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
Phase: PHASE3
Conditions: Thermal Burns
Sponsor: MediWound Ltd

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 1 of 10 
 
FINAL 
 
CONFIDENTIAL 
SYNOPSIS 
Protocol Number: 
MW 2012-01-01 
Name of Investigational 
Medicinal Product 
(IMP): 
NexoBrid  
EudraCT.-No.: 
2014-003066-24 
IND 
065448 
Name of Active 
Ingredient: 
Concentrate of proteolytic enzymes enriched in bromelain 
Study 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 
Clinical Phase: 
3 
Study Duration: 
The total duration of the study treatment and follow up period of each 
participating 
subject 
is 
expected 
to 
be. 
at least 30 months after wound closure confirmation. Study duration 
will range from 31 months to 7 years and dependent on when the 
subject was enrolled. 
Study Population: 
Pediatric patients with thermal burn wounds defined as deep partial 
thickness and/or full thickness requiring hospitalization and who 
meet the entrance criteria will be enrolled in the study. 
Study Objective(s): 
To evaluate the safety and clinical benefit of NexoBrid in 
hospitalized children (0-18 years) with deep partial and/or full 
thickness thermal burns of 1-30% TBSA and to compare NexoBrid 
to standard of care (SOC). 
Study Design Overview: 
A total of 160 patients will be randomized into NexoBrid and SOC 
treatment (80 patients per arm)1.  
Age distribution will be managed as follows:  
o 45 patients ≥0 months and ≤23 months old 
o 45 patients ≥24 months and ≤3 years old 
o 30 patients ≥4 years and ≤11 years old 
                                                 
1 The study was completed with 145 patients (please refer to Appendix 14 – Update to study sample size due to 
COVID-19 pandemic for additional information) 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 2 of 10 
 
FINAL 
 
CONFIDENTIAL 
o 20 patients ≥12 years and <18 years old 
In addition, 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.  
Patients will be stratified on the basis of age groups (as applicable at 
each study stage): 0-23 months, 24 months-3yrs, 4-11yrs and 12-18 
yrs, on the basis of %TBSA, depth and center. 
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) from start of treatment until hospital 
discharge. Weekly follow-up assessments will be performed until 
complete 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). 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 3 of 10 
 
FINAL 
 
CONFIDENTIAL 
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 
Dosage and route of 
administration: 
Two grams or 5 grams of NexoBrid sterile powder are mixed in 20 
grams or 50 grams of sterile Gel Vehicle to obtain NexoBrid Gel. 
NexoBrid Gel is applied to the burn wound at a dose of 2g 
NexoBrid/20g Gel per 180cm² for four hours.  
In most cases, NexoBrid is effective after a single application; 
however it may be applied for a second time to the same burn area 
based on the investigator's judgment of debridement efficacy.  
NexoBrid should not be applied more than twice to the same burn 
wound area. 
NexoBrid should not be applied to more than 15% TBSA in one 
session. 
Inclusion/ Exclusion 
Criteria: 
Inclusion Criteria- Patient level 
1. 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. 
2. Thermal burns caused by fire/flame, scalds or contact. 
3. Patient total burns area  ≥ 1%  DPT and / or FT, 
4. Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or 
FT in depth,  
5. Signed written informed consent by a legal guardian can be 
obtained within 84 hours of the burn injury.  
Inclusion Criteria - Wound level 
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: 
1. Wound that is ≥ 1% TBSA (DPT and/or FT) (not including face, 
perineal or genital), 
2. 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, 
3. Wound that is intended for surgical eschar removal, 
4. Wound’s blisters can be unroofed, as judged by the investigator. 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 4 of 10 
 
FINAL 
 
CONFIDENTIAL 
Exclusion Criteria 
1. Patients weighing less than 3kg, 
2. Patients who are unable to follow study procedures and follow up 
period, 
3. Patients with electrical or chemical burns,  
4. Patient with a continuous burn area above 15% TBSA, 
5. Patients with no DPT and/or FT burn area (only SPT wounds), 
6. Patient with circumferential anterior/posterior trunk fire/flame 
burns, >15% TBSA (Circumferential is defined as encircling ≥ 
80% of the trunk circumference), 
7. The following pre-enrolment dressings: a. Flammacerium, b. 
Silver Nitrate (AgNO3), 
8. Serious pre-existing infection likely to impair the patient’s 
safety or to interfere with study procedures2   
9. Diagnosis of smoke inhalation injury, 
10. 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 >12h SSD treatment), 
11. Patients with pre-enrolment escharotomy, 
12. Pregnant women (positive pregnancy test) or nursing mothers, 
13. Poorly controlled diabetes mellitus (HbA1c>9%)3, 
14. Known 
Cardio-pulmonary 
disease, 
oxygen-dependent 
pulmonary diseases, broncho-pneumonia, uncontrolled asthma, 
15. Known conditions which interfere with circulation (peripheral 
vascular disease, edema, lymphedema, surgery to the regional 
lymph nodes, obesity), 
16. Any known conditions that would preclude safe participation in 
the study or add 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), 
                                                 
