Conditions: Thermal Burns
Keywords: fire/flame scalds contact
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 175
Healthy volunteers: no

Brief summary:
This study will be a three-arms study intending to demonstrate superiority of NexoBrid treatment over the Gel Vehicle placebo control treatment and over SOC in thermal burn subjects.

The study objectives are:

1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing complete eschar removal as compared with Gel vehicle,
2. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing earlier complete eschar removal, reduction in patients' surgical burden and its related blood loss as compared to SOC,
3. To assess the safety of NexoBrid compared to SOC, including demonstration that treatment with NexoBrid does not cause an unacceptable level of harm on wound closure outcome and long term outcomes of cosmesis and function.

Detailed description:
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.

Arms:
arm 1: NexoBrid Gel is applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile Gel Vehicle per 1% of TBSA (\~ surface of an adult palm) for four hours. arm 2: Gel Vehicle is applied to the burn wound at a dose of 20 g sterile Gel per 1% of TBSA (\~ surface of an adult palm) for four hours. arm 3: Subjects in the SOC group may be treated with a combination of surgical and non-surgical eschar removal procedures, according to the investigator's judgment.

Interventions: intervention 1: NexoBrid intervention 2: Standard of Care (SOC) intervention 3: Gel Vehicle
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
SAP_004.pdf: 
 
 
 
ADDENDUM TO STATISTICAL ANALYSIS 
PLAN 
 
Clinical Trial 
 
A multicenter, multinational, randomized, controlled, assessor blinded study, performed in 
subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid compared to Gel 
Vehicle and compared to Standard of Care (DETECT) 
 
 
Sponsor: 
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Trial protocol code: MW2010-03-02 
EudraCT number: 2014-001672-55 
IND No.: 65,448 
 
 
Competence Center for Clinical Trials Bremen - Biometry 
Author: Dr. Martin Scharpenberg 
Version of 26 February 2020, Addendum to Version V03 
 


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1. Table of Contents 
1. 
Table of Contents 
2 
2. 
Study Administrative Structure 
3 
2.1. 
Sponsor 
3 
2.2. 
Study Conduct 
3 
2.3. 
Statistics 
4 
3. 
Signatures 
5 
4. 
List of Abbreviations 
6 
5. 
Rationale for the Addendum 
7 
 


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2. Study Administrative Structure 
2.1. Sponsor 
Sponsor: 
MediWound, Ltd 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Represented by: 
Prof. Lior Rosenberg 
Chief Medical Officer 
MediWound Ltd. 
 
 
Keren David Zarbiv 
Director Clinical Affairs 
MediWound Ltd. 
 
 
Nimrod Leuw 
Director of QA/QC 
MediWound Ltd. 
2.2. Study Conduct 
Study Conduct (CRO): 
Dr. Marco Schwarzer 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen 
 
 


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2.3. Statistics 
Statisticians: 
Prof. Dr. Dr. h.c. Jürgen Timm 
Dr. Martin Scharpenberg 
Competence Center for Clinical Trials Bremen 
University of Bremen 
Linzer Str. 4 
28359 Bremen 
Germany 


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3. Signatures 
Keren David Zarbiv 
 
 
 
 
Sponsor Representative 
Signature 
 
Date 
MediWound Ltd. 
 
 
Dr. Marco Schwarzer 
 
 
 
 
Study Conduct (CRO) 
Signature 
 
Date 
GCP-Service International Ltd. & Co. KG 
 
 
Prof. Dr. Dr. h.c. Jürgen Timm 
 
 
 
 
Principal Statistician 
Signature 
 
Date 
Competence Center for Clinical Trials Bremen, 
University of Bremen 
 
Dr. Martin Scharpenberg 
 
 
 
 
Statistician/Author 
Signature 
 
Date 
Competence Center for Clinical Trials Bremen, 
University of Bremen 
 
 


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4. List of Abbreviations 
abbreviation 
meaning 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
BLA 
Biologics License Application 
CSR 
Clinical Study Report 
FDA 
Food and Drug Administration 
INR 
International Normalized Ratio 
ITT 
Intention to Treat 
KKSB 
Competence Center for Clinical Trials Bremen 
PT 
Preferred Term 
PTT 
Prothrombin Time 
SAE  
Serious Adverse Event 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TW 
Target Wound 
 
 


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Statistical Analysis Plan Addendum to V03 of 26 February 2020 
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5. Rationale for the Addendum 
This addendum describes safety data analyses to be performed in addition to the final SAP 
(Version 3, 29 November 2018). The decision to add these analyses was made after breaking 
the blinding and in knowledge of the primary statistical analysis results computed in 
accordance with the SAP.  
All originally planned analyses, as described in the final SAP, version 3, were performed and 
summarized in a Statistical Analysis Report dated 20 June 2019. Changed outputs described 
in this document will be implemented in the study CSR. The sponsor requested these ad hoc 
analyses in order to support the interpretation of the safety data statistical analysis results and 
to fulfil the FDA request for treatment emergent Adverse Events analysis as noted in the pre-
BLA meeting minutes.  
Furthermore, the calculation of some variables is adapted to be conform with the Analysis Data 
Model (ADaM) Implementation Guide v1.1. and to be consistent throughout the analysis.  


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6. General changes 
Some general changes to the layout of tables described in the SAP will be performed: 
 
For some tables, the treatment arms will be presented in columns rather than rows, to 
facilitate between-treatment-group comparisons. 
 
Descriptive statistics tables will be combined for some baseline characteristics. 
 
The number of censored observation will be added to the tables of descriptive statistics 
for time to event endpoints. 
Statistical analyses for all safety parameters which were described in the SAP are included in 
the Statistical analysis report, yet will not be included in appendix 14 of the CSR and is 
available upon request. 
Furthermore, the calculation of some variables is adapted as follows to be conform with the 
Analysis Data Model (ADaM) Implementation Guide v1.1. and to be consistent throughout the 
study: 
 
AGE (Age) = RFICDTC (Date of Informed Consent) – BRTHDTC (Date of Birth) 
In the SAP, the date of physical examination instead of the date of informed consent is 
used which leads to missing age for two screening failures. 
 
CHG (Change from baseline) = AVAL (Analysis Value) – BASE (Baseline Value)  
According to the SAP, the change from baseline should be calculated as BASE – AVAL which 
is not conform with the ADaM Implementation Guide. The calculation of pre-post differences 
is adapted accordingly (i.e. pre-post difference = post value – pre-value) to be consistent with 
the calculation of the change from baseline. However, the calculation described in the SAP will 
still be done (variable: BCHG) and form the basis of the analyses presented in the CSR. 


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7. Additional Analyses 
7.1. Central Laboratory values 
Shift tables for central laboratory values indicating shifts from baseline to post every type of 
eschar removal procedure (first application, additional application, surgical application, 
additional surgical application, and nonsurgical application) will be produced (see Table 1). 
Furthermore, shift tables indicating shifts from baseline to any low/high or no low/high values 
will be presented (see Table 2). 
Additional tables will indicate shifts from baseline to any post treatment clinically significant 
result (see Table 3). A listing of subjects experiencing such shifts will be provided. 
The above tables will be presented for biochemistry parameters, hematology parameters and 
urine analysis parameters separately, and for parameters with numeric values only. 
7.2. Local Laboratory values 
The following sets of tables will be produced separately for INR and PTT: 
 
Shift tables indicating shifts from baseline to post first application, 24 hours past start 
and 48 hours past start, similar to Table 1 
 
Shift tables indicating shifts from baseline to any low/high or no low/high values post 
treatment (see Table 2) as well as a listing of subject experiencing such shifts 
 
Shift tables indicating shifts from baseline to any post treatment clinically significant 
result (see Table 3) as well as a listing of subjects experiencing such shifts  
7.3. Vital signs 
For the vital signs assessments, shift tables will be produced indicating shifts from baseline to 
any post-treatment time point (post first treatment, post second treatment, and post third 
treatment), as well as to the daily assessments for day 1 to day 7 (see Table 4). 


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Furthermore, shift tables indicating shifts from baseline to any post treatment clinically 
significant result (as in Table 3) will be provided. A subject listing of patients experiencing such 
shifts will be provided. 
7.4. Pain 
For the pain assessment, shift tables will be produced indicating the shift from baseline to pre 
and post any treatment time point (first application, additional application, surgical application, 
additional surgical application, and nonsurgical application), as well as to the daily 
assessments for day 1 to day 7 (see Table 4). 
Furthermore, shift tables indicating shifts from baseline to any post treatment clinically 
significant result (see Table 5 ) will be provided.  
7.5. Adverse Events 
The following tables will be produced in addition to the tables described in the SAP: 
 
Summary of Treatment Emergent Adverse Events (TEAEs) on a subject level (see 
Table 6) 
 
Summary of TEAEs by System Organ Class (SOC), and Preferred Term (PT) (see 
Table 7) separately for: 
o All TEAEs 
o Treatment related TEAEs 
o General TEAEs 
o Local, not TW-related TEAEs 
o Local, TW-related TEAEs 
o TEAEs with PTs related to fever (Pyrexia, Body Temperature Increased, 
Hypothermia) 
o TEAEs with Target Wound Infections (only if Local, TW-related: Wound 
Infection Bacterial, Staphylococcal Skin Infection, Wound Infection, Wound 
Infection Staphylococcal) 
o Pain TEAEs (Pain: Pain; Post-traumatic pain; Uncontrolled pain in TW1,2 and 
3; Pain in extremity [if Local, TW-related]) 


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o TEAEs including Tachycardia PTs (Sinus Tachycardia, Tachycardia) 
 
Summary of TEAEs by SOC, PT, and time of onset (see Table 8) separately for: 
o All TEAEs 
o General TEAEs 
o Local, not TW-related TEAEs 
o Local, TW-related TEAEs 
o All Treatment Emergent Serious Adverse Events (TESAEs) 
 
Summary of TEAE by SOC, PT and maximum intensity (see Table 9). In this table, 
patients who experienced multiple AEs with the same PT, but different intensities will 
be counted only once per PT with their maximum intensity. Subjects with multiple AEs 
with the same SOC but different intensities will be counted only once per SOC with 
their maximum intensity in the SOC row. This table will be produced separately for: 
o All TEAEs 
o Treatment related TEAEs 
o General Treatment related TEAEs 
o Local, not TW-related Treatment related TEAEs 
o Local, TW-related Treatment related TEAEs 
o All TESAEs 
o Treatment related TESAEs 
All AE/SAE/TEAE/TESAE tables will be produced separately for Adverse Events occurring in 
the acute phase, in the second stage (3-12 months), and combined for the time frame 0-12 
months. 
7.6. Subgroup Analysis 
7.6.1. 
Target wounds in the anatomical area of the hand 
Additional to the subgroup analysis described in the SAP, which was defined on a subset of 
target wounds, the primary and secondary endpoint were also analyzed on a patient level using 
the subgroup of patients having at least one target wound that is found, at least partly, in the 
anatomical area of the hand. 


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7.6.1. 
Target wounds that are entirely full thickness 
Additional to the subgroup analysis described in the SAP, which was defined on a subset of 
target wounds (i.e. all target wounds that are entirely full thickness), the primary and secondary 
endpoint were also analyzed on a patient level using the subgroup of patients having at least 
one target wound that is entirely full thickness. 


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8. Lay-out and list of tables 
Table 1: Laboratory Value Shift Table for Changes from Baseline 
 
Time point 
Lab Value 
 
Treatment 
 
Baseline 
 
 
Low: 
<32 
n (%) 
Normal: 
32-50 
n (%) 
High: 
>50 
n (%) 
Missing 
n (%) 
Total 
n (%) 
 
Value [unit] 
NexoBrid 
(N = xxx) 
<32 
 
 
 
 
 
 
 
32-50 
 
 
 
 
 
 
 
>50 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Value [unit] 
SOC 
(N = xxx) 
<32 
 
 
 
 
 
 
 
32-50 
 
 
 
 
 
 
 
>50 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 


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Time point 
Lab Value 
 
Treatment 
 
Baseline 
 
 
Low: 
<32 
n (%) 
Normal: 
32-50 
n (%) 
High: 
>50 
n (%) 
Missing 
n (%) 
Total 
n (%) 
Value [unit] 
Gel Vehicle 
(N = xxx) 
<32 
 
 
 
 
 
 
 
32-50 
 
 
 
 
 
 
 
>50 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
N = number of subjects with the respective eschar removal procedure; N/A = not applicable, 
n = number of subjects with respective category, 
% = n/N*100 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 
 


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Table 2: Laboratory Value Shift Table, Shift to Any Low or High 
 
Any post-treatment time point 
Lab Value 
 
Treatment 
 
Baseline 
 
Any Low 
n (%) 
No Low 
n (%) 
 
Any High 
n (%) 
No High 
n (%) 
 
Value [unit] 
NexoBrid 
(N = xxx) 
Low 
 
 
  
 
 
 
Normal 
 
 
  
 
 
 
High 
 
 
  
 
 
 
Missing/not 
applicable 
 
 
  
 
 
 
Total 
 
 
  
 
Value [unit] 
SOC 
(N = xxx) 
Low 
 
 
  
 
 
 
Normal 
 
 
  
 
 
 
High 
 
 
  
 
 
 
Missing/not 
applicable 
 
 
  
 
 
 
Total 
 
 
  
 
Value [unit] 
Gel Vehicle 
(N = xxx) 
Low 
 
 
  
 
 
 
Normal 
 
 
  
 


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Statistical Analysis Plan Addendum to V03 of 26 February 2020 
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Any post-treatment time point 
Lab Value 
 
Treatment 
 
Baseline 
 
Any Low 
n (%) 
No Low 
n (%) 
 
Any High 
n (%) 
No High 
n (%) 
 
 
High 
 
 
  
 
 
 
Missing/not 
applicable 
 
 
  
 
 
 
Total 
 
 
  
 
 
N = number of subjects with the respective eschar removal procedure, 
n = number of subjects with respective category, 
% = n/N*100 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 
 


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Table 3: Laboratory Value Shifts from Baseline to Any Post-treatment Clinically Significant Result 
 
Any post-treatment time point 
Lab Value 
 
Treatment 
 
Baseline 
 
Any pCS 
low 
n (%) 
No pCS low 
n (%) 
Any pCS 
high 
n (%) 
No pCS 
high 
n (%) 
pCS low: ….. 
pCS high: …. 
Value [unit] 
NexoBrid 
(N = xxx) 
Low 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
High 
 
 
 
 
 
 
Missing/not 
applicable 
 
 
 
 
 
 
Total 
 
 
 
 
Value [unit] 
SOC 
(N = xxx) 
Low 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
High 
 
 
 
 
 
 
Missing/not 
applicable 
 
 
 
 
 
 
Total 
 
 
 
 
Value [unit] 
Gel Vehicle 
(N = xxx) 
Low 
 
 
 
 


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N = number of subjects in the Safety Population, 
n = number of subjects with respective category, 
% = n/N*100 
N/A = not applicable; ULN = upper limit of normal 
pCS = potentially Clinically Significant 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 
 
 
 
Normal 
 
 
 
 
 
 
High 
 
 
 
 
 
 
Missing/not 
applicable 
 
 
 
 
 
 
Total 
 
 
 
 


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Table 4: Vital Sings/Pain Changes from Baseline by Time Point 
 
Baseline Assessments 
 
NexoBrid (N= XXX) 
 
Standard of Care (N= XXX) 
 
Gel (N= XXX) 
Time 
point 
Assessment 
 
<90 
n (%) 
90-180 
n (%) 
>180 
n (%) 
Missin
g 
n (%) 
 
<90 
n (%) 
90-180 
n (%) 
>180 
n (%) 
Missin
g 
n (%) 
 
<90 
n (%) 
90-180 
n (%) 
>180 
n (%) 
Missin
g 
n (%) 
Post first 
treatment 
pCS (Low) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
no pCS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pCS (High) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of subjects in the Safety Population, 
n = number of subjects with respective category, 
% = n/N*100 
pCS = potentially Clinically Significant 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 


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Table 5: Pain Assessment Clinically Significant Results Shifts from Baseline to Any Post-treatment Time Point 
 
Any post-treatment time point 
Visual Analog Scale 
 
Treatment 
 
Baseline 
 
Any 
abnormal 
(nCS) 
n (%) 
No 
abnormal 
(nCS) 
n (%) 
 
Any 
abnormal 
(CS) 
n (%) 
No 
abnormal 
(CS) 
n (%) 
 
Pain Intensity (mm) 
NexoBrid 
(N = XXX) 
Abnormal 
(nCS) 
 
 
  
 
 
 
Normal 
 
 
  
 
 
 
Abnormal 
(CS) 
 
 
  
 
 
 
Missing/not 
applicable 
 
 
  
 
 
 
Total 
 
 
  
 
Pain Intensity (mm) 
SOC 
(N = XXX) 
Abnormal 
(nCS) 
 
 
  
 
 
 
Normal 
 
 
  
 
 
 
Abnormal 
(CS) 
 
 
  
 
 
 
Missing/not 
applicable 
 
 
  
 
 
 
Total 
 
 
  
 


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Any post-treatment time point 
Visual Analog Scale 
 
Treatment 
 
Baseline 
 
Any 
abnormal 
(nCS) 
n (%) 
No 
abnormal 
(nCS) 
n (%) 
 
Any 
abnormal 
(CS) 
n (%) 
No 
abnormal 
(CS) 
n (%) 
Pain Intensity (mm) 
Gel Vehicle 
(N = XXX) 
Abnormal 
(nCS) 
 
 
  
 
 
 
Normal 
 
 
  
 
 
 
Abnormal 
(CS) 
 
 
  
 
 
 
Missing/not 
applicable 
 
 
  
 
 
 
Total 
 
 
  
 
 
N = number of subjects in the Safety Population, 
n = number of subjects with respective category, 
% = n/N*100 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 
 


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Table 6: Summary of Treatment Emergent Adverse Events - Patient level 
 
Treatment 
Topical:NexoBrid 
Gel (N=XXX) 
Standard 
of Care 
(N=XXX) 
Topical:Gel 
Vehicle 
(N=XXX) 
n 
% 
n 
% 
n 
% 
With at least one TEAE 
 
 
 
 
 
 
With at least one mild or moderate TEAE 
 
 
 
 
 
 
With at least one severe TEAE 
 
 
 
 
 
 
With at least one TESAE 
 
 
 
 
 
 
With at least one TEAE not related or remotely related to study drug 
 
 
 
 
 
 
With at least one TEAE possibly, probably, or related to study drug 
 
 
 
 
 
 
With treatment-emergent outcome of death 
 
 
 
 
 
 
 
N = number of subjects in the Safety Population, 
n = number of subjects with respective category, 
% = n/N*100 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 


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Table 7: Summary of TEAEs/TESAEs by System Organ Class and Preferred Term 
System Organ Class 
Preferred Term 
Topical:NexoBrid 
Gel (N=XXX) 
n (%) 
Standard 
of Care 
(N=XXX) 
n (%) 
Topical:Gel 
Vehicle 
(N=XXX) 
n (%) 
System Organ Class 1 
 
 
 
     Preferred Term 1 
 
 
 
     Preferred Term 2 
 
 
 
     Preferred Term 3 
 
 
 
     Preferred Term 4 
 
 
 
System Organ Class 2 
 
 
 
     Preferred Term 1 
 
 
 
     Preferred Term 2 
 
 
 
N = number of subjects in the Safety Population, 
n = number of subjects with respective category, 
% = n/N*100 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 


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Table 8: Summary of TEAEs/TESAEs by System Organ Class, Preferred Term and Time of Onset 
System Organ Class 
Preferred Term 
Time of Onset 
Topical:NexoBrid Gel 
(N=xxx) 
n (%) 
Standard of 
Care (N=xxx) 
n (%) 
Topical:Gel 
Vehicle (N=xxx) 
n (%) 
System Organ Class 1 
Total 
 
 
 
 
During the treatment session 
 
 
 
 
1st week after treatment 
 
 
 
 
Week 2 - 4 after treatment 
 
 
 
 
Week 5 - 8 after treatment 
 
 
 
 
Later 
 
 
 
 
Missing 
 
 
 
     Preferred Term 1 
Total 
 
 
 
 
During the treatment session 
 
 
 
 
1st week after treatment 
 
 
 
 
Week 2 - 4 after treatment 
 
 
 
 
Week 5 - 8 after treatment 
 
 
 
 
Later 
 
 
 
 
Missing 
 
 
 
     Preferred Term 2 
Total 
 
 
 
 
During the treatment session 
 
 
 


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Statistical Analysis Plan Addendum to V03 of 26 February 2020 
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System Organ Class 
Preferred Term 
Time of Onset 
Topical:NexoBrid Gel 
(N=xxx) 
n (%) 
Standard of 
Care (N=xxx) 
n (%) 
Topical:Gel 
Vehicle (N=xxx) 
n (%) 
 
1st week after treatment 
 
 
 
 
Week 2 - 4 after treatment 
 
 
 
 
Week 5 - 8 after treatment 
 
 
 
 
Later 
 
 
 
 
Missing 
 
 
 
 
 
 
Adverse events are presented in alphabetic order of system organ class and descending order 
of preferred term in the Total row of the NexoBrid group 
Classifications of Adverse Events are based on the MedDRA (version 21.1) 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 
 
 


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Table 9: Summary of TEAEs/TESAEs by System Organ Class, Preferred Term and Maximum Intensity 
System Organ Class 
Preferred Term 
Topical:NexoBrid Gel (N=XXX) 
n (%) 
Standard of Care (N=XXX) 
n (%) 
Topical:Gel Vehicle (N=XXX) 
n (%) 
 
Mild 
Moderate Severe 
Total 
Mild 
Moderate Severe 
Total 
Mild 
Moderate Severe 
Total 
System Organ Class 1 
 
 
 
 
 
 
 
 
 
 
 
 
     Preferred Term 1 
 
 
 
 
 
 
 
 
 
 
 
 
     Preferred Term 2 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
 
 
 
 
 
 
 
 
     Preferred Term 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE is defined as related if causality is possibly related, probably related or related 
Subjects are counted at the maximum severity level, only once in each system organ class category, and only once in each preferred term category 
Events are counted for maximum severity level on a patient level. If an event was reported multiple times in the same patient, only the maximum severity 
is counted. 
Adverse events are presented in alphabetic order of system organ class and descending order of preferred term in the Total column of the NexoBrid group 
Classifications of Adverse Events are based on the MedDRA (version 21.1) 
 
N = number of subjects in the Safety Population, 
n = number of subjects with respective category, 
% = n/N*100 
 
Program: xxx.sas / Output run time: xxx / Data Base Extraction Date xxx 
Output File: xxx.rtf 
Source Data Set(s): ADAM.ADXX 
 

SAP_006.pdf: 
 
AMENDMENT 
STATISTICAL ANALYSIS PLAN 
 
Clinical Trial 
 
A multicenter, multinational, randomized, controlled, assessor blinded study, performed in 
subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid compared to Gel 
Vehicle and compared to Standard of Care (DETECT) 
!
 
Sponsor: 
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Trial protocol code: MW2010-03-02 
EudraCT number: 2014-001672-55 
IND No.: 65,448 
 
 
Competence Center for Clinical Trials Bremen - Biometry 
Author: Dr. Martin Scharpenberg 
Version of 29 November 2018, SAP Version V02, Amendment 01 
 


DETECT - Protocol Code: MW2010-03-02 
Page 2 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
1. Table of Contents 
1. 
Table of Contents 
2 
2. 
Reason for the Amendment 
3 
3. 
Signatures 
5 
4. 
List of Abbreviations 
6 
5. 
Changes to the statistical analyses plan 
7 
5.1. 
Primary Endpoint: Incidence of complete eschar removal in the topical arms 
7 
5.1.1. 
Primary analysis method 
7 
5.1.2. 
Handling of missing data 
7 
5.2. 
Secondary Endpoint: Incidence of surgical excision 
8 
5.3. 
Secondary Endpoint: Blood loss 
8 
5.3.1. 
Significance level of the Shapiro-Wilk test 
8 
5.3.2. 
Multiple Imputation in the presence of non-normality 
8 
5.4. 
Additional changes 
9 
6. 
Reference List 
10 
 


DETECT - Protocol Code: MW2010-03-02 
Page 3 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
2. Reason for the Amendment 
The final Statistical Analysis Plan (SAP), version 02, dated May, 15 2018, was submitted to 
the Food and Drug Agency (FDA). The FDA gave four comments on the SAP (Advice letter 
from 05 November 2018) regarding the planned statistical analysis, suggesting changes to the 
analyses and requesting clarifications on the planned analysis. The FDA comments were: 
1. For establishing efficacy in an adequate and well-controlled trial, the statistical analyses 
need to be fully prespecified to minimize bias and ensure control of Type I error. The 
description in the SAP regarding the analysis method for the primary endpoint mentions 
both logistic regression and Fisher's exact test, without clearly stating which analysis 
is the primary analysis. To ensure that the analysis for the primary endpoint is fully 
prespecified, clarify whether the primary analysis method is logistic regression or 
Fisher's exact test. 
2. As we noted in our Advice Letter dated 5/14/2015, while we acknowledge that the 
number of subjects with missing data at the end of the topical agent soaking period for 
the primary endpoint of complete eschar removal at the end of the topical agent soaking 
period and the secondary endpoint of incidence of excision is likely to be very limited, 
you will need to account for any missing subjects in the primary analysis using the total 
number of randomized subjects. 
3. You have proposed to analyze blood loss using either the Mann-Whitney test or the t-
test depending on whether the results of the Shapiro-Wilk test are significant at the 5% 
significance level. Because the Shapiro-Wilk test may be likely to reject the normality 
hypothesis when you have larger sample sizes even for relatively trivial deviations from 
normality, we recommend using a smaller significance level. 
4. You have proposed to use multiple imputation to handle missing data, however, if the 
normality condition is not satisfied, it is not clear whether the assumptions need for 
multiple imputation using the regression method would be satisfied or how the results 
from the multiple Mann-Whitney tests could be appropriately combined using Rubin's 
rules. Clarify how you will analyze the data, including missing data handling, if the 
normality assumption does not hold. 


DETECT - Protocol Code: MW2010-03-02 
Page 4 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
Following receipt of the comments from the FDA on the SAP, required changes were 
discussed. On November 20, 2018, Prof. Freedman, the statistician blinded to the data, 
recommended changes to the SAP which are implemented in this amendment. 




DETECT - Protocol Code: MW2010-03-02 
Page 6 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
4. List of Abbreviations 
abbreviation 
meaning 
FDA 
Food and Drug Agency 
KKSB 
Competence Center for Clinical Trials Bremen 
SOC 
Standard of Care 
 
 


DETECT - Protocol Code: MW2010-03-02 
Page 7 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
5. Changes to the statistical analyses plan 
Changes are highlighted in bold letters, reasons of change in italic. 
FDA comment # 1: 
5.1. 
Primary Endpoint: Incidence of complete eschar removal in the topical arms 
5.1.1. 
Primary analysis method 
Insert in Section 11.1.2 of the SAP after the second paragraph: 
“Note: The primary analysis method is Fisher´s exact test.” 
Reason: 
In comment 1, the FDA asked for clarification on whether the primary analysis method is 
logistic regression or Fisher´s exact test. 
FDA comment # 2: 
5.1.2. 
Handling of missing data 
Replace in Section 10.1.1 of the SAP in the first paragraph  
“The main analysis…of complete cases”  
by  
“The primary analysis of complete eschar removal will include patients with missing 
endpoint data in the analysis. Such patients will be counted as having failed on this 
endpoint, i.e. as not having achieved complete eschar removal.” 
In consequence, the following switch is incorporated in Section 10.1.1: 
This analysis is currently one of the specified sensitivity analyses, so it will be removed from 
the sensitivity analyses. Instead, the complete case analysis, initially planned as the main 
analysis, will serve as one of the sensitivity analyses. 
Reason: 
In SAP version 02, the main analysis of the primary endpoint is described as a complete case 
analysis, only taking into account subjects without missing data. In comment 2, the FDA 
requests changing the analysis to an analysis using the total number of randomized subjects. 
This change is in response to the FDA´s comment. 


DETECT - Protocol Code: MW2010-03-02 
Page 8 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
5.2. 
Secondary Endpoint: Incidence of surgical excision 
Replace in Section 10.1.1.1.1 the text by  
“The same procedure as for the primary endpoint will be applied for this endpoint, i.e. 
the main analysis will include all randomized patients, with those having a missing value 
assumed to have "failed", i.e. to have received surgery. Two sensitivity analyses will be 
performed. First, in each treatment group, only patients with documented surgical 
excision will be counted and this number divided by the total number of randomized 
subjects with non-missing endpoint. A second analysis will include all randomized 
patients and count all patients with missing data (for this endpoint) as positive (i.e. no 
surgical excision performed)”. 
Reason: 
In SAP version 02, the main analysis of the secondary endpoint is described as being the same 
as in the primary analysis. The above change in the text emphasizes that the changes in the 
analysis implemented for the primary endpoint will also be implemented for this secondary 
endpoint. 
FDA comment # 3: 
5.3. 
Secondary Endpoint: Blood loss 
5.3.1. 
Significance level of the Shapiro-Wilk test 
In Section 10.1.1.3 and 11.1.3.3, second paragraph (for Shapiro-Wilk test significance level) 
replace “5%” by “0.5%”. 
Reason: 
The FDA noted that the specified significance level of 5% for the Shapiro-Wilk test might be 
too large, due to the high sensitivity of the test to relatively trivial deviations from normality 
(comment 3). 
FDA comment # 4: 
5.3.2. 
Multiple Imputation in the presence of non-normality 
The description of imputation in 10.1.1.3 will be divided into two parts, depending on the 
normality test results. The text as written will be used for the case where the normality 
hypothesis is accepted, and the following addition will be inserted for the case where the 
normality hypothesis is rejected: 


DETECT - Protocol Code: MW2010-03-02 
Page 9 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
“If the normality condition is not satisfied, then the multiple imputation method known 
as predictive mean matching will be used. Random draws from the five nearest 
neighbors for each missing value, and five multiply imputed datasets will be used. 
Multiple imputation may indeed be used with the Mann-Whitney Test, combining the 
Mann-Whitney test statistics across multiply imputed datasets, as described in the 
paper by Mogg and Mehotra, Statistics in Medicine 2007; 26:484-497 [1]. The predictive 
mean matching method is implemented in the SAS procedure PROC MI. In accordance 
with the imputations specified in the SAP, the random seed for the imputations of blood 
loss values on a procedure level will be 11468. The seed for the imputations for analysis 
of blood loss, which treats the whole eschar removal process as one continuous 
procedure, the random seed, will be 12467.” 
Reason: 
FDA noted that it is not clear whether the assumptions needed for multiple imputation using 
the regression method described in the SAP would be satisfied in case the assumption of 
normally distributed data is rejected by the Shapiro-Wilk test. Furthermore, it was requested to 
clarify how the results from the multiple Mann-Whitney tests could be appropriately combined 
using Rubin's rules. 
5.4. Additional changes 
The following changes to the SAP will be employed, independent from FDA´s comments. 
To ensure better comparability between descriptive statistics tables for continuous and 
categorical variables, the table for categorical variables (Table 5 in the SAP) will be transposed. 
To ensure better comparability between the unequally sized treatment groups, bar plots for 
categorical variables will display percentages instead of counts (Figure 2 in the SAP). The 
sample sizes underlying the bar plots will be displayed in the legend. 


DETECT - Protocol Code: MW2010-03-02 
Page 10 of 10 
Amendment 01 to Statistical Analysis Plan V02, 29 November 2018 
Competence Center for Clinical Trials Bremen 
6. Reference List 
 
[1] R. Mogg and D. V. Mehrotra, "Analysis of antiretroviral immunotherapy trials with 
potentially non-normal and incomplete longitudinal data," Statistics in Medicine, vol. 26, 
pp. 484-497, 2007.  
 
 

Prot_002.pdf: 
Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 1 of 169 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
Study Title: 
A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of 
NexoBrid compared to Gel Vehicle and compared to Standard of Care   
 
 
Protocol No.: MW2010-03-02 
IND No: 65,448 
EudraCT No: 2014-001672-55 
Clinical Phase: III 
 
 
Sponsor:  
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
Tel: 972-77-9714100 
 
 
 
Chief Medical Officer: Lior Rosenberg, MD 
 
 
 
This clinical study will be conducted in accordance with Declaration of Helsinki and its updates, 
current Good Clinical Practice (GCP), the provisions of ICH (International Conference on 
Harmonisation); US Code of Federal Regulations (Title 21, CFR Part 11, 50, 54, 56 and 312) 
and/or EU Directives; local country regulations and the sponsor's Standard Operating 
Procedures (SOPs) 
 
CONFIDENTIAL 
The information in this document contains trade secrets and proprietary information of 
MediWound Ltd. and considered privileged and confidential. The Information may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board/Ethics 
Committee approval, informed consent and the approval of local regulatory authorities as 
required by local law, or unless otherwise agreed in advance and in writing by MediWound 
Ltd. 
 
All rights reserved to MediWound Ltd. 2015 
 
No part of this Protocol may be reproduced or transmitted in any form or by any means, 
electronic or mechanical, including photocopying, recording, or any information storage or 
retrieval system without the prior written permission from MediWound Ltd. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 2 of 169 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
TABLE OF CONTENT 
1 
LIST OF DEFINITIONS AND ABBREVIATIONS ....................................................................... 8 
1.1 
DEFINITIONS ........................................................................................................................................ 8 
1.2 
ABBREVIATIONS ................................................................................................................................ 11 
2 
SYNOPSIS ........................................................................................................................................ 13 
3 
INTRODUCTION ............................................................................................................................ 22 
3.1 
MEDICAL OVERVIEW ........................................................................................................................ 22 
3.2 
CLINICAL DEVELOPMENT OF NEXOBRID ......................................................................................... 24 
3.2.1 
Efficacy .............................................................................................................................................. 24 
3.2.2 
Safety .................................................................................................................................................. 27 
3.3 
RISK ASSESSMENT ............................................................................................................................. 31 
3.3.1 
General .............................................................................................................................................. 31 
3.3.2 
Extremities Wounds ............................................................................................................................ 33 
3.4 
STUDY RATIONALE ............................................................................................................................ 35 
4 
ETHICS STATEMENT................................................................................................................... 36 
5 
STUDY OBJECTIVES .................................................................................................................... 36 
6 
INVESTIGATIONAL PLAN .......................................................................................................... 37 
6.1 
PRIMARY ENDPOINTS, SECONDARY ENDPOINTS AND OTHER ENDPOINTS ...................................... 37 
6.1.1 
Primary Endpoint ............................................................................................................................... 37 
6.1.2 
Secondary Endpoints .......................................................................................................................... 37 
6.1.3 
Safety Endpoints ................................................................................................................................. 37 
6.1.4 
Exploratory Endpoint ......................................................................................................................... 38 
6.2 
STUDY DESIGN ................................................................................................................................... 38 
6.3 
MEASURES TAKEN TO MINIMIZE/AVOID BIAS ................................................................................. 40 
6.3.1 
Assessments of Clinical Measures...................................................................................................... 40 
6.3.2 
Main safety measures ......................................................................................................................... 41 
6.4 
STUDY TREATMENTS AND DOSAGE .................................................................................................. 42 
6.4.1 
NexoBrid ............................................................................................................................................ 42 
6.4.2 
Gel Vehicle ......................................................................................................................................... 42 
6.4.3 
Standard of Care ................................................................................................................................ 42 
6.5 
TRIAL PERIODS ................................................................................................................................. 43 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................................. 43 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 3 of 169 
 
 
  
 
 
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7.1 
SUBJECT ENTRANCE CRITERIA ........................................................................................................ 43 
7.1.1 
Inclusion Criteria- Patient level ......................................................................................................... 43 
7.1.2 
Inclusion Criteria – Wound level ....................................................................................................... 43 
7.1.3 
Exclusion Criteria- Patient level ........................................................................................................ 43 
7.2 
SUBJECT WITHDRAWAL CRITERIA .................................................................................................. 45 
7.2.1 
Treatment stopping rule (apply for NexoBrid or Gel Vehicle arms only) .......................................... 46 
8 
STUDY CONDUCT ......................................................................................................................... 48 
8.1 
SCREENING AND BASELINE VISIT ..................................................................................................... 48 
8.1.1 
Screening and Baseline Procedures ................................................................................................... 48 
8.1.2 
Cleansing (Debridement) and Wound Characterization .................................................................... 49 
8.1.3 
Assessments within 24hrs Prior to Eschar removal ........................................................................... 50 
8.2 
TREATMENT PROCEDURE- ESCHAR REMOVAL; NEXOBRID/SOC/ GEL VEHICLE - INITIATED 
WITHIN 72 HOURS FROM INJURY ..................................................................................................... 50 
8.2.1 
Assessments and TWs preparation 1 h prior to Eschar removal– All arms ....................................... 50 
8.2.2 
Eschar Removal ................................................................................................................................. 51 
8.3 
GENERAL ASSESSMENTS, POST ESCHAR REMOVAL.......................................................................... 59 
8.4 
POST-ESCHAR REMOVAL- WOUND MANAGEMENT ......................................................................... 60 
8.5 
WOUND MANAGEMENT PROCEDURES ............................................................................................. 62 
8.6 
FOLLOW-UP ASSESSMENTS: WEEKLY (7  2 DAYS) POST-START OF ESCHAR REMOVAL ................ 63 
8.7 
HOSPITAL DISCHARGE ...................................................................................................................... 64 
8.8 
FOLLOW-UP ASSESSMENTS: WOUND CLOSURE CONFIRMATION 2 WEEKS POST WOUND CLOSURE 64 
8.9 
FOLLOW-UP LONG TERM ASSESSMENTS ........................................................................................... 64 
8.10 
FOLLOW-UP ASSESSMENTS: RE-ADMISSION TO HOSPITAL OR DAY CARE .................................... 65 
9 
TREATMENT FLOW CHART – STUDY SCHEDULE ............................................................. 68 
10 
DRUG STORAGE AND DRUG ACCOUNTABILITY ............................................................... 72 
10.1 
ACCOUNTABILITY AND COMPLIANCE .............................................................................................. 72 
10.2 
PREVIOUS AND ON-GOING MEDICATIONS/THERAPIES. ................................................................... 72 
10.2.1 
Disallowed Previous and On-Going Medications/Therapies ............................................................. 72 
10.2.2 
Allowed Previous and On-Going Medications/Therapies .................................................................. 72 
11 
ASSESSMENT METHODS ............................................................................................................ 73 
11.1 
PRIMARY END POINT ........................................................................................................................ 73 
11.2 
SECONDARY ENDPOINTS ................................................................................................................... 73 
11.2.1 
Reduction in surgical needs ............................................................................................................... 73 
11.2.2 
Earlier eschar removal ...................................................................................................................... 73 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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11.2.3 
Blood loss ........................................................................................................................................... 73 
11.3 
SAFETY ENDPOINTS ........................................................................................................................... 75 
11.3.1 
Time to complete wound closure ........................................................................................................ 75 
11.3.2 
Cosmesis and function at 12 months from wound closure ................................................................. 76 
11.3.3 
Cosmesis and function at 24 months from wound closure ................................................................. 76 
11.3.4 
General parameters ........................................................................................................................... 77 
11.3.5 
Local parameters ............................................................................................................................... 77 
11.4 
EXPLORATORY ENDPOINTS .............................................................................................................. 77 
11.5 
ADDITIONAL ANALYSIS ..................................................................................................................... 78 
11.6 
SUBGROUP ANALYSES ....................................................................................................................... 78 
11.6.1 
Safety Laboratory Evaluations ........................................................................................................... 78 
11.6.2 
Burn Induced Compartment Syndrome Monitoring and Diagnosis ................................................... 80 
11.6.3 
Infection ............................................................................................................................................. 82 
11.6.4 
Vital Signs .......................................................................................................................................... 85 
11.6.5 
Immunogenicity Evaluation ............................................................................................................... 85 
11.6.6 
ECG (QT evaluation) ......................................................................................................................... 85 
11.6.7 
Physical Examination ........................................................................................................................ 85 
11.6.8 
Pain Assessment Using Visual Analogue Scale (Pain Scale Ruler) ................................................... 86 
11.6.9 
Concomitant Medications .................................................................................................................. 86 
11.6.10 Graft Loss ........................................................................................................................................... 86 
11.6.11 Hypothermia and pyrexia [94] ........................................................................................................... 86 
11.6.12 Cosmesis and Function assessment.................................................................................................... 86 
11.6.13 Quality of Life .................................................................................................................................... 87 
11.6.14 Function assessments ......................................................................................................................... 88 
11.6.15 Pharmacokinetic evaluation ............................................................................................................... 88 
11.6.16 Real time data capture and Independent Safety Monitoring .............................................................. 88 
12 
SAFETY AND PHARMACOVIGILANCE .................................................................................. 89 
12.1 
RELATIONSHIP TO STUDY DRUG ...................................................................................................... 89 
12.2 
ADVERSE EVENT INTENSITY ............................................................................................................. 89 
12.3 
ADVERSE EVENT REPORTING ........................................................................................................... 90 
12.4 
SERIOUS ADVERSE EVENTS .............................................................................................................. 90 
12.5 
SERIOUS ADVERSE EVENT REPORTING ............................................................................................ 91 
12.6 
PREGNANCIES .................................................................................................................................... 91 
13 
STATISTICAL ANALYSIS ............................................................................................................ 92 
13.1 
POPULATIONS .................................................................................................................................... 92 
13.1.1 
Major Protocol Violations ................................................................................................................. 92 
13.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................................................... 92 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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13.3 
EFFICACY EVALUATION .................................................................................................................... 92 
13.3.1 
Primary Endpoint ............................................................................................................................... 93 
13.3.2 
Secondary endpoints .......................................................................................................................... 93 
13.3.3 
Safety endpoints ................................................................................................................................. 94 
13.3.4 
Exploratory endpoints and additional analyses ................................................................................. 95 
13.3.5 
Subgroup Analyses ............................................................................................................................. 96 
13.4 
STATISTICAL COMPUTING ................................................................................................................ 96 
13.5 
SAMPLE SIZE CALCULATIONS .......................................................................................................... 96 
13.5.1 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. Gel) ................................. 97 
13.5.2 
Secondary Endpoint: Incidence of surgical excision ......................................................................... 97 
13.5.3 
Secondary Endpoint: Time to complete eschar removal .................................................................... 98 
13.5.4 
Summary of sample size ..................................................................................................................... 98 
13.5.5 
Safety endpoints ................................................................................................................................. 98 
13.6 
ALPHA CONTROL ............................................................................................................................... 98 
13.7 
STRATIFICATION AND RANDOMIZATION .......................................................................................... 99 
13.7.1 
Randomization Procedure: ................................................................................................................ 99 
13.7.2 
Stratification: ..................................................................................................................................... 99 
13.7.3 
Randomization algorithm: ............................................................................................................... 100 
13.8 
DATA HANDLING METHODS AND DEFINITIONS ............................................................................. 101 
13.8.1 
Multiple visits per time-point ........................................................................................................... 101 
13.8.2 
Rules for Data Derivations .............................................................................................................. 101 
13.8.3 
Multiple target wounds per patient .................................................................................................. 101 
13.8.4 
Missing data ..................................................................................................................................... 101 
13.8.5 
Stratifying by center in the analysis ................................................................................................. 102 
13.8.6 
Stages of Analysis ............................................................................................................................. 102 
14 
QUALITY ASSURANCE .............................................................................................................. 104 
14.1 
QUALITY ASSURANCE PROGRAM ................................................................................................... 104 
14.2 
MONITORING PROCEDURES ............................................................................................................ 104 
14.1 
REGULATORY AND ETHICAL CONSIDERATIONS ............................................................................. 104 
14.2 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................................... 105 
15 
INVESTIGATOR’S AGREEMENT ............................................................................................ 106 
16 
APPENDICES ................................................................................................................................ 107 
APPENDIX 1- WOUND DEPTH ASSESSMENT- CLINICAL EVALUATION ............................................................ 107 
APPENDIX 2- PAIN MANAGEMENT PROCEDURES ............................................................................................ 108 
APPENDIX 3- PHOTOGRAPHIC WOUND DOCUMENTATION ............................................................................... 111 
APPENDIX 4- POST-ESCHAR REMOVAL WOUND MANAGEMENT .................................................................... 112 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 6 of 169 
 
 
  
 
 
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APPENDIX 5- WOUND MANAGEMENT; APPROVED COVERS ............................................................................. 128 
APPENDIX 6- REGULATORY AND ETHICAL ISSUES ........................................................................................... 130 
APPENDIX 7- STUDY ADMINISTRATIVE PROCEDURES ..................................................................................... 132 
APPENDIX 8- BIOPSY & HISTOLOGIC ASSESSMENT METHOD ........................................................................ 138 
APPENDIX 9- PAIN MEASUREMENT SCALE ...................................................................................................... 139 
APPENDIX 10- PROCEDURES FOR SPECIFIC BLOOD TESTS ............................................................................... 140 
APPENDIX 11- BURN PATIENTS: POTENTIAL ADVERSE EVENTS .................................................................... 142 
APPENDIX 12- COSMESIS, FUNCTION AND QUALITY OF LIFE QUESTIONNAIRES ........................................... 143 
APPENDIX 13- ASA CLASSIFICATION SYSTEM ................................................................................................. 155 
APPENDIX 14- RANGE OF MOTION ................................................................................................................... 156 
APPENDIX 15- BLINDED ASSESSOR MEMO- SAMPLE .................................................................................... 161 
APPENDIX 16- TREATMENT DIAGRAM ............................................................................................................. 164 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 7 of 169 
 
 
  
 
 
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SIGNATURE PAGE 
 
The undersigned are the persons authorized to sign the protocol on behalf of the sponsor 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 8 of 169 
 
 
  
 
 
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CONFIDENTIAL 
1 
LIST OF DEFINITIONS AND ABBREVIATIONS 
1.1 
DEFINITIONS1  
Hereafter is a list of terms and definitions that are acceptable in the burn care area.   
TBSA: Total Body Surface Area; in burn care, referring to the (%) total body surface area 
affected by second and third degree burns [1].   
Burn eschar: A slough (area of necrotic tissue), crust or dry scab resulting from a burn. Eschar 
is structurally intact but dead and denatured dermis [1].  
Burn Depth Definitions [1]: 
Second Degree (Partial Thickness) Burns involve the epidermis and portions of the dermis and 
can be clinically categorized as superficial partial-thickness, deep partial-thickness burns or as 
most common: combination of different depths: 
Superficial partial-thickness burns heal spontaneously (most of them) in less than 3 weeks, and 
do so typically without functional impairment or hypertrophic scarring. 
Deep partial-thickness burns extend into the deeper layers of the dermis. They possess 
characteristics that are distinctly different from superficial partial-thickness burns. If infection is 
prevented and spontaneous healing is allowed to progress, these burns may heal in three to nine 
weeks.  
Indeterminate burns are usually second degree burns of changing depths difficult to diagnose 
on arrival so only after few days when the burn conversion (progression) and demarcation took 
place they can be diagnosed as deep in need of surgery or superficial. Distinguishing between 
deeper burns and shallow burns is not always straightforward, and many burn wounds have a 
mixture of superficial mid and deep burns, making precise classification of the entire wound 
difficult. 
Third Degree (Full-Thickness) Burns involve all layers of the dermis and often injure 
underlying subcutaneous adipose tissue as well. Burn eschar is structurally intact but dead and 
denatured dermis. Over days and weeks if left in situ, eschar separates (“sloughs”) from the 
underlying viable tissue, through infectious, inflammatory and maceration processes leaving an 
open, unhealed bed of granulation tissue. Without surgery, they can heal only by wound 
contracture and scarring with epithelialization exclusively from the wound margins. 
Combination wounds, mixed of second and third degrees: the depth of the wound is not 
homogeneous and many burn wounds have a mixture of all burn depths from superficial second 
degree through deep, including full thickness burns, making precise classification of the entire 
wound difficult.  
Zones of coagulation, stasis and hyperemia: Zone of coagulation is the tissue completely 
destroyed by heat and need to be removed. Zone of stasis, usually peripheral and deeper to the 
Zone of Coagulation, is characterized by decreased tissue perfusion due to congestion that is 
caused by the increased hyperemia in the surrounding tissue evoked by the inflammatory 
                                                 
1 When possible, definitions were based on the ABA White Paper 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 9 of 169 
 
 
  
 
 
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CONFIDENTIAL 
reaction (Zone of Hyperemia). The tissue in this zone is potentially salvageable if congestion 
will be resolved, preventing thrombosis and occlusion of blood vessels that will cause death of 
smaller or larger areas. The aim of burns resuscitation is to increase tissue perfusion in general as 
well as in the burned area and prevent any damage becoming irreversible. The dead, coagulated 
eschar in the zone of coagulation, adjacent to the Zones of Stasis is the main cause of local and 
systemic eschar-related infectious and inflammatory mediators that may cause burn viable zone 
of Stasis to die [2-9]. 
Burn conversion (burn propagation, progression, transformation): Superficial second 
degree burns may convert to deeper burns due to permanent vessel occlusion of the zones of 
stasis and hyperemia, desiccation of the wound, or the use of vasoactive agents during 
resuscitation from shock and infection of the eschar [1]. 
Debridement of Burn Wounds2: The removal of loose, devitalized, necrotic, and/or 
contaminated tissue, foreign bodies, and other debris on the wound using mechanical or sharp 
techniques (such as curetting, scraping, rongeuring, or cutting) [1].  
Clarification: In the USA and so in this study the removal of the necrotic tissue that ends in 
clean wound bed ready for wound closure treatment is termed “Eschar Removal” with the term 
“debridement” reserved to mechanical cleansing of the wound that ends with a wound bed still 
covered with eschar. In the rest of the world the term “debridement” refers to removal of the 
entire burn eschar ending with a clean, raw wound bed. Therefore, the term “Debridement” has 
been used in all the previous studies and in all the references as a synonym to “Eschar Removal” 
in its US terminology [1].   
Escharotomy is a surgical incision through burn eschar (necrotic skin) down to intact fat, from 
healthy skin edge to healthy skin, in order to reduce burn induced increased interstitial and 
compartment pressure and restore blood perfusion. It releases the compressed and stretched, 
constricted tissue allowing adequate perfusion to tissues and organs, maintaining their normal 
perfusion and viability [1]. 
Circumferential extremity wounds: Limb burns which encircle ≥ 80% of the limb 
circumference. 
Extremities at Risk (EAR) are circumferential DPT and/or FT burns with at least one of the 
following: 
1. Any of the 5 “P”s; Pain (Pain on passive stretch of the affected muscle), Paralysis, 
Pulselessness, Pallor, Paraesthesia, 
2. Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements 
within 30 minutes under the constricting eschar, 
3. SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity 
and the injured one [10-11],  
4. Pulse not detected by US Doppler.  
Increased interstitial pressure/compartment syndrome will be defined as following: 
Increasing pressure >25 mmHg, Difference of >20 mmHg of diastolic pressure between the 
                                                 
2 Enzymes were specifically excluded as debridement means in the White Paper. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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burned extremity to the opposite uninjured extremity, Decreased SpO2 reading during 
treatment with difference of >6% compared to an uninjured extremity, or deterioration of 
clinical signs and/or any of the 5 “P” signs (Pain (Pain on passive stretch of the affected 
muscle), Paralysis, Pulselessness, Pallor, Paraesthesia). 
Target Wound (TW): A TW is the burn area to be treated (Eschar Removal) by NexoBrid, 
SOC or Gel Vehicle as per the randomization and in accordance with the protocol. Following 
the enrollment of a patient to the study and prior to randomization, physicians identify one or 
more TWs per patient according to the following criteria and definitions: 
 TW is a continuous burn area (might include several anatomical areas) that can be 
treated in one session, DPT and/or FT in depth, 
 Minimal burned area of a single TW should be ≥ 1% TBSA (DPT and/or FT in depth)  
 Maximal burned area of a single TW should be ≤ 15% TBSA, 
 Wound is composed of DPT and/or FT in depth. Superficial partial thickness areas may be 
included in the wound area only if they cannot be separated from deeper areas (e.g. 
surrounded by or mixed with DPT areas) and trying to separate such more superficial areas, 
may interfere with the treatment of the deeper areas of that wound, 
Complete wound closure- defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits, 2 weeks apart [12]. 
Complete eschar removal is achieved at the end of the eschar removal treatment phase as 
routinely determined by burn specialists during their daily practice in burn units and is the 
basis for the medical decision to initiate the consequent wound closure phase: treatment 
towards wound closure. This stage will be determined by a designated assessor and clearly 
marked as the end of the eschar removal process and the initiation of specific treatment aimed 
to close the viable debrided bed by grafting or epithelialization. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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1.2 
ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase (ALT or SGPT, which stands for serum glutamic-pyruvic transaminase) 
AST 
Aspartate Transaminase (AST or SGOT which stands for  serum glutamic oxaloacetic transaminase ) 
BICS 
Burn-induced compartment syndrome 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
DG 
NexoBrid Gel 
DM 
Data Management 
DPT 
Deep Partial Thickness 
DSMB 
Data Safety Monitoring Board 
EAR 
Extremities At Risk 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FT 
Full Thickness 
HR 
Heart Rate 
HD 
Hospital Discharge 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product  
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 
Kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MVSS 
Modified Vancouver Scar Scale 
mg 
Milligram 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Ml 
Milliliter 
PO 
Per Os 
POSAS 
 
Patient and Observer Scar Assessment Scale 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell (Count) 
RDC 
Remote Data Capture 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SI 
Smoke Inhalation 
SOP 
Standard Operating Procedure 
SSD 
Silver Sulphadiazine 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBSA 
Total Body Surface Area 
TW 
Target Wound 
WBC 
White Blood Cell (Count) 
WP p/l 
ABA White Paper no. page/line 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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2 
SYNOPSIS 
Protocol Number: 
MW 2010-03-02 
IND Number(s): 
65,448 
Name of 
Investigational 
Medicinal 
Product (IMP): 
NexoBrid  
Name of Active 
Ingredient: 
Partially purified Bromelain  
Study Title: 
A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of 
NexoBrid compared to Gel Vehicle and compared to Standard of Care 
Clinical Phase: 
3 
Study Duration: 
The total duration of the study treatment and follow up period of each 
participating subject is approximately 25 months. 
Study Population: 
175 Hospitalized adults with Deep Partial Thickness (DPT) and Full Thickness 
(FT) thermal burns will be enrolled from about 30 sites. 
Study 
Objective(s): 
1. To demonstrate the efficacy of enzymatic eschar removal with 
NexoBrid by providing complete eschar removal as compared with Gel 
Vehicle, 
2. To demonstrate the efficacy of enzymatic eschar removal with 
NexoBrid by providing earlier complete eschar removal, reduction in 
patients’ surgical burden and its related blood loss as compared to SOC, 
3. To assess the safety of NexoBrid compared to SOC, including 
demonstration that treatment with NexoBrid does not cause an 
unacceptable level of harm on wound closure outcome and long term 
outcomes of cosmesis and function. 
Study Design 
Overview: 
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 identify one or more TWs per patient 
according to the TW definition. All subjects’ DPT and FT burns that 
comply with the specified entrance criteria are intended to receive study 
treatment per the randomized study arm and therefore, must be designated 
as TWs. This will further allow an evaluation of the subject systemic safety 
by allowing treatment of the subject’s entire deep burns as per the 
randomized study arm. After reviewing the entrance criteria, prior to 
randomization, eligible subjects will be stratified into different groups in 
order to standardize and minimise bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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patient total burn area and its depth.  
Following the stratification, patients will be randomized as per their 
stratification group 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. 
Study arms, 
Dosage and route 
of administration: 
 
Three arms will be included in the study; NexoBrid, SOC and Gel vehicle arm 
(3:3:1 ratio) and each patient will be treated in accordance with randomization.  
NexoBrid  
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for 
preparation of a gel for cutaneous use, including concentrate of proteolytic 
enzymes enriched in Bromelain as the active component. Following mixing 
of the powder with the gel vehicle, each gram of the prepared product 
contains 0.09 g partially purified Bromelain. Partially purified Bromelain is 
a mixture of enzymes extracted from the stem of Ananas comosus 
(pineapple plant). 
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 
50 grams of sterile Gel Vehicle (ratio of 1:10), respectively, to obtain sterile 
NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g 
NexoBrid sterile powder mixed with 20g sterile Gel Vehicle per 1% of TBSA (~ 
surface of an adult palm) for four hours (or 5 g NexoBrid sterile powder mixed 
with 50g sterile Gel Vehicle per 2.5% of TBSA. The NexoBrid powder and the 
Gel Vehicle are to be mixed at the patient bedside 15 min prior to use. 
NexoBrid may be applied for a second time to the same burn area, if eschar 
removal from the target wound after the first application is not complete but at 
least 50% of the eschar was removed during the first application. NexoBrid may 
only be applied twice to the same burn wound area. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Gel Vehicle  
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn 
skin. Gel Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel 
per 1% of TBSA (~ surface of an adult palm) or 50 grams per 2.5% TBSA for 
four hours.  
Gel Vehicle may be applied for a second time to the same burn area, if eschar 
removal from the target wound after the first application is not complete but at 
least 50% of the eschar was removed during the first application. The Gel 
Vehicle may only be applied twice to the same burn wound area. 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  
Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ 
dermabrasion excisions.  Non-surgical procedures will include the application of 
(collagenase ointment (e.g. Santyl), antimicrobial solutions (e.g. Dakin’s 
Solution, 
Sulfa-Nystatin 
Solution), 
ointments/creams 
(e.g. 
Bacitracin, 
Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 
The need of either non-surgical or surgical procedures will be determined by the 
burn specialists and can be repeated as needed until complete debridement.  
Inclusion/ 
Exclusion 
Criteria: 
Inclusion Criteria- Patient level 
1. Males and females; ≥ 18  and ≤ 70 years of age, 
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 ≤  15% TBSA; SPT, DPT and/or FT in 
depth, 
5. Informed consent can be obtained within 48 hours of the burn injury.  
6. Patients who are willing and able to sign a written consent form. 
Inclusion Criteria - Wound level 
At least one wound (a continuous burn area which can be treated in one session; 
may 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’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, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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2. Modified Baux index3 ≥ 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, blast or chemical burns,  
6. Patients with DPT and/or FT facial burn wounds from flame, flash, 
explosion >0.5% TBSA (scald and contact burns are allowed),  
7. Patients with circumferential DPT and/or FT burns defined as Extremities at 
Risk (EAR)4,  
8. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate 
(AgNO3), 
9. 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 SSD treatment), 
10. Patients with pre-enrolment escharotomy, 
11. Patients with diagnosed infections as described in Section 11.6.3 of study 
protocol, 
12. Any signs or history that may indicate smoke inhalation (e.g. flame burn to 
the upper body, flames in enclosed space, smoke and fumes on the patient 
and in mouth and nostrils, deep flame burns >0.5 %TBSA to the face, 
cough, hoarseness, stridor or breathing difficulty including tachypnea 
possibly related to smoke inhalation, etc.), 
13. Pregnant women (positive pregnancy test) or nursing mothers, 
14. Poorly controlled diabetes mellitus (HbA1c>9%) in patients with known 
diabetes as captured in the medical history, 
15. Patients with BMI greater than 34.0 kg/m2, 
16. ASA greater than 2 (see Appendix 15 in study protocol) 
17. Cardio-pulmonary disease (MI within 6 months prior to injury, pulmonary 
hypertension, COPD or pre-existing oxygen-dependent pulmonary diseases, 
broncho-pneumonia, steroid dependent asthma or uncontrolled asthma), 
                                                 
3 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and the presence of smoke 
inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 
4 Extremities at Risk are circumferential DPT and/or FT burns with at least  one of the following: 
Any of the 5 “P”s (Pain, Paralysis, Pulselessness, Pallor, Paraesthesia), Direct pressure measurement >25 mmHg, measured in 2 
consecutive measurements within 30 minutes under the constricting eschar, SpO2 <95% and a persisting difference of 6% between a 
healthy symmetrical extremity and the injured one,  
Pulse not detected by US Doppler.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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18. Pre-existing diseases which interfere with circulation (peripheral vascular 
disease, edema, lymphedema, surgery to regional lymph nodes, obesity, 
varicose veins), 
19. Any 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, 
cardiovascular disorder, pulmonary disorder, liver disorder including post 
alcoholic abuse impaired function or neoplastic disease), 
20. Chronic systemic steroid intake, 
21. History of allergy and/or known sensitivity to pineapples, papaya, 
Bromelain or papain, 
22. Current (within 12 months prior to screening) suicide attempt, 
23. Mentally incapacitated adults who are incapable of giving legal consent (e.g. 
dementia, psychiatric patients, etc), 
24. Enrollment in any investigational drug trial within 4 weeks prior to 
screening, 
25. Current (within 12 months prior to screening) alcohol (daily consumption > 
3 units for males and >2 units for females) or drug abuse5,  
26. Prisoners and incarcerated, 
27. Patients who might depend on the clinical study site or investigator. 
Outcome 
Measures: 
Primary Endpoint 
The below primary endpoint will be investigated at a 'per patient' level.  
Incidence of complete eschar removal- Demonstrate superiority of NexoBrid 
over Gel Vehicle for eschar removal as measured by incidence of complete 
eschar removal at the end of the topical agent soaking period by a blinded 
assessor. 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared 
between NexoBrid and SOC.  
1. Reduction in surgical need- Demonstrate superiority of NexoBrid over 
SOC in reduction of surgical need for excisional eschar removal as 
                                                 
5 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, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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measured by an analysis of incidence of surgical eschar removal (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision). 
2. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC in 
reduction of the time to achieve complete eschar removal.  
3. Blood loss- Demonstrate superiority of NexoBrid over SOC with regard to 
the blood loss incurred during the eschar removal procedures  
Safety Endpoints 
The following group of safety endpoints will be evaluated in this study and 
compared between NexoBrid and SOC. These endpoints are used to 
confirm that NexoBrid does have an inferior deleterious effect.  
1. Time to reach complete wound closure assessed in days, starting from 
Randomization.  
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.  
Additional Safety Outcome Measures:  
4. General parameters: Systemic adverse events, vital signs, pain assessment 
(using VAS), laboratory tests, units (and volume) of blood transfusion given 
during hospitalization, Immunogenicity evaluation for NexoBrid patients, 
Pyrexia and Hyperthermia, Systemic infections, Incidence of increased 
interstitial/compartment syndrome6 and QT prolongation,  
5. Additional long term functionality evaluation of the extremities using the 
‘Lower Extremity Functional Scale’, 'QuickDASH' questionnaires and 'Range 
Of Motion' measurements, 
                                                 
6 Increased interstitial pressure/compartment syndrome will be defined as following: Increasing pressure >25 mmHg, 
Difference of >20 mmHg of diastolic pressure between the burned extremity to the opposite uninjured extremity, Decreased 
SpO2 reading during treatment with difference of >6% compared to an uninjured extremity, or deterioration of clinical signs 
and/or any of the 5 “P” signs (Pain (Pain on passive stretch of the affected muscle), Paralysis, Pulselessness, Pallor, 
Paraesthesia). 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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6. Long term Quality of Life using EQ5D and Burn Specific Health Scale- Brief 
(BSHS-B). 
7. Local parameters: Local adverse events defined by treating physician or 
designee; graft loss, wound related infections, etc. 
Exploratory Endpoint  
1. Reduction in surgical needs as measured by an analysis of % wound area 
surgically excised for eschar removal (and % TBSA excised of the treated 
TW) (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities 
target wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential 
extremity wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically 
harvested donor sites wounds, 
6. Reduction in surgical need as measured by analysis of % area of surgically 
harvested donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit 
following eschar removal procedures 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor 
sites scars,  
9. PK evaluation for a subset of NexoBrid patients7, 
10. 
Autograft related parameters. 
Sample size: 
The following sample size calculations are based on the consideration of the 
primary and two secondary endpoints for this study.  
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. 
Gel) 
Estimated proportion achieving complete eschar removal in all TWs from study 
MW2004-11-02: NexoBrid 0.595 
Standard error = 0.057 
Anticipated proportion achieving complete eschar removal using NexoBrid: 
0.595-0.057/2 = 0.5665 
Estimated proportion achieving complete eschar removal using Gel vehicle in a 
previous Phase II study, MW2002-04-01: 0 (0 out of 35 patients).  
                                                 
7 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 
hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. 
(0.0 is the point estimate; 0.10 is the 97.5 upper confidence limit).   
Because numbers of complete eschar removals are anticipated to be low in the 
gel group, we calculate sample size using Fisher’s exact test. We used the 
computer program nQuery Advisor version 7.0 to calculate power for a two-
sided significance level of 5%, and thereby found the following sample size 
combination that led to approximately 90% power for detecting a statistically 
significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).   
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle 
group 13. Total sample size = 78. 
Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: 
NexoBrid 0.22; SOC 0.62 
Standard errors: NexoBrid 0.048; SOC 0.054 
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: 
NexoBrid 0.24 and SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a 
two-sided significance level of 5% is 86: 43 in the NexoBrid group and 43 in the 
SOC group. 
Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial 
yielded an estimated log hazard ratio of -1.37 (hazard ratio of 0.254) with a 
standard error of 0.28.  
Therefore target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio 
= 0.29).  
The formula for the number of events (successful complete eschar removals) is: 


2
2
log
)
(4
HR
z
z
d



 
where z = 1.96 two-sided significance level of 5%; and z = 1.28 for 90% 
power; For 90% overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required 
2
1
2
p
p
d
n


= 44 (to the nearest even number), 
22 in each of the NexoBrid and SOC groups.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 
patients (65 in the NexoBrid group, 13 in the Gel vehicle group and 43 in the 
SOC group (to match NexoBrid numbers)), we propose entering larger numbers 
to provide an extra margin of assurance in achieving positive results on the 
efficacy outcomes, and adequate information on safety outcomes to allow better 
benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 
(NexoBrid) + 75 (SOC) + 25 (Gel Vehicle). 
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 Efficacy Assessment Period 
(EAP). 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 for short-term safety endpoints (including time to wound closure). 
The analysis will be conducted, when 3 months had passed from the last patient 
reaching complete wound closure, in accordance with FDA guidance for industry 
Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for 
Treatment “Trial subjects generally should remain in the study for follow-up 
evaluation at least 3 months following complete wound closure. The purpose for 
this follow-up period is to help distinguish actual wound healing from transient 
wound coverage”. At this time-point, data will be available for nearly all patients 
on the primary end-point (proportion with complete eschar removal), the three 
secondary endpoints (proportion undergoing surgery, time to complete eschar 
removal, and blood loss) and short-term safety endpoints (including time to 
wound closure). Missing values for early drop outs etc. will be handled as 
described in Section 13.8.4  and the SAP. The complete data set documented so 
far will be locked and analyzed as described above. Although the treatment code 
will be revealed at the end of this analysis, the independent assessor of the 
cosmesis and function and QoL of an individual patient will remain blinded to 
the treatment given to that patient until after the third and final analysis (see 
below), so as to preserve the un-biasedness of the  assessments.  
The second analysis will be performed for the 12 month follow up period 
(STFU12) and will be started after the last patient has reached the 12m 
assessment. At this analysis, all accumulated safety data at the 12m follow-up 
will be analyzed, particularly the 12m MVSS assessment for cosmesis and 
function. The complete data set documented so far will be locked and analyzed 
as described above. 
The third and final analysis covers the data of the long-term safety follow up 
(LTSFU24). It will be conducted after the last patient has reached the 24m 
assessment at last 12 months after (STFU12) analysis (stage 2). At this analysis, 
all accumulated safety endpoints at the 24m follow-up will be analyzed, 
particularly the 24m MVSS assessment for cosmesis and function. The complete 
data set documented during the trial will be locked and analyzed as described 
above (hard lock). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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3 INTRODUCTION 
3.1 
MEDICAL OVERVIEW 
Optimal treatment of burn injuries requires understanding of and response to the profound local 
and systemic reactions following thermal injury.  
The treatment strategy should be planned and executed on the basis of a timely (early) 
assessment of the extent of tissue damage and remaining viable tissue available for the healing 
process. Only when the eschar is removed and the wound bed revealed, can the true damage be 
observed and assessed, and the appropriate wound closure modality prescribed [2, 9, 13]. 
As soon as the burn eschar is formed, it induces, within hours, a cascade of local and systemic 
pathologic changes. Dead eschar becomes heavily contaminated in two to three days, creating a 
source for local and systemic infection and sepsis [2-3, 8-9, 14]. Local inflammatory responses 
may lead to additional destruction of healthy surrounding tissue, extending the original 
damage. If not otherwise removed, inflammatory and autolytic processes slowly decompose 
and destroy the eschar, which will slough in approximately two weeks. The long inflammation 
based spontaneous sloughing period allows the simultaneous formation of advanced 
granulation tissue, later evolving into a heavy and deforming scar.   
Delaying the removal of the eschar increases the incidence and severity of systemic and local 
complications, especially in more extensive burns [2-6, 8-9, 14-15]. The decomposing eschar is 
a source of strong local and (if the burn is extensive) systemic mediators that induce 
inflammatory reaction and that may cause burn wound progression into potentially viable 
tissue [4, 6, 8-9, 16].  
Moreover, the eschar is non-resilient and forms a cocoon-like constricting shell around circular 
body parts. With increasing tissue edema, this increases the interstitial/compartment pressure, 
seriously compromising the viability of the still barely surviving skin by stretching and 
compressing blood supply to vital structures. An early diagnosis and response to these events, 
releasing escharotomy, is important and should be executed emergently. In this case too, delay 
in diagnosis and reluctance to perform surgical escharotomy may delay this procedure 
especially in cases where experienced burn surgeons are not readily and immediately available 
[3, 17]. 
To prevent eschar-related complications and to initiate the healing process, it is imperative to 
remove all of the offending eschar at the earliest possible opportunity. Eschar removal, 
“Debridement”, is the first stage of the comprehensive wound care process.  There is no benefit 
in the presence of the eschar on the burn.  Thus, the decision is not whether or not to remove an 
eschar but when and how. Therefore, delay or avoidance of eschar removal should have a 
specific reason. 
Estimation of burn size and depth is essential for a diagnosis-based treatment strategy, but 
cannot be accurately performed in most instances unless and until the opaque eschar has been 
completely removed. 
Immediate (within 24 hours post-burn) eschar removal may improve the potential for survival 
of the Zone of Stasis, reverse the Zone of Hyperemia and may attenuate, or avoid many of the 
systemic reactions [2, 6, 8-9, 14, 18]. Delayed eschar removal (within the first three days) may 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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not provide all the benefits of immunological and inflammatory modulation, but will reduce 
the burn bacterial load and its outcomes [3, 17, 19-20]. Delaying eschar removal up to the 
seventh day will forfeit the local and systemic benefits, but may still prevent healing by 
secondary intention potentiating better long term results (especially in terms of scarring) [8-9, 
14, 21].  
In current standard of care, removal of the eschar may be accomplished by surgery, usually 
tangential excision followed by split thickness autografting (TE&STSG) of the acute exposed 
debrided wound, or by non-surgical topical care that includes daily dressing changes, bathing, 
scraping, wet to dry dressing, macerating activity of bacteria, etc., until the eschar sloughs, 
leaving a clean wound bed for subsequent non-surgical or surgical wound closure treatment. 
This combination of debridement followed by surgical or non-surgical wound closure 
treatment is the basis of all burn wound care modalities. 
The choice of debridement method (non-surgical or surgical) depends on many variables such 
as the burn depth, anatomical site and size (expressed as % TBSA of the burn wound), the 
patient’s general condition, available donor site for autograft harvesting as well as the 
availability of surgical facilities and staff. Tangential excision should be carried down into the 
healthy intact tissue to make sure that no trace of the eschar remains. It is estimated that up to 
30–50% of healthy tissue (mainly dermis), which is essential for the spontaneous 
epithelialization potential of the wound, may be sacrificed in this procedure, thus usually 
necessitating autografting. These surgical procedures are traumatic, often long and difficult, 
require skilled personnel and sophisticated medical resources and are usually accompanied by 
bleeding [2, 9, 17, 21-22] and heat loss [23]. The surgically excised raw wound bed should be 
covered immediately, i.e., in most cases autografted. Thus, the excision is followed by 
harvesting of autografts from intact, non-injured skin areas, skin graft transplantation, and care 
of the donor sites in addition to the original burn injury. These surgical procedures are 
performed under general anesthesia that requires pre- and post-surgical fasting and recovery. In 
most centers caution and post surgery intensive care dictate that only a limited percentage of 
the affected areas (~15%TBSA) will be surgically debrided at one time in order to limit 
inflicting excessive stress on the patient. Thus, the decision to surgically debride a burn is not 
taken lightly. Reluctance, hesitation and doubts due to uncertain diagnosis delay the decision to 
perform surgery, extending the time to start and finish of the debridement from the optimal few 
hours to several days.  
In partial, mixed thickness, and intermediate depth wounds, and with difficult to diagnose 
depth “indeterminate” wounds, early surgical debridement will usually be avoided and a more 
conservative debridement approach using topical medications will be pursued. Such 
conservative non-surgical debridement lasts for days until the eschar decomposes or until a 
decision is taken to excise the offending, remaining eschar.  The non-surgical debridement 
process involves the combined activity of topical medications, contaminant microorganisms, 
autolytic tissue processes and the inflammatory process with frequent dressing changes, 
showering, mechanical scraping of loose debris etc. The infectious-inflammatory processes are 
slow (lasting between 10-14 days) and may involve significant systemic and local 
complications. Using topical anti-bacterial or anti-inflammatory medicaments may reduce the 
infectious-inflammatory processes but will also delay eschar separation (sloughing). Locally, 
all these processes prolong the removal of the eschar and lead to additional tissue damage due 
to the death of the Zones of Stasis and Hyperemia which deepen, transforming partial thickness 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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damage into a full thickness injury. The long debridement time with sustained inflammatory 
processes can lead to the formation of granulation tissue that will develop into heavy scars.  
This excerpt of literature emphasizes that timely eschar removal is, for the last 40 years, the 
goal of burn wound care initiation. Physicians today are forced to choose between or combine 
two sub optimal alternatives of eschar removal; (i) the fast and efficient surgery (TE&STSG) 
with its diagnosis-dependant often prolonged initiation, non-selective, traumatic and 
demanding results or (ii) the inefficient non-surgical prolonged debridement means with their 
associated sequelae. The lack of fast and effective non-surgical eschar removal means has left 
surgery as the available SOC for deep burns.  
The optimal solution would be a non-surgical, selective means for removing exclusively the 
eschar without harming the non injured tissues immediately or nearly immediately after 
patients’ admission and stabilization, independently of the burn depth diagnosis. Such early 
removal of the eschar will enable the physician accurate visual diagnosis of the exposed burn 
wound bed. The clean exposed bed can be treated by the most appropriate wound closure 
strategy tailored for each patient and wound area in order to achieve optimal long term results 
with minimal trauma and cost to the patient. 
These characteristics were well-demonstrated throughout the clinical development of 
NexoBrid. A recent confirmatory phase 3 study (MW 2004-11-02) demonstrated the clinical 
benefit of NexoBrid for effective and selective removal of eschar from burn wounds as was 
shown in both primary and secondary endpoints, e.g. for % treated burn wound excised, % 
treated burn wound autografted and timely eschar removal. These findings corroborated those 
from a previous Phase 2 study (MW 2002-04-01) and retrospective data collection study (35-
98-910) (Please refer to Section 3.2). 
3.2 
CLINICAL DEVELOPMENT OF NEXOBRID 
3.2.1 
Efficacy  
The clinical development of NexoBrid8 was based on clinical data retrospectively collected 
from files of hospitalized burn patients with burn wounds treated by NexoBrid and on 
discussions and guidance from regulatory authorities. 
Study 35-98-910 evaluated the safety and efficacy of NexoBrid in subjects between 0.5 and 82 
years of age with deep partial and/or full thickness burns of ≤67% TBSA, hospitalized in 
Soroka University Medical Center (Israel) Plastic Surgery and Burn Unit, from 1985-2000. 
Data from 154 subjects having complete file documentation (including signed informed 
consent form (ICF) and pre- and post-eschar removal photographs) were analyzed. 
The clinical development program of NexoBrid includes six prospective clinical studies that 
evaluated the safety and efficacy of NexoBrid in partial and full thickness burns.  
 Study MW2001-10-03 evaluated the efficacy and safety of three doses of NexoBrid. Twenty 
hospitalized adult, male and female subjects, with Deep Partial Thickness (DPT) and/or Full 
Thickness (FT) burns of 1-15% TSBA were randomized to a 1 g (6/20 subjects), 2 g (7/20 
subjects) or 4 g (7/20 subjects) dose of NexoBrid powder per 20 g of Gel Vehicle. The study 
                                                 
8 NexoBrid was formerly named Debridase and Debrase.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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further confirmed the use of 2 g NexoBrid mixed with 20g Gel per 1% TBSA as safe and 
effective dose. 
 Study MW2002-04-01 evaluated the safety and enzymatic eschar removal efficacy of 
NexoBrid as compared to SOC and Vehicle9. A total of 140 adult hospitalized male and 
female subjects, with DPT and/or FT burns ranging from 2-15% TBSA, but not more than 
30% TBSA in total, were randomized in a 2:1:1 ratio to NexoBrid, Vehicle alone (only 
Gel), or SOC treatment. 
 Study MW2005-10-05 evaluated the safety and exploratory efficacy of NexoBrid in 
comparison to Vehicle, and SOC in hospitalized male and female adult subjects, with DPT 
and/or FT burns ranging from 1-5% TBSA. Thirty hospitalized subjects were randomized to 
receive NexoBrid (10 subjects), Vehicle alone (9 subjects), or SOC treatment (11 subjects). 
 Study MW2008-09-03 (an on-going study) evaluating the safety and exploratory efficacy of 
NexoBrid, as well as the systemic absorption of NexoBrid when applied topically on 
thermal burns using a recently validated, sensitive ELISA method, through pharmacokinetic 
(PK) assessments in hospitalized adults and children, male and female subjects, aged 4 to 70 
years with partial thickness and full thickness burns of 4-30% TBSA.  
 Study MW2004-11-02 A phase III, multicenter, controlled study, that confirmed the safety 
and efficacy of NexoBrid in comparison to SOC in hospitalized adults and children, male 
and female subjects between 4 and 55 years of age with DPT and/or FT burns of 5-30% 
TBSA with total burn wounds of no more than 30%. Of the subsequently enrolled subjects, 
75 were randomized to NexoBrid and 81 subjects were randomized to SOC treatment [24].  
 Study MW2012-01-02 evaluated the long-term scar formation and Quality of Life in adults 
and children who had participated in study MW2004-11-02, 2-4 years post-wound closure 
and included blinded assessment of scars. A total of 89 patients were enrolled into this study 
including 72 adults and 17 pediatric patients [24].  
Summary of the efficacy results from the phase 2 and phase 3 studies is presented here below. 
Eschar Removal  
Eschar removal is the direct intended activity of NexoBrid and as such was evaluated in all 
clinical studies. 
Data from the two comparative studies MW 2002-04-01 and MW 2005-10-05 shows that 
eschar was effectively removed from 92.5% of the treated wound area for NexoBrid subjects as 
compared to 94.7% for the SOC subjects. The Vehicle showed negligible, if any, eschar 
removal activity (2.2% eschar removed in one case). Vehicle-subjects’ eschars were removed 
by SOC methods following end of the Vehicle gel treatment and diagnosis of eschar removal 
failure. Data from the two comparative studies MW2002-04-01 and MW2005-10-05 shows 
that the time to start of eschar removal from injury was 1.5 days in both the NexoBrid and 
Vehicle groups compared to 2.9 days in the SOC group. Time to completion of the initial 
eschar removal procedure (as designated by the protocol per treatment group) from injury was 
1.5 days in the NexoBrid group as opposed to 11.2 days in the SOC group. 
                                                 
9 Vehicle treated patients were treated by eschar removal SOC methods following end of the Vehicle Gel treatment and 
diagnosis of eschar removal failure. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Data from the Phase 3 study MW2004-11-02 showed that 90.5% (67/74) of NexoBrid subjects 
had successful eschar removal as compared to 90.1% (73/81) of the SOC-treated subjects 
(p=0.9301). Time to achieve successful eschar removal from the ICF date in the NexoBrid 
group was 0.8 days as opposed to 6.7 days in the SOC group (p< 0.0001). Thus, NexoBrid was 
able to successfully remove the eschar from the burn wounds much earlier than SOC. 
Following the EMA CHMP/COMP recommendation, study MW 2004-11-02 evaluated two co-
primary endpoints consisting of (1) % treated wound excised, and (2) % treated wound 
autografted (both on DPT wounds). These endpoints complement each other since less area 
surgically excised demonstrates the eschar removal efficacy of NexoBrid and less area grafted 
demonstrates the clinical benefit in the reduction of the extent of non-selective eschar removal 
by surgical excision of deep partial thickness wounds where viable tissue can be spared10. Both 
endpoints contribute to the overall reduction of surgery [24]. 
Area of Wound Excised 
Data from the Phase 3 study (MW2004-11-02) shows that the incidence of DPT wounds that 
were excised was only 15.1% (16/106 wounds) as compared to 62.5% (55/88 wounds) in the 
SOC. Moreover, the DPT wounds treated with NexoBrid had significantly less wound area 
excised (5.5%) compared to the SOC treated (DPT) wounds (52.0%, p<0.0001). In children 
(<18 years of age), the incidence of DPT wounds that were excised was only 21.7% (5/23 
wounds) as compared to 68.2% (15/22 wounds) in the SOC. Moreover, less wound area was 
excised (7.3%) in NexoBrid treated wounds compared to the SOC treated wounds (64.9%). In 
addition to the analyses described above, the percent treated wound excised was analyzed for 
all treated wounds, including those with third degree components, to investigate NexoBrid 
ability to remove the eschar from all burn wound depths (ITT population). In the NexoBrid 
group the incidence of wounds that were excised was 24.5% (40/163 wounds) as compared to 
70.0% (119/170 wounds) in the SOC. Significantly less treated wound area was excised in all 
the NexoBrid treated wounds (13.1%) as compared to the SOC group (56.7%); p<0.0001. This 
pattern is comparable to that seen in the DPT wounds discussed above and confirms the results 
in a greater number of wounds of all depths. 
Area of Wound Autografted 
In the Phase 3 study (MW2004-11-02) wound area autografted was evaluated in DPT wounds. 
Wounds that were entirely FT or had FT areas were excluded from the analysis of % wound 
area 
autografted 
(in 
accordance 
with 
EMA 
CHMP/COMP 
protocol 
assistance 
recommendations). 
In this study, the incidence of DPT wounds that were autografted was only 17.9% (19/106 
wounds) as compared to 34.1% (30/88 wounds) in the SOC (p=0.0099). Moreover, DPT 
wounds of all subjects had significantly less wound area autografted in the NexoBrid group 
(8.4%) compared to the SOC group (21.5%; p=0.0054). In the children subset, the incidence of 
DPT wounds that were autografted was 21.7% (5/23 wounds) as compared to 31.8% (7/22 
wounds) in the SOC. Moreover less DPT wound area was autografted in the NexoBrid group 
                                                 
10 Full thickness wounds require autografting regardless of the eschar removal technique since they have no 
remnants of viable dermis. Therefore, the clinical benefit of DGD versus the non-selective surgical approach is 
more apparent in deep partial thickness wounds where the potential tissue-sparing effect, leading to less 
autografting, is demonstrated. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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(6.1%) compared to the SOC group (24.5%). The potential tissue-sparing effect of NexoBrid 
and its applicability to the issue of reduction in autografted wound area suggest an additional 
clinical benefit to children, due to their smaller size and limited donor site area. 
Long term scar assessment results- study MW2012-01-02 
Cosmesis was assessed in study MW2012-01-02 by a blinded assessor using the Modified 
Vancouver Scar Scale (MVSS). The Vancouver Scar Scale (VSS) [25] is the first validated and 
widely used scar assessment scale developed by Sullivan et al 1990 and it includes assessments 
of 4 scar variables; vascularity, height, pliability, and pigmentation. MVSS is an improved 
version of the VSS, which includes two additional scar variables (pruritus and pain) [23]. The 
Vancouver Scar Scale is the most commonly used scale that includes multiple subjective and 
objective parameters [25-27]. 
The study included data from 89 subjects (72 adults and 17 pediatric) with whom contact was 
made and who represent the MW2004-11-02 study population based on their demographic and 
baseline wound characteristics.  
Scar assessment (per wound) using MVSS was conducted for 113 wounds in NexoBrid group 
and 78 wounds in SOC group. The total scar outcome was slightly lower (better results) in the 
NexoBrid arm compared to SOC (3.12 vs. 3.38, respectively), without statistically significant 
difference (p=0.88) (MVSS range 0-18). 
3.2.2 
 Safety 
The burn trauma is a multi-factor disease involving most if not all body systems and associated 
with many adverse events (AEs). Overall, AEs associated with NexoBrid were minimal, 
generally transient, manageable and mostly attributable to the burn process and its care and not 
to the introduction of the eschar removal agent. 
Taken together, there appear to be several common but manageable AEs, many attributable to 
the burn process and not the introduction of the debriding agent, NexoBrid. The most 
frequently reported AEs (≥3.0%) whether or not treatment–related, are summarized in the 
following Table 1 (based on the safety data from the prospective phase II and phase III 
studies). 
Table 1- Summary of Adverse Events in Descending Order of Frequency Whether or Not 
Treatment-Related and Occurring in ≥3.0% of Subjects* (Safety Population)  
Adverse Event* 
NexoBrid 
SOC 
N=208(%) 
N=127 (%) 
Pruritus 
32 (15.4%) 
24 (18.9%) 
Anemia 
13 (6.3%) 
8 (6.3%) 
Nausea 
13 (6.3%) 
6 (4.7%) 
Insomnia 
6 (2.9%) 
5 (3.9%) 
Headache 
6 (2.9%) 
5 (3.9%) 
Skin graft failure 
6 (2.9%) 
2 (1.6%) 
Diarrhoea 
6 (2.9%) 
1 (0.8%) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Adverse Event* 
NexoBrid 
SOC 
N=208(%) 
N=127 (%) 
Vomiting 
5 (2.4%) 
7 (5.5%) 
* Subjects from the five prospective studies; MW2001-03-02, MW2002-04-01, MW2005-10-05, 
MW2004-11-02 and MW2008-09-03 
 
Across all studies, pruritus was the most frequently reported AE occurring at an incidence 
>10% in both treatment groups. More subjects in the SOC group reported pruritus compared to 
the NexoBrid group (18.9% vs. 15.4%). Pruritus, that torments the patient for months, is very 
common. As reported in the literature, up to 87% of all patients will have a longer or shorter 
spell of pruritus. The scratching may be so intense that the patient might scratch-open their 
healed wounds, destroying healed grafts [1, 28-29]. 
Anemia in response to burns has been acknowledged for over 60 years, and is considered an 
acute and sub-acute complication. Close evaluation has suggested the response to thermal 
injury to include initial rapid hemolysis of thermally exposed blood proportional to the burn % 
TBSA (<18% in 24h in 15-40% TBSA burns [30]. Excisional surgery for eschar removal and 
skin graft harvesting leads to acute blood loss. Catabolic processes, inflammatory and septic 
processes and depressed bone marrow hematopoietic activity may all contribute to anemia 
though a clear etiology has yet to be established [31-33]. Anemia in NexoBrid clinical studies 
was reported at similar incidences in both treatment groups (6.3% in the NexoBrid and SOC 
group). 
Though skin grafts have been used for more than a century and considered to be a standard 
wound closure tool, the details of their use vary between centers, surgeons, patients and body 
areas. The reported incidence in the literature of graft loss ranges may reach up to 71%. 
Traditionally it was thought that wound infection is the main reason for skin graft loss but with 
use of effective and simple control means (local antibacterial soaking and systemic antibiotic) 
infection ceased to play a crucial role in graft loss. At present, the causes for skin graft loss 
(besides infection) are (by the order of importance): 1. Sub-graft collection (i.e. seroma, 
hematoma); 2. Lack of graft adherence to the wound bed (ineffective fixation, movement); 3. 
Hypoalbuminemia; 4. Granulation tissue; 5. Nature of graft (by trend: very thin, sheet, thick 
and meshed). Other mechanical factors may cause loss of smaller or greater parts of the graft, 
earlier or later after grafting. Such factors are: shearing, trauma and abrasion (scratching) of the 
graft, minimally vascularized body areas (lower extremities), areas prone to trauma (buttocks, 
legs), areas difficult to fixate and dress and mobiles joints (knees, elbows, axilla neck and 
trunk) [34-37]. Use of negative pressure wound therapy for 2-3 days to stabilize the graft 
improves its take. Late (2-3 weeks post grafting) graft loss may be caused by autografting over 
dermis that epithelializes under the graft, detaching it from the healing bed. During the clinical 
development, graft failure was reported in low percentages, 2.9% in the NexoBrid arm and 
1.6% in the SOC arm. Autografting may cause long term sequelae such as scarring at the 
edges, mesh pattern when mesh grafts are used, overgrafting when used over dermis, color 
differences and at the donor sites: weeks of painful healing process and scars on unburned skin 
areas.    
The incidence of the AEs pain, pyrexia/hyperthermia, and wound infection were analyzed 
separately for the earlier clinical studies (Group 1: MW 2001-10-03, MW 2002-04-01) and for 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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the later studies (Group 2: MW 2005-10-05, MW 2004-11-02, and MW 2008-09-03) as prior 
to the Group 2 studies, corrective measures11 were implemented for these AEs observed and 
investigated in the Group 1 studies. Data are presented in Table 2. 
Table 2- Comparison of the Incidence of Adverse Events Pain, pyrexia/ Hyperthermia 
and Wound Infection  
Adverse Event 
Group 1* 
Group 2** 
NexoBrid 
N=90 
SOC/Vehicle  
N=70 
NexoBrid 
N=118 
SOC/Vehicle  
N=101 
 
N (%) 
N (%) 
N (%) 
N (%) 
Pain 
21 (23.3) 
8 (11.4) 
4 (3.4) 
4 (4.0) 
Pyrexia/ hyperthermia 
32 (35.6) 
13(18.6) 
20 (17.0) 
16 (15.8) 
Wound infection 
6 (6.7) 
4 (5.7) 
7 (5.9) 
7 (6.9) 
* Group 1: MW 2001-10-03, MW 2002-04-01 
** Group 2: MW 2005-10-05, MW 2004-11-02, and MW 2008-09-03 
 
Pain Events 
Burn injury is associated with prolonged and significant pain. The pain can be sub-divided into 
background pain (at rest), breakthrough pain (during activities such as changing positions), and 
procedural pain during wound care such as Sulfamayalon, bathing, dressing changes, etc [38-
39]. Patient's scores vary widely from patient to patient and in the same patient: from day to 
day. Pain score are higher in the more superficial burns with procedural pain related to the 
extent of the second degree burns [38].  
As shown in Table 2, the incidence of pain in the NexoBrid group was reduced from 23.3% to 
3.4% after corrective measures had been taken for adequate pain management, as commonly 
practiced during routine dressing change to burn patients, and occurred at a comparable 
incidence in both treatment groups in the later clinical studies (3.4% vs. 4.0%). Use of 
NexoBrid requires somewhat less analgesia and anesthesia medication compared with SOC 
and so it is not medication-dependent more than any routinely used SOC treatment. 
A few prospective descriptive studies were conducted to investigate the extent of pain in burn 
patients, reporting more intense, at rest background pain in the first week, two-thirds of the 
patients had mild or less-than-mild pain, and the others reported moderate-to-severe pain. 
During therapeutic procedures, 51% of patients suffered intense pain though analgesic 
medications were administered. The burn induced pain and its long term sequelae are all 
underestimated and seem to be in many cases greatly undertreated by routine analgesia [1, 28, 
39-42]. 
Pyrexia/ Hyperthermia 
The burn patient is catabolic, with a very high basal metabolic rate (BMR), and often has 
elevated body temperature which may continue for months post healing [43-45]. The 
                                                 
11 The following instructions and protocols were implemented: Provision of a pre-treatment pain management 
protocol as commonly practiced during routine dressing change in standard of care of burns in order to prevent 
NexoBrid related pain and the use of approved topical antibacterial solutions during the soaking stages prior to 
and post-treatment in order to minimise the potential for infection and associated fever. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
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hypermetabolic process with the systemic and local inflammatory reactions involved in the 
wound healing process as well as wound contamination and/or infection contribute to pyrexia. 
However, elevated body temperature is not considered clinically reliable in predicting local or 
bloodstream infection, in some cases it starts a few hours post burn, much before any infection 
can develop. Later it may be due to exposure to catabolic and bacteria products [46-47]. 
Occlusive dressings may cause fever by reducing heat dissipation [48-49]. Therefore, 
temperature elevation is not considered clinically significant pyrexia until >39°C (102°F) and 
even then it is not always related to a clear pathology [50] or correlates consistently with 
septicaemia [46-47]. Other common sources for pyrexia may be IV catheter infection and/or 
thrombophlebitis with reported incidence of 8-57%. Urinary Tract Infection (UTI) is another 
source of pyrexia (as report suggests that most catheterized patients will have bacteruria after 
72 hours) and pneumonia with an incidence of 10-65% [51]. 
The incidence of pyrexia/hyperthermia in the NexoBrid group was reduced from 
approximately 35.6% in the earlier studies to 17.0% in the later studies and was also decreased 
from 18.6% to 15.8% in the SOC group. In the later studies pyrexia/hyperthermia occurred at a 
comparable incidence in both treatment groups (17.0% vs. 15.8%).  
Infection  
The definition of “infection” in the case of burns is a very general one and can relay to several 
different pathological entities. Some of the more common burn-related infections are burn 
wound infections with an incidence of >30% of infection and >9% of bacteraemia [51-52]. The 
general criteria of pyrexia, leucocytosis, thrombocytopenia may indicate that an infection is 
developing but will rarely point to the exact source (organ or system) of the infection. Even 
local signs of burn wound infection will not preclude differential diagnosis of other very 
common sources (i.e. IV catheter infection, thrombophlebitis, urinary tract infection so 
common in catheterized patients or pneumonia) [51]. 
Wound Infection 
All burn wounds are contaminated and clinical diagnosis between wound contaminated to 
various degrees of wound infection and invasive wound infection depends on objective criteria 
of quantitative culture and microscopic histology. Other definitions of wound infections are not 
clear, not uniformly accepted by all and greatly depended on aetiology and subjective 
impressions [51].  
Most infections in patients with burn injuries are burn wound infections. The burn wound is a 
susceptible site for opportunistic colonization by organisms of endogenous and exogenous 
origin [51-53]. Incidence of infections in children was identified in 33.9% of the patients, with 
burn wound infections being the most common: 10-24.6% [54-55]. Other studies found similar 
incidence of infection >30 % with 30-70 % of such infections reported as burn wound 
infections [56-59].  
Death in patients with infections ranged from 6 to 25% [56, 60-64]. 
In the clinical development, incidence of wound infection was similar across studies, 6.7% to 
5.9% in the NexoBrid group and 5.7% to 6.9% in the SOC group. In all studies wound 
infection occurred at a comparable incidence in both treatment groups and with comparable use 
of antibiotics between NexoBrid and SOC. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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There were 31 SAEs reported by 25 subjects. Only one SAE (skin graft failure) was considered 
possibly related to NexoBrid treatment. Fewer AEs, SAEs, and severe AEs were observed in 
children compared to adults. Nearly all cases of wound and blood infections reported as AEs 
were determined to have been not related to study treatment. 
There were six deaths in the NexoBrid clinical development program, 5/362 (1.4%) in the 
NexoBrid group and 1/127 (0.8%) in the SOC group. None of these deaths was considered to 
have been related to study treatment by the Principle Investigators and Data Safety Monitoring 
Board (DSMB). 
3.3 
RISK ASSESSMENT 
3.3.1 
General 
Any decisive treatment strategy (such as a decision to execute post eschar removal surgical 
wound closure) can only be planned and executed if the true extent of the tissue damage is 
known at each stage of the healing process. Only once the eschar is removed and the viable 
wound bed is revealed, can the true damage be observed and assessed and the appropriate 
wound closure modality can be prescribed [2, 13, 65]. 
The two major characteristics defining the burn wound severity are area, which is referred to in 
terms of % TBSA, and depth, which is referred to in terms of ‘degree’ of burn or described in 
words (please refer to Burn Wound definitions, Section 1.1).  
Depth assessment will be based on the investigators' visual assessments as used in routine burn 
care. Burn specialist visual assessment and clinical examination is the technique generally used 
for the diagnosis, monitoring and documentation of burn depth [1]. All the participating 
investigators shall be experienced, national or international burn specialists. At present, the 
burn experts' visual assessments are considered the standard diagnostic tool since efforts to 
develop and validate objective burn depth diagnostic measures have not been successful. None 
of the other tools which have been developed (e.g. tissue biopsy, ultrasound, laser Doppler 
flowmetry, Thermography, nuclear magnetic resonance imaging (MRI), reflectance under 
different illuminations, vital dyes, fluorescein and fluorometry) have been validated in large 
scale clinical trials or accepted as standard diagnostic means by national or international 
professional burn organizations. All these methods have been compared to the visual 
assessments of experts but similar results have been attained only occasionally and usually 
only to several-day old burns where the process of progression has ended and infection not yet 
started [65-66].  
Assessment of very superficial and very deep burns may be in some cases more straight-
forward, however, the most frequent burns in hospitalized patients, those of mixed or 
indeterminate depth, create a challenge in terms of both diagnosis and choice of treatment 
modalities. Indeterminate burns are usually second degree burns of changing depths difficult to 
diagnose on arrival so only after several days when the burn conversion (progression) and 
demarcation have taken place can they be diagnosed as deep in need for surgery or superficial 
[1]. These burns are the most common in hospitalized patients (>40%). In some cases they may 
eventually evolve into deep full thickness or slow to heal wounds. In other cases they may heal 
fast, and spontaneously epithelialize following maceration and separation (“sloughing”) of the 
eschar. The depth of these burns is not constant, their appearance continuously changing during 
the first days due to the burn progression and to the inflammatory/infectious processes. Due to 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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their varying appearances and behavior they pose a real diagnostic challenge and thus it is 
common practice to follow/monitor these wounds for a few days until the diagnosis becomes 
clearer and with this, realization of the preferred wound closure strategy, i.e. surgical or non-
surgical or a combination of both. When a non-surgical strategy is chosen, topical wound care 
designed to prevent infection of the necrotic eschar and promote its separation (sloughing) 
starts. This treatment includes topical medications and physical procedures (bathing and 
showering, scraping etc), follow up and monitoring until the eschar sloughs off and the clean 
bed epithelializes, or until granulation tissue appears and it becomes obvious, usually within a 
3 week period, that the wound will not heal without heavy scarring. For the later scenario, a 
surgical process including excision and autografting will usually be performed [1, 18, 67].  
In spite of the general agreement that the eschar should be removed in a timely manner, as 
soon as possible, very few centers dare to excise the entire burn eschar as early as possible 
from admission [68]. In immediate eschar removal, defined within 24hrs from injury (“primary 
eschar removal”, as coined in 1995 by Voinchet et al), one does not wait until better diagnosis 
of the burned skin depth is feasible but rather excises all the suspected tissues and grafts the 
raw wound bed.  
Since in partial, mixed thickness, and intermediate depth wounds, the extent of the burn is 
difficult to diagnose, early surgical eschar removal will usually be avoided and a more 
conservative eschar removal approach using topical medications will be pursued. The 
conservative eschar removal lasts for days until the eschar decomposes or until decision is 
taken to excise the offending burn eschar. The non-surgical eschar removal process involves 
the combined activity of topical medicaments, contaminant microorganisms, tissue autolytic 
processes and the inflammatory process. The infectious-inflammatory processes are slow 
(lasting between 10-14 days) and may involve significant systemic and local complications. 
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within several days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy.   
The optimal solution would be the use of a non-surgical, least demanding eschar removal 
means, immediately after patients’ admittance and stabilization. Such debriding means that will 
be specific to the eschar, removing it selectively without harm to the non injured bed will 
enable physician visual diagnosis of the burn wound trauma and the most appropriate choice of 
wound closure treatment for each wound area. 
There are several main characteristics of an ideal eschar removal means: 
2. Early (as early as possible), effective and thorough eschar removal that allows early direct 
visualization and assessment of the primary burn damage, prevention of eschar-related 
deterioration and complications and initiation of non-surgical or surgical wound closure 
treatment. The eschar removal should be fast enough to timely release BICS.  
3. Selective, avoiding unnecessary damage of viable, non-burned tissues, which may be 
essential for the wounds’ spontaneous epithelialization potential. 
4. Safe, both for the patients’ general and local (non- or partially-injured tissues) conditions. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Timely (as soon as possible after patients stabilization: early initiation and early completion) 
and thorough eschar removal, is the primary goal of treatment initiation. Eschar removal will 
not only stop the vicious eschar progression, eschar-induced effects and resolve (like 
escharotomy) increased burn induced interstitial/compartment syndrome, but will allow 
accurate assessment of the primary burn damage and initiation of the closure, healing process. 
In this regard, burn eschar removal does not differ from the care of all other necrotic wounds, 
where timely removal of the offending necrotic eschar is the gold standard. 
3.3.2 
Extremities Wounds 
Burns to the extremities (hands and feet) have a special place in the field of burn care, 
demanding special attention and treatment.  
In more than 80% of severely burned patients, the hand is involved [69].The functional and 
aesthetic importance of the hand, coupled with its complex and crowded anatomy, with risk of 
burn-induced increases in interstitial and compartment pressure, make hand burn care 
extremely important and with current SOC, as further elaborated below, challenging. 
Due to the special anatomy of the hand in which numerous delicate structures are crowded in a 
small space and covered by scarce sub-dermal soft tissue, surgical debridement of the burned 
tissue, or escharotomy in these areas, are technically demanding and may cause considerable 
morbidity. The maintenance of perfusion is the first and foremost aim in the acute treatment of 
hand burns. During the acute phase, deep dermal, circumferential or near circumferential burns 
should be cared for most attentively because they can cause circulatory impairment at the level 
of the nerves and muscles as well as stretching the partially burned skin and collapsing the 
marginal blood supply, transforming a partial thickness burn into a full thickness one. Even for 
experienced surgeons it is sometimes extremely difficult to determine whether an escharotomy 
of the hand will be necessary or not [69]. Technical difficulties in estimation of the burn depth 
may lead to late or even unnecessary surgical debridement, especially in light of a previous 
study which has demonstrated that the excised burn eschar often contains viable tissue: 
microscopically unaltered normal deep dermis, unaltered dermal collagen fibers and transected 
normal capillaries [70].   
Contact burns are often palmar burns. Surgical intervention is very rarely indicated because the 
skin of the palm is thick and provides good protection. Surgical debridement is difficult to 
carry out due to the palm’s distinct anatomy and the tight fibrous septi attached coherence to 
the palmar aponeurosis. Substitution of the specialized palmar skin is only applicable to a 
limited degree. These factors justify conservative treatment for 3–4 weeks, whenever possible 
[69]. 
Within the clinical development program, NexoBrid was used to treat 130 deep partial and full 
thickness burn wounds of the hands (in 101 patients; 68 adults, 33 children and adolescents), 
mainly in 2 clinical studies: retrospective data collection study 35-98-910 and the 
confirmatory, controlled phase 3 study MW2004-11-02 [71].  
In a post-hoc analysis of the subgroup of hand wounds treated with NexoBrid and SOC in 
study MW2004-11-02, the following results were generated: 
Timely Eschar Removal  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Similar number of wounds reached successful eschar removal in both groups; 90.3% (28/31) in 
the NexoBrid group and 97.6% (40/41 wounds) in the SOC group (p = 0.1843). 
Time to achieve successful eschar removal was significantly shorter in the NexoBrid group 
(mean 2.57± 1.95 days from Injury compared to the SOC group (mean 7.75± 5.41 days from 
Injury) (p<0.0001). 
Excisional Eschar Removal 
Four (4) out of 31 hand wounds (12.9%) required excisional debridement in the NexoBrid 
group as compared to 29 out of 41 (70.7%) in the SOC group (p<0.0001). 
The mean percentage of the  burn wound area excised in the NexoBrid group was 4.4 ± 13.1% 
as compared to 52.0 ± 41.4% % in the SOC (p<0.0001).  
Autograft 
In the DPT sub-population, only one of the 24 (4.2%) hand wounds was autografted in the 
NexoBrid group compared to 10 of 20 (50%) in the SOC group (p=0.0005).  
The percentage of the burn wound area autografted in the NexoBrid was 2.1 ± 10.2% as 
compared to 30.5 ± 38.4% in the SOC (p=0.0017).  
Wound Closure 
The Mean Time to wound closure measured from injury date was similar in the two treatment 
groups: NexoBrid 25.0 ± 12.5 days, SOC 28.0 ± 15.8 days (p=0.3814) 
Hand wounds were further assessed as part of the Long term study (MW200-12-01-02) which 
included a blinded assessment of scar quality. The mean total overall MVSS score was lower 
(better results) in the NexoBrid arm compared to SOC: 3.14 ± 2.59 vs. 4.05 ± 2.82, 
respectively, without yet reaching a statistically significant difference due to sample size 
(p=0.2756).  
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within several days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy (see 
below).  
Release of increased pressure can be achieved by formal surgical escharotomy, excision of the 
constricting eschar and as was observed by Krieger et al [71-72] as well as during the 
confirmatory phase 3 study MW2004-11-02, by early application of an effective, fast acting 
eschar removal agent that underwent a development program and studied for this specific 
condition such as NexoBrid [65, 72-73].  
Due to the severe complications potentially associated with the current SOC of an 
interventional measure of escharotomy (scars, bleeding & damage to deeper structures), 
physicians often choose to monitor the patient with circumferential extremity burns for a few 
hours (by clinical signs and direct pressure measurement), continuously assessing  the wound's 
condition, before committing to escharotomy [1, 64, 73, 92-96]. In the clinical development 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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program, none of the hand burns treated with NexoBrid required escharotomy. Moreover, none 
of the NexoBrid subjects’ hands had to be surgically escharotomized to resolve burn induced 
high interstitial/compartment pressure- 0% (0/130 hand wounds) in the NexoBrid arm, vs. 
9.7% (4/41) of the hands treated by SOC.  
To investigate release of pathologically elevated interstitial pressure, a sub-analysis was 
performed for the circumferential wounds that did have a measurement of elevated interstitial 
pressure prior to treatment in the confirmatory phase 3 study, MW2004-11-02. There were six 
(6) such wounds with measured high pressures that were treated with NexoBrid and two (2) 
that were treated by SOC. NexoBrid application reduced the elevated pressure below the 
threshold without  need for surgical intervention (escharotomy or excision), whereas in the 
SOC-treated wounds the pressure had to be reduced by surgical intervention (escharotomy or 
excision). Both methods effectively reduced and released burn-induced elevated pressures, but 
SOC is associated with the sequelae of surgical escharotomy. 
These results are further supported by the retrospective study (35-98-910) which demonstrated 
that enzymatic debridement decreased both the number of deep hand burn injuries that ended-
up in an operative procedure, and the wound area grafted in those who did undergo skin 
grafting [73]. 
The effective pressure release achieved with NexoBrid is also consistent with the results that 
were obtained in a controlled in vivo study. In a burn pig model, NexoBrid resolved burn 
induced compartment syndrome within 30-45 minutes after application, even before the 
complete dissolution of the eschar [72]. 
NexoBrid appears to address the unmet needs of an eschar removal means by being as fast and 
effective as surgery yet selective, non-invasive, not diagnosis-dependent, and least demanding. 
Its use resolves the first stage of wound bed preparation in the comprehensive wound care 
process and in addition, facilitates the second step of non-surgical or surgical wound closure by 
enabling earlier, direct visual assessment of the wound bed and by reducing the incidence 
and/or extent of excision, which is a substantial, demanding part of the surgical wound closure 
process. The potential tissue-sparing effect of NexoBrid that offers the option of reducing 
autografting of the healing wound suggests an additional clinical benefit to the burn victim. 
Autografting, besides being a demanding surgical procedure that needs general anaesthesia, 
OR facilities and surgical personnel, also sacrifices healthy donor site skin that needs 2-3 
weeks of painful healing and often ends with permanent scars.  
Early non surgical eschar removal and prevention/resolution of increased interstitial/ 
compartment pressure in circumferential burns of extremities reduces surgery and may 
decrease the time to resolution of such increased interstitial/compartment pressures. 
All these benefits may also have special importance in preparedness for a burn mass casualty 
disaster scenario where surgery is the main treatment bottleneck (as has been seen in the 9/11 
crisis: Dr. Bessey from Cornell, NY September 2012 & February 2013 FDA Burn Mass 
Casualty Incident Medical Countermeasures Public Workshops [74]. 
3.4 
STUDY RATIONALE  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Enzymatic eschar removal with NexoBrid allows initiating and completing the phase of 
removal of the offending eschar earlier upon admission, enabling earlier visualization of the 
wound bed for assessment of burn wound depth as well as preservation of viable tissues, as 
further elaborated and supported by previous clinical studies. The depth determination is 
important for the planning and execution of the post eschar removal stage of wound closure 
phase (grafting or spontaneous epithelialization).  
Additional clinically meaningful attributes of NexoBrid enzymatic eschar removal is the ability 
to lower surgical burden as it allows to remove eschar in wounds that otherwise would have to 
undergo surgical excision.  
This phase 3 study MW2010-03-02 will be a multi-center, multi-national, assessor blinded12, 
randomized, controlled, three-arm study intending to demonstrate superiority of NexoBrid 
treatment over Gel vehicle placebo control treatment and over Standard of Care (SOC) 
treatment, in thermal burn subjects. 
4 
ETHICS STATEMENT 
The study will be carried out in accordance with accepted international standards, which meet 
regulations relating to Good Clinical Practice (GCP). These standards are drawn from the 
following guidelines: ICH Guideline for Good Clinical Practice, 1 May 1996 amended 
September 1997 and Declaration of Helsinki (as amended in Seoul, October 2008), concerning 
medical research in humans. 
The investigator(s) will ensure that this study is conducted in full conformity with the 
principles of the "Declaration of Helsinki" and with the laws and regulations of the 
participating countries, whichever affords the greater protection to the individual.  It is the 
responsibility of the investigator to obtain informed consent in written form (according to local 
legal requirements) from each subject participating in this study. All patients will be informed 
of the aims, methods, anticipated benefits, potential hazards and confidentiality of data. 
Candidates will also be told that they are free to refuse participation at any time. 
5 
STUDY OBJECTIVES  
The study objectives are: 
1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
complete eschar removal as compared with Gel vehicle, 
2. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
earlier complete eschar removal, reduction in patients’ surgical burden and its related 
blood loss as compared to SOC, 
3. To assess the safety of NexoBrid compared to SOC, including demonstration that 
treatment with NexoBrid does not cause an unacceptable level of harm on wound 
closure outcome and long term outcomes of cosmesis and function. 
                                                 
12 Complete Eschar Removal assessment will be performed by a blinded assessor in the NexoBrid and Gel vehicle treatment arms.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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6 
INVESTIGATIONAL PLAN 
6.1 
PRIMARY ENDPOINTS, SECONDARY ENDPOINTS AND OTHER ENDPOINTS 
6.1.1 
Primary Endpoint 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to Section 1.1 for Target Wound 
definition): 
Incidence of complete eschar removal: Demonstrate superiority of NexoBrid over Gel 
Vehicle for eschar removal as measured by incidence of complete eschar removal at the end of 
the topical agent soaking period by a blinded assessor. 
6.1.2 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SOC to further support the clinical benefit of NexoBrid.  
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. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC with regard to 
the time when complete eschar removal has been achieved. For definition of complete 
eschar removal see primary endpoint. 
3. Blood loss related to eschar removal- Demonstrate superiority of NexoBrid over SOC 
with regard to the blood loss occurred during the eschar removal procedures.  
6.1.3 
Safety Endpoints 
The following group of safety endpoints will be evaluated in this study and compared 
between NexoBrid and SOC. These endpoints are used to confirm that NexoBrid does 
not cause an unacceptable level of harm 
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:  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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a. General parameters: Systemic adverse events, vital signs, pain assessment (using VAS), 
laboratory tests, units (and volume) of blood transfusion given during hospitalization, 
Immunogenicity evaluation for NexoBrid patients, Pyrexia and Hyperthermia, Systemic 
infections, Incidence of increased interstitial/compartment syndrome (as defined in Section 
1.1) and QT prolongation,  
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 Burn Specific Health Scale- Brief (BSHS-B). 
d. Local parameters: Local adverse events defined by treating physician or designee; graft 
loss, wound related infections, etc. 
6.1.4 
Exploratory Endpoint  
1. Reduction in surgical needs as measured by an analysis of % wound area surgically excised 
for eschar removal (and % TBSA excised of the treated TW) (tangential/ minor/ avulsion/ 
Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function at the long term follow up 
visits,Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
3. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
4. Reduction in surgical need as measured by analysis of incidence of surgically harvested donor 
sites, 
5. Reduction in surgical need as measured by analysis of % area of surgically harvested donor 
site, 
6. Blood loss related to eschar removal assessed by changes in Hematocrit incurred during the 
eschar removal procedures 
7. Cosmesis evaluation (MVSS and POSAS) will be used to assess the quality of the donor sites 
scars,  
8. PK evaluation for a subset of NexoBrid patients13, 
9. Autograft related parameters. 
6.2 
STUDY DESIGN 
This is a multi-center, multi-national, randomized, controlled, assessor blinded (see Section 
6.3), three-arm study aiming to demonstrate superiority of NexoBrid treatment over Gel 
vehicle control and over SOC treatment in thermal burn subjects with burns. 
175 subjects are planned to be randomized to the study in a 3:3:1 ratio (NexoBrid: SOC: Gel 
Vehicle). The study will be conducted at sites in the US and out of the US. 
                                                 
13 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Following the enrollment of a patient to the study and prior to randomization, physicians will 
identify one or more TWs per patient according to the TW definitions described in Section 1.1.  
All subjects’ DPT and FT burns that comply with the specified entrance criteria under Section 
7.1 are intended to receive study treatment per the randomized study arm and therefore, must 
be designated as TWs. This will further allow an evaluation of the subject systemic safety by 
allowing treatment of the subject’s entire deep burns as per the randomized study arm. After 
reviewing the entrance criteria, prior to randomization, eligible subjects will be stratified into 
different groups in order to standardize and minimise bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the patient total burn area 
and its depth. Please refer to Section 13.7.1 for full description of the randomization procedure. 
Following the stratification, patients will be randomized as per their stratification group 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 (as described in Section 8.2.1), subjects will be 
medicated with appropriate analgesia (please refer to Appendix 2- Pain Management 
Procedures) and undergo wound cleansing and dressing of all wounds with antibacterial 
solutions (as specified in Section 8.1). Following wound cleansing and antibacterial treatments, 
subjects will undergo the eschar removal process as per treatment assignment (NexoBrid, SOC 
or Gel Vehicle, following randomization) as further described in APPENDIX 16- Treatment 
Diagram.  
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.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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6.3 
MEASURES TAKEN TO MINIMIZE/AVOID BIAS  
This study includes 3 arms: NexoBrid, SOC and Gel Vehicle.   
In this study, wound characterization will be performed prior to randomization into treatment 
arms. The randomization procedure will be initiated only after all TWs of a patient have been 
defined and recorded in the eCRFs. All subjects’ DPT and FT burns that comply with the 
specified entrance criteria under Section 7.1 and TWs definition (Section 1.1) are intended to 
receive study treatment per the randomized study arm. Randomization will be performed by 
stratifying eligible subjects into different groups and by centers in order to standardize baseline 
characteristics and minimise potential bias between study groups in terms of efficacy and 
safety outcomes that are expected to be correlated to the patient total burn area (%TBSA) and 
patient’s TWs depths. The planned stratification by center further enables the standardization 
of the treatment of all study arms further reducing possible site effect. 
Wound size (%TBSA) will be clinically assessed by the ‘rule of palms14’. 
Using this stratification, patients will be randomized in a 3:3:1 ratio (NexoBrid: SOC: Gel 
Vehicle). Please refer to Section Error! Reference source not found. for further information.  
To further minimize bias, the Investigator will define the TWs of a patient based on the criteria 
for defining target wounds, as described in Section 1.1. All Patient’s TWs will be treated in 
accordance with the randomized treated arm; NexoBrid, Gel vehicle or SOC (as described in 
Section 6.4), thus allowing appropriate collection of safety information, which is being 
reported per patient, presenting the patient as a whole. 
A subject who was randomized, but did not receive treatment will be analyzed in the ITT 
population (see description of population in Section Error! Reference source not found.). 
6.3.1 
Assessments of Clinical Measures 
The following measures are predefined and will be taken in specific time points per the study 
protocol to ensure minimization of potential biases: 
6.3.1.1 
 Extent of eschar removal assessment using topical agent; NexoBrid or Gel Vehicle  
The topical arms are 2 different topical preparations (NexoBrid- a gold color gel and Gel 
Vehicle- a transparent gel) that are impossible to disguise in terms of preparation procedures 
and appearance, even if supplied in masked containers. Therefore, the topical product 
application (NexoBrid or Gel Vehicle) will be done by a health care professional and the 
wound assessment will be performed by a different health care professional who is blinded to 
the randomized study arm. This will allow a blinded assessment of the primary endpoint of the 
study (incidence of complete eschar removal in NexoBrid vs. Gel Vehicle arm). 
Eschar removal procedure will be initiated at the end of the cleansing and blister removal 
session (debridement), after wound soaking. Product will be applied by a health care 
professional to the wound within 15 minutes of mixing, and left on for a 4-hour period. After 4 
                                                 
14 Using the rule of palms, the surface of the patient's palm represents approximately 1% of body surface area and 
is helpful in estimating the area of small burns. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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hours, the wound bed with the remains of the dissolved eschar and topical agent will be wiped 
away and the wound bed will be soaked for an additional 2 hours to remove any remains of the 
mixture. Following removal of the soaking dressing (6 hours of treatment in total), the wound 
bed will be photographed in a standardized manner, and the extent of eschar removal will be 
clinically assessed by a different health care professional- assessor blinded to treatment 
assignment. The un-blinding tests that are done only for the NexoBrid patients (i.e PK and 
Immunogenicity) will be done by non blinded site staff and will be recorded in a separate 
worksheet for the purpose of keeping the eschar removal assessor blinded to study arm. The 
blinded assessor will sign the "blinded assessor memo" (see Appendix 15- Blinded Assessor 
Memo).    
If debridement is not complete, but at least 50% of eschar was removed, a second application 
will be performed, as described in Section 8.2.2.2.5. Similar procedures will take place 
following a second application of the topical agent Patients treated with NexoBrid or Gel 
Vehicle will undergo up to 2 topical applications.  
In cases where eschar removal was not complete following the applications of the topical 
agents, NexoBrid or Gel Vehicle, additional surgical procedures and/or non surgical treatments 
as described below will be implemented in accordance with physician judgment:  
6.3.1.2 
Surgical eschar removal (SOC arm or as additional procedure for the topical arms): 
Extent of wound area excised & incidence of excisions following each surgical excision 
procedure performed for eschar removal will be recorded in the eCRFs. Eschar removal will be 
assessed immediately after the eschar removal surgical procedure, before a temporary or 
permanent dressing will be applied. The extent of eschar removal will be clinically determined 
by the same assessor who is blinded for the topical arm. 
Surgical procedures intended for eschar removal are pre-specified in the protocol for 
standardization (i.e. tangential/minor/avulsion/Versajet/dermabrasion excision). 
6.3.1.3 
Non-surgical eschar removal (SOC arm or as additional procedure for the topical 
arms): 
Wounds will be assessed by a burn specialist as in common daily practice. Assessment will be 
done on a daily basis and following any dressing change as long as it does not involve 
unnecessary dressing change (patient manipulation). Extent of eschar removal after the last 
dressing will be clinically determined by the same assessor who is blinded for the topical arm 
and recorded in the eCRFs.  
Non-surgical procedures intended for eschar removal are pre-specified in the protocol for 
standardization and are detailed in Section 8.2.2.1.2. 
6.3.2 
Main safety measures 
To further minimize bias, main safety measures (weekly assessments for wound closure, long 
term cosmesis as well as some functionality assessment) will be performed by a blinded 
assessor, different from the first assessor who performed eschar removal assessments. This 
assessor should not be aware whether the patient was assigned to the topical arms or to the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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SOC arm. The blinded assessor will be required to sign the "blinded assessor memo" (see 
Appendix 15- Blinded Assessor Memo– blinding memo): 
 Wound closure- will be assessed on a weekly basis as described in Section 8.6. 
Complete wound closure defined as skin re-epithelialization without drainage or 
dressing requirements confirmed at two consecutive study visits, 2 weeks apart [75]. 
Wounds will be considered as closed  when the assessor marks ‘Yes’ in regards to 
complete wound closure, which will be further confirmed in the wound closure 
confirmation visit, 2 weeks later.  
 Cosmesis and Function (using MVSS)- will be assessed at the following time-points: at 
1 month from reaching complete wound closure confirmation of last  wounds and at 3, 
6, 12, 18 and 24 months from reaching complete wound closure confirmation.  
6.4 
STUDY TREATMENTS AND DOSAGE  
6.4.1 
NexoBrid 
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel 
for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the 
active component. Following mixing of the powder with the gel vehicle, each gram of the 
prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a 
mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).  
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of 
sterile Gel Vehicle (ratio of 1:10) , respectively to obtain sterile NexoBrid Gel. NexoBrid Gel 
is applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile 
Gel Vehicle per 1% of TBSA (~ surface of an adult palm) for four hours (or 5 g NexoBrid 
sterile powder mixed with 50g sterile Gel Vehicle per 2.5% of TBSA. The NexoBrid powder 
and the Gel Vehicle are to be mixed at the patient bedside 15 min prior to use. 
NexoBrid may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. NexoBrid may only be applied twice to the same burn 
wound area. 
6.4.2 
Gel Vehicle 
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn skin. Gel 
Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel per 1% of TBSA (~ 
surface of an adult palm) or 50 grams per 2.5% TBSA for four hours.  
Gel Vehicle may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. The Gel Vehicle may only be applied twice to the same 
burn wound area. 
6.4.3 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excisions.  
Non-surgical procedures will include the application of (collagenase ointment (e.g. Santyl), 
antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 
The need of either non-surgical or surgical procedures will be determined by the burn 
specialists and can be repeated as needed until complete debridement.  
6.5 
TRIAL PERIODS 
The total duration of the study treatment and follow up period of each participating subject is 
expected to be 25 months: Following initiation of the Eschar removal procedure, each subject 
will be followed up weekly (Weeks 1, 2, 3 and 4 etc.) until complete wound closure was 
achieved and 2 weeks later for wound closure confirmation, for each of the subject's TWs. 
Long term follow-up visits will be performed at 1, 3, 6,  12, 18 and 24 months post last wound 
closure confirmation visit of each patient. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
SUBJECT ENTRANCE CRITERIA 
7.1.1 
Inclusion Criteria- Patient level 
1. Males and females; ≥ 18  and ≤ 70 years of age, 
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 ≤  15% TBSA; SPT, DPT and/or FT in depth, 
5. Informed consent can be obtained within 48 hours of the burn injury,  
6. Patients who are willing and able to sign a written consent form. 
7.1.2 
Inclusion Criteria – Wound level 
At least one wound (a continuous burn area which can be treated in one session; may 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’s blisters can be removed/unroofed, as judged by the investigator. 
7.1.3 
Exclusion Criteria- Patient level  
1. Patients who are unable to follow study procedures and follow up period, 
2. Modified Baux index15 ≥ 80, 
3. Patients with burned charred fingers, 3rd degree in depth and possibly devoid of circulation,  
                                                 
15 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and the presence of smoke 
inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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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, blast or chemical burns,  
6. Patients with DPT and/or FT facial burn wounds from flame, flash, explosion > 0.5%  TBSA 
(scald and contact burns are allowed),  
7. Patients with circumferential DPT and/or FT burns defined as Extremities at Risk (EAR)16,  
8. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3), 
9. 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 SSD treatment), 
10. Patients with pre-enrollment escharotomy, 
11. Patients with diagnosed infections as described in Section 11.6.3 of study protocol, 
12. Any signs or history that may indicate smoke inhalation (e.g. flame burn to the upper body, 
flames in enclosed space, smoke and fumes on the patient and in mouth and nostrils, deep flame 
burns >0.5 %TBSA to the face, cough, hoarseness, stridor or breathing difficulty including 
tachypnea possibly related to smoke inhalation, etc.), 
13. Pregnant women (positive pregnancy test) or nursing mothers, 
14. Poorly controlled diabetes mellitus (HbA1c>9%) in patients with known diabetes as captured in 
the medical history, 
15. Patients with BMI greater than 34.0 kg/m2, 
16. ASA greater than 2 (Appendix 13- ASA classification system) 
17. Cardio-pulmonary disease (MI within 6 months prior to injury, pulmonary hypertension, COPD 
or pre-existing oxygen-dependent pulmonary diseases, broncho-pneumonia, steroid dependent 
asthma or uncontrolled asthma), 
18. Pre-existing diseases which interfere with circulation (peripheral vascular disease, edema, 
lymphedema, surgery to regional lymph nodes, obesity, varicose veins), 
19. Any 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, cardiovascular disorder, pulmonary disorder, liver 
disorder including post alcoholic abuse impaired function or neoplastic disease), 
20. Chronic systemic steroid intake, 
21. History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or papain, 
22. Current (within 12 months prior to screening) suicide attempt, 
                                                 
16 Extremities at Risk are circumferential DPT and/or FT burns with at least  one of the following: 
Any of the 5 “P”s (Pain, Paralysis, Pulselessness, Pallor, Paraesthesia), 
Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements within 30 minutes under the constricting eschar, 
SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity and the injured one,  
Pulse not detected by US Doppler.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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23. Mentally incapacitated adults who are incapable of giving legal consent (e.g. dementia, 
psychiatric patients, etc), 
24. Enrollment in any investigational drug trial within 4 weeks prior to screening, 
25. Current (within 12 months prior to screening) alcohol (daily consumption > 3 units for males 
and >2 units for females) or drug abuse17,  
26. Prisoners and incarcerated, 
27. Patients who might depend on the clinical study site or investigator. 
7.2 
SUBJECT WITHDRAWAL CRITERIA  
After screening and prior to treatment any changes in the patient's medical condition should be 
assessed. The patient should be excluded from treatment if these changes represent 
deterioration in his/her condition which may affect the patient's safety and/or suitability for the 
study (e.g. exclusion criteria).  
Throughout the course of a subject's participation in the study, he/she may be removed from 
the study as follows:  
 Whenever it is necessary to safeguard his/her welfare as judged by the Principle 
Investigator,  
 Participation in another investigational drug trial, 
 Subjects who express a desire to withdraw from the study. 
The reason for any subject withdrawal from the study should be recorded in the eCRFs and the 
occurrence should be reported to the sponsor. Early termination visit should include final 
assessments as in the Hospital Discharge visit, as applicable (please refer to Section 8.7).  
Discontinued subjects will not be replaced. 
When a subject is removed from the study treatment, he/she will receive treatment according to 
the standard of care as appropriate in the investigative site and will be followed up according to 
the study schedule, in accordance with patient’s availability. 
                                                 
17 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, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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7.2.1 
Treatment stopping rule (apply for NexoBrid or Gel Vehicle arms only) 
Treatment (eschar removal) should be stopped following a safety concerns raised by the 
treating physician or if a patient expresses his desire to withdraw from the study. In addition, in 
the following situations: 
7.2.1.1 
Burn Induced Compartment Syndrome Monitoring and Diagnosis 
Extremities developing clinical signs suspicious for the development of BICS such as swelling 
(but none of the 5 P's) and pressure approaching 25 mmHg and SpO2 stable >90% should be 
closely monitored for signs of improvement or deterioration that may require escharotomy. If 
clinical assessment and SpO2 monitoring are possible, they will be done continuously and 
recorded in the eCRFs every 2 hours. If such assessment is not practical, direct pressure will be 
measured every 2 hours from start of the eschar removal. The eschar removal process shall be 
discontinued and escharotomy will be performed in any of the following cases: 
 Increasing pressure >30 mmHg 
 Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity 
 Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity or deterioration of clinical signs 
 Any of the 5 “P” signs. 
Since in such cases the eschar removal procedure will not be completed as planned, such 
patients (if any) will still be part of ITT and any missing data usually collected during eschar 
removal (e.g. time to end of eschar removal, etc.) will be handled as missing data according to 
the protocol. 
In case of 3 consecutive cases where there is a need to disrupt the dressing and perform a 
surgical escharotomy, enrollment will be halted and a DSMB shall be convened to:  
 assess the severity of the phenomenon in a closed session 
 Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences 
As discussed above, increased interstitial/compartment pressure is a common medical 
condition in circumferential deep burns and its detection and resolution is part of daily standard 
of care. The only difference in the treatment of the patients in the study is during the eschar 
removal stage as dictated by randomization.  
7.2.1.2 
Coagulopathy during or within 24 hours of eschar removal 
It is evident that during the first 48 hours post injury there is deterioration in coagulation 
parameters in burn patients [76]. In addition, some burn patients are treated with anticoagulants 
after admission (in some burn centers all patients are treated with anticoagulants). Due to these 
facts, any stopping rule concerning coagulopathy after topical debriding agent application must 
take these factors into consideration.  
Enrollment will be halted and a DSMB will convene if 3 subjects develop the following signs 
which have been defined as life threatening coagulopathy in trauma patients: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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INR>2 or a PTT>2 times the normal range [77], in cases where the patient is not receiving 
anticoagulants that can explain the coagulopathy. 
A DSMB shall be convened to assess in a closed session the following: 
 The relationship between coagulopathy and the treatment arm 
 The severity of the phenomenon 
 Recommend on appropriate corrective measures, as applicable to prevent such reoccurrences  
DSMB investigation will consider patients’ medical history, including any anticoagulants 
given to the patient prior to start of treatment. 
7.2.1.3 
Post treatment diagnosed infection 
Following the eschar removal treatment, in case 3 subjects develop infections listed in Section 
11.6.3 and are assessed as related to the treatment arm (possibly, probably or related as defined 
in Section 12.1), enrollment will be halted and a DSMB will convene in close session to 
investigate cases reported and their relatedness and severity.  
In all the above 3 described cases, enrollment may continue in accordance with DSMB 
conclusions.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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8 
STUDY CONDUCT  
The healing and care of the burn wound may be divided into the three distinctive phases: 
1. Wound bed preparation 
2. Wound closure 
3. Scar modulation and maturation  
These phases are common to the care of all wounds and are well defined in acute wounds such 
as burns.  
In this study these phases and their treatment strategy are equal for all arms, NexoBrid, SOC, 
and Gel Vehicle, following the ABA white paper guidelines [1].  
8.1 
SCREENING AND BASELINE VISIT 
8.1.1 
  Screening and Baseline Procedures 
For subjects who are admitted to the burn unit, and who are willing to participate in the study, 
the following procedures will be performed: 
1. Signing of consent form:  
Prior to performing any study related activities/evaluations which are not considered as 
routine, the subject must be thoroughly informed about all aspects of the study, including 
scheduled study visits and activities, and must sign the informed consent form. A signed 
copy of the informed consent form must be given to the subject. Legal representative may 
be involved in the Inform Consent procedure and sign the form if this is pre approved by 
the local IRB/EC and only for subjects with temporary medical conditions related to the 
injury, subjects who might be under the influence of pain medication, sedation, etc. 
However, legal representative cannot sign the form for mentally incapacitated subjects 
(e.g. dementia, psychiatric patients, etc) who are incapable of giving legal consent 
(entrance criteria, Section 7.1), 
2. Review and documentation of complete demographics, medical history (e.g. specific 
cardiac, pulmonary, endocrine and renal diseases), and concomitant medications, 
3. Vital signs measurement including blood pressure, pulse rate, temperature and respiration 
rate, 
4. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale, Please 
refer to Appendix 9- Pain Measurement Scale), 
5. General physical examination (including smoke inhalation signs, signs for Burn Induced 
Compartment Syndrome, etc) including a record of weight and height, 
6. Obtaining burn etiology, mechanism of injury, place of injury, treatments prior to 
admission and general description of the burn wound (anatomical locations, % TBSA: 
clinically assessed by rule of palm), burn depth (as detail in Appendix 1- Wound Depth 
assessment- Clinical Evaluation) and description of the eschar (such as: white, moist, dry, 
gray, charcoal, etc.), 
7. Leukocyte count (WBC), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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8. Extremities At Risk (EAR) burns prone to develop BICS will be identified (See Burn 
wound definitions, Section 1.1). 
9. Pregnancy test for subjects of  child-bearing potential performed at local laboratory, 
10. HbA1c in patients with known diabetes as captured in the medical history, 
11. Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, 
whichever comes first, for patients with catheter,  
12. Prior to wound cleansing (Debridement), all wounds should be labelled and photographed 
(as required in Appendix 3- Photographic wound documentation), 
13. Wounds cleansing (Debridement) as described in Section 8.1.2, 
14. Post wound cleansing (Debridement), before soaking all wounds should be labelled and 
photographed (as required in Appendix 3- Photographic wound documentation), 
15. Post cleansing, before soaking the wounds with antibacterial solution (section 8.1.2, point 
3), the % TBSA (clinically assessed by the rules of palm) and burn depth (as detailed in 
Appendix 1- Wound Depth assessment- Clinical Evaluation) of each wound and of each 
TW will be recorded, 
16. Pain management medications and analgesia/sedation levels should be recorded (see pain 
management protocol provided in Appendix 2- Pain Management Procedures)  
17. Completion of the applicable eCRFs, 
18. Randomization of eligible subjects (as described in Section 13.7.1). 
8.1.2 
 Cleansing (Debridement) and Wound Characterization 
The initial care of the burn wound starts with general cleaning that removes all gross 
contaminants, soot and blisters (“Debridement”). As described in Neligan Plastic Surgery 
Textbook, volume 4 pg 403 [78], DPT burns contain large blisters. Blister fluid is known to be 
detrimental to raw exposed tissues and to wound healing as well as being prone to infection 
that will spread in this occluded space. The blisters tend also to rupture under the dressings and 
during their changes. Using aseptic techniques the blisters should be removed (“unroofed”) and 
the exposed wound treated as needed [78-82].  
Preventive analgesia/sedation medication (pain management) will be mandated as for an 
extensive dressing change as commonly practiced (see Appendix 2- Pain Management 
Procedures). The following should be performed: 
1. Topically applied medication on the wound site must be discontinued, 
2. The wound should be cleansed thoroughly with saline, soap or antibacterial solution and 
the blisters (superficial keratin layer) removed by common procedures (i.e. rubbing with 
sterile gauze, saline soaking, etc), 
3. A dressing soaked18 with an antibacterial solution, i.e. 3-5% Sulfamylon, 0.05-0.5% 
Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution, must be applied to 
                                                 
18 Soaking refers to placing gauze soaked with fluid, e.g. saline or Dakin’s Solution on dressing the wound with thick, dry absorbent 
gauze, inserting inside a feeding tube or the tip of an IV set that offers the option of adding fluids at will.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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the wound and left in place for at least 2 hours. This dressing must remain wet until it is 
removed prior to application of the eschar removal agent/procedure. In order to prevent 
desiccation of the wound; the dressing must be changed at least every 12 hours if eschar 
removal is delayed. After soaking the dressing should be removed using aseptic 
techniques, 
4. Check that the superficial keratin (blister) has been removed (NOTE: For deep charred, 
flame burns blister-keratin removal may be difficult. In a deep, charred burn a thorough 
scraping is needed to remove the charred blister from its dermal eschar). In the event that 
not all the superficial keratin layer is removed from the burn eschar, repeat steps 2 and 3 as 
the blister-keratin may be a focus for infection and will prevent the eschar dissolution by 
isolating it from the topical agent. 
8.1.3 
 Assessments within 24hrs Prior to Eschar removal  
The following standard assessments and laboratory procedures will be performed for all study 
arms within 24 hours prior to the beginning of the first eschar removal treatment:  
1. Blood culture (all arms),  
2. PK blood sample (2ml)19, (NexoBrid patients) see Appendix 10- Procedures for specific 
blood tests, 
3. Immunogenicity blood sample20 (3ml) (NexoBrid patients), see Appendix 10- Procedures 
for specific blood tests, 
4. PTT & INR (2ml) blood sample,  
Make sure at least 2 h soaking was performed and that all blister-keratin has been removed 
from the TW's eschar. If there are still blisters/keratin remains, clean the wound thoroughly and 
remove the superficial keratin layer or blisters from the wound area, as the keratin will isolate 
the eschar from direct contact with the topical agent (as described in Section 8.1.2),  
The results of the above on-site tests (describe in Section 8.1.1 and Section 8.1.3) may be used 
for study data collection prior to signing of the consent form only in case they are part of 
routine hospital care regardless of study procedures and within relevant timelines.  
8.2 
TREATMENT PROCEDURE- ESCHAR REMOVAL; NEXOBRID/SOC/ GEL VEHICLE - 
INITIATED WITHIN 72 HOURS FROM INJURY  
8.2.1 
Assessments and TWs preparation 1 h prior to Eschar removal– All 
arms 
Patients will undergo the following procedures within one hour (± 15 min) prior to start of 
eschar removal treatment:  
1. Interstitial/compartment pressure will be measured in circumferential extremity wounds 
(See Burn wound definitions, Section 1.1). The measurement will be done, as described in 
                                                 
