Electrosclerotherapy for Capillary Malformations

Study Overview
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Brief Summary
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Capillary malformations (port-wine stains) consist of abnormally developed capillary blood vessels in the skin. To date, laser therapy is the only widely accepted treatment modality for capillary malformations, but this therapy has a suboptimal effect in approximately 50-60% of patients. Intralesional bleomycin injections (sclerotherapy) are a common effective treatment option for vascular malformations with blood vessels with larger diameters. However, bleomycin cannot be injected adequately in the small sized vessels of capillary malformations. The use of an electric field over the tissue (electroporation) may solve this problem: it increases cell membrane permeability and therefore promotes localized delivery of drugs, within (endothelial) cells. Electroporation in combination with bleomycin sclerotherapy ('electrosclerotherapy') may therefore offer new therapeutic options for capillary malformations. This proof of principle study aims to explore the effectiveness, safety and feasibility of this potential treatment option in a within-patient-controlled pilot study.

Detailed Description
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Capillary malformations are congenital abnormalities of the capillaries in the skin. These abnormally developed blood vessels cause a red color of the skin (also known as 'port-wine stain'),often in combination with a cobble-stone like aspect of the skin. Currently, the only widely accepted treatment option is laser therapy, in which the abnormal blood vessels are targeted with photocoagulation. However, in approximately 50-60% of patients, treatment outcome of laser therapy is suboptimal. Furthermore, re-darkening of the capillary malformation often occurs after laser therapy. Hence, there is a need for an alternative treatment option - especially for treatment-resistant and recurrent capillary malformations. Intralesional bleomycin injections (sclerotherapy) are a common treatment option for vascular malformations of blood vessels and lymphatic vessels with a larger diameter (venous and lymphatic malformations). According to the literature, this treatment is effective in approximately 80-90% of patients. Unfortunately, the diameter of capillary blood vessels is too small, and therefore adequate localized injections of bleomycin are not possible in capillary malformations. 'Electroporation' is a physical phenomenon that causes an alteration of the structure of cell membranes through the exposure of cells to a short but intense electric field; this modification of the cell membrane increases its permeability. After electroporation, molecules that normally do not cross the cell membrane, either by diffusion or by active transport, can reach the intracellular environment. Therefore, electroporation is an ideal method for localized drug delivery, in particular for localized bleomycin delivery. The combination of electroporation and bleomycin is already used in a variety of skin lesions, such as squamous cell carcinoma, with a surprisingly high rate of complete remission. Especially in vascular tumors, such as Kaposi sarcoma, there is an extremely high percentage of complete remission (90%), since the combination of bleomycin and electroporation causes a 'vascular lock' and intravascular thrombosis of tumor vascularization, leading to tumor regression. This phenomenon (intravascular thrombosis and lesion regression) is exactly the intended effect of capillary malformation treatment. The investigators therefore hypothesize that intralesional bleomycin injections combined with electroporation (electrosclerotherapy) can be an alternative treatment option for capillary malformations. This proof of principle study aims to explore the feasibility of this potential treatment option in a small patient sample.

Official Title
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Electrosclerotherapy as a Novel Treatment Option for Capillary Malformations: A Pilot Study

Conditions
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Capillary Malformations, Vascular Malformations

Intervention / Treatment
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* Other: Electrosclerotherapy
* Drug: Intralesional bleomycin injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with ≥1 completely or partially hypertrophic capillary malformation not exclusively located in the skin of the face, the skin overlying joints or in mucosal tissue Age ≥ 18 years Fitzpatrick skin type 1-3 without evident sun tan Exclusion Criteria: Pregnant or breastfeeding women Women with childbearing potential not using contraception Patients with chronic renal dysfunction of GFR <50 ml/minute Patients with chronic pulmonary dysfunction, active pulmonary infections or previous bleomycin lung toxicity Patients with ataxia teleangiectasia Patients with previous allergic reactions to bleomycin Patients who already received the maximum dose of bleomycin (400 mg or 400000 IU/m2) Patients with implanted electrical devices such as pacemakers or ICD's Patients with clinically manifested arrhythmia Patients with epilepsy Patients who are not able to return to the hospital for follow-up visits Patients who are likely not able to understand the terms and risks of the study (e.g. cognitive impairment)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Electrosclerotherapy<br>One region of interest in the capillary malformation (approximately 1.5x1.5cm)will be treated with electrosclerotherapy | Other: Electrosclerotherapy<br>* Combination of intralesional bleomycin sclerotherapy and electroporation<br>* Other names: Electrochemotherapy;|
| Active Comparator: Intralesional bleomycin injections<br>One region of interest in the capillary malformation will be treated with intralesional bleomycin injections without electroporation | Drug: Intralesional bleomycin injection<br>* Local intralesional injections with bleomycin<br>* Other names: bleomycin sclerotherapy;|
| No Intervention: No treatment<br>One region of interest in the capillary malformation (approximately 1.5x1.5cm)will not be treated. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient and Observer global assessment of capillary malformation (POSAS instrument) | Change in patient and observer assessment of vascularity, pigmentation, thickness, pliability, relief, surface area and general opinion. | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Any adverse event or serious adverse event occurring after intervention | 7 weeks | 
| Colorimetry | Change in color of capillary malformation in relation the contralateral healthy skin | 7 weeks | 
| Optical imaging (laser speckle imaging) | Change in blood perfusion measured with non invasive imaging using light | 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bleomycin, Electroporation