Air Cold Atmospheric Pressure Plasma Treatment for Acceleration of Venous Ulcer Healing

Study Overview
=================
Brief Summary
-----------------
In this medical trial, a novel prototype of a medical device based on a Cold Atmospheric Air Plasma Jet for the treatment is clinically tested on patients with venous leg ulcers. The device is characterized by producing the first cold air plasma jet compatible with living tissues at a low heat transfer rate with a temperature on the skin surface lower than 40 ºC. It has a practical design to be used by physicians during daily practice with a special focus on unhealed ulcers.

Detailed Description
-----------------
The device to be validated in this test is an air-generating unit in a cold plasma state, a prototype of a medical device. Cold plasma-generating equipment is already available on the market and is intended for the treatment of chronic ulcers in patients. Its technology is based on the generation of a plasma jet produced with the noble gas argon. The novelty of this new plasma generator lies in the fact that its production is carried out by using atmospheric air, which implies greater efficiency and ease of use, being the first of its kind at an international level. The main mechanism of action underlying the therapeutic effect of cold atmospheric plasmas is the effect of the electric fields produced by the charged particles that make up the air in the plasma state. These fields are imperceptible to the patient, however, the effect on microcirculation in the area of application of the wound is very noticeable. The improvement in microcirculation extends for a longer time than the treatment as demonstrated by reported oxygen saturation studies using cold air plasmas DBD (Dielectric Barrier Discharge) that include clinical trials (1-4). Enhanced capillary blood flow increases local oxygen saturation and nutrient supply, thus promoting wound healing (5). In addition to the action of electric fields, there is an auxiliary decontamination mechanism generated by the emission of ultraviolet radiation, below the damage threshold for humans and excited and ionized oxygen and nitrogen molecules. This mechanism eliminates bacteria, including resistant ones, so that the regeneration capacity promoted by the main mechanism of action is enhanced (6-8). The generator chosen for this test belongs to the Spanish company ION BIOTEC S.L. (PlasmAction Med), which has obtained an international patent (9). Its use in animals has been successfully developed in veterinary clinics and the positive results obtained in the closure of torpid ulcers using cold atmospheric plasmas have been demonstrated (10-13). The plasma jet is applied directly to the lesion presented by the patient with a power of 55% and with an intensity and duration of 60 s/cm2, by means of the regulator found at the end of an application hose. It does not use consumables or produce waste.

Official Title
-----------------
Air Cold Atmospheric Pressure Plasma Treatment for Acceleration of Venous Ulcer Healing

Conditions
-----------------
Venous Leg Ulcer

Intervention / Treatment
-----------------
* Device: Cold Atmospheric Plasma Jet Treatment
* Device: Alginate Patch


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be of legal age (18 years). Signed informed consent. Presenting at least one venous ulcer larger than 1 cm2 that has not healed in the last 3 weeks from its appearance. Absence of surgical indication for ulcer coverage by skin graft. Exclusion Criteria: Uncontrolled diabetes mellitus (HbA1c > 8%). If during the trial the patient suffers a decompensation of diabetes, it will be considered an adverse event. Patient allergic to silver or any other material that will be used during the cure of the ulcer under study. Concomitant treatment with vacuum-assisted closure (VAC) therapy. Use of topical antibiotic therapy. The minimum washing time should be 48 hours. Presence of critical limb ischemia defined as an ankle-brachial index (ABI) below 0.5 or a transcutaneous O2 pressure (TcPO2) below 15 mmHg. Treatment with corticosteroids in the 14 days prior to the study or with other immunosuppressants. Presence of a chronic or active skin disorder that may negatively influence wound healing (such as Marfan or Ehlers-Danlos syndrome, systemic lupus erythematosus, systemic sclerosis, or psoriasis). Pregnancy or lactation. Advanced or metastatic stage cancer. Deficiency states. Dementia. Post radiation wounds. Sepsis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, open-label, controlled clinical trial with conventional treatment. Programming and continuous recruitment. The ulcers of the experimental group will be treated with 60 seconds/cm2 of the wound surface, carried out twice a week, and with alginate with silver. For their part, the ulcers in the control group will be treated with alginate with silver, which will also be replaced twice a week. The total duration of the trial for each patient will be 10 weeks (2 times per week) followed by 8 weeks of follow-up. The treatment will be carried out twice a week, maintaining at least 72 hours between treatments. The patients included in this trial will be all those who attend consultations or are hospitalized. They must present at least one venous ulcer larger than 1 cm2 that has not healed in the last 8 weeks from its onset and with no surgical indication for ulcer coverage by a skin graft.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cold Athmospheric Plasma Jet+Alginate patch<br>Leg Venous Ulcers will be treated in all patients belonging to the experimental arm using the PlasmAction Med cold plasma generator at atmospheric air pressure and alginate (Melgisorb Ag®) will be used after the plasma has been applied. | Device: Cold Atmospheric Plasma Jet Treatment<br>* Application of Colf Atmospheric Plasma Jet on the wound<br>Device: Alginate Patch<br>* Application of Alginate Patches on the wound<br>|
| Active Comparator: Alginate patch<br>For patients included in the control arm, alginate (Melgisorb Ag®) will be used as a cure for ulcers, size 10 X 10 cm and 5x5 (3 units), whose replacements will also be carried out twice a week. | Device: Alginate Patch<br>* Application of Alginate Patches on the wound<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ulcer Surface | The surface of the ulcer will be meassured by means of sofware image J2 | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of bacterial burden | Bacteriological cultures will be taken before and after of the treated group at 0, 5 and 10 weeks. Control groups at º, 5 and 10 weeks. | 18 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cold atmospheric plasma, venous ulcer, wound healing