited at the vascular surgery outpatient clinics of the participating centers. Patients who meet the study criteria and give written informed consent are enrolled in the study. If a patient has ulcers on both legs, the leg with the larger ulcer is designated as the one that will be followed in the trial.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria

• Venous leg ulcer and superficial venous insufficiency suitable for UGFS (and EVLA if necessary)

• Age >18 years

• Ulcer duration between 1 and 24 months

• Palpable peripheral pulses or ABI >0.80, and/or toe pressure >60 mmHg

• Ulcer diameter >5 mm

Exclusion criteria

• Diagnosis or suspicion of a non-venous etiology for the leg ulcer

• A venous leg ulcer on the index leg treated with foam sclerotherapy or endothermal ablation more than twice

• BMI >40 kg/m²

• Leg ulcers resulting from malignant disease

• Venous leg ulcers requiring surgical debridement or skin grafting

• Unsuitability for UGFS

Unsuitability for UGFS includes a diagnosed patent atrial septal defect or a history of severe adverse reactions to foam sclerosant (sodium tetradecyl sulfate or polidocanol). UGFS, ultrasound-guided foam sclerotherapy; EVLA, endovenous laser ablation; ABI, ankle-brachial index.

Clinical assessment

The diagnosis of a VLU is based on typical clinical characteristics and duplex ultrasound (DUS) examination of the leg. DUS is performed by a vascular surgeon with the patient standing. The DUS examination includes an evaluation of the truncal veins and tributaries, with superficial insufficiency defined as reflux lasting >0.5 seconds. In addition to superficial insufficiency, possible deep vein insufficiency (defined as reflux >1.0 seconds) is being assessed and recorded. Superficial venous insufficiency is treated regardless of the presence of deep vein insufficiency provided that the common femoral vein is patent. The arterial circulation of the leg is assessed as described in Table 1.

Aims of the trial

The primary aim of the trial is to evaluate the time to ulcer healing (primary outcome) when sub-ulcer UGFS is added to conventional UGFS and EVLA in patients with VLU. The trial questions are outlined in Table 2.

Table 2.

Trial questions.

• Does a venous ulcer heal faster when the sub-ulcer venous plexus is treated with ultrasound-guided foam sclerotherapy at the first visit than with the current standard treatment of superficial venous insufficiency at a separate scheduled visit and without specifically targeting the sub-ulcer venous plexus?

• Does sub-ulcer treatment affect health-related quality of life (as measured by the EQ-5D-5 L) or ulcer-specific quality of life (as measured by Wound-QoL) in the study group compared to the control group?

• Are there differences in complication rates between these two treatment strategies?

Data management

Each participating center collects its patients’ data, which are uploaded to and retained on the HUSeCRF electronic platform provided by the Hospital District of Helsinki and Uusimaa. The platform’s technical functionality is maintained by Granitics Ltd, Espoo, Finland, a producer of data system services for medical research. Access to the data is restricted to study investigators only.

Patient enrollment and randomization

Patients meeting the trial requirements are provided information on the trial both orally and in an information letter, and the patients are offered the opportunity to participate in the study. If the patient agrees to participate, written informed consent is obtained and the patient registered in the data management portal and randomized into the study or control group at a 1:1 ratio using the portal randomization tool.

Interventions

The treatment of superficial venous insufficiency includes sub-ulcer UGFS, UGFS (without specific targeting of sub-ulcer plexus), and EVLA. UGFS and EVLA are performed for both groups according to the patient’s needs, and sub-ulcer UGFS is performed only in patients assigned to the study group (see Figure 1 for the schedule of interventions).

Figure 1.

Schedule of enrollment, interventions, and follow-up in the FINNULCER trial. Patients will be randomly allocated to the study group (X1) or control group (X2). The scheduled treatment visit will be at 4 weeks or later based on the availability of intervention slots. Follow-up visits will occur between 2 and 12 months. The end-of-study assessment will be completed when the ulcer heals or at 12 months. Abbreviations: UGFS, ultrasound-guided foam sclerotherapy; EVLA, endovenous laser ablation; DUS, duplex ultrasound; EQ-5D-5 L, EuroQoL quality of life questionnaire; Wound-QoL, disease-specific quality of life. ^aThe first visit to the vascular outpatient clinic may correspond with the enrollment time point. ^bThe foam sclerotherapy will be repeated as needed if superficial insufficiency persists. *EVLA is performed in both groups when needed. ³Questionnaires will be completed at 1, 6, and 12 months as long as the ulcer is not healed and follow-up is ongoing.