19 PK will be performed for a subset of 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 hrs.   
20 Immunogenicity will be performed in NexoBrid patients only. The overall Immunogenicity sampling time points: 0, 7 days, 28 days, 
56 days, 6 months and 24 months.   
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Section 11.6.2, in addition to clinical assessment and SpO2 monitoring within 1 hour prior 
to eschar removal or Escharotomy, whichever is first, of each circumferential TW, 
2. Pre-Treatment tests to be performed at central lab: Serum chemistry, hematology and 
urinalysis (as described in Section 11.6.1), should be performed within one hour prior to 
eschar removal initiation, 
3. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed within one hour 
prior to eschar removal initiation, 
4. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 60 
± 5 min, 40 ± 5 min and 20 ± 5 min prior to start of treatment,  
5. Preventive analgesia medication (pain management) will be mandated as for an extensive 
dressing change as routinely practiced; it should be initiated at least 15 minutes prior to 
dressing change or application in order to ensure pain free care (example of a 
recommended protocol provided in Appendix 2- Pain Management Procedures). Prior to a 
surgery, preventive sedation and/or general anesthesia will be mandated as routinely 
practiced. Pain management medications and analgesia/sedation level will be recorded,   
6. Qualitative-swab wound culture (per Target Wound), 
7. Prior to treatment (post cleansing, when relevant), all Target Wounds should be labeled 
and photographed (please refer to Appendix 3- Photographic wound documentation), 
8. Prior to treatment, the % TBSA (rule of palms) and burn depth (as detailed in Appendix 1- 
Wound Depth assessment- Clinical Evaluation) of each TW will be recorded, 
8.2.2 
Eschar Removal 
Eschar Removal process will be performed in accordance with randomization: SOC, Gel 
Vehicle or NexoBrid. Parameters describing the eschar removal treatment will be documented 
in the medical records in addition to starting and completion time of each procedure, recovery 
time, analgesia/anesthesia prescribed during treatment and level of analgesia prescribed, 
manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistants and number of kits used) who participated during the above period of time 
and disposables used (number of dressings, blades, etc). 
8.2.2.1 
Standard of Care (SOC) Eschar removal procedure- (to be initiated within 72 hours 
from injury) 
Subjects in the SOC group may be treated with a combination of surgical and non-surgical 
eschar removal procedures, for each TW, according to the investigator's judgment. In case of 
indeterminate burns (second degree burns of changing depths) and/or combination wounds, 
mixed of second and third degrees, which are difficult to diagnose on arrival, non surgical 
treatments is usually being initiated for few days when the burn conversion (progression) and 
demarcation is taking place. Once a diagnosis is feasible, surgical procedures will usually be 
performed for deep wounds or additional non surgical procedures will be continued for 
superficial wounds.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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The time-point of start of the SOC eschar removal procedure should be documented. This time 
point refers to the start time of the first treatment given to the patient, for eschar removal, post 
randomization (any topical application or surgical procedure whichever is first).  
8.2.2.1.1 
Surgical eschar removal procedure 
Sedation and general anesthesia as routinely practiced will be administered before and during 
surgery and recorded. The wound will undergo surgical excision according to common SOC. 
Parameters describing the surgical procedure will be documented. Eschar removal will be 
assessed immediately after each eschar removal surgical procedure, before a temporary or 
permanent dressing will be applied. Surgical procedures intended for eschar removal are pre-
specified in the protocol for standardization and will include tangential/ minor/ avulsion/ 
Versajet/ dermabrasion excision).  
8.2.2.1.2 
Non-surgical eschar removal procedure 
Eschar removal will be assessed on a daily basis and following any dressing change as long as 
it does not involve unnecessary dressing change. Non-surgical procedures intended for eschar 
removal are pre-specified below for standardization and will include the application of Santyl 
(Collagenase ointment), antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin 
Solution), ointments/creams (e.g. Bacitracin, Polysporin, Silvadene) and/or Silver dressings 
(e.g. Mepilex Ag, Aquacel Ag, Acticoat). Non-Surgical procedure is considered as one 
procedure for whole period of any continuous dressing changes until either complete eschar 
removal is achieved or until surgical eschar removal is conducted.  
8.2.2.1.3 
Additional SOC procedures: 
In addition to pre first treatment assessment as described in Sections  8.1.3 & 8.2.1, in case that 
more than one SOC procedure is performed, 1 hour (± 15min) pre surgical treatment the 
following assessments should be repeated: 
1. Interstitial/compartment pressure will be measured in circumferential extremity wounds 
(See Burn wound definitions, Section 1.1). The measurement will be done, as described in 
Section 11.6.2, in addition to clinical assessment and SpO2 monitoring within 1 hour prior 
to eschar removal or Escharotomy, whichever is first, of each circumferential TW, 
2. Central lab blood tests: Serum chemistry, hematology and urinalysis (as described in 
Section 11.6.1), should be performed within one hour (± 15min) prior to eschar removal 
initiation, 
3. Local lab tests: PTT & INR (2ml) blood sample, within one hour (± 15min) prior to eschar 
removal initiation, 
4. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed within one hour 
prior to eschar removal initiation, 
5. Qualitative-swab wound culture (per Target Wound), 
6. Prior to treatment (post cleansing, when relevant), all Target Wounds should be labeled 
and photographed (please refer to Appendix 3- Photographic wound documentation), 
7. Prior to treatment, the % TBSA of each TW will be recorded, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 53 of 169 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
8. Sedation and general anesthesia as routinely practiced will be administered before and 
during surgery and recorded. The wound will undergo surgical excision according to 
common SOC.  
*The assessment described above should be done only prior to surgical procedures. In 
cases that non-surgical procedures are not the first treatment, the assessments described 
above should not be done, only sedation (point 8 above) should be recorded.  
8.2.2.1.4 
During the first SOC procedure: 
1. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 30 
± 10 min, 120 ± 15 min and 4 ± 0.5 hours after start of eschar removal, non surgical or 
Surgical. 
8.2.2.1.5 
Post each SOC procedure: 
1. The parameters describing the SOC procedure will be documented in the eCRFs in 
addition 
to 
starting 
and 
completion 
time 
of 
the 
eschar 
removal 
process, 
analgesia/anesthesia prescribed during treatment and level of analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
if applicable, anesthesiologists, registered nurses, practical nurses and unskilled 
assistances) who participated during the above period of time and disposables used 
(number of dressings, blades, etc), 
2. Target Wounds should be labeled and photographed at the end of each eschar removal 
treatment. The time-point of the final SOC eschar removal should be documented,  
3. Eschar removal will be assessed immediately following the completion of each procedure 
(by the same assessor who evaluate blindly the eschar removal in the topical arms) and 
recorded for each TW. TWs depth will be evaluated once, post complete eschar removal, 
4. Qualitative-swab wound culture (per Target Wound) will be taken at the end of each 
eschar removal procedure (surgical and/or non-surgical procedure), 
5. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of each eschar removal procedure (surgical and/or non-surgical procedure), 
6. Interstitial/compartment pressure will be measured (as described in Section11.6.2) post-
eschar removal, per circumferential extremity wound, after the completion of each surgical 
/ non surgical procedure or escharotomy, whichever is first, 
7. Pain assessment using a routinely accepted pain-scale (VAS) as described in Appendix 9- 
Pain Measurement Scale should be performed four hours (± 15min) after the end of each 
procedure, 
8. Local lab tests: PTT & INR (2ml) blood samples should be performed four hours (± 
15min) after start of each surgical procedure, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 54 of 169 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
9. Central lab: Serum chemistry, hematology and urinalysis, should be performed 4 hours (± 
15min) after the end of each procedure (end of surgical procedure and/or end of non 
surgical procedure),  
10. Blood culture - 4 h (± 15min) after the end of each procedure, 
11. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented, 
12. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
P
* ost non-surgical procedures, there is no need to perform VAS scale, central lab tests, 
PTT/INR, blood culture and wound culture if surgical procedure is done within 6 h  post the 
non-surgical procedure. These tests will be captured as the pre-surgical procedures. 
*Post surgical procedures, all procedures should be done, even in case that non-surgical 
procedure is followed immediately (within 6 hours). Only VAS scale pain assessment should 
be done as close as possible to the defined timeline but before dressing is applied. All the 
additional tests (e.g. central labs) should be performed within specified timelines.  
8.2.2.2 
Topical arms; NexoBrid/Gel Vehicle - Eschar removal procedure (to be initiated 
within 72 hours from injury) 
8.2.2.2.1 
Preparation 
1. Surround the area from which you wish to remove the eschar with a paraffin ointment 
adhesive barrier by applying it a few centimeters outside of the treatment area (using an 
adhesive-barrier dispenser). The paraffin layer must not come into contact with the area to 
be treated to avoid covering the eschar, thus isolating the eschar from direct contact with 
the topical agent, 
2. Sprinkle sterile isotonic (0.9%) sodium chloride solution on the burn wound. The wound 
must be kept moist during the application procedure. 
8.2.2.2.2 
Application 
Application of the product, as per the randomization, should follow the instruction for use 
described in Section 6.4, 
1. The wound should then be covered with an occlusive film dressing that adheres to the 
adhesive barrier material applied as per the instruction above. The topical agent should fill 
the entire occlusive dressing, and special care should be taken not to leave air in this 
occlusive dressing. Gentle pressing of the occlusive dressing at the area of contact with the 
adhesive barrier will ensure adherence between the occlusive film and the adhesive barrier 
and achieve complete containment of topical agent on the treatment area, 
2. The dressed wound should be covered with a loose, thick fluffy dressing, held in place 
with a bandage, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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3. The dressing should remain in place for 4 hours (± 15min),  
4. Circumferential extremity wounds should be monitored to detect EAR: If clinical 
assessment and SPO2 monitoring are possible, they will be done continuously and recorded 
in the eCRFs every 2 hours. If such assessment is not practical, direct pressure will be 
measured every 2 hours from start of the eschar removal. BICS should be treated by the 
investigator as described in Section 11.6.2. Circumferential extremity which is assessed as 
EAR at this stage should not be removed from the study but monitored as described above 
and in Section 11.6.2. 
All unused products should be kept for accountability as described in Section 10.1 (all remains 
and unused bottles). 
Starting and completion time of the eschar removal process should be documented in the 
eCRFs. 
8.2.2.2.3 
During 1st Application 
1. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 30 
± 10 min, 120 ± 15 min and 4 ± 0.5 hours after initial application of NexoBrid/Gel Vehicle 
PK blood sample (2ml) will be performed in a subset of NexoBrid patients21 at the following 
time points: 1h ± 10 min and 2h ± 10 min and 4h  ± 15 min from initial application. 
8.2.2.2.4 
Removal of topical agent 
1. Administer appropriate preventive analgesia medication, 
2. PTT & INR (2ml) will be tested at 4hrs ± 15 min after start of eschar removal procedure. 
3. After 4 hours (± 15 min) of treatment at each TW, remove the occlusive dressing using 
aseptic techniques, 
4. The adhesive barrier should be removed using a sterile blunt-edged instrument (e.g. tongue 
depressor), 
5. Remove the dissolved eschar from the wound by wiping it away with a sterile blunt-edged 
instrument, 
6. Wipe the wound thoroughly first with a large sterile dry gauze or napkin, followed by a 
sterile gauze or napkin that has been soaked with sterile isotonic (0.9%) sodium chloride 
solution. Rub the treated area until the appearance of a pinkish surface with bleeding 
points or a whitish tissue. Rubbing will not remove adhering undissolved eschar in areas 
where the treatment has been ineffective and eschar still remains, 
7. Interstitial/compartment pressure will be measured (as described in Section 11.6.2) post-
eschar removal per circumferential extremity wound after removal of dissolved eschar or 
Escharotomy, whichever is first, 
8. Apply a dressing soaked with an antibacterial solution, i.e. 3-5% Sulfamylon, 0.05-0.5% 
Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution for an additional 
                                                 
21 Only in 20 NexoBrid patients  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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2 hours. This wet-to-dry dressing will absorb and remove remaining NexoBrid and 
dissolved eschar that could not be removed by a simple wiping, 
9. Target Wounds should be labeled and photographed at the end of the 2hrs soaking,  
10. Eschar removal will be assessed immediately following the completion of 2 hrs soaking by  
an Investigator or designee, blinded to the treated arm. Parameters describing the eschar 
removal treatment will be documented in the eCRFs in addition to starting and completion 
time of the procedure, recovery time, analgesia/anesthesia prescribed during treatment, 
level of analgesia prescribed (as described in Appendix 2- Pain Management Procedures), 
manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistants and number of study drug kits used) who participated during the above 
period of time and disposables used (number of dressings, blades, etc), 
11. Qualitative wound culture (swabs), per TW, will be performed at the end of the soaking 
period. 
12. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of the soaking period. 
13. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale) as 
described in Appendix 9- Pain Measurement Scale should be performed four hours (± 
15min) after the end of the 2 hrs soaking period, 
14. Central lab: Serum chemistry, hematology and urinalysis (as described in Section 11.6.1), 
should be performed four hours (± 15min) after the end of the 2 hrs soaking period. 
15. Blood culture - four hours (± 15min) after the end of the 2 hrs soaking period. 
16. All types of blood products transfusions (e.g. units of whole blood or packed cells and 
volume) will be documented,  
17. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method), 
8.2.2.2.5 
Repeat application 
The blinded assessor will assess the completeness of eschar removal. 
1. In case eschar removal from the target wound after the first application is not complete, 
but at least 50% eschar was removed, a second eschar removal procedure using the 
randomized topical agent (NexoBrid/ Gel Vehicle) will be performed. The randomized 
drug should be re-applied to the entire TW if necessary, but can also be applied only on 
the areas of the TW left with eschar. Reasons for failure should be recorded in the eCRFs, 
2. Pre treatment assessments should be repeated as described in Section 8.2.1, excluding 
ECG and wound depth assessment. In case procedures are done continuously (or less than 
6 hours between procedures), post first treatment procedure assessments should be done as 
close as possible to the defined timelines but before second application start.  Pre treatment 
second assessments should not be done, 
3. Treatment application should be conducted as detailed above,  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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4. Topical agent removal and post treatment assessments should be repeated as described in 
Section 8.2.2.2.4,  
5. No more than two eschar removal procedures using the randomized topical agent 
(NexoBrid//Gel Vehicle) will be allowed per TW. 
6. Second eschar removal session can start immediately after the 2 hrs soaking done post the 
first application of the randomized arm (pre soaking period is not required before a second 
application of the randomized arm treatment to the same target wound),  
7. Repeat application (second application of the randomized arm treatment to the same target 
wound) should be initiated no later than 24 hours after the start time of the first 
application.  
In case of a recorded failure following the topical application/s, additional surgical and/or non 
surgical eschar removal will be allowed as described below and in Section 8.2.2.1.  
8.2.2.2.6 
Additional surgical eschar removal procedure 
Surgical 
procedures 
intended 
for 
completion 
of 
eschar 
removal 
will 
include 
tangential/minor/avulsion/Versajet/dermabrasion excision.    
8.2.2.2.7 
Additional non-surgical eschar removal procedure: 
Non-surgical procedures intended for eschar removal should include the application of any of 
the following allowed agents: (Collagenase ointment (e.g. Santyl), antimicrobial solutions (i.e. 
Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (i.e. Bacitracin, Polysporin, 
Silvadene) and/or Silver dressings (i.e. Mepilex Ag, Aquacel Ag, Acticoat). Continued 
application of NexoBrid or Gel Vehicle is not allowed at this stage. This/these will be applied 
on the cleaned and washed eschar of each TW to induce maceration and autolysis of eschar.  
8.2.2.2.8 
Pre each additional procedure: 
1 hour pre treatment assessments should be performed as described: 
1. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed within one hour 
prior to eschar removal initiation, 
2. Central lab blood tests: Serum chemistry, hematology and urinalysis (as described in 
Section 11.6.1), should be performed within one hour (± 15min) prior to eschar removal 
initiation, 
3. Qualitative-swab wound culture (per Target Wound), 
4. Preventive analgesia medication (pain management) will be mandated as for an extensive 
dressing change as routinely practiced; it should be initiated at least 15 minutes prior to 
dressing change or application in order to ensure pain free care (example of a 
recommended protocol provided in Appendix 2- Pain Management Procedures). Prior to a 
surgery, preventive sedation and/or general anesthesia will be mandated as routinely 
practiced. Pain management medications and analgesia/sedation level will be recorded,   
5. Prior to treatment (post cleansing, when relevant), all Target Wounds should be labeled 
and photographed (please refer to Appendix 3- Photographic wound documentation), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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6. Prior to treatment, the % TBSA of each TW will be recorded, 
 *Pre treatment of additional procedures should not be performed in case the procedure is 
being initiated within 6 hrs from previous procedure. Only preventive analgesia medication 
8.2.2.2.9 
Post each additional procedure: 
1. The parameters describing the additional procedure will be documented in the eCRFs in 
addition 
to 
starting 
and 
completion 
time 
of 
the 
eschar 
removal 
process, 
analgesia/anesthesia prescribed during treatment and level of analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
if applicable, anesthesiologists, registered nurses, practical nurses and unskilled 
assistances) who participated during the above period of time and disposables used 
(number of dressings, blades, etc), 
2. Target Wounds should be labeled and photographed at the end of each eschar removal 
treatment. The time-point of the final SOC eschar removal should be documented,  
3. Eschar removal will be assessed immediately following the completion of each procedure 
(by the same assessor who evaluate blindly the eschar removal in the topical arms) and 
recorded for each TW. TWs depth will be evaluated once, post complete eschar removal, 
4. Qualitative-swab wound culture (per Target Wound) will be taken at the end of each 
eschar removal procedure (surgical and/or non-surgical procedure), 
5. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of each eschar removal procedure (surgical and/or non-surgical procedure), 
6. Interstitial/compartment pressure will be measured (as described in Section 11.6.2) post-
eschar removal, per circumferential extremity wound, after the completion of each surgical 
/ non surgical procedure or escharotomy, whichever is first, 
7. Pain assessment using a routinely accepted pain-scale (VAS) as described in Appendix 9- 
Pain Measurement Scale should be performed four hours after the end of each procedure, 
8. Local lab tests: PTT & INR (2ml) blood samples should be performed four hours after 
start of each surgical procedure, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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9. Central lab: Serum chemistry, hematology and urinalysis, should be performed 4 hours ( 
after the end of each procedure (end of surgical procedure and/or end of non surgical 
procedure),  
10. Blood culture - 4 h after the end of each procedure, 
11. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented,  
12. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
P
* ost non-surgical procedures, there is no need to perform VAS scale, central lab tests, 
PTT/INR, blood culture and wound culture if surgical procedure is done within 6h post the 
non-surgical procedure. These tests will be captured as the pre-surgical procedures. 
*Post surgical procedures, all procedures should be done, even in case that non-surgical 
procedure is followed immediately (within 6h), only VAS scale pain assessment should be 
done as close as possible to the defined timeline but before dressing is applied. All the 
additional tests (e.g. central labs) should be performed within specified timelines.  
8.3 
GENERAL ASSESSMENTS, POST ESCHAR REMOVAL  
The following assessments will be performed for all arms: 
1. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be measured 
daily, in the morning time (5 AM to 10 AM), starting on the morning after the start of 
eschar removal, until hospital discharge, 
2. Pain assessments will be performed daily, in the morning time (5 AM to 10 AM) using a 
standard pain-scale ruler (VAS) (please refer to Appendix 9- Pain Measurement Scale), 
starting on the morning after the start of eschar removal, until hospital discharge, 
3. 12-lead ECG (in triplicate) will be performed, if feasible, at 12 ± 0.5 hours, 24 ± 1 hours 
and 48 ± 2 hours after start of the eschar removal treatment, 
4. PK blood sampling (2ml) will be  continued in a subset of patients22 at 12  0.5 hours, 24 
 1 hours and 48  2 hours from start of the 1st application of NexoBrid (ONLY for 
NexoBrid patients),  
5. Local lab tests: PTT & INR (2ml) blood sample, will be taken 24  1 hours and 48  2 
hours after start of Eschar removal procedures, 
6. All types of  blood product transfusions (e.g. units of whole blood or packed cells and 
volume) will be documented throughout the patient admission, The physician will be 
asked to comment on whether the blood transfused is related to any specific procedure 
performed (e.g. surgical eschar removal, preparation for an autograft, etc), 
                                                 
22 Only for 20 patients treated with NexoBrid. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 hrs.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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7. Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, 
whichever comes first, for patients with catheter, 
8. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
8.4 
POST-ESCHAR REMOVAL- WOUND MANAGEMENT 
In TWs which were assessed to reach complete eschar removal, the consequent wound closure 
phase can be initiated by grafting or epithelialization. The following section will describe 
wound management, post eschar removal, and is relevant to all TWs, regardless of the eschar 
removal method performed in accordance with the randomization. 
Following to completion of eschar removal (NexoBrid, Gel Vehicle or SOC), different sites in 
the same patient may require different treatment strategies [28]. In general, raw bed, regardless 
of the eschar removal means, should always be protected by a dressing or a topical medicament 
and never remain open or allowed to desiccate. 
Subsequently, wound management for all treatment arms should follow the normal standard 
care for open, raw surfaces based on the general principles described below. Please refer to 
Appendix 5- Wound management; approved covers for list of approved wound care products: 
1. Wounds having Full thickness defects should be grafted with autografts or permanent 
dermal substitutes (i.e. Integra, Matriderm, Hyalomatrix) as soon as possible after eschar 
removal. If permanent cover such as autografting has to be postponed, a temporary 
adherent cover (e.g. allograft, Xenograft, etc) should be used until permanent closure is 
possible. Prior to grafting the clean eschar-free bed should be refreshed by scraping it to 
open occluded capillaries and remove fibrin deposits and thrombi. In rare cases of exposed 
tendons, blood vessels or bone, flaps may be used as protection and permanent cover.  
Use of negative pressure wound therapy (e.g. VAC) on top of the autograft for 2-3 days 
promotes take by ensuring drainage, contact and adherence to the wound bed and is 
commonly used.  
2. Wherever viable dermal exists, such as in the partial thickness burns (mid and deep 
partial), healing by spontaneous epithelialization on these partial thickness areas could be 
attempted for a period of approximately 3 weeks in order to reduce surgery and autograft 
use with donor site sacrifice [96], but should be carefully evaluated for a satisfying 
progress on a weekly basis. In these cases, the following wound management should be 
performed: 
a. The raw surface should be covered with an adherent biological cover (i.e. allograft, 
Xenograft), synthetic dressings or skin substitutes (e.g. Mepilex® Ag, Mepilex® transfer 
Ag, Aquacel Ag, etc) in order to protect the raw surface (mainly from desiccation) and 
provide the microenvironment necessary for epithelialization (e.g. 5% sulfamylon, 
Bacitracin, etc). If allografts, xenografts or any film-like products are applied on the 
debrided wounds, they should be perforated or meshed (and not expanded) for drainage 
and optimal conforming to the bed. Topical medicaments can also be used as covers as 
long as they do not interfere with the healing process (as in the case of SSD or Iodine 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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preparations) and moisturize or prevent desiccating the healing bed (the above are 
suggested coverages to apply on the clean wound bed. For additional approved 
biological covers, skin substitutes and topical medications please refer to Appendix 5- 
Wound management; approved covers). 
b. Use of negative pressure wound therapy (e.g. VAC) on top of the graft or primary 
biological cover dressing including autograft for 2-3 days can ensure drainage, contact 
and adherence to the wound bed. The use of negative pressure wound therapy (NPWT) 
for a few days in order to stabilize and promote skin graft adherence and take is quite 
commonly practiced as part of the routine engraftment procedure. It is applied at the 
end of engraftment over the applied meshed or perforated autograft for 2-4 days and 
kept until first dressing change [105].   
c. The cover and dressings should be assessed for signs of contamination, infection or 
sloughing. Contamination or infection may be treated with topical antibacterial soaking 
or irrigation for a few days as well as systemic antibiotics, according to the 
investigator’s medical judgment.  Sloughing tissue should be removed by wiping away 
the non-adherent parts.  The exposed areas should be protected from desiccation and 
treated either as exposed dermis, aiming at epithelialization, or as a full thickness defect 
which should be autografted or closed by permanents skin graft or substitutes. Dry 
hydrogels, gelfoams, hydrofibres, alginates, Biobrane etc. applied on a viable raw bed 
can desiccate the wound surface and if used, should be soaked periodically to provide 
moisture to the healing wound. 
d. Re-assessment of wound should be performed at least on a weekly basis (as per Section 
8.6)[83]: 
i. 
If the non healing area is a full thickness wound, the area should be autografted 
or closed permanently as soon as possible.  
ii. 
Areas with preserved dermis should be treated with approved topical 
medications or covered with approved biological covers in order to promote 
epithelialization and control granulation tissue that may start to develop after 2 
weeks. Granulation tissue that appears on the healing surfaces should be treated 
immediately. Granulation tissue forms-in and results from the proliferative 
phase of the inflammatory response [78]. Topical corticosteroids' primary 
activity is anti-inflammatory and/or immunosuppressive effects [84-85] (e.g. 
Synalar which is indicated for the relief of the inflammatory & pruritic 
manifestations & Diprolene Ointment which is a super-high potency 
corticosteroid indicated as well for the relief of the inflammatory and pruritic 
manifestations). Granulation tissue of wound’s bed, being an inflammatory 
process, is often modulated by topical steroid preparations for short periods (2-3 
days), alternating with other topical medications. The topical steroids facilitate 
control of granulation tissue and the cover that prevents desiccation allows 
epithelialization23.     
                                                 
23 Steroid preparations are indicated and currently used as solutions, creams, ointments and also systemically for 
shorter and longer periods in most inflammatory process.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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iii. 
If the non-epithelialized areas after > 2 weeks of healing are small (< ½ %TBSA 
or < 50 cm2) with many interposing epithelializing islands, topical medication 
can be applied. Medications such as Biafin or antibiotic ointments, creams or 
hydrocolloid dressings that will prevent desiccation and will provide a good 
environment for the epithelialization process are recommended. Special 
attention should be paid upon removal of these medicated dressings so that the 
epithelializing surface will not be disrupted.  
Exposed dermis can be autografted early after eschar removal in order to expedite wound 
closure but in many cases the dermis may epithelialize under the graft, dislodging it after 2-3 
weeks or the graft may take and remain as an over-grafting.  
Conservative, non-surgical treatment by the antimicrobial Silversulfadiazine (SSD) dressing 
followed by daily dressing change and bathing is designed to slowly slough and debride the 
eschar-covered wound by autolysis without excessive infection. SSD should not be used on a 
clean bed as it decreases epithelialization. The pseudoeschar caused by SSD can sometimes 
serve as a protective layer to the areas of epithelialization process but it is often misdiagnosed 
as newly formed eschar. This pseudoeschar should not be surgically excised (thus sacrificing 
a viable dermal bed) and conservative treatment should be continued until the entire 
pseudoeschar spontaneously sloughs off. After sloughing of the pseudoeschar the resulting 
surface should be assessed and full thickness non healing areas permanently closed (grafted). 
NOTE: Tangential excision of pseudoeschar will most probably result in a full thickness 
defect even if it originally covered preserved dermis with epithelialization potential.  
A detailed overview of post eschar removal wound closure is presented in Appendix 4- Post-
Eschar removal Wound Management. 
8.5 
WOUND MANAGEMENT PROCEDURES 
The following relevant details should be recorded: 
1. Preventive analgesia medication (pain management) will be mandated for post surgical 
dressing changes as routinely practiced by the PI for a pain free extensive dressing change 
and wound care; it should be initiated at least 15 minutes prior to dressing change (example 
of a recommended protocol provided in Appendix 2- Pain Management Procedures),  
2. Target Wounds coverage type (all coverages used post-eschar removal, until hospital 
discharge) and % area applied with, 
3. Any additional tangential/minor/Versajet/dermabrasion excision(s), which is done as a 
preparation for cover/autograft should be recorded,  
4. The relevant TW should be photographed (within 1 hour before and immediately at the end 
of the excision procedure) and % of treated wound excised (out of the original debrided 
wound) should be clinically assessed, 
5. Central lab – hematology, will be taken within 1 hr prior to start of any excision and four 
hours after completion of the procedure, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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6. For any autograft performed, the TW should be photographed before (within 1 hour) and 
after any procedure. The % of treated wound autografted (out of the original wound size) 
will be clinically assessed, 
7. Any autograft performed, if not immediately (within 6 hrs) following the excision- central 
lab - hematology, should be performed within 1 hr prior to start of the procedure (including 
any preparations required) and four hours after completion of the procedure, 
8. Parameters describing the surgical procedures will be documented in the eCRFs in addition 
to 
starting 
and 
completion 
time 
of 
the 
surgical 
procedure, 
recovery 
time, 
analgesia/anesthesia prescribed during treatment, level of sedation/analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
anesthesiologists, registered nurses, practical nurses, and unskilled assistances) who 
participated during the above period of time and disposables used (e.g. number of dressings, 
blades, etc),  
9. All types of blood product transfusions (e.g. units of whole blood or packed cells and 
volume to be recorded) prescribed to a subject with a record of date and time. The physician 
will be asked to comment on whether the blood transfused is related to any specific 
procedure performed (e.g. surgical eschar removal, preparation for an autograft, etc), The 
site (anatomical area), and size of the donor site will be photographed and clinically assessed 
(by rule of palm), 
10. Donor site coverage used will be recorded in the eCRFs, 
11. Background pain should be treated according to the individual needs in order to ensure pain 
free care, 
12. Adverse events and concomitant medication will be recorded. 
8.6 
FOLLOW-UP ASSESSMENTS: WEEKLY (7  2 DAYS) POST-START OF ESCHAR 
REMOVAL 
The following assessments will be performed and recorded 7 ± 2 days post-start of eschar 
removal and, thereafter, on a weekly basis until wound closure (based on start of eschar 
removal): 
1. The target wound and donor sites should be photographed and documented (as describe in 
Appendix 3- Photographic wound documentation), 
2. Clinical assessment of % of target wound area epithelialized and/or closed by graft (see 
also wound closure assessment described in Section 6.3), and assessment of % donor site 
epithelialized, will be assessed by a second blinded assessor, blinded to all treatment arms, 
3. Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment (as describe in 
Appendix 3- Photographic wound documentation), will be assessed by a second blinded 
assessor, blinded to all treatment arms, 
4. Type of cover/dressing applied on TWs and donor sites should be recorded, 
5. 12-lead ECG (in triplicate) will be performed, if feasible, 7 ± 2 days from initial 
application,  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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6. Development of granulation tissue should be monitored. In case of initial appearance, 
treatment using approved ointment, creams or soaking during the epithelialization stages 
of wound healing should be applied. Details should be recorded in the eCRFs,  
7. Immunogenicity blood samples (3ml) should be taken in NexoBrid patients as per the 
timelines described in Section 11.6.5, per Appendix 10- Procedures for specific blood 
tests. 
8. Weekly follow-up assessments will be continued until complete wound closure for all of a 
subject's treated target wounds24 (please refer to Section 8.8). 
8.7 
HOSPITAL DISCHARGE 
The following procedures and assessments will be performed and recorded before a patient’s 
discharge from the hospital (within 24 hours prior to discharge): 
1. The target wounds and donor sites should be labeled and photographed, 
2. Assessment of % of wound area epithelialized and/or closed by graft,  
3. Assessment of % of donor site area epithelialized, 
4. Type of cover/dressing applied on TWs and donor sites should be recorded, 
5. Physical examination and weight, 
6. Date of hospital discharge. 
Weekly follow-up assessments will be continued until complete wound closure as per Section 
8.6 above. 
8.8 
FOLLOW-UP ASSESSMENTS: WOUND CLOSURE CONFIRMATION 2 WEEKS POST 
WOUND CLOSURE 
A confirmation of wound closure will be performed by a follow-up visit at day 14 ( 2 days) 
from wound closure, for each subject's target wounds. The following assessments will be 
performed: 
1. The wounds should be labeled and photographed (as describe in Appendix 3- 
Photographic wound documentation),  
2. Maintenance of complete wound closure will be confirmed, 
3. Patient diary will be provided to the patient to record any change in concomitant 
medications and or any adverse event, during the following monthly FU period.  
8.9 
FOLLOW-UP LONG TERM ASSESSMENTS 
The following assessments will be performed at 1 month (± 7 days), 3, 6, 12, 18 and 24 months 
(± 2 weeks for all time points) from the wound closure confirmatory visit: 
                                                 
24 Complete wound closure- defined as skin re-epithelialization without drainage or dressing requirements 
confirmed at two consecutive study visits, 2 weeks apart. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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1. The wounds should be labeled and photographed, 
2. Maintenance of complete wound closure (YES or NO) - only on month 1 and 3, 
3. Record of scar-modulating procedures and scar reconstructive procedures, if performed. 
This should include dates of initiation and termination of scar-modulating procedures 
including any procedure performed (compression therapy, silicone sheeting, steroid 
injections, etc.), 
4. Any Adverse Events and concomitant medications prescribed should be captured in the 
eCRFs, 
5. Quality of Life evaluation will be performed using Burn Specific Health Scale (BSHS-
B) and EQ5D as described in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire, 
6. Functionality evaluation will be performed using self completed questionnaires (as 
described in Appendix 12- Cosmesis, Function and Quality of Life Questionnaire): 
a. The “Lower Extremity Functional Scale” test for burns in the lower extremities,  
b. The “QuickDASH” outcome measure for burns in the upper extremities.  
7. Immunogenicity blood samples (3ml) should be taken in NexoBrid patients as per the 
timelines described in Section 11.6.5, per Appendix 10- Procedures for specific blood 
tests, 
8. The below evaluations will be performed by a second blinded assessor (who is blinded 
to all treatment arms): 
a. Cosmesis assessment using POSAS and MVSS for all TWs and donor sites, as 
described in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire,  
b. Range of Motion measurements of injured joints, if relevant: knee, ankle, 
shoulder, elbow, wrist and hand. Measurements will be performed on the 
patient’s own non injured joints as well for comparison to burned joints (as 
described in Appendix 14- Range of Motion). 
8.10 
FOLLOW-UP ASSESSMENTS: RE-ADMISSION TO HOSPITAL OR DAY CARE 
Persistent, small open wounds or reopening of new small areas are expected and can normally 
continue for months necessitating treatment as in- or outpatients as a part of a normal wound 
care [1]. A patient may be re-admitted to the hospital for continuation and follow-up of 
planned treatments or for unexpected events. The following procedures and assessments will 
be conducted and recorded: 
1. 
The reason for the re-admission should be recorded and any relevant TWs planned to be 
treated, 
2. 
The relevant TW/s should be labeled and photographed upon admission and before 
patient's discharge (as describe in Appendix 3- Photographic wound documentation), 
3. 
The wounds will be managed according to the guidelines described in Appendix 4- Post-
Eschar removal Wound Management, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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The following relevant details should be recorded: 
4. Preventive analgesia medication (pain management) will be mandated for post surgical 
dressing changes as routinely practiced by the PI for a pain free extensive dressing change 
and wound care; it should be initiated at least 15 minutes prior to dressing change (example 
of a recommended protocol provided in Appendix 2- Pain Management Procedures),  
5. Target Wounds coverage type (all coverages used during readmission, until re hospital 
discharge) and % area applied with, 
6. Any additional tangential/minor/Versajet/dermabrasion excision(s), which is done as a 
preparation for cover/autograft should be recorded, 
7. The relevant TW should be photographed (within 1 hour before and immediately at the end 
of the excision procedure) and % of treated wound excised (out of the original debrided 
wound) should be clinically assessed, 
8. Central lab – hematology, will be taken within 1 hr prior to start of any excision and four 
hours after completion of the procedure, 
9. For any autograft performed, the TW should be photographed before (within 1 hour) and 
after any procedure., the % of treated wound autografted (out of the original wound size) 
will be clinically assessed, 
10. Any autograft performed, if not immediately (within 6 hrs) following the excision- central 
lab - hematology, should be performed within 1 hr prior to start of the procedure 
(including any preparations required) and four hours after completion of the procedure, 
11. Parameters describing the surgical procedures will be documented in the eCRFs in 
addition to starting and completion time of the surgical procedure, recovery time, 
analgesia/anesthesia prescribed during treatment, level of sedation/analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
anesthesiologists, registered nurses, practical nurses, and unskilled assistances) who 
participated during the above period of time and disposables used (e.g. number of 
dressings, blades, etc),  
12. All types of blood product transfusions (e.g. units of whole blood or packed cells and 
volume to be recorded) prescribed to a subject with a record of date and time. The 
physician will be asked to comment on whether the blood transfused is related to any 
specific procedure performed (e.g. surgical eschar removal, preparation for an autograft, 
etc),  
13. The site (anatomical area), and size of the donor site will be photographed and clinically 
assessed (by rule of palm), 
14. Donor site coverage used will be recorded in the eCRFs, 
15. Background pain should be treated according to the individual needs in order to ensure 
pain free care, 
16. Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment (as describe in 
Appendix 3- Photographic wound documentation), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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17. Clinical assessment of wound closure by % wound area epithelialized and/or by graft will 
be recorded at discharge,  
18. Adverse events will be recorded throughout the hospital stay, 
19. Concomitant medication will be recorded throughout the hospital stay, 
20. Date of hospital discharge will be recorded.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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9 
TREATMENT FLOW CHART – STUDY SCHEDULE 
Table 3- Treatment flow chart- all arms 
#- If applicable  
* Weekly FU assessments will be performed every 7± 2 days from start of treatment until complete wound closure 
**First treatment session will include any procedure for eschar removal: the NexoBrid/ /Gel Vehicle/Surgical or non-surgical procedure, as per randomization arm 
*** Procedure can be either surgical or non-surgical. A whole period of continuous dressing changes (from first coverage application to last coverage application) is considered as one non-surgical procedure, 
assessments should not be repeated for each dressing change; Pre non surgical procedures should not be performed if the non-surgical procedure is not the first eschar removal procedure.  
Parameter 
 Screening 
tests 
Baseline-24 h 
Pre First 
treatment 
session** 
During First 
treatment 
session**  
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures*** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management & Re-
admissions1- Per procedure 
assessment 
HD or premature 
discontinuation 
visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Inform Consent signing 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Burn History2 
X 
 
 
 
 
 
 
 
 
 
ConMeds & AEs 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Physical examination3 
X 
 
 
 
 
 
 
X 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
Post S 
Post  
X 
 
 
 
 
Pain assessment 
X 
 
 
1 h pre and 4h post S 
1 h pre and 4h post  
X 
 
 
 
 
Photograph of TWs 
X4 
 
 
1 h Pre & post S 
Pre &post  
 
Pre &post  
X 
X 
X 
Clinical assessment of the 
burn5  
X 
 
 
1 h Pre first and post each 
S 
1 h Pre first and post 
each 
 
Post  
X 
X 
 
Local lab - HbA1C, WBC, 
βhCG 
X 
 
 
 
 
 
 
 
 
 
Central lab hematology/ 
biochemistry tests & 
Urinalysis 
 
 
 
1h pre P & 4 h post S 
1h pre & 4 h post  
 
 
 
 
 
                                                 
1 Burn Management may include additional excisions, Autografts, coverage used and donor site data.  
2 Data captured will include burn etiology, mechanism of injury, place of injury, treatments prior to admission and general description of the burn wound (anatomical locations and description of the eschar (such as: white, 
moist, dry, gray, charcoal, etc.), % TBSA assessments and depth 
3 Physical examination will include height and weight. Height will be taken only once, at screening. 
4 Photos should be taken before and after cleansing 
5 Clinical assessments will include % TBSA per depth, % eschar removed, % excised, % autografted, % wound epithelialization (TW and donor site, if relevant) as relevant. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Parameter 
 Screening 
tests 
Baseline-24 h 
Pre First 
treatment 
session** 
During First 
treatment 
session**  
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures*** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management & Re-
admissions1- Per procedure 
assessment 
HD or premature 
discontinuation 
visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Central lab Hematology 
 
 
 
 
 
 
Only surgical procedures: 
1h pre P & 4 h post 
 
 
 
Cleansing (Debridement)1 
X 
# 
 
 
 
 
 
 
 
 
Fluid balance2 
X 
X 
 
X 
X 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Local lab Wound culture 
 
 
 
1 h pre and post S 
1 h pre and post  
 
 
 
 
 
Local lab Blood culture 
 
X 
 
4h post S 
4 h post 
 
 
 
 
 
12-Lead ECG (if feasible) 
 
 
0.5, 2,4h 
20, 40, 60 min (only pre 
first treatment) 
20, 40, 60 min (only pre 
first 
12, 24, 48 h 
 
 
week 1 
 
PK (for a subset of 20 
NexoBrid Pts) 
 
X 
1, 2h 
 
 
4, 12, 24, 48 h 
 
 
 
 
Immunogenicity assessment  
(NexoBrid patients only) 
 
X 
 
 
 
 
 
 
weeks 
1,4,8 
6, 24 
Local lab PTT & INR  
 
X 
4 h from start 
of treatment  
 
4 h from start of the 
surgical procedure 
24,48 h  
 
 
 
 
Circumferential extremity 
wounds monitoring3 
X 
 
Each application 
of the topical 
product 
1 h pre and post R 
1h pre &  post  
 
 
 
 
 
Eschar Removal treatment 
 
 
X 
 
X 
 
 
 
 
 
Wound closure confirmation4 
 
 
 
 
 
 
 
 
X 
1, 3 
Cosmesis, Function and 
Quality Of Life5 
 
 
 
 
 
 
 
 
 
X 
scar-modulating procedures 
and scar reconstructive 
 
 
 
 
 
 
# 
 
 
# 
                                                 
1 Including a soaking period of at least 2 hours 
2  Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, whichever comes first for patients with catheter.  
3 The Extremities At Risk (EAR) burns prone to develop BICS will be identified at screening and excluded. Monitoring for the development of EAR in circumferential extremity wounds at the above specified timelines 
will be done. During each topical application (NexoBrid or gel Vehicle), clinical assessment and SpO2 monitoring will be done continuously. If such assessment is not practical, direct pressure will be measured every 2 
hours from start of eschar removal. Direct pressure will be measured before and after each eschar removal procedure and additional surgical procedures  
4 Wound closure should be confirmed 2weeks after the initial wound closure assessment for each TW. 
5 Cosmesis will be evaluated in donor site scars as well 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Parameter 
 Screening 
tests 
Baseline-24 h 
Pre First 
treatment 
session** 
During First 
treatment 
session**  
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures*** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management & Re-
admissions1- Per procedure 
assessment 
HD or premature 
discontinuation 
visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Blood transfusion (units & 
volume) 
# 
# 
 
# 
# 
# 
# 
# 
# 
# 
Histological biopsy 
# 
# 
 
# 
# 
# 
 
# 
# 
# 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Table 4- NexoBrid/ Gel vehicle Eschar Removal 
 
Preparation for Treatment 
Treatment 
At least 2 hours soaking  
X 
 
Preventive analgesia medication (pain management) will be mandated as for an extensive dressing change as routinely 
practiced; it should be initiated at least 15 minutes prior to dressing change or application in order to ensure pain free care  
X 
 
Removal of any blister-keratin remnants1 
X 
 
Surrounding of the TW with a paraffin ointment adhesive barrier2  
X 
 
Sprinkle sterile isotonic (0.9%) sodium chloride solution should be sprinkled on the burn wound3 
X 
 
Application of the product, as per the randomization, should follow the instruction for use described in Section 6.4 of the 
protocol 
 
X 
Occlusive film dressing should be applied to cover the wound 
 
X 
The dressed wound should be covered with a loose, thick fluffy dressing, held in place with a bandage 
 
X 
The dressing should remain in place for 4 hours 
 
X 
Starting and completion time of the procedure  will be recorded 
 
X 
Manpower (specify the number of surgeons, anesthesiologists, RN, nurses and unskilled assistances) who participated during 
the procedure will be recorded in the eCRFs 
 
X 
Any disposable used (number of dressings, blades, etc) will be recorded in the eCRFs 
 
X 
2 hrs soaking4  
 
X 
                                                 
1 If there are still blisters/keratin remains, clean the wound thoroughly and remove the superficial keratin layer or blisters from the wound area, as the keratin will isolate the eschar from direct contact with the 
topical agent 
2 Paraffin ointment should be applied a few centimeters outside of the treatment area (using an adhesive-barrier dispenser). The paraffin layer must not come into contact with the area to be treated to avoid 
covering the eschar, thus isolating the eschar from direct contact with the topical agent 
3 The wound must be kept moist during the application procedure 
4 Antibacterial solution, e.g. 3-5% Sulfamylon, 0.05-0.5% Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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10 
DRUG STORAGE AND DRUG ACCOUNTABILITY 
The bottles of NexoBrid powder and the Gel Vehicle must be kept refrigerated (2-8ºC).  
10.1 
ACCOUNTABILITY AND COMPLIANCE  
The principal investigator is responsible for maintaining accurate records of the receipt and 
dispensing of all investigational materials. The investigator may dispense investigational drug 
only to patients enrolled in the study. All dispensing will be conducted from the site listed in 
the Statement of Investigator. 
MediWound Ltd. will provide drug accountability forms to assist the investigator in 
maintaining current and accurate inventory records covering receipt, dispensing, and the return 
of investigational drug supplies. When a shipment is received during site's initiation or during 
the study, the investigator or pharmacist will verify the quantities received, complete an 
Inventory log form and return the acknowledgment to the study monitor or designee. The 
investigational drug accountability record includes the identification of the patient to whom the 
drug is dispensed, the quantity and the date of dispensing and any returned or unused drug. 
This record is in addition to any drug accountability information recorded on the Case Report 
Form. These records will be readily available for inspection by a monitor or MediWound Ltd. 
audits and are open to any other regulatory authority inspection at any time. 
When the supplies are returned or destroyed, the investigator or pharmacist signs the 
investigational drug return or destruction log to verify that all unused or partially used supplies 
were accounted for and confirms that no study supplies remain in the investigator’s possession. 
One copy of all inventory records and the return statement are retained by the investigator for 
the study files. 
At study termination, unless otherwise specified, all unused drug supplies including partially 
used containers and the study drug accountability log should be returned to: MediWound, Ltd., 
Clinical Research Department, 42 Hayarkon Street, North Industrial Area, Yavne, 8122745, 
Israel.  
10.2 
PREVIOUS AND ON-GOING MEDICATIONS/THERAPIES.  
10.2.1 
Disallowed Previous and On-Going Medications/Therapies 
Pre-enrollment dressings with flammacerium or silver nitrate (AgNO3) are disallowed. 
10.2.2 
Allowed Previous and On-Going Medications/Therapies 
All other systemic medications except in the above section are allowed. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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11 
ASSESSMENT METHODS 
Efficacy Assessment Methods will include: 
11.1 
PRIMARY END POINT 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to Section 1.1 for Target Wound 
definition): 
Incidence of complete eschar removal: Demonstrate superiority over Gel Vehicle for eschar 
removal as measured by incidence of complete eschar removal by the end of the topical agent 
soaking period by a blinded assessor. Complete eschar removal is achieved at the end of the 
eschar removal treatment phase as routinely determined by burn specialists during their daily 
practice in burn units and is the basis for the medical decision to initiate the consequent wound 
closure phase: treatment towards wound closure.  
Reasons for Incidence of complete Eschar Removal as Primary Endpoint 
Following the goal to seek an indication for NexoBrid that focuses on non surgical eschar 
removal, the evaluation focus is set on this measure as a primary endpoint of the study. This 
primary endpoint will assess whether non-surgical eschar removal by NexoBrid allows 
effective removal of the offending eschar compared with its comparator. Complete eschar 
removal assessment will be captured in the eCRFs for each TW and has to be marked as 
complete for all TWs to be considered as complete per patient.  
11.2 
SECONDARY ENDPOINTS 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SOC. Comparisons between NexoBrid and Gel vehicle will be carried out in the 
same manner as between NexoBrid and SOC, but will be regarded as supportive analyses. 
11.2.1 
Reduction in surgical needs 
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). 
11.2.2 
Earlier eschar removal 
Demonstrate superiority of NexoBrid over SOC with regard to the time when complete eschar 
removal has been achieved. For definition of complete eschar removal see primary endpoint. 
11.2.3 
Blood loss 
Demonstrate superiority of NexoBrid over SOC with regard to the blood loss incurred during the 
eschar removal procedures. Actual blood loss will be measured by considering the estimated 
blood loss, changes in Hemoglobin during the eschar removal procedures and the amount of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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units of blood transfused. Blood loss (Actual Blood Loss, ABL) will be calculated using the 
following formula [86]:  
ABL= (EBV * (Hbbefore- Hbafter))/((Hbbefore+ Hbafter)/2))+ (500*Tu) 
EBV= Estimated blood volume is assumed 70 cm3/Kg 
(Hbbefore- Hbafter)= Changes in Hb following each eschar removal procedure 
Tu= sum of autologous whole blood, packed red blood and cell saver units transfused. 
The ABL will be summed over all procedures carried out to remove eschar, with the HB 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during the debridement 
procedure and 4 hrs later i.e. the before-after periods that are spanned by these HB 
measurements.    
Reasons for Incidence of Surgical Excisions as Secondary Endpoint 
A further aspect of the clinically meaningful attributes of NexoBrid’s non surgical eschar 
removal is the ability to reduce surgical needs, as NexoBrid allows removal of eschar in 
wounds that otherwise would have to undergo surgical excision. Therefore, this secondary 
endpoint would provide information on treatment failures that required follow-on surgical 
management and will further provide supportive evidence of efficacy and demonstration of 
clinical benefit over SOC. 
Reasons for Earlier Eschar Removal as Secondary Endpoint 
This secondary endpoint will assess whether nonsurgical and effective eschar removal by 
NexoBrid allows for the removal of the offending eschar earlier upon admission, enabling 
earlier visualization of the wound bed for assessment of the burn wound’s depth as well as 
preservation of viable tissues [87-88]. The depth determination is important for the planning 
and execution of the post-eschar removal stage of wound closure (i.e., grafting or spontaneous 
epithelialization). The dynamic of burn wound progression of the eschar-covered burn wound 
is the first delaying factor in initiating SOC surgical eschar removal. The non sacrifice of 
healthy dermis by SOC excisional surgery and the overall surgical implications to the patient 
are the other delaying factors [1]. Therefore, it is hypothesized that NexoBrid will allow eschar 
removal earlier (post randomization), effectively and in the first few days from injury without 
the need to first determine the burn depth (as is done in the initial decision-making phase of 
surgical and non surgical SOC). 
Reasons for Blood Loss as Secondary Endpoint 
This secondary endpoint will further demonstrate NexoBrid’s clinical benefit by showing a 
decrease of total blood loss post NexoBrid eschar removal compared with the total blood loss 
in the SOC eschar removal procedures. Reduction in blood loss is considered as an outcome 
measure that could further demonstrate NexoBrid clinical benefit. Surgical blood loss is 
attributed mainly to the excisional phase  and is directly proportional to the surface excised 
measured in ml blood loss/cm2 and may reach 0.8 ml/cm2 [89-90]. Local inflammation and 
anti-aggregation treatments may involve more bleeding and need for transfusion. Many 
publications endorse different means to reduce debridement related bleeding (tourniquet, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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subcutaneous epinephrine infiltration of excised burn and donor site etc.). The calculation for 
the actual blood loss is being used in other invasive procedures as an accurate calculation that 
reflects the actual blood loss in a patient as this takes into account both the estimated blood 
loss, changes in Hb levels during the relevant procedure and total blood units transfused to a 
patient. 
11.3 
SAFETY ENDPOINTS 
The following group of safety endpoints will be evaluated in this study and compared between 
NexoBrid and SOC. These endpoints are used to ensure that NexoBrid does not cause an 
unacceptable level of harm. Comparisons between NexoBrid and SOC will be carried out using 
pre-specified clinically meaningful margins that will assist in the benefit versus risk assessment 
of the product. These safety measurements are not powered to yield statistical significant non 
inferior results. Thus their assessment will be used for supportive analyses and sources of 
additional information about NexoBrid and SOC. 
11.3.1 
Time to complete wound closure 
Time to reach complete wound closure assessed in days, starting from randomization date. 
Demonstrate that NexoBrid does not cause any clinically meaningful harm to the patients with 
respect to the wound healing process by comparing NexoBrid mean time to wound closure 
with SOC mean time to wound closure, where a difference of not more than 7.4 days 
difference will be interpreted as clinically not relevant. 
Reason for this endpoint and the definition of clinically meaningful harm:  
Time to reach complete wound closure is taken as a safety criterion because wound closure is a 
relevant parameter for patients’ quality of life and delay in wound closure may increase the risk 
of local complications. However, it can be assumed that the selective, non surgical eschar 
removal will probably increase the potential for spontaneous healing as physicians tend to 
postpone autografting in an effort to reduce autografting by exploiting the wound's preserved 
dermal potential for spontaneous epithelialization. Such spontaneous epithelialization is an 
important benefit for the patient (less autografting and less donor sites). This assumption is 
based on the results of the confirmatory phase III RCT (MW2004-11-02) in which a slight 
prolongation in time to wound closure (7 days) compared with the standard of care arm was 
observed with no deleterious effect on the long term cosmesis and function evaluation (long 
term follow up study MW2012-01-02). 
A supportive formal derivation of this margin may be based on the FDA proposal of using two 
values to derive a NI (non-inferiority) margin [91]: 
M1 denotes the effect of the standard against placebo; 
M2 denotes the largest clinically acceptable difference (towards non-effectiveness) of the test 
substance. 
M2 is usually chosen as a percentage of M1, usually 50%. If no realistic placebo result exists a 
conservative choice of keeping 80% of the M1 effect may be preferred (M2=0.2*M1). This is 
the case planning a trial with large thermal burns as a real placebo result is not available and 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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even not ethical, i.e. a placebo comparison measuring the effect of SOC on the wound closure 
scale is missing. 
The following calculation is based on the data from the pivotal study, MW2004-11-02. For a 
first derivation of a NI margin we disregard possible correlations between the different wounds 
and treat the wound closure times as independent. 
Given that SOC is an active comparator one expects at least 95% of the wounds treated with 
SOC to have a smaller time to wound closure than a (virtual) placebo mean time to wound 
closure. From the empirical distribution of the SOC wound closure times of the data set we 
derive the 95% quantile as 64 days. Taken this as the worst case scenario for a mean placebo 
wound closure time we obtain a SOC treatment effect of M1=64-27=37 days (SOC mean was 
27 days).  
M2 may then be taken as 0.2*M1=7.4 days, which is the NI margin sought. 
Therefore, a slight prolongation in mean time to wound closure might occur (up to 7.4 days) 
but will not express a clinically relevant imbalance of the risk benefit assessment as patient 
mobilization starts far before the wounds are closed and the return to pre-injury lifestyle, 
following rehabilitation and convalescence, takes weeks, if not months, long after the wounds 
are closed. Thus any difference in means of up to 7.4 days may be taken as not representing 
clinically meaningful harm for this safety endpoint. 
11.3.2 
Cosmesis and function at 12 months from wound closure 
A measure of cosmesis, using MVSS, will be used to demonstrate - that treatment with 
NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as 
compared to scars quality of burns treated with SOC, measured at 12 months from wound 
closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a 
NexoBrid group mean MVSS score higher by 2.7 or more units than the SOC group mean 
MVSS score.    
11.3.3 
Cosmesis and function at 24 months from wound closure 
A measure of cosmesis, using MVSS, will be used to demonstrate that treatment with 
NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as 
compared to scars quality of burns treated with SOC, measured at 24 months from wound 
closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a 
NexoBrid group mean MVSS score higher by 2.7 or more units than the SOC group mean 
MVSS score. 
Reasons for the cosmesis endpoint and the choice of the clinically meaningful difference: 
We propose that a clinical equivalence value of 2.7 in the MVSS scale signify NexoBrid non-
inferiority in scar quality to the SOC. This clinically meaningful difference is in agreement 
with the non-inferiority (NI) margins calculated using the MVSS data in study MW2004-11-02 
(Sponsor previous long term follow up of patients treated in the MW2004-11-02).  
The NI margin was calculated as follows:  
Two values are needed to derive a NI margin [91]:  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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M1 the effect of the standard against placebo  
M2 the largest clinically acceptable difference (towards non-effectiveness) of the test substance  
M2 is usually chosen as a percentage of M1, usually 50%. If no realistic placebo result exists a 
conservative choice of keeping 80% of the M1 effect may be preferred (M2=0.2*M1). This is 
the case when planning a trial with large thermal burns as a real placebo result is not available 
and even not ethical to measure the effect of SOC on the MVSS scale.  
The following calculation is based on the data observed during the clinical study (study 
MW2012-01-02). The margin may be calculated taking the theoretical maximum score of 18 
instead of the result of a (virtual) placebo arm. Consequently the SOC treatment effect is 18-
3.83=14.17, with 3.83 being the MVSS mean observed in the SOC group of the data (per 
patient analysis). Given the standard deviation of 2.27 from the MVSS data a 95% confidence 
interval for the SOC treatment effect is given by 14.17±0.75. The lower bound is 14.17-
0.75=13.42=M1. 
M2 may then be taken as 0.2*M1=2.7, which is the NI margin sought. 
Additional Safety Outcome Measures will include:  
11.3.4 
General parameters 
Systemic adverse events, vital signs, pain assessment (using VAS), laboratory tests, units (and 
volume) of blood transfusion given during hospitalization, Immunogenicity evaluation for 
NexoBrid patients, Pyrexia and Hypothermia, Systemic infections, Incidence of increased 
interstitial/compartment syndrome (as described in Section 1.1) and QT prolongation. 
Additional long term functionality evaluation of the extremities using the ‘Lower Extremity 
Functional Scale’, 'QuickDASH' questionnaires and 'Range Of Motion' measurements, 
Long term Quality of Life using EQ5D and Burn Specific Health Scale- Brief (BSHS-B) 
11.3.5 
Local parameters 
Local adverse events defined by treated physician or designee; graft loss, wound related 
infections, etc. 
11.4 
EXPLORATORY ENDPOINTS 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures, 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
9. PK evaluation for a subset of NexoBrid patients1, 
10. Autograft related parameters. 
11.5 
ADDITIONAL ANALYSIS 
The following analyses will be addressed as supportive efficacy analyses: 
1. Primary & secondary endpoints will be analyzed at a per wound level 
2. Secondary endpoints will be analyzed vs. the Gel Vehicle 
11.6 
SUBGROUP ANALYSES 
Descriptive statistics will be determined for all subgroup analyses.  
1. A sub group analysis will be performed on the subgroup of target wounds that are 
found, at least partly, in the anatomical area of the hand.  
2. Time to wound closure and 12m and 24m MVSS will be analyzed per TWs’ depth 
and% TBSA of the TWs.  
These subgroup analyses will be conducted at the wound level. More details will be 
provided in the SAP. 
 
11.6.1 
Safety Laboratory Evaluations 
The following tests described below will be performed. Any abnormal findings must be 
assessed for clinical significance – Abnormal Non Clinically Significant (NCS) or Abnormal 
Clinically Significant (CS):  
Serum chemistry, hematology and urinalysis testing will be performed at a central laboratory 
during the topical agent eschar removal phase. Any additional procedures require hematology 
tests, as described in the protocol, will be performed using Central lab. Pregnancy testing, 
HbA1c, leukocyte count (at Screening, in addition to central lab hematology), wound cultures, 
blood cultures and biopsies will be performed locally on-site. 
The following tests will be performed in special laboratories: Pharmacokinetics test, 
Immunogenicity evaluation and evaluation of QT prolongation (using multiple ECG tests). 
Serum Chemistry: 
                                                 
1 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4 , 12, 24 and 48 
hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Urea, Creatinine, Glucose, Total Bilirubin, Cholesterol, Triglycerides, Uric Acid, Total 
Protein, Albumin, Globulin, Calcium (Ca++), Phosphorous, Sodium (Na+), Potassium (K+), 
Chloride (Cl-), Alkaline Phosphatase, SGOT (ASAT), SGPT (ALAT), LDH. 
Hematology: 
Hemoglobin, Hematocrit, RBC, MCV, MCH, MCHC, Platelets, Leukocyte count (WBC) with 
differential count.   
HbA1c will be assessed at a local lab at Screening for diabetic patients as captured during the 
medical history.  
PTT and INR will be tested at a local lab pre treatment and 4 hrs after start of eschar removal. 
Pregnancy Testing: 
A serum pregnancy (HCG) will be performed at a local lab for women of child bearing 
potential.  
Urinalysis: 
pH, Ketone, Specific gravity, Protein, , Glucose, Bilirubin, Microscopic examination. 
Qualitative Wound Culture: 
Test burn wound for microbial flora (swab). 
Blood Culture: 
Test blood for microbial flora. 
Diagnosis of Invasive Burn Wound Infection is based on Quantitative (Histological) Wound 
Culture Biopsy: 
Infection should be assessed clinically by symptoms and signs that include local burn wound signs 
purulent drainage, erythema, warmth, exudation, odor, pain, and systemic signs that may or may 
not be related to the burn wound, such as fever, and leukocytosis as well as wound size and time to 
wound healing. Histological Biopsy may be performed to rule out suspicion of a clinical 
invasive burn wound infection (please refer to Appendix 8- Biopsy & Histologic Assessment 
Method) [93]. 
Clinical Burn Wound Infection will be defined when an Invasive Burn Wound Infection is 
diagnosed by quantitative bacterial count of >105 organisms per gram of tissue and histological 
signs of bacterial invasion of healthy tissues will define a positive invasive burn wound 
infection. At least one of the following histological signs of invasive burn wound infection is 
required:  
 
Microorganisms presence in viable unburned tissue 
 
Small vessel thrombosis and ischemic necrosis of unburned tissue 
 
Inflammation evident in unburned tissue 
 
Hemorrhage in uninjured tissue 
 
Evidence of microbial proliferation 
 
Variable migration of microorganisms along hair follicle and sweat glands 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 
Dense growth of nonviable-viable tissue interface (subeschar space)  
 
Intracellular viral inclusion 
 
Light microscopy 
 
Type A Cowdry bodies: herpes simplex virus-1 
 
Owl's eye inclusion bodies: cytomegalovirus 
 
Electron microscopy 
 
Intracellular virions 
11.6.2 
Burn Induced Compartment Syndrome Monitoring and Diagnosis 
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within few days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy (see 
below).  
The BICS diagnosis is based on clinical and instrumental originated data: 
Clinical signs (the 5 “P”) are [10]: 
 Pain (on passive digital extension)- Pain on passive stretch of the affected muscle 
 Paralysis 
 Pulselessness 
 Pallor 
 Paraesthesia 
In addition:  
 Pulse oximeter SpO2 (when measurement is possible in non vaso-constricted patients) bellow 
90% in otherwise healthy individuals or a dynamic decrease over time or a difference of >6% 
between the injured and a healthy symmetrical site. 
 Direct interstitial/compartment measurement: increased pressure under the constricting eschar. 
 Ultrasound Doppler may be used for the detection of pulsating arteries but even with distal 
digital artery pulsation damage may still happen. Laser Doppler blood flow is reported to be the 
least dependable.  
 
Extremities At Risk (EAR) group:  
The EAR burns may be prone to develop BICS. Extremities at Risk are circumferential DPT 
and/or FT burns with at least one of the following: 
1. Any of the 5 “P”s described above (Pain, Paralysis, Pulselessness, Pallor, Paraesthesia),  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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2. Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements 
within 30 minutes under the constricting eschar, 
3. SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity 
and the injured one [10-11],  
4. Pulse not detected by US Doppler.  
 
Monitoring:  
Monitoring will be performed for all extremities using the above mentioned criteria (clinical 5 
“P”, direct pressure measurement and SpO2 [83]). 
The monitoring and diagnosis step include: 
 Observation of the extremity for swelling and color 
 Asking the patient about pain on finger extension or other sensations 
 Pressing the skin to diagnose blanching and tension 
 Sensitivity assessment (from superficial to deep sensation, ending with passive extension of 
the fingers, which is the specific test for muscle ischemia). 
Pulse may be used as supportive to other signs as occasionally it might be difficult to assess.  
The above sequence of tests should start by: 
 (i) asking the patient to move his/her fingers 
(ii) skin sensation 
(iii) skin tension and appearance (pallor) 
(iv) assessing pain at passive extension  
(v) palpation for pulse.  
The above monitoring measures should be initiated at screening and continue during topical 
eschar removal treatment.  
Intervention:  
Direct pressure measurement is a reliable method when frequently measuring the pressure.     
Prior to randomization: Patients with circumferential DPT and/or FT burns defined as 
Extremities at Risk (EAR) should be indentified1 (see Exclusion Criteria, Section 7.1.3). 
Post randomization and prior to eschar removal procedure: In accordance with current 
standard of care, wounds should be monitored to detect high interstitial/ compartment pressure 
and diagnosed BICS should be treated by the investigator as per SOC. 
During the 4 hours eschar removal procedure: As per current SOC, patients with 
circumferential wounds may be monitored for few hours before executing surgical 
escharotomy. Hands and feet developing clinical evidence (such as swelling, pallor but no 
                                                 
1 For direct pressure measurement >25 mmHg, a second measurement will be taken within 30 minutes. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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paralysis and pain on passive extension) and pressure approaching 25 mmHg and SpO2 stable 
>90% should be closely monitored for signs of improvement or deterioration that may require 
escharotomy. If clinical assessment and SpO2 monitoring are possible, they will be done 
continuously and recorded in the eCRFs every 2 hours. If such assessment is not practical, 
direct pressure will be measured every 2 hours from start of the eschar removal. The eschar 
removal process shall be discontinued and escharotomy will be performed in the case of the 
following: 
 Increasing pressure >30 mmHg 
 Difference of >20 mmHg of diastolic pressure between the opposite extremities 
 Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity or deterioration of clinical signs 
 Any of the 5 “P” signs described above. 
 
Since in such cases eschar removal procedure will not be completed as planned, such patients 
(if any) will still be part of ITT and any missing data usually collected during eschar removal 
(e.g. time to end of eschar removal, etc.) will be handled as missing data according to the 
protocol. 
Post eschar removal procedure: 
In accordance with current standard of care, wounds should be monitored to detect high 
interstitial/ compartment pressure and diagnosed BICS should be treated by the investigator as 
per SOC. 
The direct interstitial/compartment pressure measurement will be performed using one of the 
following: 
1. A 19 gauge IV needle or catheter connected to a pressure transducer (e.g. CVP set, direct 
blood pressure monitors, Striker system). The needle is inserted: 
 
Into the interstitial subcutaneous tissue at the anterior compartment region of upper or 
lower extremities, in the case of circular burn extending up to the elbow or knee.   
 
Into the palmar or plantar compartment, in the case of isolated circumferential burn 
limited to the hand or foot. 
Before reading the pressure, the system should be flushed with 0.2-0.5 cc. (depends of the 
length of the connecting tube) of normal saline. 
2. Intra-Compartmental Pressure monitor (ICP monitor) by Stryker®. 
These measurements, similar in their pain and discomfort to IV treatment, are well tolerated by 
patients and in DPT/FT wounds this measure is entirely painless.        
11.6.3 
Infection 
All definitions of infection, wound infection, invasive burn wound infection etc. will follow the 
American Burn Association Consensus Conference to Define Sepsis and Infection in Burns 
[94] as presented in chapter 12, “Treatment of infection in burns” in the Total Burn Care 4th 
edition, edited by D. Herndon pages 137-156 that included also input from The Society of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Critical Care Medicine (SCCM) and the American College of Chest Physicians (ACCP). 
Nevertheless, it should be remembered that in spite of the enormous effort invested for so long 
by so many, often even the simple differential diagnosis between burn wound erithema and 
burn wound infection or even the etiology of a sepsis is difficult. In order to have a pure as 
possible study that will assess exclusively the burn related phenomena, the principle is to enroll 
healthy individuals with fresh thermal burn wounds without any confounding co morbidities or 
trauma.        
 Sepsis [94]  
Sepsis is a change in the burn patient that triggers the concern for infection. It is a presumptive 
diagnosis where antibiotics are usually started and a search for a cause of infection should be 
initiated. While clinical interpretation is required, the diagnosis needs to be tied to the 
discovery of a specific infection source (defined below in section C).  
The trigger includes at least three of the following: 
I. 
Temperature >39.0° or <36.5°C 
II. 
Progressive tachycardia 
o Adults >110 bpm 
III. 
Progressive tachypnea 
o Adults >25 bpm not ventilated, or minute ventilation >12 L/min ventilated 
IV. 
Thrombocytopenia (will not apply until 3 days after initial resuscitation) 
o Adults <100,000/mcl 
V. 
Hyperglycemia (in the absence of pre-existing diabetes mellitus) 
o Untreated plasma glucose  >200 mg/dl or equivalent mM/L 
o Insulin resistance—examples include 
 >7 units of insulin/hr intravenous drip (adults) 
 Significant resistance to insulin (>25% increase in insulin requirements over 24 
hours) 
VI. 
Inability to continue enteral feedings >24 hours 
o Abdominal distension 
o Enteral feeding intolerance (residual >150 ml/hr in children or two times feeding rate 
in adults) 
o Uncontrollable diarrhea ( >2500 ml/d for adults or >400 ml/d in children) 
In addition, it is required that a documented infection is identified: 
I. 
Culture positive infection, or 
II. 
Pathologic tissue source identified, or 
III. 
Clinical response to antimicrobials 
 
A. Continuous fever > 38.50C present during the week before sustaining burn injury. 
B. The below are assessed as present on physical examination or per history during the week 
before injury according to the described signs [89]  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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 Rhinitis including mucopurulent nasal discharge  
 Sinusitis including cough, headache, stufinness, purulent nasal discharge  
 Stomatitis  including localized pain in mouth, difficulty swallowing 
 Pharyngitis 
 
including 
sore 
throat, 
pharyngeal 
erythema/exudate, 
neck 
lymphadenopathy 
 Pharyngeal abscess 
 Otitis including ear ache, signs per otoscopy 
 Infections of the Lower Respiratory Tract [95] 
Pneumonia including cough, fever, bronchial breath sounds, crackles, radiographic signs 
 Infections of the Heart [95] 
Endocarditis 
 Infections of the Skin and Soft Tissues (other than in the burns) [95] 
Folliculitis 
Impetigo 
Varicella-Zoster Virus infection 
Erysipelas 
Cellulitis  
Necrotizing Fasciitis 
 Intra-Abdominal Abscess and Peritonitis [95] 
Infectous Gastroenteritis 
 Bone and Joint Infections [95] 
Septic Arthritis including joint pain, swelling, erythema, limitation of movement 
Osteomyelitis including pain, tenderness, radiographic evidence 
 Urinary Tract Infections [95] 
Urethritis including pain and burning sensation of the urethra during urination. 
Urinary Tract Infection including pain, burning sensations, abdominal pain, positive urine 
culture 
 Burn Wound Infection – Heavily Contaminated Burns [94] 
o Invasive Infection: Presence of pathogens in a burn wound at concentrations 
sufficient in conjunction with depth, surface area involved and age of patient to 
cause suppurative, purulant separation of eschar or graft loss, invasion of 
adjacent unburned tissue or cause the systemic response of sepsis syndrome. 
Pathogen present in the wound at high concentrations (frequently >105 
pathogens/g tissue). Invasion or destruction of unburned skin/tissue. Invasive 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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infection may occur with or without sepsis. Many burn wound invasive 
infections, however, are life threatening and need urgent treatment (usually 
wound excision). 
o Cellulitis: Bacteria present in the wound and/or wound eschar at high 
concentrations. Examination of surrounding tissue reveals advancing erythema, 
induration, warmth and tenderness. Sepsis must be present. 
o (Cellulitis that appears usually after few days (5-7 days) should be differentiated 
from Burn erythema: Redness around the wound in the first 3 days post injury 
and is rather benign and may not require treatment). 
o Necrotizing Infection/Fasciitis: Aggressive, invasive infection with underlying 
(beneath the skin) tissue necrosis. 
Burns diagnosed of Invasive Infection, Cellulites and Necrotizing Infection/Fasciitis are 
considered heavily contaminated burns. 
11.6.4 
Vital Signs 
Vital signs (temperature, pulse, blood pressure and respiration rate) will be completed 24 hours 
prior to start of treatment and once daily for one week post start of eschar removal. 
Blood pressure and pulse should be recorded in a supine position after resting for 5 minutes.  
All measurements and time of measurements will be recorded in the source documents. 
11.6.5 
Immunogenicity Evaluation 
Antibodies presence will be determined based on a three-tiered approach analysis of plasma 
samples drawn prior to start of eschar removal and at the following timelines in NexoBrid 
patients: 
 At day 7±2 days (week 1 visit) from start of treatment, 
 At day 28±7 days (week 4 visit) from start of treatment, 
 At day 56 ±14 days (week 8 visit) from start of treatment,  
 At months 6 & 24, as part of the long term follow up visits. 
Please refer to Appendix 10- Procedures for specific blood tests for further instructions. 
11.6.6 
ECG (QT evaluation) 
12-lead ECG will be performed (if feasible) in triplicates as part of the QT prolongation 
evaluation at the following time-points: baseline 60 ± 5 min, 40 ± 5 min and 20 ± 5 minutes 
prior to start of Eschar removal process and at 30 ± 10 min, 120 ± 15 min, 4 ± 0.5 hrs, 12 ± 0.5 
hrs, 24 ± 1 hrs, 48 ± 2 hrs and 1 week after start of eschar removal.  
11.6.7 
Physical Examination 
A physical examination will be performed and documented by the investigator or a qualified 
designee. Any abnormal findings, assessed by the investigator as clinically significant, should 
be recorded in the relevant eCRFs modules (e.g. adverse event). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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11.6.8 
Pain Assessment Using Visual Analogue Scale (Pain Scale Ruler)  
Pain experience will be recorded using standard widely used pain scale ruler (Visual Analogue 
Scale=VAS) on admission, (baseline pain assessment) within 24 hours prior to start of eschar 
removal, One-hour before and following eschar removal procedure and daily for one week post 
start of eschar removal. Please refer to Appendix 9- Pain Measurement Scale for instructions. 
11.6.9 
Concomitant Medications 
Concomitant medications will be recorded throughout the study, starting from signing on ICF 
and will include those prescribed for common burn management practice. Any record should 
include dose, frequency, route, start and stop date and indication. 
Unit of blood transfused (whole blood or blood packed cells) with the appropriate volume will 
be captured for the entire patient’s duration in the study and recorded in the concomitant 
medications form. Any analgesia and anesthesia administered per subject will be recorded in 
the eCRFs. Incidence & number of procedures for wound care requiring anesthesia will be 
analyzed. 
11.6.10 
Graft Loss 
An event of graft loss is defined in study protocol as an event in which an autograft needed to 
be re-applied. This event, once occurred, will be recorded in the eCRFs as an AE. 
11.6.11 
 Hypothermia and pyrexia [94] 
Hypothermia will be defined as temperature <36.0°c, measured twice, 30 minutes apart. 
Pyrexia will be defined in patients with elevated temperature >39.0°c in the first days (before 
the beginning of any infectious process) measured twice, 30 minutes apart. These criteria, once 
met, should be monitored closely. The Investigator may still report hypothermia at higher 
temperatures and Pyrexia at lower temperatures, if these events are considered by the 
Investigator to be adverse events. The Investigator will be further reminded to evaluate the 
need to report an AE in case the temperature is higher than 39.0°c or lower than 36.5°c. 
11.6.12 
Cosmesis and Function assessment 
11.6.12.1 MVSS 
Cosmesis and Function assessment will be performed based on the Modified Vancouver Scar 
Scale (MVSS) at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 
burn wound specialist who is masked to randomized wound treatment and to the other outcome 
assessments of the same wound 
 The MVSS method is composed of the following: 
Pigmentation 
Pliability 
Height Vascularity Pain 
Pruritus 
(0) Normal 
(0) Normal 
(0) Flat 
(0) 
Normal 
(0) None 
(0)None 
(1) 
Hypopigme
(1) Supple-flexible with 
minimal resistance 
(1)  
(1) Pink 
(1) 
Occasional 
(1) 
Occasional 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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ntation 
<2mm 
(2) Mixed 
(2) Yielding- giving way 
to pressure 
 
(2) 2-5 
mm 
(2) Red 
(2) 
Requiring 
medication 
(2) 
Requiring 
medication 
(3) 
Hyperpigme
ntation 
(3) Firm- inflexible, not 
easily moved, resistance to 
manual pressure 
 
(3) 
>5mm 
(3) 
Purple 
 
 
 
(4) Banding-rope-like 
tissue that blanches with 
extension of the scar 
 
 
 
 
 
 
(5) Contracutre-perment 
shortening of scar, 
producing deformity or 
distortion  
 
 
 
 
 
 
11.6.12.2 POSAS 
Additional Cosmesis and Function evaluation will be performed using the Patient and Observer 
Scar Assessment Scale (POSAS) version 2.0 at 1, 3, 6, 12, 18 and 24 months after the wound 
closure confirmation visit by a burn wound specialist who is masked to randomized wound 
treatment and to the other outcome assessments of the same wound. POSAS version 2.0 was 
published in 2005 in Plast. Reconstr. Surg. 116: 514-522 by van de Kar et al.  
The POSAS consists of two parts: a Patient Scale and an Observer Scale. Both scales contain 
six items that are scored numerically and make up a ‘Total Score’ of the Patient and Observer 
Scale. The POSAS has been developed for all types of scars and has been tested in linear scars, 
burn scars and keloids and was found to be validated and reliable [111-112].  
Each item of both scales has a 10-point score, with 10 indicating the worst imaginable scar or 
sensation. The lowest score is ‘1’, and corresponds to the situation of normal skin (normal 
pigmentation, no itching etc), and goes up to the worst imaginable. The Total Score can be 
simply calculated by summing up the scores of each of the six items. The Total Score will 
therefore range from 6 to 60 (observer and patient) and 12-120 in total. 
11.6.13 
Quality of Life 
Quality of Life evaluation will be performed in adults using Burn Specific Health Scale 
(BSHS-B) and EQ5D as describe in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire, at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 
burn wound specialist who is masked to randomized wound treatment and to the other outcome 
assessments of the same wound. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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11.6.14 
Function assessments 
Functionality tests were implemented in the proposed protocol MW2010-03-02 for the 
assessment of specific anatomical function. This evaluation will be composed of the following: 
 Self completed questionnaires: 
o The “Lower Extremity Functional Scale” test for burns in the lower extremities,  
o The “QuickDASH” outcome measure for burns in the upper extremities.  
 Range of Motion measurements of injured joints, if relevant: knee, ankle, shoulder, elbow, 
wrist and hand. Measurements will be performed on the patient’s own non injured joints as 
well for comparison to burned joints.  
The above tests will be performed at 1, 3, 6, 12, 18 and 24 months after the wound closure 
confirmation visit by a burn wound specialist who is masked to randomized wound treatment 
and to the other outcome assessments of the same wound. ROM will be evaluated at 1, 3, 6, 12, 
18 and 24 months after the wound closure confirmation visit.  
11.6.15 
Pharmacokinetic evaluation 
Blood samples (2ml) for a pharmacokinetic profile to measure NexoBrid absorption will be 
taken from a subset of patients treated with NexoBrid in accordance with the randomization 
arm (20 patients, randomingly selected) and will be analyzed throughout the study for each 
patient in an ongoing process. Blood samples will be taken pre treatment and at 1, 2, 4, 12, 24 
and 48 hours after start of treatment.  
11.6.16 
Real time data capture and Independent Safety Monitoring 
The study data will be collected using an Internet-based, validated, electronic data capture 
system which allows for “real time” safety reviews via the Internet.  
An independent study Medical Monitor, masked to the treatment arms, shall review all 
Adverse Events (AE’s) from the entries on the eCRFs on a quarterly basis. SAEs will be 
reviewed and evaluated on a per case basis, following the occurrence of an SAE, as detailed in 
the Sponsor’s SOPs. In case any concerns are raised by the medical monitor, additional 
convention of the DSMB could be performed (see Section 14.2).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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12 
SAFETY AND PHARMACOVIGILANCE  
An adverse event is an undesirable or unintentional event that occurs during use of the study 
Drug, whether or not considered related to the Drug; this includes clinically significant changes 
in laboratory values and therapeutic failures. Regardless of the severity or relationship to the 
investigational Drug, all adverse events occurring during the study period should be recorded 
in a subject's CRFs. The phrase "associated with the use of the Drug" is defined as a reasonable 
possibility that the event may have been caused by the investigational Drug. 
12.1 
 RELATIONSHIP TO STUDY DRUG 
The following definitions to assess the relationship between an adverse event and the study 
Drug should be used.   
Not Related: The event is clearly related to other factors such as a patient's clinical state, 
therapeutic interventions or concomitant medications. 
Remotely Related: The event was most likely produced by other factors such as a patient's 
clinical state, therapeutic interventions or concomitant medications and does not follow a 
known response pattern to the study Drug. 
Possibly Related: The event has a reasonable temporal relationship to study Drug 
administration and follows a known response pattern to the study Drug.  However, a potential 
alternate etiology may be responsible for the event.  The effect of Drug withdrawal is unclear. 
Rechallenge information is unclear or lacking. 
Probably Related: The event follows a reasonable temporal sequence from the time of Drug 
administration and follows a known response pattern to the study Drug and cannot be 
reasonably explained by other factors.  There is a reasonable response to withdrawal of the 
Drug.  Re-challenge information is not available or advisable. 
Related: The event follows a temporal sequence from the time of Drug administration and 
follows a known response pattern to the study Drug and either occurs immediately following 
study Drug administration, or improves on stopping the Drug, or reappears on repeat exposure. 
AEs assessed as possible, probably or related will be addressed as Adverse Drug Reaction 
(AEs related to study arm). 
12.2 
 ADVERSE EVENT INTENSITY 
Mild Adverse Events: A mild adverse event is one that the symptoms are barely noticeable to a 
patient. It does not influence performance or prevent a patient from carrying on with normal 
life activities. 
Moderate Adverse Events: A moderate adverse event is one that the symptoms make a patient 
uncomfortable and causes some impairment to normal life activities. Treatment for symptom(s) 
may be required. 
Severe Adverse Events: A severe adverse event is one that the symptoms cause severe 
discomfort to a patient and severely limits the patient's normal daily activities.  Treatment for 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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symptom(s) is given. Note that serious and severe are not synonymous.  A serious adverse 
event must fulfill the requirements listed in the definition below. 
12.3 
 ADVERSE EVENT REPORTING 
Signing of Inform Consent is considered to be the start date of AEs monitoring. All adverse 
events must be recorded in the eCRFs. When an adverse event occurs, the following 
information and assessments should be recorded in the adverse event section of the eCRFs: 
 The signs, symptoms or diagnosis or the event, 
 The date and time of onset of the event using the 24 hour clock where midnight is 00:00 
and noon is 12:00, 
 The adverse event severity using the criteria outlined above, 
 The relationship of the event to the study Drug as outlined above,  
 The description of any action taken regarding study Drug disposition, 
 Any required therapy, medication, treatment or diagnostic procedure. 
Follow-up of a patient should be conducted until resolution of the adverse event. The 
investigator is responsible for the appropriate medical management of all adverse events.  
12.4 
 SERIOUS ADVERSE EVENTS 
A serious adverse event is an event that is: a) fatal b) life-threatening c) results in persistent or 
significant disability/incapacity d) requires or prolongs inpatient unexpected hospitalization ) is 
a congenital anomaly or birth defect or f) is a medically important event. 
Life Threatening is defined as an event in which a patient is at risk of death at the time of the 
event. It does not refer to an event that hypothetically might have caused death if it was more 
severe. Disability is defined as a substantial disruption of a person's ability to conduct normal 
life functions. Medically important events that may not result in death, be life-threatening or 
require hospitalization may be considered as SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above. 
When patient’s hospitalization is planned by the treated Investigator, no AE should be reported 
and thus, no SAE should be reported. Note to File will be completed and signed by the 
Investigator. 
 
An unexpected adverse event is one that has not been previously observed, or one that is of a 
specificity or severity not consistent with the current investigator brochure. 
All adverse drug reactions (a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility) that are both serious and unexpected are subject to 
expedited reporting as defined in ICH E2A “Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting”. An Unexpected event is one that is not consistent 
with the applicable product information as described in the current investigator brochure.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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12.5 
 SERIOUS ADVERSE EVENT REPORTING 
The investigator shall report all serious adverse events to the Pharmacovigilance by telephone 
or fax immediately after the event (within of 24 hours, in accordance with MediWound’s 
SOPs). The initial report should be followed-up with a detailed written report within three 
days. Full details of the event, any sequelae and an assessment of the relationship to the study 
Drug must be provided in the report.  
Fatal or life-threatening SUSARs should be notified as soon as possible but no later than 7 
calendar days after Pharmacovigilance has first knowledge of the minimum criteria for 
expedited reporting. All other SUSARs must be reported as soon as possible but no later than 
15 calendar days after Pharmacovigilance has first knowledge of the minimum criteria for 
expedited reporting. Further relevant follow-up information should be given as soon as 
possible. 
 
12.6 
PREGNANCIES 
In the long term follow up period of the study, no special contraception methods are deemed 
necessary for the study due to the single short term use of the investigational product and its 
known pharmacokinetic profile were no remnants of NexoBrid were observed after 48 hours 
had passed from first application. In the early acute phase of the burn wounds, during their 
hospital stay, patients are hospitalized and thus are not expected to be subject to sexual 
intercourse. If sexual abstinence within one month after study treatment is not possible 
acceptable contraception methods should be used by the patient. 
1) Acceptable methods of contraception (a Pearl Index < 1%) include: 
- 
hormonal methods (oral contraceptives, patches or medroxyprogesterone acetate) 
- 
An intrauterine device (IUD) with a documented failure rate of less than 1% per year 
 
NOTE: Females who have been surgically sterilized (e.g., hysterectomy or bilateral tubal 
ligation) or who are postmenopausal (total cessation of menses for >1 year) will not be 
considered as “females of childbearing potential.” 
 
Nevertheless, to ensure patient safety, each pregnancy in a female patient of childbearing 
potential on study drug should be reported to the treated physician during the study course. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on the 
form provided by MediWound and reported by the investigator to MediWound. The telephone 
and fax number of the contact persons are listed on the form provided. Pregnancy follow-up 
should be recorded on a form provided by MediWound as well and should include an 
assessment of the possible relationship to the study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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13 
STATISTICAL ANALYSIS  
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. 
13.1 
POPULATIONS 
Enrolled population consists of all subjects who passed through the screening processes and 
signed inform consent. 
Intent-to-Treat (ITT) population includes all patients who are randomized into the trial. 
Evaluable (per protocol)(PP) population includes all subjects who fulfill all inclusion/exclusion 
criteria and do not have major protocol violations. Analysis of the PP population is for 
supportive purposes, whereas the analysis of the ITT population provides the primary and 
secondary efficacy and the comparative safety analyses.  
Safety population (SP) includes all patients receiving a treatment and analysis is focused on the 
treatment actually performed. 
13.1.1 
Major Protocol Violations 
Major protocol violations will be evaluated by clinical personnel and detailed information will 
be listed. List of protocol violation will be included in the study monitoring plan. 
13.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and relevant baseline information (medical history, physical examination, 
treatments prior to admission, burn description, distribution of wound depth and size, TWs 
description, primary TW description, etc.) will be presented and summarized with appropriate 
descriptive statistics. Chi-squared tests (or in case of small estimated cell counts Fisher’s exact 
test) for categorical variables and one-way analysis of variance for continuous variables will be 
used to assess the comparability of the baseline factors between the treatment groups.   
If either of the baseline factors, gender or age, are found to be significantly different between 
the treatment groups, then the factor will be included as an extra adjusting covariate in the 
supportive analysis models for the primary and secondary efficacy endpoints and the 
comparative analyses of safety endpoints. 
Relevant medical history will be tabulated and presented by treatment group.  
These summaries will be based on the ITT population. 
13.3 
EFFICACY EVALUATION 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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13.3.1 
Primary Endpoint 
The primary endpoint will be analyzed as described below. Missing data will be handled by the 
methods described in Section13.8.4. NexoBrid will be compared with Gel Vehicle for the 
primary endpoint. 
13.3.1.1 Incidence of complete eschar removal measured at the end of the topical agent 
soaking period. 
The proportions of patients who reached complete eschar removal at the end of the 
topical agent soaking period will be compared using logistic regression. The primary 
analysis will be based on the binary variable (yes/no): ‘has complete eschar removal been 
achieved in all TWs’ and will compare NexoBrid with the Gel Vehicle (for further 
definition and explanation of complete eschar removal see Section 1.1). For handling of 
missing data see Section 13.8.4. The statistical test will be based on Fisher’s exact test 
because of the small numbers expected in the Gel vehicle group. 
If numerically possible, the comparison will supportively be adjusted for the stratification 
factors (see Section 13.7) by including each of them in alogistic regression model 
together with the treatment variable (NexoBrid vs. Gel Vehicle) and treatment center (see 
Section 13.8.5). Statistical inference will be based upon exact distribution methods. The 
odds ratio of achieving complete eschar removal for NexoBrid versus Gel Vehicle will 
be estimated from this supportive model, as well as 95% confidence intervals and the 
level of statistical significance. 
13.3.2 
Secondary endpoints 
The secondary endpoints will be analyzed as described below and will compare efficacy in the 
NexoBrid group with the SOC group. Missing data will be handled by the methods described 
in Section 13.8.4.  
13.3.2.1 Surgical excision performed  
This is a binary yes/no variable and the proportion of patients who need excision for eschar 
removal will be compared using logistic regression. The explanatory variables in the model 
will include treatment, and the for the following stratification variables (for definitions, see 
Section 13.7): treatment center, overall area with burns as percent of total body surface area 
(%TBSA), overall TW depth and proportion of SPT per patient, and number of TWs (1, 2, 3-
4,≥5). The odds ratio of requiring surgery for NexoBrid versus SOC will be estimated from the 
model, as well as 95% confidence intervals and the level of statistical significance.  
13.3.2.2 Timely eschar removal 
Time until complete eschar removal will be defined as the time until complete eschar removal 
has been achieved at a patient level, i.e. for all TW’s of an individual patient. This will be 
measured as time from the randomization date (days). For patients who do not reach complete 
eschar removal, their time will be censored at the initiation of the wound closure treatment 
phase. Kaplan-Meier curves will be presented graphically to display the distribution of time to 
complete eschar removal under the two treatments. Median time to complete eschar removal 
will be estimated for each treatment group with a 95% confidence interval. The treatment 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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groups will be compared using a Cox regression model. The comparison will be adjusted for 
the same stratification variables as mentioned in Section 13.3.2.1, by including each of them in 
the Cox regression model together with the treatment variable (NexoBrid vs. SOC). The 
treatment groups will be compared by testing the null hypothesis of no difference, comparing 
the ratio of the estimated treatment coefficient to its standard error to a standard normal 
distribution. 
Secondary analyses of this secondary endpoint will include checking the proportional hazards 
assumption, adding other baseline variables that are imbalanced, and investigating interactions 
between baseline variables and the treatment groups. The comparison between treatments 
using Cox regression will also be conducted on the time of complete eschar removal measured 
from the date of ICF as a supportive analysis.  
13.3.2.3 Blood loss 
The measure of blood loss defined in Section 11.2 will be computed for each patient, and the 
distribution in the NexoBrid group will be compared with that in the SOC group. Means, 
standard deviations, medians, and interquartile ranges will be calculated, and differences in 
distribution between NexoBrid and SOC will be tested using a t-test (or if the data are highly 
non-normal a Mann-Whitney test). Supportive analyses will include adjustments for the same 
covariates as mentioned in Section 13.3.2.1. 
13.3.3 
Safety endpoints 
13.3.3.1 Time to reach complete wound closure 
Based on the observations from the MW2004-11-02 study, little or no censoring is expected in 
this endpoint. Thus, time to reach complete wound closure will be compared between the 
NexoBrid and SOC using a linear mixed model. The model will include patient as a random 
effect and treatment and %TBSA as fixed effects.By this procedure the within patient 
correlation of wound closure times will be accounted for. A sensitivity analysis will 
additionally include an interaction term for %TBSAand treatment, as well as adjustment for the 
other stratification variables, TW depth at the wound level, and treatment center at the patient 
level. A clinically meaningful margin will be incorporated into the analysis that will represent a 
7.4-day advantage to the SOC group, so that the analysis will show whether the NexoBrid 
group is estimated to have on average a time to wound closure that is not later than 7.4 days 
after wound closure for the SOC group. If censoring occurs it will be integrated into the model 
as further specified in the SAP (More details will be provided in the SAP).  
13.3.3.2 Cosmesis and Function evaluation using MVSS 
The MVSS score for a patient will be the MVSS score averaged over all TW’s of that patient. 
The mean and standard error of this MVSS score at 12 and 24 months will be estimated for 
each treatment group. The evaluations at these two time points will represent two separate 
endpoints. The treatment groups will be compared using a linear model with MVSS score as 
the dependent variable. The explanatory variables in the model will include treatment, and the 
same stratification variables as specified in Section 13.3.2.2. The coefficient corresponding to 
the treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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factors. For handling of missing data see Section 13.8.4. A clinically meaningful difference 
will be incorporated into the analysis that will represent a 2.7 or more units advantage to the 
SOC group, so that the analysis will show whether the NexoBrid group is estimated to have on 
average a MVSS score that is not worse by more than 2.7 units than the score for the SOC 
group. 
Additional Safety Outcome Measures will include:  
These parameters will be analyzed in a descriptive way only. More details will be provided in the 
statistical analysis plan. 
13.3.3.3 General parameters of safety 
Systemic adverse events, vital signs, pain assessment (using VAS), laboratory tests, units (and 
volume) of blood transfusion given during hospitalization, Immunogenicity evaluation for 
NexoBrid patients, Pyrexia and Hyperthermia, Systemic infections, Incidence of increased 
interstitial/compartment syndrome and QT prolongation. 
13.3.3.4 Local parameters of safety 
Local adverse events defined by treated physician or designee; graft loss, wound related 
infections, etc. 
13.3.3.5 Further parameters of safety 
Functionality evaluation 
The following scales will be used: QuickDASH questionnaire, LEFS (Lower Extremity 
Functional Scale) and Range of Motion (ROM) measurements. Each scale will be assessed at 
the following time points: 1 month after reaching complete wound closure and at 3, 6, 12, 18 
and 24 months after wound closure. The ROM measurement will be classified as normal or 
abnormal status. 
Quality of life evaluation 
The following scales will be used: EQ5D health questionnaire and BHSH-B (Burn Specific 
Health Scale). Each scale will be assessed at 1, 3, 6, 12, 18 and 24 months after reaching 
complete wound closure.   
13.3.4 
Exploratory endpoints and additional analyses 
These parameters will be analyzed in a descriptive way only. Additional details will be provided 
in the statistical analysis plan. 
13.3.4.1 Exploratory endpoints 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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3. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds, 
6. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
9. PK evaluation for a subset of NexoBrid patients1, 
10. Autograft related parameters. 
13.3.4.2 Additional Analyses 
The following analyses will be addressed as supportive efficacy analyses: 
1. Primary & secondary endpoints will be analyzed at a per wound level 
2. Secondary endpoints will be analyzed vs. the Gel Vehicle  
13.3.5 
Subgroup Analyses 
Descriptive statistics will be determined for all subgroup analyses.  
1. A sub group analysis will be performed on the subgroup of target wounds that are 
found, at least partly, in the anatomical area of the hand.  
2. Time to wound closure and 12m and 24m MVSS will be analyzed per TWs’ depth 
and% TBSA of the TWs.  
These subgroup analyses will be conducted at the wound level. More details will be 
provided in the SAP. 
13.4 
STATISTICAL COMPUTING 
The data will be analyzed using the SAS ® version 9.1 (SAS Institute, Cary North Carolina). 
13.5 
SAMPLE SIZE CALCULATIONS 
The following sample size calculations are based on the consideration of the primary and two 
secondary endpoints for this study.  
                                                 
1 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 
hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Estimated effects of NexoBrid from study MW2004-11-02 were used to design the study with 
adequate statistical power using the following steps.  
(a) Sample size calculations were based on study MW2004-11-02; 
(b) The effect of NexoBrid versus standard of care was estimated together with the standard 
error of the estimate; the effect of NexoBrid versus gel was estimated based on study 
MW2002-04-01, previous phase II study, which included 35 patients treated with gel 
vehicle.  
The size of the effect to be detected in this study, MW2010-03-02, was taken as the previous 
estimate decreased by half its standard error, in order to use a conservative value. 
13.5.1 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. 
Gel) 
Estimated proportion achieving complete eschar removal (for further definition and 
explanation see Section 11.1) in all TWs from study MW2004-11-02: NexoBrid 0.595 
Standard error = 0.057 
Anticipated proportion achieving complete eschar removal using NexoBrid: 0.595-0.057/2 = 
0.5665 
Estimated proportion achieving complete eschar removal using Gel vehicle in a previous Phase 
II study, MW2002-04-01: 0 (0 out of 35 patients).  
Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. (0.0 is the 
point estimate; 0.10 is the 97.5 upper confidence limit).   
Because numbers of complete eschar removals are anticipated to be low in the gel group, we 
calculate sample size using Fisher’s exact test. We used the computer program nQuery Advisor 
version 7.0 to calculate power for a two-sided significance level of 5%, and thereby found the 
following sample size combination that led to approximately 90% power for detecting a 
statistically significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).   
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle group 13. 
Total sample size = 78. 
13.5.2 
Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.22; 
SOC 0.62 
Standard errors: NexoBrid 0.048; SOC 0.054 
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: NexoBrid 0.24 and 
SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a two-sided 
significance level of 5% is 86: 43 in the NexoBrid group and 43 in the SOC group. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.5.3 
Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial yielded an estimated 
log hazard ratio of -1.37 (hazard ratio of 0.254) with a standard error of 0.28.  
Therefore target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio = 0.29).  
The formula for the number of events (successful complete eschar removals) is:


2
2
log
)
(4
HR
z
z
d



 
where z = 1.96 two-sided significance level of 5%; and z = 1.28 for 90% power;For 90% 
overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required 
2
1
2
p
p
d
n


= 44 (to the nearest even number), 22 in each of 
the NexoBrid and SOC groups.  
13.5.4 
Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 patients (65 in the 
NexoBrid group, 13 in the Gel vehicle group and 43 in the SOC group (to match NexoBrid 
numbers)), we propose entering larger numbers to provide an extra margin of assurance in achieving 
positive results on the efficacy outcomes, and adequate information on safety outcomes to allow 
better benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 (NexoBrid) + 75 (SOC) + 
25 (Gel Vehicle). 
13.5.5 
Safety endpoints 
Because of the importance of the time to wound closure and MVSS safety endpoints, we examined 
for these two endpoints, under the chosen sample size of 75 patients per group in the NexoBrid and 
SOC groups, the probability of demonstrating that the observed average value in the NexoBrid does 
not exceed the observed average in the SOC group by more than the clinically meaningful margin.  
For time to wound closure, assuming, based on previous data, that in reality NexoBrid has an 
average time that is longer than SOC by 5.77 days (based on wound closure data from study 
MW2004-11-02 analyzed per the suggested analysis in Section 13.3.3.1), the probability that the 
observed average NexoBrid time to wound closure will be longer than the observed average SOC 
time by more than 7.4 days is calculated to be 0.26. 
For MVSS, assuming, based on previous data, that in reality NexoBrid has a score that is less (better) 
than SOC by 0.51 units, the probability that the observed average NexoBrid score will not be larger 
(worse) than the observed average SOC score by more than 2.7 units is calculated to be less than 
0.001 for MVSS at 12m and 24m.  
13.6 
ALPHA CONTROL 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. The primary and secondary endpoints of 
efficacy will be tested in a hierarchy, so as to preserve the nominal significance levels: 1. 
Primary; 2. Incidence of surgery; 3.Time to complete eschar removal; 4. Blood loss.  
13.7 
STRATIFICATION AND RANDOMIZATION 
13.7.1 
Randomization Procedure: 
To enter a patient and obtain the randomized treatment allocation, the following information 
should be verified and uploaded into the eCRFs: 
i. 
Eligibility of the patient (entrance criteria are met) 
ii. 
ICF date 
iii. 
Patient’s demographics (date of birth, gender, ethnicity, race) 
iv. 
Patient’s burn history and burn description (identification of all wounds and target 
wounds (TWs) assigning an identifying number to each wound, and providing its 
anatomical site, its %TBSA, its depth and where relevant its proportion of superficial 
partial thickness (SPT) area 
v. 
The overall %TBSA and its category A1 or A2 (see definition below) 
vi. 
The overall depth and proportion of SPT, according to its category B1-B5 (see definition 
below) 
vii. 
The treatment center 
 
Upon finalization of this process, randomization will be performed as described below and a 
designated person will receive the allocated treatment. With regard to this designated person, this 
person must understand that the information regarding the allocated treatment must not be given 
to the designated person who is assessing the TWs following treatment, as further described in 
the study protocol. 
13.7.2 
Stratification: 
Eligible subjects will be stratified into different groups in order to balance the treatment groups 
with respect to factors that may be related to efficacy and safety outcomes. Two factors will be 
used to stratify the subjects.  
A. Overall total area of burns measured by % of TBSA  
A1: (3% to 9%), inclusive 
A2: (>9% to 15%) 
B. Overall depth and proportion of SPT per patient 
B1: All TWs are full thickness; 
B2: Mixed TWs – full thickness and deep partial thickness and proportion of SPT < 20%; 
B3: Mixed TWs – full thickness and deep partial thickness and proportion of SPT ≥ 20%; 
B4: All TWs are deep partial thickness, and proportion of SPT < 20%; 
 
B5: All TWs are deep partial thickness, and proportion of SPT ≥ 20%. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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C. Clinical center, so as to address possible differences in SOC procedures between sites (if any), 
to allow comparison of the results within centre and to reduce the likelihood of a center 
including patients in only one arm of the study.  
Using this stratification, patients will be randomized in a 3:3:1 ratio (NexoBrid: SOC: 
Vehicle). 
13.7.3 
Randomization algorithm: 
The treatment allocation will be performed using the method of minimization [96] with 
stratification by the factors A, B, and C described in the subsection above: overall %TBSA of 
all TW wounds, overall depth, proportion of SPT and clinical center. This method has been 
used successfully and carries advantages in maintaining balance across treatment groups in 
clinical trials with a moderate sample size and several important stratification factors.  
The algorithm will be calculated as follows:  
At any point in the trial a new patient is to be entered into the trial, the four above described 
factors have to be collected for that particular patient. The value for each factor of this patient 
is denoted by Ai, Bi and Ci, respectively, where i is corresponding to the value of each factor, 
which is i=1 or 2 for factor A, i=1, 2, 3, 4 or 5for factor B, and i=1,...m for factor C, with m 
being the number of participating clinical centers.  
For example: a patient, with overall total area of burns of 3% - 9%, with TWs being of mixed 
deep partial and full thickness, with a proportion of SPT < 20%, and to be recruited in the 5th 
clinical center, would have the combination (A1, B2, C5).  
The different treatment groups are denoted by j where j=1 corresponds to the NexoBrid group, 
j=2 to the SOC group and j=3 to the Gel vehicle group. The numbers of patients in each 
stratum A, B, C receiving the j-th treatment and having the i-th factor are denoted by Aij,Bij 
and Cij.  
When a new patient is to be allocated a treatment, a score for each treatment group j is 
determined based on the patient’s specific factors and on the number of patients already 
allocated to the treatments. This score is denoted by Nj and is calculated by the sum of Aij,Bij 
and Cij. In our example the new patient has the factors A1, B2, and C5, hence the numbers of 
patients for each factor in treatment group j=1 which is the NexoBrid treatment are A11, B21 
and C51 respectively and the score N1 and can be calculated as N1 = A11 + B21 + C51. The 
score for the other two treatments N2 and N3 can be calculated similarly: N2 = A12 + B22 + 
C52 and N3 = A13 + B23 + C53.  
To determine which treatment is allocated to the next patient, these three scores are 
compared.If 1:1:1 randomization were to be used, then the patient would be allocated to the 
treatment group with the smallest value among these three score values. However in our trial, 
to take the 3:3:1 randomization into account, the score of the Vehicle group is multiplied by3. 
Hence the allocation decision is based on min(N1, N2, 3*N3). If there is a tie among a subset 
of the 3 values, with two values equal to the minimum, then simple randomization between the 
treatments in this subset is used with probabilities of selection to NexoBrid or SOC three times 
larger than those for Vehicle (NexoBrid vs. SOC: 0.5 vs. 0.5; NexoBrid vs. Gel or SOC vs. 
Gel: 0.75 v 0.25; NexoBrid v SOC v Gel: 0.43 vs. 0.43 vs.0.14).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The algorithm will be prepared and automated by an independent study biostatistician, and will 
operate through the central site with which the clinics will communicate. Note that the clinical 
personnel at each center will be unaware of the total numbers of patients allocated to each 
treatment within the various strata and will therefore be unable to reproduce the minimization 
algorithm in order to predict the next allocation, even if they so wished. 
13.8 
DATA HANDLING METHODS AND DEFINITIONS 
13.8.1 
Multiple visits per time-point 
Study visit time-points are scheduled at screening, pre eschar removal, eschar removal 
(treatment), post-treatment, hospital discharge, follow-up (weekly until wound closure, wound 
closure confirmation, three monthly visits post wound closure), long term follow-up at 6, 12, 
18 months and 24 months post wound closure confirmation and re-admission to hospital/day 
care (if done). One visit is expected for each time-point. The following approach is used if 
there are multiple visits per patient per time-point.  
For the endpoints incidence of complete eschar removal, reduction in surgical needs, summary 
of blood loss and the cosmesis endpoints of safety, if a subject has more than one visit with 
data at a time-point, the later non-missing evaluation will be used for analyses. An exception to 
this rule is in the analyses of time to eschar removal and time to wound closure; for these 
parameters a value other than the last one or more than one value per visit time-point may be 
taken into account. More details will be provided in the SAP.  
13.8.2 
Rules for Data Derivations 
The SAP will identify the necessary data transformations and rules for data derivation. 
13.8.3 
Multiple target wounds per patient 
Patients may have multiple wounds being treated (target wounds). All target wounds will be taken 
into account in the primary and secondary analyses. The methods of analysis are specified in the 
efficacy analysis subsection. The following calculations will be used for each patient: 
1) Total treated burn surface area (%TBSA): is defined as the sum of areas of all target wounds 
for that patient. 
2) MVSS at 12m and 24m are defined as the score averaged over the TWs.  
13.8.4 
Missing data 
Missing data in the primary and secondary outcomes is the main concern. 
Little or no missing data are expected for the primary endpoint, since the outcome is assessed only 
several hours after the start of treatment. The main analysis will be a complete-case analysis. In each 
treatment group, only patients with documented total eschar removal (at the end of the eschar 
removal soaking period) will be counted and this number divided by the number of all patients 
evaluable for this endpoint. Two sensitivity analyses will be conducted for this endpoint. A best case 
analysis will count all patients with missing data (for this endpoint) as positive ( i.e. complete eschar 
removal) and a worst case analysis will count all patients with missing data as negative (i.e. no 
complete eschar removal).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The same procedure will be applied for the secondary endpoint, reduction of surgical need.  
The analysis of the secondary endpoint time to eschar removal will compute missing values as 
censored. 
Missing blood loss values for some eschar removal procedures may occur within a certain patient. A 
regression model containing main prognostic factors (wound area, depth of wound and type of 
procedure) for blood loss of eschar removal procedures will be computed. On this basis a multiple 
imputation will be calculated.  
Missing wound closure times are not expected (see Section 13.3.3.1), but if they occur, they will be 
handled by a multiple imputation procedure to be defined in the SAP. 
A higher ratio of missing values is expected in the case of later MVSS values, especially for 24 
months. In order to avoid unnecessary complex imputation for this descriptive endpoint simple 
LOCF imputation will be done. It is expected that at least one early MVSS value exists. If this is not 
the case no MVSS imputation will take place. A best case – worst case imputation using information 
about the reasons of drop out documented in the CRF will be used as a supporting sensitivity 
analysis.   
The Statistical Analysis Plan will provide more details on the strategy outlined above for handling of 
missing data. 
13.8.5 
Stratifying by center in the analysis 
Randomization will be stratified by center as detailed in the Section 13.7.1. However, some 
centers may enroll very few patients so that there are insufficient subjects to conduct a 
stratified analysis efficiently. To ameliorate this problem, for stratified analysis at the end of 
trial, “small centers” will be pooled as follows:  
All centers will be classified by region (assuming that those in the same region will have a 
similar standard of care treatment modality) and number of patients randomized. If a center has 
less than 7 patients randomized, this center will be pooled with the next smallest center within 
the same region until the pooled center has 7 or more patients. If a region has less than 7 
patients randomized, this region will be pooled with a region that is geographically close to it. 
The pooling strategy will be finalized prior to database lock by a statistician who is blind to the 
outcome data. 
13.8.6 
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 Efficacy Assessment Period (EAP). 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 for short-term safety endpoints 
(including time to wound closure). The analysis will be conducted, when 3 months had passed 
from the last patient reaching complete wound closure, in accordance with FDA guidance for 
industry Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for Treatment 
“Trial subjects generally should remain in the study for follow-up evaluation at least 3 months 
following complete wound closure. The purpose for this follow-up period is to help distinguish 
actual wound healing from transient wound coverage”. At this time-point, data will be 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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available for nearly all patients on the primary end-point (proportion with complete eschar 
removal), the three secondary endpoints (proportion undergoing surgery, time to complete 
eschar removal, and blood loss) and short-term safety endpoints (including time to wound 
closure). Missing values for early drop outs etc. will be handled as described in Section 13.8.4  
and the SAP. The complete data set documented so far will be locked and analyzed as 
described above. Although the treatment code will be revealed at the end of this analysis, the 
independent assessor of the cosmesis and function and QoL of an individual patient will 
remain blinded to the treatment given to that patient until after the third and final analysis (see 
below), so as to preserve the un-biasedness of the  assessments.  
The second analysis will be performed for the 12 month follow up period (STFU12) and will 
be started after the last patient has reached the 12m assessment. At this analysis, all 
accumulated safety data at the 12m follow-up will be analyzed, particularly the 12m MVSS 
assessment for cosmesis and function. The complete data set documented so far will be locked 
and analyzed as described above. 
The third and final analysis covers the data of the long-term safety follow up (LTSFU24). It 
will be conducted after the last patient has reached the 24m assessment at last 12 months after 
(STFU12) analysis (stage 2). At this analysis, all accumulated safety endpoints at the 24m 
follow-up will be analyzed, particularly the 24m MVSS assessment for cosmesis and function. 
The complete data set documented during the trial will be locked and analyzed as described 
above (hard lock). 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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14 
QUALITY ASSURANCE  
14.1 
QUALITY ASSURANCE PROGRAM 
This clinical trial may be audited according to the MediWound Quality Assurance (QA) 
program.  
The purpose of these audits is to determine whether the study is being conducted and 
monitored in compliance with the protocol and recognized GCP guidelines and local 
regulations. These audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent inspection by any regulatory authority.  Such 
audits, if necessary, will be pre-arranged with the site and conducted within a reasonable time 
frame. 
14.2 
MONITORING PROCEDURES 
The conduct of the study will be closely monitored by representatives of MediWound to verify 
adherence to ICH GCP guidelines and applicable SOPs. Reports of these monitorings will be 
archived with the study report.  
The Investigator will allow the designated MediWound representatives and/or any regulatory 
agency to have direct access to all study records, eCRFs, corresponding subject medical 
records, study drug dispensing records and the study drug storage area, and any other 
documents considered source documentation. The Investigator also agrees to assist the 
representative if required. 
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information in eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).  
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. MediWound monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
 
14.1 REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, and the ICH Harmonized Tripartite Guidelines for Good Clinical 
Practice in compliance with local regulatory requirements. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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14.2 
DATA SAFETY MONITORING BOARD (DSMB) 
A Data Safety monitoring Board (DSMB) will convene at least twice a year, as routine, during 
the enrollment period, to assess safety data as described in the agreed DSMB chart. During the 
follow up period, a DSMB will convene at least once a year. 
All DSMB conventions will be in closed session format. 
These activities will be coordinated by MediWound Ltd. and the recommendation shall be 
directed to MediWound Ltd. The DSMB will consist of three independent individuals 
including burn specialist(s) and a biostatistician. Following selection and agreement to serve, 
the committee will meet in person or by teleconference to be briefed fully on the procedures 
defined in the Protocol and Statistical Plan. MediWound Ltd. shall be formally informed of 
recommendations by the DSMB prior to implementation of said recommendation(s) and must 
approve, in writing, any new analyses being recommended by the DSMB. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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15 
INVESTIGATOR’S AGREEMENT 
I have carefully read the foregoing protocol including all appendices and agree that it contains 
all the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the current 
GCP guidelines and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information submitted by the sponsor relating 
to pre-clinical and prior clinical experience to all personnel for whom I am responsible that 
participate in the study. I will discuss this information with them to assure that they are 
adequately informed regarding the drug and conduct of the study. 
I agree to keep records on all subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) in accordance with the current GCP 
and local regulations. 
 
Site Principal Investigator’s name 
MediWound Representative's name 
Signature 
Title 
Date (dd/mmm/yyyy) 
Signature 
Institution 
Date (dd/mmm/yyyy) 
 
 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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16 
APPENDICES 
APPENDIX 1- WOUND DEPTH ASSESSMENT- CLINICAL EVALUATION 
The burn literature [18, 97] suggests that clinical evaluation of the burn wound is the most 
widely used method of assessing burn wound depth. This was, but also recognized in the FDA 
Guidance for Industry Chronic Cutaneous Ulcer and Burn Wounds, June 20061 and also the 
burn depth assessment method accepted by the ABA [1]. In accordance with the above, further 
to assessing wound appearance, the following tests will be included [98]: 
1. Capillary blanching 
2. Capillary refill 
3. Capillary staining 
4. Wound sensibility to touch 
5. Pin prick 
Using the above criteria will allow the Investigator to differentiate between the SPT and DPT 
areas as is widely acceptance in the US [99], according to the following below criteria in 
addition to the visual assessment: 
 SPT burns extend into the papillary dermis and form blisters. Once the blister is 
removed from a SPT wound, the wound is pink, wet and hypersensitive to touch. These 
wounds are painful and blanch with pressure.  
 DPT wounds extend into the reticular dermis. They also blister but the wound surface 
appears mottled pink and white. The patient complains of discomfort and pressure 
rather than pain and when a pressure is applied to the burn, capillaries refill slowly or 
not at all. The wound is less sensitive to pinprick. 
                                                 
1 Section IV D, pharagraph 2. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 2- PAIN MANAGEMENT PROCEDURES 
Pain Management Procedures 
For topical arms treatment, preventive analgesia medication (pain management) will be 
mandated as for an extensive burn dressing-change. 
During NexoBrid treatment it has been observed that the two painful stages are during the first 
30 minutes of the treatment and during the dressing removal which is followed by cleansing 
and dressing (30-45 minutes).  Thus, the principle of the suggested pain management is to 
prevent pain by starting the treatment with sufficient basic analgesia/sedation as detailed 
below. Once the first painful stage has ended, background analgesia can be administered and 
the sedation/analgesia regimen stopped. 
Before NexoBrid dressing removal the sedation administration should normally be started 
ensuring that the patient is pain-free until the first post-eschar removal soaking dressing is in 
place. 
Sedation administration can be repeated two hours later, before the removal of the soaking-
dressing. 
  
Objective: 
The object of the analgesia is to ensure that the entire treatment course is performed in a safe 
and comfortable manner. During the treatment the patient should be free of significant pain and 
easily arousable, without interference with vital functions. 
In the majority of cases the pain can be managed without the need for deep sedation, by the 
pre-administration of oral analgesics and being prepared to administer intravenous Morphine as 
needed to control pain surge.  
If sedation is used the patient should not need intubation and it should be easily and quickly 
reversible by discontinuing administration of the sedation agent. Sedation can normally be 
discontinued after the first painful wave that lasts for 30-60 minutes from NexoBrid 
application; it should be reinitiated before and during dressing removal and wiping of the 
dissolved eschar, a process that may last for another 30 minutes. 
Attention should be given to background analgesia during the interval between these 
procedures. 
During procedures, the patient should as a minimum be monitored frequently for: 
 Blood Pressure (non-invasive)  
 Cardiac activity (ECG) 
 Respiratory rate 
 Oxygen saturation (pulse oximetry) 
Example of a medication regimen: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Bolus intravenous analgesia/sedation using appropriate combinations of fentanyl, and 
midazolam and ketamine. Suggested initial doses are: 
Fentanyl- 2 microgram/Kg 
Midazolam- 0.06 mg/Kg (1 mg/15 Kg) 
Ketamine HCl- 0.5 mg/Kg  
Maintenance doses will typically be one-third to one-half of the initial dose at 10-20 minute 
intervals; considerable inter-patient variation should be expected.   
Intravenous continuous sedation using a syringe driver or target-controlled infusion (TCI) 
driver is a very acceptable technique, using propofol + alfentanil, propofol + remifentanil, or 
remifentanil alone.   
 
Continuum of depth sedation: Definition of general anesthesia and levels of 
sedation/analgesia*- American Society of Anesthesiologists 
 
  
Minimal 
Sedation 
Anxiolysis 
Moderate 
Sedation/ 
Analgesia 
(“Conscious 
Sedation”)  
Deep Sedation/ 
Analgesia  
General 
Anesthesia  
Responsiveness  
Normal response 
to verbal 
stimulation  
Purposeful** 
response to 
verbal or  
tactile 
stimulation  
Purposeful** 
response 
following 
repeated or 
painful 
stimulation  
Unarousable 
even with painful 
stimulus  
Airway  
Unaffected  
No intervention 
required  
Intervention may 
be required  
Intervention 
often required  
Spontaneous 
Ventilation  
Unaffected  
Adequate  
May be 
inadequate  
Frequently 
inadequate  
Cardiovascular 
Function  
Unaffected  
Usually 
maintained  
Usually 
maintained  
May be impaired  
  
 Minimal Sedation (Anxiolysis) is a drug-induced state during which patients 
respond normally to verbal commands. Although cognitive function and physical 
coordination may be impaired, airway reflexes, and ventilatory and cardiovascular 
functions are unaffected.  
Moderate Sedation/Analgesia (“Conscious Sedation”) is a drug-induced 
depression of consciousness during which patients respond purposefully** to verbal 
commands, either alone or accompanied by light tactile stimulation. No interventions 
are required to maintain a patent airway, and spontaneous ventilation is adequate. 
Cardiovascular function is usually maintained.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Deep Sedation/Analgesia is a drug-induced depression of consciousness during 
which patients cannot be easily aroused but respond purposefully** following 
repeated or painful stimulation. The ability to independently maintain ventilatory 
function may be impaired. Patients may require assistance in maintaining a patent 
airway, and spontaneous ventilation may be inadequate. Cardiovascular function is 
usually maintained.  
General Anesthesia is a drug-induced loss of consciousness during which patients 
are not arousable, even by painful stimulation. The ability to independently maintain 
ventilatory function is often impaired. Patients often require assistance in 
maintaining a patent airway, and positive pressure ventilation may be required 
because of depressed spontaneous ventilation or drug-induced depression of 
neuromuscular function. Cardiovascular function may be impaired.  
Because sedation is a continuum, it is not always possible to predict how an 
individual patient will respond. Hence, practitioners intending to produce a given 
level of sedation should be able to rescue*** patients whose level of sedation 
becomes deeper than initially intended. Individuals administering Moderate 
Sedation/Analgesia (“Conscious Sedation”) should be able to rescue*** patients 
who enter a state of Deep Sedation/Analgesia, while those administering Deep 
Sedation/Analgesia should be able to rescue*** patients who enter a state of General 
Anesthesia.  
* Monitored Anesthesia Care (“MAC”) does not describe the continuum of depth of 
sedation, rather it describes “a specific anesthesia service in which an 
anesthesiologist has been requested to participate in the care of a patient undergoing 
a diagnostic or therapeutic procedure.”  
** Reflex withdrawal from a painful stimulus is NOT considered a purposeful 
response.  
*** Rescue of a patient from a deeper level of sedation than intended is an 
intervention by a practitioner proficient in airway management and advanced life 
support. The qualified practitioner corrects adverse physiologic consequences of the 
deeper-than-intended level of sedation (such as hypoventilation, hypoxia and 
hypotension) and returns the patient to the originally intended level of sedation. It is 
not appropriate to continue the procedure at an unintended level of sedation. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 3- PHOTOGRAPHIC WOUND DOCUMENTATION 
In accordance with FDA guidance, the photography methods will be standardized in all centers with 
standard camera type and control of the distance/size (zoom), color, exposure, (lighting) and color 
bend tag (as a reference for color and size) of the acquired picture. This will be performed using 
patient ID label (see below) which will be identical in size and content (colors scale) for all patients 
and should be used as detail below. Photographs will be uploaded into the eCRF. 
Photographic Documentation 
1. Each wound area is considered an independent entity and should be documented as such. 
2. Each wound site should be photographed using a standard digital camera with flash card 
memory which together with sterile photography patient ID labels, are supplied by 
MediWound.   
3. Site number, patient ID, exact date and time, and wound location (as specified on the ID 
labels) should be noted on each label. The photograph is taken (i.e. pre-cleansing, pre-
treatment, post-soaking, 24hrs, hospital discharge, weekly visits and monthly visit, etc). 
4. Each photographed field (wound site) should include the patient ID label.  
5. The photograph should be taken using the zoom facility (camera as near as possible to the 
patient) while including the entire treated area. 
6. In order to ensure patient confidentiality, facial photographs are not allowed. 
 
 
 
 
 
 
 
 
 
 
Recording Kit 
The recording kit consists of: 
1. Sterile photography patient ID labels, 
2. One digital camera, 
3. Flash cards. 
 
MW2010-03-02 
Visit: _______________________________ 
MW2010-03-02 
Visit: _______________________________ 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 4- POST-ESCHAR REMOVAL WOUND MANAGEMENT 
Post Eschar removal Burn Wound Bed(s) 
An ideal burn debriding agent should effectively and quickly debride the burn eschar but also 
preserve viable tissues to source and allow spontaneous healing by epithelialization. It should 
combine the non-invasiveness of the ineffective and slow non-surgical debriding means and 
the efficacy and speed of surgery. 
Following any eschar removal process, whether surgical or non surgical one, the wound is 
being assessed for eschar removal efficacy and for presence of residual viable dermis by 
experienced plastic/burn surgeon. Usually, following an effective eschar removal with 
visualization of the viable tissue bed, a more accurate burn depth diagnosis can be made. 
Macroscopically, the components of the human integument are from epidermal, dermal and 
subdermal origins. Few colors are involved in the final visual appearance of the healthy tissues: 
the brown-black of the melanin, hemoglobin's shades of reds (depending on the oxygenation 
level) and the pearly-white of the collagen. Below the skin a yellow fat add another color.  
The debrided wounds can be divided into four groups based on the debrided bed condition:  
1. Complete eschar removal revealing residual viable dermis. 
2. Complete eschar removal revealing a full thickness skin defect requiring permanent 
cover. 
3. Complete eschar removal revealing a wound bed with areas of viable dermis and areas 
of full thickness defect.    
4. Incomplete eschar removal to various degrees. 
Several means and strategies can be used to remove the eschar, each ending in a typical bed: 
Surgically debrided beds:  
Sharp dissection (using dermatomes, dermabtasion or hydro dissection such as Versajet) will 
leave a smooth bed that is composed, in the case of complete eschar removal, of transected 
structures such as dermis and blood vessels or subcutaneous fat.  This bed will readily accept 
autograft with good take if adherence and drainage are assured.  
Autolytically debrided beds:   
Slow decomposition and maceration will cause eventually the sloughing of the necrotic tissue 
but simultaneously, at the end of the second week granulation tissue will start to form and 
epithelial cell will start to epithelialize clean exposed dermis originating from the edges or the 
appendages (hair follicles, sweat and sebaceous glands). Granulation tissue will form if wound 
closure (by epithelialization, grafting or wound edges approximation) is delayed developing 
into scar. Granulation tissue will, if not infected, readily accept autograft but may contract later 
pulling with it the wound’s edges. In case of significant bacterial infection the process can 
invade surrounding healthy tissues (Invasive Infection) extending the damage. Infection 
together with other wound healing intervening factors (e.g. diabetes, hypoproteinaemia, etc) 
can cause the wound healing process to stop and become chronic. Chronic wounds may be 
highly contaminated or chronically covered with biofilm with only slowly granulation tissue 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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formation. Such wounds may behave as chronic, recalcitrant wounds, and will not heal easily 
or support graft. 
NexoBrid- Enzymatically debrided bed  
NexoBrid is an enzymatic debriding agent provided for eschar removal of the eschar. The raw 
surface that is left after this eschar removal is the Interface Layer (IL), which is comprised of 
the upper layer of healthy tissue that is made of exposed viable tissues. After wiping away the 
dissolved eschar the dermal IL has a whitish hue due to the dermal collagen matrix seeded with 
punctuated bleeding capillaries. The dissolved ends of the collagen fibres are made of 
unferruled collagen fibrils that may give a “furred” aspect to the surface. This layer preserves 
all viable components such as deep epithelial elements inside the adnexae and deep dermal 
remnants (collagen fibres, subdermal fat and blood vessels). In all but the deepest wounds, the 
presence of the dermal Interface Layer permits spontaneous healing (epithelialisation over 
dermal remnants); however, the majority of transacted blood vessels are still occluded at their 
ends. In the event that skin grafting is required (a full thickness burns or after the spontaneous 
healing potential has been exhausted or when an immediate wound closure is required) a 
graftable bed is obtained by simple scrubbing the Interface Layer with a dry swab or a sterile 
nail brush to expose the blood vessels during the graft application session. 
Wound bed assessment 
Any effective eschar removal will reveal the surface of the exposed viable tissue with its 
components and structures and the exact extent of the original damage (Figure 1). Being aware 
of the cutaneous three dimensional macroscopical structures, the form and color of the various 
components, it is rather easy to assess the depth of the debrided bed. The first step is to assess 
visually the presence or absence of epidermis which is the criterion of second degree (dermal) 
burn. Residual, none removed eschar appears opaque, yellowish-grey clearly differing from the 
pearly-white viable collagen. Bleeding vessels on the background of white collagen indicate 
that the eschar removal process reached viable tissue. Once the dermis is revealed the bleeding 
pattern that characterizes the different dermal levels clearly indicates the depth. Very fine, 
homogeneous bleeding characterizes the superficial papillary dermis (superficial, II° dermal 
burns). Deeper the burn is, the bleeding vessels are set wider and wider apart. In mid and deep 
dermal burns, only few bleeders can be seen on the background of white collagen matrix 
background. The few deep dermal capillary complexes that are situated around the adnexae 
may give the dermis a pinkish hew. When most of the dermis is removed the yellow subdermal 
fat gives the debrided bed a yellowish hew. Reaching the deepest part of the dermis, at the 
transition to the subdermal layer, one can see the yellow fat lobules protrude through the loose 
net of collagen fibers with few bleeders. This “quasi” full thickness burn behaves as a full 
thickness 
burn 
and 
only 
rarely 
will 
heal 
spontaneously.    


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Figure 1- Wound bed assessment 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Non burned skin, uninjured by NexoBrid 
b. 
Superficial dermal burn with bleeding 
c. 
Mid depth dermal burn with well preserved dermal collagen matrix 
d. 
Deep dermal burn with larger and wider spaced bleeding capillaries and a very thin dermal matrix 
e. 
Full Thickness burn 
f. 
Non dissolved eschar protected by the blister that was not removed prior to NexoBrid application 
 
Wound healing options post eschar removal 
In general, burn wound closure can be achieved by:  
Primary Intention: closure of the wound bed by graft that covers and obliterates the raw 
surface and “heals” the wound completely, similar to using sutures for bringing together the 
surgical wound’s edges. This approach requires a completely clean and viable bed with all 
cellular and non cellular components exposed for the healing process. The severed end of the 
blood vessels should be opened to allow endothelial cells to bud and connect the graft’s raw 
underside and eventually supply the graft with the necessary life giving blood. The graft 
survives the first days by “imbibition’s phenomenon”: graft’s nutrition by the serous exudates 
from the wound bed but its continuous survival depends on blood vessels connection and 
integration with the graft’s capillary bed. The capillary bed in the dermal papillary layer 
indirectly supplies the epidermis (that does not have any capillary bed of it own) with the 
necessary nutrients and oxygen so autograft needs a certain dermal layer to provide nutrient to 
the epidermis for survival. Graft adhesion during first days will provide good contact to the 
recipient bed, decreased danger of exudates’ collection and a better chance of take. Such graft 
stabilization and adherence is achieved by compressive dressings or using sub atmospheric 
(vacuum) external dressing over the graft that will stabilize the graft to its bed and remove 
exudates that can interfere with graft take.        
a
d
c
f 
e 
b


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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Protocol: MW 2010-03-02 
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Autograft: grafting the raw bed with autograft that includes epidermis and a thicker or thinner 
layer of dermis. If the graft take >95% – the engrafted wound is practically closed.  
Autografting requires surgery under general anesthesia, sacrifice of healthy donor site skin area 
and surgical facilities (OR, surgical team etc.). The donor site will heal spontaneously during 
2-3 weeks by epithelialization but may be scarred and infected. Thicker the harvested dermal 
layer is better the functional and aesthetic results are but more damage is inflicted on the donor 
site, longer its healing is and higher is the likelihood to develop scars. Thicker the graft is, 
higher are the demands of the transplanted tissue from the wound’s bed and so are the risks of 
graft failure. 
Permanent Skin Substitutes: products such as Matriderm, Integra and Jalomatrix can be applied 
on the debrided bed, serving as regenerating matrix for the development of new dermis. Here 
too the debrided bed should be free of necrotic eschar and contain opened capillaries ends as 
the source for endothelial cells that will integrate, together with the native fibroblasts, into the 
artificial matrix forming the neodermis. All these products have to be engrafted sooner or later 
also with thin autograft (Matriderm immediately and Integra and Jalomatrix, 2-4 weeks later) 
that contains mainly the epidermal layer. The grafting procedure will necessitate surgical 
facilities as in a formal autografting but the donor sites heal faster (< 2 weeks) as the harvested 
graft is thinner with much less sacrificed dermis.  The cost and success rate of these products is 
a severe limiting factor.   
Allograft, xenograft and adherent biological covers: will adhere to the bed (assisted by vacuum 
dressing in the first days), preserve moisture and provide conditions for epithelialization or 
autograft for later stage, following removal of the temporary dressings.  
Epithelialization over preserved dermis: Full thickness defect greater than few cm2 should be 
closed by grafting but exposed dermis can heal by epithelialization that will close the wound 
without granulation and scar formation. When sufficient dermal elements exist, epidermal cells 
(Keratocytes) originating from the wound’s edges, the skin appendages (hair follicles, sweat 
and sebaceous glands) or Keratocytes cultures/ suspension can proliferate and propagate over 
the dermal bed creating a new epidermis.  This process requires a healthy and clean dermal bed 
and a dressing that will protect the exposed, raw dermal bed from desiccation and infection and 
provide the epithelialization process with the necessary conditions (moisture and propagation 
surfaces for the Keratocytes). There is a plethora of products that can be used for this purpose 
each with its advantages and disadvantages, each fulfilling a specific need in the healing 
process. 
Healing By Secondary Intention: As real regeneration of full thickness skin defect is 
impossible, the natural healing process of these wounds is aimed at creating first a temporary 
protection mechanism followed by a “plug” that fills the defect, replacing the missing, normal 
skin. Following a generalized inflammation-healing process of three overlapping phases of 
Inflammation, Proliferation and Modulation the granulation tissue forms, covering the wound 
bed and slowly filling the defect. Granulation tissue originates from connective tissue, 
containing fibroblasts, macrophages, white blood cells elements and endothelial cells from the 
severed blood vessels all forming a tortuous mass of new capillaries imbedded in new 
connective tissue. Keratocytes from the wound’s edge slowly strive to cover the granulation 
tissue but very often their progress is extremely slow and may be completely denied by the 
fibroblasts. The granulation tissue with all the local and systemic defense mechanisms provides 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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protection against infection. The fibroblasts deposit collagen and the fibroblasts–originating 
miofibroblasts pull-in the wound’s edges forming a scar with more or less contracture element. 
The progressive development of the granulation tissue (proliferative phase) may be controlled 
and decreased by the influence of the epithelial cells, the Keratocytes. Once the granulation 
tissue is entirely covered by the Keratocytes, its growth will decrease and the granulation tissue 
becomes a scar that will start to mature, often also to contract. Granulation tissue proliferation 
may be attenuated by topical corticosteroid ointment short (few days) treatment course 
exploiting the controlling affect of corticosteroids on inflammatory processes.  In the 
granulation tissue, the fibroblasts deposit collagen and the entire tissue undergoes modulation 
to become fibrous, hard scar filling the original defect. The scar contracts by the miofibroblast, 
pulling-in the healthy skin margin, reducing the scar’s surface but these contractures, 
especially across joints will interfere with function and cosmesis.   
Grafting granulation tissue is a routinely practiced: during surgery the granulation tissue is 
forcefully scraped with a blunt edge surgical instrument (spoon, scalpel handle, metal ruler, 
etc.), removing the superficial layer with its bacterial load and opening the multitude of 
capillaries to accept the graft. In burn care healing by secondary intention with granulation 
tissue scarring and contractions is undesirable and often the scarring is more incapacitating and 
dangerous than the acute burn itself.  The lengthy (sometimes years) of the scar modulation 
process may be influenced by application of continuous pressure on the scar by made-to-
measure pressure “garment” dressings that applies a constant pressure and silicon sheets 
applied directly on the scar under the pressure garment.  
Healing by tertiary (delayed primary) intention: In some cases primary closure by wound 
edges approximation (suturing) or grafting is not feasible mainly due to local infection, 
patient’s general condition or external restrictions (surgical team, OR, other facilities or graft 
donor site availability). Another condition is when wounds closed by suturing disrupt (dehisce) 
or the grafts do not “take” to the wound bed and slough off. In most cases it is either an 
infection process of the underlining wound bed or edges or collection (blood, serum, pus). Re-
suturing or re-grafting the contaminated bed will end only with another closure failure and 
probably also with spreading the infectious process to adjacent tissues. The accepted practice is 
to leave the wound open, to treat the infection by topical and sometimes also systemic 
medications and once the infection is resolved the wound can be closed again. Formation of 
granulation tissue during the treatment course can favor graft take by providing additional 
blood supply to the graft but later may promote scar formation. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Summary of wound healing strategy in burns 
 Ideally burns wounds should be debrided and closed as soon as possible after injury. At 
present that means: immediate or very early after injury tangential excision and autografting. 
Due to diagnosis difficulties mainly of the dermal burns, the interest of avoiding the surgical 
related trauma, morbidity and the surgical needed facilities/costs with the potential (and hope) 
that the burn may heal spontaneously, the surgical treatment may be delayed. Once the eschar 
is not surgically debrided a slower, non surgical eschar removal approach is practiced. It is 
based on the best possible anti-infection care with the promotion of the eschar separation 
(sloughing) or disintegration (necrosis). This is a slow process that may lead to local and 
systemic infection and additional tissue damage. The time needed for this non surgical process 
allows also the formation of granulation tissue. The granulation tissue protects the open wound 
and offers a good bed for grafting but in many cases will form a heavy, contracted scar in few 
weeks. During this healing process an educated, cyclic (short spells of 2-3 days) of 
corticosteroid ointment will reduce the granulation tissue and will offer the bed a better 
grafting bed.  
To graft or not to graft: Full thickness defect will not heal properly without grafting and need 
always autograft or permanent skin substitute to prevent healing by secondary intention and 
scaring. Clean dermal bed that can epithelialize spontaneously can be grafted as well in order 
to close the wound immediately. Several factors should be considered when striving to close 
the wound "as soon as possible".  The true benefit to the burn patient in earlier burn wound 
closure by few days (the difference between grafted and epithelialized dermal burn) not always 
is truly advantageous. Autograft involves surgery, surgical and anaesthesia related trauma, 
donor site morbidity and the healing time of the donor site by epithelialization (≈2 weeks) is 
very similar to the epithelialization of the burn wound exposed dermis. Donor site morbidity 
includes infection, pain, additional dressing changes and scars. Grafting will not speed early 
subject mobilization as the latest normally starts much before wound closure ends and a return 
to work/normal lifestyle requires at least several weeks of recovery and rehabilitation after the 
wound is closed.  Thus, the decision to graft exposed dermis in order to shorten by few days 
wound healing should take into consideration the comprehensive well being and benefit to the 
patient. Issues such as length of treatment course and hospitalization depend on the nature of 
the dressing and wound care that in many cases allow early hospital discharge and prevent 
open wound related complications. 
Following wound closure the healed wound is dressed with a thin protective primary dressing 
or silicon sheet followed by pressure “garment” dressing modulating their modulation to a 
smooth, pale and pliable skin-like scar.   
 
