A Study to Evaluate the Efficacy and Safety of NexoBrid in Children With Thermal Burns Compared the Standard of Care

Study Overview
=================
Brief Summary
-----------------
This study will be a two-arms study intending to demonstrate superiority of NexoBrid treatment over SOC in children with thermal burns. The study objective is to evaluate the safety and clinical benefit of NexoBrid in hospitalized children (0-17 years) with deep partial and/or full thickness thermal burns of 1-30% TBSA and to compare NexoBrid to standard of care (SOC).

Detailed Description
-----------------
A total of 160 patients will be randomized into NexoBrid and SOC treatment (80 patients per arm). Age distribution will be managed as follows: 45 patients 0-23 months old 45 patients 24 months-3 years old 30 patients 4-11 years old 20 patients 12-17 years old The remaining 20 patients will be enrolled to any of the above groups, per their age during enrollment. The study will be conducted in three stages. In Stage I, at least 24 children age 4-18 years, hospitalized in burn units, with deep partial thickness burns ranging from 1%-30% TBSA, and who meet the entrance criteria, will be enrolled. Upon completion of stage I, a safety analysis will be performed on safety parameters and the results will be evaluated by a Data Safety Monitoring Board (DSMB) as defined in the agreed charter. If the DSMB does not have any safety concerns, Stage II will commence, this time enrolling at least 26 additional children aged of 1-18 years according to the study procedures. A DSMB will be convened to assess the safety data of the first 50 patients enrolled at stages 1 & 2. If the DSMB has not found any safety concerns, stage III will commence in which patients from the age of birth to 18 years will be included (stage III will include 110 remaining patients required to reach a total of 160 patients). Following the enrollment of a subject to the study and prior to randomization, physicians will define one or more Target Wounds (TWs) per subject according to TWs definition. All subjects' DPT and FT burns that fit the specified criteria are intended to receive study treatment per randomized study arm and therefore, must be designated as TWs. Prior to eschar removal treatment with NexoBrid or SOC 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 or SOC, following randomization). Subsequent to eschar removal, all wounds will be assessed and treated in the same manner, in accordance with post-eschar removal wound care strategy. Furthermore, subjects will undergo daily assessments (Vital signs (VS) and pain assessments) for one week and weekly assessments thereafter, until wound closure. Following wound closure, subjects will be followed up at 6 weeks, 12 weeks, and after that, at 6, 12, 18 and 24 months (for a blinded assessment of cosmesis, function and QoL evaluation). All subjects will be invited to one additional extended follow up visit that will occur at least 30 months after wound closure confirmation for a blinded assessment of cosmesis, function and QoL evaluation.

Official Title
-----------------
A Multicenter, Multinational, Randomized, Controlled, Open Label Study, Performed in Children With Thermal Burns, to Evaluate the Efficacy and Safety of NexoBrid as Compared to Standard of Care (SOC) Treatment

Conditions
-----------------
Thermal Burns

Intervention / Treatment
-----------------
* Drug: NexoBrid
* Procedure: Standard of Care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Stage 1: Males and females between 4 years to 18 years of age, Stage 2 (upon DSMB review): Males and females between 1 year to 18 years of age, Stage 3 (upon DSMB review): Males and females between 0 years to 18 years of age. Thermal burns caused by fire/flame, scalds or contact. Patient total burns area ≥ 1% DPT and / or FT, Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or FT in depth, Signed written informed consent by a legal guardian can be obtained within 84 hours of the burn injury. At least one wound (a continuous burn area which can be treated in one session; might include several anatomical areas) in a patient should meet all following criteria: Wound that is ≥ 1% TBSA (DPT and/or FT) (not including face, perineal or genital), Wound is composed of DPT and/or FT in depth. Superficial partial thickness areas may be included in the wound area only if cannot be separated from deeper areas (e.g. surrounded by or mixed with DPT areas) and might interfere with the treatment of the deeper areas, Wound that is potentially intended for surgical eschar removal, Wound's blisters can be unroofed, as judged by the investigator. Exclusion Criteria: Patients weighing less than 3kg, Patients who are unable to follow study procedures and follow up period, Patients with electrical or chemical burns, Patient with a continuous burn area above 15% TBSA, Patients with no DPT and/or FT burn area (only SPT wounds), Patient with circumferential anterior/posterior trunk fire/flame burns, >15% TBSA (Circumferential is defined as encircling ≥ 80% of the trunk circumference), The following pre-enrolment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3), Patients with diagnosed infections, Diagnosis of smoke inhalation injury, Patients with pre-enrolment wounds which are covered by eschar saturated with iodine or by SSD pseudoeschar (e.g. pseudoeschar as a result of >12h SSD treatment), Patients with pre-enrolment escharotomy, Pregnant women (positive pregnancy test) or nursing mothers, Poorly controlled diabetes mellitus (HbA1c>9%), Known Cardio-pulmonary disease, oxygen-dependent pulmonary diseases, broncho-pneumonia, uncontrolled asthma, Known conditions which interfere with circulation (peripheral vascular disease, edema, lymphedema, surgery to the regional lymph nodes, obesity), Any known conditions that would preclude safe participation in the study or adding further risk to the basic acute burn trauma (such as immuno-compromising diseases, life threatening trauma, severe pre-existing coagulation disorder, pulmono-cardiovascular, liver or neoplastic disease), ASA greater than 2 Chronic systemic steroid intake, History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or papain, Current (within 12 months prior to screening) suicide attempt, Enrollment in any investigational drug trial within 4 weeks prior to screening, Current (within 12 months prior to screening) alcohol (daily consumption > 3 units for males and >2 units for females) or drug abuse, Prisoners and incarcerated Patients who might depend on the clinical study site or investigator. Patient expresses objection to participate in the study. Patients with other severe cutaneous trauma at the same sites as the burns (i.e. blunt, avulsion or deep abrasion) or previous burn(s) at the same treatment site(s) General condition of patient would contraindicate surgery

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 17 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NexoBrid Gel<br>NexoBrid Gel is applied to the burn wound at a dose of 2g or 5g NexoBrid sterile powder mixed with 20g or 50g sterile Gel Vehicle per 180cm^2 of TBSA for four hours. | Drug: NexoBrid<br>* NexoBrid is an enzymatic debriding agent for Eschar Removal.<br>|
| Active Comparator: Standard of Care<br>Non surgical and Surgical Debridement | Procedure: Standard of Care<br>* Surgical or Non-Surgical methods for Eschar Removal<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Earlier eschar removal (in days) | Demonstrate superiority over SOC for eschar removal as measured by a survival analysis of incidence of complete eschar removal as a function of time. Eschar removal will be measured at the end of the debridement starting from randomization date. | participants will be followed from randomization date and daily for the duration of hospital stay, an expected average of 3 weeks |