2 as described in Section Error! Reference source not found.of study protocol 
3 For patients weighing under 18 kg at screening, HbA1C will not be collected as a screening test. If an HbA1C result is 
available from the past 3 months, the result can be taken into consideration for inclusion. Otherwise, diabetic patients weighing 
less than 18 kg cannot be included. 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 5 of 10 
 
FINAL 
 
CONFIDENTIAL 
17. ASA greater than 2 (see Appendix 13 in study protocol) 
18. Chronic systemic steroid intake, 
19. History of allergy and/or known sensitivity to pineapples, 
papaya, Bromelain or papain, 
20. Current (within 12 months prior to screening) suicide attempt, 
21. Enrollment in any investigational drug trial within 4 weeks prior 
to screening, 
22. Current (within 12 months prior to screening) alcohol (daily 
consumption > 3 units for males and >2 units for females) or 
drug abuse4,  
23. Prisoners and incarcerated  
24. Patients who might depend on the clinical study site or 
investigator. 
25. Patient expresses objection to participate in the study. 
26. 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)  
27. General condition of patient would contraindicate surgery 
Outcome Measures: 
Primary Endpoint 
The below primary endpoint will be investigated primarily at the 
subject level, on the ITT population (please refer to Section Error! 
Reference source not found.).  
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. 
                                                 
4 DSM-IV Criteria for substance abuse: 
A pattern of substance use leading to significant impairment or distress, as manifested by one or more of the following during in the past 
12 month period:  
Failure to fulfill major role obligations at work, school, home such as repeated absences or poor work performance related to substance 
use; substance-related absences, suspensions, or expulsions from school; neglect of children or household  
Frequent use of substances in situation in which it is physically hazardous (e.g., driving an automobile or operating a machine when 
impaired by substance use)  
Frequent legal problems (e.g. arrests, disorderly conduct) for substance abuse  
Continued use despite having persistent or recurrent social or interpersonal problems (e.g., arguments with spouse about consequences 
of intoxication, physical fights)  
 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 6 of 10 
 
FINAL 
 
CONFIDENTIAL 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study 
and compared between NexoBrid and SOC on the ITT population, 
unless otherwise specified (please refer to Section Error! Reference 
source not found.).  
1. Reduction in surgical need- Demonstrate superiority of 
NexoBrid over SOC in reduction of surgical need for 
excisional eschar removal as measured by an analysis of 
incidence of surgical eschar removal (tangential/ minor/ 
avulsion/ Versajet and/or dermabrasion excision).  
2. Blood loss related to eschar removal- Demonstrate 
superiority of NexoBrid over SOC with regard to the blood 
loss occurred during the eschar removal procedures. 
3. Reduction in the need for autograft - Percent area of deep 
partial thickness wounds autografted 
4. Reduction in the need for autograft - Incidence of autograft 
performed in deep partial thickness wounds 
Safety Outcome Measures:  
1. Time to reach complete wound closure assessed in days, 
starting from randomization date  
2. Cosmesis and Function- will be measured using MVSS, 
to demonstrate that treatment with NexoBrid does not 
have any clinically meaningful deleterious effect on 
burns scars quality as compared to the quality of burns 
scars treated with SOC, measured at 12 months from 
wound closure date, by a blinded assessor.  
3. Cosmesis and Function- will be measured using MVSS, 
to demonstrate that treatment with NexoBrid does not 
have any clinically meaningful deleterious effect on 
burns scars quality as compared to the quality of burns 
scars treated with SOC, measured at 24 months from 
wound closure date, by a blinded assessor.  
4. Additional Safety Outcome Measures:  
a. General parameters: Systemic adverse events, vital 
signs, pain assessment (using FPS-R and as reported as 
AEs), laboratory tests, units (and volume) of blood 
transfusion given during hospitalization, 
Immunogenicity evaluation for NexoBrid patients, 
Pyrexia and Hyperthermia, Systemic infections, Extent 
of antibiotic use (i.e. number of days of exposure), Rates 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 7 of 10 
 