Wound healing requirements 
The general prerequisites for good wound healing are based on adequate conditions and 
microenvironment for this dynamic process. 
Tissue factors 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 Adequate blood supply: adequate arterial supply, adequate venous return, healthy capillary 
bed (example to potential problematic conditions: PVD, Varicose Veins, arterial or venous 
insufficiency, diabetes, peripheral edema of any kind, hypertension, etc.)   
 Clean wound bed: no eschar, foreign bodies or materials: all the followings can interfere 
with the healing process: necrotic eschar such as in burns, pressure sores, exposed bone, 
tendon or orthopedic implant and suturing material, foreign bodies introduced during injury, 
intradermal or subdermal hematomas or seromas. 
 No severe wound infection: < 10 5 count /cm3, purulent discharge, invasive wound infection, 
signs of cellulites, fungal infection.   
 Balanced healing dynamics: offering adequate conditions for epithelialization propagation 
and preventing overgranulation and its stagnation.    
 Systemic factors such as chronic steroid intake, anticancer drugs, malnutrition, diabetes, etc. 
 Post radiation tissue damage 
 Avoiding local medication that can interfere with the desired healing process (e.g. SSD, 
pseudoeschar formation, desiccating dressings). 
Local wound bed conditions that promote wound healing 
 The healing process is a cell-based process with different cells requiring different conditions 
besides the very general ones of blood supply and contact with the bed: 
 Moist wound surface: desiccation of the healing bed is one of the main dangers. All cells 
need moist environment for their survival. An occlusive dressing, any adherent- to-the-bed 
dressing, hydrogels (hydrating dressings) and ointment (oil based medicament) will create a 
thin moist environment underneath.    
 Three-dimensional wound bed topography: 
o Propagation surfaces: Keratocytes “prefer” to propagate and epithelialize on a 
collagen/HA, dermal surface under guiding, protective, scab like surface.   
o Contact inhibition: Fibroblasts and endothelial cells tend to develop granulation tissue in 
the direction of the wound’s open space.   
o Surface modulation of inflammation process: granular and fibrous surfaces   
macrophages, fibroblasts, etc.      
 Infection free surfaces: early treatment of any apparent infection  
 Adherent dressing will keep the undersurface moist, infection free, provide propagation 
surface and protects from mechanical insults. Usually an adherent dressing is the sign of a 
safely healing wound though desiccating, hydrophilic dressings may also desiccate a viable 
bed, deepening the damage. 
Wound-bed, Interface Layer (IL)’ Contact, Primary Dressings-Covers: Main Demands  
The primary dressing, the dressing that is in immediate contact with the IL exposed raw tissue 
has very well defined role: to protect and promote care and healing. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The followings are the factors that are important in these aspects: 
1. 
Adheres to the Interface Layer (with its special characteristics) 
2. 
Moisture regulation 
3. 
Epithelialization enhancement 
4. 
Fibroblastic activity modulation 
5. 
Infection control 
6. 
Trans-Dressing Diagnosis of changing conditions (TDD)  
7. 
Trans-Dressing Intervention (TDI) 
1. Adherents to the Interface Layer: Dressing’s adherence is important as it provides the 
protection against microorganism contamination and propagation, serving as a mechanical 
barrier shielding the healing wound from external insults and maintaining a thin moisture 
layer over the healing bed. In general, the dressing’s adherence may be due to the 
following situations: 
a. Incorporating, ingrowths of the wound bed tissue into the dressing structure (as may be 
seen in Allografts, Xenografts, cotton gauze or some of the sponge dressings). 
b. The “dressing” is an integral structural part of the wound (a desiccated eschar, the 
desiccated, upper layer of the bed or a planned mummification of the eschar by cerium 
nitrate [Flamacerium] or iodine will preserve the original collagen fibers ties with the 
bed’s matrix. 
c. There may be a physical/chemical layer that “bonds” the dressing to the underlying bed 
(such as scab formation where the fibrin and fibrous clot will adhere and bond dry 
hydrofiber [Aquacell], cellulose [Velloderm] etc. dressings). Dressings such as some of the 
Hyluronic acid [Jaloskin], Collagen [Biobran] or DL-Lactide (Vicryl like poliglycolic acid 
[Suprathel]) dressings may adhere by their undersurface, deeper layer that serves as 
adhering layer with the bed. In these cases very often, if the bed’s viability is maintained 
(not desiccated) the epithelial or granulation tissue will grow underneath and their 
advancing fronts will separate the dressing from the healing bed.  
In some of these dressings this bonding surface can bond the dressing also to a not 
completely debrided beds. If the eschar is very thin and not too contaminated there is a 
good chance that the dressing will remain adherent and the bed, slowly healing with the 
eschar remnants, will disintegrate as the healing front progresses. This characteristic is 
very important as it allows an effective cover to a wide range of wound beds.   
Unfortunately an adherent dressing to the wound bed may also form a barrier to the 
propagating healing process. The dressings from groups a. & b. above, though they may 
effectively prevent infection will not allow propagation of the epithelialization fronts 
underneath and may also prevent the formation of granulation tissue. The dressings from 
group c. may become also occlusive and increase microorganisme spreading and infection.      
2. Moisture regulation: The optimal moisture at the wound’s surface should be delicately 
balanced between desiccation that leads to cell death and matrix changes and 
overhydration that leads to maceration. Adherent dressing may normally keep the optimal 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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moisture unless they are hydrophilic (desiccating) by nature and in this case may desiccate 
the wound. Hydrating dressing with high water content may overhydrate the wound acting 
also as occlusive dressings increasing the danger of infection and infection propagation. 
The moisture condition in the individual wound is dynamic and may change within hours. 
A “moist” highly exudating wounds that may need drainage by absorbing dressing may 
become dry, recalcitrant wound by too active desiccation or even exposure. In the case of 
burn, “weeping” surface of a dermal scald burn or a fresh, raw donor site may desiccate in 
few hours of exposure and develop a layer of neo-eschar: a layer of desiccated, newly 
“killed” dermis. This dry, adhering layer can, if not infected, serve as a biological dressing 
but at a price: death of tissue that could be instrumental in the healing process and a danger 
of contamination and infection of this new eschar.   
All vital functions of healing and proliferation, healing factors and cellular activity need 
moist environment for their function. Nevertheless, microorganism survival and 
propagation need also moisture. The dressing we use should allow us to intervene and 
correct these changing conditions.  
Dressings from the group of “hydrogels”, “gelfoams”, all occlusive dressings-films, some 
of the adhering dressings, all topical gels, creams and ointments will maintain the bed 
moist and offer good healing conditions but a continuous monitoring should be maintained 
to intervene in time to prevent too much moisture, maceration and/or infection.               
3. Epithelialization enhancement: The progression of the epithelialization process is a 
complex one, involving the inbuilt epithelial progression based on the contact inhibition 
phenomenon with the proliferation of the keratocytes from the wound’s exposed edges and 
the epithelial islands originated in the skin adnexae. The Keratocytes propagate slowly 
over the dermal matrix in a moist atmosphere. The following are conditions that the 
propagation and the entire epithelialization process may be disturbed even in presence of 
sufficient epithelial sources (epidermal wounds edges, skin adnexae or autografts):  
 Mechanical disruption: dressing change, forced scraping or wiping of the healing wound 
will peel off the friable new epithelium from its bed  
 Mechanical barrier: such as to adherent dressing 
 Infection: may destroy keratocytes  
 Eschar presence: beside being a mechanical barrier that will not allow epithlialization over 
viable bed is also  a potent source for infection 
 Actively granulating tissue: (“overgranulation”) that will stop epithelialization by forming 
a physical barrier and biological competition by the fibroblastic activity. 
 Topical medications: may be noxious to the proliferating keratocytes (i.e. SSD, Iodine 
compounds)  
 Systemic conditions: mainly malnutrition as expressed by hypoproteinaemia and 
hypoalbuminaemia or Oncological drugs.  
4. Fibroblastic activity modulation: The Keratocytes and Fibroblasts originate from two 
different embryonic cellular origins: ectodermis and mesodermis. In spite of a very 
intimate relation in structuring the skin and forming the Epidermis and Dermis each of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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them exerts an inhibitory effect on the other. Fibroblasts are very active cells that 
proliferate in wound beds forming the three dimensional granulation tissue (together with 
new blood vessels by endothelial cells, also from Mesodermal origin). The Keratocytes, 
proliferate and propagate along the dermal superficial plan striving to from the Epidermis. 
They exert an inhibitory effect on the granulation tissue formation, arresting its 
development as soon as they cover it with the newly formed epidermis. The Fibroblasts 
and the granulation process are more robust than the thin epidermal, Keratocytes 
unicellular epithelialization healing front. Thus, if epithelialization process will not cover 
the healing bed, modulating and arresting the formation of rich granulation tissue the 
granulation tissue can become Overgranulation, forming a barrier to the Keratocytes and 
the epithelialization process and eventually becoming a heavy, contracting and deforming 
scar.  
In view of such a situation of developing granulation tissue in front of epithelialization 
process we can intervene by providing the Keratocytes with the optimal conditions 
(moisture, propagation surfaces and protection) and trying to interfere and decrease the 
overgranulation process. This can be done by mechanically scraping the overgranulation 
tissue, chemically destroying its surface (AgNO3) or using short (2-4 days) courses of 
topical corticosteroid treatment. The later treatment will effectively inhibit the granulation 
process allowing epithelialization to propagate and exert it own inhibitory effect on the 
fibroblasts. Topical steroids in given in shorts spells of few days each for over a month 
will not exert systemic effect and may be considered as safe. A wound healing dressing 
should promote epithelialization (that controls granulation) and allow us to intervene 
medically 
or 
mechanically 
interfering 
with 
overgranulation 
and 
promoting 
epithelialization.      
5. Infection control: Adherent dressing will prevent infection and occlusive conditions may 
favor it. Some dressings may be the source or serve as a medium for microorganisme 
growth (rejected allografts or xenografts, infected collagen or HA based dermal substitutes 
such as Integra, Hyalomatrix,). The dressing’s structure may itself harbor, as a foreign 
body, microrganismes (fibrous dressings such as cotton gauzes, some of the foams, other 
absorbing materials- Hydrogels and even hydrofibres-Aquacel to a certain point). Some of 
the dressings contain antibacterial agents (mainly silver) but they are not innocent. In such 
case that the dressing itself became contaminated we may wish either to replace it or be 
able to treat it with anti bacterial agents.        
6. Trans-Dressing Diagnosis of changing conditions (TDD): Being aware to the rather fast 
dynamic process, beneficial or not, that may happen in the healing wound the dressing 
should allow the diagnosis of emerging situations that may need our intervention. Process 
such as infection, granulation, overgranulation and epithelialization should be diagnosed 
and monitored in real time. An opaque, adherent, unchanged dressing may make such a 
diagnosis difficult. Dressings that are changed frequently (every 1-3 days at most, i.e. all 
topical medications, hydrogels, etc.) make such a diagnosis (on dressing change) easy. 
Some transparent dressings allow diagnosis through them (i.e. Jaloskin) or staining of their 
external surface when exudates from the wound ooze through (i.e. Aquacel, Polymem).    
7. Trans-Dressing Intervention (TDI): Adherent dressings that can remain for days, 
preventing infection, offering optimal healing conditions and allowing diagnosis of the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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processes that take place underneath are obviously ideal. The last possible criterion for an 
optimal dressing is the possibility to treat the wound bed through the dressing without 
disrupting it. Some of the occlusive dressings (Occludress, VAC+ all vacuum assisted 
dressings) could be connected to intake ports others, absorbing dressings such as gauze 
could be soaked without disruption.    
Wound Dressings and Covers 
The effect of the dressing’s physical properties 
As previously mentioned the role of the dressing is to protect and create an optimal healing 
microenvironment. Moisture and temperature that allow gases exchange and surfaces for 
epithelial migration, function of cells such as macrophages, neutrophils and fibroblasts. 
Another alternative are all the topical medications that need replacing or renewing daily or 
every other day.  
Absorbing & Non-absorbing 
The absorption function may depend on the physical structure (filament, fibers, hydrofibres, 
foams, etc.) or specific absorbing (hydrophilic mostly) materials the impregnate the dressing 
(starch, HA, alginates, collagen to a lesser measure, etc.). The passage of the fluids (exudates, 
soaking solutions, etc.) to or from the wound surface depend on the concentration gradient 
between the wound and the dressing and the characteristics of the dressing itself (potential 
fluid capacity, hydrophilic characteristics). Once fluid completely saturates the dressing the 
absorption power is cancelled and moisture at the wound surface increases to the point of 
maceration. Dressings with high absorption power may desiccate the wound to the point of 
tissue death. In order to maintain the absorption function the dressing should always be under 
its maximal saturation. This can be done by replacing the dressing before saturation or adding 
an external dressing that will absorb, through the primary dressing the fluid access. 
a. 
Antibacterial Topical Creams and Ointments 
Topical medicaments in the form of creams and ointments are innumerable, based on various 
antiseptic and/or antibiotic in different excipients preparations (few examples: Bacitracin, 
mupirocin, silver sulfadiazine, neomycin, polymyxin, honey inhibine, HA based creams) 
Indications: prophylaxis of infection, ointment maintain moist wound environment and can be 
used as covers in wound healing process.    
Burns care involves often the more effective combination of soaking and creams/ointments 
(silver nitrate compresses, chlorhexidine gluconate, mafenide acetate cream 0.5%, povidone 
iodine, nitrafurazone, silver sulfadiazine). 
Application: once or twice a day after washing and cleansing the wound.  
Contraindications: Allergic reactions, decreased cellular activity and viability. 
Complications: Drug specific, usually without risk of systemic toxicity. Local adverse effects 
include contact dermatitis (i.e., neomycin is as high as 34%). Application of silver sulfadiazine 
has been associated with neutropenia and epithelialization inhibition. 
Special points:  Bacitracin zinc is extremely popular because of low cost, low toxicity, and low 
allergic contact dermatitis. Relatively safe; topical antibiotics have low systemic absorption. 
HA based creams have additional benefit due to the HA base. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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b. 
Solutions for Irrigation & Soakings.  
Topical medicaments solutions are routinely used for soaking and irrigation of wound over a 
primary dressing, usually gauze. They are used for initial cleansing, being effective 
antimicrobial agents and mechanically washing away contaminants particles. With 
antibacterial agents they may be used for infection control. Corticosteroid addition will control 
topical inflammation and over granulation and with hypertonic solutions they can reduce 
cellulites, edema and swelling and even be used as antiseptics. Leaving the soaked gauze to dry 
will “suck in” the superficial dissolved materials be it dirt, bacteria or dissolved eschar 
allowing its removal. If the gauze is allowed to desiccate and bond to the bed surface its 
removal will tear off the surface (“wet to dry” cleansing). The following are common solutions 
used in burn and wound care: Saline (0.9%), Hypertonic Saline (<20%), MgSO4 (<10%), 
Chlorhexidine acetate (0.5%), Chlorhexidine gluconate (0.05%-0.1%), Sulfamylon 3%-5%, 
povidone-iodine, AgNO3 (0.5%), corticosteroid solutions,  antibiotic +/-corticosteroid 
solutions, PHMB (Polyhexamethylen biguanide) solution, Prontosan® (Betain + PHMB).  
Tissue toxicity is possible, caution should be used in the management of open wounds as well 
as wound desiccation. Corticosteroid long term (weeks), continuous soaking may cause 
transient, systemic Cushingoid symptoms. 
c. 
Gauze, gauze-like: woven & non-woven, cotton-base, not-cotton-based 
Cotton or cotton-like fibrous materials are used since antiquity as dressings. The pliability, 
adherence, absorption and their capacity to serve as a matrix to many medicaments and 
materials made them the current choice in wound care. This characteristic make them serve as 
a“reinforcement” for the creation of the scab that is the natural dressing for the healing wound. 
The fibrin from the raw bed is absorbed by the dressing that remains embedded in the 
solidified fibrin, forming a strengthened scab that by its nature (it is nature’s raw bed’s 
dressing) adheres to the bed. Due to their fibrous structure they serve also as wicks for soaking, 
passing the solution and bathing the bed. They can also serve as absorbing dressings passing 
the exudates to the surface, to be reabsorbed by additional, external, absorbing dressings. 
Normally, they will not adhere to full thickness wounds unless adhere through fibrous bonds 
that in every dressing-change (daily) will damage re-epithelialized layer delaying healing. The 
problem with such dressings is that they may shed particles that some become embedded in the 
healing bed, forming later foreign body inclusion cysts.   
d. 
Impregnated Dressings including Silver Dressings 
Dressings coated or impregnated with any material that is conceived to be beneficial to any of 
the wound healing phases or factors are produced by all wound care companies. Each of these 
agents has its advantages and its potential risks and drawbacks and should be assessed 
individually. The dressings can be made of many kinds of matrixes (cotton woven or non 
woven, films of various permeabilities and geometries, foams, hydrofibres, alginates, etc.).  
The choice of the dressing should be done according to the matrix characteristics (e.g. the 
difference in the properties of cotton gauze and hydrofibres) and the impregnating medication 
(e.g. the difference between SSD and Paraffin ointment) considering the specific requirement/s 
of the wound and its healing phase.  Few examples are:   
Paraffin with or without antimicrobial medicaments, coating woven, non woven or other 
primary form of dressings (such as Jelonet, Neotulle, Aquaphor-Gauze, Paranet, Unitulle, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Bactigras etc.): It will keep it moist, will not adhere to the bed, may increase infection danger, 
should be changed every 2 days at most. 
Silver compounds of different formulations (Acticoat, Silvelon, Atrauman Ag, Biatain Ag, 
Aquacel Ag, Contreet Hydrocolloid, Mepilex, Physiotulle Ag, PolyMem Silver, Silvercel, 
Suprasorb A+Ag, Tegaderm Alginate Ag, Urgocell Silver, Urgotul Silver): Silver ions (Ag+) 
have antibacterial effects, hyper sensitivity and arginosis (staining by silver oxide) of tissues 
has been reported. 
 SSD impregnated matrixes (Allevyn Ag, Urgotul SSD):widely used as a local antimicrobial, 
not to be used in sensitive to silver or sulfa drugs, known to delay epithelialization, 
kerenicterus has been reported.   
e. 
Biological covers (autografts, allografts, xenograft, skin substitutes and equivalents) 
The biological covers have a complex three dimensional collagen or collagen-like matrix, 
saturated by mucopolisaccaride compounds such as Hyluronic Acid and usually covered by 
semi permeable layer (epidermis, silicone).  They are applied on clean, viable surfaces, initially 
adhere by fibrin bonding and serum imbibition followed by in-growth of new vessels and 
fibroblasts from the bed. When they adhere (“take”) on a clean and viable bed all provide good 
protection and healing conditions.  The ones with antigenic potential (allograft and xenograft) 
should be replaced before immune rejection occurs. 
o Autografts are the classical means for permanent wound closure. In full thickness defects 
they provide a complete closure by primary intention healing. Deep dermal defect will also 
heal in a similar way by accepting the graft as a permanent cover but dermal remnants that 
contain epidermal foci (skin appendages) may also heal by epithelialization under the graft 
forming cysts or unsightly overgrafting patches. Autograft is a costly means, requiring 
surgery and sacrifice of healthy donor site skin areas and should be reserved for permanent 
closure for full thickness defects where spontaneous healing is impossible or when a fast 
closure is so important as to abandon the somewhat slower epithelialization of the dermal 
surface. 
o Allograft (fresh or cryopreserved) is used as a temporary solution to close the wound. It 
will “take” as autograft but will be rejected by the immune reaction 7-14 days later. On a 
clean IL bed they provide good healing conditions for the dermal IL and a temporary 
closure for full thickness defect. The epithelialization process will take place under the graft 
protection with the sloughing graft exposing the healing bed. The allograft keratocyte’s 
growth factors can promote the process but infection may harm the healing process. As the 
allograft is practically occlusive it is advisable to perforate or mesh it without expanding it 
to allow for a drainage and potential treatment medication. Use of allograft does not require 
surgical facilities but the availability of allograft may pose a problem in some countries. 
Their availability may be limited to the skin bank services and their shelf life is limited to a 
week when fresh and 3-4 years when frozen. Glycerol preserved allografts have a longer 
shelf life and do not need skin bank preservation facilities but are not viable, do not “take” 
but bond to the surface by fibrin, being less effective than fresh or cryopreserved. 
o Xenograft (fresh or cryopreserved, Mediskin I) usually from porcine origin, as allografts 
they are used as a temporary cover to “close” the wound. Fresh or cryopreserved, it will 
“take” as allograft but will be rejected by the immune reaction in few days. On a clean IL 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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bed they provide good healing conditions for the dermal IL and a very temporary closure for 
full thickness defect. The epithelialization process will take place under the graft protection 
with the sloughing graft exposing the healing bed. It is more infection-prone and should be 
applied meshed and medicated with antimicrobial agents. The glycerolized xenograft has a 
better shelf life but is even less effective and more infection-prone. Use of xenograft does 
not require surgical facilities but its availability may pose a problem in some countries.  
Skin Substitutes, Biodegradable & Non-biodegradable: Collagen, Hyluronic Acid (HA), 
Synthetic (DL-Lactide)  
There are number of materials that the inflammatory and healing process can degrade thus 
avoiding removing them at the end of the healing process. The problem is always to decide 
whether we want this degradation process in addition to the normal inflammatory, healing one. 
Biological materials such as Collagen, Hyluronic acid or DL Lactide- polyglactin (the raw 
material for Vicryl sutures) are all used as films or three dimensional sponge-like structures. In 
full thickness wounds, some are designed to serve as templates for new dermis formation 
(Collagen: Integra, Matriderm, HA: Hyalomatrix) by providing a growth matrix for capillaries 
and fibroblasts to be grafted with thin autograft when their survival (“take”) is secured. Similar 
approach is shared by other products: Dermagraft (non-immunogenic neonatal fibroblast on 
polyglactin mesh), OrCel (Fibroblasts layered onto bovine collagen matrix), TransCyte 
(Shipped frozen for use on partial- and full-thickness burns, epidermal layer with dead 
fibroblasts layered onto a nylon mesh), Apligraf (dermis-like matrix from cultured 
heterogenous human foreskins and bovine collagen type 1, has epidermal and dermal 
components), Oasis (porcine, small-intestine submucosal dehydrated dressing with longer 
shelf-life, rehydrate when needed with a secondary dressing to prevent desiccation), Alloderm 
(Freeze-dried, cell-free).  
Another group is design to serve as a cover for clean, dermal wounds providing healing 
(epithelialization) conditions and disintegrating when epithelialization is completed (Collagen 
films and sponges, HA Jaloskin or DL Lactide Suprathel).  All need a clean bed to adhere to, 
with Suprathel in need of a meticulously dermabraded bed. All are sensitive to infection. 
Collagen and HA can be used to coat synthetic matrixes or fabric (Nylon-Biobrane).  Biobrane 
is common in wound care, peeling off at the end of epithelialization but is prone to desiccation 
of the bed and infection.  
f. 
Inert, synthetic materials 
The alternative to biodegradable materials are the ones that are completely inert, most are 
synthetic providing the required conditions to the wound bed but are not part of the healing 
process and peel-off, trimmed away as wound heals by the epithelializing front. Another 
alternative are all the topical medications that need replacing or renewing daily or every other 
day.  
g. 
Foams  
Synthetic (i.e. polyurethane or silicone) foams may by more or less absorbent depending on 
their structure (large or small, open or partially open cells) and the additive materials (e.g. 
starch, SSD, silver) (i.e. Allevyn, Flexzan, Lyofoam, Sof-Foam). 
They may be considered as a farther development of more simple dressings such as: 
impregnated multilayer gauze, Polyurethane or gel film coated, hydrophilic or hydrophobic, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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semiocclusive, bilaminated dressings. Foam dressings offer most of the advantages of 
medicated gauze with a better absorption and protection in most cases. Very often they adhere 
to the bed (incorporation by ingrowths of granulation tissue and/or bonding by fibrin), creating 
the required adhering, moist environment and absorbing exudates from discharging wounds 
thus reducing the need for dressing changes. Foams provide also mechanical protection but in 
many cases their permeability can be obstructed by hardened exudates transforming them to 
opaque, occlusive dressings that are prone to infection. 
h. 
Films, permeable, non permeable 
These dressings, may be completely occlusive or permeable to gas and water vapors, but are a 
barrier to bacteria and water. Films, Semiocclusive/semipermeable made of polyurethane or 
copolyester, approximately 0.2 mm thick (Bioclusive, Polyskin II, OpSite, Tegaderm).  They 
are elastic and transparent but difficult to occlude larger that few cm2 areas. They are 
commonly used as occlusive dressings, sometimes with additional medicated gauze or topical 
medication underneath as a primary dressing, creating a microenvironment over the wound that 
can contain gazes (02, 03, or vacuum etc.) or medicaments. On clean beds they may adhere 
through the bonding effect of the wound exudates and fibrin but usually are transparent 
allowing easy assessment of the wound bed. When adhering to the bed they are generally 
reserved for the definitive closure of superficial, shallow partial thickness wounds where 
comfort and ease of management are important. The dressings can be left in place for several 
days, but their occlusive nature and accumulated exudates make them extremely prone for 
infection and daily monitoring is important. 
i. 
Hydrocolloids   
These dressings are non adhesive, water and gas impermeable membranes (Comfeel, Cutinova, 
DuoDERM, Intrasite, Replicare, Hyprapad Tegagel®, Intrasite etc.). Composed mainly of 
water held in a complex network or fibres that keep the polymer gel intact. Water is released to 
keep the wound moist.  
When the inner layer comes into contact with exudates, it forms a gel providing adequate 
moisture, the liquefied gel and exudates fill the dressing that has to be changed. If the dressing 
dries it may adhere to the bed interfering with healing and may damage, tear-off new 
epithelium when removed. Obviously the occluded moist atmosphere is prone to infection 
propagation and sometime to overhydration and maceration.  Hydrocolloids can be applied 
directly to clean wound but not on eschar or tendons. Perform dressing changes every 3 to 7 
days with saline irrigation cleans colloidal layer. Hypersensitivity to materials can develop. 
j. 
Aquacel (with or without Ag.) 
Soft non-woven pad made from sodium carboxymethylcellulose fibres. These Hydrofibres 
absorb exudates and fluids from the wound becoming a gel like material. Germs thus absorbed 
are eliminated from the wound surface but the dressing itself may dry to become a dry adherent 
shell. The desiccation may dry viable surface extending the original damage but the dry shell 
allows discharge before wound is closed with epithelial cells slowly separating the dry dressing 
from its bed.   
k. 
Alginates 
Composed of calcium alginate (a seaweed component). When in contact with wound, calcium 
in the dressing is exchanged with sodium from wound fluid and this turns dressing into a gel 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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that maintains a moist wound environment. Do not use on low exudating wounds as this will 
desiccate the wound. Dressing should be changed daily to avoid desiccation. 
E.g. Kaltostat, Sorbsan Alginates are derivatives of seaweed are in the form of dry non-woven 
mats, absorbing wound exudates to become a hydrophilic gel like hydrocolloids and behave in 
a similar way (Kaltostat, Sorbsan, Algosteril, AlgiSite, Kaltostat, Sorbsan etc.).  Jellified 
alginates are not adhesive, they are easily washed away but applied on a moist, clean bed they 
may strongly adhere to become a hard shell that will protect the wound but may slow the 
healing process and be hard to remove, injuring and stripping the healing bed. It is a strong 
hemostatic that can be used on bleeding wounds (post tangential excision or graft harvesting) 
but can interfere with healing later. A secondary wet dressing may prevent desiccation. 
Soaking and irrigation of the desiccated dressing will jellify it again and ease changing. 
Hypersensitivity to materials. Thyroid abnormalities can develop. 
l. 
Hydrogels-gelfoams 
These gels are usually based on starch polymers providing ample moisture (Carrasyn, Intrasite, 
Lamin, Nu-gel, Vigilon, etc.). Hydrogels are best suited to autolyse dry necrotic wounds, but 
they also absorb exudates while maintaining the products of tissue repair and degradation, 
including growth factors and lysosomes, in contact with the wound. If the wound is clean, the 
gel only needs to be replaced once or twice a week providing good healing conditions but these 
conditions are also favorable for infection propagation (especially gram negative bacteria). 
m. 
Negative Pressure Wound Therapy 
It is still a constantly evolving technology based on an occlusive dressing connected to a 
vacuum pump, containing a fibrous or foam matrix that distribute the sub-atmospheric pressure 
onto the wound bed. There are numerous similar available systems differing mainly in price 
and nature of matrix. Used initially mainly for chronic ulcers, it is quite effective as a 
secondary dressing to secure skin graft adherence and take.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 5- WOUND MANAGEMENT; APPROVED COVERS 
General remark: the guidelines of this appendix follow the ABA White Paper guidelines with 
detailed additions of some commonly used topical treatments.  
All dressings that are films, sheet-like (including biological dressings such as autografts, 
allograft and xenografts) and even foams, hydrocolloids and gauzes can become occlusive 
(sometimes by desiccated exudates) and pose danger associated with occlusion to healing 
wounds. It is recommended to perforate or mesh (without expansion) such dressings and if 
possible, apply a negative pressure dressing (e.g. VAC, etc.) on top of them for few days to 
ensure adherence and “take”). There are many additional dressings that strive to fulfill wound 
healing goals beside the approved to be used in the study detailed below. Some of them, 
beneficial as they may, are not standard. If the PI wishes to use then in this study, MediWound 
clinical department should be approached to verify and approve their use.  
Below is a list of the approved wound care products in the study which are all legally marketed 
in the US as detailed in the ABA guidelines. 
In the study protocol, there are 2 main categorizes of wound care products: 
Skin substitute [commercial product]: A biomaterial, engineered tissue or combination of 
materials and cells or tissues that can be substituted for skin autograft or allograft in a clinical 
procedure.  
Skin replacement: A tissue or graft that permanently replaces lost skin with healthy skin. 
 
Temporary Wound Coverage  
Temporary skin substitutes are used when the wound is too extensive to be closed in one stage 
because there is not enough donor skin available, because the patient is too ill to undergo the 
creation of another wound that results when skin is harvested from a donor site, because there 
is a question regarding the viability of the recipient bed, or because of a concern regarding 
potential infectious complications. The gold standard temporary skin substitute is cadaver 
allograft. Other temporary skin substitutes are used to provide transient wound coverage and 
to create a physiologically homeostatic environment such as- Skin Xenografts—also termed 
heterografts. 
Biobrane® is a silicone membrane pressed onto a flexible nylon fabric which has been coated 
with porcine dermal collagen. Used as a temporary wound cover, it is considered a dressing by 
the FDA and CPT Editorial Panel.  
Transcyte®, a related product, is not a dressing. It is classified as a temporary skin substitute 
and is composed of Biobrane® and cultured newborn human fibroblasts, which secrete growth 
factors and matrix proteins onto the wound surface. TransCyte® must be applied to a clean 
wound bed and monitored closely because it is prone to infection. It can be used in ways 
similar to Allograft and Xenograft.  
Permanent Wound Coverage  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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A full-thickness skin graft contains all components of the skin: epidermis, dermis, hair 
follicles and nerve endings. The most important advantage of full-thickness grafts is decreased 
scar formation; however, because there is no dermis to regenerate epithelial coverage, the 
donor site of a full-thickness skin graft must be closed either with primary direct closure or 
with a split-thickness skin graft; local advancement of skin flaps is a rarely used option. Full-
thickness grafts are thus usually used to cover small, functionally and cosmetically important 
areas (such as eyelids and digits).  
The split-thickness skin graft is the most common method used to achieve permanent wound 
coverage. It includes the entire epidermis but the dermal layer is split by the dermatome blade. 
With thicker split-thickness grafts, more dermis is transferred with the skin graft (such as 
15/1000 of inch or greater). This reduces the risk of scar formation at the recipient site, but it 
takes longer for the donor site to heal. Furthermore, the thicker the graft, the more likely the 
donor site will heal with a scar and the less likely the donor site may be reharvested for further 
grafts. 
There are a number of commercially available products to facilitate permanent wound 
coverage. Acellular human dermal allograft (Alloderm®) is devoid of epidermis and must 
be covered by a thin split-thickness autograft at the time of the initial operation; however, it 
replaces a portion of the missing dermis on the newly covered wound, thus reducing 
postoperative scarring. Another permanent wound coverage product is a dermal regenerative 
template (Integra®) constructed with bovine collagen and shark chondroitin sulfate with a 
silicone surface layer. This is applied to an excised wound bed that is well vascularized and 
free from infection, and provides wound coverage much like other skin substitutes; however, 
after the template becomes vascularized, it forms a neodermis (usually within 10 days to three 
weeks) and when the silicone layer is removed, an epidermal autograft (< 0.008 inch thickness) 
can be applied. This intermingling of autograft on a biosynthetic neodermis is permanent, 
unlike the wound coverage provided by temporary skin substitutes. This approach may be 
lifesaving and provides quality skin coverage.  
Cultured epidermal autograft (CEA; Epicel®), also referred to as “test tube” skin, was 
introduced by Rhinewald & Green in 1975 and is often employed to provide permanent skin 
coverage for patients with extensive burns.  
 
All of the above surgical or non surgical agents and covers are routinely used in the US, 
specified in the protocol and are allowed to be used in the proposed study based on the 
investigator’s medical judgment for the specific wound condition or patient. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 6- REGULATORY AND ETHICAL ISSUES 
Compliance with Regulations Applicable to Clinical Trials 
The study will be conducted according to the laws, regulations and administrative provisions 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use, as applicable by national legislation and EU Directives and 
US 21 CFR Part 11, 50, 54, 56, 312. 
This clinical trial will be registered on the “clinicaltrials.gov” clinical trial registry website as 
required by 42 USC 282(j) and the State of Maine’s PL 205, c. 392, §1. 
Informed Consent 
The principles of Informed Consent, conducted in accordance with Declaration of Helsinki and 
its updates, current Good Clinical Practice (GCP), the provisions of ICH (International 
Conference on Harmonisation); US Code of Federal Regulations (Title 21, CFR Part 50,) 
and/or EU Directives; local country regulations and the sponsor's Standard Operating 
Procedures (SOPs) will be followed. A subject is not allowed to enter a clinical study until 
he/she has been properly informed, has been given time to contemplate participation, and has 
freely given his/her consent by signing and dating the Ethics Committee/Institutional Review 
Board (EC/IRB) approved informed consent form.  This must be done prior to performing any 
study related procedures. 
The proposed consent form and any other documents relevant to the consent process must be 
submitted to the EC/IRB, together with the protocol, and must be approved prior to study start. 
A copy of the fully signed and dated Informed Consent Form and any other documents relevant 
to the consent process will be given to the subject and the original will be maintained at the 
site. 
Subject Confidentiality 
All subject data will be identified only by a subject identification number, subject initials (may 
be dummy) and date of birth.  
The investigator should keep the initials given in the “Subject Identification Log”. After 
obtaining subject’s consent, the investigator will permit the study monitor, independent auditor 
or regulatory agency personnel to review that portion of the subject’s medical record that is 
directly related to the study. This shall include all study relevant documentation including 
subject medical history to verify eligibility, laboratory tests results, admission/discharge 
summaries for hospital admissions occurring while the subject is on study, and autopsy reports 
for deaths occurring during the study (if applicable). 
Good Clinical Practice 
The study described in this protocol will be carried out according to the local regulatory 
requirements (FDA, EU, other) and ICH accepted standards of Good Clinical Practice. 
Ethics Committee (EC) / Institutional Review Board (IRB) 
The study must have unconditional approval in writing, by an appropriate Ethics 
Committee/Institutional Review Board (EC/IRB). A copy of the Letter of Approval from the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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EC/IRB, which contains specific identification of the documents approved, must be received 
by local Sponsor prior to site activation. 
Any amendments to the protocol or subsequent changes to the informed consent form as a 
result of changes to the protocol and/or investigator brochure that is approved by MediWound, 
must also be approved by the EC/IRB and documentation of this approval provided to 
MediWound. Records of the EC/IRB review and approval of all documents pertaining to this 
study must be kept on file by the investigator and are subject to the sponsor’s audit and/or 
regulatory authority inspection, during or after completion of the study.  
Serious adverse events (SAEs) must also be reported to the EC/IRB by the investigator or the 
sponsor according to local regulations. 
The investigator must submit a periodic status reports to their EC/IRB as required, as well as 
notification of completion of the study and a final report where applicable. A copy of all 
reports submitted to the EC/IRB must be sent to the sponsor. 
Protocol Amendments 
Protocol amendments must be prepared by sponsor or designee and approved by the sponsor, 
Competent Authorities (if applicable), Central EC/IRB and/or each respective site’s EC/IRB (if 
applicable), prior to implementation.  
Changes to the protocol can only be made by an approved protocol amendment. In case of 
urgent safety amendment ICH GCP guideline, should be followed. 
For clinical trial sites located in EU Member States, the procedures outlined in Directive 
2001/20/EC, Article 10(a), are applicable. 
Declaration of the End of the Clinical Trial 
For clinical trial sites located in EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC, Article 10(c) and for those 
countries outside EU local regulations will be followed. 
Liability And Insurance (If Applicable)  
A Certificate of Clinical Trials Insurance will be provided to the study centers by MediWound 
Ltd. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 7- STUDY ADMINISTRATIVE PROCEDURES 
This study will be conducted, recorded and reported according to ICH E6 requirements 
“Guideline for Good Clinical Practice” and its other implementing directives and guidelines.  
Study Site Initiation 
After the investigator files were updated with the following documents, the site may begin 
patient recruitment:  
1. CV and Medical License of the Principal Investigator, 
2. A signed and dated Investigator Protocol Agreement, 
3. A Financial Disclosure form, 
4. Signed Agreement between MediWound and the trial site, 
5. The laboratory certification or proficiency ratings, the normal ranges for laboratory 
determinations required by the protocol and the curriculum vitae of the laboratory director, 
6. A copy of competent authority written notification of protocol approval (EU sites), study-
specific informed consent form and any advertisements, notices or bulletins to be used in 
this study, 
7. A copy of the ethics committee/IRB approval,  
8. The ethics committee name, address and a list of ethics committee members including 
occupations and institutional affiliations, 
9. Signed Investigator Brochure receipt. 
 
Informed Consent 
Protection of clinical trial subjects will be performed as follows: 
A clinical trial may be undertaken only if the following elements are fulfilled: 
1. The study may be initiated only if the ethics committee and the competent authority come to 
a conclusion that the anticipated therapeutic benefit justifies the foreseeable risks and 
inconveniences.  
a. Prior to signing the informed consent, the trial subject had a discussion with the 
investigator or a member of the investigating team concerning the objectives, risks and 
inconveniences of the trial and the conditions and has been informed of his right to 
withdraw from the study at any time. 
b. Neither minor nor patients not being able to consent on their own are not included in the 
study However, legal representative may be involved in the Inform Consent procedure 
and sign the form if this is pre approved by the local IRB/EC and only for subjects with 
temporary medical conditions related to the injury, subjects who might be under the 
influence of pain medication, sedation, etc (see Section 8.1.1).   
c. The rights of the subject to physical and mental integrity, to privacy and to protection of 
the data concerning him are safeguarded. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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d. If the subject is unable to write, an oral consent in the presence of at least one witness 
may be given in exceptional cases, as provided in national legislation. 
e. Provision has been made for insurance or indemnity to cover the liability of the 
investigator and the sponsor. 
f. The medical care given to, and medical decisions made on behalf of, subjects shall be the 
responsibility of an appropriately qualified physician. The subjects shall be provided with 
a contact where he may obtain further information. 
2. In addition to the above restrictions the following elements are to be fulfilled in clinical 
trials on minors and incapacitated adults: 
a. The subject should receive information regarding the trial, the risks and benefits, from an 
experienced staff, 
b. The investigator should consider explicit wish of the subject who is capable of forming 
an opinion, to refuse participation or to be withdrawn from the clinical trial at any time, 
c. No incentives or financial inducements will be given except compensation, 
d. The study should relate directly to the clinical condition from which the subject 
concerned suffers, 
e. The study is designed to minimize pain, discomfort, fear and any other foreseeable risk, 
f. The ethics committee, with expertise in the relevant disease and the patient population 
concerned or after taking advice in clinical, ethical and psychosocial problems in the 
field in the subject’s population involved, has endorsed the protocol, 
g. The interests of the patient always prevail over those of science and society. 
 
3. The following issues should be included in the Informed Consent discussion and the written 
Informed Consent Form: 
a. A statement that the study involves research, 
b. Discussion with the subject should include: an explanation of the purposes of the 
 
research and the expected duration of the subject's participation, a description of the 
procedures to be followed and identification of any procedures that are experimental, 
c. The trial treatment(s) and the probability for random assignment to each treatment, 
d. Disclosure of any available alternative procedures or courses of treatment that might be 
advantageous to the subject, 
e. A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and that notes the possibility that the regulatory 
authorities, the institutional ethics committee or MediWound or designee may inspect the 
records, 
f. A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled and that the subject 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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may discontinue participation at any time without penalty or loss of benefits to which the 
subject is normally entitled, 
g. The subject’s responsibilities,  
h. A statement that the particular treatment or procedure may involve risks to the subject (or 
the embryo or fetus if the subject is, or may become, pregnant) that are currently 
unforeseeable, 
i. Anticipated circumstances under which the subject's participation may be terminated by 
the investigator without regard to the subject's consent,  
j. Any additional costs to the subject that may result from participation in the research,  
k. A statement that significant new findings developed during the course of the research, 
which may relate to the subject's willingness to continue participation, will be provided 
to the subject, 
l. The approximate number of subjects involved in the study, 
m. The person(s) to contact for further information regarding the trial and the rights of trial 
subjects. 
 
The Principal Investigator or designee is responsible for obtaining written informed consent 
from potential subjects prior to entry into the study. The investigator must keep each subject's 
signed consent form on file.  A copy of the signed document must be given to the subject. 
Competent Authority (CA)1 and the Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) 
This study must be approved by the CA (EU sites) and the ethics committee prior to patient 
enrollment.MediWound will obtain a EudraCT number before submitting an application to the 
CA. Each member state CA shall be provided with a list of CAs to which application was 
made, with a copy of their decisions as soon as it is available. 
The investigator must maintain an accurate and complete record of all submissions made to the 
CA including a list of all reports and documents submitted. The investigator agrees to promptly 
report to the ethics committee all unanticipated problems involving risks to human subjects or 
others.  
MediWound will inform the CA and the ethics committee of any new information relating to 
the conduct of the trial or the development of the IP where it is likely to affect the safety of 
subjects. Any safety measures taken should be reported to the authorities. Periodic status 
reports must be submitted at least yearly to the IRB/IEC.  
MediWound Ltd. shall notify the competent authorities of the member states concerned and the 
ethics committees that the clinical trial has ended within 90 days of the end of trial. If the trial 
has been terminated earlier than expected, notification should be made within 15 days and 
reasons clearly explained. 
                                                 
1 Relevant for sites located in the EU. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Electronic Case Report Forms (eCRFs) 
No data will be directly entered into the e-CRF without source documentation. 
The CRF is an integral part of the study and subsequent reports. The Case Report Form 
provided by MediWound Ltd. must be used to capture all study data recorded in the subject’s 
medical record. The CRF must be kept current to reflect subject status during the course of the 
study. Only a subject identification number and subject initials will be used to identify the 
subject. The investigator must keep a separate log of subject names and medical record 
numbers (or other personal identifiers). 
The protocol will use an Internet-Based Remote Data Entry System, primarily to collect 
clinical trial data at the investigational sites.  The system will comply with 21 CFR Part 11 and 
ICH E6. The system will be used to enter, modify, maintain, archive, retrieve, and transmit 
data. Paper source documents are to be retained to enable a reconstruction and evaluation of 
the trial. No original observations will be entered directly into the computerized system. Source 
documents include the hospital patient files and study worksheets provided by the Sponsor. 
Data will be recorded in the study worksheets as appropriate in order to complete and/or clarify 
source data. 
The design of a computerized system complies with all applicable regulatory requirements for 
record keeping and record retention in clinical trials (21 CFR Part 11 and ICH E6 Good 
Clinical Practice) to the same degree of confidence as is provided with paper systems. Clinical 
investigators must retain either the original or a certified copy of all source documents sent to a 
sponsor or contract research organization, including query resolution correspondence. The 
system is designed so that changes to any record do not obscure the original information.  The 
audit record clearly indicates that a change was made and clearly provides a means to locate 
and read the prior information. All changes to the data have an electronic audit trail, in 
accordance with 21 CFR 11.10(e). Electronic signatures will be used in conformance with 21 
CFR Part 11. 
Corrections are made in source documents by crossing out the error with a single line, making 
the correct entry in close proximity to the data field, then initialing and dating the strike-
through and the new entry. 
Maintenance of Study Files 
All essential documents listed in ICH Guideline CPMP/ICH/135/95 should be filed in an 
organized way that will facilitate management of the clinical trial and audit.  
Agreements between the involved parties, all Institutional Review Board correspondence 
including notification of protocol and consent form approval and all annual reports along with 
the final report to the IRB must be retained.   
Study records including patient source documents, Case Report Forms, all test results and 
signed informed consent forms must be kept on file by the investigator.   
Other documents pertaining to the conduct of the study including laboratory normal values, 
laboratory certification, monitor logs and telephone reports and all written correspondence 
must also be kept as part of the permanent record. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Storage conditions: Essential documents should be maintained in a legible condition and so 
that they can be promptly retrieved. Any change in the ownership and location of the 
documentation should be documented in order to allow tracking of stored records. 
The investigator should make the sponsor aware of the storage arrangements for the 
documents. If the investigator for any reason cannot keep the study records, MediWound Ltd. 
should be notified in writing so that alternative arrangements can be agreed upon. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending applications or at least 2 years elapsed 
since the formal discontinuation of clinical development of the investigational product. It is the 
responsibility of the MediWound Ltd. to inform the investigator/ institution as to when these 
documents no longer need to be retained. 
These regulations are described in: Detailed Guidelines on Trial Master File and Archiving – 
July, 2006. 
Monitoring Procedures 
Investigational sites will be monitored periodically to assure satisfactory patient enrollment, 
data recording and protocol adherence. The frequency of monitoring may vary depending on 
enrollment rate and the quantity of data collection.  The investigator and staff are expected to 
cooperate with the study monitor and provide to study monitor all relevant study 
documentation.  It is essential that the investigator and study coordinator set aside a sufficient 
amount of time for these visits to permit an adequate review of the study's progress and of 
completed Case Report Forms. 
Changes in Study Personnel  
The ‘Authorization Signature Log’ which is a list of appropriate qualified persons to whom the 
Principal Investigator has delegated significant trial-related duties, should be updated if there is 
a change or addition of any personnel initially listed. CVs and other relevant documents 
evidencing qualifications should be provided to MediWound Ltd. 
On-Site Inspections/Audits 
In accordance with section 1.29 in ICH E6 inspections may be requested and coordinated by 
the European Medicines Agency or the FDA. Inspections may take place at various times: 
before, during and/or after the conduct of the clinical trial. The investigator and staff are 
requested to cooperate with all such audits. The investigator must notify MediWound Ltd. of 
any expected inspection as soon as possible. A representative or designee of MediWound, Ltd. 
Clinical Research Department, may also conduct similar auditing procedures. 
Disclosure and Publication of Information 
All proprietary information including: MediWound Ltd. operations, patent applications, 
formulas, manufacturing processes, basic scientific data and formulation information provided 
to the investigator or the methodologies used in this study, as well as proprietary information 
obtained during the course of the study are confidential and will remain the sole property of 
MediWound Ltd.  The investigator agrees not to disclose any proprietary information supplied 
by MediWound Ltd. in any way without prior written permission. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Individual patient data obtained during this study are confidential and will not be disclosed to 
third parties with the following exceptions: 
When the data is needed by a patient's personal physician or other medical personnel 
responsible for the patient's welfare, 
For data inspection and verification by MediWound Ltd. or designee, European Medicine 
Agency inspectors or by the Institutional Review Board (IRB). 
Any manuscript or abstract produced by an investigator must be provided to MediWound Ltd. 
for review 45 days prior to submission. Individual patient identity must not be divulged in any 
publication. 
Protocol Changes or Amendments 
The investigator also agrees not to make any changes in the study protocol or its conduct 
except when necessary to prevent immediate hazards to human life.   
Substantial amendments in protocol may be made only by written amendment by the 
MediWound Ltd. Substantial amendment to the conduct of the clinical trial may arise from 
changes in the protocol that have impact on safety or physical or mental integrity of the 
subjects, the scientific value of the trial, conduct or management of the trial or the quality or 
safety of any IP used in the trial. The Ethics committee and the competent authority must 
approve protocol amendments prior to implementation.  Documentation of IRB/IEC approval 
for such amendments must be kept on file by the investigator and forwarded to MediWound 
Ltd. 
Notification to the ethics committee/IRBs and the competent authorities (EU sites) on non-
substantial amendments should follow the local regulatory policies. Such amendments should 
be recorded and be available for inspection. 
These regulations are described in: Detailed Guidance for the request for authorization of a 
clinical trial on a medicinal product for human use to the competent authorities, notification 
and substantial amendments and declaration of the end of the trial – April, 2002. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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APPENDIX 8- BIOPSY & HISTOLOGIC ASSESSMENT METHOD 
Burn Wound Infection - Biopsy & Histologic Assessment Method  
1. Using a scalpel, a 500 mg lenticular sample of eschar and underlying, unburned 
subcutaneous tissue is harvested from the area of the burn wound showing the most marked 
changes characteristic of infection.   
2. If local anesthetic is required, it should be injected around the planned margin of the biopsy 
to minimize distortion of the architecture of the biopsied tissue.   
3. One-half of the specimen is sent to the quantitative microbiology laboratory for culture and 
antibiotic sensitivity determinations, and the other half of the specimen is processed for 
histologic examination by a frozen section technique (requiring 45 minutes) or a rapid 
section technique (requiring 3.5 to 4.0 hours).   
4. If the frozen section technique is utilized, the tissue should be subsequently processed by 
rapid section technique for definitive examination, since the frozen section method is 
associated with a 3.6% false-negative rate which can be corrected by careful examination of 
permanent sections. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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APPENDIX 9- PAIN MEASUREMENT SCALE 
Pain scores will be measured using a Visual Analogue Scale (VAS) for the adult population at 
the required timelines. VAS is a measurement instrument that tries to measure a characteristic 
or attitude that is believed to range across a continuum of values and cannot easily be directly 
measured.  
As illustrated in Figure 2, the patient marks on the line (100 mm line), the point that they feel 
represents their perception of their current state. The VAS score is determined by measuring in 
millimeters from the left end of the line to the point that the patient marks. 
Figure 2- Visual Analogue Scale 
 
 
 
No Pain 
Worst Pain Ever 
No Pain 
Worst Pain Ever 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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APPENDIX 10- PROCEDURES FOR SPECIFIC BLOOD TESTS 
Immunogenicity blood Samples 
Serum samples for antibodies to NexoBrid will be obtained prior to application (time 0), and at 
the following time points:  
 At day 7±2 days (week 1 visit) from start of treatment, 
 At day 28±7 days (week 4 visit) from start of treatment, 
 At day 56±14 days (week 8 visit) from start of treatment. 
 At the 6 months FU visit 
 At the 24 months FU visit  
 
The blood sampling should be taken after an overnight fast (at least 8 hours if possible) at 
about the same time of the day (± 2 hours and before noon) due to potential daily fluctuations 
in the levels of immunological responses. The serum samples will be kept at (-) 20oC until 
delivery for analysis.  
Sample preparation procedures are as follows: 
1. For each immunogenicity sample at each time point, draw 3 ml whole blood into a 5 ml pre-
labeled tube and check the label for subject number, time point, and type of test. 
2. Place the tube in the refrigerator at 2-8oC for 0.5hrs - 2 hours for clotting. Important Note: Do 
not leave the serum with the clot longer than 2 hours in the refrigerator or at room 
temperature.  
3. Centrifuge the sample at a minimum of 1100 g for 10 minutes, at ambient temperature for red 
blood cells sedimentation.  
4. Divide the serum equally (the upper liquid layer, approximately 1.5 ml) into four pre-labeled 
1 ml conical bottom cryotubes resulting in at least 0.3 ml serum each. Check the subject 
number, time point, and type of test and fill DATE and TIME, 2 cryotubes will be used for 
analysis and 2 for backup.  
5. Store the cryotubes at (-) 20 ± 5 oC or below until shipped for analysis at Covance.  
6. The shipment of samples will be in (-) 20 ± 5 oC or below.  
If possible, storage and shipment are preferred in (-) 70o±10°C conditions.  
7. The set of 2 samples for analysis should be shipped to Covance first. The samples should be 
sent at the end of the study. Please contact your CRA when shipment is required.  
8. The second set of samples (backup) should be dispatched to Covance in a subsequent and 
separate shipment, after confirmation that the first set has been received, but only if asked by 
the lab. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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Procedures for Pharmacokinetic Samples 
PK samples will be obtained prior to application (time 0), and at the following time points:  
1, 2, 4, 12, 24 and 48 hrs post start of the treatment. 
Please carefully follow the procedure below for handling the PK blood samples: 
1. For each PK sample at each time point, draw 2 ml whole blood into a 5 ml pre-labeled tube and 
check the label for subject number, time point, and type of test. 
2. Place the tube at room temperature for approximately 30 minutes for clotting.  
3. Store the sample at refrigeration (2-8 ºC) for approximately 120 minutes. 
4. Following the refrigeration period, Centrifuge the sample for approximately 20 minutes at 2800 
to 3000 x g at a temperature of 2-8 ºC. 
5. Divide the serum equally (the upper liquid layer) into pre-labeled 1 ml conical bottom cryotubes. 
Check the subject number, time point, and type of test and fill DATE and TIME. 
6. Store the cryotubes in (-) 20 ± 5 ºC or below until shipment for analysis at Quintiles. The 
shipment of samples will be in (-) 20 ± 5 ºC or below.  
7. If possible, storage and shipment are preferred in (-) 80 ± 10°C conditions.  
8. The samples should be shipped to Quintiles after 4 patients completed the 48hrs  test, but no 
more than 10 months post first sample was drawn (in that case you may send samples of less 
than 4 patients). Please contact your CRA when shipment is required. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 142 of 169 
 
 
  
 
 
 
142 
APPENDIX 11- BURN PATIENTS: POTENTIAL ADVERSE EVENTS 
Cardiovascular 
Hypotension 
(decrease of either 
systolic or diastolic 
for >/= 2hrs) 
Pressor or inotrope 
requirement for 
normotension 
Sinus tachycardia 
Dysrhythmia 
Hypertension 
Pulmonary 
Tachypnea 
Pulmonary edema 
Pneumonia 
Pneumothorax 
Pleural Effusions 
Atelectasis 
Pulmonary 
Infiltrates 
Inhalation injury 
and/or airway (req. 
intubation) 
Respiratory failure 
Neurological 
Mental status 
changes 
Sedation 
Confusion/delirium 
Substance 
withdrawal 
GI 
Nausea 
Vomiting (>/= 
2/shift or >/= 
6/day) 
Diarrhea (>/= 
2/shift or >/= 
6/day) 
Constipation 
Ileus during bum 
shock 
Renal 
Acute renal failure 
(BUN >/= 24; Cr 
>/= 1.19) 
Renal failure 
 
Urinary tract infections 
Urinary tract infection, 
early 
Urinary retention 
Fluctuation in UOP during 
burn resuscitation 
«1mllkg/hr for 2 hrs) 
Blood 
Anemia (chronic or acute) 
(based on hemoglobin 
gm/dL) 
Thrombocytopenia (plt </= 
145,000) 
Thrombocytosis (plt >/= 
350) 
C-Reactive Protein (>/=30) 
Mild 
coagulopathy 
as 
evidenced by ele PT/PTT 
(PT> 12.3, PTT>36.5) 
Asymptomatic electrolyte 
imbalance 
(see 
norm 
ranges) 
Hyperglycemia 
(glycosuria, insulin drip) 
Leukocytosis 
WBC 
2: 
highest normal range 
Leukopenia WBC ~lowest 
normal range 
Other hematologic 
Coagulopathy 
ODE III/DDDP 
Mise 
Pain from primary injury 
Pruritis 
Microbial colonization of 
burn wounds 
Wound infection 
Other infection 
 
Excision and grafting of burn injury 
Graft loss «/= to 10% ofthe extent 
grafted) 
Hands 
Sepsis / septicemia 
Line infection 
Compartment syndrome (extremity) 
Hypothermia «37.2C for 2hrs) 
Hyperthermia (>/=39.5C) 
Amputation of extremities/digits 
from deep burn 
Cellulitis 
Traumatic injury 
Graft site contracture requiring 
release or revision 
Death 
Multiple organ failure / multi-system 
organ failure 
Permanent neuro/vascular deficit not 
r/t sev of inj 
Unplanned surgical intervention 
Autografting to donor site for failure 
to heal 
Repeat autografting to same body site 
(>10% org grafted) 
Auto Graft/regraft 
CSS regraft 
Intubation due to declining 
respiratory status not related to 
edema or inhalation injury 
Acute Respiratory Distress Syndrome 
(ARDS) 
Abdominal Compartment Syndrome 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 143 of 169 
 
 
  
 
 
 
143 
APPENDIX 12- COSMESIS, FUNCTION AND QUALITY OF LIFE QUESTIONNAIRES  
Modified Vancouver Scar Scale (MVSS) 
The six parameters listed below are evaluated on a point system (please tick the correct 
answer): 
1. Pigmentation 
□ (0) Normal 
□ (1) Hypopigmented 
□ (2) Mixed 
□ (3) Hyperpigmented 
2. Pliability  
□ (0) Normal 
□ (1) Supple- flexible with minimal resistance 
□ (2) Yielding- giving way to pressure 
□ (3) Firm- inflexible, not easily moved, resistant to manual pressure 
□ (4) Banding- rope- like tissue that blanches with extension of the scar 
□ (5) Contracture- permanent shortening of scar, producing deformity or distortion 
3. Height  
□ (0) Flat 
□ (1) <2mm 
□ (2) 2 to 5mm 
□ (3) >5mm 
4. Vascularity  
□ (0) Normal 
□ (1) Pink 
□ (2) Red 
□ (3) Purple 
5. Pain 
□ (0) None 
□ (1) Occasional 
□ (2) Requiring medication 
6. Pruritus 
□ (0) None 
□ (1) Occasional 
□ (2) Requiring medication 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 144 of 169 
 
 
  
 
 
 
144 
 
Patient and Observer Scar Assessment Scale (POSAS) 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 145 of 169 
 
 
  
 
 
 
145 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 146 of 169 
 
 
  
 
 
 
146 
EQ-5D (QoL) 
EQ-5D is a standardized measure of health status developed in order to provide a simple, generic 
measure of health for clinical and economic appraisal. Applicable to a wide range of health conditions 
and treatments, it provides a simple descriptive profile and a single index value for health status that can 
be used in the clinical and economic evaluation of health care as well as in population health surveys. 
EQ-5D is designed for self-completion by respondents and is ideally suited for use in postal surveys, in 
clinics, and in face-to-face interviews. 
EQ-5D essentially consists of 2 pages - the EQ-5D descriptive system (Figure 3) and the EQ visual 
analogue scale (EQ VAS) (Figure 4). The EQ-5D descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 3 levels: no problems, some problems, severe problems. The respondent is asked to indicate his/her 
health 
state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 
dimensions. This decision results in a 1-digit number expressing the level selected for that dimension.  
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale where the 
endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 147 of 169 
 
 
  
 
 
 
147 
Figure 3- EQ-5D Descriptive system 
 
EQ-5D (UK English version) 
By placing a tick in one box in each group below, please indicate which statements best describe your 
own health state today. 
 
Mobility 
I have no problems in walking about  
 
 
� 
I have some problems in walking about  
 
 
� 
I am confined to bed   
 
 
 
� 
 
Self-Care 
I have no problems with self-care  
 
 
� 
I have some problems washing or dressing myself  
 
� 
I am unable to wash or dress myself  
 
 
� 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities  
� 
I have some problems with performing my usual activities  
� 
I am unable to perform my usual activities   
 
� 
 
Pain/Discomfort 
I have no pain or discomfort  
 
 
 
� 
I have moderate pain or discomfort  
 
 
� 
I have extreme pain or discomfort  
 
 
� 
 
Anxiety/Depression 
I am not anxious or depressed  
 
 
 
� 
I am moderately anxious or depressed  
 
 
� 
I am extremely anxious or depressed  
 
 
� 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 148 of 169 
 
 
  
 
 
 
148 
To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
WE WOULD LIKE YOU TO INDICATE 
ON THIS SCALE HOW GOOD OR BAD 
YOUR OWN HEALTH IS TODAY, IN 
YOUR OPINION. PLEASE DO THIS BY 
DRAWING A LINE FROM THE BOX 
BELOW TO WHICHEVER POINT ON THE 
SCALE INDICATES HOW GOOD OR BAD 
YOUR HEALTH STATE IS TODAY. 
To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
WE WOULD LIKE YOU TO INDICATE 
ON THIS SCALE HOW GOOD OR BAD 
YOUR OWN HEALTH IS TODAY, IN 
YOUR OPINION. PLEASE DO THIS BY 
DRAWING A LINE FROM THE BOX 
BELOW TO WHICHEVER POINT ON THE 
SCALE INDICATES HOW GOOD OR BAD 
YOUR HEALTH STATE IS TODAY. 
 
Figure 4- EQ visual analogue scale (EQ VAS) 
 
Your 
own 
health 
state


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 149 of 169 
 
 
  
 
 
 
149 
Burn Specific Health Scale-Brief 
 
 
extreme(ly)  
quite a bit 
moderate(ly) 
a little bit 
None (not at all) 
1. Bathing independently 
 
 
 
 
 
2. Dressing by yourself 
 
 
 
 
 
3. Getting in and out of a chair 
 
 
 
 
 
4. Signing your name 
 
 
 
 
 
5. Eating with utensils 
 
 
 
 
 
6. Tying shoelaces, bows, etc 
 
 
 
 
 
7. Picking up coins from a flat surface 
 
 
 
 
 
8. Unlocking a door 
 
 
 
 
 
9. Working in your old job performing your old duties 
 
 
 
 
 
10. I am troubled by feelings of loneliness 
 
 
 
 
 
11. I often feel sad or blue 
 
 
 
 
 
12. At times, I think I have had an emotional problem 
 
 
 
 
 
13. I am not interested in doing things with my friends 
 
 
 
 
 
14. I don’t enjoy visiting people 
 
 
 
 
 
15. I have no one to talk to about my problems 
 
 
 
 
 
16. I have feelings of being trapped or caught 
 
 
 
 
 
17. My injury has put me further away from my family 
 
 
 
 
 
18. I would rather be alone than with my family 
 
 
 
 
 
19. I don’t like the way my family acts around me 
 
 
 
 
 
20.My family would be better off without me 
 
 
 
 
 
21. I feel frustrated because I cannot be sexually aroused as well as I 
d
 
 
 
 
 
22. I am simply not interested in sex any more 
 
 
 
 
 
23. I no longer hug, hold or kiss 
 
 
 
 
 
24. Sometimes, I would like to forget that my appearance has changed 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 150 of 169 
 
 
  
 
 
 
150 
25. I feel that my burn is unattractive to others 
 
 
 
 
 
26. My general appearance really bothers me 
 
 
 
 
 
27. The appearance of my scars bothers me 
 
 
 
 
 
28. Being out in the sun bothers me 
 
 
 
 
 
29. Hot weather bothers me 
 
 
 
 
 
30. I can’t get out and do things in hot weather 
 
 
 
 
 
31. It bothers me that I can’t get out in the sun 
 
 
 
 
 
32. My skin is more sensitive than before 
 
 
 
 
 
33. Taking care of my skin is a bother 
 
 
 
 
 
34. There are things that I’ve been told to do for my burn that I dislike 
d i
 
 
 
 
 
35. I wish that I didn’t have to do so many things to take care of my burn 
 
 
 
 
 
36. I have a hard time doing all the things I’ve been told to take care of my 
b
 
 
 
 
 
37. Taking care of my burn makes it hard to do other things that are 
i
 
 
 
 
 
38. My burn interferes with my work 
 
 
 
 
 
39. Being burned has affected my ability to work 
 
 
 
 
 
40. My burn has caused problems with my working 
 
 
 
 
 
.. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 151 of 169 
 
 
  
 
 
 
151 
QuickDASH 
QuickDASH outcome measure for burns in the upper extremities. The Disabilities of the Arm, 
Shoulder and Hand (DASH) Outcome Measure is a 30-item, self-report questionnaire designed 
to measure physical function and symptoms in patients with any or several musculoskeletal 
disorders of the upper limb. The questionnaire was designed to help describe the disability 
experienced by people with upper-limb disorders and also to monitor changes in symptoms and 
function over time. Testing has shown that the DASH performs well in both these roles. 
It gives clinicians and researchers the advantage of having a single, reliable instrument that can 
be used to assess any or all joints in the upper extremity. 
The DASH Outcome Measure contains two optional, four-item modules intended to measure 
symptoms and function in athletes, performing artists and other workers whose jobs require a 
high degree of physical performance. Because they may be having difficulties only at high 
performance levels–which are beyond the scope of the 30-item DASH Outcome Measure–
clinicians may find the modules, which are scored separately from the DASH, useful in 
assessing these special patients.  
The DASH Outcome Measure was jointly developed by the Institute for Work & Health and 
the American Academy of Orthopaedic Surgeons (AAOS). The project was supported by the 
American Association for Hand Surgery, the American Orthopaedic Society for Sports 
Medicine, the American Shoulder & Elbow Surgeons, the American Society for Surgery of the 
Hand, the Arthroscopy Association of North America and the American Society of Plastic and 
Reconstructive Surgeons. 
The QuickDASH is a shortened version of the DASH Outcome Measure. Instead of 30 items, 
the QuickDASH uses 11 items to measure physical function and symptoms in persons with any 
or multiple musculoskeletal disorders of the upper limb. Like the DASH, the QuickDASH also 
has two four-item optional modules that are scored separately. The QuickDASH was found to 
be valid and repeatable in patients with upper limb burns and supports the use of the 
QuickDASH in this population to help assess change in functional level [100-101]. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 152 of 169 
 
 
  
 
 
 
152 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 153 of 169 
 
 
  
 
 
 
153 
Lower Extremity Functional Scale test (Binkley et al, 2011) 
The Lower Extremity Functional Scale (LEFS) is a questionnaire containing 20 questions 
about a person’s ability to perform everyday tasks. The LEFS can be used by clinicians as a 
measure of patients' initial function, ongoing progress and outcome, as well as to set functional 
goals. The LEFS can be used to evaluate the functional impairment of a patient with a disorder 
of one or both lower extremities. It can be used to monitor the patient over time and to evaluate 
the effectiveness of an intervention.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 154 of 169 
 
 
  
 
 
 
154 
 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 155 of 169 
 
 
  
 
 
 
155 
APPENDIX 13- ASA CLASSIFICATION SYSTEM 
 
The ASA physical status classification system is a system for assessing the fitness of patients 
before surgery. These are: 
ASA Physical Status 1 - A normal healthy patient 
ASA Physical Status 2 - A patient with mild systemic disease 
ASA Physical Status 3 - A patient with severe systemic disease 
ASA Physical Status 4 - A patient with severe systemic disease that is a constant threat to life 
ASA Physical Status 5 - A moribund patient who is not expected to survive without the 
operation 
ASA Physical Status 6 - A declared brain-dead patient whose organs are being removed for 
donor purposes 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
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156 
APPENDIX 14- RANGE OF MOTION 
In this study, passive ROM will be measured in which the motion is being created by the 
patient contracting the muscles around the joint. A goniometer will be used in this study to 
measure joint angles (joint range of motion).  
Instructions for using a goniometer 
1. Align the fulcrum of the device with the joint to be measured 
2. Align the stationary arm of the device with the limb being measured 
3. Hold the arms of the goniometer in place while the joint is moved through its range of 
motion. 
The degree between the endpoints represents the entire range of motion. 
Important tips: 
1. Stabilize the stationary of the body. This is the part of the body that is proximal (closer to the 
midline of the body) to the joint you are testing. It is important that the patient does not move 
his body while moving the joint; this step isolates the joint movement for a more accurate 
measurement. 
2. Look at the reading on the goniometer before moving it from the patient’s body. Ensure that 
you take an accurate reading of the degree of motion on the geometer, and that you 
consistently use the same stationary and movable landmarks on the body when measuring, to 
ensure consistency. Be sure to record the range of motion for the joint. 
Range of Motion measurements 
16.1.1.1 Shoulder Joint 
The shoulder joint has the following normal ranges of movement: Flexion, Extension, 
Adduction, Abduction and Medial Rotation. Flexion, Extension, Adduction and Abduction will 
be measured: 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 157 of 169 
 
 
  
 
 
 
157 
Shoulder normal ranges: 
Movement 
Degree 
Description 
Flexion (Vertical) 
180° 
Raise arm straight forward 
Extension 
(Vertical) 
60° 
Raise arm straight backward 
Abduction 
90° 
Bring arm up sideways 
Adduction 
45° 
Bring arm toward the midline of the 
body 
 
Elbow joint 
The elbow joint has the following normal ranges of movement: Flexion, Extension, Pronation 
and Supination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elbow normal ranges: 
Movement 
Degree 
Description 
Flexion 
150° 
Bring lower arm to the biceps 
Extension 
180° 
Straighten out lower arm 
Pronation 
90° 
Turn lower arm so palm faces down 
Supination 
90° 
Turn lower arm so palm of hand faces 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 158 of 169 
 
 
  
 
 
 
158 
up 
Wrist joint 
The wrist joint has the following normal ranges of movement: Flexion, Extension, Adduction, 
Abduction and Circumduction. Flexion, Extension, Adduction and Abduction will be 
measured: 
 
 
 
 
 
 
 
Wrist normal ranges: 
Movement 
Degree 
Description 
Flexion 
80-90° 
Bend wrist so palm nears lower arm 
Extension 
70° 
Bend wrist in opposite direction 
Abduction 
20° 
Bend wrist so thumb nears radius 
Adduction 
30-50° 
Bend wrist so pinky finger nears ulna 
 
Palm and Fingers 
Normal ranges of the palm & fingers joints will include the following joints (see Figure 5):  
 The fingers IP joints;  
o Distal Interphalangeal (DIP) joints 
o Proximal Interphalangeal (PIP) joints 
  The thumb joints; 
o Proximal Interphalangeal (PIP) joint 
o Metacarpophalangeal (MTP) joint 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 159 of 169 
 
 
  
 
 
 
159 
 
 
 
 
 
 
 
 
 
Figure 5- Hand fingers joints 
 
Joints normal ranges: 
Movement 
Degree 
Description 
Thumb IP 
Hyperextension/Flexion 
0/80 
Thumb MTP 
Hyperextension/Flexion 
0/55 
Finger DIP joints 
Extension/Flexion  
0/60  
Finger PIP joints 
Extension/Flexion  
0/100 
Finger MCP joints (see 
Figure 6) 
Hyperextension/Flexion 
10/90 
 
 
 
 
 
 
 
 
 
Figure 6- Finger MCP hyperextension (a) and flexion (b) 
 
a 
b 
MTP 
j i
MTP
PIP 
jointsPIP 
DIP jointsDIP 
joints
 
 
 
a 
b 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 160 of 169 
 
 
  
 
 
 
160 
Knee joint 
The knee joint has the following normal ranges of movement: Flexion and Extension. 
 
 
 
 
 
 
Knee normal ranges: 
Movement 
Degree 
Description 
Flexion 
130° 
Touch calf to hamstring 
Extension 
15° 
Straighten out knee as much as 
possible 
 
Ankle joint 
The ankle joint has the following normal ranges of movement: Plantar Flexion, Dorsi Flexion, 
Inversion and Eversion. Dorsi and Plantar flexion will be measured in this study: 
 
 
 
 
 
 
 
Knee normal ranges: 
Movement 
Degree 
Description 
Flexion 
45° 
Bend ankle so toes point up 
Extension 
20° 
Bend ankle so toes point down 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 161 of 169 
 
 
  
 
 
 
161 
 
 
APPENDIX 15- BLINDED ASSESSOR MEMO- SAMPLE 
In accordance with study protocol, for patients who are randomized to one of the topical arms, 
NexoBrid or Gel Vehicle, eschar removal assessment will be done by assessor blinded to the 
treatment arm. This assessor will evaluate eschar removal in all study arm (but will be blinded 
only to the topical arms) and for all procedures until complete eschar removal.  
In addition, weekly evaluations of wound closure and long term cosmesis and function will be 
done by a second assessor blinded to all treatment arms.  
The following procedures and assessments will be performed by the blinded assessors at the 
following time-points:  
First blinded assessor:  
Eschar Removal assessment- For the topical arms (NexoBrid/Gel Vehicle), eschar removal 
assessment will be performed immediately following removal of the soaking dressing (6 hours 
after start of 1st and 2nd treatment and after any additional procedure until complete eschar 
removal. The assessment will include photograph, wound depth assessment and clinical 
assessment of the extent of eschar removal.  
Eschar removal in the SOC arm will be evaluated by the same assessor, but he will not be 
blinded to the SOC arm.  
Second blinded assessor (blinded to all treatment arms): 
Weekly follow up visits and wound closure confirmation visit-  
The following procedures will be performed by the blinded assessor: 
o All wounds should be photographed.   
o Clinical assessment of % of target wound area epithelialized and/or closed by graft and 
assessment of % donor site epithelialized, 
o Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment  
Long term follow up visits-  
The following procedures will be performed by the blinded assessor: 
o 
All wounds should be photographed.   
o 
The following questionnaires will be filled by the blinded assessor: 
 
Patient and Observer Scar Assessment Scale (POSAS) 
 
A modified Vancouver Scar Scale (MVSS) 
o 
Range of Motion measurements (injured and non-injured joints) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 162 of 169 
 
 
  
 
 
 
162 
In order to maintain the blinding, the sponsor would like your site to implement measures, as 
best as possible, to ensure that the blinded assessors will not be aware of the treatment 
assignments for the duration of the study. The blinded assessors should not be involved with 
product application and PK and Immunogenicity blood sampling should not be taken at the 
same time of the blinded assessment. 
The topical (NexoBrid/Gel Vehicle) treatment allocation will not be accessible through the 
subject’s electronic case report forms. Paper source documents that could unblind the assessor 
will be kept in a separate folder, appropriately labeled. The blinded assessor should not review 
subject’s data that will include randomization reports, PK and Immunogenicity blood 
collection, drug accountability records, and any other data that could unblind the assessor for 
the topical arms. In addition, all Investigational Products (used and unused) should be stored, 
dispensed, and administered out of the sight of the blinded assessor.  
Treatment allocation to the SOC group cannot be reconciled from all eCRFs and SD. The 
weekly and long term follow up set of source documents worksheets are in separated sections 
and not reviling the treatment arm. 
The second blinded assessor who evaluates the weekly and long term effects of the treatment 
should not review other sections of source worksheets and will not access to eCRFs. 
The Sponsor's medical team will be blinded to the topical arms treatment, and can provide 
support blindly when needed during the eschar removal treatment.  
You are being required to sign this memo to acknowledge and certify that you will make all 
attempts to comply with these requirements. 
Acknowledgement (To be signed at the start of the study): 
 I acknowledge that I fully understand my role in maintaining the blind and assure that I will 
not access subject’s data except for the information relevant to the conduct the blinded 
assessments listed above. 
 
Eschar removal assessor:  
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 Wound closure, cosmesis and function assessor: 
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 
 
Certification (To be signed at completion of study):  
I certify and confirm that I did not review subject’s data except for the information relevant to 
the conduct of the blinded assessments. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 163 of 169 
 
 
  
 
 
 
163 
 
Eschar removal assessor:  
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 Wound closure, cosmesis and function assessor: 
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 164 of 169 
 
 
  
 
 
 
164 
APPENDIX 16- TREATMENT DIAGRAM 
 
 
 
 
 
 
 
 
  
Complete 
Failure 
Failure <50% 
eschar removal 
Complete eschar 
removal 
 >50% 
eschar 
removal 
but 
not complete 
Randomization 
Treatment assignment per randomization 
Applying NexoBrid/Gel Vehicle - 4hrs treatment, 
removal of remnants and 2 hrs soaking 
Blinded assessment of eschar removal 
efficacy  
Assessment of eschar removal efficacy 
Applying 2nd application of NexoBrid/Gel 
Vehicle - 4hrs treatment, removal of 
remnants and 2 hrs soaking 
Cleansing & Soaking for at least 2 hrs 
‘Moving’ from the Eschar Removal phase 
to the Wound Management phase (wound 
closure procedure phase, consequent 
treatment up to hospital discharge and 
continued follow up for long term 
assessment) 
Additional surgical and/or non surgical procedures will be repeated until complete Eschar Removal: 
- Surgical procedures may include tangential/ minor/ avulsion/ Versajet/ Dermabrasion excision.  
 -Non-surgical procedures may include collagenase (e.g. Santyl) antimicrobial treatment using), 
antimicrobial solutions (i.e. Dakin’s Solution, Sulfa-Nystatin Solution), antimicrobial ointments (i.e. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (i.e. Mepilex Ag, Aquacel Ag, Acticoat).  
Complete eschar removal 
SOC – surgical and/or non surgical 
procedure 
Complete eschar 
removal 
 Eschar 
removal not 
complete 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 8- 22 February 2015 
Page 165 of 169 
 
 
  
 
 
 
165 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
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compared to Gel Vehicle and compared to Standard of Care 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
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compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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SAP_003.pdf: 
 
ADDENDUM TO STATISTICAL ANALYSIS 
PLAN 
 
Clinical Trial 
 
A multicenter, multinational, randomized, controlled, assessor blinded study, performed in 
subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid compared to Gel 
Vehicle and compared to Standard of Care (MW 2010-03-02) DETECT) 
 
 
 
Sponsor: 
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Trial protocol code: MW2010-03-02 
EudraCT number: 2014-001672-55 
IND No.: 65,448 
 
 
Competence Center for Clinical Trials Bremen - Biometry 
Author: Dr. Martin Scharpenberg 
Version of 23 August 2020, Addendum 2 to Version V03 
 


DETECT - Protocol Code: MW2010-03-02 
Page 2 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
1. Table of Contents 
1. 
Table of Contents 
2 
2. 
Study Administrative Structure 
3 
2.1. 
Sponsor 
3 
2.2. 
Study Conduct 
3 
2.3. 
Statistics 
4 
3. 
Signatures 
5 
4. 
List of Abbreviations 
6 
5. 
Rationale for the Addendum 
7 
6. 
Handling of missing values 
8 
7. 
Analysis of Safety Endpoint Cosmesis and Function at 24 months 
9 
7.1. 
Handling of data from earlier/delayed visits 
9 
7.2. 
Handling of remotely captured data 
10 
8. 
Exploratory and Subgroup Analyses of MVSS and POSAS 
11 
9. 
Further analyses 
12 
10. 
Attachment: Note to file 
13 
 


DETECT - Protocol Code: MW2010-03-02 
Page 3 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
2. Study Administrative Structure 
2.1. Sponsor 
Sponsor: 
MediWound, Ltd 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Represented by: 
Prof. Lior Rosenberg 
Chief Medical Officer 
MediWound Ltd. 
 
 
Keren David Zarbiv 
VP Clinical Affairs 
MediWound Ltd. 
 
 
Nimrod Leuw 
 VP  QA/QC 
MediWound Ltd. 
2.2. Study Conduct 
Study Conduct (CRO): 
Dr. Marco Schwarzer 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen 
 
 


DETECT - Protocol Code: MW2010-03-02 
Page 4 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
2.3. Statistics 
Statisticians: 
Prof. Dr. Dr. h.c. Jürgen Timm 
Dr. Martin Scharpenberg 
Competence Center for Clinical Trials Bremen 
University of Bremen 
Linzer Str. 4 
28359 Bremen 
Germany 


DETECT - Protocol Code: MW2010-03-02 
Page 5 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
3. Signatures 
Keren David Zarbiv 
 
 
 
 
Sponsor Representative 
Signature 
 
Date 
MediWound Ltd. 
 
 
Dr. Marco Schwarzer 
 
 
 
 
Study Conduct (CRO) 
Signature 
 
Date 
GCP-Service International Ltd. & Co. KG 
 
 
Prof. Dr. Dr. h.c. Jürgen Timm 
 
 
 
 
Principal Statistician 
Signature 
 
Date 
Competence Center for Clinical Trials Bremen, 
University of Bremen 
 
Dr. Martin Scharpenberg 
 
 
 
 
Statistician/Author 
Signature 
 
Date 
Competence Center for Clinical Trials Bremen, 
University of Bremen 
 
 


DETECT - Protocol Code: MW2010-03-02 
Page 6 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
4. List of Abbreviations 
abbreviation 
meaning 
ANOVA 
Analysis of Variance 
COVID-19 
Corona virus infectious disease 19 
MVSS 
Modified Vancouver Scar Assessment Scale 
POSAS 
Patient Observer Scar Assessment Scale 
 
 


DETECT - Protocol Code: MW2010-03-02 
Page 7 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
5. Rationale for the Addendum 
Due to COVID-19 restrictions, the sponsor has submitted a protocol memo, dated 09 Apr 2020, 
to sites allowing them to perform the 24-month visit with a deviation of up to 6 months (between 
April 1st to Sep 1st), or to perform the visit remotely. In addition, due to lack of resources, some 
sites may not be able to perform the 24-month MVSS and POSAS assessments.  (See 
“Protocol Memo”, attachment 1) 
This addendum describes how deviations related to COVID-19 will be handled in the analysis. 
 
 


DETECT - Protocol Code: MW2010-03-02 
Page 8 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
6. Handling of missing values 
Data missing due to COVID-19 will be handled in the same way as missing data for any other 
reason, i.e. the procedures for handling of missing data described in the SAP in section 10.1 
will also be applied to missing values due to COVID-19. 


DETECT - Protocol Code: MW2010-03-02 
Page 9 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
7. Analysis of Safety Endpoint Cosmesis and Function at 24 months 
7.1. Handling of data from earlier/delayed visits 
One concern for the analysis of this endpoint is that, for some individuals, the 24-month visit 
was completed up to 3 months early (i.e. month 21) or up to 6 months late (i.e. month 30). 
From a medical perspective, it is assumed that data captured at an earlier or delayed visit will 
not be that different from data subsequently collected at 24 months; therefore, these data will 
be analyzed together with the data captured at 24 months (i.e. this endpoint will be analyzed 
as MVSS at 21-30 months). 
All data handling procedures and analyses described in the SAP will be applied to the 21-30 
months MVSS data. 
As a sensitivity analysis, for subjects with a delayed 24-month visit (within the time frame 24-
30 months) the MVSS at 24 months will be linearly interpolated from the delayed value and 
the last MVSS value captured before 24 months. In the same analysis, for subjects with an 
earlier 24-months visit (but within the time frame 21-24 months), the MVSS at 24 months will 
be linearly extrapolated from the earlier value and the last MVSS value captured before that. 
Following such interpolation, the same imputation techniques for missing data (regression 
imputation, best case, worst case) and the same analyses as described in the SAP will be 
applied. This implies that a new regression imputation model will be fitted to the data. 
In addition, treatment groups will be compared with respect to the timing of the last visit 
(planned at 24 months). The allowed per protocol window for the 24-month visit is 23 months 
and 2 weeks to 24 months and 2 weeks. The following five categorical time-windows will be 
defined:  
 
21 months to 23 months and 2 weeks,  
 
23 months and 2 weeks to 24 months and 2 weeks,  
 
24 months and 2 weeks to 27 months,  
 
28 months to 30 months, and  
 
No visit between 21 months and 30 months.  


DETECT - Protocol Code: MW2010-03-02 
Page 10 of 17 
Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
A table of MVSS values (mean and SE) will be produced by these follow-up categories and 
treatment group.  
In the event of imbalance of these time window categories across the treatment groups 
(defined as an absolute difference of 20% or more in the percentage of a category in the two 
groups) this categorical variable will be included as an extra explanatory variable in the 
regression model for comparing the treatment groups with respect to the 24-Month MVSS 
assessment, as additional sensitivity analysis. 
7.2. Handling of remotely captured data 
A small fraction of MVSS assessments are expected to be collected remotely. To account for 
this, the main analysis of the 24-month MVSS will be repeated, as supportive analysis, treating 
remotely assessed values as missing. I.e. the multiple imputation procedure described in the 
SAP section 10.1.2.2 will be repeated, fitting a new imputation model to the data. 
The descriptive statistics table described in the SAP will be produced for all MVSS values with 
on-site collected values and remotely collected values listed separately. The p-values 
described in the SAP will be computed based on all values as a main analysis. As an additional 
analysis, the p-values will also be computed without remotely collected data. 


DETECT - Protocol Code: MW2010-03-02 
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Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
8. Exploratory and Subgroup Analyses of MVSS and POSAS 
The exploratory analyses of target wound and donor site POSAS and MVSS assessments, as 
well as the subgroup analyses of 24-month MVSS will be modified to account for the fact that 
some assessments of these scores were done remotely. 
The descriptive statistics tables described in the SAP sections 11.3.4.3 and 11.3.5 will be 
produced for all POSAS/MVSS values as well as for on-site collected values and remotely 
collected values listed separately. The ANOVA p-values described in the SAP will be computed 
based on all values as a main analysis. As an additional analysis the p-values will also be 
computed without remotely collected data. 


DETECT - Protocol Code: MW2010-03-02 
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Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
Competence Center for Clinical Trials Bremen 
9. Further analyses 
All endpoints apart from MVSS and POSAS assessments are self-reported. Therefore, no 
influence of remote study visits is expected. The analyses of the other endpoints will be 
conducted as described in the SAP sections 11.3.4.7-11 (including the first Addendum, dated 
26 February 2020). 


DETECT - Protocol Code: MW2010-03-02 
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10. Attachment: Note to file 
 
 


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Statistical Analysis Plan Addendum 2 to V03 of 23 August 2020 
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Prot_001.pdf: 
Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 1 of 169 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
Study Title: 
A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of 
NexoBrid compared to Gel Vehicle and compared to Standard of Care   
 
 
Protocol No.: MW2010-03-02 
IND No: 65,448 
EudraCT No: 2014-001672-55 
Clinical Phase: III 
 
 
Sponsor:  
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
Tel: 972-77-9714100 
 
 
 
Chief Medical Officer: Lior Rosenberg, MD 
 
 
 
This clinical study will be conducted in accordance with Declaration of Helsinki and its updates, 
current Good Clinical Practice (GCP), the provisions of ICH (International Conference on 
Harmonisation); US Code of Federal Regulations (Title 21, CFR Part 11, 50, 54, 56 and 312) 
and/or EU Directives; local country regulations and the sponsor's Standard Operating 
Procedures (SOPs) 
 
CONFIDENTIAL 
The information in this document contains trade secrets and proprietary information of 
MediWound Ltd. and considered privileged and confidential. The Information may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board/Ethics 
Committee approval, informed consent and the approval of local regulatory authorities as 
required by local law, or unless otherwise agreed in advance and in writing by MediWound 
Ltd. 
 
All rights reserved to MediWound Ltd. 2015 
 
No part of this Protocol may be reproduced or transmitted in any form or by any means, 
electronic or mechanical, including photocopying, recording, or any information storage or 
retrieval system without the prior written permission from MediWound Ltd. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 2 of 169 
 
 
  
 
 
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TABLE OF CONTENT 
1 
LIST OF DEFINITIONS AND ABBREVIATIONS ....................................................................... 8 
1.1 
DEFINITIONS ........................................................................................................................................ 8 
1.2 
ABBREVIATIONS ................................................................................................................................ 11 
2 
SYNOPSIS ........................................................................................................................................ 13 
3 
INTRODUCTION ............................................................................................................................ 22 
3.1 
MEDICAL OVERVIEW ........................................................................................................................ 22 
3.2 
CLINICAL DEVELOPMENT OF NEXOBRID ......................................................................................... 24 
3.2.1 
Efficacy .............................................................................................................................................. 24 
3.2.2 
Safety .................................................................................................................................................. 27 
3.3 
RISK ASSESSMENT ............................................................................................................................. 31 
3.3.1 
General .............................................................................................................................................. 31 
3.3.2 
Extremities Wounds ............................................................................................................................ 33 
3.4 
STUDY RATIONALE ............................................................................................................................ 35 
4 
ETHICS STATEMENT................................................................................................................... 36 
5 
STUDY OBJECTIVES .................................................................................................................... 36 
6 
INVESTIGATIONAL PLAN .......................................................................................................... 37 
6.1 
PRIMARY ENDPOINTS, SECONDARY ENDPOINTS AND OTHER ENDPOINTS ...................................... 37 
6.1.1 
Primary Endpoint ............................................................................................................................... 37 
6.1.2 
Secondary Endpoints .......................................................................................................................... 37 
6.1.3 
Safety Endpoints ................................................................................................................................. 37 
6.1.4 
Exploratory Endpoint ......................................................................................................................... 38 
6.2 
STUDY DESIGN ................................................................................................................................... 38 
6.3 
MEASURES TAKEN TO MINIMIZE/AVOID BIAS ................................................................................. 40 
6.3.1 
Assessments of Clinical Measures...................................................................................................... 40 
6.3.2 
Main safety measures ......................................................................................................................... 41 
6.4 
STUDY TREATMENTS AND DOSAGE .................................................................................................. 42 
6.4.1 
NexoBrid ............................................................................................................................................ 42 
6.4.2 
Gel Vehicle ......................................................................................................................................... 42 
6.4.3 
Standard of Care ................................................................................................................................ 42 
6.5 
TRIAL PERIODS ................................................................................................................................. 43 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................................. 43 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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7.1 
SUBJECT ENTRANCE CRITERIA ........................................................................................................ 43 
7.1.1 
Inclusion Criteria- Patient level ......................................................................................................... 43 
7.1.2 
Inclusion Criteria – Wound level ....................................................................................................... 43 
7.1.3 
Exclusion Criteria- Patient level ........................................................................................................ 43 
7.2 
SUBJECT WITHDRAWAL CRITERIA .................................................................................................. 45 
7.2.1 
Treatment stopping rule (apply for NexoBrid or Gel Vehicle arms only) .......................................... 46 
8 
STUDY CONDUCT ......................................................................................................................... 48 
8.1 
SCREENING AND BASELINE VISIT ..................................................................................................... 48 
8.1.1 
Screening and Baseline Procedures ................................................................................................... 48 
8.1.2 
Cleansing (Debridement) and Wound Characterization .................................................................... 49 
8.1.3 
Assessments within 24hrs Prior to Eschar removal ........................................................................... 50 
8.2 
TREATMENT PROCEDURE- ESCHAR REMOVAL; NEXOBRID/SOC/ GEL VEHICLE - INITIATED 
WITHIN 72 HOURS FROM INJURY ..................................................................................................... 50 
8.2.1 
Assessments and TWs preparation 1 h prior to Eschar removal– All arms ....................................... 50 
8.2.2 
Eschar Removal ................................................................................................................................. 51 
8.3 
GENERAL ASSESSMENTS, POST ESCHAR REMOVAL.......................................................................... 59 
8.4 
POST-ESCHAR REMOVAL- WOUND MANAGEMENT ......................................................................... 60 
8.5 
WOUND MANAGEMENT PROCEDURES ............................................................................................. 62 
8.6 
FOLLOW-UP ASSESSMENTS: WEEKLY (7  2 DAYS) POST-START OF ESCHAR REMOVAL ................ 63 
8.7 
HOSPITAL DISCHARGE ...................................................................................................................... 64 
8.8 
FOLLOW-UP ASSESSMENTS: WOUND CLOSURE CONFIRMATION 2 WEEKS POST WOUND CLOSURE 64 
8.9 
FOLLOW-UP LONG TERM ASSESSMENTS ........................................................................................... 64 
8.10 
FOLLOW-UP ASSESSMENTS: RE-ADMISSION TO HOSPITAL OR DAY CARE .................................... 65 
9 
TREATMENT FLOW CHART – STUDY SCHEDULE ............................................................. 68 
10 
DRUG STORAGE AND DRUG ACCOUNTABILITY ............................................................... 72 
10.1 
ACCOUNTABILITY AND COMPLIANCE .............................................................................................. 72 
10.2 
PREVIOUS AND ON-GOING MEDICATIONS/THERAPIES. ................................................................... 72 
10.2.1 
Disallowed Previous and On-Going Medications/Therapies ............................................................. 72 
10.2.2 
Allowed Previous and On-Going Medications/Therapies .................................................................. 72 
11 
ASSESSMENT METHODS ............................................................................................................ 73 
11.1 
PRIMARY END POINT ........................................................................................................................ 73 
11.2 
SECONDARY ENDPOINTS ................................................................................................................... 73 
11.2.1 
Reduction in surgical needs ............................................................................................................... 73 
11.2.2 
Earlier eschar removal ...................................................................................................................... 73 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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11.2.3 
Blood loss ........................................................................................................................................... 73 
11.3 
SAFETY ENDPOINTS ........................................................................................................................... 75 
11.3.1 
Time to complete wound closure ........................................................................................................ 75 
11.3.2 
Cosmesis and function at 12 months from wound closure ................................................................. 76 
11.3.3 
Cosmesis and function at 24 months from wound closure ................................................................. 76 
11.3.4 
General parameters ........................................................................................................................... 77 
11.3.5 
Local parameters ............................................................................................................................... 77 
11.4 
EXPLORATORY ENDPOINTS .............................................................................................................. 77 
11.5 
ADDITIONAL ANALYSIS ..................................................................................................................... 78 
11.6 
SUBGROUP ANALYSES ....................................................................................................................... 78 
11.6.1 
Safety Laboratory Evaluations ........................................................................................................... 78 
11.6.2 
Burn Induced Compartment Syndrome Monitoring and Diagnosis ................................................... 80 
11.6.3 
Infection ............................................................................................................................................. 82 
11.6.4 
Vital Signs .......................................................................................................................................... 85 
11.6.5 
Immunogenicity Evaluation ............................................................................................................... 85 
11.6.6 
ECG (QT evaluation) ......................................................................................................................... 85 
11.6.7 
Physical Examination ........................................................................................................................ 85 
11.6.8 
Pain Assessment Using Visual Analogue Scale (Pain Scale Ruler) ................................................... 86 
11.6.9 
Concomitant Medications .................................................................................................................. 86 
11.6.10 Graft Loss ........................................................................................................................................... 86 
11.6.11 Hypothermia and pyrexia [94] ........................................................................................................... 86 
11.6.12 Cosmesis and Function assessment.................................................................................................... 86 
11.6.13 Quality of Life .................................................................................................................................... 87 
11.6.14 Function assessments ......................................................................................................................... 88 
11.6.15 Pharmacokinetic evaluation ............................................................................................................... 88 
11.6.16 Real time data capture and Independent Safety Monitoring .............................................................. 88 
12 
SAFETY AND PHARMACOVIGILANCE .................................................................................. 89 
12.1 
RELATIONSHIP TO STUDY DRUG ...................................................................................................... 89 
12.2 
ADVERSE EVENT INTENSITY ............................................................................................................. 89 
12.3 
ADVERSE EVENT REPORTING ........................................................................................................... 90 
12.4 
SERIOUS ADVERSE EVENTS .............................................................................................................. 90 
12.5 
SERIOUS ADVERSE EVENT REPORTING ............................................................................................ 91 
12.6 
PREGNANCIES .................................................................................................................................... 91 
13 
STATISTICAL ANALYSIS ............................................................................................................ 92 
13.1 
POPULATIONS .................................................................................................................................... 92 
13.1.1 
Major Protocol Violations ................................................................................................................. 92 
13.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................................................... 92 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.3 
EFFICACY EVALUATION .................................................................................................................... 92 
13.3.1 
Primary Endpoint ............................................................................................................................... 93 
13.3.2 
Secondary endpoints .......................................................................................................................... 93 
13.3.3 
Safety endpoints ................................................................................................................................. 94 
13.3.4 
Exploratory endpoints and additional analyses ................................................................................. 96 
13.3.5 
Subgroup Analyses ............................................................................................................................. 97 
13.4 
STATISTICAL COMPUTING ................................................................................................................ 97 
13.5 
SAMPLE SIZE CALCULATIONS .......................................................................................................... 97 
13.5.1 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. Gel) ................................. 97 
13.5.2 
Secondary Endpoint: Incidence of surgical excision ......................................................................... 98 
13.5.3 
Secondary Endpoint: Time to complete eschar removal .................................................................... 98 
13.5.4 
Summary of sample size ..................................................................................................................... 99 
13.5.5 
Safety endpoints ................................................................................................................................. 99 
13.6 
ALPHA CONTROL ............................................................................................................................... 99 
13.7 
STRATIFICATION AND RANDOMIZATION .......................................................................................... 99 
13.7.1 
Randomization Procedure: ................................................................................................................ 99 
13.7.2 
Stratification: ................................................................................................................................... 100 
13.7.3 
Randomization algorithm: ............................................................................................................... 100 
13.8 
DATA HANDLING METHODS AND DEFINITIONS ............................................................................. 100 
13.8.1 
Multiple visits per time-point ........................................................................................................... 100 
13.8.2 
Rules for Data Derivations .............................................................................................................. 101 
13.8.3 
Multiple target wounds per patient .................................................................................................. 101 
13.8.4 
Missing data ..................................................................................................................................... 101 
13.8.5 
Stratifying by center in the analysis ................................................................................................. 102 
13.8.6 
Stages of Analysis ............................................................................................................................. 102 
14 
QUALITY ASSURANCE .............................................................................................................. 104 
14.1 
QUALITY ASSURANCE PROGRAM ................................................................................................... 104 
14.2 
MONITORING PROCEDURES ............................................................................................................ 104 
14.1 
REGULATORY AND ETHICAL CONSIDERATIONS ............................................................................. 104 
14.2 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................................... 105 
15 
INVESTIGATOR’S AGREEMENT ............................................................................................ 106 
16 
APPENDICES ................................................................................................................................ 107 
APPENDIX 1- WOUND DEPTH ASSESSMENT- CLINICAL EVALUATION ............................................................ 107 
APPENDIX 2- PAIN MANAGEMENT PROCEDURES ............................................................................................ 108 
APPENDIX 3- PHOTOGRAPHIC WOUND DOCUMENTATION ............................................................................... 111 
APPENDIX 4- POST-ESCHAR REMOVAL WOUND MANAGEMENT .................................................................... 112 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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APPENDIX 5- WOUND MANAGEMENT; APPROVED COVERS ............................................................................. 128 
APPENDIX 6- REGULATORY AND ETHICAL ISSUES ........................................................................................... 130 
APPENDIX 7- STUDY ADMINISTRATIVE PROCEDURES ..................................................................................... 132 
APPENDIX 8- BIOPSY & HISTOLOGIC ASSESSMENT METHOD ........................................................................ 138 
APPENDIX 9- PAIN MEASUREMENT SCALE ...................................................................................................... 139 
APPENDIX 10- PROCEDURES FOR SPECIFIC BLOOD TESTS ............................................................................... 140 
APPENDIX 11- BURN PATIENTS: POTENTIAL ADVERSE EVENTS .................................................................... 142 
APPENDIX 12- COSMESIS, FUNCTION AND QUALITY OF LIFE QUESTIONNAIRES ........................................... 143 
APPENDIX 13- ASA CLASSIFICATION SYSTEM ................................................................................................. 155 
APPENDIX 14- RANGE OF MOTION ................................................................................................................... 156 
APPENDIX 15- BLINDED ASSESSOR MEMO- SAMPLE .................................................................................... 161 
APPENDIX 16- TREATMENT DIAGRAM ............................................................................................................. 164 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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SIGNATURE PAGE 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 8 of 169 
 
 
  
 
 
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1 
LIST OF DEFINITIONS AND ABBREVIATIONS 
1.1 
DEFINITIONS1  
Hereafter is a list of terms and definitions that are acceptable in the burn care area.   
TBSA: Total Body Surface Area; in burn care, referring to the (%) total body surface area 
affected by second and third degree burns [1].   
Burn eschar: A slough (area of necrotic tissue), crust or dry scab resulting from a burn. Eschar 
is structurally intact but dead and denatured dermis [1].  
Burn Depth Definitions [1]: 
Second Degree (Partial Thickness) Burns involve the epidermis and portions of the dermis and 
can be clinically categorized as superficial partial-thickness, deep partial-thickness burns or as 
most common: combination of different depths: 
Superficial partial-thickness burns heal spontaneously (most of them) in less than 3 weeks, and 
do so typically without functional impairment or hypertrophic scarring. 
Deep partial-thickness burns extend into the deeper layers of the dermis. They possess 
characteristics that are distinctly different from superficial partial-thickness burns. If infection is 
prevented and spontaneous healing is allowed to progress, these burns may heal in three to nine 
weeks.  
Indeterminate burns are usually second degree burns of changing depths difficult to diagnose 
on arrival so only after few days when the burn conversion (progression) and demarcation took 
place they can be diagnosed as deep in need of surgery or superficial. Distinguishing between 
deeper burns and shallow burns is not always straightforward, and many burn wounds have a 
mixture of superficial mid and deep burns, making precise classification of the entire wound 
difficult. 
Third Degree (Full-Thickness) Burns involve all layers of the dermis and often injure 
underlying subcutaneous adipose tissue as well. Burn eschar is structurally intact but dead and 
denatured dermis. Over days and weeks if left in situ, eschar separates (“sloughs”) from the 
underlying viable tissue, through infectious, inflammatory and maceration processes leaving an 
open, unhealed bed of granulation tissue. Without surgery, they can heal only by wound 
contracture and scarring with epithelialization exclusively from the wound margins. 
Combination wounds, mixed of second and third degrees: the depth of the wound is not 
homogeneous and many burn wounds have a mixture of all burn depths from superficial second 
degree through deep, including full thickness burns, making precise classification of the entire 
wound difficult.  
Zones of coagulation, stasis and hyperemia: Zone of coagulation is the tissue completely 
destroyed by heat and need to be removed. Zone of stasis, usually peripheral and deeper to the 
Zone of Coagulation, is characterized by decreased tissue perfusion due to congestion that is 
caused by the increased hyperemia in the surrounding tissue evoked by the inflammatory 
                                                 
1 When possible, definitions were based on the ABA White Paper 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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reaction (Zone of Hyperemia). The tissue in this zone is potentially salvageable if congestion 
will be resolved, preventing thrombosis and occlusion of blood vessels that will cause death of 
smaller or larger areas. The aim of burns resuscitation is to increase tissue perfusion in general as 
well as in the burned area and prevent any damage becoming irreversible. The dead, coagulated 
eschar in the zone of coagulation, adjacent to the Zones of Stasis is the main cause of local and 
systemic eschar-related infectious and inflammatory mediators that may cause burn viable zone 
of Stasis to die [2-9]. 
Burn conversion (burn propagation, progression, transformation): Superficial second 
degree burns may convert to deeper burns due to permanent vessel occlusion of the zones of 
stasis and hyperemia, desiccation of the wound, or the use of vasoactive agents during 
resuscitation from shock and infection of the eschar [1]. 
Debridement of Burn Wounds2: The removal of loose, devitalized, necrotic, and/or 
contaminated tissue, foreign bodies, and other debris on the wound using mechanical or sharp 
techniques (such as curetting, scraping, rongeuring, or cutting) [1].  
Clarification: In the USA and so in this study the removal of the necrotic tissue that ends in 
clean wound bed ready for wound closure treatment is termed “Eschar Removal” with the term 
“debridement” reserved to mechanical cleansing of the wound that ends with a wound bed still 
covered with eschar. In the rest of the world the term “debridement” refers to removal of the 
entire burn eschar ending with a clean, raw wound bed. Therefore, the term “Debridement” has 
been used in all the previous studies and in all the references as a synonym to “Eschar Removal” 
in its US terminology [1].   
Escharotomy is a surgical incision through burn eschar (necrotic skin) down to intact fat, from 
healthy skin edge to healthy skin, in order to reduce burn induced increased interstitial and 
compartment pressure and restore blood perfusion. It releases the compressed and stretched, 
constricted tissue allowing adequate perfusion to tissues and organs, maintaining their normal 
perfusion and viability [1]. 
Circumferential extremity wounds: Limb burns which encircle ≥ 80% of the limb 
circumference. 
Extremities at Risk (EAR) are circumferential DPT and/or FT burns with at least one of the 
following: 
1. Any of the 5 “P”s; Pain (Pain on passive stretch of the affected muscle), Paralysis, 
Pulselessness, Pallor, Paraesthesia, 
2. Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements 
within 30 minutes under the constricting eschar, 
3. SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity 
and the injured one [10-11],  
4. Pulse not detected by US Doppler.  
Increased interstitial pressure/compartment syndrome will be defined as following: 
Increasing pressure >25 mmHg, Difference of >20 mmHg of diastolic pressure between the 
                                                 
2 Enzymes were specifically excluded as debridement means in the White Paper. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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burned extremity to the opposite uninjured extremity, Decreased SpO2 reading during 
treatment with difference of >6% compared to an uninjured extremity, or deterioration of 
clinical signs and/or any of the 5 “P” signs (Pain (Pain on passive stretch of the affected 
muscle), Paralysis, Pulselessness, Pallor, Paraesthesia). 
Target Wound (TW): A TW is the burn area to be treated (Eschar Removal) by NexoBrid, 
SOC or Gel Vehicle as per the randomization and in accordance with the protocol. Following 
the enrollment of a patient to the study and prior to randomization, physicians identify one or 
more TWs per patient according to the following criteria and definitions: 
 TW is a continuous burn area (might include several anatomical areas) that can be 
treated in one session, DPT and/or FT in depth, 
 Minimal burned area of a single TW should be ≥ 1% TBSA (DPT and/or FT in depth)  
 Maximal burned area of a single TW should be ≤ 15% TBSA, 
 Wound is composed of DPT and/or FT in depth. Superficial partial thickness areas may be 
included in the wound area only if they cannot be separated from deeper areas (e.g. 
surrounded by or mixed with DPT areas) and trying to separate such more superficial areas, 
may interfere with the treatment of the deeper areas of that wound, 
Complete wound closure- defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits, 2 weeks apart [12]. 
Complete eschar removal is achieved at the end of the eschar removal treatment phase as 
routinely determined by burn specialists during their daily practice in burn units and is the 
basis for the medical decision to initiate the consequent wound closure phase: treatment 
towards wound closure. This stage will be determined by a designated assessor and clearly 
marked as the end of the eschar removal process and the initiation of specific treatment aimed 
to close the viable debrided bed by grafting or epithelialization. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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1.2 
ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase (ALT or SGPT, which stands for serum glutamic-pyruvic transaminase) 
AST 
Aspartate Transaminase (AST or SGOT which stands for  serum glutamic oxaloacetic transaminase ) 
BICS 
Burn-induced compartment syndrome 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
DG 
NexoBrid Gel 
DM 
Data Management 
DPT 
Deep Partial Thickness 
DSMB 
Data Safety Monitoring Board 
EAR 
Extremities At Risk 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FT 
Full Thickness 
HR 
Heart Rate 
HD 
Hospital Discharge 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product  
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 
Kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MVSS 
Modified Vancouver Scar Scale 
mg 
Milligram 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Ml 
Milliliter 
PO 
Per Os 
POSAS 
 
Patient and Observer Scar Assessment Scale 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell (Count) 
RDC 
Remote Data Capture 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SI 
Smoke Inhalation 
SOP 
Standard Operating Procedure 
SSD 
Silver Sulphadiazine 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBSA 
Total Body Surface Area 
TW 
Target Wound 
WBC 
White Blood Cell (Count) 
WP p/l 
ABA White Paper no. page/line 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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2 
SYNOPSIS 
Protocol Number: 
MW 2010-03-02 
IND Number(s): 
65,448 
Name of 
Investigational 
Medicinal 
Product (IMP): 
NexoBrid  
Name of Active 
Ingredient: 
Partially purified Bromelain  
Study Title: 
A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of 
NexoBrid compared to Gel Vehicle and compared to Standard of Care 
Clinical Phase: 
3 
Study Duration: 
The total duration of the study treatment and follow up period of each 
participating subject is approximately 25 months. 
Study Population: 
175 Hospitalized adults with Deep Partial Thickness (DPT) and Full Thickness 
(FT) thermal burns will be enrolled from about 30 sites. 
Study 
Objective(s): 
1. To demonstrate the efficacy of enzymatic eschar removal with 
NexoBrid by providing complete eschar removal as compared with Gel 
Vehicle, 
2. To demonstrate the efficacy of enzymatic eschar removal with 
NexoBrid by providing earlier complete eschar removal, reduction in 
patients’ surgical burden and its related blood loss as compared to SOC, 
3. To assess the safety of NexoBrid compared to SOC, including 
demonstration that treatment with NexoBrid does not cause an 
unacceptable level of harm on wound closure outcome and long term 
outcomes of cosmesis and function. 
Study Design 
Overview: 
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 identify one or more TWs per patient 
according to the TW definition. All subjects’ DPT and FT burns that 
comply with the specified entrance criteria are intended to receive study 
treatment per the randomized study arm and therefore, must be designated 
as TWs. This will further allow an evaluation of the subject systemic safety 
by allowing treatment of the subject’s entire deep burns as per the 
randomized study arm. After reviewing the entrance criteria, prior to 
randomization, eligible subjects will be stratified into different groups in 
order to standardize and minimise bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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patient total burn area and its depth.  
Following the stratification, patients will be randomized as per their 
stratification group 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. 
Study arms, 
Dosage and route 
of administration: 
 
Three arms will be included in the study; NexoBrid, SOC and Gel vehicle arm 
(3:3:1 ratio) and each patient will be treated in accordance with randomization.  
NexoBrid  
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for 
preparation of a gel for cutaneous use, including concentrate of proteolytic 
enzymes enriched in Bromelain as the active component. Following mixing 
of the powder with the gel vehicle, each gram of the prepared product 
contains 0.09 g partially purified Bromelain. Partially purified Bromelain is 
a mixture of enzymes extracted from the stem of Ananas comosus 
(pineapple plant). 
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 
50 grams of sterile Gel Vehicle (ratio of 1:10), respectively, to obtain sterile 
NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g 
NexoBrid sterile powder mixed with 20g sterile Gel Vehicle per 1% of TBSA (~ 
surface of an adult palm) for four hours (or 5 g NexoBrid sterile powder mixed 
with 50g sterile Gel Vehicle per 2.5% of TBSA. The NexoBrid powder and the 
Gel Vehicle are to be mixed at the patient bedside 15 min prior to use. 
NexoBrid may be applied for a second time to the same burn area, if eschar 
removal from the target wound after the first application is not complete but at 
least 50% of the eschar was removed during the first application. NexoBrid may 
only be applied twice to the same burn wound area. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Gel Vehicle  
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn 
skin. Gel Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel 
per 1% of TBSA (~ surface of an adult palm) or 50 grams per 2.5% TBSA for 
four hours.  
Gel Vehicle may be applied for a second time to the same burn area, if eschar 
removal from the target wound after the first application is not complete but at 
least 50% of the eschar was removed during the first application. The Gel 
Vehicle may only be applied twice to the same burn wound area. 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  
Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ 
dermabrasion excisions.  Non-surgical procedures will include the application of 
(collagenase ointment (e.g. Santyl), antimicrobial solutions (e.g. Dakin’s 
Solution, 
Sulfa-Nystatin 
Solution), 
ointments/creams 
(e.g. 
Bacitracin, 
Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 
The need of either non-surgical or surgical procedures will be determined by the 
burn specialists and can be repeated as needed until complete debridement.  
Inclusion/ 
Exclusion 
Criteria: 
Inclusion Criteria- Patient level 
1. Males and females; ≥ 18  and ≤ 70 years of age, 
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 ≤  15% TBSA; SPT, DPT and/or FT in 
depth, 
5. Informed consent can be obtained within 48 hours of the burn injury.  
6. Patients who are willing and able to sign a written consent form. 
Inclusion Criteria - Wound level 
At least one wound (a continuous burn area which can be treated in one session; 
may 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’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, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 16 of 169 
 
 
  
 
 
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2. Modified Baux index3 ≥ 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, blast or chemical burns,  
6. Patients with DPT and/or FT facial burn wounds from flame, flash, 
explosion >0.5% TBSA (scald and contact burns are allowed),  
7. Patients with circumferential DPT and/or FT burns defined as Extremities at 
Risk (EAR)4,  
8. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate 
(AgNO3), 
9. 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 SSD treatment), 
10. Patients with pre-enrolment escharotomy, 
11. Patients with diagnosed infections as described in Section 11.6.3 of study 
protocol, 
12. Any signs or history that may indicate smoke inhalation (e.g. flame burn to 
the upper body, flames in enclosed space, smoke and fumes on the patient 
and in mouth and nostrils, deep flame burns >0.5 %TBSA to the face, 
cough, hoarseness, stridor or breathing difficulty including tachypnea 
possibly related to smoke inhalation, etc.), 
13. Pregnant women (positive pregnancy test) or nursing mothers, 
14. Poorly controlled diabetes mellitus (HbA1c>9%) in patients with known 
diabetes as captured in the medical history, 
15. Patients with BMI greater than 34.0 kg/m2, 
16. ASA greater than 2 (see Appendix 15 in study protocol) 
17. Cardio-pulmonary disease (MI within 6 months prior to injury, pulmonary 
hypertension, COPD or pre-existing oxygen-dependent pulmonary diseases, 
broncho-pneumonia, steroid dependent asthma or uncontrolled asthma), 
                                                 
3 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and the presence of smoke 
inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 
4 Extremities at Risk are circumferential DPT and/or FT burns with at least  one of the following: 
Any of the 5 “P”s (Pain, Paralysis, Pulselessness, Pallor, Paraesthesia), Direct pressure measurement >25 mmHg, measured in 2 
consecutive measurements within 30 minutes under the constricting eschar, SpO2 <95% and a persisting difference of 6% between a 
healthy symmetrical extremity and the injured one,  
Pulse not detected by US Doppler.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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18. Pre-existing diseases which interfere with circulation (peripheral vascular 
disease, edema, lymphedema, surgery to regional lymph nodes, obesity, 
varicose veins), 
19. Any 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, 
cardiovascular disorder, pulmonary disorder, liver disorder including post 
alcoholic abuse impaired function or neoplastic disease), 
20. Chronic systemic steroid intake, 
21. History of allergy and/or known sensitivity to pineapples, papaya, 
Bromelain or papain, 
22. Current (within 12 months prior to screening) suicide attempt, 
23. Mentally incapacitated adults who are incapable of giving legal consent (e.g. 
dementia, psychiatric patients, etc), 
24. Enrollment in any investigational drug trial within 4 weeks prior to 
screening, 
25. Current (within 12 months prior to screening) alcohol (daily consumption > 
3 units for males and >2 units for females) or drug abuse5,  
26. Prisoners and incarcerated, 
27. Patients who might depend on the clinical study site or investigator. 
Outcome 
Measures: 
Primary Endpoint 
The below primary endpoint will be investigated at a 'per patient' level.  
Incidence of complete eschar removal- Demonstrate superiority of NexoBrid 
over Gel Vehicle for eschar removal as measured by incidence of complete 
eschar removal at the end of the topical agent soaking period by a blinded 
assessor. 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared 
between NexoBrid and SOC.  
1. Reduction in surgical need- Demonstrate superiority of NexoBrid over 
SOC in reduction of surgical need for excisional eschar removal as 
                                                 
5 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, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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measured by an analysis of incidence of surgical eschar removal (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision). 
2. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC in 
reduction of the time to achieve complete eschar removal.  
3. Blood loss- Demonstrate superiority of NexoBrid over SOC with regard to 
the blood loss incurred during the eschar removal procedures  
Safety Endpoints 
The following group of safety endpoints will be evaluated in this study and 
compared between NexoBrid and SOC. These endpoints are used to 
confirm that NexoBrid does have an inferior deleterious effect.  
1. Time to reach complete wound closure assessed in days, starting from 
Randomization.  
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.  
Additional Safety Outcome Measures:  
4. General parameters: Systemic adverse events, vital signs, pain assessment 
(using VAS), laboratory tests, units (and volume) of blood transfusion given 
during hospitalization, Immunogenicity evaluation for NexoBrid patients, 
Pyrexia and Hyperthermia, Systemic infections, Incidence of increased 
interstitial/compartment syndrome6 and QT prolongation,  
5. Additional long term functionality evaluation of the extremities using the 
‘Lower Extremity Functional Scale’, 'QuickDASH' questionnaires and 'Range 
Of Motion' measurements, 
                                                 
6 Increased interstitial pressure/compartment syndrome will be defined as following: Increasing pressure >25 mmHg, 
Difference of >20 mmHg of diastolic pressure between the burned extremity to the opposite uninjured extremity, Decreased 
SpO2 reading during treatment with difference of >6% compared to an uninjured extremity, or deterioration of clinical signs 
and/or any of the 5 “P” signs (Pain (Pain on passive stretch of the affected muscle), Paralysis, Pulselessness, Pallor, 
Paraesthesia). 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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6. Long term Quality of Life using EQ5D and Burn Specific Health Scale- Brief 
(BSHS-B). 
7. Local parameters: Local adverse events defined by treating physician or 
designee; graft loss, wound related infections, etc. 
Exploratory Endpoint  
1. Reduction in surgical needs as measured by an analysis of % wound area 
surgically excised for eschar removal (and % TBSA excised of the treated 
TW) (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities 
target wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential 
extremity wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically 
harvested donor sites wounds, 
6. Reduction in surgical need as measured by analysis of % area of surgically 
harvested donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit 
following eschar removal procedures 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor 
sites scars,  
9. PK evaluation for a subset of NexoBrid patients7, 
10. 
Autograft related parameters. 
Sample size: 
The following sample size calculations are based on the consideration of the 
primary and two secondary endpoints for this study.  
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. 
Gel) 
Estimated proportion achieving complete eschar removal in all TWs from study 
MW2004-11-02: NexoBrid 0.595 
Standard error = 0.057 
Anticipated proportion achieving complete eschar removal using NexoBrid: 
0.595-0.057/2 = 0.5665 
Estimated proportion achieving complete eschar removal using Gel vehicle in a 
previous Phase II study, MW2002-04-01: 0 (0 out of 35 patients).  
                                                 
7 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 
hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. 
(0.0 is the point estimate; 0.10 is the 97.5 upper confidence limit).   
Because numbers of complete eschar removals are anticipated to be low in the 
gel group, we calculate sample size using Fisher’s exact test. We used the 
computer program nQuery Advisor version 7.0 to calculate power for a two-
sided significance level of 5%, and thereby found the following sample size 
combination that led to approximately 90% power for detecting a statistically 
significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).   
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle 
group 13. Total sample size = 78. 
Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: 
NexoBrid 0.22; SOC 0.62 
Standard errors: NexoBrid 0.048; SOC 0.054 
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: 
NexoBrid 0.24 and SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a 
two-sided significance level of 5% is 86: 43 in the NexoBrid group and 43 in the 
SOC group. 
Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial 
yielded an estimated log hazard ratio of -1.37 (hazard ratio of 0.254) with a 
standard error of 0.28.  
Therefore target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio 
= 0.29).  
The formula for the number of events (successful complete eschar removals) is: 


2
2
log
)
(4
HR
z
z
d



 
where z = 1.96 two-sided significance level of 5%; and z = 1.28 for 90% 
power; For 90% overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required 
2
1
2
p
p
d
n


= 44 (to the nearest even number), 
22 in each of the NexoBrid and SOC groups.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 
patients (65 in the NexoBrid group, 13 in the Gel vehicle group and 43 in the 
SOC group (to match NexoBrid numbers)), we propose entering larger numbers 
to provide an extra margin of assurance in achieving positive results on the 
efficacy outcomes, and adequate information on safety outcomes to allow better 
benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 
(NexoBrid) + 75 (SOC) + 25 (Gel Vehicle). 
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 Efficacy Assessment Period 
(EAP). 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 for short-term safety endpoints (including time to wound closure). 
The analysis will be conducted, when 3 months had passed from the last patient 
reaching complete wound closure, in accordance with FDA guidance for industry 
Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for 
Treatment “Trial subjects generally should remain in the study for follow-up 
evaluation at least 3 months following complete wound closure. The purpose for 
this follow-up period is to help distinguish actual wound healing from transient 
wound coverage”. At this time-point, data will be available for nearly all patients 
on the primary end-point (proportion with complete eschar removal), the three 
secondary endpoints (proportion undergoing surgery, time to complete eschar 
removal, and blood loss) and short-term safety endpoints (including time to 
wound closure). Missing values for early drop outs etc. will be handled as 
described in Section 13.8.4  and the SAP. The complete data set documented so 
far will be locked and analyzed as described above. Although the treatment code 
will be revealed at the end of this analysis, the independent assessor of the 
cosmesis and function and QoL of an individual patient will remain blinded to 
the treatment given to that patient until after the third and final analysis (see 
below), so as to preserve the un-biasedness of the  assessments.  
The second analysis will be performed for the 12 month follow up period 
(STFU12) and will be started after the last patient has reached the 12m 
assessment. At this analysis, all accumulated safety data at the 12m follow-up 
will be analyzed, particularly the 12m MVSS assessment for cosmesis and 
function. The complete data set documented so far will be locked and analyzed 
as described above. 
The third and final analysis covers the data of the long-term safety follow up 
(LTSFU24). It will be conducted after the last patient has reached the 24m 
assessment at last 12 months after (STFU12) analysis (stage 2). At this analysis, 
all accumulated safety endpoints at the 24m follow-up will be analyzed, 
particularly the 24m MVSS assessment for cosmesis and function. The complete 
data set documented during the trial will be locked and analyzed as described 
above (hard lock). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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3 INTRODUCTION 
3.1 
MEDICAL OVERVIEW 
Optimal treatment of burn injuries requires understanding of and response to the profound local 
and systemic reactions following thermal injury.  
The treatment strategy should be planned and executed on the basis of a timely (early) 
assessment of the extent of tissue damage and remaining viable tissue available for the healing 
process. Only when the eschar is removed and the wound bed revealed, can the true damage be 
observed and assessed, and the appropriate wound closure modality prescribed [2, 9, 13]. 
As soon as the burn eschar is formed, it induces, within hours, a cascade of local and systemic 
pathologic changes. Dead eschar becomes heavily contaminated in two to three days, creating a 
source for local and systemic infection and sepsis [2-3, 8-9, 14]. Local inflammatory responses 
may lead to additional destruction of healthy surrounding tissue, extending the original 
damage. If not otherwise removed, inflammatory and autolytic processes slowly decompose 
and destroy the eschar, which will slough in approximately two weeks. The long inflammation 
based spontaneous sloughing period allows the simultaneous formation of advanced 
granulation tissue, later evolving into a heavy and deforming scar.   
Delaying the removal of the eschar increases the incidence and severity of systemic and local 
complications, especially in more extensive burns [2-6, 8-9, 14-15]. The decomposing eschar is 
a source of strong local and (if the burn is extensive) systemic mediators that induce 
inflammatory reaction and that may cause burn wound progression into potentially viable 
tissue [4, 6, 8-9, 16].  
Moreover, the eschar is non-resilient and forms a cocoon-like constricting shell around circular 
body parts. With increasing tissue edema, this increases the interstitial/compartment pressure, 
seriously compromising the viability of the still barely surviving skin by stretching and 
compressing blood supply to vital structures. An early diagnosis and response to these events, 
releasing escharotomy, is important and should be executed emergently. In this case too, delay 
in diagnosis and reluctance to perform surgical escharotomy may delay this procedure 
especially in cases where experienced burn surgeons are not readily and immediately available 
[3, 17]. 
To prevent eschar-related complications and to initiate the healing process, it is imperative to 
remove all of the offending eschar at the earliest possible opportunity. Eschar removal, 
“Debridement”, is the first stage of the comprehensive wound care process.  There is no benefit 
in the presence of the eschar on the burn.  Thus, the decision is not whether or not to remove an 
eschar but when and how. Therefore, delay or avoidance of eschar removal should have a 
specific reason. 
Estimation of burn size and depth is essential for a diagnosis-based treatment strategy, but 
cannot be accurately performed in most instances unless and until the opaque eschar has been 
completely removed. 
Immediate (within 24 hours post-burn) eschar removal may improve the potential for survival 
of the Zone of Stasis, reverse the Zone of Hyperemia and may attenuate, or avoid many of the 
systemic reactions [2, 6, 8-9, 14, 18]. Delayed eschar removal (within the first three days) may 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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not provide all the benefits of immunological and inflammatory modulation, but will reduce 
the burn bacterial load and its outcomes [3, 17, 19-20]. Delaying eschar removal up to the 
seventh day will forfeit the local and systemic benefits, but may still prevent healing by 
secondary intention potentiating better long term results (especially in terms of scarring) [8-9, 
14, 21].  
In current standard of care, removal of the eschar may be accomplished by surgery, usually 
tangential excision followed by split thickness autografting (TE&STSG) of the acute exposed 
debrided wound, or by non-surgical topical care that includes daily dressing changes, bathing, 
scraping, wet to dry dressing, macerating activity of bacteria, etc., until the eschar sloughs, 
leaving a clean wound bed for subsequent non-surgical or surgical wound closure treatment. 
This combination of debridement followed by surgical or non-surgical wound closure 
treatment is the basis of all burn wound care modalities. 
The choice of debridement method (non-surgical or surgical) depends on many variables such 
as the burn depth, anatomical site and size (expressed as % TBSA of the burn wound), the 
patient’s general condition, available donor site for autograft harvesting as well as the 
availability of surgical facilities and staff. Tangential excision should be carried down into the 
healthy intact tissue to make sure that no trace of the eschar remains. It is estimated that up to 
30–50% of healthy tissue (mainly dermis), which is essential for the spontaneous 
epithelialization potential of the wound, may be sacrificed in this procedure, thus usually 
necessitating autografting. These surgical procedures are traumatic, often long and difficult, 
require skilled personnel and sophisticated medical resources and are usually accompanied by 
bleeding [2, 9, 17, 21-22] and heat loss [23]. The surgically excised raw wound bed should be 
covered immediately, i.e., in most cases autografted. Thus, the excision is followed by 
harvesting of autografts from intact, non-injured skin areas, skin graft transplantation, and care 
of the donor sites in addition to the original burn injury. These surgical procedures are 
performed under general anesthesia that requires pre- and post-surgical fasting and recovery. In 
most centers caution and post surgery intensive care dictate that only a limited percentage of 
the affected areas (~15%TBSA) will be surgically debrided at one time in order to limit 
inflicting excessive stress on the patient. Thus, the decision to surgically debride a burn is not 
taken lightly. Reluctance, hesitation and doubts due to uncertain diagnosis delay the decision to 
perform surgery, extending the time to start and finish of the debridement from the optimal few 
hours to several days.  
In partial, mixed thickness, and intermediate depth wounds, and with difficult to diagnose 
depth “indeterminate” wounds, early surgical debridement will usually be avoided and a more 
conservative debridement approach using topical medications will be pursued. Such 
conservative non-surgical debridement lasts for days until the eschar decomposes or until a 
decision is taken to excise the offending, remaining eschar.  The non-surgical debridement 
process involves the combined activity of topical medications, contaminant microorganisms, 
autolytic tissue processes and the inflammatory process with frequent dressing changes, 
showering, mechanical scraping of loose debris etc. The infectious-inflammatory processes are 
slow (lasting between 10-14 days) and may involve significant systemic and local 
complications. Using topical anti-bacterial or anti-inflammatory medicaments may reduce the 
infectious-inflammatory processes but will also delay eschar separation (sloughing). Locally, 
all these processes prolong the removal of the eschar and lead to additional tissue damage due 
to the death of the Zones of Stasis and Hyperemia which deepen, transforming partial thickness 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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damage into a full thickness injury. The long debridement time with sustained inflammatory 
processes can lead to the formation of granulation tissue that will develop into heavy scars.  
This excerpt of literature emphasizes that timely eschar removal is, for the last 40 years, the 
goal of burn wound care initiation. Physicians today are forced to choose between or combine 
two sub optimal alternatives of eschar removal; (i) the fast and efficient surgery (TE&STSG) 
with its diagnosis-dependant often prolonged initiation, non-selective, traumatic and 
demanding results or (ii) the inefficient non-surgical prolonged debridement means with their 
associated sequelae. The lack of fast and effective non-surgical eschar removal means has left 
surgery as the available SOC for deep burns.  
The optimal solution would be a non-surgical, selective means for removing exclusively the 
eschar without harming the non injured tissues immediately or nearly immediately after 
patients’ admission and stabilization, independently of the burn depth diagnosis. Such early 
removal of the eschar will enable the physician accurate visual diagnosis of the exposed burn 
wound bed. The clean exposed bed can be treated by the most appropriate wound closure 
strategy tailored for each patient and wound area in order to achieve optimal long term results 
with minimal trauma and cost to the patient. 
These characteristics were well-demonstrated throughout the clinical development of 
NexoBrid. A recent confirmatory phase 3 study (MW 2004-11-02) demonstrated the clinical 
benefit of NexoBrid for effective and selective removal of eschar from burn wounds as was 
shown in both primary and secondary endpoints, e.g. for % treated burn wound excised, % 
treated burn wound autografted and timely eschar removal. These findings corroborated those 
from a previous Phase 2 study (MW 2002-04-01) and retrospective data collection study (35-
98-910) (Please refer to Section 3.2). 
3.2 
CLINICAL DEVELOPMENT OF NEXOBRID 
3.2.1 
Efficacy  
The clinical development of NexoBrid8 was based on clinical data retrospectively collected 
from files of hospitalized burn patients with burn wounds treated by NexoBrid and on 
discussions and guidance from regulatory authorities. 
Study 35-98-910 evaluated the safety and efficacy of NexoBrid in subjects between 0.5 and 82 
years of age with deep partial and/or full thickness burns of ≤67% TBSA, hospitalized in 
Soroka University Medical Center (Israel) Plastic Surgery and Burn Unit, from 1985-2000. 
Data from 154 subjects having complete file documentation (including signed informed 
consent form (ICF) and pre- and post-eschar removal photographs) were analyzed. 
The clinical development program of NexoBrid includes six prospective clinical studies that 
evaluated the safety and efficacy of NexoBrid in partial and full thickness burns.  
 Study MW2001-10-03 evaluated the efficacy and safety of three doses of NexoBrid. Twenty 
hospitalized adult, male and female subjects, with Deep Partial Thickness (DPT) and/or Full 
Thickness (FT) burns of 1-15% TSBA were randomized to a 1 g (6/20 subjects), 2 g (7/20 
subjects) or 4 g (7/20 subjects) dose of NexoBrid powder per 20 g of Gel Vehicle. The study 
                                                 
8 NexoBrid was formerly named Debridase and Debrase.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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further confirmed the use of 2 g NexoBrid mixed with 20g Gel per 1% TBSA as safe and 
effective dose. 
 Study MW2002-04-01 evaluated the safety and enzymatic eschar removal efficacy of 
NexoBrid as compared to SOC and Vehicle9. A total of 140 adult hospitalized male and 
female subjects, with DPT and/or FT burns ranging from 2-15% TBSA, but not more than 
30% TBSA in total, were randomized in a 2:1:1 ratio to NexoBrid, Vehicle alone (only 
Gel), or SOC treatment. 
 Study MW2005-10-05 evaluated the safety and exploratory efficacy of NexoBrid in 
comparison to Vehicle, and SOC in hospitalized male and female adult subjects, with DPT 
and/or FT burns ranging from 1-5% TBSA. Thirty hospitalized subjects were randomized to 
receive NexoBrid (10 subjects), Vehicle alone (9 subjects), or SOC treatment (11 subjects). 
 Study MW2008-09-03 (an on-going study) evaluating the safety and exploratory efficacy of 
NexoBrid, as well as the systemic absorption of NexoBrid when applied topically on 
thermal burns using a recently validated, sensitive ELISA method, through pharmacokinetic 
(PK) assessments in hospitalized adults and children, male and female subjects, aged 4 to 70 
years with partial thickness and full thickness burns of 4-30% TBSA.  
 Study MW2004-11-02 A phase III, multicenter, controlled study, that confirmed the safety 
and efficacy of NexoBrid in comparison to SOC in hospitalized adults and children, male 
and female subjects between 4 and 55 years of age with DPT and/or FT burns of 5-30% 
TBSA with total burn wounds of no more than 30%. Of the subsequently enrolled subjects, 
75 were randomized to NexoBrid and 81 subjects were randomized to SOC treatment [24].  
 Study MW2012-01-02 evaluated the long-term scar formation and Quality of Life in adults 
and children who had participated in study MW2004-11-02, 2-4 years post-wound closure 
and included blinded assessment of scars. A total of 89 patients were enrolled into this study 
including 72 adults and 17 pediatric patients [24].  
Summary of the efficacy results from the phase 2 and phase 3 studies is presented here below. 
Eschar Removal  
Eschar removal is the direct intended activity of NexoBrid and as such was evaluated in all 
clinical studies. 
Data from the two comparative studies MW 2002-04-01 and MW 2005-10-05 shows that 
eschar was effectively removed from 92.5% of the treated wound area for NexoBrid subjects as 
compared to 94.7% for the SOC subjects. The Vehicle showed negligible, if any, eschar 
removal activity (2.2% eschar removed in one case). Vehicle-subjects’ eschars were removed 
by SOC methods following end of the Vehicle gel treatment and diagnosis of eschar removal 
failure. Data from the two comparative studies MW2002-04-01 and MW2005-10-05 shows 
that the time to start of eschar removal from injury was 1.5 days in both the NexoBrid and 
Vehicle groups compared to 2.9 days in the SOC group. Time to completion of the initial 
eschar removal procedure (as designated by the protocol per treatment group) from injury was 
1.5 days in the NexoBrid group as opposed to 11.2 days in the SOC group. 
                                                 
9 Vehicle treated patients were treated by eschar removal SOC methods following end of the Vehicle Gel treatment and 
diagnosis of eschar removal failure. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Data from the Phase 3 study MW2004-11-02 showed that 90.5% (67/74) of NexoBrid subjects 
had successful eschar removal as compared to 90.1% (73/81) of the SOC-treated subjects 
(p=0.9301). Time to achieve successful eschar removal from the ICF date in the NexoBrid 
group was 0.8 days as opposed to 6.7 days in the SOC group (p< 0.0001). Thus, NexoBrid was 
able to successfully remove the eschar from the burn wounds much earlier than SOC. 
Following the EMA CHMP/COMP recommendation, study MW 2004-11-02 evaluated two co-
primary endpoints consisting of (1) % treated wound excised, and (2) % treated wound 
autografted (both on DPT wounds). These endpoints complement each other since less area 
surgically excised demonstrates the eschar removal efficacy of NexoBrid and less area grafted 
demonstrates the clinical benefit in the reduction of the extent of non-selective eschar removal 
by surgical excision of deep partial thickness wounds where viable tissue can be spared10. Both 
endpoints contribute to the overall reduction of surgery [24]. 
Area of Wound Excised 
Data from the Phase 3 study (MW2004-11-02) shows that the incidence of DPT wounds that 
were excised was only 15.1% (16/106 wounds) as compared to 62.5% (55/88 wounds) in the 
SOC. Moreover, the DPT wounds treated with NexoBrid had significantly less wound area 
excised (5.5%) compared to the SOC treated (DPT) wounds (52.0%, p<0.0001). In children 
(<18 years of age), the incidence of DPT wounds that were excised was only 21.7% (5/23 
wounds) as compared to 68.2% (15/22 wounds) in the SOC. Moreover, less wound area was 
excised (7.3%) in NexoBrid treated wounds compared to the SOC treated wounds (64.9%). In 
addition to the analyses described above, the percent treated wound excised was analyzed for 
all treated wounds, including those with third degree components, to investigate NexoBrid 
ability to remove the eschar from all burn wound depths (ITT population). In the NexoBrid 
group the incidence of wounds that were excised was 24.5% (40/163 wounds) as compared to 
70.0% (119/170 wounds) in the SOC. Significantly less treated wound area was excised in all 
the NexoBrid treated wounds (13.1%) as compared to the SOC group (56.7%); p<0.0001. This 
pattern is comparable to that seen in the DPT wounds discussed above and confirms the results 
in a greater number of wounds of all depths. 
Area of Wound Autografted 
In the Phase 3 study (MW2004-11-02) wound area autografted was evaluated in DPT wounds. 
Wounds that were entirely FT or had FT areas were excluded from the analysis of % wound 
area 
autografted 
(in 
accordance 
with 
EMA 
CHMP/COMP 
protocol 
assistance 
recommendations). 
In this study, the incidence of DPT wounds that were autografted was only 17.9% (19/106 
wounds) as compared to 34.1% (30/88 wounds) in the SOC (p=0.0099). Moreover, DPT 
wounds of all subjects had significantly less wound area autografted in the NexoBrid group 
(8.4%) compared to the SOC group (21.5%; p=0.0054). In the children subset, the incidence of 
DPT wounds that were autografted was 21.7% (5/23 wounds) as compared to 31.8% (7/22 
wounds) in the SOC. Moreover less DPT wound area was autografted in the NexoBrid group 
                                                 
10 Full thickness wounds require autografting regardless of the eschar removal technique since they have no 
remnants of viable dermis. Therefore, the clinical benefit of DGD versus the non-selective surgical approach is 
more apparent in deep partial thickness wounds where the potential tissue-sparing effect, leading to less 
autografting, is demonstrated. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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(6.1%) compared to the SOC group (24.5%). The potential tissue-sparing effect of NexoBrid 
and its applicability to the issue of reduction in autografted wound area suggest an additional 
clinical benefit to children, due to their smaller size and limited donor site area. 
Long term scar assessment results- study MW2012-01-02 
Cosmesis was assessed in study MW2012-01-02 by a blinded assessor using the Modified 
Vancouver Scar Scale (MVSS). The Vancouver Scar Scale (VSS) [25] is the first validated and 
widely used scar assessment scale developed by Sullivan et al 1990 and it includes assessments 
of 4 scar variables; vascularity, height, pliability, and pigmentation. MVSS is an improved 
version of the VSS, which includes two additional scar variables (pruritus and pain) [23]. The 
Vancouver Scar Scale is the most commonly used scale that includes multiple subjective and 
objective parameters [25-27]. 
The study included data from 89 subjects (72 adults and 17 pediatric) with whom contact was 
made and who represent the MW2004-11-02 study population based on their demographic and 
baseline wound characteristics.  
Scar assessment (per wound) using MVSS was conducted for 113 wounds in NexoBrid group 
and 78 wounds in SOC group. The total scar outcome was slightly lower (better results) in the 
NexoBrid arm compared to SOC (3.12 vs. 3.38, respectively), without statistically significant 
difference (p=0.88) (MVSS range 0-18). 
3.2.2 
 Safety 
The burn trauma is a multi-factor disease involving most if not all body systems and associated 
with many adverse events (AEs). Overall, AEs associated with NexoBrid were minimal, 
generally transient, manageable and mostly attributable to the burn process and its care and not 
to the introduction of the eschar removal agent. 
Taken together, there appear to be several common but manageable AEs, many attributable to 
the burn process and not the introduction of the debriding agent, NexoBrid. The most 
frequently reported AEs (≥3.0%) whether or not treatment–related, are summarized in the 
following Table 1 (based on the safety data from the prospective phase II and phase III 
studies). 
Table 1- Summary of Adverse Events in Descending Order of Frequency Whether or Not 
Treatment-Related and Occurring in ≥3.0% of Subjects* (Safety Population)  
Adverse Event* 
NexoBrid 
SOC 
N=208(%) 
N=127 (%) 
Pruritus 
32 (15.4%) 
24 (18.9%) 
Anemia 
13 (6.3%) 
8 (6.3%) 
Nausea 
13 (6.3%) 
6 (4.7%) 
Insomnia 
6 (2.9%) 
5 (3.9%) 
Headache 
6 (2.9%) 
5 (3.9%) 
Skin graft failure 
6 (2.9%) 
2 (1.6%) 
Diarrhoea 
6 (2.9%) 
1 (0.8%) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Adverse Event* 
NexoBrid 
SOC 
N=208(%) 
N=127 (%) 
Vomiting 
5 (2.4%) 
7 (5.5%) 
* Subjects from the five prospective studies; MW2001-03-02, MW2002-04-01, MW2005-10-05, 
MW2004-11-02 and MW2008-09-03 
 
Across all studies, pruritus was the most frequently reported AE occurring at an incidence 
>10% in both treatment groups. More subjects in the SOC group reported pruritus compared to 
the NexoBrid group (18.9% vs. 15.4%). Pruritus, that torments the patient for months, is very 
common. As reported in the literature, up to 87% of all patients will have a longer or shorter 
spell of pruritus. The scratching may be so intense that the patient might scratch-open their 
healed wounds, destroying healed grafts [1, 28-29]. 
Anemia in response to burns has been acknowledged for over 60 years, and is considered an 
acute and sub-acute complication. Close evaluation has suggested the response to thermal 
injury to include initial rapid hemolysis of thermally exposed blood proportional to the burn % 
TBSA (<18% in 24h in 15-40% TBSA burns [30]. Excisional surgery for eschar removal and 
skin graft harvesting leads to acute blood loss. Catabolic processes, inflammatory and septic 
processes and depressed bone marrow hematopoietic activity may all contribute to anemia 
though a clear etiology has yet to be established [31-33]. Anemia in NexoBrid clinical studies 
was reported at similar incidences in both treatment groups (6.3% in the NexoBrid and SOC 
group). 
Though skin grafts have been used for more than a century and considered to be a standard 
wound closure tool, the details of their use vary between centers, surgeons, patients and body 
areas. The reported incidence in the literature of graft loss ranges may reach up to 71%. 
Traditionally it was thought that wound infection is the main reason for skin graft loss but with 
use of effective and simple control means (local antibacterial soaking and systemic antibiotic) 
infection ceased to play a crucial role in graft loss. At present, the causes for skin graft loss 
(besides infection) are (by the order of importance): 1. Sub-graft collection (i.e. seroma, 
hematoma); 2. Lack of graft adherence to the wound bed (ineffective fixation, movement); 3. 
Hypoalbuminemia; 4. Granulation tissue; 5. Nature of graft (by trend: very thin, sheet, thick 
and meshed). Other mechanical factors may cause loss of smaller or greater parts of the graft, 
earlier or later after grafting. Such factors are: shearing, trauma and abrasion (scratching) of the 
graft, minimally vascularized body areas (lower extremities), areas prone to trauma (buttocks, 
legs), areas difficult to fixate and dress and mobiles joints (knees, elbows, axilla neck and 
trunk) [34-37]. Use of negative pressure wound therapy for 2-3 days to stabilize the graft 
improves its take. Late (2-3 weeks post grafting) graft loss may be caused by autografting over 
dermis that epithelializes under the graft, detaching it from the healing bed. During the clinical 
development, graft failure was reported in low percentages, 2.9% in the NexoBrid arm and 
1.6% in the SOC arm. Autografting may cause long term sequelae such as scarring at the 
edges, mesh pattern when mesh grafts are used, overgrafting when used over dermis, color 
differences and at the donor sites: weeks of painful healing process and scars on unburned skin 
areas.    
The incidence of the AEs pain, pyrexia/hyperthermia, and wound infection were analyzed 
separately for the earlier clinical studies (Group 1: MW 2001-10-03, MW 2002-04-01) and for 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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the later studies (Group 2: MW 2005-10-05, MW 2004-11-02, and MW 2008-09-03) as prior 
to the Group 2 studies, corrective measures11 were implemented for these AEs observed and 
investigated in the Group 1 studies. Data are presented in Table 2. 
Table 2- Comparison of the Incidence of Adverse Events Pain, pyrexia/ Hyperthermia 
and Wound Infection  
Adverse Event 
Group 1* 
Group 2** 
NexoBrid 
N=90 
SOC/Vehicle  
N=70 
NexoBrid 
N=118 
SOC/Vehicle  
N=101 
 