Sub-ulcer ultrasound-guided foam sclerotherapy

Patients assigned to the study group undergo sub-ulcer UGFS at their first visit to the vascular outpatient clinic. This procedure is repeated at subsequent visits if the sub-ulcer venous plexus remains patent after the first treatment.

To access the sub-ulcer plexus, refluxing superficial veins around and distal to the ulcer—either the distal truncal veins (GSV or SSV) or tributary veins leading to the ulcer area—are cannulated under ultrasound guidance. Multiple cannulas are used for some foam sclerosant injections to achieve an adequate sclerosant concentration in the insufficient superficial veins while minimizing foam leakage into the deep veins. To reduce the risk of iatrogenic infection, avoiding the most indurated skin or areas immediately adjacent to the ulcer is recommended.

The foam sclerosant is prepared using either Fibrovein® 1% (STD Pharmaceutical Products Ltd, Hereford, UK) or 1% polidocanol (Aethoxysklerol®, Kreussler Pharma, Wiesbaden, Germany) following Tessari’s technique.¹² The foam volume is adjusted according to the size of the sub-ulcer venous plexus and the ulcer, with larger veins and ulcers requiring more foam than smaller veins and ulcers. The success of sub-ulcer foam sclerotherapy is being recorded based on echogenic foam visualization under the sub-ulcer plexus.

Endovenous laser ablation

EVLA is performed in both groups when a suitable (i.e., not too tortuous) insufficient truncal vein is present. The procedure is carried out during the scheduled treatment visit using a 1470 nm laser catheter with a power setting of 8-12 W, aiming for a linear endovenous energy density of 70 J/cm, under local tumescent anesthesia. The EVLA treatment strategy for truncal insufficiency is determined by the treating vascular surgeon in accordance with the manufacturer’s instructions.

Ultrasound-guided foam sclerotherapy

UGFS is performed as a concomitant treatment at the scheduled visit after EVLA or at a follow-up visit. UGFS is used in both study groups. However, in patients with recurrent venous disease and/or recurrent VLUs, UGFS may be the only treatment if no insufficient truncal veins are available for EVLA.

The foam sclerosant is prepared as described previously and its distribution monitored by ultrasound. As with sub-ulcer foam sclerotherapy, multiple cannulas are often required. This approach ensures an adequate sclerosant concentration in all insufficient superficial veins while minimizing deep vein leakage. The total amount of foam used is recorded.

Post-treatment management

After treatment, the puncture sites are covered with adhesive pads and local ulcer debridement performed under topical anesthesia if necessary. Compression therapy is applied. Upon discharge, patients are advised to move regularly for the remainder of the treatment day to reduce the risk of deep vein thrombosis. The need for thrombosis prophylaxis is determined by the operating vascular surgeon. Procedure details and any periprocedural complications are being recorded in the trial registry. Between outpatient visits at the study center, wound care continues at the primary healthcare center. In the event of major complications, such as suspected infection or deep vein thrombosis, the patients are instructed to contact the vascular outpatient clinic or emergency unit.

Compression therapy

The recommended choice for compression is a thigh-high class 2 compression stocking (23–32 mmHg) worn daily until the ulcer is completely healed. If the patient is unable to wear thigh-high class 2 compression (e.g., due to pain caused by the compression or difficulties putting it on or taking it off), the compression therapy is tailored to the patient’s needs (e.g., class 2 knee-high compression, class 1 thigh- or knee-high compression, or elastic compression bandages). If the patient is completely unable to use compression, it is not applied.

Outcome measures and follow-up

The primary outcome of the trial is the time to complete epithelialization of the ulcer, measured in days, with a follow-up period of 1 year. The exact date of the primary outcome is being obtained from the patient or from the primary healthcare patient records during follow-up visits. Secondary outcomes include patient-reported quality of life assessments using the health-related quality of life (EQ-5D-5 L) and disease-specific quality of life (Wound-QoL) questionnaires, as well as procedure-related outcomes, including the success of previous interventions, the need for further venous interventions, current intervention details, complications, and changes in the ulcer area and diameter. In the study group, the success of sub-ulcer foam sclerotherapy is assessed by ultrasound.

