A Double Blind Study Performed to Evaluate the Efficacy and the Safety of EscharEx in Debridement of VLU (VALUE)

Inclusion Criteria:

1. Men or women, older than 18 years of age,

2. Patients with a VLU (determined by medical history, physical examination, and adocumented ultrasound scan demonstrating venous insufficiency),

3. Wound is present for at least 4 weeks but no longer than 1 year,

4. The necrotic/slough/fibrin non-viable tissue area is 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 protocolregimen, and provides a written informed consent prior to any study procedure.

Exclusion Criteria:

1. Wound size decreased by > 20% after 1 week of standard-of-care-only period (screening period),

2. Patients with more than one leg ulcer , on the leg of the target wound, with an areagreater than or equal to 2 cm2,

3. Signs of clinical infection of the wound or peri-wound, including purulentdischarge, deep-tissue abscess, erysipelas, cellulitis, etc.,

4. Severely damaged skin (e.g. abrasion, erosion, exfoliation) extending >2 cm aroundthe wound's edge,

5. Presence of gangrene, signs of systemic infection, sepsis, or osteomyelitis duringscreening phase,

6. Clinical suspicion of skin cancer (e.g., basal cell carcinoma (BCC), squamous cellcarcinoma (SCC), melanoma, or sarcoma), near the target wound, which was not ruledout by biopsy,

7. Patients with skin disorders unrelated to the wound that are presented adjacent tothe wound,

8. Patients suffering from chronic skin disorders (Idiopathic Pruritus, Psoriasis,Panniculitis, Pyoderma gangrenosum, etc.) that might deteriorate as a result oflocal trauma or debridement,

9. Wound has sinus tracts or tunnels extending under healthy tissue or penetrating intoperiosteum, fascia or bone,

10. Patients with primary lymphatic edema (Lymphedema),

11. A significant decrease in the arterial blood flow of the extremity ,

12. Known small vessels disease (PVD) of any etiology,

13. Patients with pre-enrolment wounds which are covered by eschar heavily saturatedwith iodine or by silver sulfadiazine (SSD) pseudoeschar (i.e. pseudoeschar as aresult of SSD treatment),

14. History of allergy or atopic disease or a known sensitivity to pineapples,bromelain, papaya or papain, as well as known sensitivity to latex proteins (knownas latex-fruit syndrome), bee venom or olive tree pollen,

15. Patients with poor nutritional status: albumin < 2.5g/dl, poorly controlled diabetesMellitus (HbA1c > 12%), anemia (hemoglobin<8 g/dL), a leukocyte counts < 3,000/μl or >15000/μl, neutrophil count ≤1000/ μl, platelets <100,000/μl, abnormal liverfunction (AST, ALT>2 x upper limit of normal range), renal failure (Cr > 2.5 mg/dland eGFR < 30ml/ min /1.73m2), BMI>48,

16. INR>2 or PTT > x 2 ULN (unless the patient receives coumarin derivativesanticoagulants (e.g. warfarin), and the INR and PTT levels are in their requiredlevels and are stable),

17. Patients undergoing renal or peritoneal dialysis,

18. Any condition that would preclude safe participation in the study, e.g. significantor unstable cardiovascular, pulmonary, liver, hematological, immunological,neoplastic disease, active COVID-19, or any immediate life threatening condition,

19. Recent history or concurrent acute injury or disease that might compromise thepatient's welfare, according to investigator discretion,

20. Patient is currently receiving, or has received at any time within three monthsprior to enrollment, or is planned to receive during trial period, any medicationsor treatments known to affect the wound healing processes; these include chronicsystemic steroid intake with topical skin changes (i.e. thin, fragile skin withmultiple heamatomas or previous laceration history) immuno-suppressive drugs,immunomodulating medications, chemotherapy and radiation therapy,

21. In case the subject is treated with Pentoxifylline, dosing is stable less than 4weeks,

22. Mentally 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 three months prior to enrollment, oranticipated participation in another investigational drug trial or otherintervention trial, while enrolled in the study.