N (%) 
N (%) 
N (%) 
N (%) 
Pain 
21 (23.3) 
8 (11.4) 
4 (3.4) 
4 (4.0) 
Pyrexia/ hyperthermia 
32 (35.6) 
13(18.6) 
20 (17.0) 
16 (15.8) 
Wound infection 
6 (6.7) 
4 (5.7) 
7 (5.9) 
7 (6.9) 
* Group 1: MW 2001-10-03, MW 2002-04-01 
** Group 2: MW 2005-10-05, MW 2004-11-02, and MW 2008-09-03 
 
Pain Events 
Burn injury is associated with prolonged and significant pain. The pain can be sub-divided into 
background pain (at rest), breakthrough pain (during activities such as changing positions), and 
procedural pain during wound care such as Sulfamayalon, bathing, dressing changes, etc [38-
39]. Patient's scores vary widely from patient to patient and in the same patient: from day to 
day. Pain score are higher in the more superficial burns with procedural pain related to the 
extent of the second degree burns [38].  
As shown in Table 2, the incidence of pain in the NexoBrid group was reduced from 23.3% to 
3.4% after corrective measures had been taken for adequate pain management, as commonly 
practiced during routine dressing change to burn patients, and occurred at a comparable 
incidence in both treatment groups in the later clinical studies (3.4% vs. 4.0%). Use of 
NexoBrid requires somewhat less analgesia and anesthesia medication compared with SOC 
and so it is not medication-dependent more than any routinely used SOC treatment. 
A few prospective descriptive studies were conducted to investigate the extent of pain in burn 
patients, reporting more intense, at rest background pain in the first week, two-thirds of the 
patients had mild or less-than-mild pain, and the others reported moderate-to-severe pain. 
During therapeutic procedures, 51% of patients suffered intense pain though analgesic 
medications were administered. The burn induced pain and its long term sequelae are all 
underestimated and seem to be in many cases greatly undertreated by routine analgesia [1, 28, 
39-42]. 
Pyrexia/ Hyperthermia 
The burn patient is catabolic, with a very high basal metabolic rate (BMR), and often has 
elevated body temperature which may continue for months post healing [43-45]. The 
                                                 
11 The following instructions and protocols were implemented: Provision of a pre-treatment pain management 
protocol as commonly practiced during routine dressing change in standard of care of burns in order to prevent 
NexoBrid related pain and the use of approved topical antibacterial solutions during the soaking stages prior to 
and post-treatment in order to minimise the potential for infection and associated fever. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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hypermetabolic process with the systemic and local inflammatory reactions involved in the 
wound healing process as well as wound contamination and/or infection contribute to pyrexia. 
However, elevated body temperature is not considered clinically reliable in predicting local or 
bloodstream infection, in some cases it starts a few hours post burn, much before any infection 
can develop. Later it may be due to exposure to catabolic and bacteria products [46-47]. 
Occlusive dressings may cause fever by reducing heat dissipation [48-49]. Therefore, 
temperature elevation is not considered clinically significant pyrexia until >39°C (102°F) and 
even then it is not always related to a clear pathology [50] or correlates consistently with 
septicaemia [46-47]. Other common sources for pyrexia may be IV catheter infection and/or 
thrombophlebitis with reported incidence of 8-57%. Urinary Tract Infection (UTI) is another 
source of pyrexia (as report suggests that most catheterized patients will have bacteruria after 
72 hours) and pneumonia with an incidence of 10-65% [51]. 
The incidence of pyrexia/hyperthermia in the NexoBrid group was reduced from 
approximately 35.6% in the earlier studies to 17.0% in the later studies and was also decreased 
from 18.6% to 15.8% in the SOC group. In the later studies pyrexia/hyperthermia occurred at a 
comparable incidence in both treatment groups (17.0% vs. 15.8%).  
Infection  
The definition of “infection” in the case of burns is a very general one and can relay to several 
different pathological entities. Some of the more common burn-related infections are burn 
wound infections with an incidence of >30% of infection and >9% of bacteraemia [51-52]. The 
general criteria of pyrexia, leucocytosis, thrombocytopenia may indicate that an infection is 
developing but will rarely point to the exact source (organ or system) of the infection. Even 
local signs of burn wound infection will not preclude differential diagnosis of other very 
common sources (i.e. IV catheter infection, thrombophlebitis, urinary tract infection so 
common in catheterized patients or pneumonia) [51]. 
Wound Infection 
All burn wounds are contaminated and clinical diagnosis between wound contaminated to 
various degrees of wound infection and invasive wound infection depends on objective criteria 
of quantitative culture and microscopic histology. Other definitions of wound infections are not 
clear, not uniformly accepted by all and greatly depended on aetiology and subjective 
impressions [51].  
Most infections in patients with burn injuries are burn wound infections. The burn wound is a 
susceptible site for opportunistic colonization by organisms of endogenous and exogenous 
origin [51-53]. Incidence of infections in children was identified in 33.9% of the patients, with 
burn wound infections being the most common: 10-24.6% [54-55]. Other studies found similar 
incidence of infection >30 % with 30-70 % of such infections reported as burn wound 
infections [56-59].  
Death in patients with infections ranged from 6 to 25% [56, 60-64]. 
In the clinical development, incidence of wound infection was similar across studies, 6.7% to 
5.9% in the NexoBrid group and 5.7% to 6.9% in the SOC group. In all studies wound 
infection occurred at a comparable incidence in both treatment groups and with comparable use 
of antibiotics between NexoBrid and SOC. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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There were 31 SAEs reported by 25 subjects. Only one SAE (skin graft failure) was considered 
possibly related to NexoBrid treatment. Fewer AEs, SAEs, and severe AEs were observed in 
children compared to adults. Nearly all cases of wound and blood infections reported as AEs 
were determined to have been not related to study treatment. 
There were six deaths in the NexoBrid clinical development program, 5/362 (1.4%) in the 
NexoBrid group and 1/127 (0.8%) in the SOC group. None of these deaths was considered to 
have been related to study treatment by the Principle Investigators and Data Safety Monitoring 
Board (DSMB). 
3.3 
RISK ASSESSMENT 
3.3.1 
General 
Any decisive treatment strategy (such as a decision to execute post eschar removal surgical 
wound closure) can only be planned and executed if the true extent of the tissue damage is 
known at each stage of the healing process. Only once the eschar is removed and the viable 
wound bed is revealed, can the true damage be observed and assessed and the appropriate 
wound closure modality can be prescribed [2, 13, 65]. 
The two major characteristics defining the burn wound severity are area, which is referred to in 
terms of % TBSA, and depth, which is referred to in terms of ‘degree’ of burn or described in 
words (please refer to Burn Wound definitions, Section 1.1).  
Depth assessment will be based on the investigators' visual assessments as used in routine burn 
care. Burn specialist visual assessment and clinical examination is the technique generally used 
for the diagnosis, monitoring and documentation of burn depth [1]. All the participating 
investigators shall be experienced, national or international burn specialists. At present, the 
burn experts' visual assessments are considered the standard diagnostic tool since efforts to 
develop and validate objective burn depth diagnostic measures have not been successful. None 
of the other tools which have been developed (e.g. tissue biopsy, ultrasound, laser Doppler 
flowmetry, Thermography, nuclear magnetic resonance imaging (MRI), reflectance under 
different illuminations, vital dyes, fluorescein and fluorometry) have been validated in large 
scale clinical trials or accepted as standard diagnostic means by national or international 
professional burn organizations. All these methods have been compared to the visual 
assessments of experts but similar results have been attained only occasionally and usually 
only to several-day old burns where the process of progression has ended and infection not yet 
started [65-66].  
Assessment of very superficial and very deep burns may be in some cases more straight-
forward, however, the most frequent burns in hospitalized patients, those of mixed or 
indeterminate depth, create a challenge in terms of both diagnosis and choice of treatment 
modalities. Indeterminate burns are usually second degree burns of changing depths difficult to 
diagnose on arrival so only after several days when the burn conversion (progression) and 
demarcation have taken place can they be diagnosed as deep in need for surgery or superficial 
[1]. These burns are the most common in hospitalized patients (>40%). In some cases they may 
eventually evolve into deep full thickness or slow to heal wounds. In other cases they may heal 
fast, and spontaneously epithelialize following maceration and separation (“sloughing”) of the 
eschar. The depth of these burns is not constant, their appearance continuously changing during 
the first days due to the burn progression and to the inflammatory/infectious processes. Due to 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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their varying appearances and behavior they pose a real diagnostic challenge and thus it is 
common practice to follow/monitor these wounds for a few days until the diagnosis becomes 
clearer and with this, realization of the preferred wound closure strategy, i.e. surgical or non-
surgical or a combination of both. When a non-surgical strategy is chosen, topical wound care 
designed to prevent infection of the necrotic eschar and promote its separation (sloughing) 
starts. This treatment includes topical medications and physical procedures (bathing and 
showering, scraping etc), follow up and monitoring until the eschar sloughs off and the clean 
bed epithelializes, or until granulation tissue appears and it becomes obvious, usually within a 
3 week period, that the wound will not heal without heavy scarring. For the later scenario, a 
surgical process including excision and autografting will usually be performed [1, 18, 67].  
In spite of the general agreement that the eschar should be removed in a timely manner, as 
soon as possible, very few centers dare to excise the entire burn eschar as early as possible 
from admission [68]. In immediate eschar removal, defined within 24hrs from injury (“primary 
eschar removal”, as coined in 1995 by Voinchet et al), one does not wait until better diagnosis 
of the burned skin depth is feasible but rather excises all the suspected tissues and grafts the 
raw wound bed.  
Since in partial, mixed thickness, and intermediate depth wounds, the extent of the burn is 
difficult to diagnose, early surgical eschar removal will usually be avoided and a more 
conservative eschar removal approach using topical medications will be pursued. The 
conservative eschar removal lasts for days until the eschar decomposes or until decision is 
taken to excise the offending burn eschar. The non-surgical eschar removal process involves 
the combined activity of topical medicaments, contaminant microorganisms, tissue autolytic 
processes and the inflammatory process. The infectious-inflammatory processes are slow 
(lasting between 10-14 days) and may involve significant systemic and local complications. 
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within several days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy.   
The optimal solution would be the use of a non-surgical, least demanding eschar removal 
means, immediately after patients’ admittance and stabilization. Such debriding means that will 
be specific to the eschar, removing it selectively without harm to the non injured bed will 
enable physician visual diagnosis of the burn wound trauma and the most appropriate choice of 
wound closure treatment for each wound area. 
There are several main characteristics of an ideal eschar removal means: 
2. Early (as early as possible), effective and thorough eschar removal that allows early direct 
visualization and assessment of the primary burn damage, prevention of eschar-related 
deterioration and complications and initiation of non-surgical or surgical wound closure 
treatment. The eschar removal should be fast enough to timely release BICS.  
3. Selective, avoiding unnecessary damage of viable, non-burned tissues, which may be 
essential for the wounds’ spontaneous epithelialization potential. 
4. Safe, both for the patients’ general and local (non- or partially-injured tissues) conditions. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Timely (as soon as possible after patients stabilization: early initiation and early completion) 
and thorough eschar removal, is the primary goal of treatment initiation. Eschar removal will 
not only stop the vicious eschar progression, eschar-induced effects and resolve (like 
escharotomy) increased burn induced interstitial/compartment syndrome, but will allow 
accurate assessment of the primary burn damage and initiation of the closure, healing process. 
In this regard, burn eschar removal does not differ from the care of all other necrotic wounds, 
where timely removal of the offending necrotic eschar is the gold standard. 
3.3.2 
Extremities Wounds 
Burns to the extremities (hands and feet) have a special place in the field of burn care, 
demanding special attention and treatment.  
In more than 80% of severely burned patients, the hand is involved [69].The functional and 
aesthetic importance of the hand, coupled with its complex and crowded anatomy, with risk of 
burn-induced increases in interstitial and compartment pressure, make hand burn care 
extremely important and with current SOC, as further elaborated below, challenging. 
Due to the special anatomy of the hand in which numerous delicate structures are crowded in a 
small space and covered by scarce sub-dermal soft tissue, surgical debridement of the burned 
tissue, or escharotomy in these areas, are technically demanding and may cause considerable 
morbidity. The maintenance of perfusion is the first and foremost aim in the acute treatment of 
hand burns. During the acute phase, deep dermal, circumferential or near circumferential burns 
should be cared for most attentively because they can cause circulatory impairment at the level 
of the nerves and muscles as well as stretching the partially burned skin and collapsing the 
marginal blood supply, transforming a partial thickness burn into a full thickness one. Even for 
experienced surgeons it is sometimes extremely difficult to determine whether an escharotomy 
of the hand will be necessary or not [69]. Technical difficulties in estimation of the burn depth 
may lead to late or even unnecessary surgical debridement, especially in light of a previous 
study which has demonstrated that the excised burn eschar often contains viable tissue: 
microscopically unaltered normal deep dermis, unaltered dermal collagen fibers and transected 
normal capillaries [70].   
Contact burns are often palmar burns. Surgical intervention is very rarely indicated because the 
skin of the palm is thick and provides good protection. Surgical debridement is difficult to 
carry out due to the palm’s distinct anatomy and the tight fibrous septi attached coherence to 
the palmar aponeurosis. Substitution of the specialized palmar skin is only applicable to a 
limited degree. These factors justify conservative treatment for 3–4 weeks, whenever possible 
[69]. 
Within the clinical development program, NexoBrid was used to treat 130 deep partial and full 
thickness burn wounds of the hands (in 101 patients; 68 adults, 33 children and adolescents), 
mainly in 2 clinical studies: retrospective data collection study 35-98-910 and the 
confirmatory, controlled phase 3 study MW2004-11-02 [71].  
In a post-hoc analysis of the subgroup of hand wounds treated with NexoBrid and SOC in 
study MW2004-11-02, the following results were generated: 
Timely Eschar Removal  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Similar number of wounds reached successful eschar removal in both groups; 90.3% (28/31) in 
the NexoBrid group and 97.6% (40/41 wounds) in the SOC group (p = 0.1843). 
Time to achieve successful eschar removal was significantly shorter in the NexoBrid group 
(mean 2.57± 1.95 days from Injury compared to the SOC group (mean 7.75± 5.41 days from 
Injury) (p<0.0001). 
Excisional Eschar Removal 
Four (4) out of 31 hand wounds (12.9%) required excisional debridement in the NexoBrid 
group as compared to 29 out of 41 (70.7%) in the SOC group (p<0.0001). 
The mean percentage of the  burn wound area excised in the NexoBrid group was 4.4 ± 13.1% 
as compared to 52.0 ± 41.4% % in the SOC (p<0.0001).  
Autograft 
In the DPT sub-population, only one of the 24 (4.2%) hand wounds was autografted in the 
NexoBrid group compared to 10 of 20 (50%) in the SOC group (p=0.0005).  
The percentage of the burn wound area autografted in the NexoBrid was 2.1 ± 10.2% as 
compared to 30.5 ± 38.4% in the SOC (p=0.0017).  
Wound Closure 
The Mean Time to wound closure measured from injury date was similar in the two treatment 
groups: NexoBrid 25.0 ± 12.5 days, SOC 28.0 ± 15.8 days (p=0.3814) 
Hand wounds were further assessed as part of the Long term study (MW200-12-01-02) which 
included a blinded assessment of scar quality. The mean total overall MVSS score was lower 
(better results) in the NexoBrid arm compared to SOC: 3.14 ± 2.59 vs. 4.05 ± 2.82, 
respectively, without yet reaching a statistically significant difference due to sample size 
(p=0.2756).  
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within several days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy (see 
below).  
Release of increased pressure can be achieved by formal surgical escharotomy, excision of the 
constricting eschar and as was observed by Krieger et al [71-72] as well as during the 
confirmatory phase 3 study MW2004-11-02, by early application of an effective, fast acting 
eschar removal agent that underwent a development program and studied for this specific 
condition such as NexoBrid [65, 72-73].  
Due to the severe complications potentially associated with the current SOC of an 
interventional measure of escharotomy (scars, bleeding & damage to deeper structures), 
physicians often choose to monitor the patient with circumferential extremity burns for a few 
hours (by clinical signs and direct pressure measurement), continuously assessing  the wound's 
condition, before committing to escharotomy [1, 64, 73, 92-96]. In the clinical development 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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program, none of the hand burns treated with NexoBrid required escharotomy. Moreover, none 
of the NexoBrid subjects’ hands had to be surgically escharotomized to resolve burn induced 
high interstitial/compartment pressure- 0% (0/130 hand wounds) in the NexoBrid arm, vs. 
9.7% (4/41) of the hands treated by SOC.  
To investigate release of pathologically elevated interstitial pressure, a sub-analysis was 
performed for the circumferential wounds that did have a measurement of elevated interstitial 
pressure prior to treatment in the confirmatory phase 3 study, MW2004-11-02. There were six 
(6) such wounds with measured high pressures that were treated with NexoBrid and two (2) 
that were treated by SOC. NexoBrid application reduced the elevated pressure below the 
threshold without  need for surgical intervention (escharotomy or excision), whereas in the 
SOC-treated wounds the pressure had to be reduced by surgical intervention (escharotomy or 
excision). Both methods effectively reduced and released burn-induced elevated pressures, but 
SOC is associated with the sequelae of surgical escharotomy. 
These results are further supported by the retrospective study (35-98-910) which demonstrated 
that enzymatic debridement decreased both the number of deep hand burn injuries that ended-
up in an operative procedure, and the wound area grafted in those who did undergo skin 
grafting [73]. 
The effective pressure release achieved with NexoBrid is also consistent with the results that 
were obtained in a controlled in vivo study. In a burn pig model, NexoBrid resolved burn 
induced compartment syndrome within 30-45 minutes after application, even before the 
complete dissolution of the eschar [72]. 
NexoBrid appears to address the unmet needs of an eschar removal means by being as fast and 
effective as surgery yet selective, non-invasive, not diagnosis-dependent, and least demanding. 
Its use resolves the first stage of wound bed preparation in the comprehensive wound care 
process and in addition, facilitates the second step of non-surgical or surgical wound closure by 
enabling earlier, direct visual assessment of the wound bed and by reducing the incidence 
and/or extent of excision, which is a substantial, demanding part of the surgical wound closure 
process. The potential tissue-sparing effect of NexoBrid that offers the option of reducing 
autografting of the healing wound suggests an additional clinical benefit to the burn victim. 
Autografting, besides being a demanding surgical procedure that needs general anaesthesia, 
OR facilities and surgical personnel, also sacrifices healthy donor site skin that needs 2-3 
weeks of painful healing and often ends with permanent scars.  
Early non surgical eschar removal and prevention/resolution of increased interstitial/ 
compartment pressure in circumferential burns of extremities reduces surgery and may 
decrease the time to resolution of such increased interstitial/compartment pressures. 
All these benefits may also have special importance in preparedness for a burn mass casualty 
disaster scenario where surgery is the main treatment bottleneck (as has been seen in the 9/11 
crisis: Dr. Bessey from Cornell, NY September 2012 & February 2013 FDA Burn Mass 
Casualty Incident Medical Countermeasures Public Workshops [74]. 
3.4 
STUDY RATIONALE  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Enzymatic eschar removal with NexoBrid allows initiating and completing the phase of 
removal of the offending eschar earlier upon admission, enabling earlier visualization of the 
wound bed for assessment of burn wound depth as well as preservation of viable tissues, as 
further elaborated and supported by previous clinical studies. The depth determination is 
important for the planning and execution of the post eschar removal stage of wound closure 
phase (grafting or spontaneous epithelialization).  
Additional clinically meaningful attributes of NexoBrid enzymatic eschar removal is the ability 
to lower surgical burden as it allows to remove eschar in wounds that otherwise would have to 
undergo surgical excision.  
This phase 3 study MW2010-03-02 will be a multi-center, multi-national, assessor blinded12, 
randomized, controlled, three-arm study intending to demonstrate superiority of NexoBrid 
treatment over Gel vehicle placebo control treatment and over Standard of Care (SOC) 
treatment, in thermal burn subjects. 
4 
ETHICS STATEMENT 
The study will be carried out in accordance with accepted international standards, which meet 
regulations relating to Good Clinical Practice (GCP). These standards are drawn from the 
following guidelines: ICH Guideline for Good Clinical Practice, 1 May 1996 amended 
September 1997 and Declaration of Helsinki (as amended in Seoul, October 2008), concerning 
medical research in humans. 
The investigator(s) will ensure that this study is conducted in full conformity with the 
principles of the "Declaration of Helsinki" and with the laws and regulations of the 
participating countries, whichever affords the greater protection to the individual.  It is the 
responsibility of the investigator to obtain informed consent in written form (according to local 
legal requirements) from each subject participating in this study. All patients will be informed 
of the aims, methods, anticipated benefits, potential hazards and confidentiality of data. 
Candidates will also be told that they are free to refuse participation at any time. 
5 
STUDY OBJECTIVES  
The study objectives are: 
1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
complete eschar removal as compared with Gel vehicle, 
2. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
earlier complete eschar removal, reduction in patients’ surgical burden and its related 
blood loss as compared to SOC, 
3. To assess the safety of NexoBrid compared to SOC, including demonstration that 
treatment with NexoBrid does not cause an unacceptable level of harm on wound 
closure outcome and long term outcomes of cosmesis and function. 
                                                 
12 Complete Eschar Removal assessment will be performed by a blinded assessor in the NexoBrid and Gel vehicle treatment arms.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6 
INVESTIGATIONAL PLAN 
6.1 
PRIMARY ENDPOINTS, SECONDARY ENDPOINTS AND OTHER ENDPOINTS 
6.1.1 
Primary Endpoint 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to Section 1.1 for Target Wound 
definition): 
Incidence of complete eschar removal: Demonstrate superiority of NexoBrid over Gel 
Vehicle for eschar removal as measured by incidence of complete eschar removal at the end of 
the topical agent soaking period by a blinded assessor. 
6.1.2 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SOC to further support the clinical benefit of NexoBrid.  
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. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC with regard to 
the time when complete eschar removal has been achieved. For definition of complete 
eschar removal see primary endpoint. 
3. Blood loss related to eschar removal- Demonstrate superiority of NexoBrid over SOC 
with regard to the blood loss occurred during the eschar removal procedures.  
6.1.3 
Safety Endpoints 
The following group of safety endpoints will be evaluated in this study and compared 
between NexoBrid and SOC. These endpoints are used to confirm that NexoBrid does 
not cause an unacceptable level of harm 
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:  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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a. General parameters: Systemic adverse events, vital signs, pain assessment (using VAS), 
laboratory tests, units (and volume) of blood transfusion given during hospitalization, 
Immunogenicity evaluation for NexoBrid patients, Pyrexia and Hyperthermia, Systemic 
infections, Incidence of increased interstitial/compartment syndrome (as defined in Section 
1.1) and QT prolongation,  
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 Burn Specific Health Scale- Brief (BSHS-B). 
d. Local parameters: Local adverse events defined by treating physician or designee; graft 
loss, wound related infections, etc. 
6.1.4 
Exploratory Endpoint  
1. Reduction in surgical needs as measured by an analysis of % wound area surgically excised 
for eschar removal (and % TBSA excised of the treated TW) (tangential/ minor/ avulsion/ 
Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function at the long term follow up 
visits,Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
3. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
4. Reduction in surgical need as measured by analysis of incidence of surgically harvested donor 
sites, 
5. Reduction in surgical need as measured by analysis of % area of surgically harvested donor 
site, 
6. Blood loss related to eschar removal assessed by changes in Hematocrit incurred during the 
eschar removal procedures 
7. Cosmesis evaluation  (MVSS and POSAS) will be used to assess the quality of the donor sites 
scars,  
8. PK evaluation for a subset of NexoBrid patients13, 
9. Autograft related parameters. 
6.2 
STUDY DESIGN 
This is a multi-center, multi-national, randomized, controlled, assessor blinded (see Section 
6.3), three-arm study aiming to demonstrate superiority of NexoBrid treatment over Gel 
vehicle control and over SOC treatment in thermal burn subjects with burns. 
175 subjects are planned to be randomized to the study in a 3:3:1 ratio (NexoBrid: SOC: Gel 
Vehicle). The study will be conducted at sites in the US and out of the US. 
                                                 
13 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Following the enrollment of a patient to the study and prior to randomization, physicians will 
identify one or more TWs per patient according to the TW definitions described in Section 1.1.  
All subjects’ DPT and FT burns that comply with the specified entrance criteria under Section 
7.1 are intended to receive study treatment per the randomized study arm and therefore, must 
be designated as TWs. This will further allow an evaluation of the subject systemic safety by 
allowing treatment of the subject’s entire deep burns as per the randomized study arm. After 
reviewing the entrance criteria, prior to randomization, eligible subjects will be stratified into 
different groups in order to standardize and minimise bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the patient total burn area 
and its depth. Please refer to Section 13.7.1 for full description of the randomization procedure. 
Following the stratification, patients will be randomized as per their stratification group 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 (as described in Section 8.2.1), subjects will be 
medicated with appropriate analgesia (please refer to Appendix 2- Pain Management 
Procedures) and undergo wound cleansing and dressing of all wounds with antibacterial 
solutions (as specified in Section 8.1). Following wound cleansing and antibacterial treatments, 
subjects will undergo the eschar removal process as per treatment assignment (NexoBrid, SOC 
or Gel Vehicle, following randomization) as further described in APPENDIX 16- Treatment 
Diagram.  
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.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6.3 
MEASURES TAKEN TO MINIMIZE/AVOID BIAS  
This study includes 3 arms: NexoBrid, SOC and Gel Vehicle.   
In this study, wound characterization will be performed prior to randomization into treatment 
arms. The randomization procedure will be initiated only after all TWs of a patient have been 
defined and recorded in the eCRFs. All subjects’ DPT and FT burns that comply with the 
specified entrance criteria under Section 7.1 and TWs definition (Section 1.1) are intended to 
receive study treatment per the randomized study arm. Randomization will be performed by 
stratifying eligible subjects into different groups and by center in order to standardize baseline 
characteristics and minimise potential bias between study groups in terms of efficacy and 
safety outcomes that are expected to be correlated to the depths of the patient’s TWs. The 
planned stratification by center further enables the standardization of the treatment of all study 
arms further reducing possible site effect. 
Wound size (%TBSA) will be clinically assessed by the ‘rule of palms14’. 
Using this stratification, patients will be randomized in a 3:3:1 ratio (NexoBrid: SOC: Gel 
Vehicle). Please refer to Section 13.7 for further information.  
To further minimize bias, the Investigator will define the TWs of a patient based on the criteria 
for defining target wounds, as described in Section 1.1. All Patient’s TWs will be treated in 
accordance with the randomized treated arm; NexoBrid, Gel vehicle or SOC (as described in 
Section 6.4), thus allowing appropriate collection of safety information, which is being 
reported per patient, presenting the patient as a whole. 
A subject who was randomized, but did not receive treatment will be analyzed in the ITT 
population (see description of population in Section 13.1). 
6.3.1 
Assessments of Clinical Measures 
The following measures are predefined and will be taken in specific time points per the study 
protocol to ensure minimization of potential biases: 
6.3.1.1 
 Extent of eschar removal assessment using topical agent; NexoBrid or Gel Vehicle  
The topical arms are 2 different topical preparations (NexoBrid- a gold color gel and Gel 
Vehicle- a transparent gel) that are impossible to disguise in terms of preparation procedures 
and appearance, even if supplied in masked containers. Therefore, the topical product 
application (NexoBrid or Gel Vehicle) will be done by a health care professional and the 
wound assessment will be performed by a different health care professional who is blinded to 
the randomized study arm. This will allow a blinded assessment of the primary endpoint of the 
study (incidence of complete eschar removal in NexoBrid vs. Gel Vehicle arm). 
Eschar removal procedure will be initiated at the end of the cleansing and blister removal 
session (debridement), after wound soaking. Product will be applied by a health care 
professional to the wound within 15 minutes of mixing, and left on for a 4-hour period. After 4 
                                                 
14 Using the rule of palms, the surface of the patient's palm represents approximately 1% of body surface area and 
is helpful in estimating the area of small burns. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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hours, the wound bed with the remains of the dissolved eschar and topical agent will be wiped 
away and the wound bed will be soaked for an additional 2 hours to remove any remains of the 
mixture. Following removal of the soaking dressing (6 hours of treatment in total), the wound 
bed will be photographed in a standardized manner, and the extent of eschar removal will be 
clinically assessed by a different health care professional- assessor blinded to treatment 
assignment. The un-blinding tests that are done only for the NexoBrid patients (i.e PK and 
Immunogenicity) will be done by non blinded site staff and will be recorded in a separate 
worksheet for the purpose of keeping the eschar removal assessor blinded to study arm. The 
blinded assessor will sign the "blinded assessor memo" (see Appendix 15- Blinded Assessor 
Memo).    
If debridement is not complete, but at least 50% of eschar was removed, a second application 
will be performed, as described in Section 8.2.2.2.5. Similar procedures will take place 
following a second application of the topical agent Patients treated with NexoBrid or Gel 
Vehicle will undergo up to 2 topical applications.  
In cases where eschar removal was not complete following the applications of the topical 
agents, NexoBrid or Gel Vehicle, additional surgical procedures and/or non surgical treatments 
as described below will be implemented in accordance with physician judgment:  
6.3.1.2 
Surgical eschar removal (SOC arm or as additional procedure for the topical arms): 
Extent of wound area excised & incidence of excisions following each surgical excision 
procedure performed for eschar removal will be recorded in the eCRFs. Eschar removal will be 
assessed immediately after the eschar removal surgical procedure, before a temporary or 
permanent dressing will be applied. The extent of eschar removal will be clinically determined 
by the same assessor who is blinded for the topical arm. 
Surgical procedures intended for eschar removal are pre-specified in the protocol for 
standardization (i.e. tangential/minor/avulsion/Versajet/dermabrasion excision). 
6.3.1.3 
Non-surgical eschar removal (SOC arm or as additional procedure for the topical 
arms): 
Wounds will be assessed by a burn specialist as in common daily practice. Assessment will be 
done on a daily basis and following any dressing change as long as it does not involve 
unnecessary dressing change (patient manipulation). Extent of eschar removal after the last 
dressing will be clinically determined by the same assessor who is blinded for the topical arm 
and recorded in the eCRFs.  
Non-surgical procedures intended for eschar removal are pre-specified in the protocol for 
standardization and are detailed in Section 8.2.2.1.2. 
6.3.2 
Main safety measures 
To further minimize bias, main safety measures (weekly assessments for wound closure, long 
term cosmesis as well as some functionality assessment) will be performed by a blinded 
assessor, different from the first assessor who performed eschar removal assessments. This 
assessor should not be aware whether the patient was assigned to the topical arms or to the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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SOC arm. The blinded assessor will be required to sign the "blinded assessor memo" (see 
Appendix 15- Blinded Assessor Memo– blinding memo): 
 Wound closure- will be assessed on a weekly basis as described in Section 8.6. 
Complete wound closure defined as skin re-epithelialization without drainage or 
dressing requirements confirmed at two consecutive study visits, 2 weeks apart [75]. 
Wounds will be considered as closed  when the assessor marks ‘Yes’ in regards to 
complete wound closure, which will be further confirmed in the wound closure 
confirmation visit, 2 weeks later.  
 Cosmesis and Function (using MVSS)- will be assessed at the following time-points: at 
1 month from reaching complete wound closure confirmation of last  wounds and at 3, 
6, 12, 18 and 24 months from reaching complete wound closure confirmation.  
6.4 
STUDY TREATMENTS AND DOSAGE  
6.4.1 
NexoBrid 
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel 
for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the 
active component. Following mixing of the powder with the gel vehicle, each gram of the 
prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a 
mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).  
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of 
sterile Gel Vehicle (ratio of 1:10) , respectively to obtain sterile NexoBrid Gel. NexoBrid Gel 
is applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile 
Gel Vehicle per 1% of TBSA (~ surface of an adult palm) for four hours (or 5 g NexoBrid 
sterile powder mixed with 50g sterile Gel Vehicle per 2.5% of TBSA. The NexoBrid powder 
and the Gel Vehicle are to be mixed at the patient bedside 15 min prior to use. 
NexoBrid may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. NexoBrid may only be applied twice to the same burn 
wound area. 
6.4.2 
Gel Vehicle 
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn skin. Gel 
Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel per 1% of TBSA (~ 
surface of an adult palm) or 50 grams per 2.5% TBSA for four hours.  
Gel Vehicle may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. The Gel Vehicle may only be applied twice to the same 
burn wound area. 
6.4.3 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excisions.  
Non-surgical procedures will include the application of (collagenase ointment (e.g. Santyl), 
antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 
The need of either non-surgical or surgical procedures will be determined by the burn 
specialists and can be repeated as needed until complete debridement.  
6.5 
TRIAL PERIODS 
The total duration of the study treatment and follow up period of each participating subject is 
expected to be 25 months: Following initiation of the Eschar removal procedure, each subject 
will be followed up weekly (Weeks 1, 2, 3 and 4 etc.) until complete wound closure was 
achieved and 2 weeks later for wound closure confirmation, for each of the subject's TWs. 
Long term follow-up visits will be performed at 1, 3, 6,  12, 18 and 24 months post last wound 
closure confirmation visit of each patient. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
SUBJECT ENTRANCE CRITERIA 
7.1.1 
Inclusion Criteria- Patient level 
1. Males and females; ≥ 18  and ≤ 70 years of age, 
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 ≤  15% TBSA; SPT, DPT and/or FT in depth, 
5. Informed consent can be obtained within 48 hours of the burn injury,  
6. Patients who are willing and able to sign a written consent form. 
7.1.2 
Inclusion Criteria – Wound level 
At least one wound (a continuous burn area which can be treated in one session; may 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’s blisters can be removed/unroofed, as judged by the investigator. 
7.1.3 
Exclusion Criteria- Patient level  
1. Patients who are unable to follow study procedures and follow up period, 
2. Modified Baux index15 ≥ 80, 
3. Patients with burned charred fingers, 3rd degree in depth and possibly devoid of circulation,  
                                                 
15 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and the presence of smoke 
inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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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, blast or chemical burns,  
6. Patients with DPT and/or FT facial burn wounds from flame, flash, explosion > 0.5%  TBSA 
(scald and contact burns are allowed),  
7. Patients with circumferential DPT and/or FT burns defined as Extremities at Risk (EAR)16,  
8. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3), 
9. 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 SSD treatment), 
10. Patients with pre-enrollment escharotomy, 
11. Patients with diagnosed infections as described in Section 11.6.3 of study protocol, 
12. Any signs or history that may indicate smoke inhalation (e.g. flame burn to the upper body, 
flames in enclosed space, smoke and fumes on the patient and in mouth and nostrils, deep flame 
burns >0.5 %TBSA to the face, cough, hoarseness, stridor or breathing difficulty including 
tachypnea possibly related to smoke inhalation, etc.), 
13. Pregnant women (positive pregnancy test) or nursing mothers, 
14. Poorly controlled diabetes mellitus (HbA1c>9%) in patients with known diabetes as captured in 
the medical history, 
15. Patients with BMI greater than 34.0 kg/m2, 
16. ASA greater than 2 (Appendix 13- ASA classification system) 
17. Cardio-pulmonary disease (MI within 6 months prior to injury, pulmonary hypertension, COPD 
or pre-existing oxygen-dependent pulmonary diseases, broncho-pneumonia, steroid dependent 
asthma or uncontrolled asthma), 
18. Pre-existing diseases which interfere with circulation (peripheral vascular disease, edema, 
lymphedema, surgery to regional lymph nodes, obesity, varicose veins), 
19. Any 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, cardiovascular disorder, pulmonary disorder, liver 
disorder including post alcoholic abuse impaired function or neoplastic disease), 
20. Chronic systemic steroid intake, 
21. History of allergy and/or known sensitivity to pineapples, papaya, Bromelain or papain, 
22. Current (within 12 months prior to screening) suicide attempt, 
                                                 
16 Extremities at Risk are circumferential DPT and/or FT burns with at least  one of the following: 
Any of the 5 “P”s (Pain, Paralysis, Pulselessness, Pallor, Paraesthesia), 
Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements within 30 minutes under the constricting eschar, 
SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity and the injured one,  
Pulse not detected by US Doppler.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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23. Mentally incapacitated adults who are incapable of giving legal consent (e.g. dementia, 
psychiatric patients, etc), 
24. Enrollment in any investigational drug trial within 4 weeks prior to screening, 
25. Current (within 12 months prior to screening) alcohol (daily consumption > 3 units for males 
and >2 units for females) or drug abuse17,  
26. Prisoners and incarcerated, 
27. Patients who might depend on the clinical study site or investigator. 
7.2 
SUBJECT WITHDRAWAL CRITERIA  
After screening and prior to treatment any changes in the patient's medical condition should be 
assessed. The patient should be excluded from treatment if these changes represent 
deterioration in his/her condition which may affect the patient's safety and/or suitability for the 
study (e.g. exclusion criteria).  
Throughout the course of a subject's participation in the study, he/she may be removed from 
the study as follows:  
 Whenever it is necessary to safeguard his/her welfare as judged by the Principle 
Investigator,  
 Participation in another investigational drug trial, 
 Subjects who express a desire to withdraw from the study. 
The reason for any subject withdrawal from the study should be recorded in the eCRFs and the 
occurrence should be reported to the sponsor. Early termination visit should include final 
assessments as in the Hospital Discharge visit, as applicable (please refer to Section 8.7).  
Discontinued subjects will not be replaced. 
When a subject is removed from the study treatment, he/she will receive treatment according to 
the standard of care as appropriate in the investigative site and will be followed up according to 
the study schedule, in accordance with patient’s availability. 
                                                 
17 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, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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7.2.1 
Treatment stopping rule (apply for NexoBrid or Gel Vehicle arms only) 
Treatment (eschar removal) should be stopped following a safety concerns raised by the 
treating physician or if a patient expresses his desire to withdraw from the study. In addition, in 
the following situations: 
7.2.1.1 
Burn Induced Compartment Syndrome Monitoring and Diagnosis 
Extremities developing clinical signs suspicious for the development of BICS such as swelling 
(but none of the 5 P's) and pressure approaching 25 mmHg and SpO2 stable >90% should be 
closely monitored for signs of improvement or deterioration that may require escharotomy. If 
clinical assessment and SpO2 monitoring are possible, they will be done continuously and 
recorded in the eCRFs every 2 hours. If such assessment is not practical, direct pressure will be 
measured every 2 hours from start of the eschar removal. The eschar removal process shall be 
discontinued and escharotomy will be performed in any of the following cases: 
 Increasing pressure >30 mmHg 
 Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity 
 Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity or deterioration of clinical signs 
 Any of the 5 “P” signs. 
Since in such cases the eschar removal procedure will not be completed as planned, such 
patients (if any) will still be part of ITT and any missing data usually collected during eschar 
removal (e.g. time to end of eschar removal, etc.) will be handled as missing data according to 
the protocol. 
In case of 3 consecutive cases where there is a need to disrupt the dressing and perform a 
surgical escharotomy, enrollment will be halted and a DSMB shall be convened to:  
 assess the severity of the phenomenon in a closed session 
 Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences 
As discussed above, increased interstitial/compartment pressure is a common medical 
condition in circumferential deep burns and its detection and resolution is part of daily standard 
of care. The only difference in the treatment of the patients in the study is during the eschar 
removal stage as dictated by randomization.  
7.2.1.2 
Coagulopathy during or within 24 hours of eschar removal 
It is evident that during the first 48 hours post injury there is deterioration in coagulation 
parameters in burn patients [76]. In addition, some burn patients are treated with anticoagulants 
after admission (in some burn centers all patients are treated with anticoagulants). Due to these 
facts, any stopping rule concerning coagulopathy after topical debriding agent application must 
take these factors into consideration.  
Enrollment will be halted and a DSMB will convene if 3 subjects develop the following signs 
which have been defined as life threatening coagulopathy in trauma patients: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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INR>2 or a PTT>2 times the normal range [77], in cases where the patient is not receiving 
anticoagulants that can explain the coagulopathy. 
A DSMB shall be convened to assess in a closed session the following: 
 The relationship between coagulopathy and the treatment arm 
 The severity of the phenomenon 
 Recommend on appropriate corrective measures, as applicable to prevent such reoccurrences  
DSMB investigation will consider patients’ medical history, including any anticoagulants 
given to the patient prior to start of treatment. 
7.2.1.3 
Post treatment diagnosed infection 
Following the eschar removal treatment, in case 3 subjects develop infections listed in Section 
11.6.3 and are assessed as related to the treatment arm (possibly, probably or related as defined 
in Section 12.1), enrollment will be halted and a DSMB will convene in close session to 
investigate cases reported and their relatedness and severity.  
In all the above 3 described cases, enrollment may continue in accordance with DSMB 
conclusions.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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8 
STUDY CONDUCT  
The healing and care of the burn wound may be divided into the three distinctive phases: 
1. Wound bed preparation 
2. Wound closure 
3. Scar modulation and maturation  
These phases are common to the care of all wounds and are well defined in acute wounds such 
as burns.  
In this study these phases and their treatment strategy are equal for all arms, NexoBrid, SOC, 
and Gel Vehicle, following the ABA white paper guidelines [1].  
8.1 
SCREENING AND BASELINE VISIT 
8.1.1 
  Screening and Baseline Procedures 
For subjects who are admitted to the burn unit, and who are willing to participate in the study, 
the following procedures will be performed: 
1. Signing of consent form:  
Prior to performing any study related activities/evaluations which are not considered as 
routine, the subject must be thoroughly informed about all aspects of the study, including 
scheduled study visits and activities, and must sign the informed consent form. A signed 
copy of the informed consent form must be given to the subject. Legal representative may 
be involved in the Inform Consent procedure and sign the form if this is pre approved by 
the local IRB/EC and only for subjects with temporary medical conditions related to the 
injury, subjects who might be under the influence of pain medication, sedation, etc. 
However, legal representative cannot sign the form for mentally incapacitated subjects 
(e.g. dementia, psychiatric patients, etc) who are incapable of giving legal consent 
(entrance criteria, Section 7.1), 
2. Review and documentation of complete demographics, medical history (e.g. specific 
cardiac, pulmonary, endocrine and renal diseases), and concomitant medications, 
3. Vital signs measurement including blood pressure, pulse rate, temperature and respiration 
rate, 
4. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale, Please 
refer to Appendix 9- Pain Measurement Scale), 
5. General physical examination (including smoke inhalation signs, signs for Burn Induced 
Compartment Syndrome, etc) including a record of weight and height, 
6. Obtaining burn etiology, mechanism of injury, place of injury, treatments prior to 
admission and general description of the burn wound (anatomical locations, % TBSA: 
clinically assessed by rule of palm), burn depth (as detail in Appendix 1- Wound Depth 
assessment- Clinical Evaluation) and description of the eschar (such as: white, moist, dry, 
gray, charcoal, etc.), 
7. Leukocyte count (WBC), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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8. Extremities At Risk (EAR) burns prone to develop BICS will be identified (See Burn 
wound definitions, Section 1.1). 
9. Pregnancy test for subjects of  child-bearing potential performed at local laboratory, 
10. HbA1c in patients with known diabetes as captured in the medical history, 
11. Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, 
whichever comes first, for patients with catheter,  
12. Prior to wound cleansing (Debridement), all wounds should be labelled and photographed 
(as required in Appendix 3- Photographic wound documentation), 
13. Wounds cleansing (Debridement) as described in Section 8.1.2, 
14. Post wound cleansing (Debridement), before soaking all wounds should be labelled and 
photographed (as required in Appendix 3- Photographic wound documentation), 
15. Post cleansing, before soaking the wounds with antibacterial solution (section 8.1.2, point 
3), the % TBSA (clinically assessed by the rules of palm) and burn depth (as detailed in 
Appendix 1- Wound Depth assessment- Clinical Evaluation) of each wound and of each 
TW will be recorded, 
16. Pain management medications and analgesia/sedation levels should be recorded (see pain 
management protocol provided in Appendix 2- Pain Management Procedures)  
17. Completion of the applicable eCRFs, 
18. Randomization of eligible subjects (as described in Section 13.7.1). 
8.1.2 
 Cleansing (Debridement) and Wound Characterization 
The initial care of the burn wound starts with general cleaning that removes all gross 
contaminants, soot and blisters (“Debridement”). As described in Neligan Plastic Surgery 
Textbook, volume 4 pg 403 [78], DPT burns contain large blisters. Blister fluid is known to be 
detrimental to raw exposed tissues and to wound healing as well as being prone to infection 
that will spread in this occluded space. The blisters tend also to rupture under the dressings and 
during their changes. Using aseptic techniques the blisters should be removed (“unroofed”) and 
the exposed wound treated as needed [78-82].  
Preventive analgesia/sedation medication (pain management) will be mandated as for an 
extensive dressing change as commonly practiced (see Appendix 2- Pain Management 
Procedures). The following should be performed: 
1. Topically applied medication on the wound site must be discontinued, 
2. The wound should be cleansed thoroughly with saline, soap or antibacterial solution and 
the blisters (superficial keratin layer) removed by common procedures (i.e. rubbing with 
sterile gauze, saline soaking, etc), 
3. A dressing soaked18 with an antibacterial solution, i.e. 3-5% Sulfamylon, 0.05-0.5% 
Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution, must be applied to 
                                                 
18 Soaking refers to placing gauze soaked with fluid, e.g. saline or Dakin’s Solution on dressing the wound with thick, dry absorbent 
gauze, inserting inside a feeding tube or the tip of an IV set that offers the option of adding fluids at will.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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the wound and left in place for at least 2 hours. This dressing must remain wet until it is 
removed prior to application of the eschar removal agent/procedure. In order to prevent 
desiccation of the wound; the dressing must be changed at least every 12 hours if eschar 
removal is delayed. After soaking the dressing should be removed using aseptic 
techniques, 
4. Check that the superficial keratin (blister) has been removed (NOTE: For deep charred, 
flame burns blister-keratin removal may be difficult. In a deep, charred burn a thorough 
scraping is needed to remove the charred blister from its dermal eschar). In the event that 
not all the superficial keratin layer is removed from the burn eschar, repeat steps 2 and 3 as 
the blister-keratin may be a focus for infection and will prevent the eschar dissolution by 
isolating it from the topical agent. 
8.1.3 
 Assessments within 24hrs Prior to Eschar removal  
The following standard assessments and laboratory procedures will be performed for all study 
arms within 24 hours prior to the beginning of the first eschar removal treatment:  
1. Blood culture (all arms),  
2. PK blood sample (2ml)19, (NexoBrid patients) see Appendix 10- Procedures for specific 
blood tests, 
3. Immunogenicity blood sample20 (3ml) (NexoBrid patients), see Appendix 10- Procedures 
for specific blood tests, 
4. PTT & INR (2ml) blood sample,  
Make sure at least 2 h soaking was performed and that all blister-keratin has been removed 
from the TW's eschar. If there are still blisters/keratin remains, clean the wound thoroughly and 
remove the superficial keratin layer or blisters from the wound area, as the keratin will isolate 
the eschar from direct contact with the topical agent (as described in Section 8.1.2),  
The results of the above on-site tests (describe in Section 8.1.1 and Section 8.1.3) may be used 
for study data collection prior to signing of the consent form only in case they are part of 
routine hospital care regardless of study procedures and within relevant timelines.  
8.2 
TREATMENT PROCEDURE- ESCHAR REMOVAL; NEXOBRID/SOC/ GEL VEHICLE - 
INITIATED WITHIN 72 HOURS FROM INJURY  
8.2.1 
Assessments and TWs preparation 1 h prior to Eschar removal– All 
arms 
Patients will undergo the following procedures within one hour (± 15 min) prior to start of 
eschar removal treatment:  
1. Interstitial/compartment pressure will be measured in circumferential extremity wounds 
(See Burn wound definitions, Section 1.1). The measurement will be done, as described in 
                                                 
19 PK will be performed for a subset of 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 hrs.   
20 Immunogenicity will be performed in NexoBrid patients only. The overall Immunogenicity sampling time points: 0, 7 days, 28 days, 
56 days, 6 months and 24 months.   
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Section 11.6.2, in addition to clinical assessment and SpO2 monitoring within 1 hour prior 
to eschar removal or Escharotomy, whichever is first, of each circumferential TW, 
2. Pre-Treatment tests to be performed at central lab: Serum chemistry, hematology and 
urinalysis (as described in Section 11.6.1), should be performed within one hour prior to 
eschar removal initiation, 
3. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed within one hour 
prior to eschar removal initiation, 
4. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 60 
± 5 min, 40 ± 5 min and 20 ± 5 min prior to start of treatment,  
5. Preventive analgesia medication (pain management) will be mandated as for an extensive 
dressing change as routinely practiced; it should be initiated at least 15 minutes prior to 
dressing change or application in order to ensure pain free care (example of a 
recommended protocol provided in Appendix 2- Pain Management Procedures). Prior to a 
surgery, preventive sedation and/or general anesthesia will be mandated as routinely 
practiced. Pain management medications and analgesia/sedation level will be recorded,   
6. Qualitative-swab wound culture (per Target Wound), 
7. Prior to treatment (post cleansing, when relevant), all Target Wounds should be labeled 
and photographed (please refer to Appendix 3- Photographic wound documentation), 
8. Prior to treatment, the % TBSA (rule of palms) and burn depth (as detailed in Appendix 1- 
Wound Depth assessment- Clinical Evaluation) of each TW will be recorded, 
8.2.2 
Eschar Removal 
Eschar Removal process will be performed in accordance with randomization: SOC, Gel 
Vehicle or NexoBrid. Parameters describing the eschar removal treatment will be documented 
in the medical records in addition to starting and completion time of each procedure, recovery 
time, analgesia/anesthesia prescribed during treatment and level of analgesia prescribed, 
manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistants and number of kits used) who participated during the above period of time 
and disposables used (number of dressings, blades, etc). 
8.2.2.1 
Standard of Care (SOC) Eschar removal procedure- (to be initiated within 72 hours 
from injury) 
Subjects in the SOC group may be treated with a combination of surgical and non-surgical 
eschar removal procedures, for each TW, according to the investigator's judgment. In case of 
indeterminate burns (second degree burns of changing depths) and/or combination wounds, 
mixed of second and third degrees, which are difficult to diagnose on arrival, non surgical 
treatments is usually being initiated for few days when the burn conversion (progression) and 
demarcation is taking place. Once a diagnosis is feasible, surgical procedures will usually be 
performed for deep wounds or additional non surgical procedures will be continued for 
superficial wounds.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The time-point of start of the SOC eschar removal procedure should be documented. This time 
point refers to the start time of the first treatment given to the patient, for eschar removal, post 
randomization (any topical application or surgical procedure whichever is first).  
8.2.2.1.1 
Surgical eschar removal procedure 
Sedation and general anesthesia as routinely practiced will be administered before and during 
surgery and recorded. The wound will undergo surgical excision according to common SOC. 
Parameters describing the surgical procedure will be documented. Eschar removal will be 
assessed immediately after each eschar removal surgical procedure, before a temporary or 
permanent dressing will be applied. Surgical procedures intended for eschar removal are pre-
specified in the protocol for standardization and will include tangential/ minor/ avulsion/ 
Versajet/ dermabrasion excision).  
8.2.2.1.2 
Non-surgical eschar removal procedure 
Eschar removal will be assessed on a daily basis and following any dressing change as long as 
it does not involve unnecessary dressing change. Non-surgical procedures intended for eschar 
removal are pre-specified below for standardization and will include the application of Santyl 
(Collagenase ointment), antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin 
Solution), ointments/creams (e.g. Bacitracin, Polysporin, Silvadene) and/or Silver dressings 
(e.g. Mepilex Ag, Aquacel Ag, Acticoat). Non-Surgical procedure is considered as one 
procedure for whole period of any continuous dressing changes until either complete eschar 
removal is achieved or until surgical eschar removal is conducted.  
8.2.2.1.3 
Additional SOC procedures: 
In addition to pre first treatment assessment as described in Sections  8.1.3 & 8.2.1, in case that 
more than one SOC procedure is performed, 1 hour (± 15min) pre surgical treatment the 
following assessments should be repeated: 
1. Interstitial/compartment pressure will be measured in circumferential extremity wounds 
(See Burn wound definitions, Section 1.1). The measurement will be done, as described in 
Section 11.6.2, in addition to clinical assessment and SpO2 monitoring within 1 hour prior 
to eschar removal or Escharotomy, whichever is first, of each circumferential TW, 
2. Central lab blood tests: Serum chemistry, hematology and urinalysis (as described in 
Section 11.6.1), should be performed within one hour (± 15min) prior to eschar removal 
initiation, 
3. Local lab tests: PTT & INR (2ml) blood sample, within one hour (± 15min) prior to eschar 
removal initiation, 
4. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed within one hour 
prior to eschar removal initiation, 
5. Qualitative-swab wound culture (per Target Wound), 
6. Prior to treatment (post cleansing, when relevant), all Target Wounds should be labeled 
and photographed (please refer to Appendix 3- Photographic wound documentation), 
7. Prior to treatment, the % TBSA of each TW will be recorded, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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8. Sedation and general anesthesia as routinely practiced will be administered before and 
during surgery and recorded. The wound will undergo surgical excision according to 
common SOC.  
*The assessment described above should be done only prior to surgical procedures. In 
cases that non-surgical procedures are not the first treatment, the assessments described 
above should not be done, only sedation (point 8 above) should be recorded.  
8.2.2.1.4 
During the first SOC procedure: 
1. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 30 
± 10 min, 120 ± 15 min and 4 ± 0.5 hours after start of eschar removal, non surgical or 
Surgical. 
8.2.2.1.5 
Post each SOC procedure: 
1. The parameters describing the SOC procedure will be documented in the eCRFs in 
addition 
to 
starting 
and 
completion 
time 
of 
the 
eschar 
removal 
process, 
analgesia/anesthesia prescribed during treatment and level of analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
if applicable, anesthesiologists, registered nurses, practical nurses and unskilled 
assistances) who participated during the above period of time and disposables used 
(number of dressings, blades, etc), 
2. Target Wounds should be labeled and photographed at the end of each eschar removal 
treatment. The time-point of the final SOC eschar removal should be documented,  
3. Eschar removal will be assessed immediately following the completion of each procedure 
(by the same assessor who evaluate blindly the eschar removal in the topical arms) and 
recorded for each TW. TWs depth will be evaluated once, post complete eschar removal, 
4. Qualitative-swab wound culture (per Target Wound) will be taken at the end of each 
eschar removal procedure (surgical and/or non-surgical procedure), 
5. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of each eschar removal procedure (surgical and/or non-surgical procedure), 
6. Interstitial/compartment pressure will be measured (as described in Section11.6.2) post-
eschar removal, per circumferential extremity wound, after the completion of each surgical 
/ non surgical procedure or escharotomy, whichever is first, 
7. Pain assessment using a routinely accepted pain-scale (VAS) as described in Appendix 9- 
Pain Measurement Scale should be performed four hours (± 15min) after the end of each 
procedure, 
8. Local lab tests: PTT & INR (2ml) blood samples should be performed four hours (± 
15min) after start of each surgical procedure, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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9. Central lab: Serum chemistry, hematology and urinalysis, should be performed 4 hours (± 
15min) after the end of each procedure (end of surgical procedure and/or end of non 
surgical procedure),  
10. Blood culture - 4 h (± 15min) after the end of each procedure, 
11. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented, 
12. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
P
* ost non-surgical procedures, there is no need to perform VAS scale, central lab tests, 
PTT/INR, blood culture and wound culture if surgical procedure is done within 6 h  post the 
non-surgical procedure. These tests will be captured as the pre-surgical procedures. 
*Post surgical procedures, all procedures should be done, even in case that non-surgical 
procedure is followed immediately (within 6 hours). Only VAS scale pain assessment should 
be done as close as possible to the defined timeline but before dressing is applied. All the 
additional tests (e.g. central labs) should be performed within specified timelines.  
8.2.2.2 
Topical arms; NexoBrid/Gel Vehicle - Eschar removal procedure (to be initiated 
within 72 hours from injury) 
8.2.2.2.1 
Preparation 
1. Surround the area from which you wish to remove the eschar with a paraffin ointment 
adhesive barrier by applying it a few centimeters outside of the treatment area (using an 
adhesive-barrier dispenser). The paraffin layer must not come into contact with the area to 
be treated to avoid covering the eschar, thus isolating the eschar from direct contact with 
the topical agent, 
2. Sprinkle sterile isotonic (0.9%) sodium chloride solution on the burn wound. The wound 
must be kept moist during the application procedure. 
8.2.2.2.2 
Application 
Application of the product, as per the randomization, should follow the instruction for use 
described in Section 6.4, 
1. The wound should then be covered with an occlusive film dressing that adheres to the 
adhesive barrier material applied as per the instruction above. The topical agent should fill 
the entire occlusive dressing, and special care should be taken not to leave air in this 
occlusive dressing. Gentle pressing of the occlusive dressing at the area of contact with the 
adhesive barrier will ensure adherence between the occlusive film and the adhesive barrier 
and achieve complete containment of topical agent on the treatment area, 
2. The dressed wound should be covered with a loose, thick fluffy dressing, held in place 
with a bandage, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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3. The dressing should remain in place for 4 hours (± 15min),  
4. Circumferential extremity wounds should be monitored to detect EAR: If clinical 
assessment and SPO2 monitoring are possible, they will be done continuously and recorded 
in the eCRFs every 2 hours. If such assessment is not practical, direct pressure will be 
measured every 2 hours from start of the eschar removal. BICS should be treated by the 
investigator as described in Section 11.6.2. Circumferential extremity which is assessed as 
EAR at this stage should not be removed from the study but monitored as described above 
and in Section 11.6.2. 
All unused products should be kept for accountability as described in Section 10.1 (all remains 
and unused bottles). 
Starting and completion time of the eschar removal process should be documented in the 
eCRFs. 
8.2.2.2.3 
During 1st Application 
1. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 30 
± 10 min, 120 ± 15 min and 4 ± 0.5 hours after initial application of NexoBrid/Gel Vehicle 
PK blood sample (2ml) will be performed in a subset of NexoBrid patients21 at the following 
time points: 1h ± 10 min and 2h ± 10 min and 4h  ± 15 min from initial application. 
8.2.2.2.4 
Removal of topical agent 
1. Administer appropriate preventive analgesia medication, 
2. PTT & INR (2ml) will be tested at 4hrs ± 15 min after start of eschar removal procedure. 
3. After 4 hours (± 15 min) of treatment at each TW, remove the occlusive dressing using 
aseptic techniques, 
4. The adhesive barrier should be removed using a sterile blunt-edged instrument (e.g. tongue 
depressor), 
5. Remove the dissolved eschar from the wound by wiping it away with a sterile blunt-edged 
instrument, 
6. Wipe the wound thoroughly first with a large sterile dry gauze or napkin, followed by a 
sterile gauze or napkin that has been soaked with sterile isotonic (0.9%) sodium chloride 
solution. Rub the treated area until the appearance of a pinkish surface with bleeding 
points or a whitish tissue. Rubbing will not remove adhering undissolved eschar in areas 
where the treatment has been ineffective and eschar still remains, 
7. Interstitial/compartment pressure will be measured (as described in Section 11.6.2) post-
eschar removal per circumferential extremity wound after removal of dissolved eschar or 
Escharotomy, whichever is first, 
8. Apply a dressing soaked with an antibacterial solution, i.e. 3-5% Sulfamylon, 0.05-0.5% 
Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution for an additional 
                                                 
21 Only in 20 NexoBrid patients  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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2 hours. This wet-to-dry dressing will absorb and remove remaining NexoBrid and 
dissolved eschar that could not be removed by a simple wiping, 
9. Target Wounds should be labeled and photographed at the end of the 2hrs soaking,  
10. Eschar removal will be assessed immediately following the completion of 2 hrs soaking by  
an Investigator or designee, blinded to the treated arm. Parameters describing the eschar 
removal treatment will be documented in the eCRFs in addition to starting and completion 
time of the procedure, recovery time, analgesia/anesthesia prescribed during treatment, 
level of analgesia prescribed (as described in Appendix 2- Pain Management Procedures), 
manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistants and number of study drug kits used) who participated during the above 
period of time and disposables used (number of dressings, blades, etc), 
11. Qualitative wound culture (swabs), per TW, will be performed at the end of the soaking 
period. 
12. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of the soaking period. 
13. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale) as 
described in Appendix 9- Pain Measurement Scale should be performed four hours (± 
15min) after the end of the 2 hrs soaking period, 
14. Central lab: Serum chemistry, hematology and urinalysis (as described in Section 11.6.1), 
should be performed four hours (± 15min) after the end of the 2 hrs soaking period. 
15. Blood culture - four hours (± 15min) after the end of the 2 hrs soaking period. 
16. All types of blood products transfusions (e.g. units of whole blood or packed cells and 
volume) will be documented,  
17. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method), 
8.2.2.2.5 
Repeat application 
The blinded assessor will assess the completeness of eschar removal. 
1. In case eschar removal from the target wound after the first application is not complete, 
but at least 50% eschar was removed, a second eschar removal procedure using the 
randomized topical agent (NexoBrid/ Gel Vehicle) will be performed. The randomized 
drug should be re-applied to the entire TW if necessary, but can also be applied only on 
the areas of the TW left with eschar. Reasons for failure should be recorded in the eCRFs, 
2. Pre treatment assessments should be repeated as described in Section 8.2.1, excluding 
ECG and wound depth assessment. In case procedures are done continuously (or less than 
6 hours between procedures), post first treatment procedure assessments should be done as 
close as possible to the defined timelines but before second application start.  Pre treatment 
second assessments should not be done, 
3. Treatment application should be conducted as detailed above,  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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4. Topical agent removal and post treatment assessments should be repeated as described in 
Section 0,  
5. No more than two eschar removal procedures using the randomized topical agent 
(NexoBrid//Gel Vehicle) will be allowed per TW. 
6. Second eschar removal session can start immediately after the 2 hrs soaking done post the 
first application of the randomized arm (pre soaking period is not required before a second 
application of the randomized arm treatment to the same target wound),  
7. Repeat application (second application of the randomized arm treatment to the same target 
wound) should be initiated no later than 24 hours after the start time of the first 
application.  
In case of a recorded failure following the topical application/s, additional surgical and/or non 
surgical eschar removal will be allowed as described below and in Section 8.2.2.1.  
8.2.2.2.6 
Additional surgical eschar removal procedure 
Surgical 
procedures 
intended 
for 
completion 
of 
eschar 
removal 
will 
include 
tangential/minor/avulsion/Versajet/dermabrasion excision.    
8.2.2.2.7 
Additional non-surgical eschar removal procedure: 
Non-surgical procedures intended for eschar removal should include the application of any of 
the following allowed agents: (Collagenase ointment (e.g. Santyl), antimicrobial solutions (i.e. 
Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (i.e. Bacitracin, Polysporin, 
Silvadene) and/or Silver dressings (i.e. Mepilex Ag, Aquacel Ag, Acticoat). Continued 
application of NexoBrid or Gel Vehicle is not allowed at this stage. This/these will be applied 
on the cleaned and washed eschar of each TW to induce maceration and autolysis of eschar.  
8.2.2.2.8 
Pre each additional procedure: 
1 hour pre treatment assessments should be performed as described: 
1. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed within one hour 
prior to eschar removal initiation, 
2. Central lab blood tests: Serum chemistry, hematology and urinalysis (as described in 
Section 11.6.1), should be performed within one hour (± 15min) prior to eschar removal 
initiation, 
3. Qualitative-swab wound culture (per Target Wound), 
4. Preventive analgesia medication (pain management) will be mandated as for an extensive 
dressing change as routinely practiced; it should be initiated at least 15 minutes prior to 
dressing change or application in order to ensure pain free care (example of a 
recommended protocol provided in Appendix 2- Pain Management Procedures). Prior to a 
surgery, preventive sedation and/or general anesthesia will be mandated as routinely 
practiced. Pain management medications and analgesia/sedation level will be recorded,   
5. Prior to treatment (post cleansing, when relevant), all Target Wounds should be labeled 
and photographed (please refer to Appendix 3- Photographic wound documentation), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6. Prior to treatment, the % TBSA of each TW will be recorded, 
 *Pre treatment of additional procedures should not be performed in case the procedure is 
being initiated within 6 hrs from previous procedure. Only preventive analgesia medication 
8.2.2.2.9 
Post each additional procedure: 
1. The parameters describing the additional procedure will be documented in the eCRFs in 
addition 
to 
starting 
and 
completion 
time 
of 
the 
eschar 
removal 
process, 
analgesia/anesthesia prescribed during treatment and level of analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
if applicable, anesthesiologists, registered nurses, practical nurses and unskilled 
assistances) who participated during the above period of time and disposables used 
(number of dressings, blades, etc), 
2. Target Wounds should be labeled and photographed at the end of each eschar removal 
treatment. The time-point of the final SOC eschar removal should be documented,  
3. Eschar removal will be assessed immediately following the completion of each procedure 
(by the same assessor who evaluate blindly the eschar removal in the topical arms) and 
recorded for each TW. TWs depth will be evaluated once, post complete eschar removal, 
4. Qualitative-swab wound culture (per Target Wound) will be taken at the end of each 
eschar removal procedure (surgical and/or non-surgical procedure), 
5. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of each eschar removal procedure (surgical and/or non-surgical procedure), 
6. Interstitial/compartment pressure will be measured (as described in Section 11.6.2) post-
eschar removal, per circumferential extremity wound, after the completion of each surgical 
/ non surgical procedure or escharotomy, whichever is first, 
7. Pain assessment using a routinely accepted pain-scale (VAS) as described in Appendix 9- 
Pain Measurement Scale should be performed four hours after the end of each procedure, 
8. Local lab tests: PTT & INR (2ml) blood samples should be performed four hours after 
start of each surgical procedure, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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9. Central lab: Serum chemistry, hematology and urinalysis, should be performed 4 hours ( 
after the end of each procedure (end of surgical procedure and/or end of non surgical 
procedure),  
10. Blood culture - 4 h after the end of each procedure, 
11. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented,  
12. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
P
* ost non-surgical procedures, there is no need to perform VAS scale, central lab tests, 
PTT/INR, blood culture and wound culture if surgical procedure is done within 6h post the 
non-surgical procedure. These tests will be captured as the pre-surgical procedures. 
*Post surgical procedures, all procedures should be done, even in case that non-surgical 
procedure is followed immediately (within 6h), only VAS scale pain assessment should be 
done as close as possible to the defined timeline but before dressing is applied. All the 
additional tests (e.g. central labs) should be performed within specified timelines.  
8.3 
GENERAL ASSESSMENTS, POST ESCHAR REMOVAL  
The following assessments will be performed for all arms: 
1. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be measured 
daily, in the morning time (5 AM to 10 AM), starting on the morning after the start of 
eschar removal, until hospital discharge, 
2. Pain assessments will be performed daily, in the morning time (5 AM to 10 AM) using a 
standard pain-scale ruler (VAS) (please refer to Appendix 9- Pain Measurement Scale), 
starting on the morning after the start of eschar removal, until hospital discharge, 
3. 12-lead ECG (in triplicate) will be performed, if feasible, at 12 ± 0.5 hours, 24 ± 1 hours 
and 48 ± 2 hours after start of the eschar removal treatment, 
4. PK blood sampling (2ml) will be  continued in a subset of patients22 at 12  0.5 hours, 24 
 1 hours and 48  2 hours from start of the 1st application of NexoBrid (ONLY for 
NexoBrid patients),  
5. Local lab tests: PTT & INR (2ml) blood sample, will be taken 24  1 hours and 48  2 
hours after start of Eschar removal procedures, 
6. All types of  blood product transfusions (e.g. units of whole blood or packed cells and 
volume) will be documented throughout the patient admission, The physician will be 
asked to comment on whether the blood transfused is related to any specific procedure 
performed (e.g. surgical eschar removal, preparation for an autograft, etc), 
                                                 
22 Only for 20 patients treated with NexoBrid. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 hrs.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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7. Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, 
whichever comes first, for patients with catheter, 
8. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
8.4 
POST-ESCHAR REMOVAL- WOUND MANAGEMENT 
In TWs which were assessed to reach complete eschar removal, the consequent wound closure 
phase can be initiated by grafting or epithelialization. The following section will describe 
wound management, post eschar removal, and is relevant to all TWs, regardless of the eschar 
removal method performed in accordance with the randomization. 
Following to completion of eschar removal (NexoBrid, Gel Vehicle or SOC), different sites in 
the same patient may require different treatment strategies [28]. In general, raw bed, regardless 
of the eschar removal means, should always be protected by a dressing or a topical medicament 
and never remain open or allowed to desiccate. 
Subsequently, wound management for all treatment arms should follow the normal standard 
care for open, raw surfaces based on the general principles described below. Please refer to 
Appendix 5- Wound management; approved covers for list of approved wound care products: 
1. Wounds having Full thickness defects should be grafted with autografts or permanent 
dermal substitutes (i.e. Integra, Matriderm, Hyalomatrix) as soon as possible after eschar 
removal. If permanent cover such as autografting has to be postponed, a temporary 
adherent cover (e.g. allograft, Xenograft, etc) should be used until permanent closure is 
possible. Prior to grafting the clean eschar-free bed should be refreshed by scraping it to 
open occluded capillaries and remove fibrin deposits and thrombi. In rare cases of exposed 
tendons, blood vessels or bone, flaps may be used as protection and permanent cover.  
Use of negative pressure wound therapy (e.g. VAC) on top of the autograft for 2-3 days 
promotes take by ensuring drainage, contact and adherence to the wound bed and is 
commonly used.  
2. Wherever viable dermal exists, such as in the partial thickness burns (mid and deep 
partial), healing by spontaneous epithelialization on these partial thickness areas could be 
attempted for a period of approximately 3 weeks in order to reduce surgery and autograft 
use with donor site sacrifice [96], but should be carefully evaluated for a satisfying 
progress on a weekly basis. In these cases, the following wound management should be 
performed: 
a. The raw surface should be covered with an adherent biological cover (i.e. allograft, 
Xenograft), synthetic dressings or skin substitutes (e.g. Mepilex® Ag, Mepilex® transfer 
Ag, Aquacel Ag, etc) in order to protect the raw surface (mainly from desiccation) and 
provide the microenvironment necessary for epithelialization (e.g. 5% sulfamylon, 
Bacitracin, etc). If allografts, xenografts or any film-like products are applied on the 
debrided wounds, they should be perforated or meshed (and not expanded) for drainage 
and optimal conforming to the bed. Topical medicaments can also be used as covers as 
long as they do not interfere with the healing process (as in the case of SSD or Iodine 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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preparations) and moisturize or prevent desiccating the healing bed (the above are 
suggested coverages to apply on the clean wound bed. For additional approved 
biological covers, skin substitutes and topical medications please refer to Appendix 5- 
Wound management; approved covers). 
b. Use of negative pressure wound therapy (e.g. VAC) on top of the graft or primary 
biological cover dressing including autograft for 2-3 days can ensure drainage, contact 
and adherence to the wound bed. The use of negative pressure wound therapy (NPWT) 
for a few days in order to stabilize and promote skin graft adherence and take is quite 
commonly practiced as part of the routine engraftment procedure. It is applied at the 
end of engraftment over the applied meshed or perforated autograft for 2-4 days and 
kept until first dressing change [105].   
c. The cover and dressings should be assessed for signs of contamination, infection or 
sloughing. Contamination or infection may be treated with topical antibacterial soaking 
or irrigation for a few days as well as systemic antibiotics, according to the 
investigator’s medical judgment.  Sloughing tissue should be removed by wiping away 
the non-adherent parts.  The exposed areas should be protected from desiccation and 
treated either as exposed dermis, aiming at epithelialization, or as a full thickness defect 
which should be autografted or closed by permanents skin graft or substitutes. Dry 
hydrogels, gelfoams, hydrofibres, alginates, Biobrane etc. applied on a viable raw bed 
can desiccate the wound surface and if used, should be soaked periodically to provide 
moisture to the healing wound. 
d. Re-assessment of wound should be performed at least on a weekly basis (as per Section 
8.6)[83]: 
i. 
If the non healing area is a full thickness wound, the area should be autografted 
or closed permanently as soon as possible.  
ii. 
Areas with preserved dermis should be treated with approved topical 
medications or covered with approved biological covers in order to promote 
epithelialization and control granulation tissue that may start to develop after 2 
weeks. Granulation tissue that appears on the healing surfaces should be treated 
immediately. Granulation tissue forms-in and results from the proliferative 
phase of the inflammatory response [78]. Topical corticosteroids' primary 
activity is anti-inflammatory and/or immunosuppressive effects [84-85] (e.g. 
Synalar which is indicated for the relief of the inflammatory & pruritic 
manifestations & Diprolene Ointment which is a super-high potency 
corticosteroid indicated as well for the relief of the inflammatory and pruritic 
manifestations). Granulation tissue of wound’s bed, being an inflammatory 
process, is often modulated by topical steroid preparations for short periods (2-3 
days), alternating with other topical medications. The topical steroids facilitate 
control of granulation tissue and the cover that prevents desiccation allows 
epithelialization23.     
                                                 
23 Steroid preparations are indicated and currently used as solutions, creams, ointments and also systemically for 
shorter and longer periods in most inflammatory process.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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iii. 
If the non-epithelialized areas after > 2 weeks of healing are small (< ½ %TBSA 
or < 50 cm2) with many interposing epithelializing islands, topical medication 
can be applied. Medications such as Biafin or antibiotic ointments, creams or 
hydrocolloid dressings that will prevent desiccation and will provide a good 
environment for the epithelialization process are recommended. Special 
attention should be paid upon removal of these medicated dressings so that the 
epithelializing surface will not be disrupted.  
Exposed dermis can be autografted early after eschar removal in order to expedite wound 
closure but in many cases the dermis may epithelialize under the graft, dislodging it after 2-3 
weeks or the graft may take and remain as an over-grafting.  
Conservative, non-surgical treatment by the antimicrobial Silversulfadiazine (SSD) dressing 
followed by daily dressing change and bathing is designed to slowly slough and debride the 
eschar-covered wound by autolysis without excessive infection. SSD should not be used on a 
clean bed as it decreases epithelialization. The pseudoeschar caused by SSD can sometimes 
serve as a protective layer to the areas of epithelialization process but it is often misdiagnosed 
as newly formed eschar. This pseudoeschar should not be surgically excised (thus sacrificing 
a viable dermal bed) and conservative treatment should be continued until the entire 
pseudoeschar spontaneously sloughs off. After sloughing of the pseudoeschar the resulting 
surface should be assessed and full thickness non healing areas permanently closed (grafted). 
NOTE: Tangential excision of pseudoeschar will most probably result in a full thickness 
defect even if it originally covered preserved dermis with epithelialization potential.  
A detailed overview of post eschar removal wound closure is presented in Appendix 4- Post-
Eschar removal Wound Management. 
8.5 
WOUND MANAGEMENT PROCEDURES 
The following relevant details should be recorded: 
1. Preventive analgesia medication (pain management) will be mandated for post surgical 
dressing changes as routinely practiced by the PI for a pain free extensive dressing change 
and wound care; it should be initiated at least 15 minutes prior to dressing change (example 
of a recommended protocol provided in Appendix 2- Pain Management Procedures),  
2. Target Wounds coverage type (all coverages used post-eschar removal, until hospital 
discharge) and % area applied with, 
3. Any additional tangential/minor/Versajet/dermabrasion excision(s), which is done as a 
preparation for cover/autograft should be recorded,  
4. The relevant TW should be photographed (within 1 hour before and immediately at the end 
of the excision procedure) and % of treated wound excised (out of the original debrided 
wound) should be clinically assessed, 
5. Central lab – hematology, will be taken within 1 hr prior to start of any excision and four 
hours after completion of the procedure, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6. For any autograft performed, the TW should be photographed before (within 1 hour) and 
after any procedure. The % of treated wound autografted (out of the original wound size) 
will be clinically assessed, 
7. Any autograft performed, if not immediately (within 6 hrs) following the excision- central 
lab - hematology, should be performed within 1 hr prior to start of the procedure (including 
any preparations required) and four hours after completion of the procedure, 
8. Parameters describing the surgical procedures will be documented in the eCRFs in addition 
to 
starting 
and 
completion 
time 
of 
the 
surgical 
procedure, 
recovery 
time, 
analgesia/anesthesia prescribed during treatment, level of sedation/analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
anesthesiologists, registered nurses, practical nurses, and unskilled assistances) who 
participated during the above period of time and disposables used (e.g. number of dressings, 
blades, etc),  
9. All types of blood product transfusions (e.g. units of whole blood or packed cells and 
volume to be recorded) prescribed to a subject with a record of date and time. The physician 
will be asked to comment on whether the blood transfused is related to any specific 
procedure performed (e.g. surgical eschar removal, preparation for an autograft, etc), The 
site (anatomical area), and size of the donor site will be photographed and clinically assessed 
(by rule of palm), 
10. Donor site coverage used will be recorded in the eCRFs, 
11. Background pain should be treated according to the individual needs in order to ensure pain 
free care, 
12. Adverse events and concomitant medication will be recorded. 
8.6 
FOLLOW-UP ASSESSMENTS: WEEKLY (7  2 DAYS) POST-START OF ESCHAR 
REMOVAL 
The following assessments will be performed and recorded 7 ± 2 days post-start of eschar 
removal and, thereafter, on a weekly basis until wound closure (based on start of eschar 
removal): 
1. The target wound and donor sites should be photographed and documented (as describe in 
Appendix 3- Photographic wound documentation), 
2. Clinical assessment of % of target wound area epithelialized and/or closed by graft (see 
also wound closure assessment described in Section 6.3), and assessment of % donor site 
epithelialized, will be assessed by a second blinded assessor, blinded to all treatment arms, 
3. Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment (as describe in 
Appendix 3- Photographic wound documentation), will be assessed by a second blinded 
assessor, blinded to all treatment arms, 
4. Type of cover/dressing applied on TWs and donor sites should be recorded, 
5. 12-lead ECG (in triplicate) will be performed, if feasible, 7 ± 2 days from initial 
application,  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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6. Development of granulation tissue should be monitored. In case of initial appearance, 
treatment using approved ointment, creams or soaking during the epithelialization stages 
of wound healing should be applied. Details should be recorded in the eCRFs,  
7. Immunogenicity blood samples (3ml) should be taken in NexoBrid patients as per the 
timelines described in Section 11.6.5, per Appendix 10- Procedures for specific blood 
tests. 
8. Weekly follow-up assessments will be continued until complete wound closure for all of a 
subject's treated target wounds24 (please refer to Section 8.8). 
8.7 
HOSPITAL DISCHARGE 
The following procedures and assessments will be performed and recorded before a patient’s 
discharge from the hospital (within 24 hours prior to discharge): 
1. The target wounds and donor sites should be labeled and photographed, 
2. Assessment of % of wound area epithelialized and/or closed by graft,  
3. Assessment of % of donor site area epithelialized, 
4. Type of cover/dressing applied on TWs and donor sites should be recorded, 
5. Physical examination and weight, 
6. Date of hospital discharge. 
Weekly follow-up assessments will be continued until complete wound closure as per Section 
8.6 above. 
8.8 
FOLLOW-UP ASSESSMENTS: WOUND CLOSURE CONFIRMATION 2 WEEKS POST 
WOUND CLOSURE 
A confirmation of wound closure will be performed by a follow-up visit at day 14 ( 2 days) 
from wound closure, for each subject's target wounds. The following assessments will be 
performed: 
1. The wounds should be labeled and photographed (as describe in Appendix 3- 
Photographic wound documentation),  
2. Maintenance of complete wound closure will be confirmed, 
3. Patient diary will be provided to the patient to record any change in concomitant 
medications and or any adverse event, during the following monthly FU period.  
8.9 
FOLLOW-UP LONG TERM ASSESSMENTS 
The following assessments will be performed at 1 month (± 7 days), 3, 6, 12, 18 and 24 months 
(± 2 weeks for all time points) from the wound closure confirmatory visit: 
                                                 
24 Complete wound closure- defined as skin re-epithelialization without drainage or dressing requirements 
confirmed at two consecutive study visits, 2 weeks apart. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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1. The wounds should be labeled and photographed, 
2. Maintenance of complete wound closure (YES or NO) - only on month 1 and 3, 
3. Record of scar-modulating procedures and scar reconstructive procedures, if performed. 
This should include dates of initiation and termination of scar-modulating procedures 
including any procedure performed (compression therapy, silicone sheeting, steroid 
injections, etc.), 
4. Any Adverse Events and concomitant medications prescribed should be captured in the 
eCRFs, 
5. Quality of Life evaluation will be performed using Burn Specific Health Scale (BSHS-
B) and EQ5D as described in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire, 
6. Functionality evaluation will be performed using self completed questionnaires (as 
described in Appendix 12- Cosmesis, Function and Quality of Life Questionnaire): 
a. The “Lower Extremity Functional Scale” test for burns in the lower extremities,  
b. The “QuickDASH” outcome measure for burns in the upper extremities.  
7. Immunogenicity blood samples (3ml) should be taken in NexoBrid patients as per the 
timelines described in Section 11.6.5, per Appendix 10- Procedures for specific blood 
tests, 
8. The below evaluations will be performed by a second blinded assessor (who is blinded 
to all treatment arms): 
a. Cosmesis assessment using POSAS and MVSS for all TWs and donor sites, as 
described in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire,  
b. Range of Motion measurements of injured joints, if relevant: knee, ankle, 
shoulder, elbow, wrist and hand. Measurements will be performed on the 
patient’s own non injured joints as well for comparison to burned joints (as 
described in Appendix 14- Range of Motion). 
8.10 
FOLLOW-UP ASSESSMENTS: RE-ADMISSION TO HOSPITAL OR DAY CARE 
Persistent, small open wounds or reopening of new small areas are expected and can normally 
continue for months necessitating treatment as in- or outpatients as a part of a normal wound 
care [1]. A patient may be re-admitted to the hospital for continuation and follow-up of 
planned treatments or for unexpected events. The following procedures and assessments will 
be conducted and recorded: 
1. 
The reason for the re-admission should be recorded and any relevant TWs planned to be 
treated, 
2. 
The relevant TW/s should be labeled and photographed upon admission and before 
patient's discharge (as describe in Appendix 3- Photographic wound documentation), 
3. 
The wounds will be managed according to the guidelines described in Appendix 4- Post-
Eschar removal Wound Management, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The following relevant details should be recorded: 
4. Preventive analgesia medication (pain management) will be mandated for post surgical 
dressing changes as routinely practiced by the PI for a pain free extensive dressing change 
and wound care; it should be initiated at least 15 minutes prior to dressing change (example 
of a recommended protocol provided in Appendix 2- Pain Management Procedures),  
5. Target Wounds coverage type (all coverages used during readmission, until re hospital 
discharge) and % area applied with, 
6. Any additional tangential/minor/Versajet/dermabrasion excision(s), which is done as a 
preparation for cover/autograft should be recorded, 
7. The relevant TW should be photographed (within 1 hour before and immediately at the end 
of the excision procedure) and % of treated wound excised (out of the original debrided 
wound) should be clinically assessed, 
8. Central lab – hematology, will be taken within 1 hr prior to start of any excision and four 
hours after completion of the procedure, 
9. For any autograft performed, the TW should be photographed before (within 1 hour) and 
after any procedure., the % of treated wound autografted (out of the original wound size) 
will be clinically assessed, 
10. Any autograft performed, if not immediately (within 6 hrs) following the excision- central 
lab - hematology, should be performed within 1 hr prior to start of the procedure 
(including any preparations required) and four hours after completion of the procedure, 
11. Parameters describing the surgical procedures will be documented in the eCRFs in 
addition to starting and completion time of the surgical procedure, recovery time, 
analgesia/anesthesia prescribed during treatment, level of sedation/analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
anesthesiologists, registered nurses, practical nurses, and unskilled assistances) who 
participated during the above period of time and disposables used (e.g. number of 
dressings, blades, etc),  
12. All types of blood product transfusions (e.g. units of whole blood or packed cells and 
volume to be recorded) prescribed to a subject with a record of date and time. The 
physician will be asked to comment on whether the blood transfused is related to any 
specific procedure performed (e.g. surgical eschar removal, preparation for an autograft, 
etc),  
13. The site (anatomical area), and size of the donor site will be photographed and clinically 
assessed (by rule of palm), 
14. Donor site coverage used will be recorded in the eCRFs, 
15. Background pain should be treated according to the individual needs in order to ensure 
pain free care, 
16. Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment (as describe in 
Appendix 3- Photographic wound documentation), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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17. Clinical assessment of wound closure by % wound area epithelialized and/or by graft will 
be recorded at discharge,  
18. Adverse events will be recorded throughout the hospital stay, 
19. Concomitant medication will be recorded throughout the hospital stay, 
20. Date of hospital discharge will be recorded.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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9 
TREATMENT FLOW CHART – STUDY SCHEDULE 
Table 3- Treatment flow chart- all arms 
#- If applicable  
* Weekly FU assessments will be performed every 7± 2 days from start of treatment until complete wound closure 
**First treatment session will include any procedure for eschar removal: the NexoBrid/ /Gel Vehicle/Surgical or non-surgical procedure, as per randomization arm 
*** Procedure can be either surgical or non-surgical. A whole period of continuous dressing changes (from first coverage application to last coverage application) is considered as one non-surgical procedure, 
assessments should not be repeated for each dressing change; Pre non surgical procedures should not be performed if the non-surgical procedure is not the first eschar removal procedure.  
Parameter 
 Screening 
tests 
Baseline-24 h 
Pre First 
treatment 
session** 
During First 
treatment 
session**  
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures*** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management & Re-
admissions1- Per procedure 
assessment 
HD or premature 
discontinuation 
visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Inform Consent signing 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Burn History2 
X 
 
 
 
 
 
 
 
 
 
ConMeds & AEs 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Physical examination3 
X 
 
 
 
 
 
 
X 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
Post S 
Post  
X 
 
 
 
 
Pain assessment 
X 
 
 
1 h pre and 4h post S 
1 h pre and 4h post  
X 
 
 
 
 
Photograph of TWs 
X4 
 
 
1 h Pre & post S 
Pre &post  
 
Pre &post  
X 
X 
X 
Clinical assessment of the 
burn5  
X 
 
 
1 h Pre first and post each 
S 
1 h Pre first and post 
each 
 
Post  
X 
X 
 
Local lab - HbA1C, WBC, 
βhCG 
X 
 
 
 
 
 
 
 
 
 
Central lab hematology/ 
biochemistry tests & 
Urinalysis 
 
 
 
1h pre P & 4 h post S 
1h pre & 4 h post  
 
 
 
 
 
                                                 
1 Burn Management may include additional excisions, Autografts, coverage used and donor site data.  
2 Data captured will include burn etiology, mechanism of injury, place of injury, treatments prior to admission and general description of the burn wound (anatomical locations and description of the eschar (such as: white, 
moist, dry, gray, charcoal, etc.), % TBSA assessments and depth 
3 Physical examination will include height and weight. Height will be taken only once, at screening. 
4 Photos should be taken before and after cleansing 
5 Clinical assessments will include % TBSA per depth, % eschar removed, % excised, % autografted, % wound epithelialization (TW and donor site, if relevant) as relevant. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Parameter 
 Screening 
tests 
Baseline-24 h 
Pre First 
treatment 
session** 
During First 
treatment 
session**  
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures*** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management & Re-
admissions1- Per procedure 
assessment 
HD or premature 
discontinuation 
visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Central lab Hematology 
 
 
 
 
 
 
Only surgical procedures: 
1h pre P & 4 h post 
 
 
 
Cleansing (Debridement)1 
X 
# 
 
 
 
 
 
 
 
 
Fluid balance2 
X 
X 
 
X 
X 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Local lab Wound culture 
 
 
 
1 h pre and post S 
1 h pre and post  
 
 
 
 
 
Local lab Blood culture 
 
X 
 
4h post S 
4 h post 
 
 
 
 
 
12-Lead ECG (if feasible) 
 
 
0.5, 2,4h 
20, 40, 60 min (only pre 
first treatment) 
20, 40, 60 min (only pre 
first 
12, 24, 48 h 
 
 
week 1 
 
PK (for a subset of 20 
NexoBrid Pts) 
 
X 
1, 2h 
 
 
4, 12, 24, 48 h 
 
 
 
 
Immunogenicity assessment  
(NexoBrid patients only) 
 
X 
 
 
 
 
 
 
weeks 
1,4,8 
6, 24 
Local lab PTT & INR  
 
X 
4 h from start 
of treatment  
 
4 h from start of the 
surgical procedure 
24,48 h  
 
 
 
 
Circumferential extremity 
wounds monitoring3 
X 
 
Each application 
of the topical 
product 
1 h pre and post R 
1h pre &  post  
 
 
 
 
 
Eschar Removal treatment 
 
 
X 
 
X 
 
 
 
 
 
Wound closure confirmation4 
 
 
 
 
 
 
 
 
X 
1, 3 
Cosmesis, Function and 
Quality Of Life5 
 
 
 
 
 
 
 
 
 
X 
scar-modulating procedures 
and scar reconstructive 
 
 
 
 
 
 
# 
 
 
# 
                                                 
1 Including a soaking period of at least 2 hours 
2  Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, whichever comes first for patients with catheter.  
3 The Extremities At Risk (EAR) burns prone to develop BICS will be identified at screening and excluded. Monitoring for the development of EAR in circumferential extremity wounds at the above specified timelines 
will be done. During each topical application (NexoBrid or gel Vehicle), clinical assessment and SpO2 monitoring will be done continuously. If such assessment is not practical, direct pressure will be measured every 2 
hours from start of eschar removal. Direct pressure will be measured before and after each eschar removal procedure and additional surgical procedures  
4 Wound closure should be confirmed 2weeks after the initial wound closure assessment for each TW. 
5 Cosmesis will be evaluated in donor site scars as well 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Parameter 
 Screening 
tests 
Baseline-24 h 
Pre First 
treatment 
session** 
During First 
treatment 
session**  
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures*** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management & Re-
admissions1- Per procedure 
assessment 
HD or premature 
discontinuation 
visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Blood transfusion (units & 
volume) 
# 
# 
 
# 
# 
# 
# 
# 
# 
# 
Histological biopsy 
# 
# 
 
# 
# 
# 
 
# 
# 
# 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Table 4- NexoBrid/ Gel vehicle Eschar Removal 
 
Preparation for Treatment 
Treatment 
At least 2 hours soaking  
X 
 
Preventive analgesia medication (pain management) will be mandated as for an extensive dressing change as routinely 
practiced; it should be initiated at least 15 minutes prior to dressing change or application in order to ensure pain free care  
X 
 
Removal of any blister-keratin remnants1 
X 
 
Surrounding of the TW with a paraffin ointment adhesive barrier2  
X 
 
Sprinkle sterile isotonic (0.9%) sodium chloride solution should be sprinkled on the burn wound3 
X 
 
Application of the product, as per the randomization, should follow the instruction for use described in Section 6.4 of the 
protocol 
 
X 
Occlusive film dressing should be applied to cover the wound 
 
X 
The dressed wound should be covered with a loose, thick fluffy dressing, held in place with a bandage 
 
X 
The dressing should remain in place for 4 hours 
 
X 
Starting and completion time of the procedure  will be recorded 
 
X 
Manpower (specify the number of surgeons, anesthesiologists, RN, nurses and unskilled assistances) who participated during 
the procedure will be recorded in the eCRFs 
 
X 
Any disposable used (number of dressings, blades, etc) will be recorded in the eCRFs 
 
X 
2 hrs soaking4  
 
X 
                                                 
1 If there are still blisters/keratin remains, clean the wound thoroughly and remove the superficial keratin layer or blisters from the wound area, as the keratin will isolate the eschar from direct contact with the 
topical agent 
2 Paraffin ointment should be applied a few centimeters outside of the treatment area (using an adhesive-barrier dispenser). The paraffin layer must not come into contact with the area to be treated to avoid 
covering the eschar, thus isolating the eschar from direct contact with the topical agent 
3 The wound must be kept moist during the application procedure 
4 Antibacterial solution, e.g. 3-5% Sulfamylon, 0.05-0.5% Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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10 
DRUG STORAGE AND DRUG ACCOUNTABILITY 
The bottles of NexoBrid powder and the Gel Vehicle must be kept refrigerated (2-8ºC).  
10.1 
ACCOUNTABILITY AND COMPLIANCE  
The principal investigator is responsible for maintaining accurate records of the receipt and 
dispensing of all investigational materials. The investigator may dispense investigational drug 
only to patients enrolled in the study. All dispensing will be conducted from the site listed in 
the Statement of Investigator. 
MediWound Ltd. will provide drug accountability forms to assist the investigator in 
maintaining current and accurate inventory records covering receipt, dispensing, and the return 
of investigational drug supplies. When a shipment is received during site's initiation or during 
the study, the investigator or pharmacist will verify the quantities received, complete an 
Inventory log form and return the acknowledgment to the study monitor or designee. The 
investigational drug accountability record includes the identification of the patient to whom the 
drug is dispensed, the quantity and the date of dispensing and any returned or unused drug. 
This record is in addition to any drug accountability information recorded on the Case Report 
Form. These records will be readily available for inspection by a monitor or MediWound Ltd. 
audits and are open to any other regulatory authority inspection at any time. 
When the supplies are returned or destroyed, the investigator or pharmacist signs the 
investigational drug return or destruction log to verify that all unused or partially used supplies 
were accounted for and confirms that no study supplies remain in the investigator’s possession. 
One copy of all inventory records and the return statement are retained by the investigator for 
the study files. 
At study termination, unless otherwise specified, all unused drug supplies including partially 
used containers and the study drug accountability log should be returned to: MediWound, Ltd., 
Clinical Research Department, 42 Hayarkon Street, North Industrial Area, Yavne, 8122745, 
Israel.  
10.2 
PREVIOUS AND ON-GOING MEDICATIONS/THERAPIES.  
10.2.1 
Disallowed Previous and On-Going Medications/Therapies 
Pre-enrollment dressings with flammacerium or silver nitrate (AgNO3) are disallowed. 
10.2.2 
Allowed Previous and On-Going Medications/Therapies 
All other systemic medications except in the above section are allowed. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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11 
ASSESSMENT METHODS 
Efficacy Assessment Methods will include: 
11.1 
PRIMARY END POINT 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to Section 1.1 for Target Wound 
definition): 
Incidence of complete eschar removal: Demonstrate superiority over Gel Vehicle for eschar 
removal as measured by incidence of complete eschar removal by the end of the topical agent 
soaking period by a blinded assessor. Complete eschar removal is achieved at the end of the 
eschar removal treatment phase as routinely determined by burn specialists during their daily 
practice in burn units and is the basis for the medical decision to initiate the consequent wound 
closure phase: treatment towards wound closure.  
Reasons for Incidence of complete Eschar Removal as Primary Endpoint 
Following the goal to seek an indication for NexoBrid that focuses on non surgical eschar 
removal, the evaluation focus is set on this measure as a primary endpoint of the study. This 
primary endpoint will assess whether non-surgical eschar removal by NexoBrid allows 
effective removal of the offending eschar compared with its comparator. Complete eschar 
removal assessment will be captured in the eCRFs for each TW and has to be marked as 
complete for all TWs to be considered as complete per patient.  
11.2 
SECONDARY ENDPOINTS 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SOC. Comparisons between NexoBrid and Gel vehicle will be carried out in the 
same manner as between NexoBrid and SOC, but will be regarded as supportive analyses. 
11.2.1 
Reduction in surgical needs 
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). 
11.2.2 
Earlier eschar removal 
Demonstrate superiority of NexoBrid over SOC with regard to the time when complete eschar 
removal has been achieved. For definition of complete eschar removal see primary endpoint. 
11.2.3 
Blood loss 
Demonstrate superiority of NexoBrid over SOC with regard to the blood loss incurred during the 
eschar removal procedures. Actual blood loss will be measured by considering the estimated 
blood loss, changes in Hemoglobin during the eschar removal procedures and the amount of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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units of blood transfused. Blood loss (Actual Blood Loss, ABL) will be calculated using the 
following formula [86]:  
ABL= (EBV * (Hbbefore- Hbafter))/((Hbbefore+ Hbafter)/2))+ (500*Tu) 
EBV= Estimated blood volume is assumed 70 cm3/Kg 
(Hbbefore- Hbafter)= Changes in Hb following each eschar removal procedure 
Tu= sum of autologous whole blood, packed red blood and cell saver units transfused. 
The ABL will be summed over all procedures carried out to remove eschar, with the HB 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during the debridement 
procedure and 4 hrs later i.e. the before-after periods that are spanned by these HB 
measurements.    
Reasons for Incidence of Surgical Excisions as Secondary Endpoint 
A further aspect of the clinically meaningful attributes of NexoBrid’s non surgical eschar 
removal is the ability to reduce surgical needs, as NexoBrid allows removal of eschar in 
wounds that otherwise would have to undergo surgical excision. Therefore, this secondary 
endpoint would provide information on treatment failures that required follow-on surgical 
management and will further provide supportive evidence of efficacy and demonstration of 
clinical benefit over SOC. 
Reasons for Earlier Eschar Removal as Secondary Endpoint 
This secondary endpoint will assess whether nonsurgical and effective eschar removal by 
NexoBrid allows for the removal of the offending eschar earlier upon admission, enabling 
earlier visualization of the wound bed for assessment of the burn wound’s depth as well as 
preservation of viable tissues [87-88]. The depth determination is important for the planning 
and execution of the post-eschar removal stage of wound closure (i.e., grafting or spontaneous 
epithelialization). The dynamic of burn wound progression of the eschar-covered burn wound 
is the first delaying factor in initiating SOC surgical eschar removal. The non sacrifice of 
healthy dermis by SOC excisional surgery and the overall surgical implications to the patient 
are the other delaying factors [1]. Therefore, it is hypothesized that NexoBrid will allow eschar 
removal earlier (post randomization), effectively and in the first few days from injury without 
the need to first determine the burn depth (as is done in the initial decision-making phase of 
surgical and non surgical SOC). 
Reasons for Blood Loss as Secondary Endpoint 
This secondary endpoint will further demonstrate NexoBrid’s clinical benefit by showing a 
decrease of total blood loss post NexoBrid eschar removal compared with the total blood loss 
in the SOC eschar removal procedures. Reduction in blood loss is considered as an outcome 
measure that could further demonstrate NexoBrid clinical benefit. Surgical blood loss is 
attributed mainly to the excisional phase  and is directly proportional to the surface excised 
measured in ml blood loss/cm2 and may reach 0.8 ml/cm2 [89-90]. Local inflammation and 
anti-aggregation treatments may involve more bleeding and need for transfusion. Many 
publications endorse different means to reduce debridement related bleeding (tourniquet, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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subcutaneous epinephrine infiltration of excised burn and donor site etc.). The calculation for 
the actual blood loss is being used in other invasive procedures as an accurate calculation that 
reflects the actual blood loss in a patient as this takes into account both the estimated blood 
loss, changes in Hb levels during the relevant procedure and total blood units transfused to a 
patient. 
11.3 
SAFETY ENDPOINTS 
The following group of safety endpoints will be evaluated in this study and compared between 
NexoBrid and SOC. These endpoints are used to ensure that NexoBrid does not cause an 
unacceptable level of harm. Comparisons between NexoBrid and SOC will be carried out using 
pre-specified clinically meaningful margins that will assist in the benefit versus risk assessment 
of the product. These safety measurements are not powered to yield statistical significant non 
inferior results. Thus their assessment will be used for supportive analyses and sources of 
additional information about NexoBrid and SOC. 
11.3.1 
Time to complete wound closure 
Time to reach complete wound closure assessed in days, starting from randomization date. 
Demonstrate that NexoBrid does not cause any clinically meaningful harm to the patients with 
respect to the wound healing process by comparing NexoBrid mean time to wound closure 
with SOC mean time to wound closure, where a difference of not more than 7.4 days 
difference will be interpreted as clinically not relevant. 
Reason for this endpoint and the definition of clinically meaningful harm:  
Time to reach complete wound closure is taken as a safety criterion because wound closure is a 
relevant parameter for patients’ quality of life and delay in wound closure may increase the risk 
of local complications. However, it can be assumed that the selective, non surgical eschar 
removal will probably increase the potential for spontaneous healing as physicians tend to 
postpone autografting in an effort to reduce autografting by exploiting the wound's preserved 
dermal potential for spontaneous epithelialization. Such spontaneous epithelialization is an 
important benefit for the patient (less autografting and less donor sites). This assumption is 
based on the results of the confirmatory phase III RCT (MW2004-11-02) in which a slight 
prolongation in time to wound closure (7 days) compared with the standard of care arm was 
observed with no deleterious effect on the long term cosmesis and function evaluation (long 
term follow up study MW2012-01-02). 
A supportive formal derivation of this margin may be based on the FDA proposal of using two 
values to derive a NI (non-inferiority) margin [91]: 
M1 denotes the effect of the standard against placebo; 
M2 denotes the largest clinically acceptable difference (towards non-effectiveness) of the test 
substance. 
M2 is usually chosen as a percentage of M1, usually 50%. If no realistic placebo result exists a 
conservative choice of keeping 80% of the M1 effect may be preferred (M2=0.2*M1). This is 
the case planning a trial with large thermal burns as a real placebo result is not available and 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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even not ethical, i.e. a placebo comparison measuring the effect of SOC on the wound closure 
scale is missing. 
The following calculation is based on the data from the pivotal study, MW2004-11-02. For a 
first derivation of a NI margin we disregard possible correlations between the different wounds 
and treat the wound closure times as independent. 
Given that SOC is an active comparator one expects at least 95% of the wounds treated with 
SOC to have a smaller time to wound closure than a (virtual) placebo mean time to wound 
closure. From the empirical distribution of the SOC wound closure times of the data set we 
derive the 95% quantile as 64 days. Taken this as the worst case scenario for a mean placebo 
wound closure time we obtain a SOC treatment effect of M1=64-27=37 days (SOC mean was 
27 days).  
M2 may then be taken as 0.2*M1=7.4 days, which is the NI margin sought. 
Therefore, a slight prolongation in mean time to wound closure might occur (up to 7.4 days) 
but will not express a clinically relevant imbalance of the risk benefit assessment as patient 
mobilization starts far before the wounds are closed and the return to pre-injury lifestyle, 
following rehabilitation and convalescence, takes weeks, if not months, long after the wounds 
are closed. Thus any difference in means of up to 7.4 days may be taken as not representing 
clinically meaningful harm for this safety endpoint. 
11.3.2 
Cosmesis and function at 12 months from wound closure 
A measure of cosmesis, using MVSS, will be used to demonstrate - that treatment with 
NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as 
compared to scars quality of burns treated with SOC, measured at 12 months from wound 
closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a 
NexoBrid group mean MVSS score higher by 2.7 or more units than the SOC group mean 
MVSS score.    
11.3.3 
Cosmesis and function at 24 months from wound closure 
A measure of cosmesis, using MVSS, will be used to demonstrate that treatment with 
NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as 
compared to scars quality of burns treated with SOC, measured at 24 months from wound 
closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a 
NexoBrid group mean MVSS score higher by 2.7 or more units than the SOC group mean 
MVSS score. 
Reasons for the cosmesis endpoint and the choice of the clinically meaningful difference: 
We propose that a clinical equivalence value of 2.7 in the MVSS scale signify NexoBrid non-
inferiority in scar quality to the SOC. This clinically meaningful difference is in agreement 
with the non-inferiority (NI) margins calculated using the MVSS data in study MW2004-11-02 
(Sponsor previous long term follow up of patients treated in the MW2004-11-02).  
The NI margin was calculated as follows:  
Two values are needed to derive a NI margin [91]:  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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M1 the effect of the standard against placebo  
M2 the largest clinically acceptable difference (towards non-effectiveness) of the test substance  
M2 is usually chosen as a percentage of M1, usually 50%. If no realistic placebo result exists a 
conservative choice of keeping 80% of the M1 effect may be preferred (M2=0.2*M1). This is 
the case when planning a trial with large thermal burns as a real placebo result is not available 
and even not ethical to measure the effect of SOC on the MVSS scale.  
The following calculation is based on the data observed during the clinical study (study 
MW2012-01-02). The margin may be calculated taking the theoretical maximum score of 18 
instead of the result of a (virtual) placebo arm. Consequently the SOC treatment effect is 18-
3.83=14.17, with 3.83 being the MVSS mean observed in the SOC group of the data (per 
patient analysis). Given the standard deviation of 2.27 from the MVSS data a 95% confidence 
interval for the SOC treatment effect is given by 14.17±0.75. The lower bound is 14.17-
0.75=13.42=M1. 
M2 may then be taken as 0.2*M1=2.7, which is the NI margin sought. 
Additional Safety Outcome Measures will include:  
11.3.4 
General parameters 
Systemic adverse events, vital signs, pain assessment (using VAS), laboratory tests, units (and 
volume) of blood transfusion given during hospitalization, Immunogenicity evaluation for 
NexoBrid patients, Pyrexia and Hypothermia, Systemic infections, Incidence of increased 
interstitial/compartment syndrome (as described in Section 1.1) and QT prolongation. 
Additional long term functionality evaluation of the extremities using the ‘Lower Extremity 
Functional Scale’, 'QuickDASH' questionnaires and 'Range Of Motion' measurements, 
Long term Quality of Life using EQ5D and Burn Specific Health Scale- Brief (BSHS-B) 
11.3.5 
Local parameters 
Local adverse events defined by treated physician or designee; graft loss, wound related 
infections, etc. 
11.4 
EXPLORATORY ENDPOINTS 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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6. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures, 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
9. PK evaluation for a subset of NexoBrid patients1, 
10. Autograft related parameters. 
11.5 
ADDITIONAL ANALYSIS 
The following analyses will be addressed as supportive efficacy analyses: 
1. Primary & secondary endpoints will be analyzed at a per wound level 
2. Secondary endpoints will be analyzed vs. the Gel Vehicle 
11.6 
SUBGROUP ANALYSES 
Descriptive statistics will be determined for all subgroup analyses.  
1. A sub group analysis will be performed on the subgroup of target wounds that are 
found, at least partly, in the anatomical area of the hand.  
2. Time to wound closure and 12m and 24m MVSS will be analyzed per TWs’ depth.  
These subgroup analyses will be conducted at the wound level. More details will be 
provided in the SAP. 
 
11.6.1 
Safety Laboratory Evaluations 
The following tests described below will be performed. Any abnormal findings must be 
assessed for clinical significance – Abnormal Non Clinically Significant (NCS) or Abnormal 
Clinically Significant (CS):  
Serum chemistry, hematology and urinalysis testing will be performed at a central laboratory 
during the topical agent eschar removal phase. Any additional procedures require hematology 
tests, as described in the protocol, will be performed using Central lab. Pregnancy testing, 
HbA1c, leukocyte count (at Screening, in addition to central lab hematology), wound cultures, 
blood cultures and biopsies will be performed locally on-site. 
The following tests will be performed in special laboratories: Pharmacokinetics test, 
Immunogenicity evaluation and evaluation of QT prolongation (using multiple ECG tests). 
Serum Chemistry: 
                                                 
1 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4 , 12, 24 and 48 
hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Urea, Creatinine, Glucose, Total Bilirubin, Cholesterol, Triglycerides, Uric Acid, Total 
Protein, Albumin, Globulin, Calcium (Ca++), Phosphorous, Sodium (Na+), Potassium (K+), 
Chloride (Cl-), Alkaline Phosphatase, SGOT (ASAT), SGPT (ALAT), LDH. 
Hematology: 
Hemoglobin, Hematocrit, RBC, MCV, MCH, MCHC, Platelets, Leukocyte count (WBC) with 
differential count.   
HbA1c will be assessed at a local lab at Screening for diabetic patients as captured during the 
medical history.  
PTT and INR will be tested at a local lab pre treatment and 4 hrs after start of eschar removal. 
Pregnancy Testing: 
A serum pregnancy (HCG) will be performed at a local lab for women of child bearing 
potential.  
Urinalysis: 
pH, Ketone, Specific gravity, Protein, , Glucose, Bilirubin, Microscopic examination. 
Qualitative Wound Culture: 
Test burn wound for microbial flora (swab). 
Blood Culture: 
Test blood for microbial flora. 
Diagnosis of Invasive Burn Wound Infection is based on Quantitative (Histological) Wound 
Culture Biopsy: 
Infection should be assessed clinically by symptoms and signs that include local burn wound signs 
purulent drainage, erythema, warmth, exudation, odor, pain, and systemic signs that may or may 
not be related to the burn wound, such as fever, and leukocytosis as well as wound size and time to 
wound healing. Histological Biopsy may be performed to rule out suspicion of a clinical 
invasive burn wound infection (please refer to Appendix 8- Biopsy & Histologic Assessment 
Method) [93]. 
Clinical Burn Wound Infection will be defined when an Invasive Burn Wound Infection is 
diagnosed by quantitative bacterial count of >105 organisms per gram of tissue and histological 
signs of bacterial invasion of healthy tissues will define a positive invasive burn wound 
infection. At least one of the following histological signs of invasive burn wound infection is 
required:  
 
Microorganisms presence in viable unburned tissue 
 
Small vessel thrombosis and ischemic necrosis of unburned tissue 
 
Inflammation evident in unburned tissue 
 
Hemorrhage in uninjured tissue 
 
Evidence of microbial proliferation 
 
Variable migration of microorganisms along hair follicle and sweat glands 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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 
Dense growth of nonviable-viable tissue interface (subeschar space)  
 
Intracellular viral inclusion 
 
Light microscopy 
 
Type A Cowdry bodies: herpes simplex virus-1 
 
Owl's eye inclusion bodies: cytomegalovirus 
 
Electron microscopy 
 
Intracellular virions 
11.6.2 
Burn Induced Compartment Syndrome Monitoring and Diagnosis 
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within few days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy (see 
below).  
The BICS diagnosis is based on clinical and instrumental originated data: 
Clinical signs (the 5 “P”) are [10]: 
 Pain (on passive digital extension)- Pain on passive stretch of the affected muscle 
 Paralysis 
 Pulselessness 
 Pallor 
 Paraesthesia 
In addition:  
 Pulse oximeter SpO2 (when measurement is possible in non vaso-constricted patients) bellow 
90% in otherwise healthy individuals or a dynamic decrease over time or a difference of >6% 
between the injured and a healthy symmetrical site. 
 Direct interstitial/compartment measurement: increased pressure under the constricting eschar. 
 Ultrasound Doppler may be used for the detection of pulsating arteries but even with distal 
digital artery pulsation damage may still happen. Laser Doppler blood flow is reported to be the 
least dependable.  
 
Extremities At Risk (EAR) group:  
The EAR burns may be prone to develop BICS. Extremities at Risk are circumferential DPT 
and/or FT burns with at least one of the following: 
1. Any of the 5 “P”s described above (Pain, Paralysis, Pulselessness, Pallor, Paraesthesia),  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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2. Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements 
within 30 minutes under the constricting eschar, 
3. SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity 
and the injured one [10-11],  
4. Pulse not detected by US Doppler.  
 
Monitoring:  
Monitoring will be performed for all extremities using the above mentioned criteria (clinical 5 
“P”, direct pressure measurement and SpO2 [83]). 
The monitoring and diagnosis step include: 
 Observation of the extremity for swelling and color 
 Asking the patient about pain on finger extension or other sensations 
 Pressing the skin to diagnose blanching and tension 
 Sensitivity assessment (from superficial to deep sensation, ending with passive extension of 
the fingers, which is the specific test for muscle ischemia). 
Pulse may be used as supportive to other signs as occasionally it might be difficult to assess.  
The above sequence of tests should start by: 
 (i) asking the patient to move his/her fingers 
(ii) skin sensation 
(iii) skin tension and appearance (pallor) 
(iv) assessing pain at passive extension  
(v) palpation for pulse.  
The above monitoring measures should be initiated at screening and continue during topical 
eschar removal treatment.  
Intervention:  
Direct pressure measurement is a reliable method when frequently measuring the pressure.     
Prior to randomization: Patients with circumferential DPT and/or FT burns defined as 
Extremities at Risk (EAR) should be indentified1 (see Exclusion Criteria, Section 7.1.3). 
Post randomization and prior to eschar removal procedure: In accordance with current 
standard of care, wounds should be monitored to detect high interstitial/ compartment pressure 
and diagnosed BICS should be treated by the investigator as per SOC. 
During the 4 hours eschar removal procedure: As per current SOC, patients with 
circumferential wounds may be monitored for few hours before executing surgical 
escharotomy. Hands and feet developing clinical evidence (such as swelling, pallor but no 
                                                 
1 For direct pressure measurement >25 mmHg, a second measurement will be taken within 30 minutes. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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paralysis and pain on passive extension) and pressure approaching 25 mmHg and SpO2 stable 
>90% should be closely monitored for signs of improvement or deterioration that may require 
escharotomy. If clinical assessment and SpO2 monitoring are possible, they will be done 
continuously and recorded in the eCRFs every 2 hours. If such assessment is not practical, 
direct pressure will be measured every 2 hours from start of the eschar removal. The eschar 
removal process shall be discontinued and escharotomy will be performed in the case of the 
following: 
 Increasing pressure >30 mmHg 
 Difference of >20 mmHg of diastolic pressure between the opposite extremities 
 Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity or deterioration of clinical signs 
 Any of the 5 “P” signs described above. 
 
Since in such cases eschar removal procedure will not be completed as planned, such patients 
(if any) will still be part of ITT and any missing data usually collected during eschar removal 
(e.g. time to end of eschar removal, etc.) will be handled as missing data according to the 
protocol. 
Post eschar removal procedure: 
In accordance with current standard of care, wounds should be monitored to detect high 
interstitial/ compartment pressure and diagnosed BICS should be treated by the investigator as 
per SOC. 
The direct interstitial/compartment pressure measurement will be performed using one of the 
following: 
1. A 19 gauge IV needle or catheter connected to a pressure transducer (e.g. CVP set, direct 
blood pressure monitors, Striker system). The needle is inserted: 
 
Into the interstitial subcutaneous tissue at the anterior compartment region of upper or 
lower extremities, in the case of circular burn extending up to the elbow or knee.   
 
Into the palmar or plantar compartment, in the case of isolated circumferential burn 
limited to the hand or foot. 
Before reading the pressure, the system should be flushed with 0.2-0.5 cc. (depends of the 
length of the connecting tube) of normal saline. 
2. Intra-Compartmental Pressure monitor (ICP monitor) by Stryker®. 
These measurements, similar in their pain and discomfort to IV treatment, are well tolerated by 
patients and in DPT/FT wounds this measure is entirely painless.        
11.6.3 
Infection 
All definitions of infection, wound infection, invasive burn wound infection etc. will follow the 
American Burn Association Consensus Conference to Define Sepsis and Infection in Burns 
[94] as presented in chapter 12, “Treatment of infection in burns” in the Total Burn Care 4th 
edition, edited by D. Herndon pages 137-156 that included also input from The Society of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Critical Care Medicine (SCCM) and the American College of Chest Physicians (ACCP). 
Nevertheless, it should be remembered that in spite of the enormous effort invested for so long 
by so many, often even the simple differential diagnosis between burn wound erithema and 
burn wound infection or even the etiology of a sepsis is difficult. In order to have a pure as 
possible study that will assess exclusively the burn related phenomena, the principle is to enroll 
healthy individuals with fresh thermal burn wounds without any confounding co morbidities or 
trauma.        
 Sepsis [94]  
Sepsis is a change in the burn patient that triggers the concern for infection. It is a presumptive 
diagnosis where antibiotics are usually started and a search for a cause of infection should be 
initiated. While clinical interpretation is required, the diagnosis needs to be tied to the 
discovery of a specific infection source (defined below in section C).  
The trigger includes at least three of the following: 
I. 
Temperature >39.0° or <36.5°C 
II. 
Progressive tachycardia 
o Adults >110 bpm 
III. 
Progressive tachypnea 
o Adults >25 bpm not ventilated, or minute ventilation >12 L/min ventilated 
IV. 
Thrombocytopenia (will not apply until 3 days after initial resuscitation) 
o Adults <100,000/mcl 
V. 
Hyperglycemia (in the absence of pre-existing diabetes mellitus) 
o Untreated plasma glucose  >200 mg/dl or equivalent mM/L 
o Insulin resistance—examples include 
 >7 units of insulin/hr intravenous drip (adults) 
 Significant resistance to insulin (>25% increase in insulin requirements over 24 
hours) 
VI. 
Inability to continue enteral feedings >24 hours 
o Abdominal distension 
o Enteral feeding intolerance (residual >150 ml/hr in children or two times feeding rate 
in adults) 
o Uncontrollable diarrhea ( >2500 ml/d for adults or >400 ml/d in children) 
In addition, it is required that a documented infection is identified: 
I. 
Culture positive infection, or 
II. 
Pathologic tissue source identified, or 
III. 
Clinical response to antimicrobials 
 
A. Continuous fever > 38.50C present during the week before sustaining burn injury. 
B. The below are assessed as present on physical examination or per history during the week 
before injury according to the described signs [89]  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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 Rhinitis including mucopurulent nasal discharge  
 Sinusitis including cough, headache, stufinness, purulent nasal discharge  
 Stomatitis  including localized pain in mouth, difficulty swallowing 
 Pharyngitis 
 
including 
sore 
throat, 
pharyngeal 
erythema/exudate, 
neck 
lymphadenopathy 
 Pharyngeal abscess 
 Otitis including ear ache, signs per otoscopy 
 Infections of the Lower Respiratory Tract [95] 
Pneumonia including cough, fever, bronchial breath sounds, crackles, radiographic signs 
 Infections of the Heart [95] 
Endocarditis 
 Infections of the Skin and Soft Tissues (other than in the burns) [95] 
Folliculitis 
Impetigo 
Varicella-Zoster Virus infection 
Erysipelas 
Cellulitis  
Necrotizing Fasciitis 
 Intra-Abdominal Abscess and Peritonitis [95] 
Infectous Gastroenteritis 
 Bone and Joint Infections [95] 
Septic Arthritis including joint pain, swelling, erythema, limitation of movement 
Osteomyelitis including pain, tenderness, radiographic evidence 
 Urinary Tract Infections [95] 
Urethritis including pain and burning sensation of the urethra during urination. 
Urinary Tract Infection including pain, burning sensations, abdominal pain, positive urine 
culture 
 Burn Wound Infection – Heavily Contaminated Burns [94] 
o Invasive Infection: Presence of pathogens in a burn wound at concentrations 
sufficient in conjunction with depth, surface area involved and age of patient to 
cause suppurative, purulant separation of eschar or graft loss, invasion of 
adjacent unburned tissue or cause the systemic response of sepsis syndrome. 
Pathogen present in the wound at high concentrations (frequently >105 
pathogens/g tissue). Invasion or destruction of unburned skin/tissue. Invasive 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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infection may occur with or without sepsis. Many burn wound invasive 
infections, however, are life threatening and need urgent treatment (usually 
wound excision). 
o Cellulitis: Bacteria present in the wound and/or wound eschar at high 
concentrations. Examination of surrounding tissue reveals advancing erythema, 
induration, warmth and tenderness. Sepsis must be present. 
o (Cellulitis that appears usually after few days (5-7 days) should be differentiated 
from Burn erythema: Redness around the wound in the first 3 days post injury 
and is rather benign and may not require treatment). 
o Necrotizing Infection/Fasciitis: Aggressive, invasive infection with underlying 
(beneath the skin) tissue necrosis. 
Burns diagnosed of Invasive Infection, Cellulites and Necrotizing Infection/Fasciitis are 
considered heavily contaminated burns. 
11.6.4 
Vital Signs 
Vital signs (temperature, pulse, blood pressure and respiration rate) will be completed 24 hours 
prior to start of treatment and once daily for one week post start of eschar removal. 
Blood pressure and pulse should be recorded in a supine position after resting for 5 minutes.  
All measurements and time of measurements will be recorded in the source documents. 
11.6.5 
Immunogenicity Evaluation 
Antibodies presence will be determined based on a three-tiered approach analysis of plasma 
samples drawn prior to start of eschar removal and at the following timelines in NexoBrid 
patients: 
 At day 7±2 days (week 1 visit) from start of treatment, 
 At day 28±7 days (week 4 visit) from start of treatment, 
 At day 56 ±14 days (week 8 visit) from start of treatment,  
 At months 6 & 24, as part of the long term follow up visits. 
Please refer to Appendix 10- Procedures for specific blood tests for further instructions. 
11.6.6 
ECG (QT evaluation) 
12-lead ECG will be performed (if feasible) in triplicates as part of the QT prolongation 
evaluation at the following time-points: baseline 60 ± 5 min, 40 ± 5 min and 20 ± 5 minutes 
prior to start of Eschar removal process and at 30 ± 10 min, 120 ± 15 min, 4 ± 0.5 hrs, 12 ± 0.5 
hrs, 24 ± 1 hrs, 48 ± 2 hrs and 1 week after start of eschar removal.  
11.6.7 
Physical Examination 
A physical examination will be performed and documented by the investigator or a qualified 
designee. Any abnormal findings, assessed by the investigator as clinically significant, should 
be recorded in the relevant eCRFs modules (e.g. adverse event). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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11.6.8 
Pain Assessment Using Visual Analogue Scale (Pain Scale Ruler)  
Pain experience will be recorded using standard widely used pain scale ruler (Visual Analogue 
Scale=VAS) on admission, (baseline pain assessment) within 24 hours prior to start of eschar 
removal, One-hour before and following eschar removal procedure and daily for one week post 
start of eschar removal. Please refer to Appendix 9- Pain Measurement Scale for instructions. 
11.6.9 
Concomitant Medications 
Concomitant medications will be recorded throughout the study, starting from signing on ICF 
and will include those prescribed for common burn management practice. Any record should 
include dose, frequency, route, start and stop date and indication. 
Unit of blood transfused (whole blood or blood packed cells) with the appropriate volume will 
be captured for the entire patient’s duration in the study and recorded in the concomitant 
medications form. Any analgesia and anesthesia administered per subject will be recorded in 
the eCRFs. Incidence & number of procedures for wound care requiring anesthesia will be 
analyzed. 
11.6.10 
Graft Loss 
An event of graft loss is defined in study protocol as an event in which an autograft needed to 
be re-applied. This event, once occurred, will be recorded in the eCRFs as an AE. 
11.6.11 
 Hypothermia and pyrexia [94] 
Hypothermia will be defined as temperature <36.0°c, measured twice, 30 minutes apart. 
Pyrexia will be defined in patients with elevated temperature >39.0°c in the first days (before 
the beginning of any infectious process) measured twice, 30 minutes apart. These criteria, once 
met, should be monitored closely. The Investigator may still report hypothermia at higher 
temperatures and Pyrexia at lower temperatures, if these events are considered by the 
Investigator to be adverse events. The Investigator will be further reminded to evaluate the 
need to report an AE in case the temperature is higher than 39.0°c or lower than 36.5°c. 
11.6.12 
Cosmesis and Function assessment 
11.6.12.1 MVSS 
Cosmesis and Function assessment will be performed based on the Modified Vancouver Scar 
Scale (MVSS) at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 
burn wound specialist who is masked to randomized wound treatment and to the other outcome 
assessments of the same wound 
 The MVSS method is composed of the following: 
Pigmentation 
Pliability 
Height Vascularity Pain 
Pruritus 
(0) Normal 
(0) Normal 
(0) Flat 
(0) 
Normal 
(0) None 
(0)None 
(1) 
Hypopigme
(1) Supple-flexible with 
minimal resistance 
(1)  
(1) Pink 
(1) 
Occasional 
(1) 
Occasional 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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ntation 
<2mm 
(2) Mixed 
(2) Yielding- giving way 
to pressure 
 
(2) 2-5 
mm 
(2) Red 
(2) 
Requiring 
medication 
(2) 
Requiring 
medication 
(3) 
Hyperpigme
ntation 
(3) Firm- inflexible, not 
easily moved, resistance to 
manual pressure 
 
(3) 
>5mm 
(3) 
Purple 
 
 
 
(4) Banding-rope-like 
tissue that blanches with 
extension of the scar 
 
 
 
 
 
 
(5) Contracutre-perment 
shortening of scar, 
producing deformity or 
distortion  
 
 
 
 
 
 
11.6.12.2 POSAS 
Additional Cosmesis and Function evaluation will be performed using the Patient and Observer 
Scar Assessment Scale (POSAS) version 2.0 at 1, 3, 6, 12, 18 and 24 months after the wound 
closure confirmation visit by a burn wound specialist who is masked to randomized wound 
treatment and to the other outcome assessments of the same wound. POSAS version 2.0 was 
published in 2005 in Plast. Reconstr. Surg. 116: 514-522 by van de Kar et al.  
The POSAS consists of two parts: a Patient Scale and an Observer Scale. Both scales contain 
six items that are scored numerically and make up a ‘Total Score’ of the Patient and Observer 
Scale. The POSAS has been developed for all types of scars and has been tested in linear scars, 
burn scars and keloids and was found to be validated and reliable [111-112].  
Each item of both scales has a 10-point score, with 10 indicating the worst imaginable scar or 
sensation. The lowest score is ‘1’, and corresponds to the situation of normal skin (normal 
pigmentation, no itching etc), and goes up to the worst imaginable. The Total Score can be 
simply calculated by summing up the scores of each of the six items. The Total Score will 
therefore range from 6 to 60 (observer and patient) and 12-120 in total. 
11.6.13 
Quality of Life 
Quality of Life evaluation will be performed in adults using Burn Specific Health Scale 
(BSHS-B) and EQ5D as describe in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire, at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 
burn wound specialist who is masked to randomized wound treatment and to the other outcome 
assessments of the same wound. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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11.6.14 
Function assessments 
Functionality tests were implemented in the proposed protocol MW2010-03-02 for the 
assessment of specific anatomical function. This evaluation will be composed of the following: 
 Self completed questionnaires: 
o The “Lower Extremity Functional Scale” test for burns in the lower extremities,  
o The “QuickDASH” outcome measure for burns in the upper extremities.  
 Range of Motion measurements of injured joints, if relevant: knee, ankle, shoulder, elbow, 
wrist and hand. Measurements will be performed on the patient’s own non injured joints as 
well for comparison to burned joints.  
The above tests will be performed at 1, 3, 6, 12, 18 and 24 months after the wound closure 
confirmation visit by a burn wound specialist who is masked to randomized wound treatment 
and to the other outcome assessments of the same wound. ROM will be evaluated at 1, 3, 6, 12, 
18 and 24 months after the wound closure confirmation visit.  
11.6.15 
Pharmacokinetic evaluation 
Blood samples (2ml) for a pharmacokinetic profile to measure NexoBrid absorption will be 
taken from a subset of patients treated with NexoBrid in accordance with the randomization 
arm (20 patients, randomingly selected) and will be analyzed throughout the study for each 
patient in an ongoing process. Blood samples will be taken pre treatment and at 1, 2, 4, 12, 24 
and 48 hours after start of treatment.  
11.6.16 
Real time data capture and Independent Safety Monitoring 
The study data will be collected using an Internet-based, validated, electronic data capture 
system which allows for “real time” safety reviews via the Internet.  
An independent study Medical Monitor, masked to the treatment arms, shall review all 
Adverse Events (AE’s) from the entries on the eCRFs on a quarterly basis. SAEs will be 
reviewed and evaluated on a per case basis, following the occurrence of an SAE, as detailed in 
the Sponsor’s SOPs. In case any concerns are raised by the medical monitor, additional 
convention of the DSMB could be performed (see Section 14.2).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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12 
SAFETY AND PHARMACOVIGILANCE  
An adverse event is an undesirable or unintentional event that occurs during use of the study 
Drug, whether or not considered related to the Drug; this includes clinically significant changes 
in laboratory values and therapeutic failures. Regardless of the severity or relationship to the 
investigational Drug, all adverse events occurring during the study period should be recorded 
in a subject's CRFs. The phrase "associated with the use of the Drug" is defined as a reasonable 
possibility that the event may have been caused by the investigational Drug. 
12.1 
 RELATIONSHIP TO STUDY DRUG 
The following definitions to assess the relationship between an adverse event and the study 
Drug should be used.   
Not Related: The event is clearly related to other factors such as a patient's clinical state, 
therapeutic interventions or concomitant medications. 
Remotely Related: The event was most likely produced by other factors such as a patient's 
clinical state, therapeutic interventions or concomitant medications and does not follow a 
known response pattern to the study Drug. 
Possibly Related: The event has a reasonable temporal relationship to study Drug 
administration and follows a known response pattern to the study Drug.  However, a potential 
alternate etiology may be responsible for the event.  The effect of Drug withdrawal is unclear. 
Rechallenge information is unclear or lacking. 
Probably Related: The event follows a reasonable temporal sequence from the time of Drug 
administration and follows a known response pattern to the study Drug and cannot be 
reasonably explained by other factors.  There is a reasonable response to withdrawal of the 
Drug.  Re-challenge information is not available or advisable. 
Related: The event follows a temporal sequence from the time of Drug administration and 
follows a known response pattern to the study Drug and either occurs immediately following 
study Drug administration, or improves on stopping the Drug, or reappears on repeat exposure. 
AEs assessed as possible, probably or related will be addressed as Adverse Drug Reaction 
(AEs related to study arm). 
12.2 
 ADVERSE EVENT INTENSITY 
Mild Adverse Events: A mild adverse event is one that the symptoms are barely noticeable to a 
patient. It does not influence performance or prevent a patient from carrying on with normal 
life activities. 
Moderate Adverse Events: A moderate adverse event is one that the symptoms make a patient 
uncomfortable and causes some impairment to normal life activities. Treatment for symptom(s) 
may be required. 
Severe Adverse Events: A severe adverse event is one that the symptoms cause severe 
discomfort to a patient and severely limits the patient's normal daily activities.  Treatment for 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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symptom(s) is given. Note that serious and severe are not synonymous.  A serious adverse 
event must fulfill the requirements listed in the definition below. 
12.3 
 ADVERSE EVENT REPORTING 
Signing of Inform Consent is considered to be the start date of AEs monitoring. All adverse 
events must be recorded in the eCRFs. When an adverse event occurs, the following 
information and assessments should be recorded in the adverse event section of the eCRFs: 
 The signs, symptoms or diagnosis or the event, 
 The date and time of onset of the event using the 24 hour clock where midnight is 00:00 
and noon is 12:00, 
 The adverse event severity using the criteria outlined above, 
 The relationship of the event to the study Drug as outlined above,  
 The description of any action taken regarding study Drug disposition, 
 Any required therapy, medication, treatment or diagnostic procedure. 
Follow-up of a patient should be conducted until resolution of the adverse event. The 
investigator is responsible for the appropriate medical management of all adverse events.  
12.4 
 SERIOUS ADVERSE EVENTS 
A serious adverse event is an event that is: a) fatal b) life-threatening c) results in persistent or 
significant disability/incapacity d) requires or prolongs inpatient unexpected hospitalization ) is 
a congenital anomaly or birth defect or f) is a medically important event. 
Life Threatening is defined as an event in which a patient is at risk of death at the time of the 
event. It does not refer to an event that hypothetically might have caused death if it was more 
severe. Disability is defined as a substantial disruption of a person's ability to conduct normal 
life functions. Medically important events that may not result in death, be life-threatening or 
require hospitalization may be considered as SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above. 
When patient’s hospitalization is planned by the treated Investigator, no AE should be reported 
and thus, no SAE should be reported. Note to File will be completed and signed by the 
Investigator. 
 
An unexpected adverse event is one that has not been previously observed, or one that is of a 
specificity or severity not consistent with the current investigator brochure. 
All adverse drug reactions (a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility) that are both serious and unexpected are subject to 
expedited reporting as defined in ICH E2A “Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting”. An Unexpected event is one that is not consistent 
with the applicable product information as described in the current investigator brochure.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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12.5 
 SERIOUS ADVERSE EVENT REPORTING 
The investigator shall report all serious adverse events to the Pharmacovigilance by telephone 
or fax immediately after the event (within of 24 hours, in accordance with MediWound’s 
SOPs). The initial report should be followed-up with a detailed written report within three 
days. Full details of the event, any sequelae and an assessment of the relationship to the study 
Drug must be provided in the report.  
Fatal or life-threatening SUSARs should be notified as soon as possible but no later than 7 
calendar days after Pharmacovigilance has first knowledge of the minimum criteria for 
expedited reporting. All other SUSARs must be reported as soon as possible but no later than 
15 calendar days after Pharmacovigilance has first knowledge of the minimum criteria for 
expedited reporting. Further relevant follow-up information should be given as soon as 
possible. 
 
12.6 
PREGNANCIES 
In the long term follow up period of the study, no special contraception methods are deemed 
necessary for the study due to the single short term use of the investigational product and its 
known pharmacokinetic profile were no remnants of NexoBrid were observed after 48 hours 
had passed from first application. In the early acute phase of the burn wounds, during their 
hospital stay, patients are hospitalized and thus are not expected to be subject to sexual 
intercourse. If sexual abstinence within one month after study treatment is not possible 
acceptable contraception methods should be used by the patient. 
1) Acceptable methods of contraception (a Pearl Index < 1%) include: 
- 
hormonal methods (oral contraceptives, patches or medroxyprogesterone acetate) 
- 
An intrauterine device (IUD) with a documented failure rate of less than 1% per year 
 
NOTE: Females who have been surgically sterilized (e.g., hysterectomy or bilateral tubal 
ligation) or who are postmenopausal (total cessation of menses for >1 year) will not be 
considered as “females of childbearing potential.” 
 
Nevertheless, to ensure patient safety, each pregnancy in a female patient of childbearing 
potential on study drug should be reported to the treated physician during the study course. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on the 
form provided by MediWound and reported by the investigator to MediWound. The telephone 
and fax number of the contact persons are listed on the form provided. Pregnancy follow-up 
should be recorded on a form provided by MediWound as well and should include an 
assessment of the possible relationship to the study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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13 
STATISTICAL ANALYSIS  
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. 
13.1 
POPULATIONS 
Enrolled population consists of all subjects who passed through the screening processes and 
signed inform consent. 
Intent-to-Treat (ITT) population includes all patients who are randomized into the trial. 
Evaluable (per protocol)(PP) population includes all subjects who fulfill all inclusion/exclusion 
criteria and do not have major protocol violations. Analysis of the PP population is for 
supportive purposes, whereas the analysis of the ITT population provides the primary and 
secondary efficacy and the comparative safety analyses.  
Safety population (SP) includes all patients receiving a treatment and analysis is focused on the 
treatment actually performed. 
13.1.1 
Major Protocol Violations 
Major protocol violations will be evaluated by clinical personnel and detailed information will 
be listed. List of protocol violation will be included in the study monitoring plan. 
13.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and relevant baseline information (medical history, physical examination, 
treatments prior to admission, burn description, distribution of wound depth and size, TWs 
description, primary TW description, etc.) will be presented and summarized with appropriate 
descriptive statistics. Chi-squared tests (or in case of small estimated cell counts Fisher’s exact 
test) for categorical variables and one-way analysis of variance for continuous variables will be 
used to assess the comparability of the baseline factors between the treatment groups.   
If either of the baseline factors, gender or age, are found to be significantly different between 
the treatment groups, then the factor will be included as an extra adjusting covariate in the 
supportive analysis models for the primary and secondary efficacy endpoints and the 
comparative analyses of safety endpoints. 
Relevant medical history will be tabulated and presented by treatment group.  
These summaries will be based on the ITT population. 
13.3 
EFFICACY EVALUATION 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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13.3.1 
Primary Endpoint 
The primary endpoint will be analyzed as described below. Missing data will be handled by the 
methods described in Section13.8.4. NexoBrid will be compared with Gel Vehicle for the 
primary endpoint. 
13.3.1.1 Incidence of complete eschar removal measured at the end of the topical agent 
soaking period. 
The proportions of patients who reached complete eschar removal at the end of the 
topical agent soaking period will be compared using logistic regression. The primary 
analysis will be based on the binary variable (yes/no): ‘has complete eschar removal been 
achieved in all TWs’ and will compare NexoBrid with the Gel Vehicle (for further 
definition and explanation of complete eschar removal see Section 1.1). For handling of 
missing data see Section 13.8.4. The statistical test will be based on Fisher’s exact test 
because of the small numbers expected in the Gel vehicle group. The odds ratio of 
achieving complete eschar removal for NexoBrid versus Gel Vehicle and its 95% 
confidence interval will be estimated using exact distribution methods. 
If numerically possible, the comparison will supportively be adjusted for the stratification 
factor wound depth (see Section 13.7) by including the factor in a logistic regression 
model together with the treatment variable (NexoBrid vs. Gel Vehicle). Similarly, if it is 
convergence of the estimation procedure can be obtained, then, in another supportive 
analysis, the factor  treatment center (see Section 13.8.5) will be included in a logistic 
regression model with the treatment variable. Statistical inference will be based upon 
exact distribution methods. 
The odds ratio of achieving complete eschar removal for NexoBrid versus Gel Vehicle 
will be estimated from these supportive models, as well as 95% confidence intervals and 
the level of statistical significance. 
13.3.2 
Secondary endpoints 
The secondary endpoints will be analyzed as described below and will compare efficacy in the 
NexoBrid group with the SOC group. Missing data will be handled by the methods described 
in Section 13.8.4.  
13.3.2.1 Surgical excision performed  
This is a binary yes/no variable and the proportion of patients who need excision for eschar 
removal will be compared using logistic regression. The explanatory variables in the model 
will include treatment, and the following variables: overall TW depth (for definitions, see 
Section 13.7) and number of TWs (1, 2, ,≥3). The odds ratio of requiring surgery for NexoBrid 
versus SOC will be estimated from the model, as well as 95% confidence intervals and the 
level of statistical significance.  
If numerically possible, as a supportive analysis, the variable treatment center (see Section 
13.8.5) will be added into the logistic regression model and the analysis repeated.    