Follow-up

The schematic diagram of trial enrollment, interventions, and follow-up is presented in Figure 1. During each visit, superficial reflux is assessed by DUS and recorded in the patient registry to evaluate the effect of previous treatments and determine whether further treatment is required. Health-related quality of life questionnaires are completed at 1, 6, and 12 months as long as the ulcer is not healed and follow-up is ongoing.

For patients randomized to the study group, both UGFS and sub-ulcer UGFS are performed during the enrollment visit, which can coincide with the first visit to the vascular outpatient clinic. In both groups, a scheduled treatment visit occurs ≥4 weeks later depending on the availability of intervention slots. During the scheduled treatment visit, EVLA is the recommended treatment for truncal insufficiency based on the vascular surgeon’s evaluation. UGFS is performed to treat distal truncal reflux, tributaries, and insufficient veins originating from perforating veins. If EVLA cannot be performed due to factors such as tortuous truncal vein anatomy or insufficiency from neovascularization, foam sclerosant is used exclusively instead.

At follow-up visits to the vascular outpatient clinic, UGFS (and sub-ulcer UGFS for the study group) is performed as needed. The primary aim in treating superficial insufficiency is the complete elimination of all ulcer-related insufficiency. Follow-up is intended to continue until the ulcer is healed or for a maximum of 12 months.

Sample size

The primary outcome of the trial is VLU healing, defined as complete epithelialization of the ulcer. The sample size calculation was based on retrospective data from Oulu University Hospital indicating that first-visit foam sclerotherapy is associated with a 1.5-fold higher healing rate (hazard ratio = 1.5) compared to standard treatment, which consists of endovenous intervention 4 to 8 weeks after randomization.

Using a significance level of α = 0.05 and a power of 80% (β = 0.20) with equal allocation between groups (1:1 randomization), the required total sample size is 222 patients. To account for potential dropouts, we are recruiting 10% more than the calculated number, setting the target number of patients at 248.

Statistical analysis

Summary statistics are presented as the mean and standard deviation or median and interquartile range (25th–75th percentiles). The primary outcome is analyzed using the proportional hazards Cox model. The results of the Cox model are presented as hazard ratios with 95% confidence intervals (CIs). Repeatedly measured secondary outcomes are analyzed using a linear mixed model or generalized linear mixed model with time, group, and time × group interaction as fixed factors and patient as a random factor. The difference in complication rates is analyzed using a logistic regression model and presented as odds ratios with 95% CIs. Mean differences or percent-unit differences with 95% CIs are presented for the tertiary analyses. All primary and secondary analyses are adjusted for study site. Two-tailed p-values are presented only for primary and secondary outcome variables.

Discussion

Non-randomized studies on the technique known as terminal interruption of the reflux source (TIRS) suggest that peri-ulcer foam sclerotherapy may be effective in promoting VLU healing.¹³ A retrospective study¹⁴ at Oulu University Hospital analyzed data from 134 patients who received sub-ulcer foam sclerotherapy and found a low overall complication rate (3%). Furthermore, a single-center randomized controlled trial¹⁵ conducted at the same institution demonstrated a significant reduction in the ulcer area 1 month after sub-ulcer foam sclerotherapy. In contrast, no significant reduction was observed in the control group that received compression therapy alone. The FINNULCER trial aims to further explore the effects of sub-ulcer UGFS in patients with VLUs.

Footnotes

Author contributions

Original idea: T.P., M.P. Conceptualization and methodology: T.P., P.O., H.H., J.V., M.V., K.H., M.P. Funding acquisition: M.P. Statistical analysis: T.P., P.O., M.P.. Patient recruitment and treatment: T.P., H.H., J.V., T.K., M.V., K.H., M.P. Writing – original draft, reviewing, and editing: T.P., P.P., H.P., J.P., T.P., M.V., K.H., M.P.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This trial is supported by Finland’s state funding for university hospitals; 24771/K47859.

Ethics statement

Informed consent

Consent for publication was obtained from the study participants at the same time as consent to participate.

Guarantor

Matti Pokela

ORCID iDs

Toni Pihlaja

Harri Hakovirta

Data availability statement

The data collected and analyzed during the current study are not publicly available. Access to the data is restricted to study investigators only.*

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