A Study to Evaluate the Efficacy and Safety of NexoBrid in Subjects With Thermal Burns

This is a multi-center, multi-national, randomized, controlled, assessor blinded, three-arm
study aiming to demonstrate superiority of NexoBrid treatment over Gel Vehicle control and
over SOC treatment in thermal burn subjects with burns. Following the enrollment of a patient
to the study and prior to randomization Physicians will define one or more Target Wounds
(TWs) per subject according to TWs definition. All subjects' deep (DPT and FT) burns that
comply with the specified entrance criteria are intended to receive study treatment per the
randomized study arm.

The randomization procedure will be initiated only after all Target wounds of a subject have
been defined. Patients will be assigned to the treatment arm in a 3:3:1 ratio (NexoBrid: SOC
: Gel Vehicle).

Patients will be treated in the same way in all study arms (NexoBrid, SOC or Gel vehicle)
except for the eschar removal stage which will be performed as per the randomization study
arm.

Prior to initiation of eschar removal treatment, subjects will be medicated with appropriate
analgesia and undergo wound cleansing and dressing of all wounds with antibacterial solutions
. Following wound cleansing and antibacterial treatments, subjects will undergo the eschar
removal process as per treatment assignment (NexoBrid, SOC or Gel Vehicle, following
randomization).

Subsequent to complete eschar removal, all wounds will be assessed and treated in the same
manner, in accordance with post-eschar removal wound care strategy. Post eschar removal,
subjects will undergo daily vital signs and pain assessments, until hospital discharge (HD)
and weekly assessments of wound progress, until wound closure. Following wound closure
confirmation visit, subjects will be followed up at 1, 3, 6, 12, 18 and 24 months post wound
closure for long term outcomes evaluation.

Inclusion Criteria- Patient level

1. Males and females; ≥ 18

2. Thermal burns caused by fire/flame, scalds or contact,

3. Patient total burns area ≥ 3% DPT and / or FT,

4. Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or FT in depth,

5. Informed consent can be obtained within 84 hours of the burn injury,

6. Patients who are willing and able to sign a written consent form.

Inclusion Criteria - Wound level

1. At least one wound (a continuous burn area) that is ≥0.5% TBSA (DPT and/or FT) (this
minimal wound size should not including face, perineal or genital area.

All planned target wounds (TWs) should meet the following criteria:

2. SPT area that cannot be demarcated from DPT and FT areas should be less than 50% of
the % TBSA of the TW.

3. Wound's blisters can be removed/ unroofed, as judged by the investigator.

Exclusion Criteria- Patient level

1. Patients who are unable to follow study procedures and follow up period.

2. Modified Baux index ≥ 80,

3. Patients with burned charred fingers, 3rd degree in depth and possibly devoid of
circulation,

4. Patients with abraded wound/s that cannot be treated by an enzymatic debrider
application (NexoBrid) will be excluded from the study,

5. Patients with electrical or chemical burns,

6. Patients with circumferential (≥ 80% of the limb circumference) DPT and/or FT burns
defined as Extremities at Risk (EAR) 2 as described in the protocol.

7. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3),

8. Patients with pre-enrolment wounds which are covered by eschar heavily saturated with
iodine or by SSD pseudoeschar (e.g. pseudoeschar as a result of > 12 hours SSD
treatment),

9. Patients with pre-enrollment escharotomy.

10. Patients with diagnosed infections as described in Section 11.9 of study protocol,

11. Diagnosis of smoke inhalation injury.

12. Pregnant women (positive pregnancy test) or nursing mothers.

13. Poorly controlled diabetes mellitus (HbA1c>11%) in patients with known diabetes as
captured in the medical history.

14. BMI greater than 39.0 kg/m2 in patients with burn area up to 15% TBSA or BMI greater
than 34.0 kg/m2 in patients with burn area more than 15% TBSA.

15. ASA greater than 2 (Appendix 13- ASA classification system)

16. Cardio-pulmonary disease (MI within 6 months prior to injury, severe pulmonary
hypertension, severe COPD or pre-existing oxygen-dependent pulmonary diseases, severe
broncho-pneumonia within 1 month prior to injury , steroid dependent asthma or
uncontrolled asthma).

17. Pre-existing diseases which interfere with circulation (severe peripheral vascular
disease, edema, lymphedema, regional lymph nodes, significant varicose veins),

18. Any conditions that would preclude safe participation in the study or adding further
risk to the basic acute burn trauma (such as severe immuno-compromising diseases, life
threatening trauma, severe pre-existing coagulation disorder,severe cardiovascular
disorder,significant pulmonary disorder, significant liver disorder including post
alcoholic abuse impaired function or neoplastic disease, blast injury)

19. Chronic systemic steroid intake,

20. History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or
papain,

21. Current (within 12 months prior to screening) suicide attempt,

22. Mentally incapacitated adults who are incapable of giving legal consent

23. Enrollment in any investigational drug trial within 4 weeks prior to screening,

24. Current (within 12 months prior to screening) alcohol or drug abuse (see definition in
section 1.1)

25. Prisoners and incarcerated,

26. Patients who might depend on the clinical study site or investigator.