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.3.2.2 Timely eschar removal 
Time until complete eschar removal will be defined as the time until complete eschar removal 
has been achieved at a patient level, i.e. for all TW’s of an individual patient. This will be 
measured as time from the randomization date (days). For patients who do not reach complete 
eschar removal, their time will be censored at the initiation of the wound closure treatment 
phase. Kaplan-Meier curves will be presented graphically to display the distribution of time to 
complete eschar removal under the two treatments. Median time to complete eschar removal 
will be estimated for each treatment group with a 95% confidence interval. The treatment 
groups will be compared using a Cox regression model. The comparison will be adjusted for 
the same explanatory variables as mentioned in Section 13.3.2.1, by including each of them in 
the Cox regression model together with the treatment variable (NexoBrid vs. SOC). The 
treatment groups will be compared by testing the null hypothesis of no difference, comparing 
the ratio of the estimated treatment coefficient to its standard error to a standard normal 
distribution. 
The Cox Regression analysis outlined above will be performed if  the proportional hazards 
assumption appears to hold. This will be checked by including in the regression model a 
variable representing the interaction between time since randomization and treatment group. If 
the coefficient for this time variable is non-significant at the 5% significance level then the Cox 
Regression analysis will be adopted. If the time-treatment group interaction is significant, then 
we will adopt a  parametric frailty model in place of the Cox Regression analysis. Either 
method can be implemented in SAS (see Gharibvand and Liu, 2009).  
Supportive analyses will include adjustment for other baseline variables that are imbalanced, 
and investigating interactions between baseline variables and the treatment groups.  
Another supportive analysis will be the comparison of treatments based on the time of 
complete eschar removal measured from the date of ICF using the same methods as for the 
time measured from randomization.  
13.3.2.3 Blood loss 
The measure of blood loss defined in Section 11.2 will be computed for each patient, and the 
distribution in the NexoBrid group will be compared with that in the SOC group. Means, 
standard deviations, medians, and interquartile ranges will be calculated. The normality of the 
data will be tested on each treatment group using the Shapiro-Wilk test. If the normal 
distribution hypothesis is not rejected at the 5% significance level in either group, then 
differences in distribution between NexoBrid and SOC will be tested using a t-test. If the  
normal distribution hypothesis is rejected either in the NexoBrid group or in the SOC group, 
then the differences in distribution between the treatment groups will be tested using a Mann-
Whitney test. Supportive analyses will include adjustments for the same covariates as 
mentioned in Section 13.3.2.1. 
13.3.3 
Safety endpoints 
13.3.3.1 Time to reach complete wound closure 
Time to reach complete wound closure will be compared between the NexoBrid and SOC at a 
patient level using a method of survival analysis with clustered data that is based on 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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appropriate assumptions. By “clustered data”, we refer to the multiple target wounds that can 
occur in a patient. First the proportional hazards assumption will be checked in the same way 
as in the analysis of the timely eschar removal endpoint. If the proportional hazards assumption 
is appropriate we will use Cox regression analysis with a robust sandwich estimator. If not, 
then we will use a parametric frailty model. Either method can be implemented in SAS (see 
Gharibvand and Liu, 2009). These methods include information on all the target wounds of 
each patient and account for any within-patient correlation. Missing information due to 
incomplete follow-up is incorporated naturally into such analyses as censored observations.  
The comparison will be adjusted for the same stratification variables as mentioned in Section 
13.3.2.1. A non-inferiority margin will be incorporated into the analysis that will represent a 
7.4-day advantage to the SOC group, so that the analysis will show whether the NexoBrid 
group is estimated to have on average a time to wound closure that is not later than 7.4 days 
after wound closure for the SOC group. 
13.3.3.2 Cosmesis and Function evaluation using MVSS 
The MVSS score for a patient will be the MVSS score averaged over all TW’s of that patient. 
The mean and standard error of this MVSS score at 12 and 24 months will be estimated for 
each treatment group. The evaluations at these two time points will represent two separate 
endpoints. The treatment groups will be compared using a linear model with MVSS score as 
the dependent variable. The explanatory variables in the model will include treatment, and the 
same stratification variables as specified in Section 13.3.2.2. The coefficient corresponding to 
the treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 
factors. For handling of missing data see Section 13.8.4. A clinically meaningful difference 
will be incorporated into the analysis that will represent a 2.7 or more units advantage to the 
SOC group, so that the analysis will show whether the NexoBrid group is estimated to have on 
average a MVSS score that is not worse by more than 2.7 units than the score for the SOC 
group. 
Additional Safety Outcome Measures will include:  
These parameters will be analyzed in a descriptive way only. More details will be provided in the 
statistical analysis plan. 
13.3.3.3 General parameters of safety 
Systemic adverse events, vital signs, pain assessment (using VAS), laboratory tests, units (and 
volume) of blood transfusion given during hospitalization, Immunogenicity evaluation for 
NexoBrid patients, Pyrexia and Hyperthermia, Systemic infections, Incidence of increased 
interstitial/compartment syndrome and QT prolongation. 
13.3.3.4 Local parameters of safety 
Local adverse events defined by treated physician or designee; graft loss, wound related 
infections, etc. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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13.3.3.5 Further parameters of safety 
Functionality evaluation 
The following scales will be used: QuickDASH questionnaire, LEFS (Lower Extremity 
Functional Scale) and Range of Motion (ROM) measurements. Each scale will be assessed at 
the following time points: 1 month after reaching complete wound closure and at 3, 6, 12, 18 
and 24 months after wound closure. The ROM measurement will be classified as normal or 
abnormal status. 
Quality of life evaluation 
The following scales will be used: EQ5D health questionnaire and BHSH-B (Burn Specific 
Health Scale). Each scale will be assessed at 1, 3, 6, 12, 18 and 24 months after reaching 
complete wound closure.   
13.3.4 
Exploratory endpoints and additional analyses 
These parameters will be analyzed in a descriptive way only. Additional details will be provided 
in the statistical analysis plan. 
13.3.4.1 Exploratory endpoints 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds, 
6. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
9. PK evaluation for a subset of NexoBrid patients1, 
10. Autograft related parameters. 
                                                 
1 PK will be performed for 20 NexoBrid patients. The overall PK sampling time points: 0, 1, 2, 4, 12, 24 and 48 
hrs.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.3.4.2 Additional Analyses 
The following analyses will be addressed as supportive efficacy analyses: 
1. Primary & secondary endpoints will be analyzed at a per wound level 
2. Secondary endpoints will be analyzed vs. the Gel Vehicle  
13.3.5 
Subgroup Analyses 
Descriptive statistics will be determined for all subgroup analyses.  
1. A sub group analysis will be performed on the subgroup of target wounds that are 
found, at least partly, in the anatomical area of the hand.  
2. Time to wound closure and 12m and 24m MVSS will be analyzed per TWs’ depth 
and% TBSA of the TWs.  
These subgroup analyses will be conducted at the wound level. More details will be 
provided in the SAP. 
13.4 
STATISTICAL COMPUTING 
The data will be analyzed using the SAS ® version 9.1 (SAS Institute, Cary North Carolina). 
13.5 
SAMPLE SIZE CALCULATIONS 
The following sample size calculations are based on the consideration of the primary and two 
secondary endpoints for this study.  
Estimated effects of NexoBrid from study MW2004-11-02 were used to design the study with 
adequate statistical power using the following steps.  
(a) Sample size calculations were based on study MW2004-11-02; 
(b) The effect of NexoBrid versus standard of care was estimated together with the standard 
error of the estimate; the effect of NexoBrid versus gel was estimated based on study 
MW2002-04-01, previous phase II study, which included 35 patients treated with gel 
vehicle.  
The size of the effect to be detected in this study, MW2010-03-02, was taken as the previous 
estimate decreased by half its standard error, in order to use a conservative value. 
13.5.1 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. 
Gel) 
Estimated proportion achieving complete eschar removal (for further definition and 
explanation see Section 11.1) in all TWs from study MW2004-11-02: NexoBrid 0.595 
Standard error = 0.057 
Anticipated proportion achieving complete eschar removal using NexoBrid: 0.595-0.057/2 = 
0.5665 
Estimated proportion achieving complete eschar removal using Gel vehicle in a previous Phase 
II study, MW2002-04-01: 0 (0 out of 35 patients).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. (0.0 is the 
point estimate; 0.10 is the 97.5 upper confidence limit).   
Because numbers of complete eschar removals are anticipated to be low in the gel group, we 
calculate sample size using Fisher’s exact test. We used the computer program nQuery Advisor 
version 7.0 to calculate power for a two-sided significance level of 5%, and thereby found the 
following sample size combination that led to approximately 90% power for detecting a 
statistically significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).   
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle group 13. 
Total sample size = 78. 
13.5.2 
Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.22; 
SOC 0.62 
Standard errors: NexoBrid 0.048; SOC 0.054 
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: NexoBrid 0.24 and 
SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a two-sided 
significance level of 5% is 86: 43 in the NexoBrid group and 43 in the SOC group. 
13.5.3 
Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial yielded an estimated 
log hazard ratio of -1.37 (hazard ratio of 0.254) with a standard error of 0.28.  
Therefore target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio = 0.29).  
The formula for the number of events (successful complete eschar removals) is:


2
2
log
)
(4
HR
z
z
d



 
where z = 1.96 two-sided significance level of 5%; and z = 1.28 for 90% power;For 90% 
overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required 
2
1
2
p
p
d
n


= 44 (to the nearest even number), 22 in each of 
the NexoBrid and SOC groups.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.5.4 
Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 patients (65 in the 
NexoBrid group, 13 in the Gel vehicle group and 43 in the SOC group (to match NexoBrid 
numbers)), we propose entering larger numbers to provide an extra margin of assurance in achieving 
positive results on the efficacy outcomes, and adequate information on safety outcomes to allow 
better benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 (NexoBrid) + 75 (SOC) + 
25 (Gel Vehicle). 
13.5.5 
Safety endpoints 
Because of the importance of the time to wound closure and MVSS safety endpoints, we examined 
for these two endpoints, under the chosen sample size of 75 patients per group in the NexoBrid and 
SOC groups, the probability of demonstrating that the observed average value in the NexoBrid does 
not exceed the observed average in the SOC group by more than the clinically meaningful margin.  
For time to wound closure, assuming, based on previous data, that in reality NexoBrid has an 
average time that is longer than SOC by 5.77 days (based on wound closure data from study 
MW2004-11-02 analyzed per the suggested analysis in Section 13.3.3.1), the probability that the 
observed average NexoBrid time to wound closure will be longer than the observed average SOC 
time by more than 7.4 days is calculated to be 0.26. 
For MVSS, assuming, based on previous data, that in reality NexoBrid has a score that is less (better) 
than SOC by 0.51 units, the probability that the observed average NexoBrid score will not be larger 
(worse) than the observed average SOC score by more than 2.7 units is calculated to be less than 
0.001 for MVSS at 12m and 24m.  
13.6 
ALPHA CONTROL 
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. The primary and secondary endpoints of 
efficacy will be tested in a hierarchy, so as to preserve the nominal significance levels: 1. 
Primary; 2. Incidence of surgery; 3.Time to complete eschar removal; 4. Blood loss.  
13.7 
STRATIFICATION AND RANDOMIZATION 
13.7.1 
Randomization Procedure: 
To enter a patient and obtain the randomized treatment allocation, the following information 
should be verified and uploaded into the eCRFs: 
i. 
Eligibility of the patient (entrance criteria are met) 
ii. 
ICF date 
iii. 
Patient’s demographics (date of birth, gender, ethnicity, race) 
iv. 
Patient’s burn history and burn description (identification of all wounds and target 
wounds (TWs) assigning an identifying number to each wound, and providing its 
anatomical site, its %TBSA, its depth and where relevant its proportion of superficial 
partial thickness (SPT) area 
v. 
The overall depth, according to its category A1-A3 (see definition below) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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vi. 
The treatment center 
 
Upon finalization of this process, randomization will be performed as described below and a 
designated person will receive the allocated treatment. With regard to this designated person, this 
person must understand that the information regarding the allocated treatment must not be given 
to the designated person who is assessing the TWs following treatment, as further described in 
the study protocol. 
13.7.2 
Stratification: 
Eligible subjects will be stratified into different groups in order to balance the treatment groups 
with respect to factors that may be related to efficacy and safety outcomes. Two factors will be 
used to stratify the subjects.  
 
A. Overall depth per patient 
A1: All TWs are full thickness; 
A2: Mixed TWs – full thickness and deep partial thickness  
A3: All TWs are deep partial thickness. 
 
 
B. Clinical center, so as to address possible differences in SOC procedures between sites (if any), 
to allow comparison of the results within centre and to reduce the likelihood of a center 
including patients in only one arm of the study.  
Using this stratification, patients will be randomized in a 3:3:1 ratio (NexoBrid: SOC: 
Vehicle). 
13.7.3 
Randomization algorithm: 
The treatment allocation will be performed using the method of block randomization with 
stratification by the factors A and B, described in the subsection above: overall depth of TWs, 
and clinical center. The method will be implemented by computer generation of permuted 
sequences of treatments NexoBrid, SOC or Gel Vehicle in the ratio of 3:3:1 in blocks of a 
certain length. The length of the blocks will not be disclosed so as to prevent prediction of the 
next patient’s allocation.  
 The algorithm will be prepared and automated by an independent study biostatistician, and 
will operate through the central site with which the clinics will communicate.   
13.8 
DATA HANDLING METHODS AND DEFINITIONS 
13.8.1 
Multiple visits per time-point 
Study visit time-points are scheduled at screening, pre eschar removal, eschar removal 
(treatment), post-treatment, hospital discharge, follow-up (weekly until wound closure, wound 
closure confirmation, three monthly visits post wound closure), long term follow-up at 6, 12, 
18 months and 24 months post wound closure confirmation and re-admission to hospital/day 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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care (if done). One visit is expected for each time-point. The following approach is used if 
there are multiple visits per patient per time-point.  
For the endpoints incidence of complete eschar removal, reduction in surgical needs, summary 
of blood loss and the cosmesis endpoints of safety, if a subject has more than one visit with 
data at a time-point, the later non-missing evaluation will be used for analyses. An exception to 
this rule is in the analyses of time to eschar removal and time to wound closure; for these 
parameters a value other than the last one or more than one value per visit time-point may be 
taken into account. More details will be provided in the SAP.  
13.8.2 
Rules for Data Derivations 
The SAP will identify the necessary data transformations and rules for data derivation. 
13.8.3 
Multiple target wounds per patient 
Patients may have multiple wounds being treated (target wounds). All target wounds will be taken 
into account in the primary and secondary analyses. The methods of analysis are specified in the 
efficacy analysis subsection. The following calculations will be used for each patient: 
1) Total treated burn surface area (%TBSA): is defined as the sum of areas of all target wounds 
for that patient. 
2) MVSS at 12m and 24m are defined as the score averaged over the TWs.  
13.8.4 
Missing data 
Missing data in the primary and secondary outcomes is the main concern. 
Little or no missing data are expected for the primary endpoint, since the outcome is assessed only 
several hours after the start of treatment. The main analysis will be a complete-case analysis. In each 
treatment group, only patients with documented total eschar removal (at the end of the eschar 
removal soaking period) will be counted and this number divided by the total number of randomized 
subjects. Two sensitivity analyses will be conducted for this endpoint. A first analysis will count all 
patients with missing data (for this endpoint) as positive (i.e. complete eschar removal) and a second 
analysis will count all patients with missing data as negative (i.e. no complete eschar removal).  
The same procedure will be applied for the secondary endpoint, reduction of surgical need.  
The analysis of the secondary endpoint time to eschar removal will compute missing values as 
censored. 
Missing blood loss values for some eschar removal procedures may occur within a certain patient. A 
regression model containing main prognostic factors (wound area, depth of wound and type of 
procedure) for blood loss of eschar removal procedures will be computed. On this basis a multiple 
imputation will be calculated.  
Missing wound closure times are not expected (see Section 13.3.3.1), but if they occur, they will be 
handled by a multiple imputation procedure. For each missing value 10 imputations will be 
computed as predictions of a linear model with the variables mentioned in 13.3.2.1 and also wound 
area and adding a random term which originates from a normal distribution with zero mean and 
standard deviation equal to the standard deviation of the prognoses from the linear model using 
RAND function in SAS. The random seed will be set to 13569. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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A higher ratio of missing values is expected in the case of later MVSS values, especially for 24 
months. In order to avoid unnecessary complex imputation for this descriptive endpoint simple 
LOCF imputation will be done. It is expected that at least one early MVSS value exists. If this is not 
the case the missing MVSS values will be replaced by the mean MVSS value of all patients who 
belong to the same treatment group and the same stratum (see Section 13.7.2) at each time point. A 
best case – worst case imputation using information about the reasons of drop out documented in the 
CRF will be used as a supporting sensitivity analysis. 
The Statistical Analysis Plan will provide more details on the strategy outlined above for handling of 
missing data. 
13.8.5 
Stratifying by center in the analysis 
Randomization will be stratified by center as detailed in the Section 13.7.1. However, some 
centers may enroll very few patients so that there are insufficient subjects to conduct a 
stratified analysis efficiently. To ameliorate this problem, for stratified analysis at the end of 
trial, “small centers” will be pooled as follows:  
All centers will be classified by region (assuming that those in the same region will have a 
similar standard of care treatment modality) and number of patients randomized. If a center has 
less than 14 patients randomized, this center will be pooled with the next smallest center within 
the same region until the pooled center has 14 or more patients. If a region has less than 14 
patients randomized, this region will be pooled with a region that is geographically close to it. 
The pooling strategy will be finalized prior to database lock by a statistician who is blind to the 
outcome data. 
13.8.6 
Stages of Analysis 
The analysis is planned to be carried out in three stages, as described below.  
1. The first analysis will be performed at the end of the Efficacy Assessment Period (EAP). 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 for short-term safety endpoints 
(including time to wound closure). The analysis will be conducted, when 3 months had passed 
from the last patient reaching complete wound closure, in accordance with FDA guidance for 
industry Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for Treatment 
“Trial subjects generally should remain in the study for follow-up evaluation at least 3 months 
following complete wound closure. The purpose for this follow-up period is to help distinguish 
actual wound healing from transient wound coverage”. At this time-point, data will be available 
for nearly all patients on the primary end-point (proportion with complete eschar removal), the 
three secondary endpoints (proportion undergoing surgery, time to complete eschar removal, and 
blood loss) and short-term safety endpoints (including time to wound closure). Missing values 
for early drop outs etc. will be handled as described in Section 13.8.4  and the SAP. The 
complete data set documented so far will be locked and analyzed as described above. MVSS 
data, although captured in the eCRF for a few of the subjects at the stage of EAP, will not be 
included, revealed or analyzed during the EAP analyses. Furthermore, to assure that patients’ 
treatment codes will not be revealed during the EAP analyses, all patients’ identification 
numbers will be Pseudonyms by data management before analysis is being performed and 
presented.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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The second analysis will be performed for the 12 month follow up period (STFU12) and will 
be started after the last patient has reached the 12m assessment. At this analysis, all 
accumulated safety data at the 12m follow-up will be analyzed, particularly the 12m MVSS 
assessment for cosmesis and function. The complete data set documented so far will be locked 
and analyzed as described above. 
The third and final analysis covers the data of the long-term safety follow up (LTSFU24). It 
will be conducted after the last patient has reached the 24m assessment at last 12 months after 
(STFU12) analysis (stage 2). At this analysis, all accumulated safety endpoints at the 24m 
follow-up will be analyzed, particularly the 24m MVSS assessment for cosmesis and function. 
The complete data set documented during the trial will be locked and analyzed as described 
above (hard lock). 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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14 
QUALITY ASSURANCE  
14.1 
QUALITY ASSURANCE PROGRAM 
This clinical trial may be audited according to the MediWound Quality Assurance (QA) 
program.  
The purpose of these audits is to determine whether the study is being conducted and 
monitored in compliance with the protocol and recognized GCP guidelines and local 
regulations. These audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent inspection by any regulatory authority.  Such 
audits, if necessary, will be pre-arranged with the site and conducted within a reasonable time 
frame. 
14.2 
MONITORING PROCEDURES 
The conduct of the study will be closely monitored by representatives of MediWound to verify 
adherence to ICH GCP guidelines and applicable SOPs. Reports of these monitorings will be 
archived with the study report.  
The Investigator will allow the designated MediWound representatives and/or any regulatory 
agency to have direct access to all study records, eCRFs, corresponding subject medical 
records, study drug dispensing records and the study drug storage area, and any other 
documents considered source documentation. The Investigator also agrees to assist the 
representative if required. 
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information in eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).  
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. MediWound monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
 
14.1 REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, and the ICH Harmonized Tripartite Guidelines for Good Clinical 
Practice in compliance with local regulatory requirements. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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14.2 
DATA SAFETY MONITORING BOARD (DSMB) 
A Data Safety monitoring Board (DSMB) will convene at least twice a year, as routine, during 
the enrollment period, to assess safety data as described in the agreed DSMB chart. During the 
follow up period, a DSMB will convene at least once a year. 
All DSMB conventions will be in closed session format. 
These activities will be coordinated by MediWound Ltd. and the recommendation shall be 
directed to MediWound Ltd. The DSMB will consist of three independent individuals 
including burn specialist(s) and a biostatistician. Following selection and agreement to serve, 
the committee will meet in person or by teleconference to be briefed fully on the procedures 
defined in the Protocol and Statistical Plan. MediWound Ltd. shall be formally informed of 
recommendations by the DSMB prior to implementation of said recommendation(s) and must 
approve, in writing, any new analyses being recommended by the DSMB. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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15 
INVESTIGATOR’S AGREEMENT 
I have carefully read the foregoing protocol including all appendices and agree that it contains 
all the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the current 
GCP guidelines and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information submitted by the sponsor relating 
to pre-clinical and prior clinical experience to all personnel for whom I am responsible that 
participate in the study. I will discuss this information with them to assure that they are 
adequately informed regarding the drug and conduct of the study. 
I agree to keep records on all subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) in accordance with the current GCP 
and local regulations. 
 
Site Principal Investigator’s name 
MediWound Representative's name 
Signature 
Title 
Date (dd/mmm/yyyy) 
Signature 
Institution 
Date (dd/mmm/yyyy) 
 
 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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16 
APPENDICES 
APPENDIX 1- WOUND DEPTH ASSESSMENT- CLINICAL EVALUATION 
The burn literature [18, 97] suggests that clinical evaluation of the burn wound is the most 
widely used method of assessing burn wound depth. This was, but also recognized in the FDA 
Guidance for Industry Chronic Cutaneous Ulcer and Burn Wounds, June 20061 and also the 
burn depth assessment method accepted by the ABA [1]. In accordance with the above, further 
to assessing wound appearance, the following tests will be included [98]: 
1. Capillary blanching 
2. Capillary refill 
3. Capillary staining 
4. Wound sensibility to touch 
5. Pin prick 
Using the above criteria will allow the Investigator to differentiate between the SPT and DPT 
areas as is widely acceptance in the US [99], according to the following below criteria in 
addition to the visual assessment: 
 SPT burns extend into the papillary dermis and form blisters. Once the blister is 
removed from a SPT wound, the wound is pink, wet and hypersensitive to touch. These 
wounds are painful and blanch with pressure.  
 DPT wounds extend into the reticular dermis. They also blister but the wound surface 
appears mottled pink and white. The patient complains of discomfort and pressure 
rather than pain and when a pressure is applied to the burn, capillaries refill slowly or 
not at all. The wound is less sensitive to pinprick. 
                                                 
1 Section IV D, pharagraph 2. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 2- PAIN MANAGEMENT PROCEDURES 
Pain Management Procedures 
For topical arms treatment, preventive analgesia medication (pain management) will be 
mandated as for an extensive burn dressing-change. 
During NexoBrid treatment it has been observed that the two painful stages are during the first 
30 minutes of the treatment and during the dressing removal which is followed by cleansing 
and dressing (30-45 minutes).  Thus, the principle of the suggested pain management is to 
prevent pain by starting the treatment with sufficient basic analgesia/sedation as detailed 
below. Once the first painful stage has ended, background analgesia can be administered and 
the sedation/analgesia regimen stopped. 
Before NexoBrid dressing removal the sedation administration should normally be started 
ensuring that the patient is pain-free until the first post-eschar removal soaking dressing is in 
place. 
Sedation administration can be repeated two hours later, before the removal of the soaking-
dressing. 
  
Objective: 
The object of the analgesia is to ensure that the entire treatment course is performed in a safe 
and comfortable manner. During the treatment the patient should be free of significant pain and 
easily arousable, without interference with vital functions. 
In the majority of cases the pain can be managed without the need for deep sedation, by the 
pre-administration of oral analgesics and being prepared to administer intravenous Morphine as 
needed to control pain surge.  
If sedation is used the patient should not need intubation and it should be easily and quickly 
reversible by discontinuing administration of the sedation agent. Sedation can normally be 
discontinued after the first painful wave that lasts for 30-60 minutes from NexoBrid 
application; it should be reinitiated before and during dressing removal and wiping of the 
dissolved eschar, a process that may last for another 30 minutes. 
Attention should be given to background analgesia during the interval between these 
procedures. 
During procedures, the patient should as a minimum be monitored frequently for: 
 Blood Pressure (non-invasive)  
 Cardiac activity (ECG) 
 Respiratory rate 
 Oxygen saturation (pulse oximetry) 
Example of a medication regimen: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Bolus intravenous analgesia/sedation using appropriate combinations of fentanyl, and 
midazolam and ketamine. Suggested initial doses are: 
Fentanyl- 2 microgram/Kg 
Midazolam- 0.06 mg/Kg (1 mg/15 Kg) 
Ketamine HCl- 0.5 mg/Kg  
Maintenance doses will typically be one-third to one-half of the initial dose at 10-20 minute 
intervals; considerable inter-patient variation should be expected.   
Intravenous continuous sedation using a syringe driver or target-controlled infusion (TCI) 
driver is a very acceptable technique, using propofol + alfentanil, propofol + remifentanil, or 
remifentanil alone.   
 
Continuum of depth sedation: Definition of general anesthesia and levels of 
sedation/analgesia*- American Society of Anesthesiologists 
 
  
Minimal 
Sedation 
Anxiolysis 
Moderate 
Sedation/ 
Analgesia 
(“Conscious 
Sedation”)  
Deep Sedation/ 
Analgesia  
General 
Anesthesia  
Responsiveness  
Normal response 
to verbal 
stimulation  
Purposeful** 
response to 
verbal or  
tactile 
stimulation  
Purposeful** 
response 
following 
repeated or 
painful 
stimulation  
Unarousable 
even with painful 
stimulus  
Airway  
Unaffected  
No intervention 
required  
Intervention may 
be required  
Intervention 
often required  
Spontaneous 
Ventilation  
Unaffected  
Adequate  
May be 
inadequate  
Frequently 
inadequate  
Cardiovascular 
Function  
Unaffected  
Usually 
maintained  
Usually 
maintained  
May be impaired  
  
 Minimal Sedation (Anxiolysis) is a drug-induced state during which patients 
respond normally to verbal commands. Although cognitive function and physical 
coordination may be impaired, airway reflexes, and ventilatory and cardiovascular 
functions are unaffected.  
Moderate Sedation/Analgesia (“Conscious Sedation”) is a drug-induced 
depression of consciousness during which patients respond purposefully** to verbal 
commands, either alone or accompanied by light tactile stimulation. No interventions 
are required to maintain a patent airway, and spontaneous ventilation is adequate. 
Cardiovascular function is usually maintained.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Deep Sedation/Analgesia is a drug-induced depression of consciousness during 
which patients cannot be easily aroused but respond purposefully** following 
repeated or painful stimulation. The ability to independently maintain ventilatory 
function may be impaired. Patients may require assistance in maintaining a patent 
airway, and spontaneous ventilation may be inadequate. Cardiovascular function is 
usually maintained.  
General Anesthesia is a drug-induced loss of consciousness during which patients 
are not arousable, even by painful stimulation. The ability to independently maintain 
ventilatory function is often impaired. Patients often require assistance in 
maintaining a patent airway, and positive pressure ventilation may be required 
because of depressed spontaneous ventilation or drug-induced depression of 
neuromuscular function. Cardiovascular function may be impaired.  
Because sedation is a continuum, it is not always possible to predict how an 
individual patient will respond. Hence, practitioners intending to produce a given 
level of sedation should be able to rescue*** patients whose level of sedation 
becomes deeper than initially intended. Individuals administering Moderate 
Sedation/Analgesia (“Conscious Sedation”) should be able to rescue*** patients 
who enter a state of Deep Sedation/Analgesia, while those administering Deep 
Sedation/Analgesia should be able to rescue*** patients who enter a state of General 
Anesthesia.  
* Monitored Anesthesia Care (“MAC”) does not describe the continuum of depth of 
sedation, rather it describes “a specific anesthesia service in which an 
anesthesiologist has been requested to participate in the care of a patient undergoing 
a diagnostic or therapeutic procedure.”  
** Reflex withdrawal from a painful stimulus is NOT considered a purposeful 
response.  
*** Rescue of a patient from a deeper level of sedation than intended is an 
intervention by a practitioner proficient in airway management and advanced life 
support. The qualified practitioner corrects adverse physiologic consequences of the 
deeper-than-intended level of sedation (such as hypoventilation, hypoxia and 
hypotension) and returns the patient to the originally intended level of sedation. It is 
not appropriate to continue the procedure at an unintended level of sedation. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 3- PHOTOGRAPHIC WOUND DOCUMENTATION 
In accordance with FDA guidance, the photography methods will be standardized in all centers with 
standard camera type and control of the distance/size (zoom), color, exposure, (lighting) and color 
bend tag (as a reference for color and size) of the acquired picture. This will be performed using 
patient ID label (see below) which will be identical in size and content (colors scale) for all patients 
and should be used as detail below. Photographs will be uploaded into the eCRF. 
Photographic Documentation 
1. Each wound area is considered an independent entity and should be documented as such. 
2. Each wound site should be photographed using a standard digital camera with flash card 
memory which together with sterile photography patient ID labels, are supplied by 
MediWound.   
3. Site number, patient ID, exact date and time, and wound location (as specified on the ID 
labels) should be noted on each label. The photograph is taken (i.e. pre-cleansing, pre-
treatment, post-soaking, 24hrs, hospital discharge, weekly visits and monthly visit, etc). 
4. Each photographed field (wound site) should include the patient ID label.  
5. The photograph should be taken using the zoom facility (camera as near as possible to the 
patient) while including the entire treated area. 
6. In order to ensure patient confidentiality, facial photographs are not allowed. 
 
 
 
 
 
 
 
 
 
 
Recording Kit 
The recording kit consists of: 
1. Sterile photography patient ID labels, 
2. One digital camera, 
3. Flash cards. 
 
MW2010-03-02 
Visit: _______________________________ 
MW2010-03-02 
Visit: _______________________________ 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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APPENDIX 4- POST-ESCHAR REMOVAL WOUND MANAGEMENT 
Post Eschar removal Burn Wound Bed(s) 
An ideal burn debriding agent should effectively and quickly debride the burn eschar but also 
preserve viable tissues to source and allow spontaneous healing by epithelialization. It should 
combine the non-invasiveness of the ineffective and slow non-surgical debriding means and 
the efficacy and speed of surgery. 
Following any eschar removal process, whether surgical or non surgical one, the wound is 
being assessed for eschar removal efficacy and for presence of residual viable dermis by 
experienced plastic/burn surgeon. Usually, following an effective eschar removal with 
visualization of the viable tissue bed, a more accurate burn depth diagnosis can be made. 
Macroscopically, the components of the human integument are from epidermal, dermal and 
subdermal origins. Few colors are involved in the final visual appearance of the healthy tissues: 
the brown-black of the melanin, hemoglobin's shades of reds (depending on the oxygenation 
level) and the pearly-white of the collagen. Below the skin a yellow fat add another color.  
The debrided wounds can be divided into four groups based on the debrided bed condition:  
1. Complete eschar removal revealing residual viable dermis. 
2. Complete eschar removal revealing a full thickness skin defect requiring permanent 
cover. 
3. Complete eschar removal revealing a wound bed with areas of viable dermis and areas 
of full thickness defect.    
4. Incomplete eschar removal to various degrees. 
Several means and strategies can be used to remove the eschar, each ending in a typical bed: 
Surgically debrided beds:  
Sharp dissection (using dermatomes, dermabtasion or hydro dissection such as Versajet) will 
leave a smooth bed that is composed, in the case of complete eschar removal, of transected 
structures such as dermis and blood vessels or subcutaneous fat.  This bed will readily accept 
autograft with good take if adherence and drainage are assured.  
Autolytically debrided beds:   
Slow decomposition and maceration will cause eventually the sloughing of the necrotic tissue 
but simultaneously, at the end of the second week granulation tissue will start to form and 
epithelial cell will start to epithelialize clean exposed dermis originating from the edges or the 
appendages (hair follicles, sweat and sebaceous glands). Granulation tissue will form if wound 
closure (by epithelialization, grafting or wound edges approximation) is delayed developing 
into scar. Granulation tissue will, if not infected, readily accept autograft but may contract later 
pulling with it the wound’s edges. In case of significant bacterial infection the process can 
invade surrounding healthy tissues (Invasive Infection) extending the damage. Infection 
together with other wound healing intervening factors (e.g. diabetes, hypoproteinaemia, etc) 
can cause the wound healing process to stop and become chronic. Chronic wounds may be 
highly contaminated or chronically covered with biofilm with only slowly granulation tissue 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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formation. Such wounds may behave as chronic, recalcitrant wounds, and will not heal easily 
or support graft. 
NexoBrid- Enzymatically debrided bed  
NexoBrid is an enzymatic debriding agent provided for eschar removal of the eschar. The raw 
surface that is left after this eschar removal is the Interface Layer (IL), which is comprised of 
the upper layer of healthy tissue that is made of exposed viable tissues. After wiping away the 
dissolved eschar the dermal IL has a whitish hue due to the dermal collagen matrix seeded with 
punctuated bleeding capillaries. The dissolved ends of the collagen fibres are made of 
unferruled collagen fibrils that may give a “furred” aspect to the surface. This layer preserves 
all viable components such as deep epithelial elements inside the adnexae and deep dermal 
remnants (collagen fibres, subdermal fat and blood vessels). In all but the deepest wounds, the 
presence of the dermal Interface Layer permits spontaneous healing (epithelialisation over 
dermal remnants); however, the majority of transacted blood vessels are still occluded at their 
ends. In the event that skin grafting is required (a full thickness burns or after the spontaneous 
healing potential has been exhausted or when an immediate wound closure is required) a 
graftable bed is obtained by simple scrubbing the Interface Layer with a dry swab or a sterile 
nail brush to expose the blood vessels during the graft application session. 
Wound bed assessment 
Any effective eschar removal will reveal the surface of the exposed viable tissue with its 
components and structures and the exact extent of the original damage (Figure 1). Being aware 
of the cutaneous three dimensional macroscopical structures, the form and color of the various 
components, it is rather easy to assess the depth of the debrided bed. The first step is to assess 
visually the presence or absence of epidermis which is the criterion of second degree (dermal) 
burn. Residual, none removed eschar appears opaque, yellowish-grey clearly differing from the 
pearly-white viable collagen. Bleeding vessels on the background of white collagen indicate 
that the eschar removal process reached viable tissue. Once the dermis is revealed the bleeding 
pattern that characterizes the different dermal levels clearly indicates the depth. Very fine, 
homogeneous bleeding characterizes the superficial papillary dermis (superficial, II° dermal 
burns). Deeper the burn is, the bleeding vessels are set wider and wider apart. In mid and deep 
dermal burns, only few bleeders can be seen on the background of white collagen matrix 
background. The few deep dermal capillary complexes that are situated around the adnexae 
may give the dermis a pinkish hew. When most of the dermis is removed the yellow subdermal 
fat gives the debrided bed a yellowish hew. Reaching the deepest part of the dermis, at the 
transition to the subdermal layer, one can see the yellow fat lobules protrude through the loose 
net of collagen fibers with few bleeders. This “quasi” full thickness burn behaves as a full 
thickness 
burn 
and 
only 
rarely 
will 
heal 
spontaneously.    


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Figure 1- Wound bed assessment 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Non burned skin, uninjured by NexoBrid 
b. 
Superficial dermal burn with bleeding 
c. 
Mid depth dermal burn with well preserved dermal collagen matrix 
d. 
Deep dermal burn with larger and wider spaced bleeding capillaries and a very thin dermal matrix 
e. 
Full Thickness burn 
f. 
Non dissolved eschar protected by the blister that was not removed prior to NexoBrid application 
 
Wound healing options post eschar removal 
In general, burn wound closure can be achieved by:  
Primary Intention: closure of the wound bed by graft that covers and obliterates the raw 
surface and “heals” the wound completely, similar to using sutures for bringing together the 
surgical wound’s edges. This approach requires a completely clean and viable bed with all 
cellular and non cellular components exposed for the healing process. The severed end of the 
blood vessels should be opened to allow endothelial cells to bud and connect the graft’s raw 
underside and eventually supply the graft with the necessary life giving blood. The graft 
survives the first days by “imbibition’s phenomenon”: graft’s nutrition by the serous exudates 
from the wound bed but its continuous survival depends on blood vessels connection and 
integration with the graft’s capillary bed. The capillary bed in the dermal papillary layer 
indirectly supplies the epidermis (that does not have any capillary bed of it own) with the 
necessary nutrients and oxygen so autograft needs a certain dermal layer to provide nutrient to 
the epidermis for survival. Graft adhesion during first days will provide good contact to the 
recipient bed, decreased danger of exudates’ collection and a better chance of take. Such graft 
stabilization and adherence is achieved by compressive dressings or using sub atmospheric 
(vacuum) external dressing over the graft that will stabilize the graft to its bed and remove 
exudates that can interfere with graft take.        
a
d
c
f 
e 
b


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Autograft: grafting the raw bed with autograft that includes epidermis and a thicker or thinner 
layer of dermis. If the graft take >95% – the engrafted wound is practically closed.  
Autografting requires surgery under general anesthesia, sacrifice of healthy donor site skin area 
and surgical facilities (OR, surgical team etc.). The donor site will heal spontaneously during 
2-3 weeks by epithelialization but may be scarred and infected. Thicker the harvested dermal 
layer is better the functional and aesthetic results are but more damage is inflicted on the donor 
site, longer its healing is and higher is the likelihood to develop scars. Thicker the graft is, 
higher are the demands of the transplanted tissue from the wound’s bed and so are the risks of 
graft failure. 
Permanent Skin Substitutes: products such as Matriderm, Integra and Jalomatrix can be applied 
on the debrided bed, serving as regenerating matrix for the development of new dermis. Here 
too the debrided bed should be free of necrotic eschar and contain opened capillaries ends as 
the source for endothelial cells that will integrate, together with the native fibroblasts, into the 
artificial matrix forming the neodermis. All these products have to be engrafted sooner or later 
also with thin autograft (Matriderm immediately and Integra and Jalomatrix, 2-4 weeks later) 
that contains mainly the epidermal layer. The grafting procedure will necessitate surgical 
facilities as in a formal autografting but the donor sites heal faster (< 2 weeks) as the harvested 
graft is thinner with much less sacrificed dermis.  The cost and success rate of these products is 
a severe limiting factor.   
Allograft, xenograft and adherent biological covers: will adhere to the bed (assisted by vacuum 
dressing in the first days), preserve moisture and provide conditions for epithelialization or 
autograft for later stage, following removal of the temporary dressings.  
Epithelialization over preserved dermis: Full thickness defect greater than few cm2 should be 
closed by grafting but exposed dermis can heal by epithelialization that will close the wound 
without granulation and scar formation. When sufficient dermal elements exist, epidermal cells 
(Keratocytes) originating from the wound’s edges, the skin appendages (hair follicles, sweat 
and sebaceous glands) or Keratocytes cultures/ suspension can proliferate and propagate over 
the dermal bed creating a new epidermis.  This process requires a healthy and clean dermal bed 
and a dressing that will protect the exposed, raw dermal bed from desiccation and infection and 
provide the epithelialization process with the necessary conditions (moisture and propagation 
surfaces for the Keratocytes). There is a plethora of products that can be used for this purpose 
each with its advantages and disadvantages, each fulfilling a specific need in the healing 
process. 
Healing By Secondary Intention: As real regeneration of full thickness skin defect is 
impossible, the natural healing process of these wounds is aimed at creating first a temporary 
protection mechanism followed by a “plug” that fills the defect, replacing the missing, normal 
skin. Following a generalized inflammation-healing process of three overlapping phases of 
Inflammation, Proliferation and Modulation the granulation tissue forms, covering the wound 
bed and slowly filling the defect. Granulation tissue originates from connective tissue, 
containing fibroblasts, macrophages, white blood cells elements and endothelial cells from the 
severed blood vessels all forming a tortuous mass of new capillaries imbedded in new 
connective tissue. Keratocytes from the wound’s edge slowly strive to cover the granulation 
tissue but very often their progress is extremely slow and may be completely denied by the 
fibroblasts. The granulation tissue with all the local and systemic defense mechanisms provides 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 116 of 169 
 
 
  
 
 
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protection against infection. The fibroblasts deposit collagen and the fibroblasts–originating 
miofibroblasts pull-in the wound’s edges forming a scar with more or less contracture element. 
The progressive development of the granulation tissue (proliferative phase) may be controlled 
and decreased by the influence of the epithelial cells, the Keratocytes. Once the granulation 
tissue is entirely covered by the Keratocytes, its growth will decrease and the granulation tissue 
becomes a scar that will start to mature, often also to contract. Granulation tissue proliferation 
may be attenuated by topical corticosteroid ointment short (few days) treatment course 
exploiting the controlling affect of corticosteroids on inflammatory processes.  In the 
granulation tissue, the fibroblasts deposit collagen and the entire tissue undergoes modulation 
to become fibrous, hard scar filling the original defect. The scar contracts by the miofibroblast, 
pulling-in the healthy skin margin, reducing the scar’s surface but these contractures, 
especially across joints will interfere with function and cosmesis.   
Grafting granulation tissue is a routinely practiced: during surgery the granulation tissue is 
forcefully scraped with a blunt edge surgical instrument (spoon, scalpel handle, metal ruler, 
etc.), removing the superficial layer with its bacterial load and opening the multitude of 
capillaries to accept the graft. In burn care healing by secondary intention with granulation 
tissue scarring and contractions is undesirable and often the scarring is more incapacitating and 
dangerous than the acute burn itself.  The lengthy (sometimes years) of the scar modulation 
process may be influenced by application of continuous pressure on the scar by made-to-
measure pressure “garment” dressings that applies a constant pressure and silicon sheets 
applied directly on the scar under the pressure garment.  
Healing by tertiary (delayed primary) intention: In some cases primary closure by wound 
edges approximation (suturing) or grafting is not feasible mainly due to local infection, 
patient’s general condition or external restrictions (surgical team, OR, other facilities or graft 
donor site availability). Another condition is when wounds closed by suturing disrupt (dehisce) 
or the grafts do not “take” to the wound bed and slough off. In most cases it is either an 
infection process of the underlining wound bed or edges or collection (blood, serum, pus). Re-
suturing or re-grafting the contaminated bed will end only with another closure failure and 
probably also with spreading the infectious process to adjacent tissues. The accepted practice is 
to leave the wound open, to treat the infection by topical and sometimes also systemic 
medications and once the infection is resolved the wound can be closed again. Formation of 
granulation tissue during the treatment course can favor graft take by providing additional 
blood supply to the graft but later may promote scar formation. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 117 of 169 
 
 
  
 
 
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Summary of wound healing strategy in burns 
 Ideally burns wounds should be debrided and closed as soon as possible after injury. At 
present that means: immediate or very early after injury tangential excision and autografting. 
Due to diagnosis difficulties mainly of the dermal burns, the interest of avoiding the surgical 
related trauma, morbidity and the surgical needed facilities/costs with the potential (and hope) 
that the burn may heal spontaneously, the surgical treatment may be delayed. Once the eschar 
is not surgically debrided a slower, non surgical eschar removal approach is practiced. It is 
based on the best possible anti-infection care with the promotion of the eschar separation 
(sloughing) or disintegration (necrosis). This is a slow process that may lead to local and 
systemic infection and additional tissue damage. The time needed for this non surgical process 
allows also the formation of granulation tissue. The granulation tissue protects the open wound 
and offers a good bed for grafting but in many cases will form a heavy, contracted scar in few 
weeks. During this healing process an educated, cyclic (short spells of 2-3 days) of 
corticosteroid ointment will reduce the granulation tissue and will offer the bed a better 
grafting bed.  
To graft or not to graft: Full thickness defect will not heal properly without grafting and need 
always autograft or permanent skin substitute to prevent healing by secondary intention and 
scaring. Clean dermal bed that can epithelialize spontaneously can be grafted as well in order 
to close the wound immediately. Several factors should be considered when striving to close 
the wound "as soon as possible".  The true benefit to the burn patient in earlier burn wound 
closure by few days (the difference between grafted and epithelialized dermal burn) not always 
is truly advantageous. Autograft involves surgery, surgical and anaesthesia related trauma, 
donor site morbidity and the healing time of the donor site by epithelialization (≈2 weeks) is 
very similar to the epithelialization of the burn wound exposed dermis. Donor site morbidity 
includes infection, pain, additional dressing changes and scars. Grafting will not speed early 
subject mobilization as the latest normally starts much before wound closure ends and a return 
to work/normal lifestyle requires at least several weeks of recovery and rehabilitation after the 
wound is closed.  Thus, the decision to graft exposed dermis in order to shorten by few days 
wound healing should take into consideration the comprehensive well being and benefit to the 
patient. Issues such as length of treatment course and hospitalization depend on the nature of 
the dressing and wound care that in many cases allow early hospital discharge and prevent 
open wound related complications. 
Following wound closure the healed wound is dressed with a thin protective primary dressing 
or silicon sheet followed by pressure “garment” dressing modulating their modulation to a 
smooth, pale and pliable skin-like scar.   
 
Wound healing requirements 
The general prerequisites for good wound healing are based on adequate conditions and 
microenvironment for this dynamic process. 
Tissue factors 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 118 of 169 
 
 
  
 
 
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 Adequate blood supply: adequate arterial supply, adequate venous return, healthy capillary 
bed (example to potential problematic conditions: PVD, Varicose Veins, arterial or venous 
insufficiency, diabetes, peripheral edema of any kind, hypertension, etc.)   
 Clean wound bed: no eschar, foreign bodies or materials: all the followings can interfere 
with the healing process: necrotic eschar such as in burns, pressure sores, exposed bone, 
tendon or orthopedic implant and suturing material, foreign bodies introduced during injury, 
intradermal or subdermal hematomas or seromas. 
 No severe wound infection: < 10 5 count /cm3, purulent discharge, invasive wound infection, 
signs of cellulites, fungal infection.   
 Balanced healing dynamics: offering adequate conditions for epithelialization propagation 
and preventing overgranulation and its stagnation.    
 Systemic factors such as chronic steroid intake, anticancer drugs, malnutrition, diabetes, etc. 
 Post radiation tissue damage 
 Avoiding local medication that can interfere with the desired healing process (e.g. SSD, 
pseudoeschar formation, desiccating dressings). 
Local wound bed conditions that promote wound healing 
 The healing process is a cell-based process with different cells requiring different conditions 
besides the very general ones of blood supply and contact with the bed: 
 Moist wound surface: desiccation of the healing bed is one of the main dangers. All cells 
need moist environment for their survival. An occlusive dressing, any adherent- to-the-bed 
dressing, hydrogels (hydrating dressings) and ointment (oil based medicament) will create a 
thin moist environment underneath.    
 Three-dimensional wound bed topography: 
o Propagation surfaces: Keratocytes “prefer” to propagate and epithelialize on a 
collagen/HA, dermal surface under guiding, protective, scab like surface.   
o Contact inhibition: Fibroblasts and endothelial cells tend to develop granulation tissue in 
the direction of the wound’s open space.   
o Surface modulation of inflammation process: granular and fibrous surfaces   
macrophages, fibroblasts, etc.      
 Infection free surfaces: early treatment of any apparent infection  
 Adherent dressing will keep the undersurface moist, infection free, provide propagation 
surface and protects from mechanical insults. Usually an adherent dressing is the sign of a 
safely healing wound though desiccating, hydrophilic dressings may also desiccate a viable 
bed, deepening the damage. 
Wound-bed, Interface Layer (IL)’ Contact, Primary Dressings-Covers: Main Demands  
The primary dressing, the dressing that is in immediate contact with the IL exposed raw tissue 
has very well defined role: to protect and promote care and healing. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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The followings are the factors that are important in these aspects: 
1. 
Adheres to the Interface Layer (with its special characteristics) 
2. 
Moisture regulation 
3. 
Epithelialization enhancement 
4. 
Fibroblastic activity modulation 
5. 
Infection control 
6. 
Trans-Dressing Diagnosis of changing conditions (TDD)  
7. 
Trans-Dressing Intervention (TDI) 
1. Adherents to the Interface Layer: Dressing’s adherence is important as it provides the 
protection against microorganism contamination and propagation, serving as a mechanical 
barrier shielding the healing wound from external insults and maintaining a thin moisture 
layer over the healing bed. In general, the dressing’s adherence may be due to the 
following situations: 
a. Incorporating, ingrowths of the wound bed tissue into the dressing structure (as may be 
seen in Allografts, Xenografts, cotton gauze or some of the sponge dressings). 
b. The “dressing” is an integral structural part of the wound (a desiccated eschar, the 
desiccated, upper layer of the bed or a planned mummification of the eschar by cerium 
nitrate [Flamacerium] or iodine will preserve the original collagen fibers ties with the 
bed’s matrix. 
c. There may be a physical/chemical layer that “bonds” the dressing to the underlying bed 
(such as scab formation where the fibrin and fibrous clot will adhere and bond dry 
hydrofiber [Aquacell], cellulose [Velloderm] etc. dressings). Dressings such as some of the 
Hyluronic acid [Jaloskin], Collagen [Biobran] or DL-Lactide (Vicryl like poliglycolic acid 
[Suprathel]) dressings may adhere by their undersurface, deeper layer that serves as 
adhering layer with the bed. In these cases very often, if the bed’s viability is maintained 
(not desiccated) the epithelial or granulation tissue will grow underneath and their 
advancing fronts will separate the dressing from the healing bed.  
In some of these dressings this bonding surface can bond the dressing also to a not 
completely debrided beds. If the eschar is very thin and not too contaminated there is a 
good chance that the dressing will remain adherent and the bed, slowly healing with the 
eschar remnants, will disintegrate as the healing front progresses. This characteristic is 
very important as it allows an effective cover to a wide range of wound beds.   
Unfortunately an adherent dressing to the wound bed may also form a barrier to the 
propagating healing process. The dressings from groups a. & b. above, though they may 
effectively prevent infection will not allow propagation of the epithelialization fronts 
underneath and may also prevent the formation of granulation tissue. The dressings from 
group c. may become also occlusive and increase microorganisme spreading and infection.      
2. Moisture regulation: The optimal moisture at the wound’s surface should be delicately 
balanced between desiccation that leads to cell death and matrix changes and 
overhydration that leads to maceration. Adherent dressing may normally keep the optimal 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 120 of 169 
 
 
  
 
 
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moisture unless they are hydrophilic (desiccating) by nature and in this case may desiccate 
the wound. Hydrating dressing with high water content may overhydrate the wound acting 
also as occlusive dressings increasing the danger of infection and infection propagation. 
The moisture condition in the individual wound is dynamic and may change within hours. 
A “moist” highly exudating wounds that may need drainage by absorbing dressing may 
become dry, recalcitrant wound by too active desiccation or even exposure. In the case of 
burn, “weeping” surface of a dermal scald burn or a fresh, raw donor site may desiccate in 
few hours of exposure and develop a layer of neo-eschar: a layer of desiccated, newly 
“killed” dermis. This dry, adhering layer can, if not infected, serve as a biological dressing 
but at a price: death of tissue that could be instrumental in the healing process and a danger 
of contamination and infection of this new eschar.   
All vital functions of healing and proliferation, healing factors and cellular activity need 
moist environment for their function. Nevertheless, microorganism survival and 
propagation need also moisture. The dressing we use should allow us to intervene and 
correct these changing conditions.  
Dressings from the group of “hydrogels”, “gelfoams”, all occlusive dressings-films, some 
of the adhering dressings, all topical gels, creams and ointments will maintain the bed 
moist and offer good healing conditions but a continuous monitoring should be maintained 
to intervene in time to prevent too much moisture, maceration and/or infection.               
3. Epithelialization enhancement: The progression of the epithelialization process is a 
complex one, involving the inbuilt epithelial progression based on the contact inhibition 
phenomenon with the proliferation of the keratocytes from the wound’s exposed edges and 
the epithelial islands originated in the skin adnexae. The Keratocytes propagate slowly 
over the dermal matrix in a moist atmosphere. The following are conditions that the 
propagation and the entire epithelialization process may be disturbed even in presence of 
sufficient epithelial sources (epidermal wounds edges, skin adnexae or autografts):  
 Mechanical disruption: dressing change, forced scraping or wiping of the healing wound 
will peel off the friable new epithelium from its bed  
 Mechanical barrier: such as to adherent dressing 
 Infection: may destroy keratocytes  
 Eschar presence: beside being a mechanical barrier that will not allow epithlialization over 
viable bed is also  a potent source for infection 
 Actively granulating tissue: (“overgranulation”) that will stop epithelialization by forming 
a physical barrier and biological competition by the fibroblastic activity. 
 Topical medications: may be noxious to the proliferating keratocytes (i.e. SSD, Iodine 
compounds)  
 Systemic conditions: mainly malnutrition as expressed by hypoproteinaemia and 
hypoalbuminaemia or Oncological drugs.  
4. Fibroblastic activity modulation: The Keratocytes and Fibroblasts originate from two 
different embryonic cellular origins: ectodermis and mesodermis. In spite of a very 
intimate relation in structuring the skin and forming the Epidermis and Dermis each of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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them exerts an inhibitory effect on the other. Fibroblasts are very active cells that 
proliferate in wound beds forming the three dimensional granulation tissue (together with 
new blood vessels by endothelial cells, also from Mesodermal origin). The Keratocytes, 
proliferate and propagate along the dermal superficial plan striving to from the Epidermis. 
They exert an inhibitory effect on the granulation tissue formation, arresting its 
development as soon as they cover it with the newly formed epidermis. The Fibroblasts 
and the granulation process are more robust than the thin epidermal, Keratocytes 
unicellular epithelialization healing front. Thus, if epithelialization process will not cover 
the healing bed, modulating and arresting the formation of rich granulation tissue the 
granulation tissue can become Overgranulation, forming a barrier to the Keratocytes and 
the epithelialization process and eventually becoming a heavy, contracting and deforming 
scar.  
In view of such a situation of developing granulation tissue in front of epithelialization 
process we can intervene by providing the Keratocytes with the optimal conditions 
(moisture, propagation surfaces and protection) and trying to interfere and decrease the 
overgranulation process. This can be done by mechanically scraping the overgranulation 
tissue, chemically destroying its surface (AgNO3) or using short (2-4 days) courses of 
topical corticosteroid treatment. The later treatment will effectively inhibit the granulation 
process allowing epithelialization to propagate and exert it own inhibitory effect on the 
fibroblasts. Topical steroids in given in shorts spells of few days each for over a month 
will not exert systemic effect and may be considered as safe. A wound healing dressing 
should promote epithelialization (that controls granulation) and allow us to intervene 
medically 
or 
mechanically 
interfering 
with 
overgranulation 
and 
promoting 
epithelialization.      
5. Infection control: Adherent dressing will prevent infection and occlusive conditions may 
favor it. Some dressings may be the source or serve as a medium for microorganisme 
growth (rejected allografts or xenografts, infected collagen or HA based dermal substitutes 
such as Integra, Hyalomatrix,). The dressing’s structure may itself harbor, as a foreign 
body, microrganismes (fibrous dressings such as cotton gauzes, some of the foams, other 
absorbing materials- Hydrogels and even hydrofibres-Aquacel to a certain point). Some of 
the dressings contain antibacterial agents (mainly silver) but they are not innocent. In such 
case that the dressing itself became contaminated we may wish either to replace it or be 
able to treat it with anti bacterial agents.        
6. Trans-Dressing Diagnosis of changing conditions (TDD): Being aware to the rather fast 
dynamic process, beneficial or not, that may happen in the healing wound the dressing 
should allow the diagnosis of emerging situations that may need our intervention. Process 
such as infection, granulation, overgranulation and epithelialization should be diagnosed 
and monitored in real time. An opaque, adherent, unchanged dressing may make such a 
diagnosis difficult. Dressings that are changed frequently (every 1-3 days at most, i.e. all 
topical medications, hydrogels, etc.) make such a diagnosis (on dressing change) easy. 
Some transparent dressings allow diagnosis through them (i.e. Jaloskin) or staining of their 
external surface when exudates from the wound ooze through (i.e. Aquacel, Polymem).    
7. Trans-Dressing Intervention (TDI): Adherent dressings that can remain for days, 
preventing infection, offering optimal healing conditions and allowing diagnosis of the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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processes that take place underneath are obviously ideal. The last possible criterion for an 
optimal dressing is the possibility to treat the wound bed through the dressing without 
disrupting it. Some of the occlusive dressings (Occludress, VAC+ all vacuum assisted 
dressings) could be connected to intake ports others, absorbing dressings such as gauze 
could be soaked without disruption.    
Wound Dressings and Covers 
The effect of the dressing’s physical properties 
As previously mentioned the role of the dressing is to protect and create an optimal healing 
microenvironment. Moisture and temperature that allow gases exchange and surfaces for 
epithelial migration, function of cells such as macrophages, neutrophils and fibroblasts. 
Another alternative are all the topical medications that need replacing or renewing daily or 
every other day.  
Absorbing & Non-absorbing 
The absorption function may depend on the physical structure (filament, fibers, hydrofibres, 
foams, etc.) or specific absorbing (hydrophilic mostly) materials the impregnate the dressing 
(starch, HA, alginates, collagen to a lesser measure, etc.). The passage of the fluids (exudates, 
soaking solutions, etc.) to or from the wound surface depend on the concentration gradient 
between the wound and the dressing and the characteristics of the dressing itself (potential 
fluid capacity, hydrophilic characteristics). Once fluid completely saturates the dressing the 
absorption power is cancelled and moisture at the wound surface increases to the point of 
maceration. Dressings with high absorption power may desiccate the wound to the point of 
tissue death. In order to maintain the absorption function the dressing should always be under 
its maximal saturation. This can be done by replacing the dressing before saturation or adding 
an external dressing that will absorb, through the primary dressing the fluid access. 
a. 
Antibacterial Topical Creams and Ointments 
Topical medicaments in the form of creams and ointments are innumerable, based on various 
antiseptic and/or antibiotic in different excipients preparations (few examples: Bacitracin, 
mupirocin, silver sulfadiazine, neomycin, polymyxin, honey inhibine, HA based creams) 
Indications: prophylaxis of infection, ointment maintain moist wound environment and can be 
used as covers in wound healing process.    
Burns care involves often the more effective combination of soaking and creams/ointments 
(silver nitrate compresses, chlorhexidine gluconate, mafenide acetate cream 0.5%, povidone 
iodine, nitrafurazone, silver sulfadiazine). 
Application: once or twice a day after washing and cleansing the wound.  
Contraindications: Allergic reactions, decreased cellular activity and viability. 
Complications: Drug specific, usually without risk of systemic toxicity. Local adverse effects 
include contact dermatitis (i.e., neomycin is as high as 34%). Application of silver sulfadiazine 
has been associated with neutropenia and epithelialization inhibition. 
Special points:  Bacitracin zinc is extremely popular because of low cost, low toxicity, and low 
allergic contact dermatitis. Relatively safe; topical antibiotics have low systemic absorption. 
HA based creams have additional benefit due to the HA base. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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b. 
Solutions for Irrigation & Soakings.  
Topical medicaments solutions are routinely used for soaking and irrigation of wound over a 
primary dressing, usually gauze. They are used for initial cleansing, being effective 
antimicrobial agents and mechanically washing away contaminants particles. With 
antibacterial agents they may be used for infection control. Corticosteroid addition will control 
topical inflammation and over granulation and with hypertonic solutions they can reduce 
cellulites, edema and swelling and even be used as antiseptics. Leaving the soaked gauze to dry 
will “suck in” the superficial dissolved materials be it dirt, bacteria or dissolved eschar 
allowing its removal. If the gauze is allowed to desiccate and bond to the bed surface its 
removal will tear off the surface (“wet to dry” cleansing). The following are common solutions 
used in burn and wound care: Saline (0.9%), Hypertonic Saline (<20%), MgSO4 (<10%), 
Chlorhexidine acetate (0.5%), Chlorhexidine gluconate (0.05%-0.1%), Sulfamylon 3%-5%, 
povidone-iodine, AgNO3 (0.5%), corticosteroid solutions,  antibiotic +/-corticosteroid 
solutions, PHMB (Polyhexamethylen biguanide) solution, Prontosan® (Betain + PHMB).  
Tissue toxicity is possible, caution should be used in the management of open wounds as well 
as wound desiccation. Corticosteroid long term (weeks), continuous soaking may cause 
transient, systemic Cushingoid symptoms. 
c. 
Gauze, gauze-like: woven & non-woven, cotton-base, not-cotton-based 
Cotton or cotton-like fibrous materials are used since antiquity as dressings. The pliability, 
adherence, absorption and their capacity to serve as a matrix to many medicaments and 
materials made them the current choice in wound care. This characteristic make them serve as 
a“reinforcement” for the creation of the scab that is the natural dressing for the healing wound. 
The fibrin from the raw bed is absorbed by the dressing that remains embedded in the 
solidified fibrin, forming a strengthened scab that by its nature (it is nature’s raw bed’s 
dressing) adheres to the bed. Due to their fibrous structure they serve also as wicks for soaking, 
passing the solution and bathing the bed. They can also serve as absorbing dressings passing 
the exudates to the surface, to be reabsorbed by additional, external, absorbing dressings. 
Normally, they will not adhere to full thickness wounds unless adhere through fibrous bonds 
that in every dressing-change (daily) will damage re-epithelialized layer delaying healing. The 
problem with such dressings is that they may shed particles that some become embedded in the 
healing bed, forming later foreign body inclusion cysts.   
d. 
Impregnated Dressings including Silver Dressings 
Dressings coated or impregnated with any material that is conceived to be beneficial to any of 
the wound healing phases or factors are produced by all wound care companies. Each of these 
agents has its advantages and its potential risks and drawbacks and should be assessed 
individually. The dressings can be made of many kinds of matrixes (cotton woven or non 
woven, films of various permeabilities and geometries, foams, hydrofibres, alginates, etc.).  
The choice of the dressing should be done according to the matrix characteristics (e.g. the 
difference in the properties of cotton gauze and hydrofibres) and the impregnating medication 
(e.g. the difference between SSD and Paraffin ointment) considering the specific requirement/s 
of the wound and its healing phase.  Few examples are:   
Paraffin with or without antimicrobial medicaments, coating woven, non woven or other 
primary form of dressings (such as Jelonet, Neotulle, Aquaphor-Gauze, Paranet, Unitulle, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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Bactigras etc.): It will keep it moist, will not adhere to the bed, may increase infection danger, 
should be changed every 2 days at most. 
Silver compounds of different formulations (Acticoat, Silvelon, Atrauman Ag, Biatain Ag, 
Aquacel Ag, Contreet Hydrocolloid, Mepilex, Physiotulle Ag, PolyMem Silver, Silvercel, 
Suprasorb A+Ag, Tegaderm Alginate Ag, Urgocell Silver, Urgotul Silver): Silver ions (Ag+) 
have antibacterial effects, hyper sensitivity and arginosis (staining by silver oxide) of tissues 
has been reported. 
 SSD impregnated matrixes (Allevyn Ag, Urgotul SSD):widely used as a local antimicrobial, 
not to be used in sensitive to silver or sulfa drugs, known to delay epithelialization, 
kerenicterus has been reported.   
e. 
Biological covers (autografts, allografts, xenograft, skin substitutes and equivalents) 
The biological covers have a complex three dimensional collagen or collagen-like matrix, 
saturated by mucopolisaccaride compounds such as Hyluronic Acid and usually covered by 
semi permeable layer (epidermis, silicone).  They are applied on clean, viable surfaces, initially 
adhere by fibrin bonding and serum imbibition followed by in-growth of new vessels and 
fibroblasts from the bed. When they adhere (“take”) on a clean and viable bed all provide good 
protection and healing conditions.  The ones with antigenic potential (allograft and xenograft) 
should be replaced before immune rejection occurs. 
o Autografts are the classical means for permanent wound closure. In full thickness defects 
they provide a complete closure by primary intention healing. Deep dermal defect will also 
heal in a similar way by accepting the graft as a permanent cover but dermal remnants that 
contain epidermal foci (skin appendages) may also heal by epithelialization under the graft 
forming cysts or unsightly overgrafting patches. Autograft is a costly means, requiring 
surgery and sacrifice of healthy donor site skin areas and should be reserved for permanent 
closure for full thickness defects where spontaneous healing is impossible or when a fast 
closure is so important as to abandon the somewhat slower epithelialization of the dermal 
surface. 
o Allograft (fresh or cryopreserved) is used as a temporary solution to close the wound. It 
will “take” as autograft but will be rejected by the immune reaction 7-14 days later. On a 
clean IL bed they provide good healing conditions for the dermal IL and a temporary 
closure for full thickness defect. The epithelialization process will take place under the graft 
protection with the sloughing graft exposing the healing bed. The allograft keratocyte’s 
growth factors can promote the process but infection may harm the healing process. As the 
allograft is practically occlusive it is advisable to perforate or mesh it without expanding it 
to allow for a drainage and potential treatment medication. Use of allograft does not require 
surgical facilities but the availability of allograft may pose a problem in some countries. 
Their availability may be limited to the skin bank services and their shelf life is limited to a 
week when fresh and 3-4 years when frozen. Glycerol preserved allografts have a longer 
shelf life and do not need skin bank preservation facilities but are not viable, do not “take” 
but bond to the surface by fibrin, being less effective than fresh or cryopreserved. 
o Xenograft (fresh or cryopreserved, Mediskin I) usually from porcine origin, as allografts 
they are used as a temporary cover to “close” the wound. Fresh or cryopreserved, it will 
“take” as allograft but will be rejected by the immune reaction in few days. On a clean IL 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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bed they provide good healing conditions for the dermal IL and a very temporary closure for 
full thickness defect. The epithelialization process will take place under the graft protection 
with the sloughing graft exposing the healing bed. It is more infection-prone and should be 
applied meshed and medicated with antimicrobial agents. The glycerolized xenograft has a 
better shelf life but is even less effective and more infection-prone. Use of xenograft does 
not require surgical facilities but its availability may pose a problem in some countries.  
Skin Substitutes, Biodegradable & Non-biodegradable: Collagen, Hyluronic Acid (HA), 
Synthetic (DL-Lactide)  
There are number of materials that the inflammatory and healing process can degrade thus 
avoiding removing them at the end of the healing process. The problem is always to decide 
whether we want this degradation process in addition to the normal inflammatory, healing one. 
Biological materials such as Collagen, Hyluronic acid or DL Lactide- polyglactin (the raw 
material for Vicryl sutures) are all used as films or three dimensional sponge-like structures. In 
full thickness wounds, some are designed to serve as templates for new dermis formation 
(Collagen: Integra, Matriderm, HA: Hyalomatrix) by providing a growth matrix for capillaries 
and fibroblasts to be grafted with thin autograft when their survival (“take”) is secured. Similar 
approach is shared by other products: Dermagraft (non-immunogenic neonatal fibroblast on 
polyglactin mesh), OrCel (Fibroblasts layered onto bovine collagen matrix), TransCyte 
(Shipped frozen for use on partial- and full-thickness burns, epidermal layer with dead 
fibroblasts layered onto a nylon mesh), Apligraf (dermis-like matrix from cultured 
heterogenous human foreskins and bovine collagen type 1, has epidermal and dermal 
components), Oasis (porcine, small-intestine submucosal dehydrated dressing with longer 
shelf-life, rehydrate when needed with a secondary dressing to prevent desiccation), Alloderm 
(Freeze-dried, cell-free).  
Another group is design to serve as a cover for clean, dermal wounds providing healing 
(epithelialization) conditions and disintegrating when epithelialization is completed (Collagen 
films and sponges, HA Jaloskin or DL Lactide Suprathel).  All need a clean bed to adhere to, 
with Suprathel in need of a meticulously dermabraded bed. All are sensitive to infection. 
Collagen and HA can be used to coat synthetic matrixes or fabric (Nylon-Biobrane).  Biobrane 
is common in wound care, peeling off at the end of epithelialization but is prone to desiccation 
of the bed and infection.  
f. 
Inert, synthetic materials 
The alternative to biodegradable materials are the ones that are completely inert, most are 
synthetic providing the required conditions to the wound bed but are not part of the healing 
process and peel-off, trimmed away as wound heals by the epithelializing front. Another 
alternative are all the topical medications that need replacing or renewing daily or every other 
day.  
g. 
Foams  
Synthetic (i.e. polyurethane or silicone) foams may by more or less absorbent depending on 
their structure (large or small, open or partially open cells) and the additive materials (e.g. 
starch, SSD, silver) (i.e. Allevyn, Flexzan, Lyofoam, Sof-Foam). 
They may be considered as a farther development of more simple dressings such as: 
impregnated multilayer gauze, Polyurethane or gel film coated, hydrophilic or hydrophobic, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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semiocclusive, bilaminated dressings. Foam dressings offer most of the advantages of 
medicated gauze with a better absorption and protection in most cases. Very often they adhere 
to the bed (incorporation by ingrowths of granulation tissue and/or bonding by fibrin), creating 
the required adhering, moist environment and absorbing exudates from discharging wounds 
thus reducing the need for dressing changes. Foams provide also mechanical protection but in 
many cases their permeability can be obstructed by hardened exudates transforming them to 
opaque, occlusive dressings that are prone to infection. 
h. 
Films, permeable, non permeable 
These dressings, may be completely occlusive or permeable to gas and water vapors, but are a 
barrier to bacteria and water. Films, Semiocclusive/semipermeable made of polyurethane or 
copolyester, approximately 0.2 mm thick (Bioclusive, Polyskin II, OpSite, Tegaderm).  They 
are elastic and transparent but difficult to occlude larger that few cm2 areas. They are 
commonly used as occlusive dressings, sometimes with additional medicated gauze or topical 
medication underneath as a primary dressing, creating a microenvironment over the wound that 
can contain gazes (02, 03, or vacuum etc.) or medicaments. On clean beds they may adhere 
through the bonding effect of the wound exudates and fibrin but usually are transparent 
allowing easy assessment of the wound bed. When adhering to the bed they are generally 
reserved for the definitive closure of superficial, shallow partial thickness wounds where 
comfort and ease of management are important. The dressings can be left in place for several 
days, but their occlusive nature and accumulated exudates make them extremely prone for 
infection and daily monitoring is important. 
i. 
Hydrocolloids   
These dressings are non adhesive, water and gas impermeable membranes (Comfeel, Cutinova, 
DuoDERM, Intrasite, Replicare, Hyprapad Tegagel®, Intrasite etc.). Composed mainly of 
water held in a complex network or fibres that keep the polymer gel intact. Water is released to 
keep the wound moist.  
When the inner layer comes into contact with exudates, it forms a gel providing adequate 
moisture, the liquefied gel and exudates fill the dressing that has to be changed. If the dressing 
dries it may adhere to the bed interfering with healing and may damage, tear-off new 
epithelium when removed. Obviously the occluded moist atmosphere is prone to infection 
propagation and sometime to overhydration and maceration.  Hydrocolloids can be applied 
directly to clean wound but not on eschar or tendons. Perform dressing changes every 3 to 7 
days with saline irrigation cleans colloidal layer. Hypersensitivity to materials can develop. 
j. 
Aquacel (with or without Ag.) 
Soft non-woven pad made from sodium carboxymethylcellulose fibres. These Hydrofibres 
absorb exudates and fluids from the wound becoming a gel like material. Germs thus absorbed 
are eliminated from the wound surface but the dressing itself may dry to become a dry adherent 
shell. The desiccation may dry viable surface extending the original damage but the dry shell 
allows discharge before wound is closed with epithelial cells slowly separating the dry dressing 
from its bed.   
k. 
Alginates 
Composed of calcium alginate (a seaweed component). When in contact with wound, calcium 
in the dressing is exchanged with sodium from wound fluid and this turns dressing into a gel 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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that maintains a moist wound environment. Do not use on low exudating wounds as this will 
desiccate the wound. Dressing should be changed daily to avoid desiccation. 
E.g. Kaltostat, Sorbsan Alginates are derivatives of seaweed are in the form of dry non-woven 
mats, absorbing wound exudates to become a hydrophilic gel like hydrocolloids and behave in 
a similar way (Kaltostat, Sorbsan, Algosteril, AlgiSite, Kaltostat, Sorbsan etc.).  Jellified 
alginates are not adhesive, they are easily washed away but applied on a moist, clean bed they 
may strongly adhere to become a hard shell that will protect the wound but may slow the 
healing process and be hard to remove, injuring and stripping the healing bed. It is a strong 
hemostatic that can be used on bleeding wounds (post tangential excision or graft harvesting) 
but can interfere with healing later. A secondary wet dressing may prevent desiccation. 
Soaking and irrigation of the desiccated dressing will jellify it again and ease changing. 
Hypersensitivity to materials. Thyroid abnormalities can develop. 
l. 
Hydrogels-gelfoams 
These gels are usually based on starch polymers providing ample moisture (Carrasyn, Intrasite, 
Lamin, Nu-gel, Vigilon, etc.). Hydrogels are best suited to autolyse dry necrotic wounds, but 
they also absorb exudates while maintaining the products of tissue repair and degradation, 
including growth factors and lysosomes, in contact with the wound. If the wound is clean, the 
gel only needs to be replaced once or twice a week providing good healing conditions but these 
conditions are also favorable for infection propagation (especially gram negative bacteria). 
m. 
Negative Pressure Wound Therapy 
It is still a constantly evolving technology based on an occlusive dressing connected to a 
vacuum pump, containing a fibrous or foam matrix that distribute the sub-atmospheric pressure 
onto the wound bed. There are numerous similar available systems differing mainly in price 
and nature of matrix. Used initially mainly for chronic ulcers, it is quite effective as a 
secondary dressing to secure skin graft adherence and take.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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APPENDIX 5- WOUND MANAGEMENT; APPROVED COVERS 
General remark: the guidelines of this appendix follow the ABA White Paper guidelines with 
detailed additions of some commonly used topical treatments.  
All dressings that are films, sheet-like (including biological dressings such as autografts, 
allograft and xenografts) and even foams, hydrocolloids and gauzes can become occlusive 
(sometimes by desiccated exudates) and pose danger associated with occlusion to healing 
wounds. It is recommended to perforate or mesh (without expansion) such dressings and if 
possible, apply a negative pressure dressing (e.g. VAC, etc.) on top of them for few days to 
ensure adherence and “take”). There are many additional dressings that strive to fulfill wound 
healing goals beside the approved to be used in the study detailed below. Some of them, 
beneficial as they may, are not standard. If the PI wishes to use then in this study, MediWound 
clinical department should be approached to verify and approve their use.  
Below is a list of the approved wound care products in the study which are all legally marketed 
in the US as detailed in the ABA guidelines. 
In the study protocol, there are 2 main categorizes of wound care products: 
Skin substitute [commercial product]: A biomaterial, engineered tissue or combination of 
materials and cells or tissues that can be substituted for skin autograft or allograft in a clinical 
procedure.  
Skin replacement: A tissue or graft that permanently replaces lost skin with healthy skin. 
 
Temporary Wound Coverage  
Temporary skin substitutes are used when the wound is too extensive to be closed in one stage 
because there is not enough donor skin available, because the patient is too ill to undergo the 
creation of another wound that results when skin is harvested from a donor site, because there 
is a question regarding the viability of the recipient bed, or because of a concern regarding 
potential infectious complications. The gold standard temporary skin substitute is cadaver 
allograft. Other temporary skin substitutes are used to provide transient wound coverage and 
to create a physiologically homeostatic environment such as- Skin Xenografts—also termed 
heterografts. 
Biobrane® is a silicone membrane pressed onto a flexible nylon fabric which has been coated 
with porcine dermal collagen. Used as a temporary wound cover, it is considered a dressing by 
the FDA and CPT Editorial Panel.  
Transcyte®, a related product, is not a dressing. It is classified as a temporary skin substitute 
and is composed of Biobrane® and cultured newborn human fibroblasts, which secrete growth 
factors and matrix proteins onto the wound surface. TransCyte® must be applied to a clean 
wound bed and monitored closely because it is prone to infection. It can be used in ways 
similar to Allograft and Xenograft.  
Permanent Wound Coverage  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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A full-thickness skin graft contains all components of the skin: epidermis, dermis, hair 
follicles and nerve endings. The most important advantage of full-thickness grafts is decreased 
scar formation; however, because there is no dermis to regenerate epithelial coverage, the 
donor site of a full-thickness skin graft must be closed either with primary direct closure or 
with a split-thickness skin graft; local advancement of skin flaps is a rarely used option. Full-
thickness grafts are thus usually used to cover small, functionally and cosmetically important 
areas (such as eyelids and digits).  
The split-thickness skin graft is the most common method used to achieve permanent wound 
coverage. It includes the entire epidermis but the dermal layer is split by the dermatome blade. 
With thicker split-thickness grafts, more dermis is transferred with the skin graft (such as 
15/1000 of inch or greater). This reduces the risk of scar formation at the recipient site, but it 
takes longer for the donor site to heal. Furthermore, the thicker the graft, the more likely the 
donor site will heal with a scar and the less likely the donor site may be reharvested for further 
grafts. 
There are a number of commercially available products to facilitate permanent wound 
coverage. Acellular human dermal allograft (Alloderm®) is devoid of epidermis and must 
be covered by a thin split-thickness autograft at the time of the initial operation; however, it 
replaces a portion of the missing dermis on the newly covered wound, thus reducing 
postoperative scarring. Another permanent wound coverage product is a dermal regenerative 
template (Integra®) constructed with bovine collagen and shark chondroitin sulfate with a 
silicone surface layer. This is applied to an excised wound bed that is well vascularized and 
free from infection, and provides wound coverage much like other skin substitutes; however, 
after the template becomes vascularized, it forms a neodermis (usually within 10 days to three 
weeks) and when the silicone layer is removed, an epidermal autograft (< 0.008 inch thickness) 
can be applied. This intermingling of autograft on a biosynthetic neodermis is permanent, 
unlike the wound coverage provided by temporary skin substitutes. This approach may be 
lifesaving and provides quality skin coverage.  
Cultured epidermal autograft (CEA; Epicel®), also referred to as “test tube” skin, was 
introduced by Rhinewald & Green in 1975 and is often employed to provide permanent skin 
coverage for patients with extensive burns.  
 
All of the above surgical or non surgical agents and covers are routinely used in the US, 
specified in the protocol and are allowed to be used in the proposed study based on the 
investigator’s medical judgment for the specific wound condition or patient. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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APPENDIX 6- REGULATORY AND ETHICAL ISSUES 
Compliance with Regulations Applicable to Clinical Trials 
The study will be conducted according to the laws, regulations and administrative provisions 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use, as applicable by national legislation and EU Directives and 
US 21 CFR Part 11, 50, 54, 56, 312. 
This clinical trial will be registered on the “clinicaltrials.gov” clinical trial registry website as 
required by 42 USC 282(j) and the State of Maine’s PL 205, c. 392, §1. 
Informed Consent 
The principles of Informed Consent, conducted in accordance with Declaration of Helsinki and 
its updates, current Good Clinical Practice (GCP), the provisions of ICH (International 
Conference on Harmonisation); US Code of Federal Regulations (Title 21, CFR Part 50,) 
and/or EU Directives; local country regulations and the sponsor's Standard Operating 
Procedures (SOPs) will be followed. A subject is not allowed to enter a clinical study until 
he/she has been properly informed, has been given time to contemplate participation, and has 
freely given his/her consent by signing and dating the Ethics Committee/Institutional Review 
Board (EC/IRB) approved informed consent form.  This must be done prior to performing any 
study related procedures. 
The proposed consent form and any other documents relevant to the consent process must be 
submitted to the EC/IRB, together with the protocol, and must be approved prior to study start. 
A copy of the fully signed and dated Informed Consent Form and any other documents relevant 
to the consent process will be given to the subject and the original will be maintained at the 
site. 
Subject Confidentiality 
All subject data will be identified only by a subject identification number, subject initials (may 
be dummy) and date of birth.  
The investigator should keep the initials given in the “Subject Identification Log”. After 
obtaining subject’s consent, the investigator will permit the study monitor, independent auditor 
or regulatory agency personnel to review that portion of the subject’s medical record that is 
directly related to the study. This shall include all study relevant documentation including 
subject medical history to verify eligibility, laboratory tests results, admission/discharge 
summaries for hospital admissions occurring while the subject is on study, and autopsy reports 
for deaths occurring during the study (if applicable). 
Good Clinical Practice 
The study described in this protocol will be carried out according to the local regulatory 
requirements (FDA, EU, other) and ICH accepted standards of Good Clinical Practice. 
Ethics Committee (EC) / Institutional Review Board (IRB) 
The study must have unconditional approval in writing, by an appropriate Ethics 
Committee/Institutional Review Board (EC/IRB). A copy of the Letter of Approval from the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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EC/IRB, which contains specific identification of the documents approved, must be received 
by local Sponsor prior to site activation. 
Any amendments to the protocol or subsequent changes to the informed consent form as a 
result of changes to the protocol and/or investigator brochure that is approved by MediWound, 
must also be approved by the EC/IRB and documentation of this approval provided to 
MediWound. Records of the EC/IRB review and approval of all documents pertaining to this 
study must be kept on file by the investigator and are subject to the sponsor’s audit and/or 
regulatory authority inspection, during or after completion of the study.  
Serious adverse events (SAEs) must also be reported to the EC/IRB by the investigator or the 
sponsor according to local regulations. 
The investigator must submit a periodic status reports to their EC/IRB as required, as well as 
notification of completion of the study and a final report where applicable. A copy of all 
reports submitted to the EC/IRB must be sent to the sponsor. 
Protocol Amendments 
Protocol amendments must be prepared by sponsor or designee and approved by the sponsor, 
Competent Authorities (if applicable), Central EC/IRB and/or each respective site’s EC/IRB (if 
applicable), prior to implementation.  
Changes to the protocol can only be made by an approved protocol amendment. In case of 
urgent safety amendment ICH GCP guideline, should be followed. 
For clinical trial sites located in EU Member States, the procedures outlined in Directive 
2001/20/EC, Article 10(a), are applicable. 
Declaration of the End of the Clinical Trial 
For clinical trial sites located in EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC, Article 10(c) and for those 
countries outside EU local regulations will be followed. 
Liability And Insurance (If Applicable)  
A Certificate of Clinical Trials Insurance will be provided to the study centers by MediWound 
Ltd. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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APPENDIX 7- STUDY ADMINISTRATIVE PROCEDURES 
This study will be conducted, recorded and reported according to ICH E6 requirements 
“Guideline for Good Clinical Practice” and its other implementing directives and guidelines.  
Study Site Initiation 
After the investigator files were updated with the following documents, the site may begin 
patient recruitment:  
1. CV and Medical License of the Principal Investigator, 
2. A signed and dated Investigator Protocol Agreement, 
3. A Financial Disclosure form, 
4. Signed Agreement between MediWound and the trial site, 
5. The laboratory certification or proficiency ratings, the normal ranges for laboratory 
determinations required by the protocol and the curriculum vitae of the laboratory director, 
6. A copy of competent authority written notification of protocol approval (EU sites), study-
specific informed consent form and any advertisements, notices or bulletins to be used in 
this study, 
7. A copy of the ethics committee/IRB approval,  
8. The ethics committee name, address and a list of ethics committee members including 
occupations and institutional affiliations, 
9. Signed Investigator Brochure receipt. 
 
Informed Consent 
Protection of clinical trial subjects will be performed as follows: 
A clinical trial may be undertaken only if the following elements are fulfilled: 
1. The study may be initiated only if the ethics committee and the competent authority come to 
a conclusion that the anticipated therapeutic benefit justifies the foreseeable risks and 
inconveniences.  
a. Prior to signing the informed consent, the trial subject had a discussion with the 
investigator or a member of the investigating team concerning the objectives, risks and 
inconveniences of the trial and the conditions and has been informed of his right to 
withdraw from the study at any time. 
b. Neither minor nor patients not being able to consent on their own are not included in the 
study However, legal representative may be involved in the Inform Consent procedure 
and sign the form if this is pre approved by the local IRB/EC and only for subjects with 
temporary medical conditions related to the injury, subjects who might be under the 
influence of pain medication, sedation, etc (see Section 8.1.1).   
c. The rights of the subject to physical and mental integrity, to privacy and to protection of 
the data concerning him are safeguarded. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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d. If the subject is unable to write, an oral consent in the presence of at least one witness 
may be given in exceptional cases, as provided in national legislation. 
e. Provision has been made for insurance or indemnity to cover the liability of the 
investigator and the sponsor. 
f. The medical care given to, and medical decisions made on behalf of, subjects shall be the 
responsibility of an appropriately qualified physician. The subjects shall be provided with 
a contact where he may obtain further information. 
2. In addition to the above restrictions the following elements are to be fulfilled in clinical 
trials on minors and incapacitated adults: 
a. The subject should receive information regarding the trial, the risks and benefits, from an 
experienced staff, 
b. The investigator should consider explicit wish of the subject who is capable of forming 
an opinion, to refuse participation or to be withdrawn from the clinical trial at any time, 
c. No incentives or financial inducements will be given except compensation, 
d. The study should relate directly to the clinical condition from which the subject 
concerned suffers, 
e. The study is designed to minimize pain, discomfort, fear and any other foreseeable risk, 
f. The ethics committee, with expertise in the relevant disease and the patient population 
concerned or after taking advice in clinical, ethical and psychosocial problems in the 
field in the subject’s population involved, has endorsed the protocol, 
g. The interests of the patient always prevail over those of science and society. 
 
3. The following issues should be included in the Informed Consent discussion and the written 
Informed Consent Form: 
a. A statement that the study involves research, 
b. Discussion with the subject should include: an explanation of the purposes of the 
 
research and the expected duration of the subject's participation, a description of the 
procedures to be followed and identification of any procedures that are experimental, 
c. The trial treatment(s) and the probability for random assignment to each treatment, 
d. Disclosure of any available alternative procedures or courses of treatment that might be 
advantageous to the subject, 
e. A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and that notes the possibility that the regulatory 
authorities, the institutional ethics committee or MediWound or designee may inspect the 
records, 
f. A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled and that the subject 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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may discontinue participation at any time without penalty or loss of benefits to which the 
subject is normally entitled, 
g. The subject’s responsibilities,  
h. A statement that the particular treatment or procedure may involve risks to the subject (or 
the embryo or fetus if the subject is, or may become, pregnant) that are currently 
unforeseeable, 
i. Anticipated circumstances under which the subject's participation may be terminated by 
the investigator without regard to the subject's consent,  
j. Any additional costs to the subject that may result from participation in the research,  
k. A statement that significant new findings developed during the course of the research, 
which may relate to the subject's willingness to continue participation, will be provided 
to the subject, 
l. The approximate number of subjects involved in the study, 
m. The person(s) to contact for further information regarding the trial and the rights of trial 
subjects. 
 
The Principal Investigator or designee is responsible for obtaining written informed consent 
from potential subjects prior to entry into the study. The investigator must keep each subject's 
signed consent form on file.  A copy of the signed document must be given to the subject. 
Competent Authority (CA)1 and the Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) 
This study must be approved by the CA (EU sites) and the ethics committee prior to patient 
enrollment.MediWound will obtain a EudraCT number before submitting an application to the 
CA. Each member state CA shall be provided with a list of CAs to which application was 
made, with a copy of their decisions as soon as it is available. 
The investigator must maintain an accurate and complete record of all submissions made to the 
CA including a list of all reports and documents submitted. The investigator agrees to promptly 
report to the ethics committee all unanticipated problems involving risks to human subjects or 
others.  
MediWound will inform the CA and the ethics committee of any new information relating to 
the conduct of the trial or the development of the IP where it is likely to affect the safety of 
subjects. Any safety measures taken should be reported to the authorities. Periodic status 
reports must be submitted at least yearly to the IRB/IEC.  
MediWound Ltd. shall notify the competent authorities of the member states concerned and the 
ethics committees that the clinical trial has ended within 90 days of the end of trial. If the trial 
has been terminated earlier than expected, notification should be made within 15 days and 
reasons clearly explained. 
                                                 
1 Relevant for sites located in the EU. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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Electronic Case Report Forms (eCRFs) 
No data will be directly entered into the e-CRF without source documentation. 
The CRF is an integral part of the study and subsequent reports. The Case Report Form 
provided by MediWound Ltd. must be used to capture all study data recorded in the subject’s 
medical record. The CRF must be kept current to reflect subject status during the course of the 
study. Only a subject identification number and subject initials will be used to identify the 
subject. The investigator must keep a separate log of subject names and medical record 
numbers (or other personal identifiers). 
The protocol will use an Internet-Based Remote Data Entry System, primarily to collect 
clinical trial data at the investigational sites.  The system will comply with 21 CFR Part 11 and 
ICH E6. The system will be used to enter, modify, maintain, archive, retrieve, and transmit 
data. Paper source documents are to be retained to enable a reconstruction and evaluation of 
the trial. No original observations will be entered directly into the computerized system. Source 
documents include the hospital patient files and study worksheets provided by the Sponsor. 
Data will be recorded in the study worksheets as appropriate in order to complete and/or clarify 
source data. 
The design of a computerized system complies with all applicable regulatory requirements for 
record keeping and record retention in clinical trials (21 CFR Part 11 and ICH E6 Good 
Clinical Practice) to the same degree of confidence as is provided with paper systems. Clinical 
investigators must retain either the original or a certified copy of all source documents sent to a 
sponsor or contract research organization, including query resolution correspondence. The 
system is designed so that changes to any record do not obscure the original information.  The 
audit record clearly indicates that a change was made and clearly provides a means to locate 
and read the prior information. All changes to the data have an electronic audit trail, in 
accordance with 21 CFR 11.10(e). Electronic signatures will be used in conformance with 21 
CFR Part 11. 
Corrections are made in source documents by crossing out the error with a single line, making 
the correct entry in close proximity to the data field, then initialing and dating the strike-
through and the new entry. 
Maintenance of Study Files 
All essential documents listed in ICH Guideline CPMP/ICH/135/95 should be filed in an 
organized way that will facilitate management of the clinical trial and audit.  
Agreements between the involved parties, all Institutional Review Board correspondence 
including notification of protocol and consent form approval and all annual reports along with 
the final report to the IRB must be retained.   
Study records including patient source documents, Case Report Forms, all test results and 
signed informed consent forms must be kept on file by the investigator.   
Other documents pertaining to the conduct of the study including laboratory normal values, 
laboratory certification, monitor logs and telephone reports and all written correspondence 
must also be kept as part of the permanent record. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 136 of 169 
 
 
  
 
 
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Storage conditions: Essential documents should be maintained in a legible condition and so 
that they can be promptly retrieved. Any change in the ownership and location of the 
documentation should be documented in order to allow tracking of stored records. 
The investigator should make the sponsor aware of the storage arrangements for the 
documents. If the investigator for any reason cannot keep the study records, MediWound Ltd. 
should be notified in writing so that alternative arrangements can be agreed upon. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending applications or at least 2 years elapsed 
since the formal discontinuation of clinical development of the investigational product. It is the 
responsibility of the MediWound Ltd. to inform the investigator/ institution as to when these 
documents no longer need to be retained. 
These regulations are described in: Detailed Guidelines on Trial Master File and Archiving – 
July, 2006. 
Monitoring Procedures 
Investigational sites will be monitored periodically to assure satisfactory patient enrollment, 
data recording and protocol adherence. The frequency of monitoring may vary depending on 
enrollment rate and the quantity of data collection.  The investigator and staff are expected to 
cooperate with the study monitor and provide to study monitor all relevant study 
documentation.  It is essential that the investigator and study coordinator set aside a sufficient 
amount of time for these visits to permit an adequate review of the study's progress and of 
completed Case Report Forms. 
Changes in Study Personnel  
The ‘Authorization Signature Log’ which is a list of appropriate qualified persons to whom the 
Principal Investigator has delegated significant trial-related duties, should be updated if there is 
a change or addition of any personnel initially listed. CVs and other relevant documents 
evidencing qualifications should be provided to MediWound Ltd. 
On-Site Inspections/Audits 
In accordance with section 1.29 in ICH E6 inspections may be requested and coordinated by 
the European Medicines Agency or the FDA. Inspections may take place at various times: 
before, during and/or after the conduct of the clinical trial. The investigator and staff are 
requested to cooperate with all such audits. The investigator must notify MediWound Ltd. of 
any expected inspection as soon as possible. A representative or designee of MediWound, Ltd. 
Clinical Research Department, may also conduct similar auditing procedures. 
Disclosure and Publication of Information 
All proprietary information including: MediWound Ltd. operations, patent applications, 
formulas, manufacturing processes, basic scientific data and formulation information provided 
to the investigator or the methodologies used in this study, as well as proprietary information 
obtained during the course of the study are confidential and will remain the sole property of 
MediWound Ltd.  The investigator agrees not to disclose any proprietary information supplied 
by MediWound Ltd. in any way without prior written permission. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 137 of 169 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
Individual patient data obtained during this study are confidential and will not be disclosed to 
third parties with the following exceptions: 
When the data is needed by a patient's personal physician or other medical personnel 
responsible for the patient's welfare, 
For data inspection and verification by MediWound Ltd. or designee, European Medicine 
Agency inspectors or by the Institutional Review Board (IRB). 
Any manuscript or abstract produced by an investigator must be provided to MediWound Ltd. 
for review 45 days prior to submission. Individual patient identity must not be divulged in any 
publication. 
Protocol Changes or Amendments 
The investigator also agrees not to make any changes in the study protocol or its conduct 
except when necessary to prevent immediate hazards to human life.   
Substantial amendments in protocol may be made only by written amendment by the 
MediWound Ltd. Substantial amendment to the conduct of the clinical trial may arise from 
changes in the protocol that have impact on safety or physical or mental integrity of the 
subjects, the scientific value of the trial, conduct or management of the trial or the quality or 
safety of any IP used in the trial. The Ethics committee and the competent authority must 
approve protocol amendments prior to implementation.  Documentation of IRB/IEC approval 
for such amendments must be kept on file by the investigator and forwarded to MediWound 
Ltd. 
Notification to the ethics committee/IRBs and the competent authorities (EU sites) on non-
substantial amendments should follow the local regulatory policies. Such amendments should 
be recorded and be available for inspection. 
These regulations are described in: Detailed Guidance for the request for authorization of a 
clinical trial on a medicinal product for human use to the competent authorities, notification 
and substantial amendments and declaration of the end of the trial – April, 2002. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 138 of 169 
 
 
  
 
 
 
138 
APPENDIX 8- BIOPSY & HISTOLOGIC ASSESSMENT METHOD 
Burn Wound Infection - Biopsy & Histologic Assessment Method  
1. Using a scalpel, a 500 mg lenticular sample of eschar and underlying, unburned 
subcutaneous tissue is harvested from the area of the burn wound showing the most marked 
changes characteristic of infection.   
2. If local anesthetic is required, it should be injected around the planned margin of the biopsy 
to minimize distortion of the architecture of the biopsied tissue.   
3. One-half of the specimen is sent to the quantitative microbiology laboratory for culture and 
antibiotic sensitivity determinations, and the other half of the specimen is processed for 
histologic examination by a frozen section technique (requiring 45 minutes) or a rapid 
section technique (requiring 3.5 to 4.0 hours).   
4. If the frozen section technique is utilized, the tissue should be subsequently processed by 
rapid section technique for definitive examination, since the frozen section method is 
associated with a 3.6% false-negative rate which can be corrected by careful examination of 
permanent sections. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 139 of 169 
 
 
  
 
 
 
139 
APPENDIX 9- PAIN MEASUREMENT SCALE 
Pain scores will be measured using a Visual Analogue Scale (VAS) for the adult population at 
the required timelines. VAS is a measurement instrument that tries to measure a characteristic 
or attitude that is believed to range across a continuum of values and cannot easily be directly 
measured.  
As illustrated in Figure 2, the patient marks on the line (100 mm line), the point that they feel 
represents their perception of their current state. The VAS score is determined by measuring in 
millimeters from the left end of the line to the point that the patient marks. 
Figure 2- Visual Analogue Scale 
 
 
 
No Pain 
Worst Pain Ever 
No Pain 
Worst Pain Ever 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 140 of 169 
 
 
  
 
 
 
140 
APPENDIX 10- PROCEDURES FOR SPECIFIC BLOOD TESTS 
Immunogenicity blood Samples 
Serum samples for antibodies to NexoBrid will be obtained prior to application (time 0), and at 
the following time points:  
 At day 7±2 days (week 1 visit) from start of treatment, 
 At day 28±7 days (week 4 visit) from start of treatment, 
 At day 56±14 days (week 8 visit) from start of treatment. 
 At the 6 months FU visit 
 At the 24 months FU visit  
 
The blood sampling should be taken after an overnight fast (at least 8 hours if possible) at 
about the same time of the day (± 2 hours and before noon) due to potential daily fluctuations 
in the levels of immunological responses. The serum samples will be kept at (-) 20oC until 
delivery for analysis.  
Sample preparation procedures are as follows: 
1. For each immunogenicity sample at each time point, draw 3 ml whole blood into a 5 ml pre-
labeled tube and check the label for subject number, time point, and type of test. 
2. Place the tube in the refrigerator at 2-8oC for 0.5hrs - 2 hours for clotting. Important Note: Do 
not leave the serum with the clot longer than 2 hours in the refrigerator or at room 
temperature.  
3. Centrifuge the sample at a minimum of 1100 g for 10 minutes, at ambient temperature for red 
blood cells sedimentation.  
4. Divide the serum equally (the upper liquid layer, approximately 1.5 ml) into four pre-labeled 
1 ml conical bottom cryotubes resulting in at least 0.3 ml serum each. Check the subject 
number, time point, and type of test and fill DATE and TIME, 2 cryotubes will be used for 
analysis and 2 for backup.  
5. Store the cryotubes at (-) 20 ± 5 oC or below until shipped for analysis at Covance.  
6. The shipment of samples will be in (-) 20 ± 5 oC or below.  
If possible, storage and shipment are preferred in (-) 70o±10°C conditions.  
7. The set of 2 samples for analysis should be shipped to Covance first. The samples should be 
sent at the end of the study. Please contact your CRA when shipment is required.  
8. The second set of samples (backup) should be dispatched to Covance in a subsequent and 
separate shipment, after confirmation that the first set has been received, but only if asked by 
the lab. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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141 
Procedures for Pharmacokinetic Samples 
PK samples will be obtained prior to application (time 0), and at the following time points:  
1, 2, 4, 12, 24 and 48 hrs post start of the treatment. 
Please carefully follow the procedure below for handling the PK blood samples: 
1. For each PK sample at each time point, draw 2 ml whole blood into a 5 ml pre-labeled tube and 
check the label for subject number, time point, and type of test. 
2. Place the tube at room temperature for approximately 30 minutes for clotting.  
3. Store the sample at refrigeration (2-8 ºC) for approximately 120 minutes. 
4. Following the refrigeration period, Centrifuge the sample for approximately 20 minutes at 2800 
to 3000 x g at a temperature of 2-8 ºC. 
5. Divide the serum equally (the upper liquid layer) into pre-labeled 1 ml conical bottom cryotubes. 
Check the subject number, time point, and type of test and fill DATE and TIME. 
6. Store the cryotubes in (-) 20 ± 5 ºC or below until shipment for analysis at Quintiles. The 
shipment of samples will be in (-) 20 ± 5 ºC or below.  
7. If possible, storage and shipment are preferred in (-) 80 ± 10°C conditions.  
8. The samples should be shipped to Quintiles after 4 patients completed the 48hrs  test, but no 
more than 10 months post first sample was drawn (in that case you may send samples of less 
than 4 patients). Please contact your CRA when shipment is required. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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142 
APPENDIX 11- BURN PATIENTS: POTENTIAL ADVERSE EVENTS 
Cardiovascular 
Hypotension 
(decrease of either 
systolic or diastolic 
for >/= 2hrs) 
Pressor or inotrope 
requirement for 
normotension 
Sinus tachycardia 
Dysrhythmia 
Hypertension 
Pulmonary 
Tachypnea 
Pulmonary edema 
Pneumonia 
Pneumothorax 
Pleural Effusions 
Atelectasis 
Pulmonary 
Infiltrates 
Inhalation injury 
and/or airway (req. 
intubation) 
Respiratory failure 
Neurological 
Mental status 
changes 
Sedation 
Confusion/delirium 
Substance 
withdrawal 
GI 
Nausea 
Vomiting (>/= 
2/shift or >/= 
6/day) 
Diarrhea (>/= 
2/shift or >/= 
6/day) 
Constipation 
Ileus during bum 
shock 
Renal 
Acute renal failure 
(BUN >/= 24; Cr 
>/= 1.19) 
Renal failure 
 
Urinary tract infections 
Urinary tract infection, 
early 
Urinary retention 
Fluctuation in UOP during 
burn resuscitation 
«1mllkg/hr for 2 hrs) 
Blood 
Anemia (chronic or acute) 
(based on hemoglobin 
gm/dL) 
Thrombocytopenia (plt </= 
145,000) 
Thrombocytosis (plt >/= 
350) 
C-Reactive Protein (>/=30) 
Mild 
coagulopathy 
as 
evidenced by ele PT/PTT 
(PT> 12.3, PTT>36.5) 
Asymptomatic electrolyte 
imbalance 
(see 
norm 
ranges) 
Hyperglycemia 
(glycosuria, insulin drip) 
Leukocytosis 
WBC 
2: 
highest normal range 
Leukopenia WBC ~lowest 
normal range 
Other hematologic 
Coagulopathy 
ODE III/DDDP 
Mise 
Pain from primary injury 
Pruritis 
Microbial colonization of 
burn wounds 
Wound infection 
Other infection 
 
Excision and grafting of burn injury 
Graft loss «/= to 10% ofthe extent 
grafted) 
Hands 
Sepsis / septicemia 
Line infection 
Compartment syndrome (extremity) 
Hypothermia «37.2C for 2hrs) 
Hyperthermia (>/=39.5C) 
Amputation of extremities/digits 
from deep burn 
Cellulitis 
Traumatic injury 
Graft site contracture requiring 
release or revision 
Death 
Multiple organ failure / multi-system 
organ failure 
Permanent neuro/vascular deficit not 
r/t sev of inj 
Unplanned surgical intervention 
Autografting to donor site for failure 
to heal 
Repeat autografting to same body site 
(>10% org grafted) 
Auto Graft/regraft 
CSS regraft 
Intubation due to declining 
respiratory status not related to 
edema or inhalation injury 
Acute Respiratory Distress Syndrome 
(ARDS) 
Abdominal Compartment Syndrome 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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143 
APPENDIX 12- COSMESIS, FUNCTION AND QUALITY OF LIFE QUESTIONNAIRES  
Modified Vancouver Scar Scale (MVSS) 
The six parameters listed below are evaluated on a point system (please tick the correct 
answer): 
1. Pigmentation 
□ (0) Normal 
□ (1) Hypopigmented 
□ (2) Mixed 
□ (3) Hyperpigmented 
2. Pliability  
□ (0) Normal 
□ (1) Supple- flexible with minimal resistance 
□ (2) Yielding- giving way to pressure 
□ (3) Firm- inflexible, not easily moved, resistant to manual pressure 
□ (4) Banding- rope- like tissue that blanches with extension of the scar 
□ (5) Contracture- permanent shortening of scar, producing deformity or distortion 
3. Height  
□ (0) Flat 
□ (1) <2mm 
□ (2) 2 to 5mm 
□ (3) >5mm 
4. Vascularity  
□ (0) Normal 
□ (1) Pink 
□ (2) Red 
□ (3) Purple 
5. Pain 
□ (0) None 
□ (1) Occasional 
□ (2) Requiring medication 
6. Pruritus 
□ (0) None 
□ (1) Occasional 
□ (2) Requiring medication 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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144 
 
Patient and Observer Scar Assessment Scale (POSAS) 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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145 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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EQ-5D (QoL) 
EQ-5D is a standardized measure of health status developed in order to provide a simple, generic 
measure of health for clinical and economic appraisal. Applicable to a wide range of health conditions 
and treatments, it provides a simple descriptive profile and a single index value for health status that can 
be used in the clinical and economic evaluation of health care as well as in population health surveys. 
EQ-5D is designed for self-completion by respondents and is ideally suited for use in postal surveys, in 
clinics, and in face-to-face interviews. 
EQ-5D essentially consists of 2 pages - the EQ-5D descriptive system (Figure 3) and the EQ visual 
analogue scale (EQ VAS) (Figure 4). The EQ-5D descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 3 levels: no problems, some problems, severe problems. The respondent is asked to indicate his/her 
health 
state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 
dimensions. This decision results in a 1-digit number expressing the level selected for that dimension.  
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale where the 
endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 147 of 169 
 
 
  
 
 
 
147 
Figure 3- EQ-5D Descriptive system 
 
EQ-5D (UK English version) 
By placing a tick in one box in each group below, please indicate which statements best describe your 
own health state today. 
 
Mobility 
I have no problems in walking about  
 
 
� 
I have some problems in walking about  
 
 
� 
I am confined to bed   
 
 
 
� 
 
Self-Care 
I have no problems with self-care  
 
 
� 
I have some problems washing or dressing myself  
 
� 
I am unable to wash or dress myself  
 
 
� 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities  
� 
I have some problems with performing my usual activities  
� 
I am unable to perform my usual activities   
 
� 
 
Pain/Discomfort 
I have no pain or discomfort  
 
 
 
� 
I have moderate pain or discomfort  
 
 
� 
I have extreme pain or discomfort  
 
 
� 
 
Anxiety/Depression 
I am not anxious or depressed  
 
 
 
� 
I am moderately anxious or depressed  
 
 
� 
I am extremely anxious or depressed  
 
 
� 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 148 of 169 
 
 
  
 
 
 
148 
To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
WE WOULD LIKE YOU TO INDICATE 
ON THIS SCALE HOW GOOD OR BAD 
YOUR OWN HEALTH IS TODAY, IN 
YOUR OPINION. PLEASE DO THIS BY 
DRAWING A LINE FROM THE BOX 
BELOW TO WHICHEVER POINT ON THE 
SCALE INDICATES HOW GOOD OR BAD 
YOUR HEALTH STATE IS TODAY. 
To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
WE WOULD LIKE YOU TO INDICATE 
ON THIS SCALE HOW GOOD OR BAD 
YOUR OWN HEALTH IS TODAY, IN 
YOUR OPINION. PLEASE DO THIS BY 
DRAWING A LINE FROM THE BOX 
BELOW TO WHICHEVER POINT ON THE 
SCALE INDICATES HOW GOOD OR BAD 
YOUR HEALTH STATE IS TODAY. 
 
Figure 4- EQ visual analogue scale (EQ VAS) 
 
Your 
own 
health 
state


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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149 
Burn Specific Health Scale-Brief 
 
 
extreme(ly)  
quite a bit 
moderate(ly) 
a little bit 
None (not at all) 
1. Bathing independently 
 
 
 
 
 
2. Dressing by yourself 
 
 
 
 
 
3. Getting in and out of a chair 
 
 
 
 
 
4. Signing your name 
 
 
 
 
 
5. Eating with utensils 
 
 
 
 
 
6. Tying shoelaces, bows, etc 
 
 
 
 
 
7. Picking up coins from a flat surface 
 
 
 
 
 
8. Unlocking a door 
 
 
 
 
 
9. Working in your old job performing your old duties 
 
 
 
 
 
10. I am troubled by feelings of loneliness 
 
 
 
 
 
11. I often feel sad or blue 
 
 
 
 
 
12. At times, I think I have had an emotional problem 
 
 
 
 
 
13. I am not interested in doing things with my friends 
 
 
 
 
 
14. I don’t enjoy visiting people 
 
 
 
 
 
15. I have no one to talk to about my problems 
 
 
 
 
 
16. I have feelings of being trapped or caught 
 
 
 
 
 
17. My injury has put me further away from my family 
 
 
 
 
 
18. I would rather be alone than with my family 
 
 
 
 
 
19. I don’t like the way my family acts around me 
 
 
 
 
 
20.My family would be better off without me 
 
 
 
 
 
21. I feel frustrated because I cannot be sexually aroused as well as I 
d
 
 
 
 
 
22. I am simply not interested in sex any more 
 
 
 
 
 
23. I no longer hug, hold or kiss 
 
 
 
 
 
24. Sometimes, I would like to forget that my appearance has changed 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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150 
25. I feel that my burn is unattractive to others 
 
 
 
 
 
26. My general appearance really bothers me 
 
 
 
 
 
27. The appearance of my scars bothers me 
 
 
 
 
 
28. Being out in the sun bothers me 
 
 
 
 
 
29. Hot weather bothers me 
 
 
 
 
 
30. I can’t get out and do things in hot weather 
 
 
 
 
 
31. It bothers me that I can’t get out in the sun 
 
 
 
 
 
32. My skin is more sensitive than before 
 
 
 
 
 
33. Taking care of my skin is a bother 
 
 
 
 
 
34. There are things that I’ve been told to do for my burn that I dislike 
d i
 
 
 
 
 
35. I wish that I didn’t have to do so many things to take care of my burn 
 
 
 
 
 
36. I have a hard time doing all the things I’ve been told to take care of my 
b
 
 
 
 
 
37. Taking care of my burn makes it hard to do other things that are 
i
 
 
 
 
 
38. My burn interferes with my work 
 
 
 
 
 
39. Being burned has affected my ability to work 
 
 
 
 
 
40. My burn has caused problems with my working 
 
 
 
 
 
.. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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151 
QuickDASH 
QuickDASH outcome measure for burns in the upper extremities. The Disabilities of the Arm, 
Shoulder and Hand (DASH) Outcome Measure is a 30-item, self-report questionnaire designed 
to measure physical function and symptoms in patients with any or several musculoskeletal 
disorders of the upper limb. The questionnaire was designed to help describe the disability 
experienced by people with upper-limb disorders and also to monitor changes in symptoms and 
function over time. Testing has shown that the DASH performs well in both these roles. 
It gives clinicians and researchers the advantage of having a single, reliable instrument that can 
be used to assess any or all joints in the upper extremity. 
The DASH Outcome Measure contains two optional, four-item modules intended to measure 
symptoms and function in athletes, performing artists and other workers whose jobs require a 
high degree of physical performance. Because they may be having difficulties only at high 
performance levels–which are beyond the scope of the 30-item DASH Outcome Measure–
clinicians may find the modules, which are scored separately from the DASH, useful in 
assessing these special patients.  
The DASH Outcome Measure was jointly developed by the Institute for Work & Health and 
the American Academy of Orthopaedic Surgeons (AAOS). The project was supported by the 
American Association for Hand Surgery, the American Orthopaedic Society for Sports 
Medicine, the American Shoulder & Elbow Surgeons, the American Society for Surgery of the 
Hand, the Arthroscopy Association of North America and the American Society of Plastic and 
Reconstructive Surgeons. 
The QuickDASH is a shortened version of the DASH Outcome Measure. Instead of 30 items, 
the QuickDASH uses 11 items to measure physical function and symptoms in persons with any 
or multiple musculoskeletal disorders of the upper limb. Like the DASH, the QuickDASH also 
has two four-item optional modules that are scored separately. The QuickDASH was found to 
be valid and repeatable in patients with upper limb burns and supports the use of the 
QuickDASH in this population to help assess change in functional level [100-101]. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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152 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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153 
Lower Extremity Functional Scale test (Binkley et al, 2011) 
The Lower Extremity Functional Scale (LEFS) is a questionnaire containing 20 questions 
about a person’s ability to perform everyday tasks. The LEFS can be used by clinicians as a 
measure of patients' initial function, ongoing progress and outcome, as well as to set functional 
goals. The LEFS can be used to evaluate the functional impairment of a patient with a disorder 
of one or both lower extremities. It can be used to monitor the patient over time and to evaluate 
the effectiveness of an intervention.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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154 
 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 13- ASA CLASSIFICATION SYSTEM 
 
The ASA physical status classification system is a system for assessing the fitness of patients 
before surgery. These are: 
ASA Physical Status 1 - A normal healthy patient 
ASA Physical Status 2 - A patient with mild systemic disease 
ASA Physical Status 3 - A patient with severe systemic disease 
ASA Physical Status 4 - A patient with severe systemic disease that is a constant threat to life 
ASA Physical Status 5 - A moribund patient who is not expected to survive without the 
operation 
ASA Physical Status 6 - A declared brain-dead patient whose organs are being removed for 
donor purposes 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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156 
APPENDIX 14- RANGE OF MOTION 
In this study, passive ROM will be measured in which the motion is being created by the 
patient contracting the muscles around the joint. A goniometer will be used in this study to 
measure joint angles (joint range of motion).  
Instructions for using a goniometer 
1. Align the fulcrum of the device with the joint to be measured 
2. Align the stationary arm of the device with the limb being measured 
3. Hold the arms of the goniometer in place while the joint is moved through its range of 
motion. 
The degree between the endpoints represents the entire range of motion. 
Important tips: 
1. Stabilize the stationary of the body. This is the part of the body that is proximal (closer to the 
midline of the body) to the joint you are testing. It is important that the patient does not move 
his body while moving the joint; this step isolates the joint movement for a more accurate 
measurement. 
2. Look at the reading on the goniometer before moving it from the patient’s body. Ensure that 
you take an accurate reading of the degree of motion on the geometer, and that you 
consistently use the same stationary and movable landmarks on the body when measuring, to 
ensure consistency. Be sure to record the range of motion for the joint. 
Range of Motion measurements 
16.1.1.1 Shoulder Joint 
The shoulder joint has the following normal ranges of movement: Flexion, Extension, 
Adduction, Abduction and Medial Rotation. Flexion, Extension, Adduction and Abduction will 
be measured: 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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157 
Shoulder normal ranges: 
Movement 
Degree 
Description 
Flexion (Vertical) 
180° 
Raise arm straight forward 
Extension 
(Vertical) 
60° 
Raise arm straight backward 
Abduction 
90° 
Bring arm up sideways 
Adduction 
45° 
Bring arm toward the midline of the 
body 
 
Elbow joint 
The elbow joint has the following normal ranges of movement: Flexion, Extension, Pronation 
and Supination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elbow normal ranges: 
Movement 
Degree 
Description 
Flexion 
150° 
Bring lower arm to the biceps 
Extension 
180° 
Straighten out lower arm 
Pronation 
90° 
Turn lower arm so palm faces down 
Supination 
90° 
Turn lower arm so palm of hand faces 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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158 
up 
Wrist joint 
The wrist joint has the following normal ranges of movement: Flexion, Extension, Adduction, 
Abduction and Circumduction. Flexion, Extension, Adduction and Abduction will be 
measured: 
 
 
 
 
 
 
 
Wrist normal ranges: 
Movement 
Degree 
Description 
Flexion 
80-90° 
Bend wrist so palm nears lower arm 
Extension 
70° 
Bend wrist in opposite direction 
Abduction 
20° 
Bend wrist so thumb nears radius 
Adduction 
30-50° 
Bend wrist so pinky finger nears ulna 
 
Palm and Fingers 
Normal ranges of the palm & fingers joints will include the following joints (see Figure 5):  
 The fingers IP joints;  
o Distal Interphalangeal (DIP) joints 
o Proximal Interphalangeal (PIP) joints 
  The thumb joints; 
o Proximal Interphalangeal (PIP) joint 
o Metacarpophalangeal (MTP) joint 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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159 
 
 
 
 
 
 
 
 
 
Figure 5- Hand fingers joints 
 
Joints normal ranges: 
Movement 
Degree 
Description 
Thumb IP 
Hyperextension/Flexion 
0/80 
Thumb MTP 
Hyperextension/Flexion 
0/55 
Finger DIP joints 
Extension/Flexion  
0/60  
Finger PIP joints 
Extension/Flexion  
0/100 
Finger MCP joints (see 
Figure 6) 
Hyperextension/Flexion 
10/90 
 
 
 
 
 
 
 
 
 
Figure 6- Finger MCP hyperextension (a) and flexion (b) 
 
a 
b 
MTP 
j i
MTP
PIP 
jointsPIP 
DIP jointsDIP 
joints
 
 
 
a 
b 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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160 
Knee joint 
The knee joint has the following normal ranges of movement: Flexion and Extension. 
 
 
 
 
 
 
Knee normal ranges: 
Movement 
Degree 
Description 
Flexion 
130° 
Touch calf to hamstring 
Extension 
15° 
Straighten out knee as much as 
possible 
 
Ankle joint 
The ankle joint has the following normal ranges of movement: Plantar Flexion, Dorsi Flexion, 
Inversion and Eversion. Dorsi and Plantar flexion will be measured in this study: 
 
 
 
 
 
 
 
Knee normal ranges: 
Movement 
Degree 
Description 
Flexion 
45° 
Bend ankle so toes point up 
Extension 
20° 
Bend ankle so toes point down 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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161 
 
APPENDIX 15- BLINDED ASSESSOR MEMO- SAMPLE 
In accordance with study protocol, for patients who are randomized to one of the topical arms, 
NexoBrid or Gel Vehicle, eschar removal assessment will be done by assessor blinded to the 
treatment arm. This assessor will evaluate eschar removal in all study arm (but will be blinded 
only to the topical arms) and for all procedures until complete eschar removal.  
In addition, weekly evaluations of wound closure and long term cosmesis and function will be 
done by a second assessor blinded to all treatment arms.  
The following procedures and assessments will be performed by the blinded assessors at the 
following time-points:  
First blinded assessor:  
Eschar Removal assessment- For the topical arms (NexoBrid/Gel Vehicle), eschar removal 
assessment will be performed immediately following removal of the soaking dressing (6 hours 
after start of 1st and 2nd treatment and after any additional procedure until complete eschar 
removal. The assessment will include photograph, wound depth assessment and clinical 
assessment of the extent of eschar removal.  
Eschar removal in the SOC arm will be evaluated by the same assessor, but he will not be 
blinded to the SOC arm.  
Second blinded assessor (blinded to all treatment arms): 
Weekly follow up visits and wound closure confirmation visit-  
The following procedures will be performed by the blinded assessor: 
o All wounds should be photographed.   
o Clinical assessment of % of target wound area epithelialized and/or closed by graft and 
assessment of % donor site epithelialized, 
o Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment  
Long term follow up visits-  
The following procedures will be performed by the blinded assessor: 
o 
All wounds should be photographed.   
o 
The following questionnaires will be filled by the blinded assessor: 
 
Patient and Observer Scar Assessment Scale (POSAS) 
 
A modified Vancouver Scar Scale (MVSS) 
o 
Range of Motion measurements (injured and non-injured joints) 
In order to maintain the blinding, the sponsor would like your site to implement measures, as 
best as possible, to ensure that the blinded assessors will not be aware of the treatment 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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162 
assignments for the duration of the study. The blinded assessors should not be involved with 
product application and PK and Immunogenicity blood sampling should not be taken at the 
same time of the blinded assessment. 
The topical (NexoBrid/Gel Vehicle) treatment allocation will not be accessible through the 
subject’s electronic case report forms. Paper source documents that could unblind the assessor 
will be kept in a separate folder, appropriately labeled. The blinded assessor should not review 
subject’s data that will include randomization reports, PK and Immunogenicity blood 
collection, drug accountability records, and any other data that could unblind the assessor for 
the topical arms. In addition, all Investigational Products (used and unused) should be stored, 
dispensed, and administered out of the sight of the blinded assessor.  
Treatment allocation to the SOC group cannot be reconciled from all eCRFs and SD. The 
weekly and long term follow up set of source documents worksheets are in separated sections 
and not reviling the treatment arm. 
The second blinded assessor who evaluates the weekly and long term effects of the treatment 
should not review other sections of source worksheets and will not access to eCRFs. 
The Sponsor's medical team will be blinded to the topical arms treatment, and can provide 
support blindly when needed during the eschar removal treatment.  
You are being required to sign this memo to acknowledge and certify that you will make all 
attempts to comply with these requirements. 
Acknowledgement (To be signed at the start of the study): 
 I acknowledge that I fully understand my role in maintaining the blind and assure that I will 
not access subject’s data except for the information relevant to the conduct the blinded 
assessments listed above. 
 
Eschar removal assessor:  
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 Wound closure, cosmesis and function assessor: 
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 
 
Certification (To be signed at completion of study):  
I certify and confirm that I did not review subject’s data except for the information relevant to 
the conduct of the blinded assessments. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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163 
Eschar removal assessor:  
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 Wound closure, cosmesis and function assessor: 
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 164 of 169 
 
 
  
 
 
 
164 
APPENDIX 16- TREATMENT DIAGRAM 
 
 
 
 
 
 
 
 
  
Complete 
Failure 
Failure <50% 
eschar removal 
Complete eschar 
removal 
 >50% 
eschar 
removal 
but 
not complete 
Randomization 
Treatment assignment per randomization 
Applying NexoBrid/Gel Vehicle - 4hrs treatment, 
removal of remnants and 2 hrs soaking 
Blinded assessment of eschar removal 
efficacy  
Assessment of eschar removal efficacy 
Applying 2nd application of NexoBrid/Gel 
Vehicle - 4hrs treatment, removal of 
remnants and 2 hrs soaking 
Cleansing & Soaking for at least 2 hrs 
‘Moving’ from the Eschar Removal phase 
to the Wound Management phase (wound 
closure procedure phase, consequent 
treatment up to hospital discharge and 
continued follow up for long term 
assessment) 
Additional surgical and/or non surgical procedures will be repeated until complete Eschar Removal: 
- Surgical procedures may include tangential/ minor/ avulsion/ Versajet/ Dermabrasion excision.  
 -Non-surgical procedures may include collagenase (e.g. Santyl) antimicrobial treatment using), 
antimicrobial solutions (i.e. Dakin’s Solution, Sulfa-Nystatin Solution), antimicrobial ointments (i.e. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (i.e. Mepilex Ag, Aquacel Ag, Acticoat).  
Complete eschar removal 
SOC – surgical and/or non surgical 
procedure 
Complete eschar 
removal 
 Eschar 
removal not 
complete 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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165 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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39. 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 167 of 169 
 
 
  
 
 
 
167 
40. 
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41. 
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42. 
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Mavrogordato, A.E., et al., A novel method to treat hyperthermia in a burns case: use 
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Taylor, G., et al., TPredominance of staphylococcal organisms in infections occurring 
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Tengvall, O.M., et al., Differences in pain patterns for infected and noninfected patients 
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McManus, A.T., et al., A decade of reduced gram-negative infections and mortality 
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61. 
Vostrugina, K., D. Gudaviciene, and A. Vitkauskiene, Bacteremias in patients with 
severe burn trauma. Medicina (Kaunas), 2006. 42: p. 576-9. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
Page 168 of 169 
 
 
  
 
 
 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 9- 12 August 2015 
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SAP_007.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Clinical Trial 
 
A multicenter, multinational, randomized, controlled, assessor blinded study, performed in 
subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid compared to Gel 
Vehicle and compared to Standard of Care (DETECT) 

 
 
Sponsor: 
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Trial protocol code: MW2010-03-02 
EudraCT number: 2014-001672-55 
IND No.: 65,448 
 
 
Competence Center for Clinical Trials Bremen - Biometry 
Author: Dr. Martin Scharpenberg 
Version of 15 May 2018, Version V02 (final) 
 


DETECT - Protocol Code: MW2010-03-02 
Page 2 of 151 
Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
1. Table of Contents 
1. 
Table of Contents 
2 
2. 
Introduction 
13 
2.1. 
Background 
13 
2.2. 
Study Objective 
17 
2.3. 
References to Study Protocol 
17 
2.4. 
Amendments 
18 
3. 
Study Administrative Structure 
19 
3.1. 
Sponsor 
19 
3.2. 
Study Conduct 
19 
3.3. 
Statistics 
20 
4. 
Signatures 
21 
5. 
List of Abbreviations 
22 
6. 
General Definitions 
25 
6.1. 
Hardware and software used 
25 
6.2. 
Reporting standards and language 
25 
6.3. 
General format and content of tables, figures and patient data listings. 
25 
6.4. 
Quality control 
25 
7. 
Details of Trial Design 
26 
7.1. 
General Information of Trial Design 
26 
7.1.1. 
Study medication 
27 
7.1.1.1. 
Topical arms 
27 
7.1.1.1.1. NexoBrid 
27 
7.1.1.1.2. Gel Vehicle 
27 


DETECT - Protocol Code: MW2010-03-02 
Page 3 of 151 
Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
7.1.1.2. 
Standard of Care 
27 
7.1.2. 
Intended dosage and duration of treatment 
28 
7.1.2.1. 
NexoBrid 
28 
7.1.2.2. 
Gel Vehicle 
28 
7.1.2.3. 
Standard of Care 
28 
7.1.3. 
Study population and choice of study invitee 
29 
7.1.3.1. 
Inclusion Criteria - Patient level 
29 
7.1.3.2. 
Inclusion Criteria - Wound level 
29 
7.1.3.3. 
Exclusion Criteria - Patient level 
29 
7.1.4. 
Drop-out criteria 
31 
7.1.4.1. 
Stopping rules (apply for NexoBrid or Gel Vehicle arms only) 
31 
7.1.5. 
Concomitant medication and treatment 
33 
7.2. 
Trial schedule 
34 
7.3. 
Criteria for evaluation 
39 
7.3.1. 
Demographic data and other baseline characteristics 
39 
7.3.2. 
Efficacy evaluation 
42 
7.3.2.1. 
Primary target variable 
42 
7.3.2.2. 
Secondary target variables 
42 
7.3.3. 
Safety evaluation 
43 
7.3.3.1. 
Time to complete wound closure 
43 
7.3.3.2. 
Cosmesis and function at 12 months from wound closure confirmation 43 
7.3.3.3. 
Cosmesis and function at 24 months from wound closure confirmation 46 
7.3.3.4. 
Adverse Events 
46 
7.3.3.5. 
Laboratory assessments and vital signs 
47 
7.3.3.6. 
Additional safety endpoints 
49 


DETECT - Protocol Code: MW2010-03-02 
Page 4 of 151 
Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
7.3.4. 
Exploratory analyses 
50 
8. 
Handling of protocol violations 
52 
9. 
Populations Analyzed 
54 
9.1. 
Sample Size 
54 
9.1.1. 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. Gel) 54 
9.2. 
Secondary Endpoint: Incidence of surgical excision 
55 
9.3. 
Secondary Endpoint: Time to complete eschar removal 
55 
9.3.1. 
Summary of sample size 
56 
9.4. 
Safety Set 
56 
9.5. 
Full analysis Set (Intent-to-Treat population) 
56 
9.6. 
Per Protocol Set 
56 
9.7. 
Enrolled population 
56 
10. 
Data Handling 
57 
10.1. 
Handling of Missing Data, Outliers and Implausible Data 
57 
10.1.1. 
Primary Endpoint: Incidence of complete eschar removal 
57 
Secondary Endpoints 
58 
10.1.1.1. 
Secondary Endpoint: Incidence of surgical excision 
58 
10.1.1.2. 
Secondary Endpoint: Time to complete eschar removal 
58 
10.1.1.3. 
Secondary Endpoint: Blood loss 
58 
10.1.2. 
Safety Endpoints 
60 
10.1.2.1. 
Safety Endpoint: Time to reach complete wound closure 
60 
10.1.2.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 60 
10.1.2.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 61 


DETECT - Protocol Code: MW2010-03-02 
Page 5 of 151 
Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
10.2. 
Handling of Withdrawals and Dropouts 
62 
10.3. 
Data Transformation 
62 
10.3.1. 
Demographic data and other baseline characteristics 
62 
10.3.1.1. 
Age 
62 
10.3.1.2. 
Height 
62 
10.3.1.3. 
Weight 
62 
10.3.1.4. 
Time since injury 
62 
10.3.1.5. 
Early grafted wounds 
63 
10.3.1.1. 
Late grafted wounds 
63 
10.3.1.2. 
Wounds at least partially found in the anatomical area of the hand 
63 
10.3.2. 
Primary Endpoint: Incidence of complete eschar removal in the topical arms 63 
10.3.3. 
Secondary Endpoints 
64 
10.3.3.1. 
Secondary Endpoint: Incidence of surgical excision 
64 
10.3.3.2. 
Secondary Endpoint: Time to complete eschar removal 
64 
10.3.3.3. 
Secondary Endpoint: Blood loss 
65 
10.3.3.3.1. Blood loss for main analysis 
65 
10.3.3.3.2. Proportion of SPT area of wounds treated per procedure 
66 
10.3.3.3.3. Proportion of DPT area of wounds treated per procedure 
66 
10.3.3.3.4. Proportion of FT area of wounds treated per procedure 
66 
10.3.3.3.5. Course of debridement procedure 
67 
10.3.4. 
Safety Endpoints 
67 
10.3.4.1. 
Safety Endpoint: Time to reach complete wound closure 
67 
10.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 67 


DETECT - Protocol Code: MW2010-03-02 
Page 6 of 151 
Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
10.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 68 
10.3.4.4. 
General Parameters of safety 
68 
10.3.5. 
Exploratory Analyses 
74 
10.3.5.1. 
%SPT area 
74 
10.3.5.2. 
%TBSA 
74 
10.3.5.3. 
Application data 
75 
10.3.5.4. 
Maintenance of complete wound closure 
75 
10.3.5.5. 
% wound area surgically excised for eschar removal 
75 
10.3.5.6. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremities target wounds 
75 
10.3.5.7. 
POSAS 
75 
10.3.5.8. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
76 
10.3.5.9. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremity wounds 
76 
10.3.5.10. Incidence of surgically harvested donor sites wounds 
77 
10.3.5.11. % area of surgically harvested donor site wounds 
77 
10.3.5.12. Blood loss using changes in hematocrit following eschar removal 
procedures 
77 
10.3.5.13. Blood loss using changes in hemoglobin following eschar removal 
procedures 
77 
10.3.5.14. Blood loss comparing NexoBrid procedures to surgical procedures 
77 
10.3.5.15. Autograft related parameters 
77 
10.3.5.16. Duration of hospitalization 
78 
10.3.5.17. Time to reach 100% wound closure 
78 


DETECT - Protocol Code: MW2010-03-02 
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Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
10.3.6. 
Laboratory values 
78 
10.4. 
Multiple visits per time point 
78 
11. 
Statistical Analysis of Target Variables 
80 
11.1. 
First stage analysis – end of efficacy assessment period (EAP) 
82 
11.1.1. 
Demographics and Other Baseline Characteristics 
82 
11.1.2. 
Primary Efficacy variable 
84 
11.1.3. 
Secondary Efficacy variables 
85 
11.1.3.1. 
Incidence of surgical excision 
85 
11.1.3.2. 
Time to complete eschar removal 
86 
11.1.3.3. 
Blood loss 
88 
11.1.4. 
Safety variables 
89 
11.1.4.1. 
Safety Endpoint: Time to wound closure 
89 
11.1.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 91 
11.1.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 91 
11.1.4.4. 
Adverse Events 
91 
11.1.4.5. 
Vital Signs 
92 
11.1.4.6. 
Pain Assessment 
92 
11.1.4.7. 
Extend of exposure to study drug 
93 
11.1.4.8. 
Medical history and concomitant diseases 
93 
11.1.4.9. 
Concomitant medication 
93 
11.1.4.10. Central laboratory values 
93 
11.1.4.11. Blood transfusions 
94 
11.1.4.12. Maintenance of complete wound closure 
94 


DETECT - Protocol Code: MW2010-03-02 
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Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
11.1.4.13. Incidence of QT prolongation 
94 
11.1.4.14. Analgesia, anesthesia and antibiotic use 
94 
11.1.4.15. Hospital readmission rates 
95 
11.1.4.16. INR/PTT change 
95 
11.1.4.17. Blood glucose change 
96 
11.1.5. 
Exploratory Analyses 
96 
11.1.5.1. 
% wound area surgically excised for eschar removal 
96 
11.1.5.2. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
96 
11.1.5.3. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremities target wounds 
97 
11.1.5.4. 
Incidence of surgically harvested donor site wounds 
97 
11.1.5.5. 
% area of surgically harvested donor site wounds 
97 
11.1.5.6. 
Blood loss using changes in hematocrit following eschar removal 
procedures 
98 
11.1.5.7. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
98 
11.1.5.8. 
Blood loss in NexoBrid procedures vs. surgical procedures 
98 
11.1.5.9. 
Autograft related parameters 
98 
11.1.5.10. Duration of hospitalization 
99 
11.1.6. 
Pharmacokinetic Variables 
99 
11.1.7. 
Multicenter Data 
100 
11.1.8. 
Handling of Multiple Comparisons 
100 
11.1.9. 
Interim analysis 
100 
11.1.10. Stratification 
100 
11.1.11. Analysis of Subgroups 
101 


DETECT - Protocol Code: MW2010-03-02 
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Statistical Analysis Plan V02 of 15 May 2018 
Competence Center for Clinical Trials Bremen 
11.1.11.1. Target wounds in the anatomical area of the hand 
101 
11.1.11.2. Patients with < 25% SPT area 
101 
11.1.11.3. Patients with ≥ 25% SPT area 
102 
11.1.11.4. Total TBSA ≤ 15% 
102 
11.1.11.5. Total TBSA > 15% 
102 
11.1.11.6. All target wounds full thickness 
102 
11.1.11.7. Mixed target wounds – full thickness and deep partial thickness 
102 
11.1.11.8. All target wounds are deep partial thickness 
102 
11.1.11.9. Wounds that are entirely full thickness 
102 
11.2. 
Second stage analysis – 12 month short-term follow-up (STFU12) 
103 
11.2.1. 
Demographics and Other Baseline Characteristics 
103 
11.2.2. 
Primary Efficacy variable 
103 
11.2.3. 
Secondary Efficacy variables 
103 
11.2.4. 
Safety variables 
103 
11.2.4.1. 
Safety Endpoint: Time to wound closure 
103 
11.2.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 103 
11.2.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 104 
11.2.4.4. 
Adverse Events 
104 
11.2.4.5. 
Concomitant medication 
105 
11.2.4.6. 
Lower Extremity Function Scale (LEFS) 
105 
11.2.4.7. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
105 
11.2.4.8. 
Range of Motion (ROM) 
105 
11.2.4.9. 
EQ-5D (Quality of Life) 
105 


DETECT - Protocol Code: MW2010-03-02 
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Statistical Analysis Plan V02 of 15 May 2018 
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11.2.4.10. Burn Specific Health Scale – Brief (BSHS-B) 
106 
11.2.5. 
Exploratory Analyses 
106 
11.2.5.1. 
POSAS 
106 
11.2.5.2. 
MVSS (target wounds) 
106 
11.2.5.3. 
MVSS (donor site scars) 
107 
11.2.6. 
Pharmacokinetic Variables 
107 
11.2.7. 
Multicenter Data 
107 
11.2.8. 
Handling of Multiple Comparisons 
107 
11.2.9. 
Interim analysis 
107 
11.2.10. Stratification 
107 
11.2.11. Analysis of Subgroups 
107 
11.2.11.1. Total TBSA ≤ 15% 
107 
11.2.11.2. Total TBSA > 15% 
108 
11.2.11.3. All target wounds full thickness 
108 
11.2.11.4. Mixed target wounds – full thickness and deep partial thickness 
108 
11.2.11.5. All target wounds are deep partial thickness 
108 
11.3. 
Third stage analysis – 24 month long-term safety follow-up (LTSFU24) 
109 
11.3.1. 
Demographics and Other Baseline Characteristics 
109 
11.3.2. 
Primary Efficacy variable 
109 
11.3.3. 
Secondary Efficacy variables 
109 
11.3.4. 
Safety variables 
109 
11.3.4.1. 
Safety Endpoint: Time to wound closure 
109 
11.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 109 


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11.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 109 
11.3.4.4. 
Adverse Events 
110 
11.3.4.5. 
Concomitant medication 
111 
11.3.4.6. 
Immunogenicity evaluation 
111 
11.3.4.7. 
Lower Extremity Function Scale (LEFS) 
111 
11.3.4.8. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
111 
11.3.4.9. 
Range of Motion (ROM) 
111 
11.3.4.10. EQ-5D (Quality of Life) 
112 
11.3.4.11. Burn Specific Health Scale – Brief (BSHS-B) 
112 
11.3.5. 
Exploratory Analyses 
112 
11.3.5.1. 
POSAS 
112 
11.3.5.1. 
MVSS (target wounds) 
113 
11.3.5.2. 
MVSS (donor site scars) 
113 
11.3.6. 
Pharmacokinetic Variables 
113 
11.3.7. 
Multicenter Data 
113 
11.3.8. 
Handling of Multiple Comparisons 
113 
11.3.9. 
Interim analysis 
113 
11.3.10. Stratification 
113 
11.3.11. Analysis of Subgroups 
114 
11.3.11.1. Total TBSA ≤ 15% 
114 
11.3.11.2. Total TBSA > 15% 
114 
11.3.11.3. All target wounds full thickness 
114 
11.3.11.4. Mixed target wounds – full thickness and deep partial thickness 
114 
11.3.11.5. All target wounds are deep partial thickness 
114 


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12. 
Reference List 
115 
13. 
Appendices 
118 
13.1. 
Definitions 
118 
13.1.1. 
General Definitions 
118 
13.1.2. 
Levels of Sedation 
118 
13.2. 
Lay-out and list of tables 
121 
13.3. 
Lay-out and list of figures 
128 
13.4. 
Lay-out and content of individual patient data listings (case wise listing) 
130 
13.4.1. 
List of AEs and SAEs 
131 
13.5. 
Details of the Amendments 
132 
13.5.1. 
Summary of Amendment of version 8 to version 9 
132 
13.5.1. 
Summary of Amendment of version 9 to version 11 
133 
 


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2. Introduction 
2.1. Background 
Optimal treatment of burn injuries requires understanding of and response to the profound 
local and systemic reactions following thermal injury.  
The treatment strategy should be planned and executed on the basis of a timely (early) 
assessment of the extent of tissue damage and remaining viable tissue available for the 
healing process. Only when the eschar is removed and the wound bed revealed, can the true 
damage be observed and assessed, and the appropriate wound closure modality prescribed 
[1] [2] [3]. 
As soon as the burn eschar is formed, it induces, within hours, a cascade of local and systemic 
pathologic changes. Dead eschar becomes heavily contaminated in two to three days, creating 
a source for local and systemic infection and sepsis [1] [4] [5] [2] [6]. Local inflammatory 
responses may lead to additional destruction of healthy surrounding tissue, extending the 
original damage. If not otherwise removed, inflammatory and autolytic processes slowly 
decompose and destroy the eschar, which will slough in approximately two weeks. The long 
inflammation based spontaneous sloughing period allows the simultaneous formation of 
advanced granulation tissue, later evolving into a heavy and deforming scar.  
Delaying the removal of the eschar increases the incidence and severity of systemic and local 
complications, especially in more extensive burns [1] [2] [4] [5] [6] [7] [8] [9] [10]. The 
decomposing eschar is a source of strong local and (if the burn is extensive) systemic 
mediators that induce inflammatory reaction and that may cause burn wound progression into 
potentially viable tissue [2] [5] [7] [9] [11]. 
Moreover, the eschar is non-resilient and forms a cocoon-like constricting shell around circular 
body parts. With increasing tissue edema, this increases the interstitial/compartment pressure, 
seriously compromising the viability of the still barely surviving skin by stretching it and 
compressing blood supply to other vital structures. An early diagnosis and response to these 
events releasing surgical escharotomy, is important and should be executed emergently. In 
this case too, delay in diagnosis and reluctance to perform surgical escharotomy may delay 


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this procedure especially in cases where experienced burn surgeons are not readily and 
immediately available [4] [12].  
To prevent eschar-related complications and to initiate the healing process, it is imperative to 
remove all of the offending eschar at the earliest possible opportunity. Eschar removal, 
“Debridement”, is the first stage of the comprehensive wound care process. There is no benefit 
in the presence of the eschar on the burn. Thus, the decision is not whether or not to remove 
an eschar but when and how. Therefore, delay or avoidance of eschar removal should have a 
specific reason.  
Estimation of burn size and depth is essential for a diagnosis-based treatment strategy, but 
cannot be accurately performed in most instances unless and until the opaque eschar has 
been completely removed.  
Immediate (within 24 hours post-burn) eschar removal may improve the potential for survival 
of the Zone of Stasis, reverse the Zone of Hyperemia and may attenuate, or avoid many of the 
systemic reactions [1] [9] [5] [2] [6] [13]. Delayed eschar removal (within the first three days) 
may not provide all the benefits of immunological and inflammatory modulation, but will reduce 
the burn bacterial load and its outcomes [4] [12] [14] [15]. Delaying eschar removal up to the 
seventh day will forfeit the local and systemic benefits, but may still prevent healing by 
secondary intention potentiating better long-term results (especially in terms of scarring) [2] [5] 
[6] [16].  
In current standard of care, removal of the eschar may be accomplished by surgery. Usually 
with tangential excision followed by split thickness autografting (TE&STSG) of the acute 
exposed debrided wound, or by non-surgical topical care that includes daily dressing changes, 
bathing, scraping, wet to dry dressing, macerating activity of bacteria, etc., until the eschar 
sloughs, leaving a clean wound bed for subsequent non-surgical or surgical wound closure 
treatment. This combination of debridement followed by surgical or non-surgical wound closure 
treatment is the basis of all burn wound care modalities.  
The choice of debridement method (non-surgical or surgical) depends on many variables such 
as the burn depth, anatomical site and size (expressed as % TBSA of the burn wound), the 
patient’s general condition, available donor site for autograft harvesting as well as the 
availability of surgical facilities and staff. Tangential excision should be carried down into the 
healthy intact tissue to make sure that no trace of the eschar remains. It is estimated that up 


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to 30–50% of healthy tissue (mainly dermis), which is essential for the spontaneous 
epithelialization potential of the wound, may be sacrificed in this procedure, thus usually 
necessitating autografting. These surgical procedures are traumatic, often long and difficult, 
require skilled personnel and sophisticated medical resources and are usually accompanied 
by bleeding [1] [2] [12] [16] [17] and heat loss [18]. The surgically excised raw wound bed 
should be covered immediately, i.e., in most cases autografted. Thus, the excision is followed 
by harvesting of autografts from intact, non-injured skin areas, skin graft transplantation, and 
care of the donor sites in addition to the original burn injury. These surgical procedures are 
performed under general anesthesia that requires pre- and post-surgical fasting and recovery. 
In most centers, caution and post surgery intensive care dictate that only a limited percentage 
of the affected areas (~15%TBSA) will be surgically debrided at one time in order to limit 
inflicting excessive stress on the patient. Thus, the decision to surgically debride a burn is not 
taken lightly. Reluctance, hesitation and doubts due to uncertain diagnosis delay the decision 
to perform surgery, extending the time to start and finish of the debridement from the optimal 
few hours to several days.  
In partial, mixed thickness, and intermediate depth wounds, and with difficult to diagnose depth 
“indeterminate” wounds, early surgical debridement will usually be avoided and a more 
conservative debridement approach using topical medications will be pursued. Such 
conservative non-surgical debridement lasts for days until the eschar decomposes or until a 
decision is taken to excise the offending, remaining eschar. The non-surgical debridement 
process involves the combined activity of topical medications, contaminant microorganisms, 
autolytic tissue processes and the inflammatory process with frequent dressing changes, 
showering, mechanical scraping of loose debris etc. The infectious-inflammatory processes 
are slow (lasting between 10-14 days) and may involve significant systemic and local 
complications. Using topical anti-bacterial or anti-inflammatory medicaments may reduce the 
infectious-inflammatory processes but will also delay eschar separation (sloughing). Locally, 
all these processes prolong the removal of the eschar and lead to additional tissue damage 
due to the death of the Zones of Stasis and Hyperemia which deepen, transforming partial 
thickness damage into a full thickness injury. The long debridement time with sustained 
inflammatory processes can lead to the formation of granulation tissue that will develop into 
heavy scars.  


