The main objective of this study is:

To assess the efficacy and safety of EscharEx (EX-03 5% formulation) compared to placebo control,in debridement and wound bed preparation of Venous Leg Ulcers (VLU).

At least 216 eligible adult patients with VLU (with a surface area between 2 cm2 and 25 cm2, and wound age between 4 weeks and 12 months), will be randomized. The patients will be treated with IMP (either EX-03 5% or placebo) in a double blinded manner.

Total duration of the study is up to 29 weeks:

1. Screening period (2 visits, 7 days apart),
2. Daily Visits Period - Debridement with IMP (up to 8 daily site visits within up to 2 weeks),
3. Weekly Visits Period - wound management (up to 13 visits within up to 12 weeks) + optional wound closure confirmation (up to 2 weeks). Wound will be managed in a standardized manner.
4. Monthly Visits Period - Wound Closure Durability Period of 12 weeks starting after wound closure confirmation (3 visits within 12 weeks) performed for all wounds.

Inclusion Criteria:

1. Men or women, older than 18 years of age,
2. Patients with a VLU (determined by medical history, physical examination, and a documented ultrasound scan demonstrating venous insufficiency),
3. Wound is present for at least 4 weeks but no longer than 1 year,
4. The adherent necrotic/thick slough/fibrin non-viable tissue area, assessed following wound cleansing with wet gauze and either sterile saline or water and mild soap, at least 50% of the wound area (assessed by clinical evaluation),
5. Target wound surface area is in the range of 2-25 cm2 (assessed by eKare inSightTM),
6. Patient understands the nature of the procedure, is able to adhere to the protocol regimen, and provides a written informed consent prior to any study procedure.

Exclusion Criteria:

1. Wound size that has decreased by > 20% after 7 (+3/-1) days of the screening period,
2. Patients with more than one leg ulcer, on the leg of the target wound, with an area greater than or equal to 2 cm2, that are between 2cm and 5cm away from the edge of the target wound,
3. Signs of clinical infection of the wound or peri-wound, including purulent discharge, deep-tissue abscess, erysipelas, cellulitis, etc.,
4. Severely damaged skin (e.g. abrasion, erosion, exfoliation) extending >2 cm around the wound's edge,
5. Presence of gangrene, signs of systemic infection, sepsis, or osteomyelitis during screening phase,
6. Clinical suspicion of skin cancer (e.g., basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma, or sarcoma), near the target wound, which was not ruled out by biopsy,
7. Patients with skin disorders unrelated to the wound that are presented adjacent to the wound,
8. Patients suffering from chronic skin disorders (Idiopathic Pruritus, Psoriasis, Panniculitis, Pyoderma gangrenosum, etc.) that might deteriorate as a result of local trauma or debridement,
9. Wound has sinus tracts or tunnels extending under healthy tissue or penetrating into periosteum, fascia or bone,
10. Patients with primary lymphatic edema (Lymphedema),
11. A significant decrease in the arterial blood flow of the extremity, as demonstrated by either Toe-Brachial Index (TBI) ≤ 0.50, Ankle-Brachial Index (ABI) ≤ 0.70, Skin Perfusion Pressure (SPP) ≤ 40 mmHg, Transcutaneous oximetry (TCOM) ≤ 40 mmHg, or lack of bi-phasic or tri-phasic doppler wave forms,
12. Patients with pre-enrollment wounds which are covered by eschar heavily saturated with iodine or by silver sulfadiazine (SSD) pseudoeschar (i.e., pseudoeschar as a result of SSD treatment),
13. History of allergy or atopic disease or a known sensitivity to pineapples, bromelain, papaya or papain, as well as known sensitivity to latex proteins (known as latex-fruit syndrome), bee venom or olive tree pollen,
14. Patients with poor nutritional status: albumin < 2.5 g/dl; poorly controlled diabetes mellitus (HbA1c > 12%); anemia (hemoglobin<8 g/dL), leukocyte count < 3,000/μl or >15000/μl; neutrophil count ≤1000/μl; platelets <100,000/μl, abnormal liver function (AST, ALT>2 x upper limit of normal range), renal failure (Cr > 2.5 mg/dl or eGFR < 30ml/min /1.73m2), BMI>48,
15. INR>2 or PTT > x 2 ULN (unless the patient receives coumarin derivatives anticoagulants (e.g. warfarin), and the INR and PTT levels are in their required levels and are stable),
16. Patients undergoing renal or peritoneal dialysis,
17. Any condition that would preclude safe participation in the study, e.g., significant or unstable cardiac, vascular, pulmonary, liver, hematological, immunological, neoplastic disease, active COVID-19 or any immediate life-threatening condition,
18. Recent history or concurrent acute injury or disease that might compromise the patient's welfare, according to investigator discretion,
19. The patient is currently receiving, has received within three months prior to enrollment, or is planned to receive during trial period, any medications or treatments at doses known to impair the wound healing processes. These include chronic systemic steroid intake5 associated with topical skin changes (i.e. thin, fragile skin with multiple hematomas or a history of laceration), immuno-suppressive drugs, immunomodulating medications, chemotherapy, and radiation therapy. Low and intermittent doses that the investigator determines as not clinically significant for wound healing, may be permitted, provided that this determination is based on appropriate clinical judgment and is documented accordingly,
20. Patients treated with Pentoxifylline within 2 weeks prior to screening,
21. Venous ablation performed within the past month in an area adjacent to the target wound,
22. Mentally incapacitated incompetent adults who are incapable of giving legal consent (e.g., dementia, psychiatric patients, etc.),
23. Concurrent use of non-approved drugs or alcohol abuse,
24. Pregnant women (positive pregnancy test) or nursing mothers,
25. Exposure to investigational intervention within one month prior to enrollment, or anticipated participation in another investigational drug trial or other intervention trial, while enrolled in the study.

double blinded