FINAL 
 
CONFIDENTIAL 
of hospital readmission, Change in INR/PTT and 
incidence of change to > upper limit of normal (after 
treatment), Change in blood glucose and incidence of 
change to above upper limit of normal (after treatment).  
b. Long term functionality evaluation of the extremities 
using the ‘Lower Extremity Functional Scale’, 
'QuickDASH' questionnaires and 'Range Of Motion' 
measurements,  
c. Long term Quality of Life using EQ5D and BOQ for a 
subset of patients.  
d. Local parameters: Local adverse events defined by 
treating physician or designee; graft loss, wound related 
infections, etc.  
Exploratory Endpoint  
1. Incidence of surgical escharotomy procedures on 
circumferential extremities target wounds, 
2. Incidence of reduction in interstitial/compartment 
pressure 
in 
circumferential 
extremity 
wounds 
(measured immediately following eschar removal), 
3. Reduction in surgical needs as measured by an analysis 
of % wound area surgically excised for eschar removal. 
4. Reduction in surgical need as measured by analysis of 
incidence of surgically harvested donor sites scars, 
5. Reduction in surgical need as measured by analysis of 
% area of surgically harvested donor site scars. 
6. Blood loss related to eschar removal assessed by changes in 
Hemoglobin incurred during the eschar removal procedures  
7. PK evaluation in NexoBrid patients 
8. Cosmesis and Function: Demonstrate non-inferiority to 
SOC in quality of scars of burns using POSAS treated 
with NexoBrid, measured at 12 months from wound 
closure, 
9. Cosmesis and Function: Demonstrate non-inferiority to 
SOC in quality of scars of burns using POSAS treated 
with NexoBrid, measured at 24 months from wound 
closure, 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 8 of 10 
 
FINAL 
 
CONFIDENTIAL 
10. Duration of hospitalization. 
 
Statistical 
Plan 
& 
Sample size: 
 
 
 
 
Primary Endpoints 
The following primary endpoint will be evaluated in this study at a 
‘per patient’ level: 
1. Earlier eschar removal- Analysis will be based on the time from 
the date of randomization. NexoBrid will be compared with SOC 
using Cox regression analysis. Kaplan-Meier curves will be 
presented graphically to display the distribution of time to 
complete eschar removal under the two treatments.  
Subgroup analyses are based on the following: Age groups 
(Comparison of 0-23 months; 24 months-3 years; 4-11 years; 12-18 
years). 
Safety 
The assessment of safety will be based on the safety collective and 
mainly on the frequency of adverse events and on the observation of 
clinically significant abnormalities of laboratory values as well as 
additional safety data (e.g., vital signs, pain by FPS-R, etc). 
PK parameters will be presented in summary tables including sample 
size, mean, SD, median, minimum and maximum values. Graphical 
presentation will be produced presenting the calculated AUC for 
each subject, a summary PK profile for all subjects, and summary PK 
profiles according to age groups and % TBSA treated. 
Antibodies presence will be determined based on a three-tiered 
approach analysis of plasma samples drawn prior to start of eschar 
removal and up to follow up visit at 24 months.  
Sample Size Calculation 
The following sample size calculation is based on the consideration 
of the primary endpoint of this study. 
Primary Endpoint: Time to Complete eschar removal 
Based on calculated HR (Hazard Ratio) from study MW2004-11-02, 
for 90% overall power, number per group = 22. 
In accordance with the European regulatory requests and planned age 
distribution, we believe that a sample size of 80 patients per arm will 
detect with a 90% power a difference on the primary endpoint, which 
is well within what would be expected based on the results from the 
previous study.  
Based on the above calculations, we plan a study with total sample 
size of 160 patients; 80 (NexoBrid) + 80 (SOC). 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 9 of 10 
 
FINAL 
 
CONFIDENTIAL 
Stages of Analysis 
The analysis is planned to be carried out in three stages, as 
described below. 
The first analysis will be performed at the end of the 12 months 
follow up period. This analysis will be the only inductive 
analysis of the trial and will include statistical tests for the 
primary and secondary endpoints as described above, as well 
as the 12 months safety endpoints. At this time-point, data will 
be available for all patients on the primary and secondary end-
points, as well as the 12 months safety endpoints. Missing 
values for early dropouts etc. will be handled as described in 
Section 15.8.4 and the SAP. The complete data set documented 
so far will be locked and analyzed as described above. The 24 
months MVSS data, although captured in the eCRF for a few 
of the subjects at this stage, will not be included, revealed (the 
medical assessor will remain blinded to the treatment arm) or 
analyzed during the first stage of analyses. 
The second analysis covers the data of the full 24 months safety 
follow up. It will be conducted after the last patient has reached the 
24 months assessment, 12 months after the first stage of analysis. At 
this analysis, all accumulated safety endpoints at the 24 months 
follow up will be evaluated. 
The third and final analysis will cover the data derived from the 
additional long term follow up visit that will be performed at least 30 
months post wound closure confirmation. Study results will be 
summarized in descriptive manner. 
Descriptive statistics for continuous variables will include n, mean, 
standard deviation, standard error of the mean, median, minimum 
and maximum.  
Descriptive statistics for categorical variables include patient counts 
and percentages. 

Running 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 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 10 of 10 
 
10