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This excerpt of literature emphasizes that timely eschar removal is, for the last 40 years, the 
goal of burn wound care initiation. Physicians today are forced to choose between or combine 
two sub optimal alternatives of eschar removal; (i) the fast and efficient surgery (TE&STSG) 
with its diagnosis-dependent often prolonged initiation, non-selective, traumatic and 
demanding results or (ii) the inefficient non-surgical prolonged debridement means with their 
associated sequelae. The lack of fast and effective non-surgical eschar removal means has 
left surgery as the available SOC for deep burns.  
An optimal treatment solution would be a non-surgical, selective means for removing 
exclusively the eschar without harming the non-injured tissues immediately or nearly 
immediately after patients’ admission and stabilization, independently of the burn depth 
diagnosis. Such early removal of the eschar will enable the physician accurate visual diagnosis 
of the exposed burn wound bed. The clean exposed bed can be treated by the most 
appropriate wound closure strategies tailored for each patient and wound area in order to 
achieve optimal long-term results with minimal trauma and cost to the patient.  
The development of NexoBrid as a product for enzymatic debridement of burns started several 
decades ago. 
The safety and efficacy of NexoBrid (for burn eschar debridement) has been extensively 
investigated in 7 clinical studies [19], including a phase 3 pivotal trial (MW 2004-11-02) [20]. 
Efficacy data generated during NexoBrid clinical program demonstrated the following direct 
beneficial effects of removal of burn eschar by NexoBrid: 
1. Effective eschar removal by NexoBrid: NexoBrid removes the necrotic tissue without 
surgery, which is an imperative first step in burn care. Non-surgical effective 
debridement facilitates debridement in children, aged and of difficult skin areas (hands, 
feet, joints etc.) 
2. Selective eschar removal: NexoBrid removes the eschar in a minimally invasive 
manner that leaves the surrounding uninjured and viable tissues unharmed and thus 
allows maximization of spontaneous healing and reduces the incidence and extent of 
skin grafting [21]. 
3. Early and fast debridement: NexoBrid allows earlier initiation and successful 
completion of the eschar removal process compared to SOC, enabling preservation of 
the underlying tissue from secondary ischemia, and allowing the healthcare provider to 


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directly visually assess the burn wound bed earlier to prescribe proper subsequent 
treatment. 
4. Avoiding escharotomy surgery and its sequelae: Early application of NexoBrid may 
reduce the elevated interstitial pressure in circumferential burns and alleviate burn-
induced compartment syndrome, thus reducing the need for eschar incision. 
Indirect beneficial effects: 
1. Reduction of incidence and extent of surgery (excision and grafting) by NexoBrid 
eschar removal treatment.  
2. Autografting can be reduced by selective debridement with increased preservation of 
uninjured dermis and potential for spontaneous epithelialization. In choosing the 
approach of epithelialization over preserved dermis, autografting is reserved to close 
full thickness wounds. In addition to the benefit of reduced surgery, decreased 
autografting reduces sacrifice of the subject’s healthy uninjured skin and accompanying 
morbidity.  
3. Blood loss is minimized by reduced excisional and autografting surgery. 
2.2. Study Objective 
1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
complete eschar removal as compared with Gel Vehicle,  
2. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing earlier 
complete eschar removal, reduction in patients’ surgical burden and its related blood loss as 
compared to SOC,  
3. To assess the safety of NexoBrid compared to SOC, including demonstration that treatment 
with NexoBrid does not cause an unacceptable level of harm on wound closure outcome and 
long-term outcomes of cosmesis and function  
2.3. References to Study Protocol 
This Statistical Analysis plan refers to the study protocol version 11 of 23 June 2016. The trial 
protocol code is MW2010-03-02. 


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2.4. Amendments 
The study was initiated under the trial protocol version 08. Since then, there have been two 
amendments (to version 9 and version 11). Details of the Amendments are provided in 
Appendix 13.5. 


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3. Study Administrative Structure 
3.1. Sponsor 
Sponsor: 
MediWound, Ltd 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Represented by: 
Prof. Lior Rosenberg 
Chief Medical Officer 
MediWound Ltd. 
 
 
Keren David Zarbiv 
Director Clinical Affairs 
MediWound Ltd. 
 
 
Nimrod Leuw 
Director of QA/QC 
MediWound Ltd. 
3.2. Study Conduct 
Study Conduct (CRO): 
Dr. Marco Schwarzer 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen 
 
 


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3.3. Statistics 
Statisticians: 
Prof. Dr. Dr. h.c. Jürgen Timm 
Dr. Martin Scharpenberg 
Competence Center for Clinical Trials Bremen 
University of Bremen 
Linzer Str. 4 
28359 Bremen 
Germany 




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5. List of Abbreviations 
abbreviation 
meaning 
ABA 
American Burn Association 
ABL 
Actual Blood loss 
AE 
Adverse Event 
AFT 
Accelerated Failure Time 
ATC 
Anatomical Therapeutical Chemical Classification 
BICS 
Burn-induced Compartment Syndrome 
BMI 
Body Mass Index 
BSHS-B 
Burn Specific Health Scale - Brief 
CS 
Clinically Significant 
DDD 
Defined Daily Dose 
DPT 
Deep Partial Thickness 
DSMB 
Data Safety Monitoring Board 
EAP 
Efficacy Assessment Period 
EAR 
Extremities at Risk 
EBV 
Estimated Blood Volume 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
ER 
Eschar Removal 
FAS 
Full Analysis Set 
FDA 
Food and Drug Agency 
FT 
Full Thickness 


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abbreviation 
meaning 
FU 
Follow up 
Hb 
Hemoglobin 
HD 
Hospital Discharge 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
INR 
International Normalized Ratio 
ITT 
Intention to Treat 
KKSB 
Competence Center for Clinical Trials Bremen 
LEFS 
Lower Extremity Function Scale 
LOCF 
Last Observation Carried Forward 
LTFU24 
24 months Long-Term follow up period 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MVSS 
Modified Vancouver Scar Scale 
NCS 
Not Clinically Significant 
PDF 
Portable Document Format 
POSAS 
Patient Observer Scar Assessment Scale 
PP 
Per Protocol 
PRBC 
Packed Red Blood Cells 
PTT 
Prothrombin Time 


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abbreviation 
meaning 
ROM 
Range of Motion 
RTF 
Rich Text Format 
SAE  
Serious Adverse Event 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
SPT 
Superficial Partial Thickness 
SSD 
Silver Sulphadiazine 
STFU12 
12 months Short-Term Follow up period 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBSA 
Total Body Surface Area 
TW 
Target Wound 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell (Count) 
 
 


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6. General Definitions 
6.1. Hardware and software used 
The statistical analysis will be performed using SAS® version 9.4. The statistical report will be 
created with Microsoft Office running on hardware of Competence Center for Clinical Trials 
Bremen (KKSB). 
6.2. Reporting standards and language 
The language of the statistical report is English. This statistical analysis report is written as 
specified in the standard operating procedure (SOP) SR01 StatisticalReport of the KKSB and 
in accordance with the ICH E3 guideline (structure and content of clinical study reports). 
6.3. General format and content of tables, figures and patient data 
listings. 
Tables, figures and listings of subjects will be created in SAS® version 9.4 and be converted 
in rich text format (RTF) or portable document format (PDF). Appendix 13 contains a detailed 
description of contents and layout of the result representation. 
6.4. Quality control 
The statistical analysis plan follows the SOPs ST01 to ST06 of the KKSB. The statistical 
analysis must follow the statistical analysis plan. 
The implementation of the analysis for the primary endpoint, the secondary endpoints, the 
safety endpoint “time to wound closure” as well as the 12 months and 24 months MVSS 
assessment will be repeated by a second statistician independent from the implementation of 
the main statistician. Possible differences will be discussed together with the quality control 
and the responsible statistician (see Section 3.3). 


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7. Details of Trial Design 
7.1. General Information of Trial Design 
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. 
One hundred and seventy five subjects (175 subjects) are planned to be randomized to the 
study in a 3:3:1 ratio (NexoBrid: SOC: Gel Vehicle). The study will be conducted at sites in the 
US and out of the US.  
Following the enrollment of a patient to the study and prior to randomization, physicians will 
identify one or more TWs per patient according to the TW definitions described in Section 1.1 
of the protocol. 
All subjects’ DPT and FT burns that comply with the specified entrance criteria under Section 
7.1.3 are intended to receive study treatment per the randomized study arm and therefore, 
must be designated as TWs. This will further allow an evaluation of the subject systemic safety 
by allowing treatment of the subject’s entire deep burns as per the randomized study arm. After 
reviewing the entrance criteria, prior to randomization, eligible subjects will be stratified into 
different groups in order to standardize and minimize bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the patient total burn area 
and its depth. Please refer to Section 13.7.1 of the protocol for full description of the 
randomization procedure. 
Following the stratification, patients will be randomized as per their stratification group (see 
Section 11.1.10) 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 (please refer to Appendix 2- Pain Management Procedures of the protocol) and 
undergo wound cleansing and dressing of all wounds with antibacterial solutions (as specified 


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in Section 8.1 of the protocol). Following wound cleansing and antibacterial treatments, 
subjects will undergo the eschar removal process as per treatment assignment (NexoBrid, 
SOC or Gel Vehicle, following randomization) as further described in APPENDIX 16- Treatment 
Diagram of the protocol. 
Subsequent to complete eschar removal, all wounds will be assessed and treated 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 complete wounds and donor sites closure. Following 
wound closure confirmation visit, subjects will be followed up at 1, 3, 6, 12, 18 and 24 months 
post last wound closure confirmation for long-term outcomes evaluation. 
7.1.1. 
Study medication 
7.1.1.1. 
Topical arms 
7.1.1.1.1. NexoBrid 
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel 
for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the 
active component. Following mixing of the powder with the gel vehicle, each gram of the 
prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a 
mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).  
7.1.1.1.2. Gel Vehicle 
The same Gel Vehicle used in the preparation of NexoBrid will be used as negative control. 
7.1.1.2. 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  
Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excisions. 
Non-surgical procedures will include the application of collagenase ointment (e.g. Santyl), 
antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 


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The need of either non-surgical or surgical procedures will be determined by the burn 
specialists and can be repeated as needed until complete debridement is achieved. 
7.1.2. 
Intended dosage and duration of treatment 
7.1.2.1. 
NexoBrid 
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of 
sterile Gel Vehicle (ratio of 1:10), respectively to obtain sterile NexoBrid Gel. NexoBrid Gel is 
applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile Gel 
Vehicle per 1% of TBSA (~ surface of an adult palm) for four hours (or 5 g NexoBrid sterile 
powder mixed with 50g sterile Gel Vehicle per 2.5% of TBSA). The NexoBrid powder and the 
Gel Vehicle are to be mixed at the patient bedside ≤ 15 min prior to use.  
NexoBrid should not be applied to more than 15% TBSA in one session.  
NexoBrid may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. NexoBrid may only be applied twice to the same burn 
wound area. 
7.1.2.2. 
Gel Vehicle 
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn skin. Gel 
Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel per 1% of TBSA (~ 
surface of an adult palm) or 50 grams per 2.5% TBSA for four hours.  
Gel Vehicle should not be applied to more than 15% TBSA in one session.  
Gel Vehicle may be applied for a second time to the same burn area, if eschar removal from 
the target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. The Gel Vehicle may only be applied twice to the same 
burn wound area. 
7.1.2.3. 
Standard of Care 
No more information on intended dosage or duration of treatment was specified in the protocol 
for the Standard of Care arm than that already given in Section 7.1.1.2.  


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7.1.3. 
Study population and choice of study invitee 
7.1.3.1. 
Inclusion Criteria - Patient level 
1. Males and females; ≥ 18 years of age,  
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.  
7.1.3.2. 
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 include face, perineal or genital),1  
All planned target wounds (TWs) should meet the following criteria:  
2. SPT areas 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.  
7.1.3.3. 
Exclusion Criteria - Patient level 
1. Patients who are unable to follow study procedures and follow up period,  
2. Modified Baux index2 ≥ 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) as described in section 11.8 of the protocol,  
                                               
1 All these wounds which are in line with this criteria should be defined as target wounds (TWs) and 
treated per randomization   
2 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and 
the presence of smoke inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 


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7. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3),  
8. Patients with pre-enrollment wounds which are covered by eschar heavily saturated 
with iodine or by SSD pseudoeschar (e.g. pseudoeschar as a result of >12 h 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 burns area of up to 15% TBSA or BMI 
greater than 34.0 kg/m2 in patients with burns area of more than 15% %TBSA,  
15. ASA greater than 2 (Appendix 13- ASA classification system of study protocol),  
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, severe edema and/or lymphedema, regional lymph nodes dissection, 
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 Enrollment in 
any investigational drug trial within 4 weeks prior to screening,  
23. Current (within 12 months prior to screening) severe alcohol or drug use disorder (see 
definition in section 1.1 of study protocol),  


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24. Prisoners and incarcerated,  
25. Patients who might depend on the clinical study site or investigator.  
7.1.4. 
Drop-out criteria 
After screening and prior to treatment any changes in the patient's medical condition should 
be assessed. The patient should be excluded from treatment if these changes represent 
deterioration in his/her condition which may affect the patient's safety and/or suitability for the 
study (e.g. exclusion criteria).  
Throughout the course of a subject's participation in the study, he/she may be removed from 
the study as follows:  
· 
Whenever it is necessary to safeguard his/her welfare as judged by the Principle 
Investigator,  
· 
Participation in another investigational drug trial,  
· 
Subjects who express a desire to withdraw from the study,  
· 
Subjects with EAR identified post randomization but prior to treatment.  
The reason for any subject withdrawal from the study should be recorded in the eCRFs and 
the occurrence should be reported to the sponsor. Early termination visit should include final 
assessments as in the Hospital Discharge visit, as applicable (please refer to Section 8.7 of 
the study protocol).  
Discontinued subjects will not be replaced.  
When a subject is removed from the study treatment, he/she will receive treatment according 
to the standard of care as appropriate in the investigative site and will be followed up according 
to the study schedule, in accordance with patient’s availability. 
7.1.4.1. 
Stopping rules (apply for NexoBrid or Gel Vehicle arms only) 
Treatment (eschar removal) should be stopped following a safety concerns raised by the 
treating physician or if a patient expresses his desire to withdraw from the study. In addition, 
in the following situations: 


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Burn Induced Compartment Syndrome (BICS) Monitoring and Diagnosis 
All circumferential wounds should be closely monitored during treatment for signs of 
improvement or deterioration that may require escharotomy. If clinical assessment and SpO2 
monitoring are possible, they will be done continuously and recorded in the eCRFs every 2 
hours. If such assessment is not practical, direct pressure will be measured every 2 hours from 
start of the eschar removal. The eschar removal process shall be discontinued (escharotomy 
may be performed at the discretion of the physician in any of the following cases: 
· 
Increasing interstitial/compartment pressure >30 mmHg  
· 
Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity  
· 
Decreased SpO2 reading during treatment with difference of >6% compared to a non 
injured extremity or deterioration of clinical signs  
· 
Deterioration of any of the 5 “P” signs: Pain, Paralysis, Pulselessness, Pallor, 
Paraesthesia  
Since in such cases the eschar removal procedure will not be completed as planned, such 
patients (if any) will still be part of the full analysis set (FAS, see Definition in Appendix 13.1.1) 
and any missing data usually collected during eschar removal (e.g. time to end of eschar 
removal, etc.) will be handled as missing data according to the protocol.  
In case of 3 consecutive cases where there is a need to disrupt the dressing and perform a 
surgical escharotomy, enrollment will be halted and a DSMB shall be convened to:  
· 
assess the severity of the phenomenon in a closed session  
· 
Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences  
As discussed above, increased interstitial/compartment pressure is a common medical 
condition in circumferential deep burns and its detection and resolution is part of daily standard 
of care. The only difference in the treatment of the patients in the study is during the eschar 
removal stage as dictated by randomization. 
Coagulopathy during or within 24 hours of eschar removal 
It is evident that during the first 48 hours post injury there is deterioration in coagulation 
parameters in burn patients [22]. In addition, some burn patients are treated with 


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anticoagulants after admission (in some burn centers all patients are treated with 
anticoagulants). Due to these facts, any stopping rule concerning coagulopathy after topical 
debriding agent application must take these factors into consideration.  
Enrollment will be halted and a DSMB will convene if 3 subjects develop the following signs 
which have been defined as life threatening coagulopathy in trauma patients:  
INR>2 or a PTT>2 times the normal range [23], in cases where the patient is not receiving 
anticoagulants that can explain the coagulopathy.  
A DSMB shall be convened to assess in a closed session the following:  
· 
The relationship between coagulopathy and the treatment arm  
· 
The severity of the phenomenon  
· 
Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences  
DSMB investigation will consider patients’ medical history, including any anticoagulants given 
to the patient prior to start of treatment. 
Post treatment diagnosed infection (until complete wound closure) 
Following the eschar removal treatment, in case 3 subjects develop infections listed in Section 
11.9 of the study protocol and are assessed as related to the treatment arm (possibly, probably 
or related as defined in section 12.1 of the study protocol), enrollment will be halted and a 
DSMB will convene in close session to investigate cases reported and their relatedness and 
severity.  
In all the above 3 described cases, enrollment may continue in accordance with DSMB 
conclusions. 
7.1.5. 
Concomitant medication and treatment 
Concomitant medications will be recorded throughout the study, starting from signing on ICF 
and will include those prescribed for common burn management practice. Any record should 
include dose, frequency, route, start and stop date and indication.  


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Unit of blood transfused (whole blood or blood packed cells) with the appropriate volume will 
be captured for the entire patient’s duration in the study and recorded in the concomitant 
medications form. Any analgesia and anesthesia administered per subject will be recorded in 
the eCRFs. Incidence & number of procedures for wound care requiring anesthesia will be 
analyzed. 
7.2. Trial schedule 
The healing and care of the burn wound may be divided into the three distinctive phases:  
1. Eschar removal treatment phase (until complete eschar removal)  
2. Wound management (until complete wound closure)  
3. Scar modulation and maturation  
These phases are common to the care of all wounds and are well defined in acute wounds 
such as burns.  
In this study, these phases and their treatment strategy are equal for all arms, NexoBrid, SOC, 
and Gel Vehicle, following the ABA white paper recommendations [24]. 
The total duration of the study treatment and follow up period of each participating subject is 
expected to be 25 months: following the Eschar removal procedure, each subject will be 
followed up weekly (Weeks 1, 2, 3 and 4 etc.) until complete wound closure is achieved and 2 
weeks later for wound closure confirmation, for each of the subject's TWs. Long-term follow-
up visits will be performed at 1, 3, 6, 12, 18 and 24 months post last wound closure confirmation 
visit (for details see Table 1). 
 


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Table 1: Treatment flow chart - all arms3 
#- If applicable  
* Weekly FU assessments will be performed every 7± 2 days from start of treatment until complete wound closure. Long-term FU will be performed 1,3,6,12,18 and 24 M after 
last wound closure confirmation.  
**First treatment session will include any procedure for eschar removal: the NexoBrid/ /Gel Vehicle/Surgical or non-surgical procedure, as per randomization arm  
** Procedure can be either surgical or non-surgical. A whole period of continuous dressing changes (from first coverage application to last coverage application) is considered 
as one non-surgical procedure, assessments should not be repeated for each dressing change; Pre procedures assessments refer only to surgical procedures. Post procedures 
assessments refer to any surgical procedures and for non-surgical procedure only if it is the last procedure 
Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
Inform Consent signing 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Burn History5 
X 
 
 
 
 
 
 
 
 
ConMeds & AEs 
X 
X 
X 
X 
X 
 
X 
X 
X 
Physical examination6 
X 
 
 
 
 
 
X 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
Post S 
Post  
X 
 
 
 
 
Pain assessment 
X 
X 
4h post R  
Pre and 4h post  
X 
 
 
 
 
Photograph of TWs 
X7 
X 
Post S 
Pre & Post  
 
Pre & Post  
 
X 
X 
                                               
3 This table differs from the corresponding table in the protocol. Minor corrections were performed. 
4Wound Management will include any, post complete eschar removal additional excisions, Autografts, and donor site data if relevant. 
5 Data captured will include burn etiology, mechanism of injury, place of injury, treatments prior to admission and general description of the burn wound (anatomical locations 
and description of the eschar (such as: white, moist, dry, gray, charcoal, etc.), % TBSA assessments and depth 
6 Physical examination will include height and weight. Height will be taken only once, at screening. 
7 Photos should be taken after cleansing 


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Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
Clinical assessment of the 
burn8 
X 
X 
Post S 
Post  
 
Post  
 
X 
 
Local lab - HbA1C, WBC, 
βhCG 
X 
 
 
 
 
 
 
 
 
Central lab hematology/ 
biochemistry tests & 
Urinalysis 
 
X 
4 h Post R  
Pre & 4 h Post  
 
 
 
 
 
Central lab Hematology 
 
 
 
 
 
1h pre & 4 h post 
 
 
 
Cleansing including at 
least 2h soaking) 
X 
# 
 
 
 
 
 
 
 
Fluid balance9 
X 
X 
X 
X 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Local lab Wound culture 
 
X 
Post S 
Pre &Post  
 
 
 
 
 
Local lab Blood culture 
 
X 
4h Post R  
4 h Post 
 
 
 
 
 
12-Lead ECG (if feasible) 
 
60, 40, 20 
min pre 
treatment 
During: 0.5, 2,4h from 
start of first application 
only 
During: 0.5, 2, 4h  
from start of first 
treatment only 
12, 24, 48h 
 
 
week 1 
 
                                               
8Clinical assessments will include % TBSA per depth, % eschar removed, % excised, % autografted, % wound epithelialization (TW and donor site, if relevant), % graft take as 
relevant. 
9 Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, whichever comes first for patients with catheter.  


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Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
PK (for a subset of 32 
NexoBrid Pts) 
 
X 
During:0.5, 2, 4h from 
start of first application 
 
12,24,48, 72h 
 
 
 
 
Immunogenicity 
assessment 
(NexoBrid patients only) 
 
X 
 
 
 
 
 
weeks 
4,810 
Long-term FU:  
6, 24 
Local lab PTT & INR  
 
X 
4 h post R - first 
application only 
4 h post- first 
treatment only 
24,48h 
 
 
 
 
Circumferential extremity 
wounds monitoring11 
X 
X 
during and post R (4 
hours from start) 
1h pre & post  
 
 
 
 
 
Eschar Removal treatment 
 
 
X 
X 
 
 
 
 
 
Coverage 
 
 
 
Start and end date , 
type of primary 
dressing 
 
Type of primary 
dressing& 
frequency 
 
 
 
                                               
10 In case that 8 weekly visit is not performed, this assessment should be taken on the relevant weekly/first visit as close as possible to 8 weeks. 
11 The Extremities At Risk (EAR) burns prone to develop BICS will be identified at screening and excluded. Monitoring for the development of EAR in circumferential extremity 
wounds at the above specified timelines will be done. During each topical application (NexoBrid or gel Vehicle), clinical assessment and SpO2 monitoring will be done 
continuously. If such assessment is not practical, direct pressure will be measured every 2 hours from start of eschar removal. Direct pressure will be measured before and 
after each eschar removal procedure and additional surgical procedures  


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Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
Wound closure 
confirmation12 
 
 
 
 
 
 
 
X 
Long-term FU:  
1, 3 
Cosmesis, Function and 
Quality Of Life13 
 
 
 
 
 
 
 
 
X 
Scar-modulating 
procedures and scar 
 
 
 
 
 
# 
 
 
# 
Blood transfusion (units & 
volume) 
# 
# 
# 
# 
# 
# 
# 
# 
# 
Histological biopsy 
# 
# 
# 
# 
# 
 
# 
# 
# 
 
 
                                               
12 Wound closure should be confirmed 2weeks after the initial wound closure assessment for each TW. 
13Cosmesis will be evaluated in donor site scars as well 


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7.3. Criteria for evaluation 
7.3.1. 
Demographic data and other baseline characteristics 
The following demographic data will be documented at screening/baseline: 
· 
Date of birth 
· 
Gender 
· 
Ethnicity 
· 
Race 
· 
Serum Pregnancy Test (βHCG) 
Furthermore, at screening the inclusion and exclusion criteria will be collected. 
At baseline the following parameters will be documented. 
Burn history / description: 
· 
Date and time of injury 
· 
Etiology of injury (Fire/Flame, Scald, Contact) 
· 
Place of injury (Outdoors, Indoors, Car, Other) 
· 
Information whether patient was transferred from another facility 
· 
Date and time of primary admission 
· 
Date and time of current admission 
General wound description: 
· 
Wound number 
· 
Anatomical location 
· 
%TBSA of 2° SPT Burns 
· 
%TBSA of 2° DPT Burns 
· 
%TBSA of 3° FT Burns 
· 
Information whether the respective wound will be designated as TW 
· 
Information whether a wounded extremity is circumferential 
· 
Extremities at risk 


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· 
Information whether eschartomy had been performed prior to randomization 
· 
Eschar description 
· 
Information whether cleansing was performed 
· 
Information whether all superficial keratin (blister) were removed from wound 
Target wound identification: 
· 
Target wound number 
· 
Anatomical location 
· 
%TBSA of 2° SPT Burns 
· 
%TBSA of 2° DPT Burns 
· 
%TBSA of 3° FT Burns 
· 
Information whether the wound was treated prior to enrollment 
Information needed for randomization: 
· 
Total wounds TBSA % per patient 
· 
TWs DPT total area (% TBSA) 
· 
TWs FT total area (% TBSA) 
· 
Overall TWs depth per patient 
· 
Overall TW area (SPT + DPT + FT) 
· 
Randomization result (treatment) 
· 
Date of randomization 
Circumferential extremity wounds: 
· 
Information whether any treated TWs were circumferential extremity wounds 
· 
Target wound number 
· 
Information whether pressure measurement was done 
· 
Interstitial pressure (mmHg) 
· 
Date and time of measurement 
Physical examination: 
· 
Height (cm or inch) 
· 
Weight (kg or lb) 
· 
BMI 


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Furthermore, for each of the following body systems 4 categories are documented 
(normal, abnormal-NCS [not clinically significant], abnormal-CS [clinically significant], 
not done). In case of abnormal findings, they have to be documented. If abnormality is 
present for another body system, this has to be documented, too. Reasons for the 
category "not done" have to be documented. 
· 
Head, eyes, ears, nose and throat (HEENT) 
· 
Respiratory system 
· 
Cardiovascular system 
· 
Abdomen 
· 
Musculoskeletal / Extremities 
· 
Neurological 
· 
Lymph Nodes 
Vital signs: 
· 
Temperature (incl. unit and method of measurement) 
· 
Heart rate (beats/min) 
· 
Respiratory rate (breaths/min) 
· 
Systolic and diastolic blood pressure (mmHg) 
· 
Assessment of vital signs (normal, abnormal-NCS, abnormal-CS) 
Pain assessment: 
· 
Pain measured via visual analogue scale (VAS, mm from the left point of the scale) 
· 
Assessment of pain (normal, abnormal-NCS, abnormal-CS) 
Local laboratory: 
· 
Leukocyte count (WBC) 
· 
Assessment of leukocyte count (normal, abnormal-NCS, abnormal-CS) 
· 
Information whether patient is diabetic 
· 
HbA1c (%) 
Information on infections as well as the medical history will be recorded. 


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7.3.2. 
Efficacy evaluation 
7.3.2.1. 
Primary target variable 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to protocol Section 1.1 for target wound 
definition) in accordance with the study protocol:  
Incidence of complete eschar removal (see definition in Appendix 13.1.1) in the topical 
arms (NexoBrid and Gel Vehicle): Incidence of complete eschar removal (ER) will be based 
on the assessment of the blinded assessor at the end of the topical agent soaking period. In 
cases where 2 applications are performed, complete ER will be based on the assessment at 
the end of the topical agent soaking period following the 2nd application. 
7.3.2.2. 
Secondary target variables 
The following secondary endpoints will be evaluated in this study: 
Reduction in surgical needs 
Reduction of surgical need for excisional eschar removal is measured by an analysis of 
incidence of surgical eschar removal (tangential/ minor/ avulsion/ Versajet and/or 
dermabrasion excision). 
Earlier eschar removal 
The time when complete eschar removal has been achieved will be assessed for each patient 
on the entire eschar removal period. For definition of complete eschar removal, see Appendix 
13.1.1. 
Blood loss 
Blood loss incurred during the eschar removal procedures will be evaluated. Actual blood loss 
will be measured by considering the estimated blood loss, changes in Hemoglobin during the 
eschar removal procedures and the amount of units of blood transfused. Blood loss (Actual 
Blood Loss, ABL) will be calculated using the following formula [25]: 


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ܣܤܮൌܧܤܸכ ൫ܪܾ௕௘௙௢௥௘െܪܾ௔௙௧௘௥൯
൫ܪܾ௕௘௙௢௥௘൅ܪܾ௔௙௧௘௥൯ʹ
Τ
൅ܸௐ஻൅ͷ
͵ ܸ௉஼ 
EBV= Estimated blood volume is assumed 70 cm3/Kg  
(Hbbefore- Hbafter)= Changes in Hb following each eschar removal procedure  
VWB= Volume [mL] of whole blood transfused 
VPC= Volume [mL] of packed red blood cells transfused. 
The ABL will be summed over all procedures carried out to remove eschar, with the Hb 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during all debridement 
procedures and 4 hrs later i.e. the before-after periods that are spanned by these Hb 
measurements. 
Additionally, ABL will also be computed using the formula above, but over the whole eschar 
removal period (not procedure wise) i.e. the eschar removal process will be considered as one 
continuous procedure. Therefore, only the Hemoglobin value before the first eschar removal 
procedure and after the last procedure will be used and all blood transfusions performed 
between these measurements will be included. 
Analyses with both blood loss values will be conducted. However, some missing values are 
expected. The analysis with less missing values will be regarded as more reliable and is 
therefore considered the main analysis. The other analysis is considered supportive. 
7.3.3. 
Safety evaluation 
7.3.3.1. 
Time to complete wound closure 
Time to reach complete wound closure (definition see Appendix 13.1.1) as assessed by the 
blinded assessor and marked in the eCRFs will be assessed in days, starting from 
randomization date. 
7.3.3.2. 
Cosmesis and function at 12 months from wound closure confirmation 
Cosmesis and Function assessment will be performed based on the Modified Vancouver Scar 
Scale (MVSS) at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 


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burn wound specialist who is masked to randomized wound treatment and to the other 
outcome assessments of the same wound. Table 2 gives an overview of the MVSS. 
 


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Table 2: Modified Vancouver Scar Scale (MVSS) 
Pigmentation 
Pliability 
Height 
Vascularity 
Pain 
Pruritus 
(0) Normal 
(0) Normal 
(0) Flat 
(0) Normal 
(0) None 
(0) None 
(1) Hypopigmentation 
(1) Supple-flexible with minimal resistance 
(1) <2mm 
(1) Pink 
(1) Occasional 
(1) Occasional 
(2) Mixed 
(2) Yielding- giving way to pressure 
(2) 2-5 mm 
(2) Red 
(2) Requiring 
medication 
(2) Requiring 
medication 
(3) Hyperpigmentation 
(3) Firm- inflexible, not easily moved, 
resistance to manual pressure 
(3) >5mm 
(3) Purple 
 
 
 
(4) Banding-rope-like tissue that blanches 
with extension of the scar 
 
 
 
 
(5) Contracutre-perment shortening of scar, 
producing deformity or distortion  
 
 
 
 
 
 


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7.3.3.3. 
Cosmesis and function at 24 months from wound closure confirmation 
See section 7.3.3.2. 
7.3.3.4. 
Adverse Events 
For each AE the following information will be determined: 
· 
AE description 
· 
AE is an infection (yes, no, unknown) 
· 
onset date and time 
· 
outcome date and time 
· 
outcome (resolved, resolved with sequelae, not resolved, death) 
· 
intensity (mild, moderate, severe) 
· 
action taken regarding study drug (yes, no) 
· 
relation to study drug (not related, remotely related, possibly related, probably related, 
related) 
· 
treatment required (none, medication, surgery, hospitalization, other) 
· 
seriousness (serious, not serious) 
The following definitions to assess the relationship between an adverse event and the study 
drug is used: 
· 
Not Related: The event is clearly related to other factors such as a patient's clinical 
state, therapeutic interventions or concomitant medications.  
· 
Remotely Related: The event was most likely produced by other factors such as a 
patient's clinical state, therapeutic interventions or concomitant medications and does 
not follow a known response pattern to the study drug.  
· 
Possibly Related: The event has a reasonable temporal relationship to study Drug 
administration and follows a known response pattern to the study Drug. However, a 
potential alternate etiology may be responsible for the event. The effect of Drug 
withdrawal is unclear. Rechallenge information is unclear or lacking.  
· 
Probably Related: The event follows a reasonable temporal sequence from the time of 
Drug administration and follows a known response pattern to the study Drug and cannot 
be reasonably explained by other factors. There is a reasonable response to withdrawal 
of the Drug. Re-challenge information is not available or advisable.  
· 
Related: The event follows a temporal sequence from the time of Drug administration 
and follows a known response pattern to the study Drug and either occurs immediately 


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following study Drug administration, or improves on stopping the Drug, or reappears 
on repeat exposure. 
For the assessment of the intensity of the AE the following definitions should be used: 
· 
Mild Adverse Events: A mild adverse event is one that the symptoms are barely 
noticeable to a patient. It does not influence performance or prevent a patient from 
carrying on with normal life activities.  
· 
Moderate Adverse Events: A moderate adverse event is one that the symptoms make 
a patient uncomfortable and causes some impairment to normal life activities. 
Treatment for symptom(s) may be required.  
· 
Severe Adverse Events: A severe adverse event is one that the symptoms cause 
severe discomfort to a patient and severely limits the patient's normal daily activities. 
Treatment for symptom(s) is given. Note that serious and severe are not synonymous. 
A serious adverse event must fulfill the requirements listed in the definition below. 
A serious adverse event is an adverse event that is:  
· 
fatal 
· 
life-threatening  
· 
results in persistent or significant disability/incapacity  
· 
requires or prolongs inpatient unexpected hospitalization  
· 
is a congenital anomaly or birth defect or  
· 
is a medically important event. 
7.3.3.5. 
Laboratory assessments and vital signs 
The following tests described below are performed. Any abnormal findings must be assessed 
for clinical significance – Abnormal NCS or Abnormal CS:  
Serum chemistry, hematology and urinalysis testing will be performed at a central laboratory 
during the eschar removal phase. Any additional procedures during the wound management 
phase require hematology tests, as described in the protocol, and will be performed using 
Central lab. Pregnancy testing, HbA1c, leukocyte count (at Screening, in addition to central 
lab hematology), wound cultures, blood cultures, PTT/INR and biopsies will be performed 
locally on-site.  
The following tests are performed in special laboratories: Pharmacokinetics test, 
Immunogenicity evaluation and evaluation of QT prolongation (using multiple ECG tests).  
Serum Chemistry:  


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Urea, Creatinine, Glucose, Total Bilirubin, Cholesterol, Triglycerides, Uric Acid, Total Protein, 
Albumin, Globulin, Calcium (Ca++), Phosphorous, Sodium (Na+), Potassium (K+), Chloride 
(Cl-), Alkaline Phosphatase, SGOT (ASAT), SGPT (ALAT), LDH.  
Hematology:  
Hemoglobin, Hematocrit, RBC, MCV, MCH, MCHC, Platelets, Leukocyte count (WBC) with 
differential count (absolute numbers). 
HbA1c will be assessed at a local lab at Screening for diabetic patients as captured during the 
medical history.  
PTT and INR will be tested at a local lab pre treatment and 4 hours after start of eschar 
removal.  
Pregnancy Testing:  
A serum pregnancy (βHCG) will be performed at a local lab for women of child bearing 
potential.  
Urinalysis:  
pH, Ketone, Specific gravity, Protein, Glucose, Bilirubin, Microscopic examination.  
Qualitative Wound Culture:  
Test burn wound for microbial flora (swab).  
Blood Culture:  
Test blood for microbial flora.  
Diagnosis of Invasive Burn Wound Infection is based on Quantitative (Histological) Wound 
Culture Biopsy:  
Infection should be assessed clinically by symptoms and signs that include local burn wound 
signs purulent drainage, erythema, warmth, exudation, odor, pain, and systemic signs that may 
or may not be related to the burn wound, such as fever, and leukocytosis as well as wound 
size and time to wound healing. Histological Biopsy may be performed to rule out suspicion of 
a clinical invasive burn wound infection (please refer to Appendix 8- Biopsy & Histologic 
Assessment Method) [26].  
Clinical Invasive Burn Wound Infection will be defined when an Invasive Burn Wound Infection 
is diagnosed by quantitative bacterial count of >105 organisms per gram of tissue and 
histological signs of bacterial invasion of healthy tissues will define a positive invasive burn 


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wound infection. At least one of the following histological signs of invasive burn wound infection 
is required:  
· 
Microorganisms presence in viable unburned tissue  
· 
Small vessel thrombosis and ischemic necrosis of unburned tissue  
· 
Inflammation evident in unburned tissue  
· 
Hemorrhage in uninjured tissue  
· 
Evidence of microbial proliferation  
· 
Variable migration of microorganisms along hair follicle and sweat glands  
· 
Dense growth of nonviable-viable tissue interface (subeschar space)  
· 
Intracellular viral inclusion  
· 
Light microscopy  
· 
Type A Cowdry bodies: herpes simplex virus-1  
· 
Owl's eye inclusion bodies: cytomegalovirus  
· 
Electron microscopy  
· 
Intracellular virions  
Vital signs (temperature, pulse, blood pressure and respiration rate) will be completed 24 
hours prior to start of treatment and once daily from start of eschar removal until hospital 
discharge. 
7.3.3.6. 
Additional safety endpoints 
Additional safety endpoints to be evaluated in this study are: 
· 
pain assessment (using VAS and as reported as AEs) 
· 
units (and volume) of blood transfusion given during hospitalization 
· 
Immunogenicity evaluation for NexoBrid patients 
· 
Incidence of increased interstitial/compartment syndrome 
· 
Incidence of QT prolongation 
· 
Extent of analgesia, anaesthesia and antibiotic use 
· 
Rates 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) 
· 
Long-term functionality evaluation of the extremities using the ‘Lower Extremity 
Functional Scale’ 
· 
'QuickDASH' questionnaires 


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· 
'Range Of Motion' measurements 
· 
Long-term Quality of Life using EQ5D and Burn Specific Health Scale- Brief (BSHS-B) 
7.3.4. 
Exploratory analyses 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ minor/ 
avulsion/ Versajet and/or dermabrasion excision),  
2. Additional Cosmesis and Function evaluation will be performed using the Patient and 
Observer Scar Assessment Scale (POSAS) version 2.0 at 1, 3, 6, 12, 18 and 24 months 
after the wound closure confirmation visit by a burn wound specialist who is masked to 
randomized wound treatment and to the other outcome assessments of the same wound. 
POSAS version 2.0 was published in 2005 in Plast. Reconstr. Surg. 116: 514-522 by van 
de Kar et al. The POSAS consists of two parts: a Patient Scale and an Observer Scale. 
Both scales contain six items that are scored numerically and make up a ‘Total Score’ of 
the Patient and Observer Scale. The POSAS has been developed for all types of scars 
and has been tested in linear scars, burn scars and keloids and was found to be validated 
and reliable [27].  
Each item of both scales has a 10-point score, with 10 indicating the worst imaginable scar 
or sensation. The lowest score is ‘1’, and corresponds to the situation of normal skin 
(normal pigmentation, no itching etc). The score goes up to the worst imaginable. The Total 
Score can be simply calculated by summing up the scores of each of the six items. The 
Total Score will therefore range from 6 to 60 (observer and patient) and 12-120 in total. 
POSAS will be evaluated for all measurement times mentioned above,  
3. Additional Cosmesis and Function evaluation will be performed using the Modified 
Vancouver Scar Assessment Scale (MVSS) measurements obtained at 1, 3, 6 and 18 
months, 
4. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds,  
5. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal),  
6. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds,  
7. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds,  


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8. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures,  
9. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
10. PK evaluation for a subset of NexoBrid patients (as described in section 11.21 of the 
protocol)  
11. Autograft related parameters.  
11.1. 
Efficacy and safety analyses for early and late grafted wounds (for definition see 
Appendix 13.1.1) 
11.2. 
Total number of target wound grafting procedures  
11.3. 
Incidence of repeated/additional grafting procedures  
11.4. 
Area of repeat grafting  
12. Duration of hospitalization  


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8. Handling of protocol violations 
Before database lock and statistical analysis, possible protocol violations will be discussed by 
data management, sponsor, PI and his/her proxy and the statisticians and classified as minor 
or major violations. The list with all protocol violations will be prepared by the data 
management. 
A protocol violation will be classified as major if 
· 
the treatment differs from the planned treatment (randomization arm), or 
· 
the documentation of a primary observation was not done or is different from the study 
protocol: i.e. assessment was not done by a blinded assessor (assessment by blinded 
assessor from photos is acceptable), or 
· 
there was drug misuse (this may include application time deviated in 25% or more, 
deviation of more than 20% in the TBSA area treated in one session at a time, if 
relevant, error in drug preparation (e.g. 2g mixed in 50g), storage temperature below -
2°C - 8°C or >24h at room temperature and used without any stability confirmation by 
sponsor), or 
· 
the first blinded assessor was unblinded, or 
· 
treatment started more than 5 days from injury, or 
· 
one of the following inclusion criteria is violated: 
o Males and females; ≥ 18 years of age,  
o Thermal burns caused by fire/flame, scalds or contact,  
o Patient total burns area ≥ 3% DPT and / or FT,  
o Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or FT in depth,  
o Informed consent can be obtained within 84 hours of the burn injury 
o At least one wound (a continuous burn area) that is ≥0.5% TBSA (DPT and/or 
FT) (this minimal wound size should not include face, perineal or genital) 
o Wound’s blisters can be removed/unroofed, as judged by the investigator 
· 
one of the following exclusion criteria is met: 
o Patients with burned charred fingers, 3rd degree in depth and possibly devoid 
of circulation 
o Patients with abraded wound/s that cannot be treated by an enzymatic debrider 
application (NexoBrid) 
o Patients with electrical or chemical burns 
o The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate 
(AgNO3) 


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o 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 h SSD treatment), 
o Patients with pre-enrollment escharotomy 
o Enrollment in any investigational drug trial within 4 weeks prior to screening 
In all other cases protocol violations will be classified as minor. 
 


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9. Populations Analyzed 
The following sample size calculation is taken from the protocol. 
9.1. Sample Size 
The following sample size calculations are based on the consideration of the primary and two 
secondary endpoints for this study.  
Estimated effects of NexoBrid from study MW2004-11-02 were used to design the study with 
adequate statistical power using the following steps.  
(a) Sample size calculations were based on study MW2004-11-02;  
(b) The effect of NexoBrid versus standard of care was estimated together with the standard 
error of the estimate; the effect of NexoBrid versus gel was estimated based on study 
MW2002-04-01, previous phase II study, which included 35 patients treated with gel vehicle.  
The size of the effect to be detected in this study, MW2010-03-02, was taken as the previous 
estimate decreased by half its standard error, in order to use a conservative value. 
9.1.1. 
Primary Endpoint: Incidence of complete eschar removal 
(NexoBrid vs. Gel) 
Estimated proportion achieving complete eschar removal (for further definition and explanation 
see section 7.3.2.1) in all TWs from study MW2004-11-02 (analyzed as post hoc): NexoBrid 
0.595  
Standard error = 0.057  
Anticipated proportion achieving complete eschar removal using NexoBrid: 0.595-0.057/2 = 
0.5665  
Estimated proportion achieving complete eschar removal using Gel vehicle in a previous 
Phase II study, MW2002-04-01: 0 (0 out of 35 patients).  
Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. (0.0 is the 
point estimate; 0.10 is the 97.5 upper confidence limit).  
Because numbers of complete eschar removals are anticipated to be low in the gel group, we 
calculate sample size using Fisher’s exact test. We used the computer program nQuery 
Advisor version 7.0 to calculate power for a two-sided significance level of 5%, and thereby 


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found the following sample size combination that led to approximately 90% power for detecting 
a statistically significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).  
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle group 13. 
Total sample size = 78. 
9.2. Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.22; 
SOC 0.62  
Standard errors: NexoBrid 0.048; SOC 0.054  
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: NexoBrid 0.24 and 
SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a two-sided 
significance level of 5% is 86: 43 in the NexoBrid group and 43 in the SOC group. 
9.3. Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial yielded an estimated 
log hazard ratio of -1.37 (hazard ratio of 0.254) with a standard error of 0.28. 
Therefore, target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio = 0.29). 
The formula for the number of events (successful complete eschar removals) is: 
݀ൌ
Ͷ൫ݖఈ൅ݖఉ൯
ଶ
ሺ ܪܴሻଶ 
where zα = 1.96 two-sided significance level of 5%; and zβ = 1.28 for 90% power; For 90% 
overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required ݊ൌ
ଶௗ
௣భା௣మൌͶͶ (to the nearest even number), 22 in each of 
the NexoBrid and SOC groups. 


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9.3.1. 
Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 patients (65 
in the NexoBrid group, 13 in the Gel vehicle group and 43 in the SOC group (to match NexoBrid 
numbers)), we propose entering larger numbers to provide an extra margin of assurance in 
achieving positive results on the efficacy outcomes, and adequate information on safety 
outcomes to allow better benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 (NexoBrid) + 75 
(SOC) + 25 (Gel Vehicle). 
9.4. Safety Set 
The safety set includes all patients who received a treatment and analysis is focused on the 
treatment actually performed. 
9.5. Full analysis Set (Intent-to-Treat population) 
The full analysis set (FAS) includes all patients who are randomized into the trial. The analysis 
is focused on the planned treatment. 
9.6. Per Protocol Set 
The per protocol (PP) set includes all subjects who do not have major protocol violations (cf. 
section 8). Analysis of the PP population is for supportive purposes, whereas the analysis of 
the ITT population (FAS) provides the primary and secondary efficacy and the comparative 
safety analyses. The PP analysis will include patients in the treatment group according to 
treatment received. 
9.7. Enrolled population 
The enrolled population consists of all subjects who passed through the screening processes 
and signed inform consent. 


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10. Data Handling 
10.1. Handling of Missing Data, Outliers and Implausible Data 
Missing data in the primary and secondary outcomes is the main concern. 
10.1.1. Primary Endpoint: Incidence of complete eschar removal 
Little or no missing data are expected for the primary endpoint, since the outcome is assessed 
only several hours after the start of treatment for both NexoBrid and Gel Vehicle groups. The 
main analysis will be a complete-case analysis. In each treatment group, only patients with 
documented total eschar removal (at the end of the eschar removal soaking period) will be 
counted and this number divided by the total number of complete cases. 
Three sensitivity analyses will be conducted for this endpoint. A first analysis will count all 
patients with missing data (for this endpoint) as positive (i.e. complete eschar removal) and a 
second analysis will count all patients with missing data as negative (i.e. no complete eschar 
removal). The third sensitivity analysis will be a tipping point analysis, in which the effect of 
missing data on the conclusion will be investigated. This analysis will be conducted as follows: 
1. Impute the entries of the incomplete data sets m = 100 times from Bernoulli 
distributions. For the imputations of the Gel Vehicle group, the event probability ݌ is 
chosen as the observed incidence of complete eschar removal in the Gel group (without 
missing data). For the NexoBrid group the event probability will be ݌ൌ݌௢௕௦െݏ, where 
ݏ is a shift parameter (see below). The random seeds for the imputations will be 
14983,…,15082. 
2. For each of the 100 imputed data sets compute Fishers exact test and calculate the 
proportion of tests that reject the null-hypothesis. 
3. Repeat steps 1. and 2. for ݏൌͲǡ ͲǤͲͷǡ ǥ as long as ݌௢௕௦െݏ is still non-negative. 
The analysis outlined here allows investigating for which assumed success probability for the 
patients with missing data in the NexoBrid group, the conclusion of the analysis remains stable. 


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Secondary Endpoints 
10.1.1.1. 
Secondary Endpoint: Incidence of surgical excision 
The same procedure as for the primary endpoint will be applied for this endpoint, i.e. the main 
analysis will be a complete-case analysis. In each treatment group, only patients with 
documented surgical excision will be counted and this number divided by the total number of 
randomized subjects with non-missing endpoint. Two sensitivity analyses will be conducted for 
this endpoint. A first analysis will count all patients with missing data (for this endpoint) as 
positive (i.e. no surgical excision performed) and a second analysis will count all patients with 
missing data as negative (i.e. surgical excision performed). 
10.1.1.2. 
Secondary Endpoint: Time to complete eschar removal 
The analysis of the secondary endpoint time to eschar removal will compute missing values 
as censored at the date of the last non-missing eschar removal assessment (typically last 
debridement procedure). 
10.1.1.3. 
Secondary Endpoint: Blood loss 
Missing blood loss values for some eschar removal procedures may occur within a certain 
patient. A regression model containing main prognostic factors (wound area, depth of wound 
and type of procedure) for blood loss of eschar removal procedures will be computed on a 
procedure level treating all procedures as independent. On this basis a multiple imputation will 
be calculated. The procedure can be described as follows: 
1. Test for normality: The Shapiro-Wilk test will be performed on the dataset of non-
missing values in each treatment group. The result of these tests will determine the 
type of the analysis on the imputed data sets (step 3). If the normal distribution 
hypothesis is not rejected at the 5% significance level in either group, then differences 
in distribution between NexoBrid and SOC will be tested using a t-test. If the normal 
distribution hypothesis is rejected either in the NexoBrid group or in the SOC group, 
then the differences in distribution between the treatment groups will be tested using a 
Mann-Whitney test. 
2. Imputation: Fit a linear regression model with target variable blood loss on a procedure 
level (as computed in Section 10.3.3.3) and dependent variables size of wounds 
treated in this procedure (wound area), proportion of area SPT of wounds treated in 
this procedure (as defined in Section 10.3.3.3.2), proportion of area DPT of wounds 
treated in this procedure (as defined in Section 10.3.3.3.3), proportion of area FT of 
wounds treated in this procedure (as defined in Section 10.3.3.3.4) and type of 


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procedure (surgical/non-surgical) to the subset containing patients with complete data 
in those variables for both treatment groups separately. Impute the missing entries of 
the incomplete data sets m = 25 times as follows: Draw a set of regression coefficient 
from their sampling distribution obtained from fitting the respective linear models 
outlined above (a different distribution for the regression coefficients will be obtained in 
the different treatment groups). With these sampled coefficients calculate the predicted 
blood loss values for the procedures with missing blood loss using the covariate 
information. To these predicted blood loss values add the realizations of a normally 
distributed random variable with zero mean and standard deviation equal to the 
residual standard deviation from the linear model fitted to the complete data set. The 
random seeds for these 25 imputations will be (11468, 11469, 11470, ..., 11492). On 
the imputed datasets calculate the blood loss on a patient level. 
3. Analysis: Analyze each of the m complete data sets with a t-test or the Mann-Whitney 
test according to the test result in step 1. This step results in m estimates of the effect 
and m estimates of the standard deviation.  
4. Pooling: Integrate the m analysis results into a final result with the SAS procedure 
PROC MIANALYZE according to Rubin’s combination rules for multiple imputation to 
obtain the final estimates of mean and variance [28]. 
For the additional analysis of blood loss which treats the whole eschar removal process as 
one continuous procedure (see section 7.3.2.2) the multiple imputation will be performed 
on a patient level. The procedure can be described as follows: 
1. Test for normality: The Shapiro-Wilk test will be performed on the dataset of non-
missing values in each treatment group. The result of these tests will determine the 
type of the analysis on the imputed data sets (step 3.). If the normal distribution 
hypothesis is not rejected at the 5% significance level in either group, then 
differences in distribution between NexoBrid and SOC will be tested using a t-test. 
If the normal distribution hypothesis is rejected either in the NexoBrid group or in 
the SOC group, then the differences in distribution between the treatment groups 
will be tested using a Mann-Whitney test. 
2. Imputation: Fit a linear regression model with target variable blood loss on a patient 
level (as computed in Section 10.3.3.3) and dependent variables wound area, depth 
of wound (categorized as described in Section 11.1.10) and course of debridement 
procedure (as defined in Section 10.3.3.3.5) to the subset containing patients with 
complete data in those variables for both treatment groups separately. Impute the 
missing entries of the incomplete data sets m = 25 times as follows: Draw a set of 


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regression coefficient from their sampling distribution obtained from fitting the 
respective linear models outlined above (a different distribution for the regression 
coefficients will be obtained in the different treatment groups). With these sampled 
coefficients calculate the predicted blood loss values for the procedures with 
missing blood loss using the covariate information. To this predicted blood loss 
values add the realization of a normally distributed random variable with zero mean 
and standard deviation equal to the residual standard deviation from the linear 
model fitted to the complete data set. The random seeds for these 25 imputations 
will be (12467, 12468, 12469, ..., 12491). On the imputed datasets calculate the 
blood loss on a patient level. 
3. Analysis: Analyze each of the m complete data sets with a t-test or the Mann-
Whitney test according to the test result in step 1. This step results in m estimates 
of the effect and m estimates of the standard deviation.  
4. Pooling: Integrate the m analysis results into a final result with the SAS procedure 
PROC MIANALYZE according to Rubin’s combination rules for multiple imputation 
to obtain the final estimates of mean and variance [28]. 
10.1.2. Safety Endpoints 
10.1.2.1. 
Safety Endpoint: Time to reach complete wound closure 
The analysis of the safety endpoint time to complete wound closure will compute missing 
values as censored at the date of the last non-missing wound closure assessment. 
10.1.2.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
A higher ratio of missing values is expected in the case of later MVSS values, especially for 
24 months. It is expected that the 1 months MVSS value exists. If this is not the case the 
missing MVSS value will be replaced by the mean MVSS value of all patients who belong to 
the same treatment group and the same stratum (see Section 11.1.10) at that time point. For 
missing MVSS values at later time points (3, 6, 12, 18 and 24 months) the following imputation 
method will be used: 
For each time point (1, 3, 6 and 12 months) and each treatment arm separately, a linear 
regression model with target variable MVSS at 12 months and explanatory variables MVSS at 
the respective time point and all stratification variables (see Section 11.1.10) is fitted to the 
data of patients having both MVSS values. Missing MVSS values at 12 months are then 


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imputed with the prediction of the linear regression model, which has the last non-missing 
MVSS value before the 12 months measurement for the individual as explanatory variable (i.e. 
for patients who have the 6 months MVSS measurement but not the 12 months measurement, 
the 12 months measurement is imputed from the 6 months measurements; for those who have 
the 3 months measurement but not the 6 months or 12 months measurement the 12 months 
measurement is imputed from the 3 months measurement; and for those who have the MVSS 
measurement at 1 month but not at 3 months, 6 months or 12 months the 12 months 
measurement will be imputed from the 1 month measurement). To this prediction, the 
realization of a normally distributed random variable with zero mean and standard deviation 
equal to the residual standard deviation from the linear model is added. The random seed for 
this imputation is 45318. 
Similarly, for each time point (1, 3, 6, 12 and 18 months) and each treatment arm separately, 
a linear regression model with target variable MVSS at 24 months and explanatory variables 
MVSS at the respective time point and all stratification variables (see Section 11.1.10) is fitted 
to the data of patients having both MVSS values. Missing MVSS values at 24 months are then 
imputed with the prediction of the linear regression model, which has the last non-missing 
MVSS value before the 24 months measurement for the individual as explanatory variable. To 
this prediction, the realization of a normally distributed random variable with zero mean and 
standard deviation equal to the residual standard deviation from the linear model is added. The 
random seed for this imputation is 45448. 
Using this imputation method deviates from the handling of missing data specified in the 
protocol. There, simple LOCF was intended. However, LOCF is not considered a suitable 
imputation method for the MVSS values as early MVSS values are not considered 
representative for late MVSS measurements in the same individual. Furthermore, LOCF is 
heavily criticized in the statistics community since it may lead to biased results even when the 
missing occurs completely at random (see [29], [30]). 
Additionally, best case – worst case imputations will be used as a supporting sensitivity 
analysis. One using the worst case MVSS value of 9 (observed maximum MVSS value in the 
SOC group in the previous study MW2004-11-02) for all missing MVSS data and one using 
the best case value of 0 (observed minimum MVSS value in the SOC group in the previous 
study MW2004-11-02). 
10.1.2.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
See 10.1.2.2. 


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10.2. Handling of Withdrawals and Dropouts 
Withdrawn subjects will be evaluated in the FAS and safety set. Missing values are imputed 
as mentioned in Section 10.1. 
10.3. Data Transformation 
For all continuous variables, mean, standard deviation, minimum, maximum, median, 25% 
quantile and 75% quantile will be calculated per treatment group and overall. 
For all categorical variables counts and frequencies of categories will be calculated per 
treatment group and overall. 
10.3.1. Demographic data and other baseline characteristics 
10.3.1.1. 
Age 
Age will be calculated as the difference in years (rounded down) between date of birth and the 
date of the baseline physical examination. 
10.3.1.2. 
Height 
A patient's height is either given in cm or inch. Height in inch will be transformed to height in 
cm and vice versa using the formulae 
݄݄݁݅݃ݐሺܿ݉ሻൌʹǤͷͶ ൈ݄݄݁݅݃ݐሺ݄݅݊ܿሻ 
݄݄݁݅݃ݐሺ݄݅݊ܿሻൌͲǤ͵ͻ͵͹ ൈ݄݄݁݅݃ݐሺܿ݉ሻ 
Hence, height data for each patient will be available in inch as well as in cm. 
10.3.1.3. 
Weight 
A patient's weight is either given in kg or lb. Weight in lb will be transformed to weight in kg 
and vice versa using the formulae 
ݓ݄݁݅݃ݐሺ݇݃ሻൌͲǤͶͷ͵͸ ൈݓ݄݁݅݃ݐሺ݈ܾሻ 
ݓ݄݁݅݃ݐሺ݈ܾሻൌʹǤʹͲͶ͸ ൈݓ݄݁݅݃ݐሺ݇݃ሻ 
Hence, weight data for each patient will be available in lb as well as in kg. 
10.3.1.4. 
Time since injury 
The time since injury will be computed as the time in hours between injury and first treatment. 


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10.3.1.5. 
Early grafted wounds 
For each target wound, a binary (yes/no) variable will be computed indicating whether it was 
early autografted (for definition see Appendix 13.1.1). 
For each patient a binary (yes/no) variable will be computed indicating whether the patient had 
at least one early grafted target wound. 
10.3.1.1. 
Late grafted wounds 
For each target wound, a binary (yes/no) variable will be computed indicating whether it was 
late autografted (for definition see Appendix 13.1.1). 
For each patient a binary (yes/no) variable will be computed indicating whether the patient had 
at least one late grafted target wound. 
10.3.1.2. 
Wounds at least partially found in the anatomical area of the hand 
For each target wound, a binary (yes/no) variable will be computed indicating whether it was 
at least partially found in the anatomical area of the hand. 
For each patient a binary (yes/no) variable will be computed indicating whether the patient had 
at least one target wound which was at least partially found in the anatomical area of the hand. 
10.3.2. Primary Endpoint: Incidence of complete eschar removal in the 
topical arms 
Information on whether complete eschar removal was obtained after the application of 
NexoBrid or Gel vehicle per target wound will be combined to a single binary variable (yes/no) 
indicating whether complete eschar removal was achieved for all target wounds of a patient at 
the end of the eschar removal treatment (after the 2 hrs soaking). The eschar removal 
treatment may contain one or two topical removal procedures. Complete eschar removal is 
judged after the last topical procedure in a patient. 
Furthermore, for all patients with at least one early grafted target wound (for definition see 
Appendix 13.1.1), a binary (yes/no) variable will be computed indicating whether complete 
eschar removal has been achieved in all early grafted wounds of the patient at the end of the 
eschar removal treatment (after the 2 hrs soaking). 
Additionally, for all patients with at least one late grafted target wound (for definition see 
Appendix 13.1.1), a binary (yes/no) variable will be computed indicating whether complete 
eschar removal has been achieved in all late grafted wounds of the patient at the end of the 
eschar removal treatment (after the 2 hrs soaking). 


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Furthermore, for patients who had at least one target wound that is found, at least partially, in 
the anatomical area of the hand, a binary (yes/no) variable will be computed, indicating whether 
complete eschar removal has been achieved in all target wound that are found, at least 
partially, in the anatomical area of the hand. 
10.3.3. Secondary Endpoints 
10.3.3.1. 
Secondary Endpoint: Incidence of surgical excision 
For each patient a binary (yes/no) variable will be computed, indicating whether this patient 
needed surgical excision for eschar removal. 
Furthermore, for patients with at least one early grafted target wound, a binary (yes/no) variable 
will be computed, indicating whether this patient needed surgical excision in an early grafted 
target wound. Similarly, for patients with at least one late grafted target wound, a binary 
(yes/no) variable will be computed, indicating whether this patient needed surgical excision in 
a late grafted target wound. 
Additionally, for patients who had at least one target wound that is found, at least partially, in 
the anatomical area of the hand, a binary (yes/no) variable will be computed, indicating whether 
this patient needed surgical excision in a target wound that is found, at least partially, in the 
anatomical area of the hand. 
For each patient the number of TWs will be computed and used as an explanatory variable in 
the analysis of this secondary endpoint. 
10.3.3.2. 
Secondary Endpoint: Time to complete eschar removal 
Information about date will be transformed to time in hours from randomization. Time until 
complete eschar removal will be calculated as the time (in hours) until complete eschar 
removal has been achieved for a TW. From these times, time to reach complete eschar 
removal at a patient level, i.e. for all TW's of an individual patient will be calculated. For 
wounds/patients that do not reach complete eschar removal, their time will be censored at the 
last non-missing eschar removal assessment (typically the last debridement procedure). 
For further analysis, for patients with at least one early grafted target wound, time to complete 
eschar removal will also be calculated as above, but taking into account only early grafted 
wounds. Additionally, for patients with at least one late grafted target wound, time to complete 
eschar removal will also be calculated as above, but taking into account only late grafted 
wounds. 


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Additionally, for patients who had at least one target wound that is found, at least partially, in 
the anatomical area of the hand, time to complete eschar removal will also be calculated as 
above, but taking into account only target wounds that are found, at least partially, in the 
anatomical area of the hand. 
For an additional analysis, time to complete eschar removal will be computed as above but in 
hours from injury. 
Furthermore, time to complete eschar removal will be computed as above but in hours from 
ICF. 
The patients’ age will be categorized into two categories: “younger than 35 years” and “35 
years or older”. The number 35 years is found to be the median age of the adult population in 
the previous study MW2004-11-02. 
10.3.3.3. 
Secondary Endpoint: Blood loss 
10.3.3.3.1. Blood loss for main analysis 
For each patient and each procedure carried out to remove eschar the estimated blood volume 
(EBV) will be calculated as  
ܧܤܸൌ͹Ͳ ܿ݉ଷ
݇݃כ ݓ݄݁݅݃ݐሺ݇݃ሻ 
Furthermore, the total volume of whole blood and packed red blood cells (PRBC) transfused 
(in milliliters) will be calculated per procedure (transfusions given during the procedure and 4 
hours ± 15 minutes later) and denoted by VWB and VPC in the following. 
From these quantities, the blood loss (Actual Blood Loss, ABL) will be calculated using the 
following formula [25]: 
ܣܤܮൌܧܤܸכ ൫ܪܾ௕௘௙௢௥௘െܪܾ௔௙௧௘௥൯
൫ܪܾ௕௘௙௢௥௘൅ܪܾ௔௙௧௘௥൯ʹ
Τ
൅ܸௐ஻൅ͷ
͵ ܸ௉஼ 
The factor of 5/3 is derived from chapter 5 of Transfusion Medicine, 4th Edition [31] and 
compensates for the fact that equal volumes of whole blood and packed red blood cells are 
not comparable. 
The ABL will be summed over all procedures carried out to remove eschar, with the Hb 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during the debridement 
procedure and 4 hrs later i.e. the before-after periods that are spanned by these Hb 
measurements. 


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Additionally, blood loss will be computed considering the whole debridement process as one 
continuous procedure. For this value, the formula for ABL given above will also be used. 
However, the ABL will be computed using the Hb measured immediately before the first 
procedure and 4 hours after completion of the last procedures. The amount of whole blood 
and packed red blood cells (PRBC) transfused will be calculated as before, but incorporating 
all such transfusions in the time frame spanned by the Hb measurements used for the 
calculation (pre first procedure to 4 hrs post last procedure (in which complete debridement 
was achieved). 
Analyses with both blood loss values will be conducted. However, some missing values are 
expected. The analysis with less missing values will be regarded as more reliable and is 
therefore considered the main analysis. The other analysis is considered supportive. 
10.3.3.3.2. Proportion of SPT area of wounds treated per procedure 
For the multiple imputation outlined in Section 10.1.1.3 information on the proportion of the 
SPT area of wounds treated per procedure will be computed using the following formula: 
ܲݎ݋݌ሺܵܲܶሻൌσ Ψܵܲܶሺܹ௜ሻכ Ψܶܤܵܣሺܹ௜ሻ
௜
σ Ψܶܤܵܣሺܹ௜ሻ
௜
ǡ 
where both sums range over all target wounds treated in a debridement procedure, Ψܵܲܶሺܹ௜ሻ 
is the percent area of SPT of target wound ݅ and Ψܶܤܵܣሺܹ௜ሻ is the area of the target wound 
݅. ܲݎ݋݌ሺܵܲܶሻ will be computed for each procedure in each patient separately. 
10.3.3.3.3. Proportion of DPT area of wounds treated per procedure 
For the multiple imputation outlined in Section 10.1.1.3 information on the proportion of the 
DPT area of wounds treated per procedure will be computed using the following formula: 
ܲݎ݋݌ሺܦܲܶሻൌσ Ψܦܲܶሺܹ௜ሻכ Ψܶܤܵܣሺܹ௜ሻ
௜
σ Ψܶܤܵܣሺܹ௜ሻ
௜
ǡ 
where both sums range over all target wounds treated in a debridement procedure, Ψܦܲܶሺܹ௜ሻ 
is the percent area of DPT of target wound ݅ and Ψܶܤܵܣሺܹ௜ሻ is the area of the target wound 
݅. ܲݎ݋݌ሺܦܲܶሻ will be computed for each procedure in each patient separately. 
10.3.3.3.4. Proportion of FT area of wounds treated per procedure 
For the multiple imputation outlined in Section 10.1.1.3 information on the proportion of the FT 
area of wounds treated per procedure will be computed using the following formula: 
ܲݎ݋݌ሺܨܶሻൌσ Ψܦܲܶሺܹ௜ሻכ Ψܶܤܵܣሺܹ௜ሻ
௜
σ Ψܶܤܵܣሺܹ௜ሻ
௜
ǡ 


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where both sums range over all target wounds treated in a debridement procedure, Ψܨܶሺܹ௜ሻ 
is the percent area of FT of target wound ݅ and Ψܶܤܵܣሺܹ௜ሻ is the area of the target wound ݅. 
ܲݎ݋݌ሺܨܶሻ will be computed for each procedure in each patient separately. 
10.3.3.3.5. Course of debridement procedure 
For the multiple imputation outlined in Section 10.1.1.3 for each patient a categorical variable 
describing the course of the debridement process will be calculated. The different levels of the 
variable are defined as: 
· 
Only non-surgical SOC debridement  
· 
Non-surgical SOC debridement followed by surgical debridement 
· 
Only surgical debridement 
· 
Only NexoBrid debridement 
· 
NexoBrid debridement followed by non-surgical SOC debridement followed by surgical 
debridement 
· 
NexoBrid debridement follow by surgical debridement 
· 
Only Gel Vehicle debridement 
· 
Gel Vehicle debridement followed by non-surgical SOC debridement followed by 
surgical debridement 
· 
Gel Vehicle debridement followed by surgical debridement 
10.3.4. Safety Endpoints 
10.3.4.1. 
Safety Endpoint: Time to reach complete wound closure 
Information about date will be transformed to time in days from randomization. Time until 
complete wound closure (for definition see Appendix 13.1.1), will be defined as the time (in 
days) until complete wound closure has been achieved at a wound level. For wounds, which 
do not reach complete wound closure, the time will be censored at last date of wound closure 
assessment. 
10.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
MVSS sub scores at 12 months for pigmentation, pliability, height, vascularity, pain and pruritus 
will be added up to obtain the overall MVSS score (range 0 to 18) at 12 months per target 
wound. The patient MVSS score will be the average of the MVSS over all TWs. Additionally, 
the average MVSS score for donor site scars will be calculated per patient. 


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10.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
MVSS sub scores at 24 months for pigmentation, pliability, height, vascularity, pain and pruritus 
will be added up to obtain the overall MVSS score (range 0 to 18) at 24 months per target 
wound. The patient MVSS score will be the average of the MVSS over all TWs. Additionally, 
the average MVSS score for donor site scars will be calculated per patient. 
10.3.4.4. 
General Parameters of safety 
Volume of blood transfusions given 
The volume of blood transfusions given during hospitalization will be computed for each patient 
as ܸௐ஻൅
ହ
ଷܸ௉஼, where VWB and VPC are the volume (in milliliters) of whole blood and packed 
red blood cells transfused. As in the calculation of blood loss in Section 10.3.3.3.1, the factor 
of 5/3 is derived from chapter 5 of Transfusion Medicine, 4th Edition [31] and compensates for 
the fact that equal volumes of whole blood and packed red blood cells are not comparable. 
The volume of blood transfused will be calculated overall, as well as separately for volumes 
transfused before start of treatment, during the ER period, within 1 week after the ER period 
and later than 1 week after the ER period for each patient. 
Extent of analgesia, anesthesia and antibiotic use 
The numbers and percentages of patients per each level of sedation (see definitions in 
Appendix 13.1.2) per procedure (in topical arms: 1st and second topical application, surgical 
rescue procedures and non-surgical rescue procedures; in SOC arms: surgical procedures 
and non-surgical procedures) will be calculated. 
The number of days of exposure to antibiotic drugs will be calculated for each patient. This will 
be done overall, for antibiotic use due to AE involvement (as indicated in the eCRF) and for 
prophylactic antibiotic use (as indicated in the eCRF) separately. 
Incidence of increased interstitial/compartment syndrome 
For each patient in the topical arms a binary (yes/no) variable is indicating whether the patient 
developed a burn-induced compartment syndrome (BICS) during the eschar removal 
procedure is given in the data. 


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Incidence of QT prolongation 
Incidence of QT prolongation will be analyzed separately. The analysis and all needed 
transformations are described in a separate document. 
Rates of hospital readmission 
For each hospital readmission, a binary (yes/no) variable will be computed indicating whether 
this readmission was planned or not. A readmission will be considered as being planned when 
the reason for readmission was indicated as “planned wound management” or “scar 
modulation” in the eCRF. Readmissions for which the reason was given as “AE” in the eCRF 
are considered as being unplanned. Hospital readmission for which the reason is given as 
“other” will be reviewed by blinded personnel of the sponsor in order to decide whether they 
are to be classified as planned or unplanned. 
For each patient a binary (yes/no) variable will be computed indicating whether this patient had 
a hospital readmission or not. Furthermore, a variable giving the number of planned hospital 
readmissions and a variable giving the number of unplanned readmissions will be computed 
for each patient. 
Relative and absolute frequencies of hospital readmission will be calculated per treatment arm. 
Change in PTT/INR 
Change in PTT/INR will be computed as change from pre Eschar Removal procedure to 4h ± 
15 min post first application (Topical arms) respectively to 4h post first SOC treatment (SOC 
arm) for each patient. Additionally, change from baseline PTT/INR will be computed for the 
first and second daily assessment post treatment (24h & 48h after start of debridement). 
The proportion of patients with a change to > upper limit of normal range PTT/INR (patients 
with normal PTT/INR at baseline and PTT/INR > upper limit of normal range at the respective 
time point) will be computed per treatment arm and time point of measurement (4h post 
treatment, 24 h, 48h). Reference count is the number of patients with normal PTT/INR values 
at baseline. For the classification of normal and abnormal PTT/INR values, the reference limits 
of the local labs will be used. 
Change in blood glucose 
Change in blood glucose will be computed as change in blood glucose value from pre first 
topical procedure to 4h post first topical procedure (4h after removal of topical) and from 


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post first topical to post second topical (if available) and from pre surgical procedure to 
post surgical procedure for each patient. In case non-surgical procedure was the only one 
performed for a SOC patient, the change in blood glucose value will be computed as 
change from pre to post procedure. Furthermore, a binary (yes/no) variable will be 
computed indicating whether there was a change to above upper limit of normal (the upper 
reference limit of the central lab) from baseline to 4h post treatment for each debridement 
procedure. This is the case if the blood glucose level at baseline was below the upper limit 
of the normal range as given in the data base and was above the upper limit at 4h post 
treatment. From this for each patient a binary variable will be computed indicating whether 
there was a change in blood glucose to > upper limit of normal range at any of the 
debridement procedures. 
Lower Extremity Function Scale (LEFS) 
The LEFS consists of 20 items which can each be answered on a scale of 0 to 4. In the 
database the answers will be coded as 1 to 5. Therefore, the total LEFS for a patient will be 
computed as 
ܮܧܨܵൌ෍ܽ௜
ଶ଴
௜ୀଵ
െʹͲǡ 
where ai is the answer to item i (coded 1 to 5). 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH consists of 11 items which are scored 1-5. At least 10 of the 11 items must 
be completed for a score to be calculated. The assigned values for all completed responses 
are simply summed and averaged, producing a score out of five. This value is then transformed 
to a score out of 100 by subtracting one and multiplying by 25. Hence, the QuickDASH score 
for a single patient is calculated by: 
ܳݑ݅ܿ݇ܦܣܵܪൌ൬ݏݑ݉݋݂݊ݎ݁݌݋݊ݏ݁ݏ
݊
െͳ൰כ ʹͷǤ 
Range of Motion (ROM) 
For each visit (12 months FU and 24 months FU), a binary (yes/no) variable is given in the 
eCRF, indicating whether the range of motion assessment for that patient was abnormal or 
not. Furthermore, for each visit (12 months FU and 24 months FU) a binary (yes/no) variable 


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will be computed, indicating whether there was at least one abnormal (NCS) ROM assessment 
for that patient. Finally, for each visit (12 months FU and 24 months FU) a binary (yes/no) 
variable will be computed, indicating whether there was at least one abnormal (CS) ROM 
assessment for that patient. 
EQ-5D (Quality of Life) 
EQ-5D consists of 5 items with 3 possible answers each. It will be evaluated per the EQ-5D-
3L user guide [32]. 
For each item relative and absolute frequencies of the answers will be computed in total and 
per age group defined in the EQ-5D-3L user guide per treatment arm and overall. Furthermore, 
summary statistics of the EQ VAS will be computed in total and per age group defined in the 
EQ-5D-3L user guide per treatment arm and overall. 
The EQ-5D states will be converted to a single summary index as described in the EQ-5D-3L 
user guide. 
Burn Specific Health Scale – Brief (BSHS-B) 
The Burn Specific Health Scale – Brief (BSHS-B) consists of 40 item which can each be scored 
with 0 – 4. In the dataset the scores will be coded as 1- 5. The 40 items can be aggregated to 
9 domains. The domains are: 
· 
Heat sensitivity (questions 28-32 of the eCRF) 
· 
Affect (questions 10-16 of the eCRF) 
· 
Hand Function (questions 4-8 of the eCRF) 
· 
Treatment Regimens (questions 33-37 of the eCRF) 
· 
Work (questions 9, 38-40 of the eCRF) 
· 
Sexuality (questions 21-23 of the eCRF) 
· 
Interpersonal Relationships (questions 17-20 of the eCRF) 
· 
Simple Abilities (questions 1-3 of the eCRF) 
· 
Body Image (questions 24-27 of the eCRF) 
For each domain a domain specific sub score is computed using the following formula: 
ܵܿ݋ݎ݁ሺܦ݋݉ܽ݅݊ሻൌͳ
݊෍
ሺܵܿ݋ݎ݁௜െͳሻǡ
௡
௜ୀଵ
 


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where ݊ is the number of items of the domain and ܵܿ݋ݎ݁௜ is the score of the ݅th item as 
coded in the data set (i.e. the domain score is the mean of the item scores as coded in the 
BSHS-B). 
An overall BSHS-B score is computed as the mean of the domain specific sub scores. 
Immunogenicity evaluation 
The immunogenicity evaluation will be done in a separate analysis and is described in a 
separate document. 
Pyrexia and hypothermia 
Pyrexia (and related terms) and hypothermia reported as AEs will be presented in the AEs 
tables. 
Systemic Infection 
For each patient a binary (yes/no) variable will be computed indicating whether the patient 
developed a systemic infection during the study. For data captured with the eCRF version from 
13 Oct 2016 the information, whether an AE is a systemic infection, is directly available in the 
AE description. For data captured before that, a medical person appointed by the sponsor will 
review all MedDRA Preferred Terms belonging to the MedDRA SOC of “Infections and 
Infestations”, as well as all other Preferred Terms reported in the study, and all reported terms 
of AEs including the word “infection”, to decide which AEs meet the definition of systemic 
infection. 
Systemic adverse events 
Counts and frequencies of systemic adverse events (marked as “general” in the eCRF) per 
treatment will be computed. This will be done separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 


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· 
Time of onset (before treatment / during the treatment session / during the first week 
after treatment / during week 2 to week 4 after treatment / during week 5 to week 8 
after treatment / more than 8 weeks after treatment) 
For each of the tree stages of analysis (see Section 11 for details), the safety data gathered in 
that stage will be analyzed separately. That is, in the acute stage analysis, all AEs reported 
until the 3 months follow-up will be analyzed. In the second stage analysis (12 months follow-
up), all AEs reported between the 3 months follow-up and the 12 months follow-up (including 
AEs from first stage that are still ongoing) will be analyzed. Analogously, in the third stage 
analysis (24 months follow-up), all AEs reported between 12 months follow-up and the 24 
months follow-up (including AEs from the first or second stage that are still ongoing) will be 
analyzed. 
Local adverse events 
Local adverse events are classified as being local – TW related or local – not TW related in 
the eCRF. Per each of these categories, counts and frequencies of adverse events per 
treatment group will be computed. This will be done separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (before treatment / during the treatment session / during the first week 
after treatment / during week 2 to week 4 after treatment / during week 5 to week 8 
after treatment / more than 8 weeks after treatment) 
For each of the tree stages of analysis (see Section 11 for details), the safety data gathered in 
that stage will be analyzed separately. That is, in the acute stage analysis, all AEs reported 
until the 3 months follow-up will be analyzed. In the second stage analysis (12 months follow-
up), all AEs reported between the 3 months follow-up and the 12 months follow-up (including 
AEs from the first stage that are still ongoing) will be analyzed. Analogously, in the third stage 
analysis (24 months follow-up), all AEs reported between 12 months follow-up and the 24 
months follow-up (including AEs from the first or second stage that are still ongoing) will be 
analyzed. 


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Vital signs 
Body temperatures given in °F will be transformed to °C using the following formula: 
ܶ݁݉݌݁ݎܽݐݑݎ݁ሾιܥሿൌͷ
ͻ ሺܶ݁݉݌݁ݎܽݐݑݎ݁ሾιܨሿെ͵ʹሻ 
Differences in the vital signs assessments (body temperature, heart rate, respiratory rate, 
systolic blood pressure, diastolic blood pressure) between daily visits will be calculated by 
ܦ݂݂݅ௗൌܸܵௗିଵെܸܵௗ 
where ܸܵௗ is the vital sign assessment at day d (daily follow-up) and d is varied from 2 to 7. 
Furthermore, pre-post differences for vital signs assessments per procedure will be calculated 
in the same way, using the screening assessment as pre first procedure and the post first 
procedure measurement as pre second procedure measurement if needed. 
Pain assessment 
For each eschar removal procedure and each daily follow-up pain assessment the change in 
pain from baseline will be calculated as  
ܦ݂݂݅ௗൌܲܽ݅݊஻௔௦௘െܲܽ݅݊ௗ 
where ܲܽ݅݊ௗ is the pain assessment at the respective time point. For the calculation of the 
difference in pain for the eschar removal procedures the pain assessment post that procedure 
will be used. 
10.3.5. Exploratory Analyses 
10.3.5.1. 
%SPT area 
For each patient the % SPT area (the area of SPT as a percentage of the total area of all TWs) 
will be calculated. From this a binary variable will be computed indicating whether % SPT area 
is < 25% or ≥ 25%. Cumulative and absolute frequencies for each category will be computed. 
10.3.5.2. 
%TBSA 
A binary variable indicating whether total %TBSA of all TWs is ≤ 15% or > 15% will be 
calculated per patient. For this variable cumulative and absolute frequencies for each category 
will be computed. 


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10.3.5.3. 
Application data 
For the patients of the NexoBrid and the gel vehicle arm the number of applications (0, 1, 2) 
will be determined. Cumulative and absolute frequencies will be computed for each category. 
Furthermore, for each patient the amount of NexoBrid gel each patient in the NexoBrid 
treatment arm has been exposed to, will be calculated. 
10.3.5.4. 
Maintenance of complete wound closure 
For each follow-up visit the information of complete wound closure for each TW will be 
aggregated to a binary variable indicating maintenance of complete wound closure on a patient 
level (i.e. complete wound closure for each TWs of a patient). Cumulative and absolute 
frequencies will be computed for each category. 
10.3.5.5. 
% wound area surgically excised for eschar removal 
% of wound area surgically excised for eschar removal, Atotal, will be calculated using the 
following formula: 
ܣ௧௢௧௔௟ൌσ ሺܽ௜כ Ψܶܤܵܣ௜ሻ
௜
σ Ψܶܤܵܣ௜
௜
 
where %TBSAi is the area of TW i (in % TBSA) and ai denotes the % of wound area surgically 
excised for eschar removal of TW i. 
10.3.5.6. 
Incidence of reduction in interstitial/compartment pressure in 
circumferential extremities target wounds 
Interstitial/compartment pressure in circumferential extremities target wounds is measured 
within 1 hour (+30 min) prior to start of each eschar removal procedure and post-eschar 
removal. For each circumferential target wound and each eschar removal procedure a binary 
(yes/no) variable will be computed indicating whether reduction in interstitial/compartment 
pressure in that wound was present. 
10.3.5.7. 
POSAS 
The Patient Observer Scar Assessment Scale (POSAS) consists of two parts: a patient scale 
and an observer scale. Both scales contain six items that are scored numerically with 1-10. 
For each wound of a patient the total score of the patient scale will be computed as: 
ܱܲܵܣܵ௉ൌ෍݌௜
଺
௜ୀଵ
ǡ 


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where pi is the score the patient assigned to item i. The total score of the observer scale will 
be computed analogously as: 
ܱܲܵܣܵைൌ෍݋௜
଺
௜ୀଵ
ǡ 
where oi is the score the observer assigned to item i. 
A total score for the POSAS is then obtained by summing the patient scale score and the 
observer scale score: 
ܱܲܵܣܵ௧௢௧ൌܱܲܵܣܵ௉൅ܱܲܵܣܵைǤ 
For each patient the mean of ܱܲܵܣܵ௧௢௧ over all TWs will be computed. Analogously the mean 
of ܱܲܵܣܵ௧௢௧ over all donor site scars will be computed. 
Additional to the quantitative scoring of the items they are also score qualitatively (for each 
item different categories are available). Absolute and relative frequencies of the categories for 
each item will be computed over all patients per treatment arm. 
The POSAS will be computed for TWs and donor site scars at the long-term follow up visits. 
10.3.5.8. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
For each circumferential extremities target wound a binary (yes/no) variable will be computed, 
indicating whether this wound was escharotomized. Furthermore, a binary (yes/no) variable 
for each patient will be computed indicating whether this patient had at least one 
circumferential extremities target wound which was escharotomized. 
10.3.5.9. 
Incidence of reduction in interstitial/compartment pressure in 
circumferential extremity wounds 
For circumferential extremity wounds the reduction in interstitial/compartment pressure will be 
computed as 
ܲݎ݁ݏݏௗ௜௙௙ൌܲݎ݁ݏݏ௕௔௦௘െܲݎ݁ݏݏ௣௢௦௧ 
where Pressbase is the interstitial/compartment pressure at baseline and Presspost is the 
interstitial/compartment pressure after eschar removal. This will be done for each topical 
eschar removal procedure. Furthermore, for each circumferential extremity wound and each 
topical eschar removal procedure a binary (yes/no) variable will be computed indicating 
whether interstitial/compartment was reduced during the procedure. 


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10.3.5.10. 
Incidence of surgically harvested donor sites wounds 
For each patient, the number of donor sites wounds will be calculated. 
10.3.5.11. 
% area of surgically harvested donor site wounds 
For each autograft procedure the % TBSA of the donor site is captured. These values will be 
summed up over all autograft procedures for each patient giving the % area of surgically 
harvested donor site wounds. 
10.3.5.12. 
Blood loss using changes in hematocrit following eschar removal 
procedures 
For each debridement procedure, the change in hematocrit will be calculated as the difference 
of the hematocrit value before the procedure and the hematocrit value 4 hours post the 
procedure. This difference in hematocrit values will be summed for each patient. 
Furthermore, for each patient, the difference of the hematocrit value prior to the first 
debridement procedure and the hematocrit value 4 hours post the last debridement procedure 
will be calculated. 
10.3.5.13. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
For each debridement procedure, the change in hemoglobin will be calculated as the difference 
of the hemoglobin value before the procedure and the hemoglobin value 4 hours post the 
procedure. This difference in hemoglobin values will be summed for each patient. 
Furthermore, for each patient, the difference of the hemoglobin value prior to the first 
debridement procedure and the hemoglobin value 4 hours post the last debridement procedure 
will be calculated. 
10.3.5.14. 
Blood loss comparing NexoBrid procedures to surgical procedures 
For a comparison of blood loss between NexoBrid procedures and surgical procedures, the 
blood loss per eschar removal procedure will be calculated as outlined in Section 10.3.3.3.1. 
10.3.5.15. 
Autograft related parameters 
The total number of grafting procedures per patient and per target wound will be computed. 
Procedure will be based on the date in the eCRFs per patient and per wound.  
Furthermore, a binary (yes/no) variable will be computed indicating whether more than one 
autografting procedure was performed on a wound level as well as on a patient level. 
The area of repeat autografting for each wound will be calculated as follows: 


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ܣݎ݁ܽ௥௘௣௘௔௧ൌ෍ܣݎ݁ܽ௜
௡
௜ୀଶ
ǡ 
where n is the total number of autografting procedures for the specific wound and Areai is the 
area autograft in the i-th grafting procedure for that wound. 
The area of repeat autografting on a patient level is calculated as the sum over the areas of 
repeat grafting over all TWs of that patient. 
10.3.5.16. 
Duration of hospitalization 
Duration of acute hospitalization will be computed as the difference in days between hospital 
admission and hospital discharge (initial hospitalization only). 
10.3.5.17. 
Time to reach 100% wound closure 
Information about date will be transformed to time in days from randomization. Time until 100% 
wound closure will be defined as the time (in days) until 100% wound closure has been 
achieved at a wound level. For wounds that do not reach 100% wound closure, the time will 
be censored at last date of wound closure assessment. In case one or more wounds do not 
reach complete wound closure, the time to wound closure at a patient level will be censored 
at the minimum of all wound wise censoring times. 
10.3.6. Laboratory values 
The following transformations will be applied to the central laboratory data obtained pre and 
post the eschar removal procedures: 
Laboratory findings that are given in various units will be transformed to standard units. 
Laboratory values will be categorized as “abnormal (low)”, “normal” and “abnormal (high)” 
based on the reference limits of the labs. 
Pre-post differences of laboratory values for each eschar removal procedure will be calculated. 
Absolute and relative frequencies of “abnormal (low)”, “normal” and “abnormal (high)” findings 
will be calculated per laboratory value, eschar removal procedure and treatment arm. 
10.4. Multiple visits per time point 
Study visit time-points are scheduled at screening, pre eschar removal, eschar removal 
(treatment), post-treatment, hospital discharge, follow-up (weekly until wound closure, wound 
closure confirmation, three monthly visits post wound closure), long-term follow-up at 6, 12, 18 


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months and 24 months post wound closure confirmation and re-admission to hospital/day care 
(if done). One visit is expected for each time-point. The following approach is used if there are 
multiple visits per patient per time-point.  
For all endpoints, if a subject has more than one visit with data at a time-point, the later non-
missing evaluation will be used for analyses. 


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11. Statistical Analysis of Target Variables 
The analysis is planned to be carried out in three stages, as described below. 
1. The first analysis will be performed at the end of the Efficacy Assessment Period (EAP). 
This analysis will be the only inductive analysis of the trial and will include statistical 
tests for the primary and secondary endpoints as described below, as well for short-
term safety endpoints (including time to wound closure). The analysis will be 
conducted, when 3 months had passed from the last patient reaching complete wound 
closure, in accordance with FDA guidance for industry Chronic Cutaneous Ulcer and 
Burn Wounds — Developing Products for Treatment “Trial subjects generally should 
remain in the study for follow-up evaluation at least 3 months following complete wound 
closure. The purpose for this follow-up period is to help distinguish actual wound 
healing from transient wound coverage”. At this time-point, data will be available for all 
patients on the primary end-point (proportion with complete eschar removal), the three 
secondary endpoints (proportion undergoing surgery, time to complete eschar removal, 
and blood loss) and short-term safety endpoints (including time to wound closure). 
Missing values for early drop outs etc. will be handled as described in Sections 10.1 
and 10.2. The complete data set documented so far will be locked and analyzed as 
described above. In the analysis of adverse events and concomitant medication, for 
each patient only the data until the 3 months follow up will be analyzed in this stage. 
Data obtained after the 3 months follow up will be analyzed in the second and third 
stage of analysis. MVSS data, although captured in the eCRF for a few of the subjects 
at the stage of EAP, will not be included, revealed or analyzed during the EAP analyses.  
 
2. The second analysis will be performed for the 12 months follow up period (STFU12) 
and will be started after the last patient has reached the 12m assessment. At this 
analysis, all accumulated safety data at the 12m follow-up will be analyzed, particularly 
the 12m MVSS assessment for cosmesis and function. The complete data set 
documented so far will be locked and analyzed as described below. In the analysis of 
adverse events for each patient only the data obtained after the 3 months follow up and 
until the 12 months follow up (including AEs and concomitant medications from the first 
stage that are ongoing) will be analyzed in this stage. 
 
3. The third and final analysis covers the data of the long-term safety follow up 
(LTSFU24). It will be conducted after the last patient has reached the 24 months 


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assessment at last 12 months after (STFU12) analysis (stage 2). At this analysis, all 
accumulated safety endpoints at the 24m follow-up will be analyzed, particularly the 
24m MVSS assessment for cosmesis and function. The complete data set 
documented during the trial will be locked and analyzed as described below (hard 
lock). In the analysis of adverse events for each patient only the data obtained after 
the 12 months follow up (including AEs and concomitant medications from the first or 
second stage that are still ongoing) will be analyzed in this stage. 
Two “blinded assessors” are appointed in each clinical site during the site initiation visit. The 
assessor signs a “blinded assessor memo” which describes the procedures required to 
maintain the investigator blinded from the treatment arm. The first blinded assessor is 
responsible for the eschar removal assessment of the topical arms and is not involved with 
product application. All patients will complete the eschar removal treatment by the time of the 
first planned analyses of the acute stage and thus, there is no risk of unblinding of the first 
blinded assessor. The second blinded assessor is responsible for the wound closure and long-
term assessments and is not involved with any eschar removal procedures. The second 
blinded assessor will remain blinded throughout the whole duration of the trial including after 
the acute and the first long-term (12 months) analysis results are available. To assure that 
patients’ treatment codes will not be revealed during the EAP analyses, all patients’ 
identification numbers will be Pseudonyms by data management before analysis is being 
performed and presented. 
The data sets for analysis will be 100% SDVd and signed by the site investigator. Therefore, 
data changes are prevented during the further conduct of the study. Data management quality 
control actions will ensure that data used in the analysis is not changed afterwards see the 
Data Management Plan for further details. 
For a better overview of this SAP, the statistical analysis of target variables described below 
will be displayed separately for these 3 stages of analyses. 
All variables not mentioned explicitly in the following will be analyzed descriptively (as part of 
the case wise listing). 
Unless otherwise specified, all statistical tests will be conducted against a two-sided 
alternative hypothesis, employing a significance level of 0.05. 


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11.1. First stage analysis – end of efficacy assessment period (EAP) 
11.1.1. Demographics and Other Baseline Characteristics 
For all considerations regarding the demographics and other baseline characteristics the full 
analysis set will be used. 
The demographic and baseline information concerning 
· 
Age 
· 
Gender 
· 
Ethnicity 
· 
Race 
· 
Height (cm) 
· 
Weight (kg) 
· 
BMI 
· 
Physical examinations (categorized as normal, abnormal-NCS, abnormal-CS, not 
done): 
· 
Head, eyes, ears, nose and throat (HEENT) 
· 
Respiratory system 
· 
Cardiovascular system 
· 
Abdomen 
· 
Musculoskeletal / Extremities 
· 
Neurological 
· 
Lymph Nodes 
· 
Vital signs: 
· 
Temperature 
· 
Heart rate 
· 
Respiratory rate 
· 
Systolic and diastolic blood pressure (mmHg) 
· 
Assessment of vital signs (normal, abnormal-NCS, abnormal-CS) 
· 
Pain assessment: 
· 
VAS (mm) 
· 
Assessment of pain (normal, abnormal-NCS, abnormal-CS) 
· 
Local laboratory: 
· 
Leukocyte count (WBC) 


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· 
Assessment of leukocyte count (normal, abnormal-NCS, abnormal-CS) 
· 
Diabetes status (yes/no) 
· 
HbA1c (%) 
· 
Infections (yes/no for infections in last week before baseline) 
· 
Relevant medical history (regarded as categorical variable) 
· 
Burn history (on a patient level): 
· 
Time since injury 
· 
Etiology of injury (Fire/Flame, Scald, Contact) 
· 
Place of injury (Outdoors, Indoors, Car, Other) 
· 
Information whether patient was transferred from another facility 
· 
General wound description (on a wound level): 
· 
Anatomical location (face, head, neck, etc.) 
· 
%TBSA of 2° SPT Burns 
· 
%TBSA of 2° DPT Burns 
· 
%TBSA of 3° FT Burns 
· 
Indicator (yes/no) of circumferential extremity involvement 
· 
Extremities at risk (not relevant, pain, paralysis, etc.) 
· 
Information whether eschartomy had been performed prior to randomization 
· 
Eschar description (white, moist, dry, etc.) 
· 
Information whether cleansing was performed 
· 
Information whether all superficial keratin (blister) were removed from wound 
· 
Target wound description: 
· 
General wound description (see above; on a wound level; for target wounds 
only) 
· 
Information whether the wound was treated prior to enrollment (TWs) 
· 
Treatment of TWs prior to enrollment (SSD, Iodine, etc.) 
· 
Target wound description (on a patient level): 
· 
Total wounds %TBSA 
· 
TWs DPT total area (%TBSA) 
· 
TWs FT total area (%TBSA) 
· 
Over TWs depth per patient (all full thickness, mixed, all deep partial thickness) 
· 
Overall TW area (SPT+DPT+FT) 
· 
%SPT area classified as <25% or ≥25% of TWs area 
· 
Number of circumferential extremity wounds per patient 


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· 
Interstitial pressure (mmHg) for circumferential extremity wounds (on a wound level) 
· 
Criteria for inclusion (met/not met) 
· 
Counts of patients/wound per strata (%TBSA cut point 15%, depth cases 1-3, center) 
will be analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles in case of numeric values and counts and 
percentages in case of categorical items to describe the study population. The analysis will be 
done by treatment group and in total. 
The descriptive results for all variables will be tabulated. Exemplary tables are presented in 
Section 13.2. Histograms will be produced for each continuous variable, bar plots for 
categorical variables. Figures can be seen in Section 13.3. 
If any of the baseline factors, gender, age, percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%), time from injury to randomization or 
number of TWs (1, 2, ≥3) are found to be significantly different between the treatment groups 
(Chi-squared tests (or in case of small estimated cell counts Fisher’s exact test) for categorical 
variables and one-way analysis of variance for continuous variables) then the factor will be 
included as an extra adjusting covariate in the supportive analysis models for the primary and 
secondary efficacy endpoints and the comparative analyses of safety endpoints. 
11.1.2. Primary Efficacy variable 
The primary efficacy variable will be analyzed using the FAS. 
The proportions of patients who reached complete eschar removal at the end of the topical 
agent soaking period will be compared using logistic regression. The primary analysis will be 
based on the binary variable (yes/no): ‘has complete eschar removal been achieved in all TWs’ 
and will compare NexoBrid with the Gel Vehicle (for further definition and explanation of 
complete eschar removal see Section 1.1 of the protocol and Section 10.3.2 of this SAP). For 
handling of missing data see Section 10.1.1. The statistical test will be based on Fisher’s exact 
test because of the small numbers expected in the Gel vehicle group. The odds ratio of 
achieving complete eschar removal for NexoBrid versus Gel Vehicle and its 95% confidence 
interval will be estimated using exact distribution methods and will be displayed as shown in 
Table 6. Bar plots will be shown for the proportions of patients who reached complete eschar 
removal. 
If numerically possible, the comparison will supportively be adjusted for the stratification factor 
wound depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness) by including 


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the factor in a logistic regression model together with the treatment variable (NexoBrid vs. Gel 
Vehicle). Similarly, if convergence of the estimation procedure can be obtained, then, in two 
other supportive analyses, the factor “Total %TBSA per patient” and the factor treatment center 
group (see Section 13.8.5 of the protocol as well as Section 11.1.7 of this SAP) will be included 
in a logistic regression model with the treatment variable. Statistical inference will be based 
upon exact distribution methods using the “exact” statement in the SAS procedure PROC 
LOGISTIC. The estimated regression coefficients of the regression analyses will be presented 
as displayed in Table 7. 
The odds ratio of achieving complete eschar removal for NexoBrid versus Gel Vehicle will be 
estimated from these supportive models, as well as 95% confidence intervals and the level of 
statistical significance. The results will be displayed as shown in Table 6. 
The primary efficacy analysis will be repeated on a wound level as an additional analysis using 
a mixed logistic regression model with a random effect for patient. 
Furthermore, as an additional sensitivity analysis, the primary analysis will be repeated using 
the PP as analysis population. 
If any of the baseline factors, gender, age, percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%), time from injury to randomization or 
number of TWs (1, 2, ≥3) are found to be significantly different between the treatment groups, 
then, if possible, the factor will be included as an extra adjusting covariate in a supportive 
analysis of the primary endpoint. 
11.1.3. Secondary Efficacy variables 
The secondary endpoints will be analyzed as described below and will compare efficacy in the 
NexoBrid group with the SOC group. Missing data will be handled by the methods described 
in Section 10.1. All secondary endpoints will be analyzed using the FAS. Sensitivity analyses 
will include analyzing the endpoints using the PP as analysis population. 
11.1.3.1. 
Incidence of surgical excision 
This is a binary yes/no variable and the proportion of patients who need excision for eschar 
removal will be compared using logistic regression. The explanatory variables in the model will 
include treatment, and the following variables: overall TW depth (all TWs full thickness, mixed 
TWs, all TWs deep partial thickness), “Total %TBSA per patient” and number of TWs (1, 2, 
≥3). The odds ratio of requiring surgery for NexoBrid versus SOC will be estimated from the 
model, as well as 95% confidence intervals and the level of statistical significance. The results 


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will be displayed as shown in Table 6 and Table 7. Bar plots will be shown for the proportions 
of patients who needed excision for eschar removal. 
If numerically possible, as a supportive analysis, the variable treatment center will be added 
into the logistic regression model and the analysis repeated. 
As a sensitivity analysis, the logistic regression outlined above will be repeated using the PP 
as analysis population. 
If any of the baseline factors, gender, age, percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%), time from injury to randomization or 
number of TWs (1, 2, ≥3) are found to be significantly different between the treatment groups, 
then the factor will be included as an extra adjusting covariate in the logistic regression model 
described above as additional analysis. 
As supportive analysis, the incidence of surgical excision for eschar removal will be compared 
between NexoBrid and Gel Vehicle using the same explanatory variables as in the main 
analysis of this endpoint. 
A further supportive analysis will repeat the analysis (NexoBrid versus SOC) as described 
above, but on a wound level. I.e. a mixed logistic regression model with explanatory variables 
treatment, TW depth, %TBSA per wound and number of TWs and a random effect for patient 
will be performed. 
11.1.3.2. 
Time to complete eschar removal 
Time until complete eschar removal will be defined as the time until complete eschar removal 
has been achieved at a patient level, i.e. for all TW’s of an individual patient. This will be 
measured as time from the randomization date (hours). For patients who do not reach 
complete eschar removal, their time will be censored at the last non-missing eschar removal 
assessment (typically the last debridement procedure). Kaplan-Meier curves will be presented 
graphically (see Figure 3) and in a table (see Table 8) to display the distribution of time to 
complete eschar removal under the two treatments (NexoBrid vs. SOC). Median time to 
complete eschar removal will be estimated for each treatment group with a 95% confidence 
interval. Additionally, time to complete eschar removal will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4. The treatment groups will be compared using a Cox 
regression model. The comparison will be adjusted for the explanatory variables overall TW 
depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness), “Total %TBSA per 
patient”, center group (as defined in Section 11.1.10) and number of TWs (1, 2, ≥3), by 


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including each of them in the Cox regression model together with the treatment variable 
(NexoBrid vs. SOC). The results of the regression analysis will be displayed as in Table 7. The 
treatment groups will be compared by testing the null hypothesis of no difference, comparing 
the ratio of the estimated treatment coefficient to its standard error to a standard normal 
distribution. 
The Cox Regression analysis outlined above will be performed if the proportional hazards 
assumption appears to hold. This will be checked by including in the regression model a 
variable representing the interaction between time since randomization and treatment group. 
If the coefficient for this time variable is non-significant at the 5% significance level, then the 
Cox Regression analysis will be adopted. If the time-treatment group interaction is significant, 
then a generalized Wilcoxon-Gehan test will be performed using the Wilcoxon option (also 
provided by default) in the SAS procedure PROC LIFETEST using the following SAS Code: 
PROC LIFETEST DATA=burn_data; 
TIME time*status(0); 
STRATA depthgroup numtw tbsagroup centergroup / GROUP = treatment_group; 
RUN;  
Here burn_data is the data set containing all necessary information. The variable time is the 
time to complete eschar removal, status is a censoring variable and depthgroup, numtw, 
tbsagroup, and centergroup are the variables, which is adjusted for. Depthgroup, tbsagroup 
and centergroup are the stratification levels defined in Section 11.1.10 and numtw is the 
number of target wounds (1, 2, ≥3). 
As sensitivity analysis the procedure outlined above will be repeated using the PP instead of 
the FAS as analysis population. 
Supportive analyses will include adjustment for other baseline variables that are imbalanced 
(i.e. gender, age, percent SPT area [the area of SPT as a percentage of the total area of all 
TWs, classified as <25% or ≥25%], time from injury to randomization or number of TWs (1, 2, 
≥3)), and investigating interactions between those variables and the treatment groups. In case 
the proportional hazards assumption could not be rejected, this will be done by including each 
of the imbalanced baseline variable as well as the interaction between that variable and the 
treatment group in a separate cox regression analysis. The results of these analyses will be 
presented as in Table 7. In case the proportional hazards assumption does not hold, the 
adjustment for the baseline variables will be done using the following SAS code: 
 
 


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PROC LIFETEST DATA=burn_data; 
TIME time*status(0); 
STRATA depthgroup numtw tbsagroup centergroup gender agegroup sptgroup / 
GROUP = treatment_group; 
RUN;  
Here burn_data is the data set containing all necessary information. The variable time is the 
time to complete eschar removal, status is a censoring variable and depthgroup, numtw, 
tbsagroup, centergroup, gender, agegroup and sptgroup are the variables, which is adjusted 
for. Agegroup is the categorical age variable computed in Section 10.1.1.2, depthgroup, 
tbsagroup and centergroup are the stratification levels defined in Section 11.1.10 and numtw 
is the number of target wounds (1, 2, ≥3). 
Another supportive analysis will be the comparison of treatments based on the time of 
complete eschar removal measured from the date of ICF using the same methods as for the 
time measured from randomization. 
Another supportive analysis will be the comparison of treatments based on the time of 
complete eschar removal measured from the date of injury using the same methods as for the 
time measured from randomization. 
As an additional analysis, time to complete eschar removal will be compared between 
NexoBrid and Gel Vehicle using the same explanatory variables as for the main analysis of 
this endpoint. 
11.1.3.3. 
Blood loss 
In Section 10.3.3.3 two blood loss estimates are defined. Analyses with both blood loss 
estimates will be conducted. However, some missing values are expected. The analysis with 
less missing values will be regarded as more reliable and is therefore considered the main 
analysis. The other analysis is considered supportive. Both analyses will be conducted as 
follows: 
The measure of blood loss defined in Section 10.3.3.3 will be computed for each patient, and 
the distribution in the NexoBrid group will be compared with that in the SOC group. Means, 
standard deviations, medians, and interquartile ranges will be calculated and presented as in 
Table 4. Furthermore, the blood loss will be described graphically by histograms. The normality 
of the data will be tested on each treatment group using the Shapiro-Wilk test. If the normal 
distribution hypothesis is not rejected at the 5% significance level in either group, then 
differences in distribution between NexoBrid and SOC will be tested using a t-test. If the normal 
distribution hypothesis is rejected either in the NexoBrid group or in the SOC group, then the 


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differences in distribution between the treatment groups will be tested using a Mann-Whitney 
test. The test results will be presented as in Table 7. 
As sensitivity analysis, the procedure outlined above will be repeated using the PP instead of 
the FAS as analysis population. 
Supportive analyses will include adjustments for the covariates overall TW depth (all TWs full 
thickness, mixed TWs, all TWs deep partial thickness), “Total %TBSA per patient”, center 
group (as defined in Section 11.1.10), number of TWs (1, 2, ≥3) and number of debridement 
procedures. This will be done by including these variables in a regression model for blood loss 
together with treatment group. 
If any of the baseline factors, gender, age, or percent SPT area (the area of SPT as a 
percentage of the total area of all TWs, classified as <25% or ≥25%), time from injury to 
randomization are found to be significantly different between the treatment groups, then the 
factor will be included as an extra adjusting covariate in a supportive analysis of blood loss (as 
described in the preceding paragraph). 
As an additional analysis, blood loss will be compared between NexoBrid and Gel Vehicle 
without covariate adjustment (similar to the main analysis of this endpoint). 
11.1.4. Safety variables 
All safety variables except for the first safety endpoint “time to wound closure” will be evaluated 
on the safety set. 
11.1.4.1. 
Safety Endpoint: Time to wound closure 
This safety endpoint will be analyzed using the FAS. A sensitivity analysis will be done by 
repeating the analysis outlined below with the PP as analysis population. 
Time to reach complete wound closure will be compared between the NexoBrid and SOC at a 
wound level using a method of survival analysis with clustered data that is based on 
appropriate assumptions. By “clustered data”, we refer to the multiple target wounds that can 
occur in a patient. As stated in the protocol, a non-inferiority margin will be incorporated into 
the analysis that will represent a 7-day advantage to the SOC group. This will be done by 
adding 7 days to the wound closure times in the SOC group. After that, the proportional 
hazards assumption will be checked in the same way as in the analysis of the timely eschar 
removal endpoint. I.e. a marginal cox regression model with a robust sandwich estimator (see 
below for further details) will be performed including the variables treatment, TW depth (on a 
wound level), %TBSA (on a wound level) and number of TWs (1, 2, ≥3) as well as a variable 


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representing the interaction between time since randomization and treatment group. If the 
coefficient for this time variable is non-significant at the 5% significance level, then the 
proportional hazards assumption will be considered appropriate. In this case we will use a 
marginal Cox regression analysis with a robust sandwich estimator. If not, then we will use an 
accelerated failure time (AFT) model with shared frailty. Note that this deviates from the 
previously planned parametric frailty model implemented in the SAS procedure PHREG. The 
latter one assumes proportional hazards and is therefore not suitable here. 
Either method can be implemented in SAS (see [33] for details). The marginal Cox regression 
model is implemented in the PHREG procedure and the robust variance option is implemented 
by specifying the COVS(AGGREGATE) option. This induces the use of the robust variance 
method of Binder et. al. [34]. The accelerated failure time model with shared frailty will be 
implemented using the following SAS-code:  
PROC NLMIXED DATA=burn_data; 
BOUNDS gamma>0; 
linp = b0 + b1*treatment_group + b2*spt + b3*dpt + b4*ft + b5*tbsa + 
b6*number_tw2+ b7*number_tw3 + b8*center2 + b9*center3 + b10*center4 + 
b11*center5 + z; 
alpha = exp(-linp); 
G_t = 1/(1+alpha*time**gamma); 
g = alpha*gamma*time**(gamma-1)/(1+alpha*time**gamma)**2; 
ll = (censor=0)*log(g) + (censor=1)*log(G_t); 
model time~general(ll); 
RANDOM z ~ normal(0,sigma) subject=subject_id; 
RUN; 
where subject_ID is a unique identification number for each patient, time is the time to wound 
closure on a wound level. Censor is a censoring indicator, treatment_group gives the treatment 
group, spt gives the % area SPT (on a wound level), dpt gives the % area DPT (on a wound 
level), ft gives the % area FT (on a wound level), TBSA gives the %TBSA (on a wound level), 
number_tw2 is an indicator variable for the subject having 2 target wounds (patient level), 
number_tw3 is an indicator variable for the subject having ≥3 target wounds (patient level), 
center2,…,center5 are indicator variables for the individual being in center group 2,…,5 
(patient level) and burn_data is a SAS data set containing the required information. 
The SAS code presented above calculates the treatment effect in an accelerated failure time 
model with shared frailty assuming a log-logistic distribution of the data. The commonly used 
Weibull-distribution is not applicable in this case, because the AFT model is equivalent to a 
proportional hazards model. 


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The presented methods include information on all the target wounds of each patient and 
account for any within-patient correlation. Missing information due to incomplete follow-up is 
incorporated naturally into such analyses as censored observations.  
Kaplan-Meier curves will be presented graphically (see Figure 3) and in a table (see Table 8) 
to display the distribution of time to complete wound closure under the two treatments. 
If any of the baseline factors, gender, age, or percent SPT area (the area of SPT as a 
percentage of the total area of all TWs, classified as <25% or ≥25%) are found to be 
significantly different between the treatment groups, then the factor will be included as an extra 
adjusting covariate in a supportive analysis of time to complete wound closure. 
Furthermore, time to reach 100% wound closure will be analyzed as outlined above as an 
additional analysis. 
11.1.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
Not applicable for this stage of analysis since the relevant information for all patients is not 
available yet. This endpoint will be analyzed in the second stage analysis (see 11.2.4.2). 
11.1.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
Not applicable for this stage of analysis since the relevant information for all patients is not 
available yet. This endpoint will be analyzed in the third stage analysis (see 11.3.4.3). 
11.1.4.4. 
Adverse Events 
In this analysis, only the adverse events occurring in the acute phase (until the 3 months follow-
up for each patient) will be analyzed. 
All adverse events will be listed (see Table 14). 
Adverse events are classified as being general, local – TW related or local – not TW related in 
the eCRF. Per each of these categories, the AEs will be listed as given in Table 9 and Table 
10. The listing will be presented separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 


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· 
Time of onset (before start of treatment / during the treatment session / during the first 
week after treatment / during week 2 to week 4 after treatment / during week 5 to week 
8 after treatment / more than 8 weeks after treatment) 
SAEs will be analyzed in the same way as AEs. 
11.1.4.5. 
Vital Signs 
All vital signs (body temperature, heart rate, respiratory rate, systolic blood pressure, diastolic 
blood pressure) will be analyzed descriptively with number of subjects, number of missing 
values, mean, standard deviation, min, max, median and quartiles as shown in Table 4 and 
compared between groups with a one way analysis of variance. A graphical representation of 
the data will be done using histograms. 
The analyses will be done for the vital signs assessments at screening, post eschar removal 
procedures, at the first 7 daily assessments as well as for the pre-post differences per 
procedure and the pre-post differences of the daily vital signs assessments described in 
Section 10.3.4.4 separately. 
Furthermore, for the vital signs assessment at screening, post eschar removal procedures and 
at the first 7 daily assessments the information whether the overall vital signs assessment was 
normal, abnormal (NCS) or abnormal (CS) is given in the eCRF. These classifications will be 
analyzed separately for each time point of vital signs assessment by displaying counts and 
percentages by treatment group (see Table 5). The proportion of normal / abnormal (NCS) and 
abnormal (CS) assessments will be compared between treatment groups using a chi square 
test (or Fisher’s exact test in case of small estimated cell counts). Bar plots of the proportions 
of patients with normal / abnormal (NCS) and abnormal (CS) assessments will be shown. 
11.1.4.6. 
Pain Assessment 
The pain assessment score will be analyzed descriptively with number of units, number of 
missing values, mean, standard deviation, min, max, median and quartiles as shown in Table 
4 and compared between groups with a one way analysis of variance. A graphical 
representation of the data will be done using histograms. Furthermore, a plot of the mean pain 
(and the mean change in pain from baseline) over time will be presented. 
The analyses will be done for the pain assessments at screening, pre and post eschar removal 
procedures, at the first 7 daily assessments as well as for the pre-post differences of the daily 
vital sings assessments (difference to baseline) described in Section 10.3.4.4 separately. 


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Furthermore, for the pain assessment at screening, pre and post eschar removal procedures 
and at the first 7 daily assessments the information whether the pain assessment was normal, 
abnormal (NCS) or abnormal (CS) is given in the eCRF. These classifications will be analyzed 
separately for each time point of vital signs assessment by displaying counts and percentages 
by treatment group (see Table 5). The proportion of normal / abnormal (NCS) and abnormal 
(CS) assessments will be compared between treatment groups using a chi square test (or 
Fisher’s exact test in case of small estimated cell counts). 
11.1.4.7. 
Extend of exposure to study drug 
Counts and percentages of patients having one respectively two applications will be presented 
as shown in Table 5 for the NexoBrid and the Gel Vehicle arm. A chi-squared test (or in case 
of small estimated cell counts Fisher’s exact test) will be used to test for any differences in the 
application data between the two treatment groups. Bar plots of the extend of exposure will be 
shown. 
Furthermore, numbers of patients in the NexoBrid arm being exposed to different grams of 
NexoBrid powder will be displayed. 
11.1.4.8. 
Medical history and concomitant diseases 
The concomitant diseases will be classified using the MedDRA dictionary. They will be 
tabulated with reference to system organ class and frequency of occurrence (see Table 9). A 
similar analysis will be conducted but on the level of preferred terms instead of system organ 
class. Concomitant diseases include all active conditions at start of trial (as documented in the 
medical history). The analysis of medical history conditions will be done and displayed 
separately for previous and ongoing diseases. 
11.1.4.9. 
Concomitant medication 
In this analysis, only the concomitant medication administered during the acute phase (until 
the 3 months follow-up for each patient) will be analyzed. The number of concomitant 
medication and patients involved will be tabulated with reference to ATC coding (see Table 
11). 
11.1.4.10. 
Central laboratory values 
Laboratory measurements obtained prior and after each eschar removal procedure as well as 
pre-post differences in laboratory values for each eschar removal procedure will be analyzed 
descriptively with number of subjects, number of missing values, mean, standard deviation, 
min, max, median and quartiles as presented in Table 4. 


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As described in Section 10.3.6, laboratory values will be categorized as “abnormal (low)”, 
“normal” and “abnormal (high)” based on the reference limits of the labs. This categorization 
will be analyzed by displaying counts and percentages of each category by treatment group 
and by procedure (see Table 5) for each laboratory value separately. 
11.1.4.11. 
Blood transfusions 
The volume of blood transfusions in milliliters (as calculated in Section 10.3.4.4) will be 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as presented in Table 4. The mean volume of blood 
transfusions between treatment groups will be compared by a one-way analysis of variance. 
Histograms will be provided to illustrate the distribution of the volume of blood transfusions in 
the treatment groups. 
The volume of blood transfusions will be presented overall, as well as separately for volumes 
transfused before start of treatment, during the ER period, within 1 week after the ER period 
and later than 1 week after the ER period. 
11.1.4.12. 
Maintenance of complete wound closure 
This is a binary (yes/no) variable (on a wound level). Maintenance of complete wound closure 
will be analyzed by displaying counts and percentages of wounds maintaining complete wound 
closure by treatment group (see Table 5). The proportion of wounds maintaining complete 
wound closure will be compared between treatment groups using a chi square test (or Fisher’s 
exact test in case of small estimated cell counts). Bar plots of the proportions of wounds 
maintaining complete wound closure will be shown. 
The analysis will be conducted for the information present at month 1 and month 3 after wound 
closure. 
11.1.4.13. 
Incidence of QT prolongation 
Incidence of QT prolongation will be analyzed separately. See separate document for the 
description of the analysis. 
11.1.4.14. 
Analgesia, anesthesia and antibiotic use 
For an analysis of the level of sedation, the number and percentage of patients per each level 
of sedation and each eschar removal procedure (in topical arms: 1st and second topical 
application, surgical rescue procedures and non-surgical rescue procedures; in SOC arms: 
surgical procedures and non-surgical procedures) will be tabulated. 


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The number of days of exposure to antibiotic drugs will be analyzed descriptively with number 
of units, number of missing values, mean, standard deviation, min, max, median and quartiles 
as shown in Table 4 and compared between groups with a one way analysis of variance. This 
analysis will be conducted for overall antibiotic use, for antibiotic use due to AE involvement 
(as indicated in the eCRF) and for prophylactic antibiotic use (as indicated in the eCRF) 
separately. 
11.1.4.15. 
Hospital readmission rates 
Hospital admission rates will be analyzed on a patient level by displaying counts and 
percentages by treatment group (see Table 5). The proportion of patients needing readmission 
to a hospital will be compared between treatment groups using a chi square test (or Fisher’s 
exact test in case of small estimated cell counts) and presented graphically using bar plots. 
Furthermore, the number of planned hospital readmissions per patient will be analyzed by 
displaying counts and percentages by treatment group (see Table 5). The number of planned 
hospital readmissions per patient will be compared between treatment groups using a chi 
square test (or Fisher’s exact test in case of small estimated cell counts) and presented 
graphically using bar plots. 
Additionally, the number of unplanned hospital readmissions per patient will be analyzed by 
displaying counts and percentages by treatment group (see Table 5). The number of 
unplanned hospital readmissions per patient will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts) and presented 
graphically using bar plots. 
Hospital readmission will also be analyzed on a readmission level. Counts and percentages of 
planned/unplanned readmissions will be displayed by treatment group (see Table 5). The 
proportion of planned/unplanned readmissions to hospitals will be compared between 
treatment groups using a chi square test (or Fisher’s exact test in case of small estimated cell 
counts) and presented graphically using bar plots 
11.1.4.16. 
INR/PTT change 
Change in INR/PTT will be evaluated at 4h post first treatment as well as on the first and 
second daily assessment post treatment separately. This is a binary (yes/no) variable 
indicating whether the patient experienced a change of INR/PTT to > normal range (reference 
limits of the local laboratories). Rates of patients with this event will be analyzed by displaying 
counts and percentages by treatment group (see Table 5) in each time point separately (4h 
post, 24h and 48h). Reference count is the number of patients with normal PTT/INR values at 


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baseline. For the classification of normal and abnormal PTT/INR values, the reference limits 
of the local labs will be used. The proportion of patients with change of INR/PTT to > normal 
range will be compared between treatment groups using a chi square test (or Fisher’s exact 
test in case of small estimated cell counts). 
INR/PTT values will be classified as normal, abnormal (NCS) and abnormal (CS) based in the 
eCRF. These will be analyzed by displaying counts and percentages by treatment group (see 
Table 5) for each time point separately (4h post, 24h and 48h). 
11.1.4.17. 
Blood glucose change 
This is a binary (yes/no) variable indicating whether the patient experienced a change of blood 
glucose to > upper limit of normal range. Rates of patients with this event will be analyzed by 
displaying counts and percentages by treatment group (see Table 5) per eschar removal 
procedure. Furthermore, bar plots will be displayed. The proportion of patients with change of 
blood glucose to > upper limit of normal range will be compared between treatment groups 
using a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
Furthermore, the change in blood glucose from baseline to 4h post treatment per patient will 
be analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as shown in Table 4 and compared between groups 
with a one way analysis of variance. A graphical representation of the data will be done using 
histograms. 
11.1.5. Exploratory Analyses 
11.1.5.1. 
% wound area surgically excised for eschar removal 
The % wound area surgically excised for eschar removal per patient (computed as in section 
10.3.5.5) will be analyzed descriptively with number of units, number of missing values, mean, 
standard deviation, min, max, median and quartiles as shown in Table 4 and compared 
between groups with a one way analysis of variance. A graphical representation of the data 
will be done using histograms. 
11.1.5.2. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
Two analyses will be done for this exploratory endpoint. The number and percentage of 
circumferential extremities target wounds that went through escharotomy will be presented by 
treatment group (see Table 5). The proportion of circumferential extremities target wounds that 


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went through escharotomy will be compared between treatment groups using a chi square test 
(or Fisher’s exact test in case of small estimated cell counts). 
The number and percentage of patients having at least one circumferential extremities target 
wound, which went through escharotomy, will be presented by treatment group (see Table 5). 
Furthermore, bar plots will be displayed. The proportion of patients having at least one 
circumferential extremities target wound which went through escharotomy will be compared 
between treatment groups using a chi square test (or Fisher’s exact test in case of small 
estimated cell counts). 
11.1.5.3. 
Incidence of reduction in interstitial/compartment pressure in 
circumferential extremities target wounds 
This is a binary (yes/no) variable indicating whether the patient experienced reduction in 
interstitial/compartment pressure in circumferential extremities target wounds for each target 
wound and each procedure separately. Rates of patients with this event will be analyzed by 
displaying counts and percentages by treatment group (see Table 5). Furthermore, bar plots 
will be displayed. The proportion of patients with reduction in interstitial/compartment pressure 
in circumferential extremities target wounds will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
11.1.5.4. 
Incidence of surgically harvested donor site wounds 
This is a counting variable, giving the number of donor site wounds per patient. Rates of 
patients with different numbers of donor site wounds will be analyzed by displaying counts and 
percentages by treatment group (see Table 5). Furthermore, bar plots will be displayed (see 
Figure 2). The number of donor site wounds will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
11.1.5.5. 
% area of surgically harvested donor site wounds 
The % wound area of surgically harvested donor site wounds per patient (computed as in 
section 10.3.5.11) will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as shown in Table 4 and 
compared between groups with a one way analysis of variance. A graphical representation of 
the data will be done using histograms. 


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11.1.5.6. 
Blood loss using changes in hematocrit following eschar removal 
procedures 
The measure of blood loss defined in Section 10.3.5.12 will be computed for each patient, 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as shown in Table 4 and compared between groups 
with a one way analysis of variance. A graphical representation of the data will be done using 
histograms. 
11.1.5.7. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
The measure of blood loss defined in Section 10.3.5.13 will be computed for each patient, 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as shown in Table 4 and compared between groups 
with a one way analysis of variance. A graphical representation of the data will be done using 
histograms. 
11.1.5.8. 
Blood loss in NexoBrid procedures vs. surgical procedures 
The measure of blood loss defined in Section 10.3.3.3.1 will be computed for each procedure, 
and analyzed descriptively with number of procedures, number of missing values, mean, 
standard deviation, min, max, median and quartiles as shown in Table 4 and compared 
between NexoBrid procedures and surgical procedures with a one way analysis of variance. 
A graphical representation of the data will be done using histograms. 
11.1.5.9. 
Autograft related parameters 
Total number of autografting procedures 
The total number of autografting procedures (per patient) will be analyzed by displaying counts 
and percentages by treatment group (see Table 5). Furthermore, bar plots will be displayed. 
The distribution of the total number of autografting procedures will compared between 
treatment groups using a chi square test (or Fisher’s exact test in case of small estimated cell 
counts). 
This analysis will be repeated on a wound level. 
Incidence of repeated autografting 
This is a binary (yes/no) variable indicating whether the patient had more than one autograft 
procedure during the study (based on different dates on the same TW). Rates of patients with 


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more than one autograft procedure will be analyzed by displaying counts and percentages by 
treatment group (see Table 5). Furthermore, bar plots will be displayed. The proportion of 
patients with repeated autograft procedures will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
This analysis will be repeated on a wound level. 
Area of repeated autografting 
The area of repeated autografting per patient will be analyzed descriptively with number of 
units, number of missing values, mean, standard deviation, min, max, median and quartiles as 
shown in Table 4 and compared between groups with a one way analysis of variance. A 
graphical representation of the data will be done using histograms. 
This analysis will be repeated on a wound level. 
Early autografted wounds 
A subgroup analysis will be performed on the subgroup of target wounds that are early grafted 
(for a definition see Appendix 13.1.1). The primary endpoint, the secondary endpoints 
“incidence of surgical excision” and “time to complete eschar removal”, as well as the safety 
endpoint “time to complete wound closure” will be analyzed while only taking wounds that are 
early grafted into account. 
Late autografted wounds 
A subgroup analysis will be performed on the subgroup of target wounds that are late grafted 
(for a definition see Appendix 13.1.1). The primary endpoint, the secondary endpoints 
“incidence of surgical excision” and “time to complete eschar removal”, as well as the safety 
endpoint “time to complete wound closure” will be analyzed while only taking wounds that are 
late grafted into account. 
11.1.5.10. 
Duration of hospitalization 
The duration of hospitalization will be analyzed descriptively with Kaplan-Meier plots (see 
Figure 3) and compared between groups with a log rank test. 
11.1.6. Pharmacokinetic Variables 
Pharmacokinetic variables will be analyzed separately. The analysis is described in a separate 
document. 


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11.1.7. Multicenter Data 
Randomization will be stratified by center group as detailed in the Section 13.7.2 of the 
protocol. 
The analyses of the primary and secondary endpoints of this trial will adjust for possible effects 
of the variable center by including it as covariate in the analyses. 
11.1.8. Handling of Multiple Comparisons 
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. The primary and secondary endpoints of 
efficacy will be tested in a hierarchy, so as to preserve the nominal significance levels:  
1. Primary 
2. Incidence of surgery 
3. Time to complete eschar removal 
4. Blood loss. 
11.1.9. Interim analysis 
No interim analyses will be performed. 
11.1.10. Stratification 
The following factors are used to stratify the study design: 
 
A. Total TBSA % per patient  
A1: Total TBSA <=15%  
A2: Total TBSA >15%  
 
B. Overall depth per patient  
B1: All TWs are full thickness;  
B2: Mixed TWs – full thickness and deep partial thickness  
B3: All TWs are deep partial thickness.  
 


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C. Center Group, to address possible differences in SOC procedures between sites (if 
any), to allow comparison of the results within group of centers and to reduce the 
likelihood of a group of centers including patients in only one arm of the study (5 groups 
of centers were formed based on similarity of SOC practice).  
 
These factors are accounted for in the analyses of the primary and secondary endpoints by 
including them as adjusting variables. 
11.1.11. Analysis of Subgroups 
The following subgroup analyses were pre planned and will be conducted to explore efficacy 
and safety within certain pre-defined subgroups of the population. All analyses presented here 
are of exploratory nature. 
11.1.11.1. 
Target wounds in the anatomical area of the hand 
A subgroup analysis will be performed on the subgroup of target wounds that are found, at 
least partly, in the anatomical area of the hand. The primary and secondary endpoints will be 
analyzed while only taking wounds that are found, at least partly, in the anatomical area of the 
hand into account. 
11.1.11.2. 
Patients with < 25% SPT area 
Patients will be classified as having < 25 % or ≥ 25% SPT area as a percentage of the area of 
all TWs. 
For the subgroup of patients with < 25 % SPT area descriptive statistics (counts and 
percentages) of patients achieving complete eschar removal will be displayed for patients 
treated with NexoBrid or Gel Vehicle as shown in Table 5. The two groups will be compared 
using Fisher’s exact test. The results will further be described by a bar plot (see Figure 2). 
For the secondary endpoint “surgical excision performed” counts and percentages of patients 
needing surgical excision will be presented (see Table 5). The treatment groups will be 
compared using a chi square test (of Fisher’s exact test in case of small expected cell counts). 
The secondary endpoint “time to complete eschar removal” Kaplan-Meier estimates will be 
presented graphically and in a table (see Figure 3 and Table 8). Time to complete eschar 
removal will be compared between treatment groups by a log rank test. 
For the secondary endpoint “blood loss” the number of subjects, number of missing values, 
means, standard deviations, medians, quartiles, minimums and maximums will be calculated 


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and presented as in Table 4. Furthermore, the blood loss will be described graphically by 
histograms (see Figure 1). Treatment groups will be compared using a t-test. 
The safety endpoint “time to reach complete wound closure” will be analyzed by presenting 
Kaplan-Meier estimates graphically and in a table (see Figure 3 and Table 8). Time to complete 
wound closure will be compared between treatment groups by a log rank test. 
11.1.11.3. 
Patients with ≥ 25% SPT area 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with ≥ 
25% SPT area. 
11.1.11.4. 
Total TBSA ≤ 15% 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
total TBSA <=15%. 
11.1.11.5. 
Total TBSA > 15% 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
total TBSA > 15%. 
11.1.11.6. 
All target wounds full thickness 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
all target wounds classified as full thickness wounds. 
11.1.11.7. 
Mixed target wounds – full thickness and deep partial thickness 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
mixed thickness target wounds (full thickness and deep partial thickness). 
11.1.11.8. 
All target wounds are deep partial thickness 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
all target wounds classified as deep partial thickness wounds. 
11.1.11.9. 
Wounds that are entirely full thickness 
The same analysis as in Section 11.1.11.1 will be performed but on the subgroup of wounds 
that are entirely full thickness wounds. 
 
 


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11.2. Second stage analysis – 12 month short-term follow-up (STFU12) 
11.2.1. Demographics and Other Baseline Characteristics 
Not applicable for this stage of analysis since all information on demographics and other 
baseline characteristics was already analyzed in the first stage analysis (see 11.1.1). 
11.2.2. Primary Efficacy variable 
Not applicable for this stage of analysis since all information on the primary efficacy variable 
was already analyzed in the first stage analysis (see 11.1.2). 
11.2.3. Secondary Efficacy variables 
Not applicable for this stage of analysis since all information on the secondary efficacy 
variables was already analyzed in the first stage analysis (see 11.1.3). 
11.2.4. Safety variables 
11.2.4.1. 
Safety Endpoint: Time to wound closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the first stage analysis (see 11.1.4.1). 
11.2.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
The MVSS score for a patient will be calculated as described in Section 10.3.4.2. The mean 
and standard error of this MVSS score (for the target wounds) at 12 months will be 
estimated for each treatment group and presented as shown in Table 4. The treatment 
groups will be compared using a linear model with MVSS score as the dependent variable. 
The explanatory variables in the model will include treatment, and the following variables: 
overall TW depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness), “Total 
%TBSA per patient” and number of TWs (1, 2, ≥3). The coefficient corresponding to the 
treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 
factors. The results of the regression analysis will be presented as in Table 7. 


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A clinically meaningful difference will be incorporated into the analysis that will represent 
a 1.9 or more units advantage to the SOC group, so that the analysis will show whether 
the NexoBrid group is estimated to have on average a MVSS score that is not worse by 
more than 1.9 units than the score for the SOC group. That is, the following hypothesis are 
about to be tested: 
ܪ଴ǣ ȟ ൒ͳǤͻݒݏǤܪଵǣ ȟ ൏ͳǤͻ 
Where ȟ is the mean difference in MVSS score between NexoBrid and SOC adjusted for 
any imbalance in the stratification factors. These hypotheses will be tested by comparing 
the 95% confidence interval for the coefficient of the treatment group from the linear model 
outlined above to the clinically meaningful difference 1.9. The null hypothesis will be 
rejected if the upper bound of this interval is smaller than 1.9. 
For handling of missing data see Section 10.1.2.2.  
11.2.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
Not applicable for this stage of analysis since the relevant information for all patients is not 
available yet. This endpoint will be analyzed in the third stage analysis (see 11.3.4.3).  
11.2.4.4. 
Adverse Events 
In this analysis, only the adverse events occurring after the 3 months follow up and until the 
12 months follow up (including AEs from the first stage that are still ongoing) will be analyzed. 
All adverse events will be listed (see Table 14). 
Adverse events are classified as being general, local – TW related or local – not TW related in 
the eCRF. Per each of these categories, the AEs will be listed as given in Table 9 and Table 
10. The listing will be presented separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (until 3 months follow up [i.e. AEs from first stage that are still ongoing] / 
between 3 months follow up and 12 months follow up) 
SAEs will be analyzed in the same way as AEs. 


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11.2.4.5. 
Concomitant medication 
In this analysis, only the concomitant medications given after the 3 months follow up and until 
the 12 months follow up (including CM with a start date before the 3 months follow up but an 
end date after that or still ongoing at 12 months) will be analyzed. 
The number of concomitant medication and patients involved will be tabulated with reference 
to ATC coding (see Table 12). 
11.2.4.6. 
Lower Extremity Function Scale (LEFS) 
The LEFS scores of the 12 months follow up assessment will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4. The mean LEFS scores between treatment groups will be 
compared by a one-way analysis of variance. Histograms will be provided to illustrate the 
distribution of LEFS values. 
11.2.4.7. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH scores of the 12 months follow up assessment will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4. The mean QuickDASH scores between treatment 
groups will be compared by a one-way analysis of variance. Histograms will be provided to 
illustrate the distribution of QuickDASH values. 
11.2.4.8. 
Range of Motion (ROM) 
The 12 months range of motion will be evaluated using 3 binary (yes/no) variables. The 
variables indicate whether all ROM were normal, whether there was at least one abnormal 
(NCS) finding and whether there was at least one abnormal (CS) finding. This information is 
present per patient and per visit. Rates of patients with this event will be analyzed by displaying 
counts and percentages by treatment group (see Table 5) per variable (all normal / at least 
one abnormal (NCS) / at least one normal (CS)) and per visit. Furthermore, bar plots will be 
displayed. The proportion of patients with all normal / at least one abnormal (NCS) / at least 
one normal (CS) range of motion will be compared between treatment groups using a chi 
square test (or Fisher’s exact test in case of small estimated cell counts). 
11.2.4.9. 
EQ-5D (Quality of Life) 
The 12 months follow up assessment of the EQ-5D will be analyzed as follows. 
The EQ-5D consists of 5 items with 3 possible answers each and an EQ visual analogue scale. 
For each item (Mobility, Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression) the 


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count and percentages of each possible answer will be presented per age group and per 
treatment group as in Tables 3 and 4 of the EQ-5D-3L user guide [32]. Furthermore, bar plots 
will be provided. The difference between treatment groups will be tested using a chi square 
test (or Fishers’ exact test in case of small expected cell counts). 
The values of the EQ visual analogue scale (EQ VAS) will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 3 of the EQ-5D-3L user guide [32]. The mean EQ VAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of EQ VAS values. 
11.2.4.10. 
Burn Specific Health Scale – Brief (BSHS-B) 
The 12 months follow up assessment of the BSHS-B will be analyzed as follows. 
Each domain specific sub score and the overall BSHS-B score will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4.The mean (sub-) score values between treatment groups 
will be compared by a one-way analysis of variance. Histograms will be provided to illustrate 
the distribution of (sub-) score values. 
11.2.5. Exploratory Analyses 
11.2.5.1. 
POSAS 
The POSAS for target wounds will be calculated as outlined in Section 10.3.5.7 and will be 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as presented in Table 4. The mean POSAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of POSAS in the treatment groups. 
The analysis will be repeated for the patient scale and for the observer scale separately. 
The analysis will be repeated for donor site scars. 
The analyses will be conducted for the POSAS assessments of 1, 3, 6 and 12 months. 
11.2.5.2. 
MVSS (target wounds) 
The MVSS for target wounds at 1, 3, and 6 months will be calculated as outlined in Section 
10.3.4.2 and will be analyzed descriptively with number of units, number of missing values, 
mean, standard deviation, min, max, median and quartiles as presented in Table 4. The mean 


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MVSS values between treatment groups will be compared by a one-way analysis of variance. 
Histograms will be provided to illustrate the distribution of MVSS in the treatment groups. 
11.2.5.3. 
MVSS (donor site scars) 
The MVSS for donor site scars at 1, 3, 6 and 12 months will be calculated as outlined in Section 
10.3.4.2 and will be analyzed descriptively with number of units, number of missing values, 
mean, standard deviation, min, max, median and quartiles as presented in Table 4. The mean 
MVSS values between treatment groups will be compared by a one-way analysis of variance. 
Histograms will be provided to illustrate the distribution of MVSS in the treatment groups. 
11.2.6. Pharmacokinetic Variables 
Not applicable. All pharmacokinetic data was already analyzed in the first stage analysis (see 
Section 11.1.6). 
11.2.7. Multicenter Data 
See Section 11.1.7. 
11.2.8. Handling of Multiple Comparisons 
Not applicable. All testing done during this second stage analysis is exploratory in nature. So 
no adjustment for multiplicity is needed. 
11.2.9. Interim analysis 
No interim analyses will be performed. 
11.2.10. Stratification 
See Section 11.1.10. 
11.2.11. Analysis of Subgroups 
11.2.11.1. 
Total TBSA ≤ 15% 
A subgroup analysis will be done for the patients with Total TBSA ≤ 15%. 
The 12 months MVSS will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 


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The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.2.11.2. 
Total TBSA > 15% 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
total TBSA > 15%. 
11.2.11.3. 
All target wounds full thickness 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
all target wounds classified as full thickness wounds. 
11.2.11.4. 
Mixed target wounds – full thickness and deep partial thickness 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
mixed thickness target wounds (full thickness and deep partial thickness). 
11.2.11.5. 
All target wounds are deep partial thickness 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
all target wounds classified as deep partial thickness wounds. 
 
 


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11.3. Third stage analysis – 24 month long-term safety follow-up 
(LTSFU24) 
11.3.1. Demographics and Other Baseline Characteristics 
Not applicable for this stage of analysis since all information on demographics and other 
baseline characteristics was already analyzed in the first stage analysis (see 11.1.1). 
11.3.2. Primary Efficacy variable 
Not applicable for this stage of analysis since all information on the primary efficacy variable 
was already analyzed in the first stage analysis (see 11.1.2). 
11.3.3. Secondary Efficacy variables 
Not applicable for this stage of analysis since all information on the secondary efficacy 
variables was already analyzed in the first stage analysis (see 11.1.3). 
11.3.4. Safety variables 
11.3.4.1. 
Safety Endpoint: Time to wound closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the first stage analysis (see 11.1.4.1). 
11.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the second stage analysis (see 11.2.4.2). 
11.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
The MVSS score for a patient will be calculated as described in Section 10.3.4.3. The mean 
and standard error of this MVSS score (for the target wounds) at 24 months will be 
estimated for each treatment group and presented as shown in Table 4. The treatment 
groups will be compared using a linear model with MVSS score as the dependent variable. 
The explanatory variables in the model will include treatment, and the following variables: 
overall TW depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness), “Total 


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%TBSA per patient” and number of TWs (1, 2, ≥3). The coefficient corresponding to the 
treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 
factors. The results of the regression analysis will be presented as in Table 7. 
A clinically meaningful difference will be incorporated into the analysis that will represent 
a 1.9 or more units advantage to the SOC group, so that the analysis will show whether 
the NexoBrid group is estimated to have on average a MVSS score that is not worse by 
more than 1.9 units than the score for the SOC group. That is, the following hypothesis are 
about to be tested: 
ܪ଴ǣ ȟ ൒ͳǤͻݒݏǤܪଵǣ ȟ ൏ͳǤͻ 
Where ȟ is the mean difference in MVSS score between NexoBrid and SOC adjusted for 
any imbalance in the stratification factors. These hypotheses will be tested by comparing 
the 95% confidence interval for the coefficient of the treatment group from the linear model 
outlined above to the clinically meaningful difference 1.9. The null hypothesis will be 
rejected if the upper bound of this interval is smaller than 1.9. 
For handling of missing data, see Section 10.1.2.2.  
11.3.4.4. 
Adverse Events 
In this analysis, only the adverse events occurring after the 12 months follow up will be 
analyzed. 
All adverse events will be listed (see Table 14). 
Adverse events are classified as being general, local – TW related or local – not TW related in 
the eCRF. Per each of these categories, the AEs will be listed as given in Table 9 and Table 
10. The listing will be presented separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (until 3 months follow up [i.e. AEs from first stage that are still ongoing] / 
between 3 months follow up and 12 months follow up [i.e. AEs from second stage that 
are still ongoing] / after 12 months follow up) 


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SAEs will be analyzed in the same way as AEs. 
11.3.4.5. 
Concomitant medication 
In this analysis, only the concomitant medications (CM) given after the 12 months follow up 
(including CM with a start date before the 12 months follow up but an end date after that or still 
ongoing) will be analyzed. 
The number of concomitant medication and patients involved will be tabulated with reference 
to ATC coding (see Table 13). The tabulation will be done by treatment group. 
11.3.4.6. 
Immunogenicity evaluation 
The immunogenicity evaluation will be done separately and is described in a separate 
document. 
11.3.4.7. 
Lower Extremity Function Scale (LEFS) 
The LEFS scores of the 24 months follow up assessment will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4. The mean LEFS scores between treatment groups will be 
compared by a one-way analysis of variance. Histograms will be provided to illustrate the 
distribution of LEFS values. 
11.3.4.8. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH scores of the 24 months follow up assessment will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4. The mean QuickDASH scores between treatment 
groups will be compared by a one-way analysis of variance. Histograms will be provided to 
illustrate the distribution of QuickDASH values. 
11.3.4.9. 
Range of Motion (ROM) 
The 24 months range of motion will be evaluated using 3 binary (yes/no) variables. The 
variables indicate whether all ROM were normal, whether there was at least one abnormal 
(NCS) finding and whether there was at least one abnormal (CS) finding. This information is 
present per patient and per visit. Rates of patients with this event will be analyzed by displaying 
counts and percentages by treatment group (see Table 5) per variable (all normal / at least 
one abnormal (NCS) / at least one normal (CS)) and per visit. Furthermore, bar plots will be 
displayed. The proportion of patients with all normal / at least one abnormal (NCS) / at least 
one normal (CS) range of motion will be compared between treatment groups using a chi 
square test (or Fisher’s exact test in case of small estimated cell counts). 


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11.3.4.10. 
EQ-5D (Quality of Life) 
The 24 months follow up assessment of the EQ-5D will be analyzed as follows. 
The EQ-5D consists of 5 items with 3 possible answers each and an EQ visual analogue scale. 
For each item (Mobility, Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression) the 
count and percentages of each possible answer will be presented per age group and per 
treatment group as in Tables 3 and 4 of the EQ-5D-3L user guide [32]. Furthermore, bar plots 
will be provided. The difference between treatment groups will be tested using a chi square 
test (or Fishers’ exact test in case of small expected cell counts). 
The values of the EQ visual analogue scale (EQ VAS) will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4 of the EQ-5D-3L user guide [32]. The mean EQ VAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of EQ VAS values. 
11.3.4.11. 
Burn Specific Health Scale – Brief (BSHS-B) 
The 24 months follow up assessment of the BSHS-B will be analyzed as follows. 
Each domain specific sub score and the overall BSHS-B score will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4. The mean (sub-) score values between treatment groups 
will be compared by a one-way analysis of variance. Histograms will be provided to illustrate 
the distribution of (sub-) score values. 
11.3.5. Exploratory Analyses 
11.3.5.1. 
POSAS 
The POSAS for target wounds will be calculated as outlined in Section 10.3.5.7 and will be 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as presented in Table 4. The mean POSAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of POSAS in the treatment groups. 
The analysis will be repeated for the patient scale and for the observer scale separately. 
The analysis will be repeated for donor site scars. 
The analyses will be conducted for the POSAS assessments of 18 and 24 months. 


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11.3.5.1. 
MVSS (target wounds) 
The MVSS for target wounds at 18 and 24 months will be calculated as outlined in Section 
10.3.4.2 and will be analyzed descriptively with number of units, number of missing values, 
mean, standard deviation, min, max, median and quartiles as presented in Table 4. The mean 
MVSS values between treatment groups will be compared by a one-way analysis of variance. 
Histograms will be provided to illustrate the distribution of MVSS in the treatment groups 
11.3.5.2. 
MVSS (donor site scars) 
The MVSS for donor site scars at 18 and 24 months will be calculated as outlined in Section 
10.3.4.3 and will be analyzed descriptively with number of units, number of missing values, 
mean, standard deviation, min, max, median and quartiles as presented in Table 4. The mean 
MVSS values between treatment groups will be compared by a one-way analysis of variance. 
Histograms will be provided to illustrate the distribution of MVSS in the treatment groups. 
11.3.6. Pharmacokinetic Variables 
Not applicable. All pharmacokinetic data was already analyzed in the first stage analysis (see 
Section 11.1.6). 
11.3.7. Multicenter Data 
See Section 11.1.7. 
11.3.8. Handling of Multiple Comparisons 
Not applicable. All testing done during this second stage analysis is exploratory in nature. So 
no adjustment for multiplicity is needed. 
11.3.9. Interim analysis 
No interim analyses will be performed. 
11.3.10. Stratification 
See Section 11.1.10. 


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11.3.11. Analysis of Subgroups 
11.3.11.1. 
Total TBSA ≤ 15% 
A subgroup analysis will be done for the patients with Total TBSA ≤ 15%. 
The 24 months MVSS will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.3.11.2. 
Total TBSA > 15% 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
total TBSA > 15%. 
11.3.11.3. 
All target wounds full thickness 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
all target wounds classified as full thickness wounds. 
11.3.11.4. 
Mixed target wounds – full thickness and deep partial thickness 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
mixed thickness target wounds (full thickness and deep partial thickness). 
11.3.11.5. 
All target wounds are deep partial thickness 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
all target wounds classified as deep partial thickness wounds. 


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12. Reference List 
 
[1]  B. Atiyeh, G. S.W. and S. Hayek, "State of the art in burn treatment," World J Surg, vol. 
29, no. 2, pp. 131-48, 2005.  
[2]  D. Young, "Burn and Electrical Injury," Second ed. Plastic Surgery, vol. 1, pp. 811-833, 
2006.  
[3]  C. Cordani, "La Peau En Chirurgie Plastique," La Faculte De Medicine De Marseille, p. 
212, 2007.  
[4]  J. Barret et al., "Total Burn Wound Excision Of Massive Paediatric Burns in The First 24 
Hours Post-Injury," Annals of Burns and Fire Disasters, vol. 12, no. 1, pp. 25-27, 1999.  
[5]  Salisbury, "Thermal burns," Plastic surgery, pp. 787-830, 1990.  
[6]  B. Press, "Thermal and electrical injuries," Plastic Surgery, pp. 675-730, 1991.  
[7]  Bessey, „Wound care,“ in Total Burn Care, Saunders elsevier, 2007.  
[8]  W. ChiaChi Kao, "Acute Burns," Plastic and Reconstructive Surgery, vol. 105, no. 7, pp. 
2482-2493, 2000.  
[9]  A. Papp et al., "The progression of burn depth in experimental burns: a histological and 
methodological study," Burns, vol. 30, no. 7, pp. 684-90, 2004.  
[10] Barrett, "Effects of burn wound excision on bacterial colonization and invasion," p. 744, 
2002.  
[11] Pham, „Evaluation of the burn wound management decisions“.Total wound care.  
[12] J. Barret and D. Herndon, "Effects of burn wound excision on bacterial colonization and 
invasion," Plast Reconstr Surg, vol. 111, no. 2, pp. 744-50, 2003.  
[13] D. Heimbach et al., "Burn depth: a review," World J Surg, vol. 16, no. 1, pp. 10-5, 1992.  
[14] E. Sherwood, "The systemic inflammatory response syndrome," Total Burn Care, 2007.  
[15] G. Kramer, T. Lund and O. Beckum, "athophysiology of burn shock and burn edema," 
Total Burn Care, pp. 93-106.  


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[16] W. Xiao-Wu et al., "Effects of delayed wound excision and grafting in severely burned 
children," Arch Surg, vol. 137, no. 9, pp. 1049-54, 2002.  
[17] Y. Ong, M. Samuel and C. Song, "Meta-analysis of early excision of burns," Burns, vol. 
32, no. 2, pp. 145-50, 2006.  
[18] M. Muller, D. Gahankari and D. Herndon, "Operative wound management," Total Burn 
Care, pp. 177-195, 2007.  
[19] L. Rosenberg, Y. Shoham, Y. Krieger, G. Rubin, F. Sander, J. Koller, K. David, D. Egosi, 
R. Ahuja and A. Singer, "Minimally invasive burn care: a review of seven clinical studies 
of rapid and selective debridement using a bromelain-based debriding enzyme 
(Nexobrid®)," Ann Burns Fire Disasters, vol. 28, no. 4, pp. 264-274, 2015.  
[20] L. Rosenberg, Y. Krieger, A. Bogdanov-Berezovski, E. Silberstein, Y. Shoham and A. 
Singer, "A novel rapid and selective enzymatic debridement," Burns, vol. 40, pp. 466-47, 
2014.  
[21] A. Singer, S. McClain, B. Taira, J. Rooney, N. Steinhauff and L. Rosenberg, "Rapid and 
selective enzymatic debridement of porcine comb burns with bromelain-derived Debrase: 
acute-phase preservation of noninjured tissue and zone of stasis," J Burn Care Res, vol. 
31, no. 2, pp. 304-9, 2010.  
[22] R. Lu et al., "Major burn injury is not associated with acute traumatic coagulopathy," J 
Trauma Acute Care Surg, vol. 74, no. 6, pp. 1474-9, 2013.  
[23] N. Cosgriff et al., "Predicting life-threatening coagulopathy in the massively transfused 
trauma patient: hypothermia and acidoses revisited," J Trauma, vol. 42, no. 5, pp. 857-
61, 1997.  
[24] R. Kagan, D. Arenholtz, W. Hickerson, J. Holmes, R. Korentager, J. Kraatz and G. 
Kotoski, "American Burn Association white paper Surgical Management of the Burn 
Wound and Use of Skin Substitutes," 2009.  
[25] T. McCullough et al., "Estimated blood loss underestimates calculated blood loss during 
radical retropubic prostatectomy," Urol Int, vol. 72, no. 1, pp. 13-6, 2004.  
[26] W. McManus, C. Goodwin, A. J. Madson and B. J. Pruitt, "Burn wound infection," J 
Trauma, vol. 21, no. 9, pp. 753-6, 1981.  


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[27] A. van de Kar, L. Corion, M. Smeulders, L. Draaijers, C. van der Horst and P. van Zuijlen, 
"Reliable and feasible evaluation of linear scars by the Patient and Observer Scar 
Assessment Scale," Plast. Reconstr. Surg., vol. 116, no. 2, pp. 514-522, 2005.  
[28] D. Rubin, "Multiple Imputation for Nonresponse in Surveys," 1987.  
[29] G. Molenberghs and M. G. Kenward, Missing Data in Clinical Studies, John Wiley & Sons, 
Ltd , 2008.  
[30] C. Mallinckrodt, „Missing Data in Clinical Trails,“ in Handbook of Missing Data 
Methodology, CRC Press, 2015, pp. 499-522. 
[31] J. McCullogh, Transfusion Medicine, 4th Edition ed., Chincester, West Sussex: John 
Wiley & Sons, 2017.  
[32] M. van Reen and M. Oppe, "EQ-5D-3L user guide," April 2015. [Online]. Available: 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-3L_UserGuide_2015.pdf. 
[Accessed 02 March 2018]. 
[33] L. Gharibvand and L. Liu, "Analysis of survival data with clustered events," SAS Global 
Forum 2009, p. 237, 2009.  
[34] D. Binder, "Fitting Cox’s proportional hazards models from survey data," Biometrika, vol. 
79, pp. 139-147, 1992.  
[35] R. J. Stephens, R. E. Langley, P. Mulvenna, M. Nankivell, A. Vail and P. M. K. B, "Interim 
results in clinical trials: Do we need to keep all interim randomised clinical trial results 
confidential?," Lung Cancer, no. 85, pp. 116-118, 2015.  
[36] R. J. Lilford, D. Braunholtz, S. Edwards and A. Stevens, "Monitoring clinical trials - interim 
data should be publicly available," BMJ, no. 323, pp. 441-2, 2001.  
 
 


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13. Appendices 
13.1. Definitions 
13.1.1. General Definitions 
Full analysis Set (FAS): The full analysis set includes all patients who are randomized into 
the trial. The analysis is focused on the planned treatment 
Complete eschar removal: Complete eschar removal is achieved at the end of the eschar 
removal treatment phase. This stage will be determined by a designated blinded assessor and 
clearly marked as the end of the eschar removal process and the initiation of specific treatment 
aimed to close the viable debrided bed by grafting or epithelialization. 
Complete wound closure: Defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits, 2 weeks apart, determined by a 
blinded assessor. 
Early grafted wounds: Early autografted wounds were defined as wounds autografted within 
7 days or less from injury date. 
Late grafted wounds: Late autografted wounds were defined as wounds autografted more 
than 7 after injury date. 
13.1.2. Levels of Sedation 
For the analysis of levels of sedation, the definition of general anesthesia and levels of 
sedation/analgesia of the American Society of Anesthesiologists (see Table 3) is used.


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Table 3: Continuum of depth sedation: Definition of general anesthesia and levels of sedation/analgesia*- American Society of 
Anesthesiologists 
 
Minimal Sedation 
Anxiolysis 
Moderate Sedation/ 
Analgesia (“Conscious 
Sedation”) 
Deep Sedation/ 
Analgesia 
General Anesthesia 
Responsiveness 
Normal response to 
verbal stimulation 
Purposeful** response to 
verbal or tactile 
stimulation 
Purposeful** response 
following repeated or 
painful stimulation 
Unarousable even with 
painful stimulus 
Airway 
Unaffected 
No intervention required 
Intervention may be 
required 
Intervention often 
required 
Spontaneous 
Ventilation 
Unaffected 
Adequate 
May be inadequate 
Frequently inadequate 
Cardiovascular 
function 
Unaffected 
Usually maintained 
Usually maintained 
May be impaired 
 
 


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Minimal Sedation (Anxiolysis) is a drug-induced state during which patients respond 
normally to verbal commands. Although cognitive function and physical coordination may be 
impaired, airway reflexes, and ventilation and cardiovascular functions are unaffected.  
Moderate Sedation/Analgesia (“Conscious Sedation”) is a drug-induced depression of 
consciousness during which patients respond purposefully** to verbal commands, either alone 
or accompanied by light tactile stimulation. No interventions are required to maintain a patent 
airway, and spontaneous ventilation is adequate. Cardiovascular function is usually 
maintained.  
Deep Sedation/Analgesia is a drug-induced depression of consciousness during which 
patients cannot be easily aroused but respond purposefully** following repeated or painful 
stimulation. The ability to independently maintain ventilatory function may be impaired. 
Patients may require assistance in maintaining a patent airway, and spontaneous ventilation 
may be inadequate. Cardiovascular function is usually maintained.  
General Anesthesia is a drug-induced loss of consciousness during which patients are not 
arousable, even by painful stimulation. The ability to independently maintain ventilation 
function is often impaired. Patients often require assistance in maintaining a patent airway, and 
positive pressure ventilation may be required because of depressed spontaneous ventilation 
or drug-induced depression of neuromuscular function. Cardiovascular function may be 
impaired.  
* Monitored Anesthesia Care (“MAC”) does not describe the continuum of depth of sedation, 
rather it describes “a specific anesthesia service in which an anesthesiologist has been 
requested to participate in the care of a patient undergoing a diagnostic or therapeutic 
procedure.”  
** Reflex withdrawal from a painful stimulus is NOT considered a purposeful response.  
 
 


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13.2. Lay-out and list of tables 
For continuous variables, descriptive statistics will be presented as follows: 
Table 4: Descriptive statistics of continuous variables per treatment. 
Treatment 
Variable 
N 
Missing 
Mean 
Std Dev 
Min 
Q1 
Median 
Q3 
Max 
NexoBrid 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
Gel Vehicle 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Table 5: Counts and (column) percentages of categorical variables per treatment. 
Variable 
Treatment 
 
Total 
NexoBrid 
SOC 
Gel Vehicle 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
Category 1 
 
 
 
 
Category 2 
 
 
 
 
.... 
 
 
 
 
Total 
 
 
 
 
 
Table 6: Confidence interval and test result for odds ratios 
Comparison 
Odds ratio 
Test 
p-value 
Lower 95 % 
confidence 
bound 
Upper 95 % 
confidence 
bound 
 
 
 
 
 
 
 


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Table 7: Presentation of test results and confidence intervals 
 
Estimate 
Std Err 
Test 
Value of 
the test 
statistic 
p-value 
Lower 95 
% 
confidence 
bound 
Upper 95 
% 
confidence 
bound 
Variable 
 
 
 
 
 
 
 
 
Table 8: Table for Kaplan-Meier estimates per treatment 
Time in 
days/hours 
NexoBrid 
SOC 
Case 
Censoring 
At risk 
% 
Case 
Censoring 
At risk 
% 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 


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Table 9: Counts and percentages of Medical History Conditions or Adverse Events by MedDRA System Organ Class. 
System Organ Class 
SOC 
NexoBrid 
Gel Vehicle 
Total 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
Infections and infestations 
 
 
 
 
 
Neoplasmsm benign, malignant and 
unspecified (incl. cysts and polyps) 
 
 
 
 
 
Blood and lymphatic system disorders 
 
 
 
 
 
… 
 
 
 
 
 
Social Circumstances 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 


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Table 10: Counts and percentages of Adverse Events by categories of a categorical variable 
Variable 
SOC 
NexoBrid 
Gel Vehicle 
Total 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
Category 1 
 
 
 
 
 
Category 2 
 
 
 
 
 
Category 3 
 
 
 
 
 
… 
 
 
 
 
 
Total 
 
 
 
 
 
 


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Table 11: Counts and percentages of concomitant medication with reference to ATC coding (1st stage analysis). 
ATC code 
Contents 
Concomitant 
medication  
Number of 
Patients 
Indication 
 
 
 
 
AE 
Prophylactic 
Pre-existing 
condition 
Other 
 
 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
A 
Alimentary tract and metabolism 
 
 
 
 
 
 
B 
Blood and blood forming organs 
 
 
 
 
 
 
C 
Cardiovascular system 
 
 
 
 
 
 
D 
Dermatologicals 
 
 
 
 
 
 
G 
Genito-urinary 
system 
and 
sex 
hormones 
 
 
 
 
 
 
H 
System 
hormonal 
preparations, 
excluding sex hormones and insulins 
 
 
 
 
 
 
J 
Antiinfectives for systemic use 
 
 
 
 
 
 
L 
Antineoplastic and immunomodulating 
agents 
 
 
 
 
 
 
M 
Musculo-skeletal system 
 
 
 
 
 
 
N 
Nervous system 
 
 
 
 
 
 
P 
Antiparasitic products, insecticides and 
repellents 
 
 
 
 
 
 
R 
Respiratory system 
 
 
 
 
 
 
S 
Sensory organs 
 
 
 
 
 
 
V 
Various 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 


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Table 12: Counts and percentages of concomitant medication with reference to ATC coding (2nd stage analysis) 
ATC 
code 
Contents 
Concomitant 
medication  
Number of 
Patients 
Indication 
Start time 
 
 
 
 
AE 
Prophylactic 
Pre-existing 
condition 
Other 
Before 3m 
FU 
After 3m FU 
 
 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
A 
Alimentary 
tract 
and 
metabolism 
 
 
 
 
 
 
 
 
 
B 
Blood and blood forming 
organs 
 
 
 
 
 
 
 
 
 
C 
Cardiovascular system 
 
 
 
 
 
 
 
 
 
D 
Dermatologicals 
 
 
 
 
 
 
 
 
 
G 
Genito-urinary system and 
sex hormones 
 
 
 
 
 
 
 
 
 
H 
System 
hormonal 
preparations, 
excluding 
sex hormones and insulins 
 
 
 
 
 
 
 
 
 
J 
Antiinfectives for systemic 
use 
 
 
 
 
 
 
 
 
 
L 
Antineoplastic 
and 
immunomodulating agents 
 
 
 
 
 
 
 
 
 
M 
Musculo-skeletal system 
 
 
 
 
 
 
 
 
 
N 
Nervous system 
 
 
 
 
 
 
 
 
 
P 
Antiparasitic 
products, 
insecticides and repellents 
 
 
 
 
 
 
 
 
 
R 
Respiratory system 
 
 
 
 
 
 
 
 
 
S 
Sensory organs 
 
 
 
 
 
 
 
 
 
V 
Various 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 


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Table 13: Counts and percentages of concomitant medication with reference to ATC coding (3rd stage analysis) 
ATC 
code 
Contents 
Concomitant 
medication  
Number of 
Patients 
Indication 
Start time 
 
 
 
 
AE 
Prophylactic 
Pre-existing 
condition 
Other 
1st 
stage 
2nd 
stage 
3rd 
stage 
 
 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
A 
Alimentary 
tract 
and 
metabolism 
 
 
 
 
 
 
 
 
 
B 
Blood and blood forming 
organs 
 
 
 
 
 
 
 
 
 
C 
Cardiovascular system 
 
 
 
 
 
 
 
 
 
D 
Dermatologicals 
 
 
 
 
 
 
 
 
 
G 
Genito-urinary system and 
sex hormones 
 
 
 
 
 
 
 
 
 
H 
System 
hormonal 
preparations, 
excluding 
sex hormones and insulins 
 
 
 
 
 
 
 
 
 
J 
Antiinfectives for systemic 
use 
 
 
 
 
 
 
 
 
 
L 
Antineoplastic 
and 
immunomodulating agents 
 
 
 
 
 
 
 
 
 
M 
Musculo-skeletal system 
 
 
 
 
 
 
 
 
 
N 
Nervous system 
 
 
 
 
 
 
 
 
 
P 
Antiparasitic 
products, 
insecticides and repellents 
 
 
 
 
 
 
 
 
 
R 
Respiratory system 
 
 
 
 
 
 
 
 
 
S 
Sensory organs 
 
 
 
 
 
 
 
 
 
V 
Various 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 


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13.3. Lay-out and list of figures 
 
Figure 1: Histogram of continuous variable per treatment 


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Figure 2: Bar plot for categorical variable by treatment 
 
Figure 3: Kaplan Meier plot for time to event data 


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13.4. Lay-out and content of individual patient data listings (case wise 
listing) 
The case wise listing will not be done by the KKSB and also not form a part of the statistical 
report. Therefore, in this SAP no lay-out and content is given. The statistical report will refer to 
the clinical report for the case wise listing.


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13.4.1. List of AEs and SAEs 
Table 14: Table for listing of all AEs and SAEs. 
AE 
Subject Id 
Start date 
Duration 
in days 
Number 
of AE 
Description 
of AE 
Severity 
grade 
Relationship 
Outcome 
Study 
treatment 
Therapy 
of AE 
SAE 
1 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.5. Details of the Amendments 
13.5.1. Summary of Amendment of version 8 to version 9 
Study title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care   
 
Study plan code: MW 2010-03-02 
IND No.:  
65,448 
EudraCT No.: 
2014-001672-55 
 
Amendment summary- protocol MW2010-03-02, version 09, 12 Aug 2015 
The following changes were performed in protocol version 9: 
1. Pages 40 and 100-102, Randomization and Stratification 
a. Changes: Stratifications levels were revised; stratification per %TBSA was 
removed and stratification per depth was revised and SPT proportion was 
removed from the stratification levels. In addition, randomization will be 
performed per blocked randomization method rather by minimization 
b. Justifications: Per FDA comments sent to the Sponsor on May 2015, 
stratification levels were reduced and will be performed in the amended 
protocol per patient’s wounds depth and per clinical center. In addition, FDA 
suggestion to perform “simple randomization” was implemented. 
2. Pages 102-104, Data Handling 
a. Changes: Missing data section was slightly revised for the efficacy & safety 
endpoints 
b. Justifications: The above changes were performed in accordance with FDA 
comments sent on May 2015. 
3. Pages 78 and 93-05 Analysis of endpoints 
a. Changes: Planned analysis of the primary, secondary & safety endpoints was 
slightly revised per FDA suggested comments (e.g. limiting the planned 
analysis to only the terms expected to have the greatest impact, pre- define a 
plan in the protocol for checking assumptions and determining which analysis 
will be used, etc) 
b. Justifications: The above revisions were implemented per FDA suggested 
comments sent on May 2015. 


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13.5.1. Summary of Amendment of version 9 to version 11 
The below table summarizes the changes to Protocol MW2010-03-02, version 9 (submitted to the FDA on August 18, 2015, 
SN0087) as was implemented in protocol, version 11.  
Line 
Section in 
version 11 
Suggested Change 
Justification 
1.  
Definition 
(section 1) 
Additions to the definition of ‘Circumferential extremity wounds’ (see in 
BOLD): “Circumferential extremity wounds: Limb DPT and/or FT burns 
which encircle ≥ 80% of the limb circumference” and “Extremities at Risk 
(EAR) are circumferential DPT and/or FT burns that may develop BICS 
during the first 3 days post injury with at least one of the following…” 
Details were added for clarity and standardization among 
sites 
Definition for ‘Increased interstitial pressure syndrome’ was revised to 
be in line with the Burn-induced compartment syndrome (BICS)- the 
common medical term 
BICS is a medical event described in the protocol which 
is being monitored by the treating physicians in 
anatomical areas of the extremities  
Additions to the definition of Target Wounds 
Details were added for clarity and standardization among 
sites. Minimal size of target wound was reduced to 0.5% 
TBSA (see further justification in line 12 below) 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
Addition of definition for substance use disorder in accordance with the 
DSM-5 
This definition was added to support exclusion # 24 (see 
line #13 below)- to better describe alcohol abuse  
Addition of assessment of complete wound closure and complete eschar 
removal- by a blinded assessor 
This addition is in line with the protocol and former 
discussions with the agency. Added in this section for 
clarity and consistency with the study protocol.  
2.  
Synopsis  
(section 2) 
The following changes were performed: 
Changes to entrance criteria (see lines #10-13 below), additional safety 
outcome measures (line #8), Study Treatments and Dosage (line #9) 
and additional exploratory endpoints (line #5). All these changes are 
further detailed below. 
In accordance with changes performed in the body of the 
protocol, similar changes are described in the synopsis 
section. Please refer to more details in the relevant lines 
below. 
3.  
Introduction 
(Section 3) 
Addition of Pharmacokinetic profile section from the recently completed 
study MW2008-09-03- Section 3.2.3 
Information could be added following recent completion 
of study MW2008-09-03  
Minor additions to section 3.3.2 -  under extremities wounds  
Additional medical information was added to this section 
4.  
General 
safety 
Endpoints 
(section 6.1.3) 
Addition of the following parameters to the general safety endpoints: 
“Number and volume of blood transfusions received throughout the 
hospital admission, Extent of analgesia, anaesthesia and antibiotic use, 
Rates of hospital readmission, Change in INR/PTT and incidence of 
change to > upper limit of normal (after treatment), Change in blood 
The proposed changes were added in an attempt to 
harmonize the protocol and meet both the FDA and 
CHMP requirements 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
glucose and incidence of change to above upper limit of normal (after 
treatment)”. 
5.  
Exploratory 
Endpoints 
(section 6.1.4) 
1. Description of planned autograft analyses were added: efficacy and 
safety analyses for early and late grafted wounds, total number of 
target wound grafting procedures, incidence of repeat/additional 
grafting procedures & area of repeat grafting 
2. Duration of hospitalization- added as additional exploratory EP 
The proposed changes were added in an attempt to 
harmonize the protocol and meet both the FDA and 
CHMP requirements 
6.  
Assessment 
of 
clinical 
measures 
(section 6.3.1.1) 
Under Extent of eschar removal assessment using topical agent; 
NexoBrid or Gel Vehicle, the following was added: “For the purpose of 
standardization, if feasible, the same blinded assessor should be 
assigned to assess eschar removal in all patients, and in all study arms”. 
This change was added to further improve the 
standardization of the eschar removal assessment 
among the sites  
7.  
Non 
surgical 
eschar removal 
(section 6.3.1.3) 
The following clarification was added (in BOLD): “Wounds will be 
assessed by a burn specialist as in common daily practice, following 
any dressing change” 
This change was added to further improve the 
standardization of the eschar removal assessment 
among the sites 
8.  
Main safety 
measures 
(6.3.2) 
The following was added: “This assessor should not be involved in 
any eschar removal procedure and should not be aware whether 
the patient was assigned to the topical arms or to the SOC arm. For 
the purpose of standardization, if feasible, the same blinded 
assessor should be assigned to assess wound closure, cosmesis 
This change was added to further improve the 
standardization of the wound closure and cosmesis and 
function assessment among the sites 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
and function (as described below) in all patients, and all study 
arms. The blinded assessor will sign the "blinded assessor memo".  
9.  
Study 
Treatments and 
Dosage (6.4) 
 
The following instruction was added: "NexoBrid/Gel vehicle should not 
be applied to more than 15% TBSA (±3% TBSA) in one session". 
 
This instruction was added to instruct how to use the 
study drug in patients with targets wounds of more than 
15% TBSA that may be included to the study following the 
change in Inclusion No 4  
10.  
Inclusion 
Criteria- patient 
level 
(section 
7.1.1) 
Inclusion No. 1- upper age of 70 was deleted: “Males and females; ≥ 
18  years of age” 
The change was implemented in accordance with the 
FDA request (letter from May 14, 2015) 
Inclusion No. 4- %TBSA was revised to be maximum of 30% TBSA: 
“Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or 
FT in depth”  
The change was implemented in accordance with the 
agreed changes discussed with the FDA (Type C TC, 
May 25, 2016) 
Inclusion No. 5 was revised as following: “Informed consent can be 
obtained within 84 hours of the burn injury”  
 
Patients will need to sign on ICF before start of treatment 
which will be no later than 84 hrs from injury (section 8.2 
in the protocol, version 11) instead of within 48 hrs. This 
will allow larger flexibility for signing consent form based 
on feedback received from clinical sites participating in 
the study. Start of treatment limitation was changed as 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
well. In protocol version 9, the allowed window to start 
treatment was 72 hrs from injury. This window was 
expanded to be 84 hrs from injury. 
11.  
Inclusion 
criteria- 
wound 
level 
(section 
7.1.2) 
Addition of inclusion Criterion: “SPT areas that cannot be demarcated 
from DPT and FT areas should be less than 50% of the % TBSA of the 
TW”. In addition, clarification was added regarding the minimum criteria 
for patient to be enrolled in a wound level. 
To increase standardization of treated wounds and to 
avoid treating wounds with large superficial areas  
12.  
Inclusion 
criteria- 
wound 
level 
(section 
7.1.2) 
Minimal wound size was reduced from 1% TBSA (FT and/or DPT) to 
0.5% TBSA. 
To avoid having patients with 3% TBSA DPT and/or FT 
wounds that most of them small and could not be defined 
as TWs, the minimum size of TW was reduced.  
13.  
Exclusion 
Criteria (section 
7.1.3) 
Exclusion #5: Blast injury was removed and inserted as part of exclusion 
#18 
As blast injury considered as an additional risk in burn 
patients, this was added to Exclusion 18 which exclude 
patients with “Any conditions that would preclude safe 
participation in the study or adding further risk to the basic 
acute burn trauma” 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
Deletion of Exclusion #6: “Patients with DPT and/or FT facial burn 
wounds from flame, flash, explosion > 0.5%  TBSA (scald and contact 
burns are allowed)” 
This exclusion was originally written in order to avoid 
inclusion of subjects with diagnosis of smoke inhalation 
injury however this  concern is being addressed by 
Exclusion criterion # 12 (see below)  
Clarification added to exclusion #7 (in BOLD): “Patients with 
circumferential (≥ 80% of the limb circumference) DPT and/or FT 
burns defined as Extremities at Risk (EAR)” 
A more accurate  definition  of circumferential injury was 
inserted into this criterion  to avoid confusion 
Exclusion criterion #12: “Any signs or history that may indicate smoke 
inhalation” was revised to be “Diagnosis of smoke inhalation injury” 
This criterion was modified to avoid exclusion of patients 
with signs which do not necessarily indicate smoke 
inhalation injury  
Exclusion criterion #14- lower limit of HbA1c for poorly controlled 
diabetes mellitus was increased from 9% to 11% 
This change does not add any safety risk, as assessed 
medically 
Exclusion #15 was revised- BMI exclusion will be based on the extent of 
burn area- patients with up to 15%TBSA will be excluded if BMI above 
39 and patients with %TBSA above 15% will be excluded if BMI above 
34.  
This revision was performed following feedback from the 
US clinical sites relate to the common US population. This 
change will not add any additional safety concern 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
Exclusion criteria #17-19- Medical conditions in injured subjects that 
should be excluded from the study were better defined (see in bold): 
1. 
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), 
2. 
Pre-existing diseases which interfere with circulation (severe 
peripheral vascular disease, severe edema and/or lymphedema, 
regional lymph nodes dissection, significant varicose veins). 
Obesity was deleted from this criterion as being addressed in 
exclusion # 14 
3. 
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) 
To avoid exclusion of patients with condition that will not 
preclude safe participation 
Exclusion criterion #24- clarification regarding alcohol and drug abuse- 
this definition was revised in the protocol, section 1 (see line 1 above):  
Substance use disorder: describes a problematic pattern of using 
alcohol or another substance that results in impairment in daily life 
To avoid exclusion of patients who used drugs/drink 
alcohol but are not abused and can sign consent and 
could comply with study procedures 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
or noticeable distress. The DSM-5 states that in order for a person 
to be diagnosed with a severe disorder due to a substance, they 
must display 6 or more of the 11 symptoms within 12-months. 
These 11 symptoms are now defined in the protocol and should be 
assessed by the sites.  
14.  
Subject 
withdrawal 
criteria (7.2) 
Addition of criteria for subject’s removal from the study- “Withdrawal of 
subjects with EAR identified post randomization but prior to 
treatment” 
This addition will allow exclusion of subjects with BICS 
diagnosed after randomization and before start of 
treatment  
15.  
BICS monitoring 
& 
diagnosis 
(section 7.2.1.1) 
· Clarification was added- all circumferential wounds should be 
closely monitored during treatment. 
· Escharotomy "will" be performed was replaced with "may"  
· Minor wording changes for clarity 
· This was added to avoid deviations and ensure close 
monitoring 
of 
circumferential 
wounds 
during 
treatment 
· Following feedback from the study PIs- SOC does not 
necessarily include escharotomy following BICS 
diagnosis as defined in the study protocol hence, 
escharotomy is at the discretion of the PI.  
16.  
Post 
treatment 
diagnosed 
infection 
(section 7.2.1.3) 
Timeframe for diagnosed infection, that may be consider as a stopping 
rule, was added - until complete wound closure 
 
The timeframe was added for clarity of standardization 
Section 8- Study conduct  


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Line 
Section in 
version 11 
Suggested Change 
Justification 
17.  
Screening 
and 
Baseline 
Procedures 
(section 8.1.1) 
Burn description (size and depth) as well as photographs were deleted 
before cleansing and will be captured only after cleansing 
Screening wound assessments will be performed only 
once after initial cleansing of wounds. Pre cleansing is 
usually done pre signing informed consent and therefore 
this assessment was deleted.  
18.  
Screening 
and 
Baseline 
Procedures 
(section 8.1.1) 
The use of schematic drawing to mark TWs location was added to the 
protocol  
This drawing is being used by the sites and the relevant 
documentation was added to the study protocol  
19.  
Assessment 
within 
24hrs 
prior to eschar 
removal (section 
8.1.3) 
Assessments and procedures previously requested within 24 hrs prior 
to start of eschar removal were moved and will be performed within 1 hr 
prior to start of treatment (8.2.1) 
All procedures before treatment will be performed at the 
same time and will prevent repeated blood tests for the 
subjects 
20.  
Treatment 
procedure- 
Eschar Removal 
(Section 8.2) 
Start of treatment was change from 72 to 84 hrs from injury 
To allow a wider time frame for treatment preparations 
(screening, ICF signing, pre treatment procedures, 
cleansing) 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
21.  
SOC & Topical 
arms- eschar 
removal 
procedures 
(sections 8.2.2 
& 8.2.3) 
Most of the changes in these sections are only editorial ones. Additional 
changes are described below 
Editorial changes were performed in order to have the 
procedures written in chronological order and with similar 
structure in both arms. 
22.  
SOC & Topical 
arms- eschar 
removal 
procedures 
(sections 8.2.2 
& 8.2.3) 
Pre procedure assessments will be done only when the additional 
procedure is surgical 
The need to perform pre assessments for additional 
topical procedure or additional SOC that is non-surgical 
were deleted, since the assessment are done post the 
previous procedure (topical or surgical) as described in 
the protocol 
23.  
sections 
8.2.2.1.4, 
8.2.2.2.3, 
8.2.3.2 & 8.4  
Addition of clarification footnote with regard to complete eschar removal 
assessment  
 
Assessment of complete eschar removal was further 
specified to improve standardization across centers.  
 
 


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24.  
Post first 
procedure (SOC 
and topical 
arms) 8.2.2.1.4 
& 8.2.3.1.6 
PTT/INR: 
· Will not be taken after surgical procedure if it is not the first 
procedure.  
· Will be taken 4 hours post treatment instead of 4 hours from start of 
treatment 
 
· To avoid duplications with 24 and 48 hours 
assessments 
· In order to reduce time points of taking blood from the 
patients, PTT/INR will be taken at the same time point 
of the safety central lab tests 
25.  
Post first & post 
second 
application 
assessments – 
8.2.3.1.6 & 
8.2.3.2.2 
Assessments post topical procedure will be collected 4 hours post 
removal of topical agent instead of 4 hours post soaking (2 hours earlier) 
This change will result in similar time point as in the SOC 
arm 
26.  
Post first 
procedure 
(8.2.2.1.4) & 
Post additional 
procedure 
(8.2.2.2.3) 
Post non-surgical assessments - Will be taken only if the non-surgical 
procedure is the last procedure – i.e. resulted in complete eschar 
removal 
If non surgical procedure is not the last it will be followed 
by a surgical procedure and assessments will be done pre 
surgical procedure.  


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27.  
General 
assessment & 
Wound 
management 
procedure 
(sections 8.3 & 
8.5) 
Coverage used as wound management will be captured until wound 
closure 
This information is important to be captured during the 
study, until wound closure 
28.  
General 
assessment 
(section 8.3) 
Additional time point for PK was added- 72 hours from start of treatment 
This point was added based on PK profile information 
collected to date  
29.  
Follow-up 
Assessments 
(section 8.6) 
Addition of clarification footnote with regard to complete wound closure 
assessment  
 
Assessment of complete wound closure was further 
specified to improve standardization across centers. 
30.  
Follow-up 
Assessments 
(section 8.6) 
Weekly FU visits will be continued until donor sites will be closed 
This assessment will provide additional safety data in 
patient level (i.e. closure of all wounds, including the 
donor sites, if relevant) 


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31.  
Hospital 
Discharge 
(section 8.7) 
The following assessments at Hospital Discharge (HD) were deleted:  
1. The target wounds and donor sites should be labeled and 
photographed, 
2. Assessment of % of wound area epithelialized and/or closed by 
graft,  
3. Assessment of % of donor site area epithelialized, 
4. Type of cover/dressing applied on TWs and donor sites should be 
recorded 
These changes were applied to avoid duplicate 
assessments of in both weekly FU visits and HD visit 
which is being performed in parallel to the weekly FU 
visits 
32.  
Follow-up 
assessments: 
wound closure 
confirmation 
(Section 8.8) 
Extent of wound closure will be documented in the confirmation visit 
This assessment was added In order to collect additional 
exploratory information 
33.  
Table 3, section 
9 
Changes performed in accordance with changes in flow of treatment  
 
34.  
Primary 
endpoint 11.1 
The assessment of the Incidence of complete eschar removal was 
clarified  
The wording was changed to stress that the assessment 
that is considered for the primary endpoint is the one done 
by  the blinded assessor and at a specific pre defined time 
point 


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35.  
Safety 
EPs- 
Time 
to 
complete wound 
closure (section 
11.3.1) 
NI margin for time to wound closure reduced to 7 days instead of 7.4 
days 
The 
proposed 
change 
was 
added 
following 
re 
assessments and taking into consideration additional 
clinical data.  
36.  
Safety 
EPs- 
Cosmesis 
& 
function at 12 
and 24 months 
(sections 11.3.2 
and 11.3.3) 
NI margin for MVSS was reduced to 1.9 
The 
proposed 
change 
was 
added 
following 
re 
assessments and further discussion with PIs.  
37.  
General 
safety 
parameters 
(section 11.3.4) 
The following were added: “Number and volume of blood 
transfusions received throughout the hospital admission, Extent of 
analgesia, anaesthesia and antibiotic use (i.e. total dose per kg 
body weight), Rates 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)” 
See line #4 above 


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38.  
Exploratory EPs 
(section 11.4)  
1. Description of planned autograft analyses were added: efficacy 
and safety analyses for early and late grafted wounds, total 
number of target wound grafting procedures, incidence of 
repeat/additional grafting procedures & area of repeat grafting 
2. Duration of hospitalization- added as additional exploratory EP.  
See line #5 above 
39.  
Additional 
analyses 
(section 11.5 & 
13.3.4.2) 
Additional analyses were added for eschar removal and wound closure  
The proposed change was added in attempt to 
harmonize the protocol and meet both the FDA and 
CHMP requirements  
40.  
Subgroup 
analyses 
(section 11.6 & 
13.3.5) 
The following sub groups were added: 
· 
Sub group analysis on entirely FT wounds 
· 
Sub group analysis on patients classified as having <25% or 
>=25% SPT area as a percentage of the area of all TWs 
· 
Sub group analysis per % TBSA  
The first 2 subgroup analyses were added in order to test 
for possible effects of wounds depth on the study results.  
The subgroup analysis per %TBSA was implemented in 
accordance with the agreed changes discussed with the 
FDA (Type C TC, May 25, 2016). See also appendix #1 
for the rational to include sub group analysis per %TBSA 
as additional analysis and not to include it in the main 
analysis (primary analysis) as discussed with the FDA 
during the TC.  


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41.  
EAR and BICS- 
Monitoring 
and 
Diagnosis 
(section 11.8) 
Revision to EAR & BICS section was performed and clarification of 
monitoring methods on each time point was added to this section 
Main reason for change is to reduce complexity in 
following protocol procedures and reduce sites’ potential 
deviations 
42.  
Immunogenicity 
evaluation 
(section 11.11) 
Week 1 test was deleted. Immunogenicity evaluation will now be 
performed based on weeks 4, 8 and 6 & 24 months visits 
The ELISA method is specific for anti NexoBrid IgG. 
Circulating anti NexoBrid IgG are not expected  one week 
after treatment and hence, this time-point was deleted  
43.  
Graft loss and 
Graft 
take 
(section 11.16)  
Added definition for graft take 
Definition was added to further allow standardization 
44.  
Pharmacokinetic 
evaluation 
(section 11.21) & 
Appendix 
10- 
Procedures 
for 
specific 
blood 
tests 
PK timelines were revised as follows:  
In subjects requiring a single application:  
Before treatment (time zero), 0.5 hours ± 10 minutes,  2 hours ± 10 minutes, 
4 hours ± 10 minutes, 12 hours ± 30 minutes, 24 hours ± 30 minutes , 48 hours 
± 30 minutes and 72 hours ± 30 minutes after NexoBrid application. 
In subjects requiring two planned applications of NexoBrid: 
1st treatment: before treatment (time 0), 0.5 hours ± 10 minutes, 2 and 4 
hours ± 10 minutes after the first NexoBrid application. 
Based on the available PK data from study MW2008-09-
03, new sampling paradigm is proposed for the Phase 3 
MW2010-03-02 study to support PK analysis after the 
first and second  applications  


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2nd treatment: time 0, 30 ± 5 minutes, 2 hours ± 10 minutes, 4 hours ± 10 
minutes, 12 hours ± 30 minutes , 24 hours ± 30 minutes, 48 and 72 hours ± 30 
minutes after the second NexoBrid application 
 
45.  
Pharmacokinetic 
evaluation 
(section 11.21) & 
Appendix 
10- 
Procedures 
The subset of patients tested for PK was modified: 
1. 16 subjects with total wounds area of  <=15% TBSA  
2. 16 subjects with total wounds area to be treated of  >15% TBSA   
 
 
This addition of PK samples in  patients with more than 
15% TBSA will provide PK information in patients with 
maximal permissible TBSA and data for second 
application  
46.  
Safety endpoint- 
Time to wound 
closure (section 
13.3.3.1) 
An addition to the planned Cox regression model 
This change was performed in accordance with the FDA 
request (letters from 14 May 2015 & 03 Nov 15) 
47.  
Stratification 
(13.7.2) 
Stratification factor of TBSA was added. Stratification levels of the factor 
Center was reduced by grouping centers into 5 groups. 
Stratification by TBSA was added due to the change in 
inclusion No 4 to include patients with TBSA of more than 
15%.  
Stratification by centre was changed to "group of centers, 
5 groups rather 30 centers to allow balance in the 
randomization. 


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48.  
Missing 
data 
(13.8.4) 
The analysis of the safety endpoint time to complete wound closure will 
compute missing values as censored. 
This change was performed in accordance with the FDA 
request (letters from 14 May 2015 & 03 Nov 15) 
49.  
Section 13 
Changes performed in sections 13.3.3.3 (general safety parameters), 
13.3.4 (exploratory), 13.3.4.2 (additional analyses) and 13.3.5 
(subgroup analyses) as described in lines 24-27 above 
Changes performed as described above 
Section 14- Quality assurance 
50.  
DSMB  
(section 14.4)  
Addition of special cases for DSMB convention- 
1.After randomization of 10 NexoBrid patients suffering from deep burns 
of more than 15% TBSA (TWs area) and were treated with 2 repeated 
applications of  NexoBrid 
2. After randomization of 25 NexoBrid patients suffering from deep 
burns of more than 15% TBSA (TWs area) and were treated with 2 
repeated applications of  NexoBrid 
This change is part of the risk mitigation plan suggested 
to support the inclusion and treatment of patients up to 
30% TBSA as was discussed with the FDA during the 
Type C meeting held on May 25, 2016 
 
DSMB  
(section 14.4) 
Timing of the routine meeting was clarified, Review of narratives by the 
DSMB was added 
The proposed changes were added in attempt to better 
clarify the DSMB role 


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51.  
Appendix 
3- 
Photographic 
wound 
documentation 
 
Details were added to the instructions in this appendix, in accordance 
with the study photograph guideline.  
Detailed instructions were added in order to ensure 
standardized digital images  
 
 

Prot_000.pdf: 
Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 1 of 173 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
Study Title: 
A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of 
NexoBrid compared to Gel Vehicle and compared to Standard of Care   
 
 
Protocol No.: MW2010-03-02 
IND No: 65,448 
EudraCT No: 2014-001672-55 
Clinical Phase: III 
 
 
Sponsor:  
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
Tel: 972-77-9714100 
 
 
 
Chief Medical Officer: Lior Rosenberg, MD 
 
 
 
This clinical study will be conducted in accordance with Declaration of Helsinki and its updates, 
current Good Clinical Practice (GCP), the provisions of ICH (International Conference on 
Harmonisation); US Code of Federal Regulations (Title 21, CFR Part 11, 50, 54, 56 and 312) 
and/or EU Directives; local country regulations and the sponsor's Standard Operating 
Procedures (SOPs) 
 
CONFIDENTIAL 
The information in this document contains trade secrets and proprietary information of 
MediWound Ltd. and considered privileged and confidential. The Information may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board/Ethics 
Committee approval, informed consent and the approval of local regulatory authorities as 
required by local law, or unless otherwise agreed in advance and in writing by MediWound 
Ltd. 
 
All rights reserved to MediWound Ltd. 2016 
 
No part of this Protocol may be reproduced or transmitted in any form or by any means, 
electronic or mechanical, including photocopying, recording, or any information storage or 
retrieval system without the prior written permission from MediWound Ltd. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 2 of 173 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
TABLE OF CONTENT 
1. 
LIST OF DEFINITIONS AND ABBREVIATIONS ....................................................................... 8 
1.1 
DEFINITIONS ........................................................................................................................................ 8 
1.2 
ABBREVIATIONS ................................................................................................................................ 12 
2. 
SYNOPSIS ........................................................................................................................................ 14 
3. 
INTRODUCTION ............................................................................................................................ 23 
3.1 
MEDICAL OVERVIEW ........................................................................................................................ 23 
3.2 
CLINICAL DEVELOPMENT OF NEXOBRID ......................................................................................... 25 
3.2.1 
Efficacy .............................................................................................................................................. 25 
3.2.2 
Safety .................................................................................................................................................. 28 
3.2.3 
Pharmacokinetic profile ..................................................................................................................... 32 
3.3 
RISK ASSESSMENT ............................................................................................................................. 32 
3.3.1 
General .............................................................................................................................................. 32 
3.3.2 
Extremities Wounds ............................................................................................................................ 34 
4. 
ETHICS STATEMENT................................................................................................................... 37 
5. 
STUDY OBJECTIVES .................................................................................................................... 38 
6. 
INVESTIGATIONAL PLAN .......................................................................................................... 38 
6.1 
PRIMARY ENDPOINTS, SECONDARY ENDPOINTS AND OTHER ENDPOINTS ...................................... 38 
6.1.1 
Primary Endpoint ............................................................................................................................... 38 
6.1.2 
Secondary Endpoints .......................................................................................................................... 38 
6.1.3 
Safety Endpoints ................................................................................................................................. 39 
6.1.4 
Exploratory Endpoint ......................................................................................................................... 39 
6.2 
STUDY DESIGN ................................................................................................................................... 40 
6.3 
MEASURES TAKEN TO MINIMIZE/AVOID BIAS ................................................................................. 42 
6.3.1 
Assessments of Clinical Measures...................................................................................................... 42 
6.3.2 
Main safety measures ......................................................................................................................... 43 
6.4 
STUDY TREATMENTS AND DOSAGE .................................................................................................. 44 
6.4.1 
NexoBrid ............................................................................................................................................ 44 
6.4.2 
Gel Vehicle ......................................................................................................................................... 44 
6.4.3 
Standard of Care ................................................................................................................................ 45 
6.5 
TRIAL PERIODS ................................................................................................................................. 45 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................................. 45 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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7.1 
SUBJECT ENTRANCE CRITERIA ........................................................................................................ 45 
7.1.1 
Inclusion Criteria- Patient level ......................................................................................................... 45 
7.1.2 
Inclusion Criteria – Wound level ....................................................................................................... 45 
7.1.3 
Exclusion Criteria- Patient level ........................................................................................................ 46 
7.2 
SUBJECT WITHDRAWAL CRITERIA .................................................................................................. 47 
7.2.1 
Stopping rules (apply for NexoBrid or Gel Vehicle arms only) ......................................................... 47 
8. 
STUDY CONDUCT ......................................................................................................................... 50 
8.1 
SCREENING AND BASELINE VISIT ..................................................................................................... 50 
8.1.1 
Screening and Baseline Procedures ................................................................................................... 50 
8.1.2 
Cleansing and Soaking ....................................................................................................................... 51 
8.2 
TREATMENT PROCEDURE- ESCHAR REMOVAL: NEXOBRID/SOC/GEL VEHICLE - INITIATED 
WITHIN 84 HOURS FROM INJURY ..................................................................................................... 52 
8.2.1 
All arms - Pre first treatment assessments- within 1 h pre treatment ................................................ 52 
8.2.2 
Standard of Care (SOC) Arm - Eschar removal procedure- (to be initiated within 84 hours from 
injury) ............................................................................................................................................ 53 
8.2.3 
Topical arms; NexoBrid/Gel Vehicle - Eschar removal procedure (to be initiated within 84 hours 
from injury) .................................................................................................................................... 57 
8.3 
GENERAL ASSESSMENTS, POST ESCHAR REMOVAL.......................................................................... 63 
8.4 
POST-ESCHAR REMOVAL- WOUND MANAGEMENT ......................................................................... 63 
8.5 
WOUND MANAGEMENT PROCEDURES – (REFER TO ANY PROCEDURE POST COMPLETE ESCHAR 
REMOVAL); ...................................................................................................................................... 66 
8.6 
FOLLOW-UP ASSESSMENTS: WEEKLY (7  2 DAYS) POST-START OF ESCHAR REMOVAL ................ 67 
8.7 
HOSPITAL DISCHARGE ...................................................................................................................... 67 
8.8 
FOLLOW-UP ASSESSMENTS: WOUND CLOSURE CONFIRMATION 2 WEEKS POST WOUND CLOSURE 67 
8.9 
FOLLOW-UP LONG TERM ASSESSMENTS ........................................................................................... 68 
8.10 
FOLLOW-UP ASSESSMENTS: RE-ADMISSION TO HOSPITAL OR DAY CARE .................................... 69 
9. 
TREATMENT FLOW CHART – STUDY SCHEDULE ............................................................. 70 
10. 
DRUG STORAGE AND DRUG ACCOUNTABILITY ............................................................... 74 
10.1 
ACCOUNTABILITY AND COMPLIANCE .............................................................................................. 74 
10.2 
PREVIOUS AND ON-GOING MEDICATIONS/THERAPIES. ................................................................... 74 
10.2.1 
Disallowed Previous and On-Going Medications/Therapies ............................................................. 74 
10.2.2 
Allowed Previous and On-Going Medications/Therapies .................................................................. 74 
11. 
ASSESSMENT METHODS ............................................................................................................ 75 
11.1 
PRIMARY END POINT ........................................................................................................................ 75 
11.2 
SECONDARY ENDPOINTS ................................................................................................................... 75 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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CONFIDENTIAL 
11.2.1 
Reduction in surgical needs ............................................................................................................... 75 
11.2.2 
Earlier eschar removal ...................................................................................................................... 75 
11.2.3 
Blood loss ........................................................................................................................................... 75 
11.3 
SAFETY ENDPOINTS ........................................................................................................................... 77 
11.3.1 
Time to complete wound closure ........................................................................................................ 77 
11.3.2 
Cosmesis and function at 12 months from wound closure ................................................................. 78 
11.3.3 
Cosmesis and function at 24 months from wound closure ................................................................. 78 
11.3.4 
General parameters ........................................................................................................................... 79 
11.3.5 
Local parameters ............................................................................................................................... 80 
11.4 
EXPLORATORY ENDPOINTS .............................................................................................................. 80 
11.5 
ADDITIONAL ANALYSIS ..................................................................................................................... 80 
11.6 
SUBGROUP ANALYSES ....................................................................................................................... 81 
11.7 
SAFETY LABORATORY EVALUATIONS .............................................................................................. 81 
11.8 
EAR AND BURN INDUCED COMPARTMENT SYNDROME MONITORING AND DIAGNOSIS ................ 83 
11.9 
INFECTION ......................................................................................................................................... 85 
11.10 
VITAL SIGNS ...................................................................................................................................... 87 
11.11 
IMMUNOGENICITY EVALUATION ...................................................................................................... 88 
11.12 
ECG (QT EVALUATION) ................................................................................................................... 88 
11.13 
PHYSICAL EXAMINATION .................................................................................................................. 88 
11.14 
PAIN ASSESSMENT USING VISUAL ANALOGUE SCALE (PAIN SCALE RULER) ................................. 88 
11.15 
CONCOMITANT MEDICATIONS ......................................................................................................... 88 
11.16 
GRAFT LOSS/GRAFT TAKE ............................................................................................................... 89 
11.17 
HYPOTHERMIA AND PYREXIA [94] .................................................................................................... 89 
11.18 
COSMESIS AND FUNCTION ASSESSMENT ........................................................................................... 89 
11.18.1 MVSS .................................................................................................................................................. 89 
11.18.2 POSAS ................................................................................................................................................ 90 
11.19 
QUALITY OF LIFE .............................................................................................................................. 90 
11.20 
FUNCTION ASSESSMENTS .................................................................................................................. 90 
11.21 
PHARMACOKINETIC EVALUATION .................................................................................................... 91 
11.21.1 Real time data capture and Independent Safety Monitoring .............................................................. 91 
12. 
SAFETY AND PHARMACOVIGILANCE .................................................................................. 92 
12.1 
RELATIONSHIP TO STUDY DRUG ...................................................................................................... 92 
12.2 
ADVERSE EVENT INTENSITY ............................................................................................................. 92 
12.3 
ADVERSE EVENT REPORTING ........................................................................................................... 93 
12.4 
SERIOUS ADVERSE EVENTS .............................................................................................................. 93 
12.5 
SERIOUS ADVERSE EVENT REPORTING ............................................................................................ 94 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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CONFIDENTIAL 
12.6 
PREGNANCIES .................................................................................................................................... 94 
13. 
STATISTICAL ANALYSIS ............................................................................................................ 95 
13.1 
POPULATIONS .................................................................................................................................... 95 
13.1.1 
Major Protocol Violations ................................................................................................................. 95 
13.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................................................... 95 
13.3 
EFFICACY EVALUATION .................................................................................................................... 95 
13.3.1 
Primary Endpoint ............................................................................................................................... 96 
13.3.2 
Secondary endpoints .......................................................................................................................... 96 
13.3.3 
Safety endpoints ................................................................................................................................. 97 
13.3.4 
Exploratory endpoints and additional analyses ................................................................................. 99 
13.3.5 
Subgroup Analyses ........................................................................................................................... 100 
13.4 
STATISTICAL COMPUTING .............................................................................................................. 101 
13.5 
SAMPLE SIZE CALCULATIONS ........................................................................................................ 101 
13.5.1 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. Gel) ............................... 101 
13.5.2 
Secondary Endpoint: Incidence of surgical excision ....................................................................... 102 
13.5.3 
Secondary Endpoint: Time to complete eschar removal .................................................................. 102 
13.5.4 
Summary of sample size ................................................................................................................... 102 
13.5.5 
Safety endpoints ............................................................................................................................... 102 
13.6 
ALPHA CONTROL ............................................................................................................................. 103 
13.7 
STRATIFICATION AND RANDOMIZATION ........................................................................................ 103 
13.7.1 
Randomization Procedure: .............................................................................................................. 103 
13.7.2 
Stratification: ................................................................................................................................... 104 
13.7.3 
Randomization algorithm: ............................................................................................................... 104 
13.8 
DATA HANDLING METHODS AND DEFINITIONS ............................................................................. 104 
13.8.1 
Multiple visits per time-point ........................................................................................................... 104 
13.8.2 
Rules for Data Derivations .............................................................................................................. 105 
13.8.3 
Multiple target wounds per patient .................................................................................................. 105 
13.8.4 
Missing data ..................................................................................................................................... 105 
13.8.5 
Stratifying by center in the analysis ................................................................................................. 106 
13.8.6 
Stages of Analysis ............................................................................................................................. 106 
14. 
QUALITY ASSURANCE .............................................................................................................. 108 
14.1 
QUALITY ASSURANCE PROGRAM ................................................................................................... 108 
14.2 
MONITORING PROCEDURES ............................................................................................................ 108 
14.3 
REGULATORY AND ETHICAL CONSIDERATIONS ............................................................................. 108 
14.4 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................................... 108 
15. 
INVESTIGATOR’S AGREEMENT ............................................................................................ 110 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 6 of 173 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
16. 
APPENDICES ................................................................................................................................ 111 
APPENDIX 1- WOUND DEPTH ASSESSMENT- CLINICAL EVALUATION ............................................................ 111 
APPENDIX 2- PAIN MANAGEMENT PROCEDURES ............................................................................................ 112 
APPENDIX 3- PHOTOGRAPHIC WOUND DOCUMENTATION ............................................................................... 115 
APPENDIX 4- POST-ESCHAR REMOVAL WOUND MANAGEMENT .................................................................... 116 
APPENDIX 5- WOUND MANAGEMENT; APPROVED COVERS ............................................................................. 132 
APPENDIX 6- REGULATORY AND ETHICAL ISSUES ........................................................................................... 134 
APPENDIX 7- STUDY ADMINISTRATIVE PROCEDURES ..................................................................................... 136 
APPENDIX 8- BIOPSY & HISTOLOGIC ASSESSMENT METHOD ........................................................................ 142 
APPENDIX 9- PAIN MEASUREMENT SCALE ...................................................................................................... 143 
APPENDIX 10- PROCEDURES FOR SPECIFIC BLOOD TESTS ............................................................................... 144 
APPENDIX 11- BURN PATIENTS: POTENTIAL ADVERSE EVENTS .................................................................... 146 
APPENDIX 12- COSMESIS, FUNCTION AND QUALITY OF LIFE QUESTIONNAIRES ........................................... 147 
APPENDIX 13- ASA CLASSIFICATION SYSTEM ................................................................................................. 159 
APPENDIX 14- RANGE OF MOTION ................................................................................................................... 160 
APPENDIX 15- BLINDED ASSESSOR MEMO- SAMPLE .................................................................................... 165 
APPENDIX 16- TREATMENT DIAGRAM ............................................................................................................. 168 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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SIGNATURE PAGE 
 
 
 
The undersigned are the persons authorized to sign the protocol on behalf of the sponsor 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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1. 
LIST OF DEFINITIONS AND ABBREVIATIONS 
1.1 
DEFINITIONS1  
Hereafter is a list of terms and definitions that are acceptable in the burn care area.   
TBSA: Total Body Surface Area; in burn care, referring to the (%) total body surface area 
affected by second and third degree burns [1].   
Burn eschar: A slough (area of necrotic tissue), crust or dry scab resulting from a burn. Eschar 
is structurally intact but dead and denatured dermis [1].  
Burn Depth Definitions [1]: 
Second Degree (Partial Thickness) Burns involve the epidermis and portions of the dermis and 
can be clinically categorized as superficial partial-thickness, deep partial-thickness burns or as 
most common: combination of different depths: 
Superficial partial-thickness burns heal spontaneously (most of them) in less than 3 weeks, 
and do so typically without functional impairment or hypertrophic scarring. 
Deep partial-thickness burns extend into the deeper layers of the dermis. They possess 
characteristics that are distinctly different from superficial partial-thickness burns. If infection 
is prevented and spontaneous healing is allowed to progress, these burns may heal in three to 
nine weeks.  
Indeterminate burns are usually second degree burns of changing depths difficult to diagnose 
on arrival so only after few days when the burn conversion (progression) and demarcation took 
place they can be diagnosed as deep in need of surgery or superficial. Distinguishing between 
deeper burns and shallow burns is not always straightforward, and many burn wounds have a 
mixture of superficial mid and deep burns, making precise classification of the entire wound 
difficult. 
Third Degree (Full-Thickness) Burns involve all layers of the dermis and often injure 
underlying subcutaneous adipose tissue as well. Burn eschar is structurally intact but dead and 
denatured dermis. Over days and weeks if left in situ, eschar separates (“sloughs”) from the 
underlying viable tissue, through infectious, inflammatory and maceration processes leaving an 
open, unhealed bed of granulation tissue. Without surgery, they can heal only by wound 
contracture and scarring with epithelialization exclusively from the wound margins. 
Combination wounds, mixed of second and third degrees: the depth of the wound is not 
homogeneous and many burn wounds have a mixture of all burn depths from superficial second 
degree through deep, including full thickness burns, making precise classification of the entire 
wound difficult.  
Zones of coagulation, stasis and hyperemia: Zone of coagulation is the tissue completely 
destroyed by heat and need to be removed. Zone of stasis, usually peripheral and deeper to the 
Zone of Coagulation, is characterized by decreased tissue perfusion due to congestion that is 
caused by the increased hyperemia in the surrounding tissue evoked by the inflammatory 
                                                 
1 Where possible, definitions were based on the ABA White Paper 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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reaction (Zone of Hyperemia). The tissue in this zone is potentially salvageable if congestion 
will be resolved, preventing thrombosis and occlusion of blood vessels that will cause death of 
smaller or larger areas. The aim of burns resuscitation is to increase tissue perfusion in general as 
well as in the burned area and prevent any damage becoming irreversible. The dead, coagulated 
eschar in the zone of coagulation, adjacent to the Zones of Stasis is the main cause of local and 
systemic eschar-related infectious and inflammatory mediators that may cause burn viable zone 
of Stasis to die [2-9]. 
Burn conversion (burn propagation, progression, transformation): Superficial second 
degree burns may convert to deeper burns due to permanent vessel occlusion of the zones of 
stasis and hyperemia, desiccation of the wound, or the use of vasoactive agents during 
resuscitation from shock and infection of the eschar [1]. 
Debridement of Burn Wounds2: The removal of loose, devitalized, necrotic, and/or 
contaminated tissue, foreign bodies, and other debris on the wound using mechanical or sharp 
techniques (such as curetting, scraping, rongeuring, or cutting) [1].  
Clarification: In the USA and so in this study the removal of the necrotic tissue that ends in 
clean wound bed ready for wound closure treatment is termed “Eschar Removal” with the term 
“debridement” reserved to mechanical cleansing of the wound that ends with a wound bed still 
covered with eschar. In the rest of the world the term “debridement” refers to removal of the 
entire burn eschar ending with a clean, raw wound bed. Therefore, the term “Debridement” has 
been used in all the previous studies and in all the references as a synonym to “Eschar Removal” 
in its US terminology [1].   
Escharotomy is a surgical incision through burn eschar (necrotic skin) down to intact fat, from 
healthy skin edge to healthy skin, in order to reduce burn induced increased interstitial and 
compartment pressure and restore blood perfusion. It releases the compressed and stretched, 
constricted tissue allowing adequate perfusion to tissues and organs, maintaining their normal 
perfusion and viability [1]. 
Circumferential extremity wounds: Limb DPT and/or FT burns which encircle ≥ 80% of the 
limb circumference. 
Extremities at Risk (EAR) are circumferential DPT and/or FT burns that may develop BICS 
during the first 3 days post injury with at least one of the following: 
1. Any of the 5 “P”s; Pain (Pain on passive extension of the fingers, stretching of the 
affected muscle), Paralysis, Pulselessness, Pallor, Paraesthesia, 
2. Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements 
within 30 minutes under the constricting eschar, 
3. SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity 
and the injured one [10-11],  
4. Pulse not detected by US Doppler.  
Burn-induced compartment syndrome (BICS): 
 Increasing interstitial/compartment pressure >30 mmHg, 
                                                 
2 Enzymes were specifically excluded as debridement means in the White Paper. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity, 
 Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity or deterioration of clinical signs, 
 Deterioration of any of the 5 “P”s: Pain, Paralysis, Pulselessness, Pallor, Paraesthesia. 
Target Wound (TW): A TW is the burn area to be treated (Eschar Removal) by NexoBrid, 
SOC or Gel Vehicle as per the randomization and in accordance with the protocol. Following 
the enrollment of a patient to the study and prior to randomization, physicians identify one or 
more TWs per patient according to the following criteria and definitions: 
 TW is a continuous burn area composed of DPT and/or FT in depth (might include 
several anatomical areas) that can be treated in one session,  
 Minimal burned area of a single TW should be ≥ 0.5% TBSA (DPT and/or FT in depth)  
 Maximal burned area of a single TW should be ≤ 15% TBSA, 
 Superficial partial thickness areas may be included in the wound area only if they cannot be 
separated from deeper areas (e.g. surrounded by or mixed with DPT areas) and trying to 
separate such more superficial areas, may interfere with the treatment of the deeper areas of 
that wound,  
 Note: TW can be a portion of a larger wound composed of SPT, DPT, and FT, if the 
superficial partial thickness areas can be separated. The site should treat only the TW area 
per the randomization. 
 Note: TW can be a portion of a larger wound that includes face, genital or perineal areas.  
Face, genital or perineal areas will be separated and not included in the TW area.  
Substance use disorder: describes a problematic pattern of using alcohol or another substance that 
results in impairment in daily life or noticeable distress. The DSM-5 states that in order for a person 
to be diagnosed with a severe disorder due to a substance, they must display 6 or more of the 
following 11 symptoms within 12-months: 
 
Consuming more alcohol or other substance than originally planned 
 
Worrying about stopping or consistently failed efforts to control one’s use 
 
Spending a large amount of time using drugs/alcohol, or doing whatever is needed to obtain 
them 
 
Use of the substance results in failure to “fulfill major role obligations” such as at home, 
work, or school 
 
“Craving” the substance (alcohol or drug) 
 
Continuing the use of a substance despite health problems caused or worsened by it. This can 
be in the domain of mental health (psychological problems may include depressed 
mood, sleep disturbance, anxiety, or “blackouts”) or physical health 
 
Continuing the use of a substance despite its having negative effects in relationships with 
others (for example, using even though it leads to fights or despite people’s objecting to it). 
 
Repeated use of the substance in a dangerous situation (for example, when having to 
operate heavy machinery, when driving a car) 
 
Giving up or reducing activities in a person’s life because of the drug/alcohol use 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 
Building up a tolerance to the alcohol or drug. Tolerance is defined by the DSM-5 as 
“either needing to use noticeably larger amounts over time to get the desired effect or 
noticing less of an effect over time after repeated use of the same amount” 
 
Experiencing withdrawal symptoms after stopping use. Withdrawal symptoms typically 
include, according to the DSM-5: “anxiety, irritability, fatigue, nausea/vomiting, hand tremor 
or seizure in the case of alcohol”. 
Complete wound closure- defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits, 2 weeks apart [12], determined by a 
blinded assessor. 
Complete eschar removal is achieved at the end of the eschar removal treatment phase. This 
stage will be determined by a designated blinded assessor and clearly marked as the end of the 
eschar removal process and the initiation of specific treatment aimed to close the viable 
debrided bed by grafting or epithelialization. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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1.2 
ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Transaminase (ALT or SGPT, which stands for serum glutamic-pyruvic transaminase) 
AST 
Aspartate Transaminase (AST or SGOT which stands for  serum glutamic oxaloacetic transaminase ) 
BICS 
Burn-induced compartment syndrome 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
DG 
NexoBrid Gel 
DM 
Data Management 
DPT 
Deep Partial Thickness 
DSMB 
Data Safety Monitoring Board 
EAR 
Extremities At Risk 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FT 
Full Thickness 
HR 
Heart Rate 
HD 
Hospital Discharge 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product  
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 
Kg 
Kilogram 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MVSS 
Modified Vancouver Scar Scale 
mg 
Milligram 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Ml 
Milliliter 
PO 
Per Os 
POSAS 
 
Patient and Observer Scar Assessment Scale 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell (Count) 
RDC 
Remote Data Capture 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SI 
Smoke Inhalation 
SOP 
Standard Operating Procedure 
SSD 
Silver Sulphadiazine 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBSA 
Total Body Surface Area 
TW 
Target Wound 
WBC 
White Blood Cell (Count) 
WP p/l 
ABA White Paper no. page/line 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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2. 
SYNOPSIS 
Protocol Number: 
MW 2010-03-02 
IND Number(s): 
65,448 
Name of 
Investigational 
Medicinal 
Product (IMP): 
NexoBrid  
Name of Active 
Ingredient: 
Partially purified Bromelain  
Study Title: 
A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of 
NexoBrid compared to Gel Vehicle and compared to Standard of Care 
Clinical Phase: 
3 
Study Duration: 
The total duration of the study treatment and follow up period of each 
participating subject is approximately 25 months. 
Study Population: 
175 Hospitalized adults with Deep Partial Thickness (DPT) and Full Thickness 
(FT) thermal burns will be enrolled from about 30 sites. 
Study 
Objective(s): 
1. To demonstrate the efficacy of enzymatic eschar removal with 
NexoBrid by providing complete eschar removal as compared with Gel 
Vehicle, 
2. To demonstrate the efficacy of enzymatic eschar removal with 
NexoBrid by providing earlier complete eschar removal, reduction in 
patients’ surgical burden and its related blood loss as compared to SOC, 
3. To assess the safety of NexoBrid compared to SOC, including 
demonstration that treatment with NexoBrid does not cause an 
unacceptable level of harm on wound closure outcome and long term 
outcomes of cosmesis and function. 
Study Design 
Overview: 
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 identify one or more TWs per patient 
according to the TW definition. All subjects’ DPT and FT burns that 
comply with the specified entrance criteria are intended to receive study 
treatment per the randomized study arm and therefore, must be designated 
as TWs. This will further allow an evaluation of the subject systemic safety 
by allowing treatment of the subject’s entire deep burns as per the 
randomized study arm. After reviewing the entrance criteria, prior to 
randomization, eligible subjects will be stratified into different groups in 
order to standardize and minimise bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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patient total burn area and its depth.  
Following the stratification, patients will be randomized as per their 
stratification group 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 start of 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. 
Study arms, 
Dosage and route 
of administration: 
 
Three arms will be included in the study; NexoBrid, SOC and Gel vehicle arm 
(3:3:1 ratio) and each patient will be treated in accordance with randomization.  
NexoBrid  
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for 
preparation of a gel for cutaneous use, including concentrate of proteolytic 
enzymes enriched in Bromelain as the active component. Following mixing of 
the powder with the gel vehicle, each gram of the prepared product contains 
0.09 g partially purified Bromelain. Partially purified Bromelain is a mixture of 
enzymes extracted from the stem of Ananas comosus (pineapple plant). 
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 
50 grams of sterile Gel Vehicle (ratio of 1:10), respectively, to obtain sterile 
NexoBrid Gel. NexoBrid Gel is applied to the burn wound at a dose of 2g 
NexoBrid sterile powder mixed with 20g sterile Gel Vehicle per 1% of TBSA (~ 
surface of an adult palm) for four hours (or 5 g NexoBrid sterile powder mixed 
with 50g sterile Gel Vehicle per 2.5% of TBSA. The NexoBrid powder and the 
Gel Vehicle are to be mixed at the patient bedside 15 min prior to use.  
NexoBrid should not be applied to more than 15% TBSA (±3% TBSA) in one 
session. 
NexoBrid may be applied for a second time to the same burn area, if eschar 
removal from the target wound after the first application is not complete but at 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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least 50% of the eschar was removed during the first application. NexoBrid may 
only be applied twice to the same burn wound area. 
Gel Vehicle  
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn 
skin. Gel Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel 
per 1% of TBSA (~ surface of an adult palm) or 50 grams per 2.5% TBSA for 
four hours.  
Gel Vehicle may be applied for a second time to the same burn area, if 
eschar removal from the target wound after the first application is not 
complete but at least 50% of the eschar was removed during the first 
application. The Gel Vehicle may only be applied twice to the same burn 
wound area.  
Gel Vehicle should not be applied to more than 15% TBSA (±3% TBSA) 
in one session. 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  
Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ 
dermabrasion excisions.  Non-surgical procedures will include the application of 
(collagenase ointment (e.g. Santyl), antimicrobial solutions (e.g. Dakin’s 
Solution, 
Sulfa-Nystatin 
Solution), 
ointments/creams 
(e.g. 
Bacitracin, 
Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 
The need of either non-surgical or surgical procedures will be determined by the 
burn specialists and can be repeated as needed until complete debridement.  
Inclusion/ 
Exclusion 
Criteria: 
Inclusion Criteria- Patient level 
Inclusion Criteria- Patient level 
1. Males and females ≥ 18  years of age, 
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. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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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 include face, perineal or 
genital)3, 
All planned Target Wounds (TWs) should meet the following criteria: 
1. SPT areas that cannot be demarcated from DPT and FT areas should be less 
than 50% of the % TBSA of the TW, 
2. 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 index4 ≥ 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) as described in section ‎11.8,  
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 hrs SSD treatment), 
9. Patients with pre-enrolment 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 burns area of up to 15% TBSA 
or BMI greater than 34.0 kg/m2 in patients with burns area of more than 15% 
%TBSA, 
                                                 
3 All these wounds which are in line with this criteria should be defined as target wounds (TWs) and treated per randomization 
4 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and the presence of smoke 
inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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15. ASA greater than 2 (see Appendix 15 in study protocol) 
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, severe edema and/or lymphedema, regional lymph nodes 
dissection, 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) severe alcohol or drug use 
disorder (see definition in section ‎1.1),  
25. Prisoners and incarcerated, 
26. Patients who might depend on the clinical study site or investigator. 
Outcome 
Measures: 
Primary Endpoint 
The below primary endpoint will be investigated at a 'per patient' level.  
1. Incidence of complete eschar removal- Demonstrate superiority of NexoBrid 
over Gel Vehicle for eschar removal as measured by incidence of complete 
eschar removal at the end of the topical agent soaking period by a blinded 
assessor. 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared 
between NexoBrid and SOC.  
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. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC in 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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reduction of the time to achieve complete eschar removal.  
3. Blood loss- Demonstrate superiority of NexoBrid over SOC with regard to 
the blood loss incurred during the eschar removal procedures  
Safety Endpoints 
The following group of safety endpoints will be evaluated in this study and 
compared between NexoBrid and SOC. These endpoints are used to confirm that 
NexoBrid does have an inferior deleterious effect.  
1. Time to reach complete wound closure assessed in days, starting from 
Randomization.  
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.  
Additional Safety Outcome Measures:  
1. General parameters: Systemic adverse events, vital signs, pain assessment 
(using VAS 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, 
Incidence of increased interstitial/compartment syndrome5 and QT 
prolongation, number and volume of blood transfusions received throughout 
the hospital admission, extent of analgesia, anaesthesia and antibiotic use (i.e. 
total dose per kg body weight), Rates 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).  
2. Additional long term functionality evaluation of the extremities using the 
‘Lower Extremity Functional Scale’, 'QuickDASH' questionnaires and 'Range 
Of Motion' measurements, 
3. Long term Quality of Life using EQ5D and Burn Specific Health Scale- Brief 
(BSHS-B). 
                                                 
5 Increased interstitial pressure/compartment syndrome will be defined as following: Increasing pressure >25 mmHg, 
Difference of >20 mmHg of diastolic pressure between the burned extremity to the opposite uninjured extremity, Decreased 
SpO2 reading during treatment with difference of >6% compared to an uninjured extremity, or deterioration of clinical signs 
and/or any of the 5 “P” signs (Pain (Pain on passive stretch of the affected muscle), Paralysis, Pulselessness, Pallor, 
Paraesthesia). 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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4. Local parameters: Local adverse events defined by treating physician or 
designee; graft loss, wound related infections, etc. 
Exploratory Endpoint  
1. Reduction in surgical needs as measured by an analysis of % wound area 
surgically excised for eschar removal (and % TBSA excised of the treated 
TW) (tangential/ minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities 
target wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential 
extremity wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically 
harvested donor sites wounds, 
6. Reduction in surgical need as measured by analysis of % area of surgically 
harvested donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit 
following eschar removal procedures, Cosmesis MVSS and POSAS will be 
used to assess the quality of the donor sites scars, 
8. PK evaluation for a subset of  NexoBrid patients, 
9. Autograft related parameters: 
I. efficacy and safety analyses for early and late grafted wounds 
II. total number of target wound grafting procedures 
III. incidence of repeat/additional grafting procedures 
IV. area of repeat grafting  
10. Duration of hospitalization. 
Sample size: 
The following sample size calculations are based on the consideration of the 
primary and two secondary endpoints for this study.  
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. 
Gel) 
Estimated proportion achieving complete eschar removal in all TWs from study 
MW2004-11-02: NexoBrid 0.595 
Standard error = 0.057 
Anticipated proportion achieving complete eschar removal using NexoBrid: 
0.595-0.057/2 = 0.5665 
Estimated proportion achieving complete eschar removal using Gel vehicle in a 
previous Phase II study, MW2002-04-01: 0 (0 out of 35 patients).  
Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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(0.0 is the point estimate; 0.10 is the 97.5 upper confidence limit).   
Because numbers of complete eschar removals are anticipated to be low in the 
gel group, we calculate sample size using Fisher’s exact test. We used the 
computer program nQuery Advisor version 7.0 to calculate power for a two-
sided significance level of 5%, and thereby found the following sample size 
combination that led to approximately 90% power for detecting a statistically 
significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).   
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle 
group 13. Total sample size = 78. 
Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: 
NexoBrid 0.22; SOC 0.62 
Standard errors: NexoBrid 0.048; SOC 0.054 
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: 
NexoBrid 0.24 and SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a 
two-sided significance level of 5% is 86: 43 in the NexoBrid group and 43 in the 
SOC group. 
Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial 
yielded an estimated log hazard ratio of -1.37 (hazard ratio of 0.254) with a 
standard error of 0.28.  
Therefore target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio 
= 0.29).  
The formula for the number of events (successful complete eschar removals) is: 


2
2
log
)
(4
HR
z
z
d



 
where z = 1.96 two-sided significance level of 5%; and z = 1.28 for 90% 
power; For 90% overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required 
2
1
2
p
p
d
n


= 44 (to the nearest even number), 
22 in each of the NexoBrid and SOC groups.  
Summary of sample size 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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Although the maximum sample size from the above calculations is a total of 121 
patients (65 in the NexoBrid group, 13 in the Gel vehicle group and 43 in the 
SOC group (to match NexoBrid numbers)), we propose entering larger numbers 
to provide an extra margin of assurance in achieving positive results on the 
efficacy outcomes, and adequate information on safety outcomes to allow better 
benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 
(NexoBrid) + 75 (SOC) + 25 (Gel Vehicle). 
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 Efficacy Assessment Period 
(EAP). 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 for short-term safety endpoints (including time to wound closure). 
The analysis will be conducted, when 3 months had passed from the last patient 
reaching complete wound closure, in accordance with FDA guidance for industry 
Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for 
Treatment “Trial subjects generally should remain in the study for follow-up 
evaluation at least 3 months following complete wound closure. The purpose for 
this follow-up period is to help distinguish actual wound healing from transient 
wound coverage”. At this time-point, data will be available for nearly all patients 
on the primary end-point (proportion with complete eschar removal), the three 
secondary endpoints (proportion undergoing surgery, time to complete eschar 
removal, and blood loss) and short-term safety endpoints (including time to 
wound closure). Missing values for early drop outs etc. will be handled as 
described in Section ‎13.8.4  and the SAP. The complete data set documented so 
far will be locked and analyzed as described above. Although the treatment code 
will be revealed at the end of this analysis, the independent assessor of the 
cosmesis and function and QoL of an individual patient will remain blinded to 
the treatment given to that patient until after the third and final analysis (see 
below), so as to preserve the un-biasedness of the  assessments.  
The second analysis will be performed for the 12 month follow up period 
(STFU12) and will be started after the last patient has reached the 12m 
assessment. At this analysis, all accumulated safety data at the 12m follow-up 
will be analyzed, particularly the 12m MVSS assessment for cosmesis and 
function. The complete data set documented so far will be locked and analyzed 
as described above. 
The third and final analysis covers the data of the long-term safety follow up 
(LTSFU24). It will be conducted after the last patient has reached the 24m 
assessment at last 12 months after (STFU12) analysis (stage 2). At this analysis, 
all accumulated safety endpoints at the 24m follow-up will be analyzed, 
particularly the 24m MVSS assessment for cosmesis and function. The complete 
data set documented during the trial will be locked and analyzed as described 
above (hard lock). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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3. INTRODUCTION 
3.1 
MEDICAL OVERVIEW 
Optimal treatment of burn injuries requires understanding of and response to the profound local 
and systemic reactions following thermal injury.  
The treatment strategy should be planned and executed on the basis of a timely (early) 
assessment of the extent of tissue damage and remaining viable tissue available for the healing 
process. Only when the eschar is removed and the wound bed revealed, can the true damage be 
observed and assessed, and the appropriate wound closure modality prescribed [2, 9, 13]. 
As soon as the burn eschar is formed, it induces, within hours, a cascade of local and systemic 
pathologic changes. Dead eschar becomes heavily contaminated in two to three days, creating a 
source for local and systemic infection and sepsis [2-3, 8-9, 14]. Local inflammatory responses 
may lead to additional destruction of healthy surrounding tissue, extending the original 
damage. If not otherwise removed, inflammatory and autolytic processes slowly decompose 
and destroy the eschar, which will slough in approximately two weeks. The long inflammation 
based spontaneous sloughing period allows the simultaneous formation of advanced 
granulation tissue, later evolving into a heavy and deforming scar.   
Delaying the removal of the eschar increases the incidence and severity of systemic and local 
complications, especially in more extensive burns [2-6, 8-9, 14-15]. The decomposing eschar is 
a source of strong local and (if the burn is extensive) systemic mediators that induce 
inflammatory reaction and that may cause burn wound progression into potentially viable 
tissue [4, 6, 8-9, 16].  
Moreover, the eschar is non-resilient and forms a cocoon-like constricting shell around circular 
body parts. With increasing tissue edema, this increases the interstitial/compartment pressure, 
seriously compromising the viability of the still barely surviving skin by stretching it and 
compressing blood supply to other vital structures. An early diagnosis and response to these 
events, releasing surgical escharotomy, is important and should be executed emergently. In this 
case too, delay in diagnosis and reluctance to perform surgical escharotomy may delay this 
procedure especially in cases where experienced burn surgeons are not readily and 
immediately available [3, 17]. 
To prevent eschar-related complications and to initiate the healing process, it is imperative to 
remove all of the offending eschar at the earliest possible opportunity. Eschar removal, 
“Debridement”, is the first stage of the comprehensive wound care process.  There is no benefit 
in the presence of the eschar on the burn.  Thus, the decision is not whether or not to remove an 
eschar but when and how. Therefore, delay or avoidance of eschar removal should have a 
specific reason. 
Estimation of burn size and depth is essential for a diagnosis-based treatment strategy, but 
cannot be accurately performed in most instances unless and until the opaque eschar has been 
completely removed. 
Immediate (within 24 hours post-burn) eschar removal may improve the potential for survival 
of the Zone of Stasis, reverse the Zone of Hyperemia and may attenuate, or avoid many of the 
systemic reactions [2, 6, 8-9, 14, 18]. Delayed eschar removal (within the first three days) may 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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not provide all the benefits of immunological and inflammatory modulation, but will reduce 
the burn bacterial load and its outcomes [3, 17, 19-20]. Delaying eschar removal up to the 
seventh day will forfeit the local and systemic benefits, but may still prevent healing by 
secondary intention potentiating better long term results (especially in terms of scarring) [8-9, 
14, 21].  
In current standard of care, removal of the eschar may be accomplished by surgery, usually 
tangential excision followed by split thickness autografting (TE&STSG) of the acute exposed 
debrided wound, or by non-surgical topical care that includes daily dressing changes, bathing, 
scraping, wet to dry dressing, macerating activity of bacteria, etc., until the eschar sloughs, 
leaving a clean wound bed for subsequent non-surgical or surgical wound closure treatment. 
This combination of debridement followed by surgical or non-surgical wound closure 
treatment is the basis of all burn wound care modalities. 
The choice of debridement method (non-surgical or surgical) depends on many variables such 
as the burn depth, anatomical site and size (expressed as % TBSA of the burn wound), the 
patient’s general condition, available donor site for autograft harvesting as well as the 
availability of surgical facilities and staff. Tangential excision should be carried down into the 
healthy intact tissue to make sure that no trace of the eschar remains. It is estimated that up to 
30–50% of healthy tissue (mainly dermis), which is essential for the spontaneous 
epithelialization potential of the wound, may be sacrificed in this procedure, thus usually 
necessitating autografting. These surgical procedures are traumatic, often long and difficult, 
require skilled personnel and sophisticated medical resources and are usually accompanied by 
bleeding [2, 9, 17, 21-22] and heat loss [23]. The surgically excised raw wound bed should be 
covered immediately, i.e., in most cases autografted. Thus, the excision is followed by 
harvesting of autografts from intact, non-injured skin areas, skin graft transplantation, and care 
of the donor sites in addition to the original burn injury. These surgical procedures are 
performed under general anesthesia that requires pre- and post-surgical fasting and recovery. In 
most centers caution and post surgery intensive care dictate that only a limited percentage of 
the affected areas (~15%TBSA) will be surgically debrided at one time in order to limit 
inflicting excessive stress on the patient. Thus, the decision to surgically debride a burn is not 
taken lightly. Reluctance, hesitation and doubts due to uncertain diagnosis delay the decision to 
perform surgery, extending the time to start and finish of the debridement from the optimal few 
hours to several days.  
In partial, mixed thickness, and intermediate depth wounds, and with difficult to diagnose 
depth “indeterminate” wounds, early surgical debridement will usually be avoided and a more 
conservative debridement approach using topical medications will be pursued. Such 
conservative non-surgical debridement lasts for days until the eschar decomposes or until a 
decision is taken to excise the offending, remaining eschar.  The non-surgical debridement 
process involves the combined activity of topical medications, contaminant microorganisms, 
autolytic tissue processes and the inflammatory process with frequent dressing changes, 
showering, mechanical scraping of loose debris etc. The infectious-inflammatory processes are 
slow (lasting between 10-14 days) and may involve significant systemic and local 
complications. Using topical anti-bacterial or anti-inflammatory medicaments may reduce the 
infectious-inflammatory processes but will also delay eschar separation (sloughing). Locally, 
all these processes prolong the removal of the eschar and lead to additional tissue damage due 
to the death of the Zones of Stasis and Hyperemia which deepen, transforming partial thickness 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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damage into a full thickness injury. The long debridement time with sustained inflammatory 
processes can lead to the formation of granulation tissue that will develop into heavy scars.  
This excerpt of literature emphasizes that timely eschar removal is, for the last 40 years, the 
goal of burn wound care initiation. Physicians today are forced to choose between or combine 
two sub optimal alternatives of eschar removal; (i) the fast and efficient surgery (TE&STSG) 
with its diagnosis-dependant often prolonged initiation, non-selective, traumatic and 
demanding results or (ii) the inefficient non-surgical prolonged debridement means with their 
associated sequelae. The lack of fast and effective non-surgical eschar removal means has left 
surgery as the available SOC for deep burns.  
The optimal solution would be a non-surgical, selective means for removing exclusively the 
eschar without harming the non injured tissues immediately or nearly immediately after 
patients’ admission and stabilization, independently of the burn depth diagnosis. Such early 
removal of the eschar will enable the physician accurate visual diagnosis of the exposed burn 
wound bed. The clean exposed bed can be treated by the most appropriate wound closure 
strategies tailored for each patient and wound area in order to achieve optimal long term results 
with minimal trauma and cost to the patient. 
These characteristics were well-demonstrated throughout the clinical development of 
NexoBrid. A recent confirmatory phase 3 study (MW 2004-11-02) demonstrated the clinical 
benefit of NexoBrid for effective and selective removal of eschar from burn wounds as was 
shown in both primary and secondary endpoints, e.g. for % treated burn wound excised, % 
treated burn wound autografted and timely eschar removal. These findings corroborated those 
from a previous Phase 2 study (MW 2002-04-01) and retrospective data collection study (35-
98-910) (Please refer to Section ‎3.2). 
3.2 
CLINICAL DEVELOPMENT OF NEXOBRID 
3.2.1 
Efficacy  
The clinical development of NexoBrid6 was based on clinical data retrospectively collected 
from files of hospitalized burn patients with burn wounds treated by NexoBrid and on 
discussions and guidance from regulatory authorities. 
Study 35-98-910 evaluated the safety and efficacy of NexoBrid in subjects between 0.5 and 82 
years of age with deep partial and/or full thickness burns of ≤67% TBSA, hospitalized in 
Soroka University Medical Center (Israel) Plastic Surgery and Burn Unit, from 1985-2000. 
Data from 154 subjects having complete file documentation (including signed informed 
consent form (ICF) and pre- and post-eschar removal photographs) were analyzed. 
The clinical development program of NexoBrid includes six prospective clinical studies that 
evaluated the safety and efficacy of NexoBrid in partial and full thickness burns.  
Study MW2001-10-03 evaluated the efficacy and safety of three doses of NexoBrid. Twenty 
hospitalized adult, male and female subjects, with Deep Partial Thickness (DPT) and/or Full 
Thickness (FT) burns of 1-15% TSBA were randomized to a 1 g (6/20 subjects), 2 g (7/20 
subjects) or 4 g (7/20 subjects) dose of NexoBrid powder per 20 g of Gel Vehicle. The study 
                                                 
6 NexoBrid was formerly named Debridase and Debrase.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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further confirmed the use of 2 g NexoBrid mixed with 20g Gel per 1% TBSA as safe and 
effective dose. 
Study MW2002-04-01 evaluated the safety and enzymatic eschar removal efficacy of NexoBrid 
as compared to SOC and Vehicle7. A total of 140 adult hospitalized male and female subjects, 
with DPT and/or FT burns ranging from 2-15% TBSA, but not more than 30% TBSA in total, 
were randomized in a 2:1:1 ratio to NexoBrid, Vehicle alone (only Gel), or SOC treatment. 
Study MW2005-10-05 evaluated the safety and exploratory efficacy of NexoBrid in comparison 
to Vehicle, and SOC in hospitalized male and female adult subjects, with DPT and/or FT burns 
ranging from 1-5% TBSA. Thirty hospitalized subjects were randomized to receive NexoBrid 
(10 subjects), Vehicle alone (9 subjects), or SOC treatment (11 subjects). 
Study MW2008-09-03 evaluating the safety and exploratory efficacy of NexoBrid, as well as 
the systemic absorption of NexoBrid when applied topically on thermal burns using a recently 
validated, sensitive ELISA method, through pharmacokinetic (PK) assessments in hospitalized 
adults and children, male and female subjects, aged 4 to 70 years with partial thickness and full 
thickness burns of 4-30% TBSA.  
Study MW2004-11-02 A phase III, multicenter, controlled study, that confirmed the safety and 
efficacy of NexoBrid in comparison to SOC in hospitalized adults and children, male and 
female subjects between 4 and 55 years of age with DPT and/or FT burns of 5-30% TBSA with 
total burn wounds of no more than 30%. Of the subsequently enrolled subjects, 75 were 
randomized to NexoBrid and 81 subjects were randomized to SOC treatment [24].  
Study MW2012-01-02 evaluated the long-term scar formation and Quality of Life in adults and 
children who had participated in study MW2004-11-02, 2-4 years post-wound closure and 
included blinded assessment of scars. A total of 89 patients were enrolled into this study 
including 72 adults and 17 pediatric patients [24].  
Summary of the efficacy results from the phase 2 and phase 3 studies is presented here below. 
Eschar Removal  
Eschar removal is the direct intended activity of NexoBrid and as such was evaluated in all 
clinical studies. 
Data from the two comparative studies MW 2002-04-01 and MW 2005-10-05 shows that 
eschar was effectively removed from 92.5% of the treated wound area for NexoBrid subjects as 
compared to 94.7% for the SOC subjects. The Vehicle showed negligible, if any, eschar 
removal activity (2.2% eschar removed in one case). Vehicle-subjects’ eschars were removed 
by SOC methods following end of the Vehicle gel treatment and diagnosis of eschar removal 
failure. Data from the two comparative studies MW2002-04-01 and MW2005-10-05 shows 
that the time to start of eschar removal from injury was 1.5 days in both the NexoBrid and 
Vehicle groups compared to 2.9 days in the SOC group. Time to completion of the initial 
eschar removal procedure (as designated by the protocol per treatment group) from injury was 
1.5 days in the NexoBrid group as opposed to 11.2 days in the SOC group. 
                                                 
7 Vehicle treated patients were treated by eschar removal SOC methods following end of the Vehicle Gel treatment and diagnosis of 
eschar removal failure. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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Data from the Phase 3 study MW2004-11-02 showed that 90.5% (67/74) of NexoBrid subjects 
had successful eschar removal as compared to 90.1% (73/81) of the SOC-treated subjects 
(p=0.9301). Time to achieve successful eschar removal from the ICF date in the NexoBrid 
group was 0.8 days as opposed to 6.7 days in the SOC group (p< 0.0001). Thus, NexoBrid was 
able to successfully remove the eschar from the burn wounds much earlier than SOC. 
Following the EMA CHMP/COMP recommendation, study MW 2004-11-02 evaluated two co-
primary endpoints consisting of (1) % treated wound excised, and (2) % treated wound 
autografted (both on DPT wounds). These endpoints complement each other since less area 
surgically excised demonstrates the eschar removal efficacy of NexoBrid and less area grafted 
demonstrates the clinical benefit in the reduction of the extent of non-selective eschar removal 
by surgical excision of deep partial thickness wounds where viable tissue can be spared8. Both 
endpoints contribute to the overall reduction of surgery [24]. 
Area of Wound Excised 
Data from the Phase 3 study (MW2004-11-02) shows that the incidence of DPT wounds that 
were excised was only 15.1% (16/106 wounds) as compared to 62.5% (55/88 wounds) in the 
SOC. Moreover, the DPT wounds treated with NexoBrid had significantly less wound area 
excised (5.5%) compared to the SOC treated (DPT) wounds (52.0%, p<0.0001). In children 
(<18 years of age), the incidence of DPT wounds that were excised was only 21.7% (5/23 
wounds) as compared to 68.2% (15/22 wounds) in the SOC. Moreover, less wound area was 
excised (7.3%) in NexoBrid treated wounds compared to the SOC treated wounds (64.9%). In 
addition to the analyses described above, the percent treated wound excised was analyzed for 
all treated wounds, including those with third degree components, to investigate NexoBrid 
ability to remove the eschar from all burn wound depths (ITT population). In the NexoBrid 
group the incidence of wounds that were excised was 24.5% (40/163 wounds) as compared to 
70.0% (119/170 wounds) in the SOC. Significantly less treated wound area was excised in all 
the NexoBrid treated wounds (13.1%) as compared to the SOC group (56.7%); p<0.0001. This 
pattern is comparable to that seen in the DPT wounds discussed above and confirms the results 
in a greater number of wounds of all depths. 
Area of Wound Autografted 
In the Phase 3 study (MW2004-11-02) wound area autografted was evaluated in DPT wounds. 
Wounds that were entirely FT or had FT areas were excluded from the analysis of % wound 
area 
autografted 
(in 
accordance 
with 
EMA 
CHMP/COMP 
protocol 
assistance 
recommendations). 
In this study, the incidence of DPT wounds that were autografted was only 17.9% (19/106 
wounds) as compared to 34.1% (30/88 wounds) in the SOC (p=0.0099). Moreover, DPT 
wounds of all subjects had significantly less wound area autografted in the NexoBrid group 
(8.4%) compared to the SOC group (21.5%; p=0.0054). In the children subset, the incidence of 
DPT wounds that were autografted was 21.7% (5/23 wounds) as compared to 31.8% (7/22 
wounds) in the SOC. Moreover less DPT wound area was autografted in the NexoBrid group 
(6.1%) compared to the SOC group (24.5%). The potential tissue-sparing effect of NexoBrid 
                                                 
8 Full thickness wounds require autografting regardless of the eschar removal technique since they have no remnants of viable dermis. 
Therefore, the clinical benefit of DGD versus the non-selective surgical approach is more apparent in deep partial thickness wounds 
where the potential tissue-sparing effect, leading to less autografting, is demonstrated. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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and its applicability to the issue of reduction in autografted wound area suggest an additional 
clinical benefit to children, due to their smaller size and limited donor site area. 
Long term scar assessment results- study MW2012-01-02 
Cosmesis was assessed in study MW2012-01-02 by a blinded assessor using the Modified 
Vancouver Scar Scale (MVSS). The Vancouver Scar Scale (VSS) [25] is the first validated and 
widely used scar assessment scale developed by Sullivan et al 1990 and it includes assessments 
of 4 scar variables; vascularity, height, pliability, and pigmentation. MVSS is an improved 
version of the VSS, which includes two additional scar variables (pruritus and pain) [23]. The 
Vancouver Scar Scale is the most commonly used scale that includes multiple subjective and 
objective parameters [25-27]. 
The study included data from 89 subjects (72 adults and 17 pediatric) with whom contact was 
made and who represent the MW2004-11-02 study population based on their demographic and 
baseline wound characteristics.  
Scar assessment (per wound) using MVSS was conducted for 113 wounds in NexoBrid group 
and 78 wounds in SOC group. The total scar outcome was slightly lower (better results) in the 
NexoBrid arm compared to SOC (3.12 vs. 3.38, respectively), without statistically significant 
difference (p=0.88) (MVSS range 0-18). 
3.2.2 
 Safety 
The burn trauma is a multi-factor disease involving most if not all body systems and associated 
with many adverse events (AEs). Overall, AEs associated with NexoBrid were minimal, 
generally transient, manageable and mostly attributable to the burn process and its care and not 
to the introduction of the eschar removal agent. 
Taken together, there appear to be several common but manageable AEs, many attributable to 
the burn process and not the introduction of the debriding agent, NexoBrid. The most 
frequently reported AEs (≥3.0%) whether or not treatment–related, are summarized in the 
following Table 1 (based on the safety data from the prospective phase II and phase III 
studies). 
Table 1- Summary of Adverse Events in Descending Order of Frequency Whether or Not 
Treatment-Related and Occurring in ≥3.0% of Subjects* (Safety Population)  
Adverse Event* 
NexoBrid 
SOC 
N=208(%) 
N=127 (%) 
Pruritus 
32 (15.4%) 
24 (18.9%) 
Anemia 
13 (6.3%) 
8 (6.3%) 
Nausea 
13 (6.3%) 
6 (4.7%) 
Insomnia 
6 (2.9%) 
5 (3.9%) 
Headache 
6 (2.9%) 
5 (3.9%) 
Skin graft failure 
6 (2.9%) 
2 (1.6%) 
Diarrhoea 
6 (2.9%) 
1 (0.8%) 
Vomiting 
5 (2.4%) 
7 (5.5%) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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* Subjects from the five prospective studies; MW2001-03-02, MW2002-04-01, MW2005-10-05, 
MW2004-11-02 and MW2008-09-03 
Across all studies, pruritus was the most frequently reported AE occurring at an incidence 
>10% in both treatment groups. More subjects in the SOC group reported pruritus compared to 
the NexoBrid group (18.9% vs. 15.4%). Pruritus, that torments the patient for months, is very 
common. As reported in the literature, up to 87% of all patients will have a longer or shorter 
spell of pruritus. The scratching may be so intense that the patient might scratch-open their 
healed wounds, destroying healed grafts [1, 28-29]. 
Anemia in response to burns has been acknowledged for over 60 years, and is considered an 
acute and sub-acute complication. Close evaluation has suggested the response to thermal 
injury to include initial rapid hemolysis of thermally exposed blood proportional to the burn % 
TBSA (<18% in 24h in 15-40% TBSA burns [30]. Excisional surgery for eschar removal and 
skin graft harvesting leads to acute blood loss. Catabolic processes, inflammatory and septic 
processes and depressed bone marrow hematopoietic activity may all contribute to anemia 
though a clear etiology has yet to be established [31-33]. Anemia in NexoBrid clinical studies 
was reported at similar incidences in both treatment groups (6.3% in the NexoBrid and SOC 
group). 
Though skin grafts have been used for more than a century and considered to be a standard 
wound closure tool, the details of their use vary between centers, surgeons, patients and body 
areas. The reported incidence in the literature of graft loss ranges may reach up to 71%. 
Traditionally it was thought that wound infection is the main reason for skin graft loss but with 
use of effective and simple control means (local antibacterial soaking and systemic antibiotic) 
infection ceased to play a crucial role in graft loss. At present, the causes for skin graft loss 
(besides infection) are (by the order of importance): 1. Sub-graft collection (i.e. seroma, 
hematoma); 2. Lack of graft adherence to the wound bed (ineffective fixation, movement); 3. 
Hypoalbuminemia; 4. Granulation tissue; 5. Nature of graft (by trend: very thin, sheet, thick 
and meshed). Other mechanical factors may cause loss of smaller or greater parts of the graft, 
earlier or later after grafting. Such factors are: shearing, trauma and abrasion (scratching) of the 
graft, minimally vascularized body areas (lower extremities), areas prone to trauma (buttocks, 
legs), areas difficult to fixate and dress and mobiles joints (knees, elbows, axilla neck and 
trunk) [34-37]. Use of negative pressure wound therapy for 2-3 days to stabilize the graft 
improves its take. Late (2-3 weeks post grafting) graft loss may be caused by autografting over 
dermis that epithelializes under the graft, detaching it from the healing bed. During the clinical 
development, graft failure was reported in low percentages, 2.9% in the NexoBrid arm and 
1.6% in the SOC arm. Autografting may cause long term sequelae such as scarring at the 
edges, mesh pattern when mesh grafts are used, overgrafting when used over dermis, color 
differences and at the donor sites: weeks of painful healing process and scars on unburned skin 
areas.    
The incidence of the AEs pain, pyrexia/hyperthermia, and wound infection were analyzed 
separately for the earlier clinical studies (Group 1: MW 2001-10-03, MW 2002-04-01) and for 
the later studies (Group 2: MW 2005-10-05, MW 2004-11-02, and MW 2008-09-03) as prior 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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to the Group 2 studies, corrective measures9 were implemented for these AEs observed and 
investigated in the Group 1 studies. Data are presented in Table 2. 
Table 2- Comparison of the Incidence of Adverse Events Pain, pyrexia/ Hyperthermia 
and Wound Infection  
Adverse Event 
Group 1* 
Group 2** 
NexoBrid 
N=90 
SOC/Vehicle  
N=70 
NexoBrid 
N=118 
SOC/Vehicle  
N=101 
 
N (%) 
N (%) 
N (%) 
N (%) 
Pain 
21 (23.3) 
8 (11.4) 
4 (3.4) 
4 (4.0) 
Pyrexia/ hyperthermia 
32 (35.6) 
13(18.6) 
20 (17.0) 
16 (15.8) 
Wound infection 
6 (6.7) 
4 (5.7) 
7 (5.9) 
7 (6.9) 
* Group 1: MW 2001-10-03, MW 2002-04-01 
** Group 2: MW 2005-10-05, MW 2004-11-02, and MW 2008-09-03 
 
Pain Events 
Burn injury is associated with prolonged and significant pain. The pain can be sub-divided into 
background pain (at rest), breakthrough pain (during activities such as changing positions), and 
procedural pain during wound care such as Sulfamayalon, bathing, dressing changes, etc [38-
39]. Patient's scores vary widely from patient to patient and in the same patient: from day to 
day. Pain score are higher in the more superficial burns with procedural pain related to the 
extent of the second degree burns [38].  
As shown in Table 2, the incidence of pain in the NexoBrid group was reduced from 23.3% to 
3.4% after corrective measures had been taken for adequate pain management, as commonly 
practiced during routine dressing change to burn patients, and occurred at a comparable 
incidence in both treatment groups in the later clinical studies (3.4% vs. 4.0%). Use of 
NexoBrid requires somewhat less analgesia and anesthesia medication compared with SOC 
and so it is not medication-dependent more than any routinely used SOC treatment. 
A few prospective descriptive studies were conducted to investigate the extent of pain in burn 
patients, reporting more intense, at rest background pain in the first week, two-thirds of the 
patients had mild or less-than-mild pain, and the others reported moderate-to-severe pain. 
During therapeutic procedures, 51% of patients suffered intense pain though analgesic 
medications were administered. The burn induced pain and its long term sequelae are all 
underestimated and seem to be in many cases greatly undertreated by routine analgesia [1, 28, 
39-42]. 
Pyrexia/ Hyperthermia 
The burn patient is catabolic, with a very high basal metabolic rate (BMR), and often has 
elevated body temperature which may continue for months post healing [43-45]. The 
hypermetabolic process with the systemic and local inflammatory reactions involved in the 
                                                 
9 The following instructions and protocols were implemented: Provision of a pre-treatment pain management protocol as commonly 
practiced during routine dressing change in standard of care of burns in order to prevent NexoBrid related pain and the use of approved 
topical antibacterial solutions during the soaking stages prior to and post-treatment in order to minimise the potential for infection and 
associated fever. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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wound healing process as well as wound contamination and/or infection contribute to pyrexia. 
However, elevated body temperature is not considered clinically reliable in predicting local or 
bloodstream infection, in some cases it starts a few hours post burn, much before any infection 
can develop. Later it may be due to exposure to catabolic and bacteria products [46-47]. 
Occlusive dressings may cause fever by reducing heat dissipation [48-49]. Therefore, 
temperature elevation is not considered clinically significant pyrexia until >39°C (102°F) and 
even then it is not always related to a clear pathology [50] or correlates consistently with 
septicaemia [46-47]. Other common sources for pyrexia may be IV catheter infection and/or 
thrombophlebitis with reported incidence of 8-57%. Urinary Tract Infection (UTI) is another 
source of pyrexia (as report suggests that most catheterized patients will have bacteruria after 
72 hours) and pneumonia with an incidence of 10-65% [51]. 
The incidence of pyrexia/hyperthermia in the NexoBrid group was reduced from 
approximately 35.6% in the earlier studies to 17.0% in the later studies and was also decreased 
from 18.6% to 15.8% in the SOC group. In the later studies pyrexia/hyperthermia occurred at a 
comparable incidence in both treatment groups (17.0% vs. 15.8%).  
Infection  
The definition of “infection” in the case of burns is a very general one and can relay to several 
different pathological entities. Some of the more common burn-related infections are burn 
wound infections with an incidence of >30% of infection and >9% of bacteraemia [51-52]. The 
general criteria of pyrexia, leucocytosis, thrombocytopenia may indicate that an infection is 
developing but will rarely point to the exact source (organ or system) of the infection. Even 
local signs of burn wound infection will not preclude differential diagnosis of other very 
common sources (i.e. IV catheter infection, thrombophlebitis, urinary tract infection so 
common in catheterized patients or pneumonia) [51]. 
Wound Infection 
All burn wounds are contaminated and clinical diagnosis between wound contaminated to 
various degrees of wound infection and invasive wound infection depends on objective criteria 
of quantitative culture and microscopic histology. Other definitions of wound infections are not 
clear, not uniformly accepted by all and greatly depended on aetiology and subjective 
impressions [51].  
Most infections in patients with burn injuries are burn wound infections. The burn wound is a 
susceptible site for opportunistic colonization by organisms of endogenous and exogenous 
origin [51-53]. Incidence of infections in children was identified in 33.9% of the patients, with 
burn wound infections being the most common: 10-24.6% [54-55]. Other studies found similar 
incidence of infection >30 % with 30-70 % of such infections reported as burn wound 
infections [56-59].  
Death in patients with infections ranged from 6 to 25% [56, 60-64]. 
In the clinical development, incidence of wound infection was similar across studies, 6.7% to 
5.9% in the NexoBrid group and 5.7% to 6.9% in the SOC group. In all studies wound 
infection occurred at a comparable incidence in both treatment groups and with comparable use 
of antibiotics between NexoBrid and SOC. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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There were 31 SAEs reported by 25 subjects. Only one SAE (skin graft failure) was considered 
possibly related to NexoBrid treatment. Fewer AEs, SAEs, and severe AEs were observed in 
children compared to adults. Nearly all cases of wound and blood infections reported as AEs 
were determined to have been not related to study treatment. 
There were six deaths in the NexoBrid clinical development program, 5/362 (1.4%) in the 
NexoBrid group and 1/127 (0.8%) in the SOC group. None of these deaths was considered to 
have been related to study treatment by the Principle Investigators and Data Safety Monitoring 
Board (DSMB). 
3.2.3 
Pharmacokinetic profile 
The pharmacokinetic evaluation of NexoBrid following single or double applications of 
NexoBrid Gel Dressing in 36 subjects with partial thickness thermal burns was performed as 
part of study MW2008-09-03. In all subjects dosed, NexoBrid exposure was observed with 
quantifiable serum concentrations through 48 hours post dose administration. Concentrations 
increased relatively rapidly after each application, with median Tmax values between 2.0 to 4.0 
hours and mean terminal half-life of 12 ± 4.4 hours. 
Systemic exposure appears to generally increase with dose and %TBSA. Statistical differences between 
the PK parameters were not observed as a function of depth of burn. 
The plasma levels calculated after the first and second administration shows only slight 
accumulation of NexoBrid in the blood after the second application indicate that on average the 
safety margins are maintained after the second application, a conclusion that is also supported 
by a similar safety profile of patients treated with 2 applications (up to 30% TBSA) that was 
consistent with the safety profile after a single application (up to 15% TBSA).  
3.3 
RISK ASSESSMENT 
3.3.1 
General 
Any decisive treatment strategy (such as a decision to execute post eschar removal surgical 
wound closure) can only be planned and executed if the true extent of the tissue damage is 
known at each stage of the healing process. Only once the eschar is removed and the viable 
wound bed is revealed, can the true damage be observed and assessed and the appropriate 
wound closure modality can be prescribed [2, 13, 65]. 
The two major characteristics defining the burn wound severity are area, which is referred to in 
terms of % TBSA, and depth, which is referred to in terms of ‘degree’ of burn or described in 
words (please refer to Burn Wound definitions, Section ‎1.1).  
Depth assessment will be based on the investigators' visual assessments as used in routine burn 
care. Burn specialist visual assessment and clinical examination is the technique generally used 
for the diagnosis, monitoring and documentation of burn depth [1]. All the participating 
investigators shall be experienced, national or international burn specialists. At present, the 
burn experts' visual assessments are considered the standard diagnostic tool since efforts to 
develop and validate objective burn depth diagnostic measures have not been successful. None 
of the other tools which have been developed (e.g. tissue biopsy, ultrasound, laser Doppler 
flowmetry, Thermography, nuclear magnetic resonance imaging (MRI), reflectance under 
different illuminations, vital dyes, fluorescein and fluorometry) have been validated in large 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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scale clinical trials or accepted as standard diagnostic means by national or international 
professional burn organizations. All these methods have been compared to the visual 
assessments of experts but similar results have been attained only occasionally and usually 
only to several-day old burns where the process of progression has ended and infection not yet 
started [65-66].  
Assessment of very superficial and very deep burns may be in some cases more straight-
forward, however, the most frequent burns in hospitalized patients, those of mixed or 
indeterminate depth, create a challenge in terms of both diagnosis and choice of treatment 
modalities. Indeterminate burns are usually second degree burns of changing depths difficult to 
diagnose on arrival so only after several days when the burn conversion (progression) and 
demarcation have taken place can they be diagnosed as deep in need for surgery or superficial 
[1]. These burns are the most common in hospitalized patients (>40%). In some cases they may 
eventually evolve into deep full thickness or slow to heal wounds. In other cases they may heal 
fast, and spontaneously epithelialize following maceration and separation (“sloughing”) of the 
eschar. The depth of these burns is not constant, their appearance continuously changing during 
the first days due to the burn progression and to the inflammatory/infectious processes. Due to 
their varying appearances and behavior they pose a real diagnostic challenge and thus it is 
common practice to follow/monitor these wounds for a few days until the diagnosis becomes 
clearer and with this, realization of the preferred wound closure strategy, i.e. surgical or non-
surgical or a combination of both. When a non-surgical strategy is chosen, topical wound care 
designed to prevent infection of the necrotic eschar and promote its separation (sloughing) 
starts. This treatment includes topical medications and physical procedures (bathing and 
showering, scraping etc), follow up and monitoring until the eschar sloughs off and the clean 
bed epithelializes, or until granulation tissue appears and it becomes obvious, usually within a 
3 week period, that the wound will not heal without heavy scarring. For the later scenario, a 
surgical process including excision and autografting will usually be performed [1, 18, 67].  
In spite of the general agreement that the eschar should be removed in a timely manner, as 
soon as possible, very few centers dare to excise the entire burn eschar as early as possible 
from admission [68]. In immediate eschar removal, defined within 24hrs from injury (“primary 
eschar removal”, as coined in 1995 by Voinchet et al), one does not wait until better diagnosis 
of the burned skin depth is feasible but rather excises all the suspected tissues and grafts the 
raw wound bed.  
Since in partial, mixed thickness, and intermediate depth wounds, the extent of the burn is 
difficult to diagnose, early surgical eschar removal will usually be avoided and a more 
conservative eschar removal approach using topical medications will be pursued. The 
conservative eschar removal lasts for days until the eschar decomposes or until decision is 
taken to excise the offending burn eschar. The non-surgical eschar removal process involves 
the combined activity of topical medicaments, contaminant microorganisms, tissue autolytic 
processes and the inflammatory process. The infectious-inflammatory processes are slow 
(lasting between 10-14 days) and may involve significant systemic and local complications. 
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within several days post injury and start to slowly decrease 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy.   
The optimal solution would be the use of a non-surgical, least demanding eschar removal 
means, immediately after patients’ admittance and stabilization. Such debriding means that will 
be specific to the eschar, removing it selectively without harm to the non injured bed will 
enable physician visual diagnosis of the burn wound trauma and the most appropriate choice of 
wound closure treatment for each wound area. 
There are several main characteristics of an ideal eschar removal means: 
1. Early (as early as possible), effective and thorough eschar removal that allows early direct 
visualization and assessment of the primary burn damage, prevention of eschar-related 
deterioration and complications and initiation of non-surgical or surgical wound closure 
treatment. The eschar removal should be fast enough to timely release BICS.  
2. Selective, avoiding unnecessary damage of viable, non-burned tissues, which may be 
essential for the wounds’ spontaneous epithelialization potential. 
3. Safe, both for the patients’ general and local (non- or partially-injured tissues) conditions. 
Timely (as soon as possible after patients stabilization: early initiation and early completion) 
and thorough eschar removal, is the primary goal of treatment initiation. Eschar removal will 
not only stop the vicious eschar progression, eschar-induced effects and resolve (like 
escharotomy) increased burn induced interstitial/compartment syndrome, but will allow 
accurate assessment of the primary burn damage and initiation of the closure, healing process. 
In this regard, burn eschar removal does not differ from the care of all other necrotic wounds, 
where timely removal of the offending necrotic eschar is the gold standard. 
3.3.2 
Extremities Wounds 
Burns to the extremities (hands and feet) have a special place in the field of burn care, 
demanding special attention and treatment.  
In more than 80% of severely burned patients, the hand is involved [69].The functional and 
aesthetic importance of the hand, coupled with its complex and crowded anatomy, with risk of 
burn-induced increases in interstitial and compartment pressure, make hand burn care 
extremely important and with current SOC, as further elaborated below, challenging. 
Due to the special anatomy of the hand in which numerous delicate structures are crowded in a 
small space and covered by scarce sub-dermal soft tissue, surgical debridement of the burned 
tissue, or escharotomy in these areas, are technically demanding and may cause considerable 
morbidity. The maintenance of perfusion is the first and foremost aim in the acute treatment of 
hand burns. During the acute phase, deep dermal, circumferential or near circumferential burns 
should be cared for most attentively because they can cause circulatory impairment at the level 
of the nerves and muscles as well as stretching the partially burned skin and collapsing the 
marginal blood supply, transforming a partial thickness burn into a full thickness one. Even for 
experienced surgeons it is sometimes extremely difficult to determine whether an escharotomy 
of the hand will be necessary or not [69]. Technical difficulties in estimation of the burn depth 
may lead to late or even unnecessary surgical debridement, especially in light of a previous 
study which has demonstrated that the excised burn eschar often contains viable tissue: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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microscopically unaltered normal deep dermis, unaltered dermal collagen fibers and transected 
normal capillaries [70].   
Contact burns are often palmar burns. Surgical intervention is very rarely indicated because the 
skin of the palm is thick and provides good protection. Surgical debridement is difficult to 
carry out due to the palm’s distinct anatomy and the tight fibrous septi attached coherence to 
the palmar aponeurosis. Substitution of the specialized palmar skin is only applicable to a 
limited degree. These factors justify conservative treatment for 3–4 weeks, whenever possible 
[69]. 
Within the clinical development program, NexoBrid was used to treat 130 deep partial and full 
thickness burn wounds of the hands (in 101 patients; 68 adults, 33 children and adolescents), 
mainly in 2 clinical studies: retrospective data collection study 35-98-910 and the 
confirmatory, controlled phase 3 study MW2004-11-02 [71].  
In a post-hoc analysis of the subgroup of hand wounds treated with NexoBrid and SOC in 
study MW2004-11-02, the following results were generated: 
Timely Eschar Removal  
Similar number of wounds reached successful eschar removal in both groups; 90.3% (28/31) in 
the NexoBrid group and 97.6% (40/41 wounds) in the SOC group (p = 0.1843). 
Time to achieve successful eschar removal was significantly shorter in the NexoBrid group 
(mean 2.57± 1.95 days from Injury compared to the SOC group (mean 7.75± 5.41 days from 
Injury) (p<0.0001). 
Excisional Eschar Removal 
Four (4) out of 31 hand wounds (12.9%) required excisional debridement in the NexoBrid 
group as compared to 29 out of 41 (70.7%) in the SOC group (p<0.0001). 
The mean percentage of the  burn wound area excised in the NexoBrid group was 4.4 ± 13.1% 
as compared to 52.0 ± 41.4% % in the SOC (p<0.0001).  
Autograft 
In the DPT sub-population, only one of the 24 (4.2%) hand wounds was autografted in the 
NexoBrid group compared to 10 of 20 (50%) in the SOC group (p=0.0005).  
The percentage of the burn wound area autografted in the NexoBrid was 2.1 ± 10.2% as 
compared to 30.5 ± 38.4% in the SOC (p=0.0017).  
Wound Closure 
The Mean Time to wound closure measured from injury date was similar in the two treatment 
groups: NexoBrid 25.0 ± 12.5 days, SOC 28.0 ± 15.8 days (p=0.3814) 
Hand wounds were further assessed as part of the Long term study (MW200-12-01-02) which 
included a blinded assessment of scar quality. The mean total overall MVSS score was lower 
(better results) in the NexoBrid arm compared to SOC: 3.14 ± 2.59 vs. 4.05 ± 2.82, 
respectively, without yet reaching a statistically significant difference due to sample size 
(p=0.2756).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a 
few hours post injury and develops during the acute, edematous stage of the first 2-3 days 
(after which edema and increased pressure subside) in deep circumferential burns. The edema 
and pressure reach their maximum within few days post injury and start to slowly decrease 
thereafter. Soft tissue can withstand temporary pressure increase for 6-8 hours without 
permanent damage, allowing 4-6 hours for decision-making regarding escharotomy (see 
below).  
Release of increased pressure can be achieved by formal surgical escharotomy, excision of the 
constricting eschar and as was observed by Krieger et al [71-72] as well as during the 
confirmatory phase 3 study MW2004-11-02, by early application of an effective, fast acting 
eschar removal agent that underwent a development program and studied for this specific 
condition such as NexoBrid [65, 72-73].  
Due to the very high incidence of hand burns and the risk of BICS (Extremity At Risk: EAR) 
all burn physicians are trained and skilled in the routine diagnosis and treatment of this clinical 
entity. Due to the severe complications potentially associated with the current SOC of the   
interventional measure of BICS release: surgical escharotomy (scars, bleeding & damage to 
deeper structures), physicians often choose to monitor the patient with circumferential 
extremity burns for a few hours (by clinical signs and direct pressure measurement), 
continuously assessing the hand’s condition, before committing to escharotomy [1, 64, 73, 92-
96]. In the clinical development program, none of the hand burns treated with NexoBrid 
required escharotomy. Moreover, none of the NexoBrid subjects’ hands had to be surgically 
escharotomized to resolve burn induced high interstitial/compartment pressure- 0% (0/130 
hand wounds) in the NexoBrid arm, vs. 9.7% (4/41) of the hands treated by SOC.  
To investigate release of pathologically elevated interstitial pressure, a sub-analysis was 
performed for the circumferential wounds that did have a measurement of elevated interstitial 
pressure prior to treatment in the confirmatory phase 3 study, MW2004-11-02. There were six 
(6) such wounds with measured high pressures that were treated with NexoBrid and two (2) 
that were treated by SOC. NexoBrid application reduced the elevated pressure below the 
threshold without  need for surgical intervention (escharotomy or excision), whereas in the 
SOC-treated wounds the pressure had to be reduced by surgical intervention (escharotomy or 
excision). Both methods effectively reduced and released burn-induced elevated pressures, but 
SOC is associated with the sequelae of surgical escharotomy. 
These results are further supported by the retrospective study (35-98-910) which demonstrated 
that enzymatic debridement decreased both the number of deep hand burn injuries that ended-
up in an operative procedure, and the wound area grafted in those who did undergo skin 
grafting [73]. 
The effective pressure release achieved with NexoBrid is also consistent with the results that 
were obtained in a controlled in vivo study. In a burn pig model, NexoBrid resolved burn 
induced compartment syndrome within 30-45 minutes after application, even before the 
complete dissolution of the eschar [72]. 
NexoBrid appears to address the unmet needs of an eschar removal means by being as fast and 
effective as surgery yet selective, non-invasive, not diagnosis-dependent, and least demanding. 
Its use resolves the first stage of wound bed preparation in the comprehensive wound care 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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process and in addition, facilitates the second step of non-surgical or surgical wound closure by 
enabling earlier, direct visual assessment of the wound bed and by reducing the incidence 
and/or extent of excision, which is a substantial, demanding part of the surgical wound closure 
process. The potential tissue-sparing effect of NexoBrid that offers the option of reducing 
autografting of the healing wound suggests an additional clinical benefit to the burn victim. 
Autografting, besides being a demanding surgical procedure that needs general anaesthesia, 
OR facilities and surgical personnel, also sacrifices healthy donor site skin that needs 2-3 
weeks of painful healing and often ends with permanent scars.  
Early non surgical eschar removal and prevention/resolution of increased interstitial/ 
compartment pressure in circumferential burns of extremities may decrease the time to 
resolution of such increased interstitial/compartment pressures reducing or  preventing the need 
for surgery.  It is especially important and beneficial to the patient and treating physician as it 
not only reduces or eliminates the need of traumatic and risky surgery but it also alleviates the 
weight of the difficult decision of performing a potentially mutilating surgical escharotomy, 
greatly extending the safety margins available for the treating physician. Such hands are 
routinely monitored before and after treatment and so were and will be the NexoBrid treated 
hands allowing intervention if needed as has been shown in its routine use.  
All these benefits may also have special importance in preparedness for a burn mass casualty 
disaster scenario where surgery is the main treatment bottleneck (as has been seen in the 9/11 
crisis: Dr. Bessey from Cornell, NY September 2012 & February 2013 FDA Burn Mass 
Casualty Incident Medical Countermeasures Public Workshops [74]. Study Rationale  
Enzymatic eschar removal with NexoBrid allows initiating and completing the phase of 
removal of the offending eschar earlier upon admission, enabling earlier visualization of the 
wound bed for assessment of burn wound depth as well as preservation of viable tissues, as 
further elaborated and supported by previous clinical studies. The depth determination is 
important for the planning and execution of the post eschar removal stage of wound closure 
phase (grafting or spontaneous epithelialization).  
Additional clinically meaningful attributes of NexoBrid enzymatic eschar removal is the ability 
to lower surgical burden as it allows to remove eschar in wounds that otherwise would have to 
undergo surgical excision.  
This phase 3 study MW2010-03-02 will be a multi-center, multi-national, assessor blinded10, 
randomized, controlled, three-arm study intending to demonstrate superiority of NexoBrid 
treatment over Gel vehicle placebo control treatment and over Standard of Care (SOC) 
treatment, in thermal burn subjects. 
4. 
ETHICS STATEMENT 
The study will be carried out in accordance with accepted international standards, which meet 
regulations relating to Good Clinical Practice (GCP). These standards are drawn from the 
following guidelines: ICH Guideline for Good Clinical Practice, 1 May 1996 amended 
September 1997 and Declaration of Helsinki (as amended in Seoul, October 2008), concerning 
medical research in humans. 
                                                 
10 Complete Eschar Removal assessment will be performed by a blinded assessor in the NexoBrid and Gel vehicle treatment arms.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The investigator(s) will ensure that this study is conducted in full conformity with the 
principles of the "Declaration of Helsinki" and with the laws and regulations of the 
participating countries, whichever affords the greater protection to the individual.  It is the 
responsibility of the investigator to obtain informed consent in written form (according to local 
legal requirements) from each subject participating in this study. All patients will be informed 
of the aims, methods, anticipated benefits, potential hazards and confidentiality of data. 
Candidates will also be told that they are free to refuse participation at any time. 
5. 
STUDY OBJECTIVES  
The study objectives are: 
1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
complete eschar removal as compared with Gel vehicle, 
2. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
earlier complete eschar removal, reduction in patients’ surgical burden and its related 
blood loss as compared to SOC, 
3. To assess the safety of NexoBrid compared to SOC, including demonstration that 
treatment with NexoBrid does not cause an unacceptable level of harm on wound 
closure outcome and long term outcomes of cosmesis and function. 
6. 
INVESTIGATIONAL PLAN 
6.1 
PRIMARY ENDPOINTS, SECONDARY ENDPOINTS AND OTHER ENDPOINTS 
6.1.1 
Primary Endpoint 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to Section ‎1.1 for Target Wound 
definition): 
Incidence of complete eschar removal: Demonstrate superiority of NexoBrid over Gel 
Vehicle for eschar removal as measured by incidence of complete eschar removal at the end of 
the topical agent soaking period by a blinded assessor. 
6.1.2 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SOC to further support the clinical benefit of NexoBrid.  
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. Earlier eschar removal- Demonstrate superiority of NexoBrid over SOC with regard to 
the time when complete eschar removal has been achieved. For definition of complete 
eschar removal see primary endpoint. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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3. Blood loss related to eschar removal- Demonstrate superiority of NexoBrid over SOC 
with regard to the blood loss occurred during the eschar removal procedures.  
6.1.3 
Safety Endpoints 
The following group of safety endpoints will be evaluated in this study and compared 
between NexoBrid and SOC. These endpoints are used to confirm that NexoBrid does 
not cause an unacceptable level of harm 
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 VAS 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, Incidence of increased interstitial/compartment 
syndrome (as defined in Section ‎1.1) and QT prolongation, Number and volume of blood 
transfusions received throughout the hospital admission, Extent of analgesia, anaesthesia 
and antibiotic use (i.e. total dose per kg body weight), Rates 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 Burn Specific Health Scale- Brief (BSHS-B). 
d. Local parameters: Local adverse events defined by treating physician or designee; graft 
loss, wound related infections, etc. 
6.1.4 
Exploratory Endpoint  
1. Reduction in surgical needs as measured by an analysis of % wound area surgically excised 
for eschar removal (and % TBSA excised of the treated TW) (tangential/ minor/ avulsion/ 
Versajet and/or dermabrasion excision), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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2. POSAS will be used to further assess cosmesis and function at the long term follow up visits, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities target wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically harvested donor 
sites, 
6. Reduction in surgical need as measured by analysis of % area of surgically harvested donor 
site, 
7. Blood loss related to eschar removal assessed by changes in Hematocrit incurred during the 
eschar removal procedures 
8. Cosmesis evaluation  (MVSS and POSAS) will be used to assess the quality of the donor sites 
scars,  
9. PK evaluation for a subset of NexoBrid patients11, 
10. Autograft related parameters: 
I. 
Efficacy and safety analyses for early and late grafted wounds 
II. 
Total number of target wound grafting procedures 
III. 
Incidence of repeated/additional grafting procedures 
IV. 
Area of repeat grafting  
11. Duration of hospitalization. 
6.2 
STUDY DESIGN 
This is a multi-center, multi-national, randomized, controlled, assessor blinded (see Section 
‎6.3), three-arm study aiming to demonstrate superiority of NexoBrid treatment over Gel 
vehicle control and over SOC treatment in thermal burn subjects with burns. 
175 subjects are planned to be randomized to the study in a 3:3:1 ratio (NexoBrid: SOC: Gel 
Vehicle). The study will be conducted at sites in the US and out of the US. 
Following the enrollment of a patient to the study and prior to randomization, physicians will 
identify one or more TWs per patient according to the TW definitions described in Section ‎1.1.  
All subjects’ DPT and FT burns that comply with the specified entrance criteria under Section 
‎7.1 are intended to receive study treatment per the randomized study arm and therefore, must 
be designated as TWs. This will further allow an evaluation of the subject systemic safety by 
allowing treatment of the subject’s entire deep burns as per the randomized study arm. After 
reviewing the entrance criteria, prior to randomization, eligible subjects will be stratified into 
different groups in order to standardize and minimise bias between study groups in terms of 
efficacy and safety outcomes that are expected to be correlated to the patient total burn area 
and its depth. Please refer to Section ‎13.7.1 for full description of the randomization procedure. 
                                                 
11 Please see Appendix 10- Procedures for specific blood tests for details. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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Following the stratification, patients will be randomized as per their stratification group 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 (please refer to Appendix 2- Pain Management Procedures) and undergo wound 
cleansing and dressing of all wounds with antibacterial solutions (as specified in Section ‎8.1). 
Following wound cleansing and antibacterial treatments, subjects will undergo the eschar 
removal process as per treatment assignment (NexoBrid, SOC or Gel Vehicle, following 
randomization) as further described in APPENDIX 16- Treatment Diagram.  
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.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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6.3 
MEASURES TAKEN TO MINIMIZE/AVOID BIAS  
This study includes 3 arms: NexoBrid, SOC and Gel Vehicle.   
In this study, wound characterization will be performed prior to randomization into treatment 
arms. The randomization procedure will be initiated only after all TWs of a patient have been 
defined and recorded in the eCRFs. All subjects’ DPT and FT burns that comply with the 
specified entrance criteria under Section ‎7.1 and TWs definition (Section ‎1.1) are intended to 
receive study treatment per the randomized study arm. Randomization will be performed by 
stratifying eligible subjects into different groups and by center in order to standardize baseline 
characteristics and minimise potential bias between study groups in terms of efficacy and 
safety outcomes that are expected to be correlated to the depths of the patient’s TWs. The 
planned stratification by center further enables the standardization of the treatment of all study 
arms further reducing possible site effect. 
Wound size (%TBSA) will be clinically assessed by the ‘rule of palms12’. 
Using this stratification, patients will be randomized in a 3:3:1 ratio (NexoBrid: SOC: Gel 
Vehicle). Please refer to Section ‎13.7 for further information.  
To further minimize bias, the Investigator will define the TWs of a patient based on the criteria 
for defining target wounds, as described in Section ‎1.1. All Patient’s TWs will be treated in 
accordance with the randomized treated arm; NexoBrid, Gel vehicle or SOC (as described in 
Section ‎6.4), thus allowing appropriate collection of safety information, which is being 
reported per patient, presenting the patient as a whole. 
A subject who was randomized, but did not receive treatment will be analyzed in the ITT 
population (see description of population in Section ‎13.1). 
6.3.1 
Assessments of Clinical Measures 
The following measures are predefined and will be taken in specific time points per the study 
protocol to ensure minimization of potential biases: 
6.3.1.1 
 Extent of eschar removal assessment using topical agent; NexoBrid or Gel 
Vehicle  
The topical arms are 2 different topical preparations (NexoBrid- a gold color gel and Gel 
Vehicle- a transparent gel) that are impossible to disguise in terms of preparation procedures 
and appearance, even if supplied in masked containers. Therefore, the topical product 
application (NexoBrid or Gel Vehicle) will be done by a health care professional and the 
wound assessment will be performed by a different health care professional who is blinded to 
the randomized study arm. This will allow a blinded assessment of the primary endpoint of the 
study (incidence of complete eschar removal in NexoBrid vs. Gel Vehicle arm). 
Eschar removal procedure will be initiated at the end of the cleansing and blister removal 
session (debridement), after wound soaking. Product will be applied by a health care 
professional to the wound within 15 minutes of mixing, and left on for a 4-hour period. After 4 
                                                 
12 Using the rule of palms, the surface of the patient's palm represents approximately 1% of body surface area and is helpful in 
estimating the area of small burns. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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hours, the wound bed with the remains of the dissolved eschar and topical agent will be wiped 
away and the wound bed will be soaked for an additional 2 hours to remove any remains of the 
mixture. Following removal of the soaking dressing (6 hours of treatment in total), the wound 
bed will be photographed in a standardized manner, and the extent of eschar removal will be 
clinically assessed by a different health care professional- assessor blinded to treatment 
assignment. The un-blinding tests that are done only for the NexoBrid patients (i.e. PK and 
Immunogenicity) will be done by non blinded site staff and will be recorded in a separate 
worksheet for the purpose of keeping the eschar removal assessor blinded to study arm. For the 
purpose of standardization, if feasible, the same blinded assessor should be assigned to assess 
eschar removal in all patients, and in all study arms. The blinded assessor will sign the "blinded 
assessor memo" (see Appendix 15- Blinded Assessor Memo).    
If debridement is not complete, but at least 50% of eschar was removed, a second application 
will be performed, as described in Section ‎8.2.3.2. Similar procedures will take place following 
a second application of the topical agent Patients treated with NexoBrid or Gel Vehicle will 
undergo up to 2 topical applications.  
In cases where eschar removal was not complete following the applications of the topical 
agents, NexoBrid or Gel Vehicle, additional surgical procedures and/or non surgical treatments 
as described below will be implemented in accordance with physician judgment:  
6.3.1.2 
Surgical eschar removal (SOC arm or as additional procedure for the topical 
arms): 
Extent of wound area excised & incidence of excisions following each surgical excision 
procedure performed for eschar removal will be recorded in the eCRFs. Eschar removal will be 
assessed immediately after the eschar removal surgical procedure, before a temporary or 
permanent dressing will be applied. The extent of eschar removal will be clinically determined 
by the same assessor who is blinded for the topical arm. 
Surgical procedures intended for eschar removal are pre-specified in the protocol for 
standardization (i.e. tangential/minor/avulsion/Versajet/dermabrasion excision). 
6.3.1.3 
Non-surgical eschar removal (SOC arm or as additional procedure for the 
topical arms): 
Wounds will be assessed by a burn specialist as in common daily practice, following any 
dressing change.  Extent of eschar removal after the last dressing will be clinically determined 
by the same assessor who is blinded for the topical arm and recorded in the eCRFs.  
Non-surgical procedures intended for eschar removal are pre-specified in the protocol for 
standardization and are detailed in Section ‎8.2.2. 
6.3.2 
Main safety measures 
To further minimize bias, main safety measures (weekly assessments for wound closure, long 
term cosmesis as well as some functionality assessment) will be performed by a blinded 
assessor, different from the first assessor who performed eschar removal assessments. This 
assessor should not be involved in any eschar removal procedure and should not be aware 
whether the patient was assigned to the topical arms (NexoBrid or Gel arms) or to the SOC 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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arm. For the purpose of standardization, if feasible, the same blinded assessor should be 
assigned to assess wound closure, cosmesis and function (as described below) in all patients, 
and all study arms. The blinded assessor will sign the "blinded assessor memo" (see Appendix 
15- Blinded Assessor Memo). 
 Wound closure- will be assessed on a weekly basis as described in Section ‎8.6. 
Complete wound closure defined as skin re-epithelialization without drainage or 
dressing requirements confirmed at two consecutive study visits, 2 weeks apart [75]. 
Wounds will be considered as closed  when the assessor marks ‘Yes’ in regards to 
complete wound closure, which will be further confirmed in the wound closure 
confirmation visit, 2 weeks later.  
 Cosmesis and Function (using MVSS)- will be assessed at the following time-points: at 
1 month from reaching complete wound closure confirmation of last  wounds and at 3, 
6, 12, 18 and 24 months from reaching complete wound closure confirmation.  
6.4 
STUDY TREATMENTS AND DOSAGE  
6.4.1 
NexoBrid 
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel 
for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the 
active component. Following mixing of the powder with the gel vehicle, each gram of the 
prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a 
mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).  
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of 
sterile Gel Vehicle (ratio of 1:10) , respectively to obtain sterile NexoBrid Gel. NexoBrid Gel 
is applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile 
Gel Vehicle per 1% of TBSA (~ surface of an adult palm) for four hours (or 5 g NexoBrid 
sterile powder mixed with 50g sterile Gel Vehicle per 2.5% of TBSA. The NexoBrid powder 
and the Gel Vehicle are to be mixed at the patient bedside 15 min prior to use. 
NexoBrid should not be applied to more than 15% TBSA (±3% TBSA) in one session. 
NexoBrid may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. NexoBrid may only be applied twice to the same burn 
wound area. 
6.4.2 
Gel Vehicle 
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn skin. Gel 
Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel per 1% of TBSA (~ 
surface of an adult palm) or 50 grams per 2.5% TBSA for four hours.  
Gel Vehicle should not be applied to more than 15% TBSA (±3% TBSA) in one session. 
Gel Vehicle may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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removed during the first application. The Gel Vehicle may only be applied twice to the same 
burn wound area. 
6.4.3 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  
Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excisions.  
Non-surgical procedures will include the application of (collagenase ointment (e.g. Santyl), 
antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 
The need of either non-surgical or surgical procedures will be determined by the burn 
specialists and can be repeated as needed until complete debridement.  
6.5 
TRIAL PERIODS 
The total duration of the study treatment and follow up period of each participating subject is 
expected to be 25 months: Following initiation of the Eschar removal procedure, each subject 
will be followed up weekly (Weeks 1, 2, 3 and 4 etc.) until complete wound closure was 
achieved and 2 weeks later for wound closure confirmation, for each of the subject's TWs. 
Long term follow-up visits will be performed at 1, 3, 6, 12, 18 and 24 months post last wound 
closure confirmation visit of each patient. 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
SUBJECT ENTRANCE CRITERIA 
7.1.1 
Inclusion Criteria- Patient level   
1. Males and females; ≥ 18  years of age, 
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. 
7.1.2 
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 include face, perineal or genital),13  
All planned target wounds (TWs) should meet the following criteria: 
2. SPT areas that cannot be demarcated from DPT and FT areas should be less than 50% of the % 
TBSA of the TW 
                                                 
13 All these wounds which are in line with this criteria should be defined as target wounds (TWs) and treated per randomization 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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3. Wound’s blisters can be removed/unroofed, as judged by the investigator. 
7.1.3 
Exclusion Criteria- Patient level  
1. Patients who are unable to follow study procedures and follow up period, 
2. Modified Baux index14 ≥ 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) as described in section ‎11.8,  
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 h 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 burns area of up to 15% TBSA or BMI greater than 
34.0 kg/m2 in patients with burns area of 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, severe 
edema and/or lymphedema, regional lymph nodes dissection, 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, 
                                                 
14 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and the presence of smoke 
inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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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) severe alcohol or drug use disorder (see definition 
in section ‎1.1),  
25. Prisoners and incarcerated, 
26. Patients who might depend on the clinical study site or investigator. 
7.2 
SUBJECT WITHDRAWAL CRITERIA  
After screening and prior to treatment any changes in the patient's medical condition should be 
assessed. The patient should be excluded from treatment if these changes represent 
deterioration in his/her condition which may affect the patient's safety and/or suitability for the 
study (e.g. exclusion criteria).  
Throughout the course of a subject's participation in the study, he/she may be removed from 
the study as follows:  
 Whenever it is necessary to safeguard his/her welfare as judged by the Principle 
Investigator,  
 Participation in another investigational drug trial, 
 Subjects who express a desire to withdraw from the study, 
 Subjects with EAR identified post randomization but prior to treatment. 
The reason for any subject withdrawal from the study should be recorded in the eCRFs and the 
occurrence should be reported to the sponsor. Early termination visit should include final 
assessments as in the Hospital Discharge visit, as applicable (please refer to Section ‎8.7).  
Discontinued subjects will not be replaced. 
When a subject is removed from the study treatment, he/she will receive treatment according to 
the standard of care as appropriate in the investigative site and will be followed up according to 
the study schedule, in accordance with patient’s availability. 
7.2.1 
Stopping rules (apply for NexoBrid or Gel Vehicle arms only)  
Treatment (eschar removal) should be stopped following a safety concerns raised by the 
treating physician or if a patient expresses his desire to withdraw from the study. In addition, in 
the following situations: 
7.2.1.1 
Burn Induced Compartment Syndrome (BICS) Monitoring and Diagnosis 
All circumferential wounds should be closely monitored during treatment for signs of 
improvement or deterioration that may require escharotomy. If clinical assessment and SpO2 
monitoring are possible, they will be done continuously and recorded in the eCRFs every 2 
hours. If such assessment is not practical, direct pressure will be measured every 2 hours from 
start of the eschar removal. The eschar removal process shall be discontinued (escharotomy 
may be performed at the discretion of the physician in any of the following cases: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 Increasing interstitial/compartment pressure >30 mmHg 
 Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity 
 Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity or deterioration of clinical signs 
 
Deterioration of any of the 5 “P” signs: Pain, Paralysis, Pulselessness, Pallor, Paraesthesia  
Since in such cases the eschar removal procedure will not be completed as planned, such 
patients (if any) will still be part of ITT and any missing data usually collected during eschar 
removal (e.g. time to end of eschar removal, etc.) will be handled as missing data according to 
the protocol. 
In case of 3 consecutive cases where there is a need to disrupt the dressing and perform a 
surgical escharotomy, enrollment will be halted and a DSMB shall be convened to:  
 assess the severity of the phenomenon in a closed session 
 Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences 
As discussed above, increased interstitial/compartment pressure is a common medical 
condition in circumferential deep burns and its detection and resolution is part of daily standard 
of care. The only difference in the treatment of the patients in the study is during the eschar 
removal stage as dictated by randomization.  
7.2.1.2 
Coagulopathy during or within 24 hours of eschar removal 
It is evident that during the first 48 hours post injury there is deterioration in coagulation 
parameters in burn patients [76]. In addition, some burn patients are treated with anticoagulants 
after admission (in some burn centers all patients are treated with anticoagulants). Due to these 
facts, any stopping rule concerning coagulopathy after topical debriding agent application must 
take these factors into consideration.  
Enrollment will be halted and a DSMB will convene if 3 subjects develop the following signs 
which have been defined as life threatening coagulopathy in trauma patients: 
INR>2 or a PTT>2 times the normal range [77], in cases where the patient is not receiving 
anticoagulants that can explain the coagulopathy. 
A DSMB shall be convened to assess in a closed session the following: 
 The relationship between coagulopathy and the treatment arm 
 The severity of the phenomenon 
 Recommend on appropriate corrective measures, as applicable to prevent such reoccurrences  
DSMB investigation will consider patients’ medical history, including any anticoagulants 
given to the patient prior to start of treatment. 
7.2.1.3 
Post treatment diagnosed infection (until complete wound closure) 
Following the eschar removal treatment, in case 3 subjects develop infections listed in Section 
‎11.9 and are assessed as related to the treatment arm (possibly, probably or related as defined 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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in Section ‎12.1), enrollment will be halted and a DSMB will convene in close session to 
investigate cases reported and their relatedness and severity.  
In all the above 3 described cases, enrollment may continue in accordance with DSMB 
conclusions.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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8. 
STUDY CONDUCT  
The healing and care of the burn wound may be divided into the three distinctive phases: 
1. Eschar removal treatment phase  (until complete eschar removal) 
2. Wound management (until complete wound closure) 
3. Scar modulation and maturation  
These phases are common to the care of all wounds and are well defined in acute wounds such 
as burns.  
In this study these phases and their treatment strategy are equal for all arms, NexoBrid, SOC, 
and Gel Vehicle, following the ABA white paper guidelines [1].  
8.1 
SCREENING AND BASELINE VISIT 
8.1.1 
  Screening and Baseline Procedures  
For subjects who are admitted to the burn unit, and who are willing to participate in the study, 
the following procedures will be performed: 
1. Signing of consent form:  
Prior to performing any study related activities/evaluations which are not considered as 
routine, the subject must be thoroughly informed about all aspects of the study, including 
scheduled study visits and activities, and must sign the informed consent form. A signed 
copy of the informed consent form must be given to the subject. Legal representative may 
be involved in the Inform Consent procedure and sign the form if this is pre approved by 
the local IRB/EC and only for subjects with temporary medical conditions related to the 
injury, subjects who might be under the influence of pain medication, sedation, etc. 
However, legal representative cannot sign the form for mentally incapacitated subjects 
who are incapable of giving legal consent (entrance criteria, Section ‎7.1), 
2. Review and documentation of complete demographics, medical history (e.g. specific 
cardiac, pulmonary, endocrine and renal diseases), and concomitant medications, 
3. Vital signs measurement including blood pressure, pulse rate, temperature and respiration 
rate, 
4. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale, 
Please refer to Appendix 9- Pain Measurement Scale), 
5. General physical examination (including diagnosis of smoke inhalation injury, signs for 
Burn Induced Compartment Syndrome, etc) including a record of weight and height, 
6. Obtaining burn etiology, mechanism of injury, place of injury, treatments prior to 
admission and description of the eschar (such as: white, moist, dry, gray, charcoal, etc.), 
7. Leukocyte count (WBC), 
8. Extremities At Risk (EAR) burns prone to develop BICS will be identified (See Section 
‎11.8). 
9. Pregnancy test for subjects of  child-bearing potential performed at local laboratory, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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10. HbA1c in patients with known diabetes as captured in the medical history, 
11. Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, 
whichever comes first, for patients with catheter,  
12. Wounds cleansing as described in Section ‎8.1.2 below, 
Post wound cleansing, preferably before soaking (to avoid unnecessary dressing removal), 
all wounds should be labelled and photographed (as required in Appendix 3- 
Photographic wound documentation). The TWs numbers assignment per their location 
will be documented on a schematic drawing of an adult. 
13. Post cleansing, preferably before soaking the wounds with antibacterial solution (section 
8.1.2, point 3), the % TBSA (clinically assessed by the rules of palm) and burn depth 
(as detailed in Appendix 1- Wound Depth assessment- Clinical Evaluation) of each wound 
and of each TW will be recorded, 
14. Pain management medications and analgesia/sedation levels should be recorded (see 
pain management protocol provided in Appendix 2- Pain Management Procedures)  
15. Completion of the applicable eCRFs, 
16. Randomization of eligible subjects (as described in Section ‎13.7.1). 
8.1.2 
 Cleansing and Soaking 
The initial care of the burn wound starts with general cleaning that removes all gross 
contaminants, soot and blisters (“Debridement”). As described in Neligan Plastic Surgery 
Textbook, volume 4 pg 403 [78], DPT burns contain large blisters. Blister fluid is known to be 
detrimental to raw exposed tissues and to wound healing as well as being prone to infection 
that will spread in this occluded space. The blisters tend also to rupture under the dressings and 
during their changes. Using aseptic techniques the blisters should be removed (“unroofed”) and 
the exposed wound treated as needed [78-82].  
Preventive analgesia/sedation medication (pain management) will be mandated as for an 
extensive dressing change as commonly practiced (see Appendix 2- Pain Management 
Procedures). The following should be performed: 
1. Topically applied medication on the wound site must be discontinued, 
2. The wound should be cleansed thoroughly with saline, soap or antibacterial solution and 
the blisters (superficial keratin layer) removed by common procedures (i.e. rubbing with 
sterile gauze, saline soaking, etc), 
3. Soaking of at least 2 hours: A dressing soaked15 with an antibacterial solution, e.g. 3-5% 
Sulfamylon, 0.05-0.5% Chlorhexidine, Dakin’s solution, hypertonic 5-10 % saline solution 
or 0.9% Saline must be applied to the wound and left in place. This dressing must remain 
wet until it is removed prior to application of the eschar removal agent/procedure. In order 
to prevent desiccation of the wound; the dressing must be changed at least every 12 hours 
if eschar removal is delayed. After soaking the dressing should be removed using aseptic 
techniques, 
                                                 
15 Soaking refers to placing gauze soaked with fluid, e.g. saline or Dakin’s Solution on dressing the wound with thick, dry absorbent 
gauze, inserting inside a feeding tube or the tip of an IV set that offers the option of adding fluids at will.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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4. Check that the superficial keratin (blister) has been removed (NOTE: For deep charred, 
flame burns blister-keratin removal may be difficult. In a deep, charred burn a thorough 
scraping is needed to remove the charred blister from its dermal eschar). In the event that 
not all the superficial keratin layer is removed from the burn eschar, repeat steps 2 and 3 as 
the blister-keratin may be a focus for infection and will prevent the eschar dissolution by 
isolating it from the topical agent. 
Note: The results of the above on-site tests (describe in Section ‎8.1.1) may be used for study 
data collection prior to signing of the consent form only in case they are part of routine hospital 
care regardless of study procedures and within relevant timelines.  
8.2 
TREATMENT PROCEDURE- ESCHAR REMOVAL: NEXOBRID/SOC/GEL VEHICLE - 
INITIATED WITHIN 84 HOURS FROM INJURY  
Eschar Removal will be performed in accordance with randomization: SOC, Gel Vehicle or 
NexoBrid.  
8.2.1 
All arms - Pre first treatment assessments- within 1 h pre treatment 
Make sure at least 2 hr soaking were performed and that all blister-keratin has been removed 
from the TW's eschar. If there are still blisters/keratin remains, clean the wound thoroughly and 
remove the superficial keratin layer or blisters from the wound area, as the keratin will isolate 
the eschar from direct contact with the topical agent (as described in Section ‎8.1.2).  
Patients will undergo the following procedures within one hour (+ 30 min) prior to start of first 
procedure for eschar removal:  
1. Blood culture,  
2. PTT & INR (2ml) blood sample,  
3. PK blood sample (2ml)   for NexoBrid patients as described in Appendix 10- Procedures 
for specific blood tests, 
4. Immunogenicity blood sample16 (3ml) (NexoBrid patients), see Appendix 10- 
Procedures for specific blood tests, 
5. Central lab blood tests: Serum chemistry, hematology and urinalysis (as described in 
Section ‎11.7) 
6. EAR monitoring:  Clinical assessments, SpO2 and the direct interstitial/compartment 
pressure measurement will be performed in circumferential extremity wounds. The 
measurement will be done, as described in Section ‎11.8,  
7. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale should be performed 12-lead ECG 
(in triplicate) will be performed, if feasible, at the following time points: 60 ± 5 min, 40 ± 
5 min and 20 ± 5 min prior to start of treatment,  
8. Preventive analgesia medication (pain management) will be mandated as for an 
extensive dressing change as routinely practiced; it should be initiated at least 15 minutes 
                                                 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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prior to dressing change or application in order to ensure pain free care (example of a 
recommended protocol provided in Appendix 2- Pain Management Procedures). Prior to a 
surgery, preventive sedation and/or general anesthesia will be mandated as routinely 
practiced. Pain management medications and analgesia/sedation level will be recorded,   
9. Qualitative-swab wound culture (per Target Wound), 
10. All Target Wounds should be labeled and photographed (please refer to Appendix 3- 
Photographic wound documentation), 
11. % TBSA assessment (using rule of palms) and burn depth (as detailed in Appendix 1- 
Wound Depth assessment- Clinical Evaluation) of each TW will be recorded. 
8.2.2 
 Standard of Care (SOC) Arm - Eschar removal procedure- (to be 
initiated within 84 hours from injury) 
Subjects in the SOC group may be treated with a combination of surgical and non-surgical 
eschar removal procedures, for each TW, according to the investigator's judgment. In case of 
indeterminate burns (second degree burns of changing depths) and/or combination wounds, 
mixed of second and third degrees, which are difficult to diagnose on arrival, non surgical 
treatments is usually being initiated for few days when the burn conversion (progression) and 
demarcation is taking place. Once a diagnosis is feasible, surgical procedures will usually be 
performed for deep wounds or additional non surgical procedures will be continued for 
superficial wounds.  
Surgical eschar removal procedure 
Surgical procedures intended for eschar removal are pre-specified for standardization and will 
include tangential/ minor/ avulsion/ Versajet/ dermabrasion excision).  
Non-surgical eschar removal procedure 
Non-surgical procedures intended for eschar removal are pre-specified for standardization and 
may include the application of Santyl (Collagenase ointment), antimicrobial solutions (e.g. 
Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. Bacitracin, Polysporin, 
Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, Acticoat). Non-Surgical 
procedure is considered as one procedure for whole period of any continuous dressing changes  
of more than 24h until either complete eschar removal is achieved or until surgical eschar 
removal is conducted.,  
8.2.2.1 
First SOC Procedure (to be initiated within 84 hours from injury) 
8.2.2.1.1 
Pre first treatment assessments- within 1 h pre treatment  
Pre first treatment assessments are described above in Section ‎8.2.1. The time-point of start of 
the SOC eschar removal procedure should be documented. This time point refers to the start 
time of the first treatment given to the patient, for eschar removal, post randomization (any 
topical application (non-surgical) or surgical procedure whichever is first).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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8.2.2.1.2 
During first SOC procedure (surgical or non-surgical), the following 
assessments will be performed: 
1. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 30 
± 15 min, 120 ± 15 min and 4 ± 0.5 hours after start of eschar removal, non surgical or 
Surgical. 
8.2.2.1.3 
Procedure (surgical or non-surgical) documentation:  
1. Completion time of the eschar removal procedure and type of procedure will be 
documented, 
2. Preventive analgesia medication (pain management) prescribed during treatment and level 
of analgesia prescribed (as described in Appendix 2- Pain Management Procedures), will 
be recorded, 
3. Manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistances) who participated during the above period of time and disposables 
used (number of dressings, blades, etc) will be recorded, if applicable,  
4. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented, 
5. If Quantitative (histological) wound culture biopsy performed, by the discretion of the 
treating physician, to rule out suspicion of a clinical invasive burn wound infection 
(Appendix 8- Biopsy & Histologic Assessment Method) it will be recorded, 
8.2.2.1.4 
Post first procedure: 
To be performed: 
i. 
For any surgical procedure 
And 
ii. 
For non-surgical – only if eschar is completely removed (i.e. the additional 
procedure is last procedure for eschar removal). 
1. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at the 
end of the eschar removal procedure, 
2. Target Wounds should be labeled and photographed at the end of the eschar removal 
treatment,  
3. Eschar removal will be assessed immediately following the completion of the procedure 
(by the same assessor who evaluate blindly the eschar removal in the topical arms) and 
recorded for each TW,  
4. TWs depth will be evaluated, and documented in the eCRFs once: post complete eschar 
removal17. For patients treated with only non-surgical treatment, TW depth assessment 
should be done post first dressing change. 
                                                 
17 More or equal to 95% 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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5. Qualitative-swab wound culture (per Target Wound) will be taken at the end the eschar 
removal procedure, 
6. Interstitial/compartment pressure will be measured and recorded (as described in Section 
‎11.8) post-eschar removal, per circumferential extremity wound, at the end of the 
procedure or escharotomy, whichever is first, 
7. Local lab tests: PTT & INR (2ml) blood sample, be performed 4 hours (± 15min) post end 
of the procedure, 
8. Pain assessment using a routinely accepted pain-scale (VAS) as described in Appendix 9- 
Pain Measurement Scale should be performed 4 hours (± 15min) after the end of the 
procedure, 
9. Central lab: Serum chemistry, hematology and urinalysis, should be performed 4 hours (± 
15min) after the end of the procedure,  
10. Blood culture: 4 h (± 15min) after the end of the procedure, 
8.2.2.2 
Additional SOC procedures: 
If eschar removal was not achieved after first eschar removal, additional SOC procedures 
(surgical or non-surgical), as detailed above, will be performed as needed until complete eschar 
removal is achieved.   
8.2.2.2.1 
Pre additional surgical treatment assessments- within 1 h pre treatment 
In addition to pre first treatment assessment as described in Section  ‎8.2.1, in case that more 
than one SOC procedure is performed, the following assessments should be repeated 1 hour (± 
15 min) pre any additional surgical treatment (do not perform if additional procedure is non-
surgical): 
1. The time-point of start of the surgical eschar removal procedure should be documented. 
2. Interstitial/compartment pressure will be measured in circumferential extremity wounds 
(See Burn wound definitions, Section ‎1.1). The measurement will be done, as described in 
Section ‎11.8, in addition to clinical assessment and SpO2 monitoring prior to eschar 
removal or Escharotomy, whichever is first, of each circumferential TW, 
3. Central lab blood tests: Serum chemistry, hematology and urinalysis (as described in 
Section ‎11.7),  
4. Pain assessment using a routinely used, standard pain-scale ruler (Visual Analogue Scale) 
as described in Appendix 9- Pain Measurement Scale, Qualitative-swab wound culture 
(per Target Wound), 
5. All Target Wounds should be labeled and photographed (please refer to Appendix 3- 
Photographic wound documentation), 
6. Preventive analgesia medication (pain management): Sedation and general anesthesia as 
routinely practiced will be administered before and during surgery and recorded.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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*  In cases that additional non-surgical procedures are performed, no need to perform 
the above. 
8.2.2.2.2 
Additional treatment documentation (surgical and non-surgical): 
1. Completion time of the eschar removal procedure and type of procedure will be 
documented, 
2. Preventive analgesia medication (pain management) prescribed during treatment and level 
of analgesia prescribed (as described in Appendix 2- Pain Management Procedures), will 
be recorded, 
3. Manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistances) who participated during the above period of time and disposables 
used (number of dressings, blades, etc) will be recorded,  
4. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented, 
5. If Quantitative (histological) wound culture biopsy performed, by the discretion of the 
treating physician, to rule out suspicion of a clinical invasive burn wound infection 
(Appendix 8- Biopsy & Histologic Assessment Method) it will be recorded, 
8.2.2.2.3 
Post additional procedure 
To be performed: 
I. 
For any surgical procedure 
And 
II. 
For non-surgical – only if eschar is completely removed (i.e. the additional 
procedure is last procedure for eschar removal). 
1. All target Wounds should be labeled and photographed at the end of the procedure.  
2. Extent of eschar removal will be assessed immediately following the completion of the 
procedure (by the same assessor who evaluate blindly the eschar removal in the topical 
arms) and recorded for each TW.  
3. TWs depth will be evaluated, and documented in the eCRF once: post complete eschar 
removal18. For patients treated with non-surgical treatment only, TW depth assessment 
should be done post first dressing change, 
4. Qualitative-swab wound culture (per Target Wound) will be taken at the end of the 
eschar removal procedure,  
5. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at 
the end of the procedure, 
                                                 
18 More or equal to 95% 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6. Interstitial/compartment pressure will be measured and recorded (as described in 
Section‎11.8) post-eschar removal, per circumferential extremity wound, after the 
completion of the procedure or escharotomy, whichever is first, 
7. Pain assessment using a routinely accepted pain-scale (VAS) as described in Appendix 
9- Pain Measurement Scale should be performed 4 hours (± 15min) after the end of the 
procedure, 
8. Central lab: Serum chemistry, hematology and urinalysis, should be performed 4 hours 
(± 15min) after the end of the procedure,  
9. Blood culture - 4 h (± 15min) after the end of the procedure. 
8.2.3 
Topical arms; NexoBrid/Gel Vehicle - Eschar removal procedure (to be 
initiated within 84 hours from injury) 
8.2.3.1 
First Application of NexoBrid/Gel Vehicle 
8.2.3.1.1 
Pre first treatment assessments- within 1 h pre treatment  
Pre first treatment assessments are described above in Section ‎8.2.1.  
The time-point of start of the eschar removal procedure should be documented.  
8.2.3.1.2 
Preparation 
1. Surround the area from which you wish to remove the eschar with Vaseline ointment 
adhesive barrier by applying it a few centimeters outside of the treatment area (using an 
adhesive-barrier dispenser). The paraffin layer must not come into contact with the area to 
be treated to avoid covering the eschar, thus isolating the eschar from direct contact with 
the topical agent, 
2. Sprinkle sterile isotonic (0.9%) sodium chloride solution on the burn wound. The wound 
must be kept moist during the application procedure. 
8.2.3.1.3 
Application 
Application of the product, as per the randomization, should follow the instruction for use 
described in Section ‎6.4. NexoBrid should not be applied to more than 15% TBSA (±3% 
TBSA) in one session. 
1. The wound should then be covered with an occlusive film dressing that adheres to the 
adhesive barrier material applied as per the instruction above. The topical agent should fill 
the entire occlusive dressing, and special care should be taken not to leave air in this 
occlusive dressing. Gentle pressing of the occlusive dressing at the area of contact with the 
adhesive barrier will ensure adherence between the occlusive film and the adhesive barrier 
and achieve complete containment of topical agent on the treatment area, 
2. The dressed wound should be covered with a loose, thick fluffy dressing, held in place 
with a bandage, 
3. The dressing should remain in place for 4 hours (± 15min), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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4. All unused products should be kept for accountability as described in Section ‎10.1 (all 
remains and unused bottles), 
8.2.3.1.4 
During 1st Application  
1. 12-lead ECG (in triplicate) will be performed, if feasible, at the following time points: 30 
± 15 min, 120 ± 15 min and 4 hours ± 30 min after initial application of NexoBrid/Gel 
Vehicle 
2. PK blood sample (2ml) will be performed in a subset of NexoBrid patients at the following 
time points: 30 ± 10 min, 120 ± 10 min and 4 hours ± 15 min from initial application. 
3. Circumferential extremity wounds should be monitored to detect EAR. If clinical 
assessment and SPO2 monitoring are possible, they will be done continuously and recorded 
in the eCRFs every 2 hours. If such assessment is not practical, direct pressure will be 
measured every 2 hours from start of the eschar removal. BICS should be treated by the 
investigator as described in Section ‎11.8. Circumferential extremity which is assessed as 
EAR at this stage should not be removed from the study but monitored as described above 
and in Section ‎11.8 
8.2.3.1.5 
Removal of topical agent 
1. Administer appropriate preventive analgesia medication, 
2. After 4 hours (± 15 min) of treatment at each TW, remove the occlusive dressing using 
aseptic technique and document the time. 
3. The adhesive barrier should be removed using a sterile blunt-edged instrument (e.g. tongue 
depressor), 
4. Remove the dissolved eschar from the wound by wiping it away with a sterile blunt-edged 
instrument, 
5. Wipe the wound thoroughly first with a large sterile dry gauze or napkin, followed by a 
sterile gauze or napkin that has been soaked with sterile isotonic (0.9%) sodium chloride 
solution. Rub the treated area until the appearance of a pinkish surface with bleeding 
points or a whitish tissue. Rubbing will not remove adhering undissolved eschar in areas 
where the treatment has been ineffective and eschar still remains, 
6. Interstitial/compartment pressure will be measured (as described in Section ‎11.8) post-
eschar removal per circumferential extremity wound after removal of dissolved eschar or 
Escharotomy, whichever is first, 
7. Apply a dressing soaked with an antibacterial solution, e.g. 3-5% Sulfamylon, 0.05-0.5% 
Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution for an additional 
2 hours. This wet-to-dry dressing will absorb and remove remaining NexoBrid and 
dissolved eschar that could not be removed by a simple wiping. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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8.2.3.1.6 
Post first application assessments  
1. Document the completion time of the 2 h soaking, 
2. Preventive analgesia medication (pain management) prescribed during treatment and level 
of analgesia prescribed (as described in Appendix 2- Pain Management Procedures), will 
be recorded, 
3. Manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistances) who participated during the above period of time and disposables 
used (number of dressings, blades, etc) will be recorded, if applicable,  
4. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented, 
5. If Quantitative (histological) wound culture biopsy performed, by the discretion of the 
treating physician, to rule out suspicion of a clinical invasive burn wound infection 
(Appendix 8- Biopsy & Histologic Assessment Method) it will be recorded, 
6. Target Wounds should be labeled and photographed at the end of the 2hrs soaking,  
Eschar removal19 will be assessed immediately following the completion of 2 hrs soaking by 
an Investigator or designee, blinded to the treated arm, 
                                                 
19 Complete eschar removal is defined as more or equal to 95% of the eschar removed 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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7. TWs depth will be evaluated following the completion of 2 hrs soaking, and documented in 
the eCRFs once: post complete eschar removal, 
8. Qualitative wound culture (swabs), per TW, will be performed at the end of the 2h soaking 
period, 
9. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at the 
end of the 2h soaking period, 
10. PTT & INR (2ml) will be tested at 4hrs ± 15 min after removal of the topical agent,(2 h 
after end of soaking) 
11. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale) as 
described in Appendix 9- Pain Measurement Scale should be performed 4 hours (± 15min) 
after removal of the topical agent , (2 h after end of soaking) 
12. Central lab: Serum chemistry, hematology and urinalysis (as described in Section ‎11.7), 
should be performed 4 hours (± 15min) after removal of the topical agent, (2 h after end of 
soaking) 
13. Blood culture - 4 hours (± 15min) after removal of the topical agent, (2 h after end of 
soaking) 
8.2.3.2 
Additional Application of NexoBrid/Gel Vehicle (within 24 hours from start of 
first application) 
Additional session can be performed in 2 scenarios: 
1. In case TWs area is more than 15% TBSA, NexoBrid should be applied in 2 separate 
sessions of up to 15% TBSA each. The second session can start immediately after the 
removal of the topical agent applied in first application but no later than 24 hrs after the 
start time of the previous application. 
2. In case eschar removal from the target wound after the first application is not complete, 
but at least 50% eschar was removed20, a second eschar removal procedure using the 
randomized topical agent (NexoBrid/ Gel Vehicle) will be performed. The randomized 
drug should be re-applied to the entire TW if necessary, but can also be applied only on 
the areas of the TW left with eschar. Reasons for failure should be recorded in the 
eCRFs. Repeat eschar removal session on the same area can start immediately after the 
2 hrs soaking done post the first application of the randomized arm (In this case pre 
soaking period is not required before a second application of the randomized arm 
treatment to the same target wound), but no later than 24 hours after the start time of 
the first application.  
No more than two eschar removal procedures using the randomized topical agent 
(NexoBrid/Gel Vehicle) will be allowed per TW. 
                                                 
20 In case that <50% eschar was removed, see section 8.2.3.3 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 Treatment preparation and application should be conducted as detailed above in sections 
‎8.2.3.1.1 and ‎8.2.3.1.3. 
8.2.3.2.1 
During treatment assessments 
1. PK samples should be taken as detailed in Appendix 10- Procedures for specific blood 
tests 
2. Circumferential extremity wounds should be monitored to detect EAR. If clinical 
assessment and SPO2 monitoring are possible, they will be done continuously and recorded 
in the eCRFs every 2 hours. If such assessment is not practical, direct pressure will be 
measured every 2 hours from start of the eschar removal. BICS should be treated by the 
investigator as described in Section ‎11.8. Circumferential extremity which is assessed as 
EAR at this stage should not be removed from the study but monitored as described above 
and in Section ‎11.8. 
Topical agent removal should be repeated as described in Section ‎8.2.3.1.5. 
8.2.3.2.2 
Post second application assessments  
1. Completion time of the eschar removal application and completion time of the 2 h soaking 
will be documented 
2. Preventive analgesia medication (pain management) prescribed during treatment and level 
of analgesia prescribed (as described in Appendix 2- Pain Management Procedures), will 
be recorded, 
3. Manpower (number of surgeons, anesthesiologists, registered nurses, practical nurses and 
unskilled assistances) who participated during the above period of time and disposables 
used (number of dressings, blades, etc) will be recorded, if applicable,  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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4. All types of bloods product transfusion (e.g. units of whole blood or packed cells and 
volume) will be documented, 
5. If Quantitative (histological) wound culture biopsy performed, by the discretion of the 
treating physician, to rule out suspicion of a clinical invasive burn wound infection 
(Appendix 8- Biopsy & Histologic Assessment Method) it will be recorded, 
6. Target Wounds should be labeled and photographed at the end of the 2hrs soaking,  
7. Eschar removal will be assessed immediately following the completion of 2 hrs soaking by 
an Investigator or designee, blinded to the treated arm,  
8. TWs depth will be evaluated following the completion of 2 hrs soaking, and documented in 
the eCRF once: post complete eschar removal, 
9. Qualitative wound culture (swabs), per TW, will be performed at the end of the 2h soaking 
period, 
10. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be taken at the 
end of the 2h soaking period, 
11. Pain assessment using a routinely accepted pain-scale ruler (Visual Analogue Scale) as 
described in Appendix 9- Pain Measurement Scale should be performed be performed four 
hours (± 15min) after removal of the topical agent, (2 h after end of soaking) 
12. Central lab: Serum chemistry, hematology and urinalysis (as described in Section ‎11.7), 
should be performed 4 hours (± 15min) after removal of the topical agent, (2 h after end of 
soaking) 
13. Blood culture - 4 hours (± 15min) after removal of the topical agent, (2 h after end of 
soaking). 
8.2.3.3 
Additional SOC (Surgical or non surgical) eschar removal procedures 
In case of a recorded failure (< 50% was removed) following the first topical application/s, or 
not complete eschar removal following 2 topical applications, additional surgical and/or non 
surgical eschar removal will be performed as needed until complete eschar removal21 is 
achieved as described in Section ‎8.2.2.2.   
 
                                                 
21 More or equal to 95% 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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8.3 
GENERAL ASSESSMENTS, POST ESCHAR REMOVAL  
The following assessments will be performed for all arms: 
1. Vital signs (blood pressure, pulse rate, temperature and respiration rate) will be measured 
daily, in the morning time (5 AM to 10 AM), starting on the morning after the start of 
eschar removal, until hospital discharge, 
2. Pain assessments will be performed daily, in the morning time (5 AM to 10 AM) using a 
standard pain-scale ruler (VAS) (please refer to Appendix 9- Pain Measurement Scale), 
starting on the morning after the start of eschar removal, until hospital discharge, 
3. Wound coverage type and % of wound covered will be documented upon each dressing 
change , post complete eschar removal until hospital discharge, if relevant,  
4. 12-lead ECG (in triplicate) will be performed, if feasible, at 12 ± 0.5 hours, 24 ± 1 hours 
and 48 ± 2 hours after start of the eschar removal treatment, 
5. PK blood sampling (2ml) will be at 12  0.5 hours, 24  1 hours, 48  2 hours  and 72  2 
hours from start of the 1st application of NexoBrid (ONLY for NexoBrid patients),  
6. Local lab tests: PTT & INR (2ml) blood sample, will be taken 24  1 hours and 48  2 
hours after start of Eschar removal procedures, 
7. All types of  blood product transfusions (e.g. units of whole blood or packed cells and 
volume) will be documented throughout the patient admission, The physician will be 
asked to comment on whether the blood transfused is related to any specific procedure 
performed (e.g. surgical eschar removal, preparation for an autograft, etc), 
8. Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, 
whichever comes first, for patients with catheter, 
9. Quantitative (histological) wound culture biopsy – will be recorded, if performed to rule 
out suspicion of a clinical invasive burn wound infection (Appendix 8- Biopsy & 
Histologic Assessment Method). 
8.4 
POST-ESCHAR REMOVAL- WOUND MANAGEMENT 
In TWs which were assessed to reach complete eschar removal22, the consequent wound 
closure phase can be initiated by grafting or epithelialization. The following section will 
describe wound management, post eschar removal, and is relevant to all TWs, regardless of the 
eschar removal method performed in accordance with the randomization. 
Following to completion of eschar removal (NexoBrid, Gel Vehicle or SOC), different sites in 
the same patient may require different treatment strategies [28]. In general, raw bed, regardless 
of the eschar removal means, should always be protected by a dressing or a topical medicament 
and never remain open or allowed to desiccate. 
                                                 
22 More or equal to 95% 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Subsequently, wound management for all treatment arms should follow the normal standard 
care for open, raw surfaces based on the general principles described below. Please refer to 
Appendix 5- Wound management; approved covers for list of approved wound care products: 
1. Wounds having Full thickness defects should be grafted with autografts or permanent 
dermal substitutes (i.e. Integra, Matriderm, Hyalomatrix) as soon as possible after eschar 
removal. If permanent cover such as autografting has to be postponed, a temporary 
adherent cover (e.g. allograft, Xenograft, etc) should be used until permanent closure is 
possible. Prior to grafting the clean eschar-free bed should be refreshed by scraping it to 
open occluded capillaries and remove fibrin deposits and thrombi. In rare cases of exposed 
tendons, blood vessels or bone, flaps may be used as protection and permanent cover.  
Use of negative pressure wound therapy (e.g. VAC) on top of the autograft for 2-3 days 
promotes take by ensuring drainage, contact and adherence to the wound bed and is 
commonly used.  
2. Wherever viable dermal exists, such as in the partial thickness burns (mid and deep 
partial), healing by spontaneous epithelialization on these partial thickness areas could be 
attempted for a period of approximately 3 weeks in order to reduce surgery and autograft 
use with donor site sacrifice [96], but should be carefully evaluated for a satisfying 
progress on a weekly basis. In these cases, the following wound management should be 
performed: 
a. The raw surface should be covered with an adherent biological cover (i.e. allograft, 
Xenograft), synthetic dressings or skin substitutes (e.g. Mepilex® Ag, Mepilex® transfer 
Ag, Aquacel Ag, etc) in order to protect the raw surface (mainly from desiccation) and 
provide the microenvironment necessary for epithelialization (e.g. 5% sulfamylon, 
Bacitracin, etc). If allografts, xenografts or any film-like products are applied on the 
debrided wounds, they should be perforated or meshed (and not expanded) for drainage 
and optimal conforming to the bed. Topical medicaments can also be used as covers as 
long as they do not interfere with the healing process (as in the case of SSD or Iodine 
preparations) and moisturize or prevent desiccating the healing bed (the above are 
suggested coverages to apply on the clean wound bed. For additional approved 
biological covers, skin substitutes and topical medications please refer to Appendix 5- 
Wound management; approved covers). 
b. Use of negative pressure wound therapy (e.g. VAC) on top of the graft or primary 
biological cover dressing including autograft for 2-3 days can ensure drainage, contact 
and adherence to the wound bed. The use of negative pressure wound therapy (NPWT) 
for a few days in order to stabilize and promote skin graft adherence and take is quite 
commonly practiced as part of the routine engraftment procedure. It is applied at the 
end of engraftment over the applied meshed or perforated autograft for 2-4 days and 
kept until first dressing change [105].   
c. The cover and dressings should be assessed for signs of contamination, infection or 
sloughing. Contamination or infection may be treated with topical antibacterial soaking 
or irrigation for a few days as well as systemic antibiotics, according to the 
investigator’s medical judgment.  Sloughing tissue should be removed by wiping away 
the non-adherent parts.  The exposed areas should be protected from desiccation and 
treated either as exposed dermis, aiming at epithelialization, or as a full thickness defect 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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which should be autografted or closed by permanents skin graft or substitutes. Dry 
hydrogels, gelfoams, hydrofibres, alginates, Biobrane etc. applied on a viable raw bed 
can desiccate the wound surface and if used, should be soaked periodically to provide 
moisture to the healing wound. 
d. Re-assessment of wound should be performed at least on a weekly basis (as per Section 
‎8.6)[83]: 
i. 
If the non healing area is a full thickness wound, the area should be autografted 
or closed permanently as soon as possible.  
ii. 
Areas with preserved dermis should be treated with approved topical 
medications or covered with approved biological covers in order to promote 
epithelialization and control granulation tissue that may start to develop after 2 
weeks. Granulation tissue that appears on the healing surfaces should be treated 
immediately. Granulation tissue forms-in and results from the proliferative 
phase of the inflammatory response [78]. Topical corticosteroids' primary 
activity is anti-inflammatory and/or immunosuppressive effects [84-85] (e.g. 
Synalar which is indicated for the relief of the inflammatory & pruritic 
manifestations & Diprolene Ointment which is a super-high potency 
corticosteroid indicated as well for the relief of the inflammatory and pruritic 
manifestations). Granulation tissue of wound’s bed, being an inflammatory 
process, is often modulated by topical steroid preparations for short periods (2-3 
days), alternating with other topical medications. The topical steroids facilitate 
control of granulation tissue and the cover that prevents desiccation allows 
epithelialization23.     
iii. 
If the non-epithelialized areas after > 2 weeks of healing are small (< ½ %TBSA 
or < 50 cm2) with many interposing epithelializing islands, topical medication 
can be applied. Medications such as Biafin or antibiotic ointments, creams or 
hydrocolloid dressings that will prevent desiccation and will provide a good 
environment for the epithelialization process are recommended. Special 
attention should be paid upon removal of these medicated dressings so that the 
epithelializing surface will not be disrupted.  
Exposed dermis can be autografted early after eschar removal in order to expedite wound 
closure but in many cases the dermis may epithelialize under the graft, dislodging it after 2-3 
weeks or the graft may take and remain as an over-grafting.  
Conservative, non-surgical treatment by the antimicrobial Silversulfadiazine (SSD) dressing 
followed by daily dressing change and bathing is designed to slowly slough and debride the 
eschar-covered wound by autolysis without excessive infection. SSD should not be used on a 
clean bed as it decreases epithelialization. The pseudoeschar caused by SSD can sometimes 
serve as a protective layer to the areas of epithelialization process but it is often misdiagnosed 
as newly formed eschar. This pseudoeschar should not be surgically excised (thus sacrificing 
a viable dermal bed) and conservative treatment should be continued until the entire 
                                                 
23 Steroid preparations are indicated and currently used as solutions, creams, ointments and also systemically for shorter and longer 
periods in most inflammatory process.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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pseudoeschar spontaneously sloughs off. After sloughing of the pseudoeschar the resulting 
surface should be assessed and full thickness non healing areas permanently closed (grafted). 
NOTE: Tangential excision of pseudoeschar will most probably result in a full thickness 
defect even if it originally covered preserved dermis with epithelialization potential.  
A detailed overview of post eschar removal wound closure is presented in Appendix 4- Post-
Eschar removal Wound Management. 
8.5 
WOUND MANAGEMENT PROCEDURES – (REFER TO ANY PROCEDURE POST 
COMPLETE ESCHAR REMOVAL); 
The following relevant details should be recorded: 
1. Target wounds and donor sites coverage type (all primary dressing used post-eschar removal 
and until complete wound closure) and the % area applied with, will be documented  
2. Any additional tangential/minor/Versajet/dermabrasion excision(s), which is done as a 
preparation for cover/autograft should be recorded,  
3. The relevant TW should be photographed within 1 hour before and immediately at the end 
of the excision procedure and % of treated wound excised (out of the original debrided 
wound) should be clinically assessed, 
4. Central lab – hematology, will be taken within 1 hr prior to start of any excision/ autograft 
and four hours after completion of the procedure, 
5. For any autograft performed, the TW should be photographed before (within 1 hour) and 
after any procedure. The % of treated wound autografted (out of the original wound size) 
will be clinically assessed, 
6. Any autograft performed, if not immediately (within 6 hrs) following the excision- central 
lab - hematology, should be performed within 1 hr prior to start of the procedure (including 
any preparations required) and four hours after completion of the procedure, 
7. Parameters describing the surgical procedures will be documented in the eCRFs in addition 
to 
starting 
and 
completion 
time 
of 
the 
surgical 
procedure, 
recovery 
time, 
analgesia/anesthesia prescribed during treatment, level of sedation/analgesia prescribed (as 
described in Appendix 2- Pain Management Procedures), manpower (number of surgeons, 
anesthesiologists, registered nurses, practical nurses, and unskilled assistances) who 
participated during the above period of time and disposables used (e.g. number of dressings, 
blades, etc),  
8. All types of blood product transfusions (e.g. units of whole blood or packed cells and 
volume to be recorded) prescribed to a subject with a record of date and time. The physician 
will be asked to comment on whether the blood transfused is related to any specific 
procedure performed (e.g. surgical eschar removal, preparation for an autograft, etc), The 
site (anatomical area), and size of the donor site will be photographed and clinically assessed 
(by rule of palm), 
9. Background pain should be treated according to the individual needs in order to ensure pain 
free care, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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10. Adverse events and concomitant medication will be recorded. 
8.6 
FOLLOW-UP ASSESSMENTS: WEEKLY (7  2 DAYS) POST-START OF ESCHAR 
REMOVAL 
The following assessments will be performed and recorded 7 ± 2 days post-start of eschar 
removal and, thereafter, on a weekly basis until all TWs and donor sites are closed (based on 
start of eschar removal): 
1. The target wound and donor sites should be photographed and documented (as describe in 
Appendix 3- Photographic wound documentation), 
2. Clinical assessment of % of target wound area epithelialized and/or closed by graft (see 
also wound closure assessment described in Section ‎6.3), and assessment of % donor site 
epithelialized, will be assessed by a second blinded assessor, blinded to all treatment arms, 
3. Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment (as describe in 
Appendix 3- Photographic wound documentation), will be assessed by a second blinded 
assessor, blinded to all treatment arms, 
4. 12-lead ECG (in triplicate) will be performed, if feasible, 7 ± 2 days from initial 
application,  
5. Development of granulation tissue should be monitored. In case of initial appearance, 
treatment using approved ointment, creams or soaking during the epithelialization stages 
of wound healing should be applied. Details should be recorded in the eCRFs,  
6. Immunogenicity blood samples (3ml) should be taken in NexoBrid patients as per the 
timelines described in Section ‎11.11, per Appendix 10- Procedures for specific blood tests. 
7. Weekly follow-up assessments will be continued until complete wound closure24 for all of 
a subject's treated target wounds25 and donor sites (Confirmation of wound closure for 
each target wound will be performed after 2 weeks, please refer to Section ‎8.8). 
8.7 
HOSPITAL DISCHARGE 
The following procedures and assessments will be performed and recorded before a patient’s 
discharge from the hospital (within 24 hours prior to discharge): 
1. Physical examination and weight, 
2. Date of hospital discharge. 
Note: Weekly follow-up assessments will be continued post hospital discharge until complete 
wound closure as per Section ‎8.6 above. 
8.8 
FOLLOW-UP ASSESSMENTS: WOUND CLOSURE CONFIRMATION 2 WEEKS POST 
WOUND CLOSURE 
                                                 
24 >95% area epithelialized or closed by graft 
25 Complete wound closure- defined as skin re-epithelialization without drainage or dressing requirements confirmed at two 
consecutive study visits, 2 weeks apart. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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A confirmation of wound closure will be performed by a follow-up visit at day 14 ( 2 days) 
from wound closure, for each subject's target wounds. The following assessments will be 
performed: 
1. The wounds should be labeled and photographed (as describe in Appendix 3- 
Photographic wound documentation),  
2. Assessment of % of wound area epithelialized and/or closed by graft,  
3. Maintenance of complete wound closure will be confirmed (Yes or No), 
4. Patient diary will be provided to the patient to record any change in concomitant 
medications and or any adverse event, during the following monthly FU period.  
8.9 
FOLLOW-UP LONG TERM ASSESSMENTS26 
The following assessments will be performed at 1 month (± 7 days), 3, 6, 12, 18 and 24 months 
(± 2 weeks for all time points) from the wound closure confirmatory visit: 
1. The wounds should be labeled and photographed, 
2. Maintenance of complete wound closure (YES or NO) - only on month 1 and 3, 
3. Record of scar-modulating procedures and scar reconstructive procedures, if performed. 
This should include dates of initiation and termination of scar-modulating procedures 
including any procedure performed (compression therapy, silicone sheeting, steroid 
injections, etc.), 
4. Any Adverse Events and concomitant medications prescribed should be captured in the 
eCRFs, 
5. Quality of Life evaluation will be performed using Burn Specific Health Scale (BSHS-
B) and EQ5D as described in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire, 
6. Functionality evaluation will be performed using self completed questionnaires (as 
described in Appendix 12- Cosmesis, Function and Quality of Life Questionnaire): 
a. The “Lower Extremity Functional Scale” test for burns in the lower extremities,  
b. The “QuickDASH” outcome measure for burns in the upper extremities.  
7. Immunogenicity blood samples (3ml) should be taken in NexoBrid patients as per the 
timelines described in Section ‎11.11, per Appendix 10- Procedures for specific blood 
tests, 
8. The below evaluations will be performed by a second blinded assessor (who is blinded 
to all treatment arms): 
a. Cosmesis assessment using POSAS and MVSS for all TWs and donor sites, as 
described in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire,  
                                                 
26 Assessments can be done at the patient's home, by the second blinded assessor, if pre approved by the local ethic committee/IRB. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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b. Range of Motion measurements of injured joints, if relevant: knee, ankle, 
shoulder, elbow, wrist and hand. Measurements will be performed on the 
patient’s own non injured joints as well for comparison to burned joints (as 
described in Appendix 14- Range of Motion). 
8.10 
FOLLOW-UP ASSESSMENTS: RE-ADMISSION TO HOSPITAL OR DAY CARE 
Persistent, small open wounds or reopening of new small areas are expected and can normally 
continue for months necessitating treatment as in- or outpatients as a part of a normal wound 
care [1]. A patient may be re-admitted to the hospital for continuation and follow-up of 
planned treatments or for unexpected events. The following procedures and assessments will 
be conducted and recorded: 
1. 
Date and  reason for the re-admission should be recorded and any relevant TWs planned to 
be treated, 
2. 
Surgical procedures done during re admission will be documented and assessments will be 
performed per section ‎8.5. 
3. 
Adverse events will be recorded throughout the hospital stay, 
4. 
Concomitant medication will be recorded throughout the hospital stay, 
5. 
Date of re hospital discharge will be recorded.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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9. 
TREATMENT FLOW CHART – STUDY SCHEDULE 
Table 3- Treatment flow chart- all arms 
#- If applicable  
* Weekly FU assessments will be performed every 7± 2 days from start of treatment until complete wound closure. Long term FU will be performed 1,3,6,12,18 and 24 M after last wound closure confirmation. 
**First treatment session will include any procedure for eschar removal: the NexoBrid/ /Gel Vehicle/Surgical or non-surgical procedure, as per randomization arm 
** Procedure can be either surgical or non-surgical. A whole period of continuous dressing changes (from first coverage application to last coverage application) is considered as one non-surgical procedure, 
assessments should not be repeated for each dressing change; Pre procedures assessments refer only to surgical procedures. Post procedures assessments refer to any surgical procedures and for non-surgical 
procedure only if it is the last procedure  
Parameter 
 Screening 
tests 
Baseline within  
1  h Pre First 
treatment session - 
All arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management 
& Re-admissions1- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Inform Consent signing 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Burn History2 
X 
 
 
 
 
 
 
 
 
ConMeds & AEs 
X 
X 
X 
X 
X 
 
X 
X 
X 
Physical examination3 
X 
 
 
 
 
 
X 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
Post S  
Post  
X 
 
 
 
 
Pain assessment 
X 
X 
 4h post R  
Pre and 4h post  
X 
 
 
 
 
Photograph of TWs 
X4 
X 
Post S  
Pre & Post  
 
Pre & Post  
X 
X 
X 
Clinical assessment of the 
burn5  
X 
X 
Post S  
Post  
 
Post  
X 
X 
 
Local lab - HbA1C, WBC, 
βhCG 
X 
 
 
 
 
 
 
 
 
                                                 
1 Wound Management will include any, post complete eschar removal additional excisions, Autografts, and donor site data if relevant..  
2 Data captured will include burn etiology, mechanism of injury, place of injury, treatments prior to admission and general description of the burn wound (anatomical locations and description of 
the eschar (such as: white, moist, dry, gray, charcoal, etc.), % TBSA assessments and depth 
3 Physical examination will include height and weight. Height will be taken only once, at screening. 
4 Photos should be taken before and after cleansing 
5 Clinical assessments will include % TBSA per depth, % eschar removed, % excised, % autografted, % wound epithelialization (TW and donor site, if relevant) as relevant. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 71 of 173 
 
 
  
 
 
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Parameter 
 Screening 
tests 
Baseline within  
1  h Pre First 
treatment session - 
All arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management 
& Re-admissions1- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Central lab hematology/ 
biochemistry tests & 
Urinalysis 
 
X 
4 h Post R  
Pre & 4 h Post  
 
 
 
 
 
Central lab Hematology 
 
 
 
 
 
 1h pre & 4 h post 
 
 
 
Cleansing  including at least 
2h soaking) 
X 
# 
 
 
 
 
 
 
 
Fluid balance1 
X 
X 
X 
X 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Local lab Wound culture 
 
X 
Post S 
Pre & Post  
 
 
 
 
 
Local lab Blood culture 
 
X 
4h Post R  
4 h Post 
 
 
 
 
 
12-Lead ECG (if feasible) 
 
60, 40, 20 min 
pre treatment 
During: 0.5, 2, 4h from 
start of first application 
only 
During: 0.5, 2, 4h  from 
start of first treatment 
only 
12, 24, 48 h 
 
 
week 1 
 
PK (for a subset of 20 
NexoBrid Pts) 
 
X 
During:0.5, 2, 4h from 
start of first application 
 
12, 24, 48, 72h 
 
 
 
 
Immunogenicity assessment  
(NexoBrid patients only) 
 
X 
 
 
 
 
 
weeks 
4,82 
Long term FU:  
 6, 24 
Local lab PTT & INR  
 
X 
4 h post R  - first 
application only 
4 h post - first treatment 
only 
24,48 h  
 
 
 
 
                                                 
1  Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, whichever comes first for patients with catheter.  
2 In case that 8 weekly visit is not performed, this assessment should be taken on the relevant weekly/first M visit as close as possible to 8 weeks. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 72 of 173 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
Parameter 
 Screening 
tests 
Baseline within  
1  h Pre First 
treatment session - 
All arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal  
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily assessments 
Wound Management 
& Re-admissions1- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long Term  FU (1, 
3, 6,12,18 & 24 
months)* 
Circumferential extremity 
wounds monitoring1 
X 
X 
, during andpost R (4 
hours from start) 
1h pre &  post  
 
 
 
 
 
Eschar Removal treatment 
 
 
X 
X 
 
 
 
 
 
Coverage 
 
 
 
Start and end date , type 
of primary dressing 
 
Type of primary 
dressing & 
frequency 
 
 
 
Wound closure confirmation2 
 
 
 
 
 
 
 
X 
Long term FU:  
1, 3 
Cosmesis, Function and 
Quality Of Life3 
 
 
 
 
 
 
 
 
X 
Scar-modulating procedures 
and scar reconstructive 
 
 
 
 
 
# 
 
 
# 
Blood transfusion (units & 
volume) 
# 
# 
# 
# 
# 
# 
# 
# 
# 
Histological biopsy 
# 
# 
# 
# 
# 
 
# 
# 
# 
                                                 
1 The Extremities At Risk (EAR) burns prone to develop BICS will be identified at screening and excluded. Monitoring for the development of EAR in circumferential extremity wounds at the 
above specified timelines will be done. During each topical application (NexoBrid or gel Vehicle), clinical assessment and SpO2 monitoring will be done continuously. If such assessment is not 
practical, direct pressure will be measured every 2 hours from start of eschar removal. Direct pressure will be measured before and after each eschar removal procedure and additional surgical 
procedures  
2 Wound closure should be confirmed 2 weeks after the initial wound closure assessment for each TW. 
3 Cosmesis will be evaluated in donor site scars as well 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Table 4- NexoBrid/ Gel vehicle Eschar Removal 
 
Preparation for Treatment 
Treatment 
At least 2 hours soaking  
X 
 
Preventive analgesia medication (pain management) will be mandated as for an extensive dressing change as routinely 
practiced; it should be initiated at least 15 minutes prior to dressing change or application in order to ensure pain free care  
X 
 
Removal of any blister-keratin remnants1 
X 
 
Surrounding of the TW with a paraffin ointment adhesive barrier2  
X 
 
Sprinkle sterile isotonic (0.9%) sodium chloride solution should be sprinkled on the burn wound3 
X 
 
Application of the product, as per the randomization, should follow the instruction for use described in Section ‎6.4 of the 
protocol 
 
X 
Occlusive film dressing should be applied to cover the wound 
 
X 
The dressed wound should be covered with a loose, thick fluffy dressing, held in place with a bandage 
 
X 
The dressing should remain in place for 4 hours 
 
X 
Starting and completion time of the procedure  will be recorded 
 
X 
Manpower (specify the number of surgeons, anesthesiologists, RN, nurses and unskilled assistances) who participated during 
the procedure will be recorded in the eCRFs 
 
X 
Any disposable used (number of dressings, blades, etc) will be recorded in the eCRFs 
 
X 
2 hrs soaking4  
 
X 
                                                 
1 If there are still blisters/keratin remains, clean the wound thoroughly and remove the superficial keratin layer or blisters from the wound area, as the keratin will isolate the eschar from direct 
contact with the topical agent 
2 Vaseline ointment should be applied a few centimeters outside of the treatment area (using an adhesive-barrier dispenser). The paraffin layer must not come into contact with the area to be 
treated to avoid covering the eschar, thus isolating the eschar from direct contact with the topical agent 
3 The wound must be kept moist during the application procedure 
4 Antibacterial solution, e.g. 3-5% Sulfamylon, 0.05-0.5% Chlorhexidine, Dakin’s solution or hypertonic 5-10 % saline solution 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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10. 
DRUG STORAGE AND DRUG ACCOUNTABILITY 
The bottles of NexoBrid powder and the Gel Vehicle must be kept refrigerated (2-8ºC).  
10.1 
ACCOUNTABILITY AND COMPLIANCE  
The principal investigator is responsible for maintaining accurate records of the receipt and 
dispensing of all investigational materials. The investigator may dispense investigational drug 
only to patients enrolled in the study. All dispensing will be conducted from the site listed in 
the Statement of Investigator. 
MediWound Ltd. will provide drug accountability forms to assist the investigator in 
maintaining current and accurate inventory records covering receipt, dispensing, and the return 
of investigational drug supplies. When a shipment is received during site's initiation or during 
the study, the investigator or pharmacist will verify the quantities received, complete an 
Inventory log form and return the acknowledgment to the study monitor or designee. The 
investigational drug accountability record includes the identification of the patient to whom the 
drug is dispensed, the quantity and the date of dispensing and any returned or unused drug. 
This record is in addition to any drug accountability information recorded on the Case Report 
Form. These records will be readily available for inspection by a monitor or MediWound Ltd. 
audits and are open to any other regulatory authority inspection at any time. 
When the supplies are returned or destroyed, the investigator or pharmacist signs the 
investigational drug return or destruction log to verify that all unused or partially used supplies 
were accounted for and confirms that no study supplies remain in the investigator’s possession. 
One copy of all inventory records and the return statement are retained by the investigator for 
the study files. 
At study termination, unless otherwise specified, all unused drug supplies including partially 
used containers and the study drug accountability log should be returned to: MediWound, Ltd., 
Clinical Research Department, 42 Hayarkon Street, North Industrial Area, Yavne, 8122745, 
Israel.  
10.2 
PREVIOUS AND ON-GOING MEDICATIONS/THERAPIES.  
10.2.1 
Disallowed Previous and On-Going Medications/Therapies 
Pre-enrollment dressings with flammacerium or silver nitrate (AgNO3) are disallowed. 
10.2.2 
Allowed Previous and On-Going Medications/Therapies 
All other systemic medications except in the above section are allowed. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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11. 
ASSESSMENT METHODS 
Efficacy Assessment Methods will include: 
11.1 
PRIMARY END POINT 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to Section ‎1.1 for Target Wound 
definition): 
Incidence of complete eschar removal: Demonstrate superiority over Gel Vehicle for eschar 
removal as measured by incidence of complete eschar removal assessed by the blinded assessor 
at the end of the topical agent soaking period (6 hours after start of the 1st topical application). 
Or, in cases where 2 applications are performed, complete ER is assessed 6 hours after start of 
the 2nd treatment 
 
Reasons for Incidence of complete Eschar Removal as Primary Endpoint 
Following the goal to seek an indication for NexoBrid that focuses on non surgical eschar 
removal, the evaluation focus is set on this measure as a primary endpoint of the study. This 
primary endpoint will assess whether non-surgical eschar removal by NexoBrid allows 
effective removal of the offending eschar compared with its comparator. Complete eschar 
removal assessment will be captured in the eCRFs for each TW and has to be marked as 
complete for all TWs to be considered as complete per patient.  
11.2 
SECONDARY ENDPOINTS 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SOC. Comparisons between NexoBrid and Gel vehicle will be carried out in the 
same manner as between NexoBrid and SOC, but will be regarded as supportive analyses. 
11.2.1 
Reduction in surgical needs 
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). 
11.2.2 
Earlier eschar removal 
Demonstrate superiority of NexoBrid over SOC with regard to the time when complete eschar 
removal has been achieved. For definition of complete eschar removal see primary endpoint. 
11.2.3 
Blood loss 
Demonstrate superiority of NexoBrid over SOC with regard to the blood loss incurred during the 
eschar removal procedures. Actual blood loss will be measured by considering the estimated 
blood loss, changes in Hemoglobin during the eschar removal procedures and the amount of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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units of blood transfused. Blood loss (Actual Blood Loss, ABL) will be calculated using the 
following formula [86]:  
ABL= (EBV * (Hbbefore- Hbafter))/((Hbbefore+ Hbafter)/2))+ (500*Tu) 
EBV= Estimated blood volume is assumed 70 cm3/Kg 
(Hbbefore- Hbafter)= Changes in Hb following each eschar removal procedure 
Tu= sum of autologous whole blood, packed red blood and cell saver units transfused. 
The ABL will be summed over all procedures carried out to remove eschar, with the HB 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during the debridement 
procedure and 4 hrs later i.e. the before-after periods that are spanned by these HB 
measurements.    
Reasons for Incidence of Surgical Excisions as Secondary Endpoint 
A further aspect of the clinically meaningful attributes of NexoBrid’s non surgical eschar 
removal is the ability to reduce surgical needs, as NexoBrid allows removal of eschar in 
wounds that otherwise would have to undergo surgical excision. Therefore, this secondary 
endpoint would provide information on treatment failures that required follow-on surgical 
management and will further provide supportive evidence of efficacy and demonstration of 
clinical benefit over SOC. 
Reasons for Earlier Eschar Removal as Secondary Endpoint 
This secondary endpoint will assess whether nonsurgical and effective eschar removal by 
NexoBrid allows for the removal of the offending eschar earlier upon admission, enabling 
earlier visualization of the wound bed for assessment of the burn wound’s depth as well as 
preservation of viable tissues [87-88]. The depth determination is important for the planning 
and execution of the post-eschar removal stage of wound closure (i.e., grafting or spontaneous 
epithelialization). The dynamic of burn wound progression of the eschar-covered burn wound 
is the first delaying factor in initiating SOC surgical eschar removal. The non sacrifice of 
healthy dermis by SOC excisional surgery and the overall surgical implications to the patient 
are the other delaying factors [1]. Therefore, it is hypothesized that NexoBrid will allow eschar 
removal earlier (post randomization), effectively and in the first few days from injury without 
the need to first determine the burn depth (as is done in the initial decision-making phase of 
surgical and non surgical SOC). 
Reasons for Blood Loss as Secondary Endpoint 
This secondary endpoint will further demonstrate NexoBrid’s clinical benefit by showing a 
decrease of total blood loss post NexoBrid eschar removal compared with the total blood loss 
in the SOC eschar removal procedures. Reduction in blood loss is considered as an outcome 
measure that could further demonstrate NexoBrid clinical benefit. Surgical blood loss is 
attributed mainly to the excisional phase  and is directly proportional to the surface excised 
measured in ml blood loss/cm2 and may reach 0.8 ml/cm2 [89-90]. Local inflammation and 
anti-aggregation treatments may involve more bleeding and need for transfusion. Many 
publications endorse different means to reduce debridement related bleeding (tourniquet, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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subcutaneous epinephrine infiltration of excised burn and donor site etc.). The calculation for 
the actual blood loss is being used in other invasive procedures as an accurate calculation that 
reflects the actual blood loss in a patient as this takes into account both the estimated blood 
loss, changes in Hb levels during the relevant procedure and total blood units transfused to a 
patient. 
11.3 
SAFETY ENDPOINTS 
The following group of safety endpoints will be evaluated in this study and compared between 
NexoBrid and SOC. These endpoints are used to ensure that NexoBrid does not cause an 
unacceptable level of harm. Comparisons between NexoBrid and SOC will be carried out using 
pre-specified clinically meaningful margins that will assist in the benefit versus risk assessment 
of the product. These safety measurements are not powered to yield statistical significant non 
inferior results. Thus their assessment will be used for supportive analyses and sources of 
additional information about NexoBrid and SOC. 
11.3.1 
Time to complete wound closure 
Time to reach complete wound closure assessed in days, starting from randomization date. 
Demonstrate that NexoBrid does not cause any clinically meaningful harm to the patients with 
respect to the wound healing process by comparing NexoBrid mean time to wound closure 
with SOC mean time to wound closure, where a difference of not more than 7days difference 
will be interpreted as clinically not relevant. 
Reason for this endpoint and the definition of clinically meaningful harm:  
Time to reach complete wound closure is taken as a safety criterion because wound closure is a 
relevant parameter for patients’ quality of life and delay in wound closure may increase the risk 
of local complications. However, it can be assumed that the selective, non surgical eschar 
removal will probably increase the potential for spontaneous healing as physicians tend to 
postpone autografting in an effort to reduce autografting by exploiting the wound's preserved 
dermal potential for spontaneous epithelialization. Such spontaneous epithelialization is an 
important benefit for the patient (less autografting and less donor sites). This assumption is 
based on the results of the confirmatory phase III RCT (MW2004-11-02) in which a slight 
prolongation in time to wound closure (7 days) compared with the standard of care arm was 
observed.  
A difference of 7 days to wound closure has no clinical significance as patient mobilization 
starts long before wound closure, and the return to pre-injury lifestyle, following rehabilitation 
and convalescence, takes weeks, if not months, long after the wounds are closed. This delay 
does not affect patients’ discharged from the hospital as was further demonstrated in the 
pivotal clinical study. The concern that the few days’ delay will cause complications (mainly 
infections) proved to be non-based as the few AEs happened long before the delay and was 
similar to the SOC.  The importance of delayed wound closure in burn treatment relates mainly 
to preventing permanent deforming scars, which affect both cosmesis and function.  
Data collected in MediWound’s clinical study (MW2012-01-02) show that the few days delay 
did not cause worse scars, and they support the suggested NI margin of 7 days. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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A supportive formal derivation of this margin may be based on the FDA proposal of using two 
values to derive a NI (non-inferiority) margin [91]: 
M1 denotes the effect of the standard against placebo; 
M2 denotes the largest clinically acceptable difference (towards non-effectiveness) of the test 
substance. 
M2 is usually chosen as a percentage of M1, usually 50%. If no realistic placebo result exists a 
conservative choice of keeping 80% of the M1 effect may be preferred (M2=0.2*M1). This is 
the case planning a trial with large thermal burns as a real placebo result is not available and 
even not ethical, i.e. a placebo comparison measuring the effect of SOC on the wound closure 
scale is missing. 
The following calculation is based on the data from the pivotal study, MW2004-11-02. For a 
first derivation of a NI margin we disregard possible correlations between the different wounds 
and treat the wound closure times as independent. 
Given that SOC is an active comparator one expects at least 95% of the wounds treated with 
SOC to have a smaller time to wound closure than a (virtual) placebo mean time to wound 
closure. From the empirical distribution of the SOC wound closure times of the data set we 
derive the 95% quantile as 64 days. Taken this as the worst case scenario for a mean placebo 
wound closure time we obtain a SOC treatment effect of M1=64-27=37 days (SOC mean was 
27 days).  
M2 may then be taken as 0.2*M1=7.4 days. 
Based on the above supportive clinical information, the MAH finds that a NI margin of 7 days 
is statistically and clinically justified. Therefore, a slight prolongation in mean time to wound 
closure might occur (up to 7 days) 
Therefore, a slight prolongation in mean time to wound closure might occur (up to 7 days) but 
will not express a clinically relevant imbalance of the risk benefit assessment as patient 
mobilization starts far before the wounds are closed and the return to pre-injury lifestyle, 
following rehabilitation and convalescence, takes weeks, if not months, long after the wounds 
are closed. Thus any difference in means of up to 7 days may be taken as not representing 
clinically meaningful harm for this safety endpoint. 
11.3.2 
Cosmesis and function at 12 months from wound closure 
A measure of cosmesis, using MVSS, will be used to demonstrate - that treatment with 
NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as 
compared to scars quality of burns treated with SOC, measured at 12 months from wound 
closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a 
NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean 
MVSS score.    
11.3.3 
Cosmesis and function at 24 months from wound closure 
A measure of cosmesis, using MVSS, will be used to demonstrate that treatment with 
NexoBrid does not cause any clinically meaningful deleterious effect on scars quality as 
compared to scars quality of burns treated with SOC, measured at 24 months from wound 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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closure date, by a blinded assessor. Clinically meaningful deleterious effect will be defined as a 
NexoBrid group mean MVSS score higher by 1.9 or more units than the SOC group mean 
MVSS score. 
Reasons for the cosmesis endpoint and the choice of the clinically meaningful difference: 
We propose that a clinical equivalence value of 1.9 in the MVSS scale signify NexoBrid non-
inferiority in scar quality to the SOC. This clinically meaningful difference is in agreement 
with the non-inferiority (NI) margins calculated using the MVSS data in study MW2004-11-02 
(Sponsor previous long term follow up of patients treated in the MW2004-11-02).  
The NI margin was calculated as follows:  
Two values are needed to derive a NI margin [91]:  
M1 the effect of the standard against placebo  
M2 the largest clinically acceptable difference (towards non-effectiveness) of the test substance  
M2 is usually chosen as a percentage of M1, usually 50%. If no realistic placebo result exists a 
conservative choice of keeping 80% of the M1 effect may be preferred (M2=0.2*M1). This is 
the case when planning a trial with large thermal burns as a real placebo result is not available 
and even not ethical to measure the effect of SOC on the MVSS scale.  
The following calculation is based on the data observed during the clinical study (study 
MW2012-01-02). The margin may be calculated taking the theoretical maximum score of 18 
instead of the result of a (virtual) placebo arm. Consequently the SOC treatment effect is 18-
3.83=14.17, with 3.83 being the MVSS mean observed in the SOC group of the data (per 
patient analysis). Given the standard deviation of 2.27 from the MVSS data a 95% confidence 
interval for the SOC treatment effect is given by 14.17±0.75. The lower bound is 14.17-
0.75=13.42=M1. 
M2 may then be taken as 0.2*M1=2.7. 
Calculating the MVSS NI margin based on FDA guideline results in a NI of 2.7. 
Survey of burn experts as to the clinically significant difference in MVSS scores was 
performed and a difference of less than 2 would was advised not be considered as clinically 
meaningful.  
Taken into consideration the statistical calculated margin of 2.7 and the expert opinions, NI 
margin which is slightly below 2 (1.9) is justified.  
 
Additional Safety Outcome Measures will include:  
11.3.4 
General parameters 
Systemic adverse events, vital signs, pain assessment (using VAS and as reported as AEs), 
laboratory tests, units (and volume) of blood transfusion given during hospitalization, 
Immunogenicity evaluation for NexoBrid patients, Pyrexia and Hypothermia, Systemic 
infections, Incidence of increased interstitial/compartment syndrome (as described in Section 
‎1.1) and QT prolongation. Number and volume of blood transfusions received throughout the 
hospital admission, Extent of analgesia, anaesthesia and antibiotic use (i.e. total dose per kg 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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body weight), Rates 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).  
 
Additional long term functionality evaluation of the extremities using the ‘Lower Extremity 
Functional Scale’, 'QuickDASH' questionnaires and 'Range Of Motion' measurements, 
Long term Quality of Life using EQ5D and Burn Specific Health Scale- Brief (BSHS-B) 
11.3.5 
Local parameters 
Local adverse events defined by treated physician or designee; graft loss, wound related 
infections, etc. 
11.4 
EXPLORATORY ENDPOINTS 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision), 
2. POSAS will be used to further assess cosmesis and function, 
3. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
4. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 
5. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds, 
6. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds, 
7. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures, 
8. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
9. PK evaluation for a subset of NexoBrid patients (as described in section‎11.21) 
10. Autograft related parameters. 
I. 
Efficacy and safety analyses for early and late grafted wounds 
II. 
Total number of target wound grafting procedures 
III. 
Incidence of repeated/additional grafting procedures 
IV. 
Area of repeat grafting  
11. Duration of hospitalization 
11.5 
ADDITIONAL ANALYSIS 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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The following additional analyses will be addressed as supportive efficacy analyses: 
1. Primary & secondary endpoints will be analyzed at a per wound level 
2. Secondary endpoints will be analyzed vs. the Gel Vehicle 
3. Time to reach 100% wound closure assessed in days, starting from randomization date  
4. Clinical assessment of complete eschar removal vs. Centralized complete eschar 
removal from photos.  
11.6 
SUBGROUP ANALYSES 
Descriptive statistics will be determined for all subgroup analyses.  
1. A subgroup analysis will be performed on the subgroup of target wounds that are 
found, at least partly, in the anatomical area of the hand,  
2. Patients will be classified as having <25% or >=25% SPT area as a percentage of the 
area of all TWs, and descriptive statistics will be provided for each subgroup, including 
data on the primary, secondary and safety endpoints,   
3. Time to wound closure and 12m and 24m MVSS will be analyzed per TWs’ depth and 
% TBSA of the TWs, 
4. An analysis restricted to wounds that are entirely FT will be provided. 
5. A subgroup analysis of the primary and secondary endpoints will be performed per % TBSA. 
The subgroups examined will be ≤15% and >15%. 
11.7 
SAFETY LABORATORY EVALUATIONS 
The following tests described below will be performed. Any abnormal findings must be 
assessed for clinical significance – Abnormal Non Clinically Significant (NCS) or Abnormal 
Clinically Significant (CS):  
Serum chemistry, hematology and urinalysis testing will be performed at a central laboratory 
during the topical agent eschar removal phase. Any additional procedures require hematology 
tests, as described in the protocol, will be performed using Central lab. Pregnancy testing, 
HbA1c, leukocyte count (at Screening, in addition to central lab hematology), wound cultures, 
blood cultures and biopsies will be performed locally on-site. 
The following tests will be performed in special laboratories: Pharmacokinetics test, 
Immunogenicity evaluation and evaluation of QT prolongation (using multiple ECG tests). 
Serum Chemistry: 
Urea, Creatinine, Glucose, Total Bilirubin, Cholesterol, Triglycerides, Uric Acid, Total 
Protein, Albumin, Globulin, Calcium (Ca++), Phosphorous, Sodium (Na+), Potassium (K+), 
Chloride (Cl-), Alkaline Phosphatase, SGOT (ASAT), SGPT (ALAT), LDH. 
Hematology: 
Hemoglobin, Hematocrit, RBC, MCV, MCH, MCHC, Platelets, Leukocyte count (WBC) with 
differential count.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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HbA1c will be assessed at a local lab at Screening for diabetic patients as captured during the 
medical history.  
PTT and INR will be tested at a local lab pre treatment and 4 hrs after start of eschar removal. 
Pregnancy Testing: 
A serum pregnancy (HCG) will be performed at a local lab for women of child bearing 
potential.  
Urinalysis: 
pH, Ketone, Specific gravity, Protein, , Glucose, Bilirubin, Microscopic examination. 
Qualitative Wound Culture: 
Test burn wound for microbial flora (swab). 
Blood Culture: 
Test blood for microbial flora. 
Diagnosis of Invasive Burn Wound Infection is based on Quantitative (Histological) Wound 
Culture Biopsy: 
Infection should be assessed clinically by symptoms and signs that include local burn wound signs 
purulent drainage, erythema, warmth, exudation, odor, pain, and systemic signs that may or may 
not be related to the burn wound, such as fever, and leukocytosis as well as wound size and time to 
wound healing. Histological Biopsy may be performed to rule out suspicion of a clinical 
invasive burn wound infection (please refer to Appendix 8- Biopsy & Histologic Assessment 
Method) [93]. 
Clinical Burn Wound Infection will be defined when an Invasive Burn Wound Infection is 
diagnosed by quantitative bacterial count of >105 organisms per gram of tissue and histological 
signs of bacterial invasion of healthy tissues will define a positive invasive burn wound 
infection. At least one of the following histological signs of invasive burn wound infection is 
required:  
 
Microorganisms presence in viable unburned tissue 
 
Small vessel thrombosis and ischemic necrosis of unburned tissue 
 
Inflammation evident in unburned tissue 
 
Hemorrhage in uninjured tissue 
 
Evidence of microbial proliferation 
 
Variable migration of microorganisms along hair follicle and sweat glands 
 
Dense growth of nonviable-viable tissue interface (subeschar space)  
 
Intracellular viral inclusion 
 
Light microscopy 
 
Type A Cowdry bodies: herpes simplex virus-1 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 
Owl's eye inclusion bodies: cytomegalovirus 
 
Electron microscopy 
 
Intracellular virions 
11.8 
EAR AND BURN INDUCED COMPARTMENT SYNDROME MONITORING AND 
DIAGNOSIS 
Burn Induced Compartment Syndrome (BICS) is an acute progressive condition that starts a few 
hours post injury and develops during the acute, edematous stage of the first 2-3 days (after which 
edema and increased pressure subside) in deep circumferential burns. The edema and pressure reach 
their maximum within few days post injury and start to slowly decrease thereafter. Soft tissue can 
withstand temporary pressure increase for 6-8 hours without permanent damage, allowing 4-6 hours 
for decision-making regarding escharotomy. 
 
Monitoring:  
Monitoring will be performed for all circumferential deep burns using the 5 “P”s (Pain, Paralysis, 
Pulselessness, Pallor, Paraesthesia and , direct pressure measurement and SpO2 . 
Clinical  monitoring and diagnosis step include: 
 Observation of the extremity for swelling and color 
 Asking the patient about ability to move his fingers and hand, pain on passive finger 
extension and other skin sensations such as paresthesia or numbness (anesthesia) 
 Pressing the skin to diagnose blanching and tension 
 Sensitivity assessment (from superficial to deep sensation, ending with passive extension of 
the fingers, which is the specific test for muscle ischemia). 
The above sequence of tests should start by: 
 (i) asking the patient to move his/her fingers 
(ii) skin sensation 
(iii) skin tension and appearance (pallor) 
(iv) assessing pain at passive extension  
(v) palpation for pulse.  
 
The direct interstitial/compartment pressure measurement will be performed using one of the 
following: 
1. A 19 gauge IV needle or catheter connected to a pressure transducer (e.g. CVP set, direct 
blood pressure monitors, Striker system). The needle is inserted: 
 
Into the interstitial subcutaneous tissue at the anterior and posterior compartment region 
of upper or lower extremities, in the case of circular burn extending up to the elbow or 
knee.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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Before reading the pressure, the system should be flushed with 0.2-0.5 cc. (depends of the 
length of the connecting tube) of normal saline. 
2. Intra-Compartmental Pressure monitor (ICP monitor) by Stryker® or similar system. 
These measurements, similar in their pain and discomfort to IV treatment, are well tolerated by 
patients and in DPT/FT  
 
 Ultrasound Doppler may be used for the detection of pulsating arteries but even with distal 
digital artery pulsation damage may still happen. Laser Doppler blood flow is reported to be the 
least dependable.  
   
Screening - Prior to randomization:  
Patients with Extremities at Risk (EAR) should be identified at screening according to the definition 
below and will be excluded from the study. 
 
Extremities at Risk are circumferential DPT and/or FT burns with either one of the following: 
1. Any of the 5 “P”s (Pain on finger extension, Paralysis, Pulselessness, Pallor, Paraesthesia),  
2. Direct pressure measurement >25 mmHg, measured in 2 consecutive measurements within 30 
minutes under the constricting eschar, 
3. SpO2 <95% and a persisting difference of 6% between a healthy symmetrical extremity and the 
injured one [10-11],  
4. Pulse not detected by US Doppler.  
*In order to include a patient with circumferential wound to the study - Points 1, 2 and 3 above 
must be tested and ruled out.  
 
1 h pre  eschar removal procedure:  
Circumferential wounds should be monitored to detect high interstitial/ compartment pressure and 
diagnosed BICS. BICS should be treated as per SOC. 
Clinical assessments, SpO2 and the direct interstitial/compartment pressure measurement will be 
performed. 
 
During the 4 hours eschar removal procedure (apply to topical arms only (1st and 2nd if 
any):  
All circumferential wounds should be monitored for signs of improvement or deterioration that may 
require escharotomy. If clinical assessment and SpO2 monitoring are possible, they will be done 
continuously and recorded in the eCRFs every 2 hours. If such assessment is not practical, direct 
pressure will be measured every 2 hours from start of the eschar removal.   
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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If BICS was diagnosed by one of the following, the treatment should be stopped and escharotomy will 
be considered: 
 
Increasing pressure >30 mmHg 
 
Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity 
 
Decreased SpO2 reading during treatment with difference of >6% compared to a non injured 
extremity  
 
Deterioration of any of the 5 “P” signs. 
 
Since in such cases eschar removal procedure will not be completed as planned, such patients 
(if any) will still be part of ITT and any missing data usually collected during eschar removal 
(e.g. time to end of eschar removal, etc.) will be handled as missing data according to the 
protocol. 
 
Post eschar removal procedure:  
Clinical assessments, SpO2 and the direct interstitial/compartment pressure measurement will be 
performed in all circumferential wounds. 
11.9 
INFECTION 
All definitions of infection, wound infection, invasive burn wound infection etc. will follow the 
American Burn Association Consensus Conference to Define Sepsis and Infection in Burns 
[94] as presented in chapter 12, “Treatment of infection in burns” in the Total Burn Care 4th 
edition, edited by D. Herndon pages 137-156 that included also input from The Society of 
Critical Care Medicine (SCCM) and the American College of Chest Physicians (ACCP). 
Nevertheless, it should be remembered that in spite of the enormous effort invested for so long 
by so many, often even the simple differential diagnosis between burn wound erithema and 
burn wound infection or even the etiology of a sepsis is difficult. In order to have a pure as 
possible study that will assess exclusively the burn related phenomena, the principle is to enroll 
healthy individuals with fresh thermal burn wounds without any confounding co morbidities or 
trauma.        
 Sepsis [94]  
Sepsis is a change in the burn patient that triggers the concern for infection. It is a presumptive 
diagnosis where antibiotics are usually started and a search for a cause of infection should be 
initiated. While clinical interpretation is required, the diagnosis needs to be tied to the 
discovery of a specific infection source (defined below in section C).  
The trigger includes at least three of the following: 
I. 
Temperature >39.0° or <36.5°C 
II. 
Progressive tachycardia 
o Adults >110 bpm 
III. 
Progressive tachypnea 
o Adults >25 bpm not ventilated, or minute ventilation >12 L/min ventilated 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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IV. 
Thrombocytopenia (will not apply until 3 days after initial resuscitation) 
o Adults <100,000/mcl 
V. 
Hyperglycemia (in the absence of pre-existing diabetes mellitus) 
o Untreated plasma glucose  >200 mg/dl or equivalent mM/L 
o Insulin resistance—examples include 
 >7 units of insulin/hr intravenous drip (adults) 
 Significant resistance to insulin (>25% increase in insulin requirements over 24 
hours) 
VI. 
Inability to continue enteral feedings >24 hours 
o Abdominal distension 
o Enteral feeding intolerance (residual >150 ml/hr in children or two times feeding rate 
in adults) 
o Uncontrollable diarrhea ( >2500 ml/d for adults or >400 ml/d in children) 
In addition, it is required that a documented infection is identified: 
I. 
Culture positive infection, or 
II. 
Pathologic tissue source identified, or 
III. 
Clinical response to antimicrobials 
 
A. Continuous fever > 38.50C present during the week before sustaining burn injury. 
B. The below are assessed as present on physical examination or per history during the week 
before injury according to the described signs [89]  
 Rhinitis including mucopurulent nasal discharge  
 Sinusitis including cough, headache, stufinness, purulent nasal discharge  
 Stomatitis  including localized pain in mouth, difficulty swallowing 
 Pharyngitis 
 
including 
sore 
throat, 
pharyngeal 
erythema/exudate, 
neck 
lymphadenopathy 
 Pharyngeal abscess 
 Otitis including ear ache, signs per otoscopy 
 Infections of the Lower Respiratory Tract [95] 
Pneumonia including cough, fever, bronchial breath sounds, crackles, radiographic signs 
 Infections of the Heart [95] 
Endocarditis 
 Infections of the Skin and Soft Tissues (other than in the burns) [95] 
Folliculitis 
Impetigo 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Varicella-Zoster Virus infection 
Erysipelas 
Cellulitis  
Necrotizing Fasciitis 
 Intra-Abdominal Abscess and Peritonitis [95] 
Infectous Gastroenteritis 
 Bone and Joint Infections [95] 
Septic Arthritis including joint pain, swelling, erythema, limitation of movement 
Osteomyelitis including pain, tenderness, radiographic evidence 
 Urinary Tract Infections [95] 
Urethritis including pain and burning sensation of the urethra during urination. 
Urinary Tract Infection including pain, burning sensations, abdominal pain, positive urine 
culture 
 Burn Wound Infection – Heavily Contaminated Burns [94] 
o Invasive Infection: Presence of pathogens in a burn wound at concentrations 
sufficient in conjunction with depth, surface area involved and age of patient to 
cause suppurative, purulant separation of eschar or graft loss, invasion of 
adjacent unburned tissue or cause the systemic response of sepsis syndrome. 
Pathogen present in the wound at high concentrations (frequently >105 
pathogens/g tissue). Invasion or destruction of unburned skin/tissue. Invasive 
infection may occur with or without sepsis. Many burn wound invasive 
infections, however, are life threatening and need urgent treatment (usually 
wound excision). 
o Cellulitis: Bacteria present in the wound and/or wound eschar at high 
concentrations. Examination of surrounding tissue reveals advancing erythema, 
induration, warmth and tenderness. Sepsis must be present. 
o (Cellulitis that appears usually after few days (5-7 days) should be differentiated 
from Burn erythema: Redness around the wound in the first 3 days post injury 
and is rather benign and may not require treatment). 
o Necrotizing Infection/Fasciitis: Aggressive, invasive infection with underlying 
(beneath the skin) tissue necrosis. 
Burns diagnosed of Invasive Infection, Cellulites and Necrotizing Infection/Fasciitis are 
considered heavily contaminated burns. 
11.10 
VITAL SIGNS 
Vital signs (temperature, pulse, blood pressure and respiration rate) will be completed 24 hours 
prior to start of treatment and once daily from start of eschar removal until hospital discharge. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Blood pressure and pulse should be recorded in a supine position after resting for 5 minutes.  
All measurements and time of measurements will be recorded in the source documents. 
11.11 
IMMUNOGENICITY EVALUATION 
Antibodies presence will be determined based on a three-tiered approach analysis of plasma 
samples drawn prior to start of eschar removal and at the following timelines in NexoBrid 
patients: 
 At day 28±7 days (week 4 visit) from start of treatment, 
 At day 56 ±14 days (week 8 visit) from start of treatment,  
 At months 6 & 24, as part of the long term follow up visits. 
Please refer to Appendix 10- Procedures for specific blood tests for further instructions. 
11.12 
ECG (QT EVALUATION) 
12-lead ECG will be performed (if feasible) in triplicates as part of the QT prolongation 
evaluation at the following time-points: baseline 60 ± 5 min, 40 ± 5 min and 20 ± 5 minutes 
prior to start of Eschar removal process and at 30 ± 15 min, 120 ± 15 min, 4 ± 0.5 hrs, 12 ± 0.5 
hrs, 24 ± 1 hrs, 48 ± 2 hrs and 1 week after start of eschar removal.  
11.13 
PHYSICAL EXAMINATION 
A physical examination will be performed and documented by the investigator or a qualified 
designee. Any abnormal findings, assessed by the investigator as clinically significant, should 
be recorded in the relevant eCRFs modules (e.g. adverse event). 
11.14 
PAIN ASSESSMENT USING VISUAL ANALOGUE SCALE (PAIN SCALE RULER)  
Pain experience will be recorded using standard widely used pain scale ruler (Visual Analogue 
Scale=VAS) on admission, (baseline pain assessment) within 24 hours prior to start of eschar 
removal, One-hour before and following eschar removal procedure and daily from start of 
eschar removal until hospital discharge. 
. Please refer to Appendix 9- Pain Measurement Scale for instructions. 
11.15 
CONCOMITANT MEDICATIONS 
Concomitant medications will be recorded throughout the study, starting from signing on ICF 
and will include those prescribed for common burn management practice. Any record should 
include dose, frequency, route, start and stop date and indication. 
Unit of blood transfused (whole blood or blood packed cells) with the appropriate volume will 
be captured for the entire patient’s duration in the study and recorded in the concomitant 
medications form. Any analgesia and anesthesia administered per subject will be recorded in 
the eCRFs. Incidence & number of procedures for wound care requiring anesthesia will be 
analyzed. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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11.16 
GRAFT LOSS/GRAFT TAKE 
An event of graft loss is defined in study protocol as an event in which an autograft needed to 
be re-applied on the same area. This event, once occurred, will be recorded in the eCRFs as an 
AE. 
Graft Take: Graft adherence and vascularisation following an eschar removal procedure. 
11.17 
HYPOTHERMIA AND PYREXIA [94] 
Hypothermia will be defined as temperature <36.0°c, measured twice, 30 minutes apart. 
Pyrexia will be defined in patients with elevated temperature >39.0°c in the first days (before 
the beginning of any infectious process) measured twice, 30 minutes apart. These criteria, once 
met, should be monitored closely. The Investigator may still report hypothermia at higher 
temperatures and Pyrexia at lower temperatures, if these events are considered by the 
Investigator to be adverse events.  
The Investigator will be reminded to evaluate the need to report an AE in case the temperature 
is higher than 39.0°c or lower than 36.0°c. 
11.18 
COSMESIS AND FUNCTION ASSESSMENT 
11.18.1 
MVSS 
Cosmesis and Function assessment will be performed based on the Modified Vancouver Scar 
Scale (MVSS) at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 
burn wound specialist who is masked to randomized wound treatment and to the other outcome 
assessments of the same wound 
 The MVSS method is composed of the following: 
Pigmentation 
Pliability 
Height Vascularity Pain 
Pruritus 
(0) Normal 
(0) Normal 
(0) Flat 
(0) 
Normal 
(0) None 
(0)None 
(1) 
Hypopigme
ntation 
(1) Supple-flexible with 
minimal resistance 
(1)  
<2mm 
(1) Pink 
(1) 
Occasional 
(1) 
Occasional 
(2) Mixed 
(2) Yielding- giving way 
to pressure 
 
(2) 2-5 
mm 
(2) Red 
(2) 
Requiring 
medication 
(2) 
Requiring 
medication 
(3) 
Hyperpigme
ntation 
(3) Firm- inflexible, not 
easily moved, resistance to 
manual pressure 
 
(3) 
>5mm 
(3) 
Purple 
 
 
 
(4) Banding-rope-like 
tissue that blanches with 
extension of the scar 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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(5) Contracutre-perment 
shortening of scar, 
producing deformity or 
distortion  
 
 
 
 
 
11.18.2 
POSAS 
Additional Cosmesis and Function evaluation will be performed using the Patient and Observer 
Scar Assessment Scale (POSAS) version 2.0 at 1, 3, 6, 12, 18 and 24 months after the wound 
closure confirmation visit by a burn wound specialist who is masked to randomized wound 
treatment and to the other outcome assessments of the same wound. POSAS version 2.0 was 
published in 2005 in Plast. Reconstr. Surg. 116: 514-522 by van de Kar et al.  
The POSAS consists of two parts: a Patient Scale and an Observer Scale. Both scales contain 
six items that are scored numerically and make up a ‘Total Score’ of the Patient and Observer 
Scale. The POSAS has been developed for all types of scars and has been tested in linear scars, 
burn scars and keloids and was found to be validated and reliable [111-112].  
Each item of both scales has a 10-point score, with 10 indicating the worst imaginable scar or 
sensation. The lowest score is ‘1’, and corresponds to the situation of normal skin (normal 
pigmentation, no itching etc), and goes up to the worst imaginable. The Total Score can be 
simply calculated by summing up the scores of each of the six items. The Total Score will 
therefore range from 6 to 60 (observer and patient) and 12-120 in total. 
11.19 
QUALITY OF LIFE 
Quality of Life evaluation will be performed in adults using Burn Specific Health Scale 
(BSHS-B) and EQ5D as describe in Appendix 12- Cosmesis, Function and Quality of Life 
Questionnaire, at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 
burn wound specialist who is masked to randomized wound treatment and to the other outcome 
assessments of the same wound. 
11.20 
FUNCTION ASSESSMENTS 
Functionality tests were implemented in the proposed protocol MW2010-03-02 for the 
assessment of specific anatomical function. This evaluation will be composed of the following: 
 Self completed questionnaires: 
o The “Lower Extremity Functional Scale” test for burns in the lower extremities,  
o The “QuickDASH” outcome measure for burns in the upper extremities.  
 Range of Motion measurements of injured joints, if relevant: knee, ankle, shoulder, elbow, 
wrist and hand. Measurements will be performed on the patient’s own non injured joints as 
well for comparison to burned joints.  
The above tests will be performed at 1, 3, 6, 12, 18 and 24 months after the wound closure 
confirmation visit by a burn wound specialist who is masked to randomized wound treatment 
and to the other outcome assessments of the same wound. ROM will be evaluated at 1, 3, 6, 12, 
18 and 24 months after the wound closure confirmation visit.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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11.21 
PHARMACOKINETIC EVALUATION 
1. Blood samples (2ml) for a pharmacokinetic profile to measure NexoBrid absorption will be 
taken from a subset of 32 patients treated with NexoBrid in accordance with the randomization 
arm, including: 16 patients with total wounds area of <=15% TBSA will be tested for PK and 
16 patients with total wounds treated area of >15% TBSA will be tested for PK and will be 
analyzed throughout the study for each patient in an ongoing process. Blood samples will be 
taken accordingly- 
 
In subjects requiring a single application:  
o 
Before treatment (time zero), 0.5 hours ± 10 minutes,  2 hours ± 10 minutes, 4 hours ± 
10 minutes, 12 hours ± 30 minutes, 24 hours ± 30 minutes , 48 hours ± 30 minutes and 
72 hours ± 30 minutes after NexoBrid application. 
 
In subjects requiring two planned applications of NexoBrid: 
o 
1st treatment: before treatment (time 0), 0.5 hours ± 10 minutes, 2 and 4 hours ± 10 
minutes after the first NexoBrid application. 
o 
2nd treatment: time 0, 0.5 hours ± 10 minutes, 2 and 4 hours ± 10 minutes, 12 hours ± 
30 minutes, 24 hours ± 30 minutes, 48 and 72 hours ± 30 minutes after the second 
NexoBrid application. 
Blood samples (2ml) for a pharmacokinetic profile will be taken from all subjects planned for 
2 NexoBrid sessions in advance. 
11.21.1 
Real time data capture and Independent Safety Monitoring 
The study data will be collected using an Internet-based, validated, electronic data capture 
system which allows for “real time” safety reviews via the Internet.  
An independent study Medical Monitor, masked to the treatment arms, shall review all 
Adverse Events (AE’s) from the entries on the eCRFs on a quarterly basis. SAEs will be 
reviewed and evaluated on a per case basis, following the occurrence of an SAE, as detailed in 
the Sponsor’s SOPs. In case any concerns are raised by the medical monitor, additional 
convention of the DSMB could be performed (see Section ‎14.4).  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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12. 
SAFETY AND PHARMACOVIGILANCE  
An adverse event is an undesirable or unintentional event that occurs during use of the study 
Drug, whether or not considered related to the Drug; this includes clinically significant changes 
in laboratory values and therapeutic failures. Regardless of the severity or relationship to the 
investigational Drug, all adverse events occurring during the study period should be recorded 
in a subject's CRFs. The phrase "associated with the use of the Drug" is defined as a reasonable 
possibility that the event may have been caused by the investigational Drug. 
12.1 
 RELATIONSHIP TO STUDY DRUG 
The following definitions to assess the relationship between an adverse event and the study 
Drug should be used.   
Not Related: The event is clearly related to other factors such as a patient's clinical state, 
therapeutic interventions or concomitant medications. 
Remotely Related: The event was most likely produced by other factors such as a patient's 
clinical state, therapeutic interventions or concomitant medications and does not follow a 
known response pattern to the study Drug. 
Possibly Related: The event has a reasonable temporal relationship to study Drug 
administration and follows a known response pattern to the study Drug.  However, a potential 
alternate etiology may be responsible for the event.  The effect of Drug withdrawal is unclear. 
Rechallenge information is unclear or lacking. 
Probably Related: The event follows a reasonable temporal sequence from the time of Drug 
administration and follows a known response pattern to the study Drug and cannot be 
reasonably explained by other factors.  There is a reasonable response to withdrawal of the 
Drug.  Re-challenge information is not available or advisable. 
Related: The event follows a temporal sequence from the time of Drug administration and 
follows a known response pattern to the study Drug and either occurs immediately following 
study Drug administration, or improves on stopping the Drug, or reappears on repeat exposure. 
AEs assessed as possible, probably or related will be addressed as Adverse Drug Reaction 
(AEs related to study arm). 
12.2 
 ADVERSE EVENT INTENSITY 
Mild Adverse Events: A mild adverse event is one that the symptoms are barely noticeable to a 
patient. It does not influence performance or prevent a patient from carrying on with normal 
life activities. 
Moderate Adverse Events: A moderate adverse event is one that the symptoms make a patient 
uncomfortable and causes some impairment to normal life activities. Treatment for symptom(s) 
may be required. 
Severe Adverse Events: A severe adverse event is one that the symptoms cause severe 
discomfort to a patient and severely limits the patient's normal daily activities.  Treatment for 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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symptom(s) is given. Note that serious and severe are not synonymous.  A serious adverse 
event must fulfill the requirements listed in the definition below. 
12.3 
 ADVERSE EVENT REPORTING 
Signing of Inform Consent is considered to be the start date of AEs monitoring. All adverse 
events must be recorded in the eCRFs. When an adverse event occurs, the following 
information and assessments should be recorded in the adverse event section of the eCRFs: 
 The signs, symptoms or diagnosis or the event, 
 The date and time of onset of the event using the 24 hour clock where midnight is 00:00 
and noon is 12:00, 
 The adverse event severity using the criteria outlined above, 
 The relationship of the event to the study Drug as outlined above,  
 The description of any action taken regarding study Drug disposition, 
 Any required therapy, medication, treatment or diagnostic procedure. 
Follow-up of a patient should be conducted until resolution of the adverse event. The 
investigator is responsible for the appropriate medical management of all adverse events.  
12.4 
 SERIOUS ADVERSE EVENTS 
A serious adverse event is an event that is: a) fatal b) life-threatening c) results in persistent or 
significant disability/incapacity d) requires or prolongs inpatient unexpected hospitalization ) is 
a congenital anomaly or birth defect or f) is a medically important event. 
Life Threatening is defined as an event in which a patient is at risk of death at the time of the 
event. It does not refer to an event that hypothetically might have caused death if it was more 
severe. Disability is defined as a substantial disruption of a person's ability to conduct normal 
life functions. Medically important events that may not result in death, be life-threatening or 
require hospitalization may be considered as SAEs when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definition above. 
When patient’s hospitalization is planned by the treated Investigator, no AE should be reported 
and thus, no SAE should be reported. Note to File will be completed and signed by the 
Investigator. 
 
An unexpected adverse event is one that has not been previously observed, or one that is of a 
specificity or severity not consistent with the current investigator brochure. 
All adverse drug reactions (a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility) that are both serious and unexpected are subject to 
expedited reporting as defined in ICH E2A “Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting”. An Unexpected event is one that is not consistent 
with the applicable product information as described in the current investigator brochure.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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12.5 
 SERIOUS ADVERSE EVENT REPORTING 
The investigator shall report all serious adverse events to the Pharmacovigilance by telephone 
or fax immediately after the event (within of 24 hours, in accordance with MediWound’s 
SOPs). The initial report should be followed-up with a detailed written report within three 
days. Full details of the event, any sequelae and an assessment of the relationship to the study 
Drug must be provided in the report.  
Fatal or life-threatening SUSARs should be notified as soon as possible but no later than 7 
calendar days after Pharmacovigilance has first knowledge of the minimum criteria for 
expedited reporting. All other SUSARs must be reported as soon as possible but no later than 
15 calendar days after Pharmacovigilance has first knowledge of the minimum criteria for 
expedited reporting. Further relevant follow-up information should be given as soon as 
possible. 
12.6 
PREGNANCIES 
In the long term follow up period of the study, no special contraception methods are deemed 
necessary for the study due to the single short term use of the investigational product and its 
known pharmacokinetic profile were no remnants of NexoBrid were observed after 48 hours 
had passed from first application. In the early acute phase of the burn wounds, during their 
hospital stay, patients are hospitalized and thus are not expected to be subject to sexual 
intercourse. If sexual abstinence within one month after study treatment is not possible 
acceptable contraception methods should be used by the patient. 
1) Acceptable methods of contraception (a Pearl Index < 1%) include: 
- 
hormonal methods (oral contraceptives, patches or medroxyprogesterone acetate) 
- 
An intrauterine device (IUD) with a documented failure rate of less than 1% per year 
 
NOTE: Females who have been surgically sterilized (e.g., hysterectomy or bilateral tubal 
ligation) or who are postmenopausal (total cessation of menses for >1 year) will not be 
considered as “females of childbearing potential.” 
Nevertheless, to ensure patient safety, each pregnancy in a female patient of childbearing 
potential on study drug should be reported to the treated physician during the study course. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on the 
form provided by MediWound and reported by the investigator to MediWound. The telephone 
and fax number of the contact persons are listed on the form provided. Pregnancy follow-up 
should be recorded on a form provided by MediWound as well and should include an 
assessment of the possible relationship to the study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13. 
STATISTICAL ANALYSIS  
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. 
13.1 
POPULATIONS 
Enrolled population consists of all subjects who passed through the screening processes and 
signed inform consent. 
Intent-to-Treat (ITT) population includes all patients who are randomized into the trial. 
Evaluable (per protocol)(PP) population includes all subjects who fulfill all inclusion/exclusion 
criteria and do not have major protocol violations. Analysis of the PP population is for 
supportive purposes, whereas the analysis of the ITT population provides the primary and 
secondary efficacy and the comparative safety analyses.  
Safety population (SP) includes all patients receiving a treatment and analysis is focused on the 
treatment actually performed. 
13.1.1 
Major Protocol Violations 
Major protocol violations will be evaluated by clinical personnel and detailed information will 
be listed. List of protocol violation will be included in the study monitoring plan. 
13.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics and relevant baseline information (medical history, physical examination, 
treatments prior to admission, burn description, distribution of wound depth and size, TWs 
description, primary TW description, etc.) will be presented and summarized with appropriate 
descriptive statistics. Chi-squared tests (or in case of small estimated cell counts Fisher’s exact 
test) for categorical variables and one-way analysis of variance for continuous variables will be 
used to assess the comparability of the baseline factors between the treatment groups.   
If any of the baseline factors, gender, age, or percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%) are found to be significantly different 
between the treatment groups, then the factor will be included as an extra adjusting covariate in 
the supportive analysis models for the primary and secondary efficacy endpoints and the 
comparative analyses of safety endpoints. 
Relevant medical history will be tabulated and presented by treatment group.  
These summaries will be based on the ITT population. 
13.3 
EFFICACY EVALUATION 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.3.1 
Primary Endpoint 
The primary endpoint will be analyzed as described below. Missing data will be handled by the 
methods described in Section‎13.8.4. NexoBrid will be compared with Gel Vehicle for the 
primary endpoint. 
13.3.1.1 Incidence of complete eschar removal measured at the end of the topical agent 
soaking period. 
The proportions of patients who reached complete eschar removal at the end of the 
topical agent soaking period will be compared using logistic regression. The primary 
analysis will be based on the binary variable (yes/no): ‘has complete eschar removal been 
achieved in all TWs’ and will compare NexoBrid with the Gel Vehicle (for further 
definition and explanation of complete eschar removal see Section ‎1.1). For handling of 
missing data see Section ‎13.8.4. The statistical test will be based on Fisher’s exact test 
because of the small numbers expected in the Gel vehicle group. The odds ratio of 
achieving complete eschar removal for NexoBrid versus Gel Vehicle and its 95% 
confidence interval will be estimated using exact distribution methods. 
If numerically possible, the comparison will supportively be adjusted for the stratification 
factor wound depth (see Section ‎13.7) by including the factor in a logistic regression 
model together with the treatment variable (NexoBrid vs. Gel Vehicle). Similarly, if 
convergence of the estimation procedure can be obtained, then, in two other supportive 
analyses, the factor %TBSA and the factor treatment center (see Section ‎13.8.5) will be 
included in a logistic regression model with the treatment variable. Statistical inference 
will be based upon exact distribution methods. 
The odds ratio of achieving complete eschar removal for NexoBrid versus Gel Vehicle 
will be estimated from these supportive models, as well as 95% confidence intervals and 
the level of statistical significance. 
13.3.2 
Secondary endpoints 
The secondary endpoints will be analyzed as described below and will compare efficacy in the 
NexoBrid group with the SOC group. Missing data will be handled by the methods described 
in Section ‎13.8.4.  
13.3.2.1 Surgical excision performed  
This is a binary yes/no variable and the proportion of patients who need excision for eschar 
removal will be compared using logistic regression. The explanatory variables in the model 
will include treatment, and the following variables: overall TW depth (for definitions, see 
Section ‎13.7), %TBSA and number of TWs (1, 2, ≥3). The odds ratio of requiring surgery for 
NexoBrid versus SOC will be estimated from the model, as well as 95% confidence intervals 
and the level of statistical significance.  
If numerically possible, as a supportive analysis, the variable treatment center (see Section 
‎13.8.5) will be added into the logistic regression model and the analysis repeated.    


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.3.2.2 Timely eschar removal 
Time until complete eschar removal will be defined as the time until complete eschar removal 
has been achieved at a patient level, i.e. for all TW’s of an individual patient. This will be 
measured as time from the randomization date (days). For patients who do not reach complete 
eschar removal, their time will be censored at the initiation of the wound closure treatment 
phase. Kaplan-Meier curves will be presented graphically to display the distribution of time to 
complete eschar removal under the two treatments. Median time to complete eschar removal 
will be estimated for each treatment group with a 95% confidence interval. The treatment 
groups will be compared using a Cox regression model. The comparison will be adjusted for 
the same explanatory variables as mentioned in Section ‎13.3.2.1, by including each of them in 
the Cox regression model together with the treatment variable (NexoBrid vs. SOC). The 
treatment groups will be compared by testing the null hypothesis of no difference, comparing 
the ratio of the estimated treatment coefficient to its standard error to a standard normal 
distribution. 
The Cox Regression analysis outlined above will be performed if the proportional hazards 
assumption appears to hold. This will be checked by including in the regression model a 
variable representing the interaction between time since randomization and treatment group. If 
the coefficient for this time variable is non-significant at the 5% significance level then the Cox 
Regression analysis will be adopted. If the time-treatment group interaction is significant, then 
we will use a generalized Wilcoxon-Gehan test. 
Supportive analyses will include adjustment for other baseline variables that are imbalanced, 
and investigating interactions between baseline variables and the treatment groups.  
Another supportive analysis will be the comparison of treatments based on the time of 
complete eschar removal measured from the date of ICF using the same methods as for the 
time measured from randomization.  
13.3.2.3 Blood loss 
The measure of blood loss defined in Section ‎11.2 will be computed for each patient, and the 
distribution in the NexoBrid group will be compared with that in the SOC group. Means, 
standard deviations, medians, and interquartile ranges will be calculated. The normality of the 
data will be tested on each treatment group using the Shapiro-Wilk test. If the normal 
distribution hypothesis is not rejected at the 5% significance level in either group, then 
differences in distribution between NexoBrid and SOC will be tested using a t-test. If the 
normal distribution hypothesis is rejected either in the NexoBrid group or in the SOC group, 
then the differences in distribution between the treatment groups will be tested using a Mann-
Whitney test. Supportive analyses will include adjustments for the same covariates as 
mentioned in Section ‎13.3.2.1. 
13.3.3 
Safety endpoints 
13.3.3.1 Time to reach complete wound closure 
Time to reach complete wound closure will be compared between the NexoBrid and SOC at a 
wound level using a method of survival analysis with clustered data that is based on 
appropriate assumptions. By “clustered data”, we refer to the multiple target wounds that can 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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occur in a patient. First the proportional hazards assumption will be checked in the same way 
as in the analysis of the timely eschar removal endpoint. If the proportional hazards assumption 
is appropriate we will use a marginal Cox regression analysis with a robust sandwich estimator. 
If not, then we will use a parametric frailty model. Either method can be implemented in SAS 
(see Gharibvand and Liu, 2009 for details). The marginal Cox regression model is 
implemented in the PHREG procedure and the robust variance option is implemented by 
specifying the COVS(AGGREGATE) option. This induces the use of the robust variance 
method of Binder et. al. [102]. The parametric frailty model will be implemented using the 
following SAS-code:  
PROC PHREG DATA=burn_data; 
     CLASS Subject_id treatment_group depth; 
     MODEL time*status(0) = treatment|group depth; 
     RANDOM Subject_id; 
     HAZARDRATIO "Frailty Model" treatment_group; 
RUN; 
 where subject_ID is a unique identification number for each patient, time is the time to wound 
closure on a wound level, status is an indicator whether the wound has achieved complete 
wound closure or not (censoring indicator), treatment_group gives the treatment group, depth 
gives the TW depth (on a wound level) and burn_data is a SAS data set containing the required 
information. These methods include information on all the target wounds of each patient and 
account for any within-patient correlation. Missing information due to incomplete follow-up is 
incorporated naturally into such analyses as censored observations.  The comparison will be 
adjusted for the same stratification variables as mentioned in Section ‎13.3.2.1. A non-
inferiority margin will be incorporated into the analysis that will represent a 7-day advantage to 
the SOC group, so that the analysis will show whether the NexoBrid group is estimated to have 
on average a time to wound closure that is not later than 7 days after wound closure for the 
SOC group. 
13.3.3.2 Cosmesis and Function evaluation using MVSS 
The MVSS score for a patient will be the MVSS score averaged over all TW’s of that patient. 
The mean and standard error of this MVSS score at 12 and 24 months will be estimated for 
each treatment group. The evaluations at these two time points will represent two separate 
endpoints. The treatment groups will be compared using a linear model with MVSS score as 
the dependent variable. The explanatory variables in the model will include treatment, and the 
same stratification variables as specified in Section ‎13.3.2.2. The coefficient corresponding to 
the treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 
factors. For handling of missing data see Section ‎13.8.4. A clinically meaningful difference 
will be incorporated into the analysis that will represent a 1.9 or more units advantage to the 
SOC group, so that the analysis will show whether the NexoBrid group is estimated to have on 
average a MVSS score that is not worse by more than 1.9 units than the score for the SOC 
group. 
Additional Safety Outcome Measures will include:  
These parameters will be analyzed in a descriptive way only. More details will be provided in the 
statistical analysis plan. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.3.3.3 General parameters of safety 
General parameters: Systemic adverse events, vital signs, pain assessment (using VAS 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, Incidence of increased interstitial/compartment syndrome (as defined in 
Section ‎1.1)  and QT prolongation, Number and volume of blood transfusions received 
throughout the hospital admission, Extent of analgesia, anaesthesia and antibiotic use (i.e. total 
dose per kg body weight), Rates 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).  
13.3.3.4  Local parameters of safety 
Local adverse events defined by treated physician or designee; graft loss, wound related 
infections, etc. 
13.3.3.5 Further parameters of safety 
Functionality evaluation 
The following scales will be used: QuickDASH questionnaire, LEFS (Lower Extremity 
Functional Scale) and Range of Motion (ROM) measurements. Each scale will be assessed at 
the following time points: 1 month after reaching complete wound closure and at 3, 6, 12, 18 
and 24 months after wound closure. The ROM measurement will be classified as normal or 
abnormal status. 
Quality of life evaluation 
The following scales will be used: EQ5D health questionnaire and BHSH-B (Burn Specific 
Health Scale). Each scale will be assessed at 1, 3, 6, 12, 18 and 24 months after reaching 
complete wound closure.   
13.3.4 
Exploratory endpoints and additional analyses 
These parameters will be analyzed in a descriptive way only. Additional details will be provided 
in the statistical analysis plan. 
13.3.4.1 Exploratory endpoints 
2. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ 
minor/ avulsion/ Versajet and/or dermabrasion excision), 
3. POSAS will be used to further assess cosmesis and function, 
4. Incidence of surgical Escharotomy procedures in circumferential extremities target 
wounds, 
5. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal), 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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6. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds, 
7. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds, 
8. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures 
9. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
10. PK evaluation for a subset of NexoBrid patients1, 
11. Autograft related parameters. 
I. 
Efficacy and safety analyses for early and late grafted wounds 
II. 
Total number of target wound grafting procedures 
III. 
Incidence of repeated/additional grafting procedures 
IV. 
Area of repeat grafting  
12. Duration of hospitalization 
13.3.4.2 Additional Analyses 
The following analyses will be addressed as supportive efficacy analyses: 
1. Primary & secondary endpoints will be analyzed at a per wound level, 
2. Secondary endpoints will be analyzed vs. the Gel Vehicle, 
3. Analysis of time to reach 100% wound closure assessed in days, starting from 
randomization date  
Clinical assessment of complete eschar removal vs. Centralized complete eschar 
removal from photos 
13.3.5 
Subgroup Analyses 
Descriptive statistics will be determined for all subgroup analyses.  
1. A subgroup analysis will be performed on the subgroup of target wounds that are 
found, at least partly, in the anatomical area of the hand.  
2. Patients will be classified as having <25% or >=25% SPT area as a percentage of the 
area of all TWs, and descriptive statistics will be provided for each subgroup, including 
data on the primary, secondary and safety endpoints,   
3. Time to wound closure and 12m and 24m MVSS will be analyzed per TWs’ depth and 
% TBSA of the TWs, 
4. An analysis restricted to wounds that are entirely FT will be provided. 
                                                 
1 For more details see Appendix 10- Procedures for specific blood tests 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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5. A subgroup analysis of the primary and secondary endpoints will be performed per % 
TBSA. The subgroups examined will be ≤15% and >15%. 
13.4 
STATISTICAL COMPUTING 
The data will be analyzed using the SAS ® version 9.1 (SAS Institute, Cary North Carolina). 
13.5 
SAMPLE SIZE CALCULATIONS 
The following sample size calculations are based on the consideration of the primary and two 
secondary endpoints for this study.  
Estimated effects of NexoBrid from study MW2004-11-02 were used to design the study with 
adequate statistical power using the following steps.  
(a) Sample size calculations were based on study MW2004-11-02; 
(b) The effect of NexoBrid versus standard of care was estimated together with the standard 
error of the estimate; the effect of NexoBrid versus gel was estimated based on study 
MW2002-04-01, previous phase II study, which included 35 patients treated with gel 
vehicle.  
The size of the effect to be detected in this study, MW2010-03-02, was taken as the previous 
estimate decreased by half its standard error, in order to use a conservative value. 
13.5.1 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. 
Gel) 
Estimated proportion achieving complete eschar removal (for further definition and 
explanation see Section ‎11.1) in all TWs from study MW2004-11-02: NexoBrid 0.595 
Standard error = 0.057 
Anticipated proportion achieving complete eschar removal using NexoBrid: 0.595-0.057/2 = 
0.5665 
Estimated proportion achieving complete eschar removal using Gel vehicle in a previous Phase 
II study, MW2002-04-01: 0 (0 out of 35 patients).  
Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. (0.0 is the 
point estimate; 0.10 is the 97.5 upper confidence limit).   
Because numbers of complete eschar removals are anticipated to be low in the gel group, we 
calculate sample size using Fisher’s exact test. We used the computer program nQuery Advisor 
version 7.0 to calculate power for a two-sided significance level of 5%, and thereby found the 
following sample size combination that led to approximately 90% power for detecting a 
statistically significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).   
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle group 13. 
Total sample size = 78. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.5.2 
Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.22; 
SOC 0.62 
Standard errors: NexoBrid 0.048; SOC 0.054 
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: NexoBrid 0.24 and 
SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a two-sided 
significance level of 5% is 86: 43 in the NexoBrid group and 43 in the SOC group. 
13.5.3 
Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial yielded an estimated 
log hazard ratio of -1.37 (hazard ratio of 0.254) with a standard error of 0.28.  
Therefore target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio = 0.29).  
The formula for the number of events (successful complete eschar removals) is:


2
2
log
)
(4
HR
z
z
d



 
where z = 1.96 two-sided significance level of 5%; and z = 1.28 for 90% power;For 90% 
overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required 
2
1
2
p
p
d
n


= 44 (to the nearest even number), 22 in each of 
the NexoBrid and SOC groups.  
13.5.4 
Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 patients (65 in the 
NexoBrid group, 13 in the Gel vehicle group and 43 in the SOC group (to match NexoBrid 
numbers)), we propose entering larger numbers to provide an extra margin of assurance in achieving 
positive results on the efficacy outcomes, and adequate information on safety outcomes to allow 
better benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 (NexoBrid) + 75 (SOC) + 
25 (Gel Vehicle). 
13.5.5 
Safety endpoints 
Because of the importance of the time to wound closure and MVSS safety endpoints, we examined 
for these two endpoints, under the chosen sample size of 75 patients per group in the NexoBrid and 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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SOC groups, the probability of demonstrating that the observed average value in the NexoBrid does 
not exceed the observed average in the SOC group by more than the clinically meaningful margin.  
For time to wound closure, assuming, based on previous data, that in reality NexoBrid has an 
average time that is longer than SOC by 5.77 days (based on wound closure data from study 
MW2004-11-02 analyzed per the suggested analysis in Section ‎13.3.3.1), the probability that the 
observed average NexoBrid time to wound closure will be longer than the observed average SOC 
time by more than 7 days is calculated to be 0.26. 
For MVSS, assuming, based on previous data, that in reality NexoBrid has a score that is less (better) 
than SOC by 0.51 units, the probability that the observed average NexoBrid score will not be larger 
(worse) than the observed average SOC score by more than 1.9 units is calculated to be less than 
0.001 for MVSS at 12m and 24m.  
13.6 
ALPHA CONTROL 
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. The primary and secondary endpoints of 
efficacy will be tested in a hierarchy, so as to preserve the nominal significance levels: 1. 
Primary; 2. Incidence of surgery; 3.Time to complete eschar removal; 4. Blood loss.  
 
13.7 
STRATIFICATION AND RANDOMIZATION 
13.7.1 
Randomization Procedure: 
To enter a patient and obtain the randomized treatment allocation, the following information 
should be verified and uploaded into the eCRFs: 
i. 
Eligibility of the patient (entrance criteria are met) 
ii. 
ICF date 
iii. 
Patient’s demographics (date of birth, gender, ethnicity, race) 
iv. 
Patient’s burn history and burn description (identification of all wounds and target 
wounds (TWs) assigning an identifying number to each wound, and providing its 
anatomical site, its %TBSA, its depth and where relevant its proportion of superficial 
partial thickness (SPT) area 
v. 
The overall depth, according to its category A1-A3 (see definition below) 
vi. 
The treatment center 
 
Upon finalization of this process, randomization will be performed as described below and a 
designated person will receive the allocated treatment. With regard to this designated person, this 
person must understand that the information regarding the allocated treatment must not be given 
to the designated person who is assessing the TWs following treatment, as further described in 
the study protocol. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.7.2 
Stratification: 
Eligible subjects will be stratified into different groups in order to balance the treatment groups 
with respect to factors that may be related to efficacy and safety outcomes. Three factors will 
be used to stratify the subjects.  
A. Total TBSA % per patient 
A1: Total TBSA <=15% 
A2: Total TBSA >15% 
 
B. Overall depth per patient 
B1: All TWs are full thickness; 
B2: Mixed TWs – full thickness and deep partial thickness  
B3: All TWs are deep partial thickness. 
 
C. Center Group, to address possible differences in SOC procedures between sites (if any), to 
allow comparison of the results within group of centres and to reduce the likelihood of a group 
of centers including patients in only one arm of the study (5 groups of centres will be formed 
based on similarity of SOC practice). 
Using this stratification, patients will be randomized in a 3:3:1 ratio (NexoBrid: SOC: 
Vehicle). 
13.7.3 
Randomization algorithm: 
The treatment allocation will be performed using the method of block randomization with 
stratification by the factors A B and C, described in the subsection above: %TBSA, overall 
depth of TWs, and clinical center group. The method will be implemented by computer 
generation of permuted sequences of treatments NexoBrid, SOC or Gel Vehicle in the ratio of 
3:3:1 in blocks of a certain length. The length of the blocks will not be disclosed so as to 
prevent prediction of the next patient’s allocation.  
 The algorithm will be prepared and automated by an independent study biostatistician, and 
will operate through the central site with which the clinics will communicate.   
13.8 
DATA HANDLING METHODS AND DEFINITIONS 
13.8.1 
Multiple visits per time-point 
Study visit time-points are scheduled at screening, pre eschar removal, eschar removal 
(treatment), post-treatment, hospital discharge, follow-up (weekly until wound closure, wound 
closure confirmation, three monthly visits post wound closure), long term follow-up at 6, 12, 
18 months and 24 months post wound closure confirmation and re-admission to hospital/day 
care (if done). One visit is expected for each time-point. The following approach is used if 
there are multiple visits per patient per time-point.  
For the endpoints incidence of complete eschar removal, reduction in surgical needs, summary 
of blood loss and the cosmesis endpoints of safety, if a subject has more than one visit with 
data at a time-point, the later non-missing evaluation will be used for analyses. An exception to 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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this rule is in the analyses of time to eschar removal and time to wound closure; for these 
parameters a value other than the last one or more than one value per visit time-point may be 
taken into account. More details will be provided in the SAP.  
13.8.2 
Rules for Data Derivations 
The SAP will identify the necessary data transformations and rules for data derivation. 
13.8.3 
Multiple target wounds per patient 
Patients may have multiple wounds being treated (target wounds). All target wounds will be taken 
into account in the primary and secondary analyses. The methods of analysis are specified in the 
efficacy analysis subsection. The following calculations will be used for each patient: 
1) Total treated burn surface area (%TBSA): is defined as the sum of areas of all target wounds 
for that patient. 
2) MVSS at 12m and 24m are defined as the score averaged over the TWs.  
13.8.4 
Missing data 
Missing data in the primary and secondary outcomes is the main concern. 
Little or no missing data are expected for the primary endpoint, since the outcome is assessed only 
several hours after the start of treatment. The main analysis will be a complete-case analysis. In each 
treatment group, only patients with documented total eschar removal (at the end of the eschar 
removal soaking period) will be counted and this number divided by the total number of randomized 
subjects. Two sensitivity analyses will be conducted for this endpoint. A first analysis will count all 
patients with missing data (for this endpoint) as positive (i.e. complete eschar removal) and a second 
analysis will count all patients with missing data as negative (i.e. no complete eschar removal).  
The same procedure will be applied for the secondary endpoint, reduction of surgical need.  
The analysis of the secondary endpoint time to eschar removal will compute missing values as 
censored. 
Missing blood loss values for some eschar removal procedures may occur within a certain patient. A 
regression model containing main prognostic factors (wound area, depth of wound and type of 
procedure) for blood loss of eschar removal procedures will be computed. On this basis a multiple 
imputation will be calculated.  
. The analysis of the safety endpoint time to complete wound closure will compute missing values as 
censored.. 
A higher ratio of missing values is expected in the case of later MVSS values, especially for 24 
months. In order to avoid unnecessary complex imputation for this descriptive endpoint simple 
LOCF imputation will be done. It is expected that at least one early MVSS value exists. If this is not 
the case the missing MVSS values will be replaced by the mean MVSS value of all patients who 
belong to the same treatment group and the same stratum (see Section ‎13.7.2) at each time point. A 
best case – worst case imputation using information about the reasons of drop out documented in the 
CRF will be used as a supporting sensitivity analysis. 
The Statistical Analysis Plan will provide more details on the strategy outlined above for handling of 
missing data. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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13.8.5 
Stratifying by center in the analysis 
Randomization will be stratified by center as detailed in the Section ‎13.7.1. However, some 
centers may enroll very few patients so that there are insufficient subjects to conduct a 
stratified analysis efficiently. To ameliorate this problem, for stratified analysis at the end of 
trial, “small centers” will be pooled as follows:  
All centers will be classified by region (assuming that those in the same region will have a 
similar standard of care treatment modality) and number of patients randomized. If a center has 
less than 14 patients randomized, this center will be pooled with the next smallest center within 
the same region until the pooled center has 14 or more patients. If a region has less than 14 
patients randomized, this region will be pooled with a region that is geographically close to it. 
The pooling strategy will be finalized prior to database lock by a statistician who is blind to the 
outcome data. 
13.8.6 
Stages of Analysis 
The analysis is planned to be carried out in three stages, as described below.  
1. The first analysis will be performed at the end of the Efficacy Assessment Period (EAP). 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 for short-term safety endpoints 
(including time to wound closure). The analysis will be conducted, when 3 months had passed 
from the last patient reaching complete wound closure, in accordance with FDA guidance for 
industry Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for Treatment 
“Trial subjects generally should remain in the study for follow-up evaluation at least 3 months 
following complete wound closure. The purpose for this follow-up period is to help distinguish 
actual wound healing from transient wound coverage”. At this time-point, data will be available 
for nearly all patients on the primary end-point (proportion with complete eschar removal), the 
three secondary endpoints (proportion undergoing surgery, time to complete eschar removal, and 
blood loss) and short-term safety endpoints (including time to wound closure). Missing values 
for early drop outs etc. will be handled as described in Section ‎13.8.4  and the SAP. The 
complete data set documented so far will be locked and analyzed as described above. MVSS 
data, although captured in the eCRF for a few of the subjects at the stage of EAP, will not be 
included, revealed or analyzed during the EAP analyses. Furthermore, to assure that patients’ 
treatment codes will not be revealed during the EAP analyses, all patients’ identification 
numbers will be Pseudonyms by data management before analysis is being performed and 
presented.  
 
The second analysis will be performed for the 12 month follow up period (STFU12) and will 
be started after the last patient has reached the 12m assessment. At this analysis, all 
accumulated safety data at the 12m follow-up will be analyzed, particularly the 12m MVSS 
assessment for cosmesis and function. The complete data set documented so far will be locked 
and analyzed as described above. 
The third and final analysis covers the data of the long-term safety follow up (LTSFU24). It 
will be conducted after the last patient has reached the 24m assessment at last 12 months after 
(STFU12) analysis (stage 2). At this analysis, all accumulated safety endpoints at the 24m 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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follow-up will be analyzed, particularly the 24m MVSS assessment for cosmesis and function. 
The complete data set documented during the trial will be locked and analyzed as described 
above (hard lock). 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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14. 
QUALITY ASSURANCE  
14.1 
QUALITY ASSURANCE PROGRAM 
This clinical trial may be audited according to the MediWound Quality Assurance (QA) 
program.  
The purpose of these audits is to determine whether the study is being conducted and 
monitored in compliance with the protocol and recognized GCP guidelines and local 
regulations. These audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent inspection by any regulatory authority.  Such 
audits, if necessary, will be pre-arranged with the site and conducted within a reasonable time 
frame. 
14.2 
MONITORING PROCEDURES 
The conduct of the study will be closely monitored by representatives of MediWound to verify 
adherence to ICH GCP guidelines and applicable SOPs. Reports of these monitoring will be 
archived with the study report.  
The Investigator will allow the designated MediWound representatives and/or any regulatory 
agency to have direct access to all study records, eCRFs, corresponding subject medical 
records, study drug dispensing records and the study drug storage area, and any other 
documents considered source documentation. The Investigator also agrees to assist the 
representative if required. 
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information in eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).  
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. MediWound monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
14.3 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, and the ICH Harmonized Tripartite Guidelines for Good Clinical 
Practice in compliance with local regulatory requirements. 
14.4 
DATA SAFETY MONITORING BOARD (DSMB) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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A Data Safety monitoring Board (DSMB) will convene  in accordance with enrollment rate i.e. 
after 25% of patients were enrolled and then again after 50%, 75% and after 100% of the 
patients were enrolled and treated (last patient discharge from the hospital) as long as not more 
than six months had passed since the previous DSMB- during the enrollment period. DSMB 
will assess safety data and narratives1 as described in the agreed DSMB chart. During the 
follow up period, a DSMB will convene at least once a year. 
In addition, special meetings could take place in the following cases:  
1. Any of the stopping rules are met, as described in Section ‎7.2, 
2. Following the randomization of 10 NexoBrid patients suffering from deep burns of 
more than 15% TBSA (TWs area) that were treated with 2 consecutive sessions,  
3. Following the randomization of 25 NexoBrid patients suffering from deep burns of 
more than 15% TBSA (TWs area) that were treated with 2 consecutive sessions. 
All DSMB conventions will be in closed session format. 
These activities will be coordinated by MediWound Ltd. and the recommendation shall be 
directed to MediWound Ltd. The DSMB will consist of three independent individuals 
including burn specialist(s) and a biostatistician. Following selection and agreement to serve, 
the committee will meet in person or by teleconference to be briefed fully on the procedures 
defined in the Protocol and Statistical Plan. MediWound Ltd. shall be formally informed of 
recommendations by the DSMB prior to implementation of said recommendation(s) and must 
approve, in writing, any new analyses being recommended by the DSMB. 
                                                 
1 All SAEs will be presented in narratives as described in MediWound’s SOPs. In addition, events of repeated 
debridement in the topical arm and repeat application of autografts to the same wound area will be summarized & 
introduced as narratives to the DSMB. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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15. 
INVESTIGATOR’S AGREEMENT 
I have carefully read the foregoing protocol including all appendices and agree that it contains 
all the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the current 
GCP guidelines and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information submitted by the sponsor relating 
to pre-clinical and prior clinical experience to all personnel for whom I am responsible that 
participate in the study. I will discuss this information with them to assure that they are 
adequately informed regarding the drug and conduct of the study. 
I agree to keep records on all subject information (case report forms, shipment and drug return 
forms and all other information collected during the study) in accordance with the current GCP 
and local regulations. 
 
Site Principal Investigator’s name 
MediWound Representative's name 
Signature 
Title 
Date (dd/mmm/yyyy) 
Signature 
Institution 
Date (dd/mmm/yyyy) 
 
 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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16. 
APPENDICES 
APPENDIX 1- WOUND DEPTH ASSESSMENT- CLINICAL EVALUATION 
The burn literature [18, 97] suggests that clinical evaluation of the burn wound is the most 
widely used method of assessing burn wound depth. This was, but also recognized in the FDA 
Guidance for Industry Chronic Cutaneous Ulcer and Burn Wounds, June 20061 and also the 
burn depth assessment method accepted by the ABA [1]. In accordance with the above, further 
to assessing wound appearance, the following tests will be included [98]: 
1. Capillary blanching 
2. Capillary refill 
3. Capillary staining 
4. Wound sensibility to touch 
5. Pin prick 
Using the above criteria will allow the Investigator to differentiate between the SPT and DPT 
areas as is widely acceptance in the US [99], according to the following below criteria in 
addition to the visual assessment: 
 SPT burns extend into the papillary dermis and form blisters. Once the blister is 
removed from a SPT wound, the wound is pink, wet and hypersensitive to touch. These 
wounds are painful and blanch with pressure.  
 DPT wounds extend into the reticular dermis. They also blister but the wound surface 
appears mottled pink and white. The patient complains of discomfort and pressure 
rather than pain and when a pressure is applied to the burn, capillaries refill slowly or 
not at all. The wound is less sensitive to pinprick. 
                                                 
1 Section IV D, pharagraph 2. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 2- PAIN MANAGEMENT PROCEDURES 
Pain Management Procedures 
For topical arms treatment, preventive analgesia medication (pain management) will be 
mandated as for an extensive burn dressing-change. 
During NexoBrid treatment it has been observed that the two painful stages are during the first 
30 minutes of the treatment and during the dressing removal which is followed by cleansing 
and dressing (30-45 minutes).  Thus, the principle of the suggested pain management is to 
prevent pain by starting the treatment with sufficient basic analgesia/sedation as detailed 
below. Once the first painful stage has ended, background analgesia can be administered and 
the sedation/analgesia regimen stopped. 
Before NexoBrid dressing removal the sedation administration should normally be started 
ensuring that the patient is pain-free until the first post-eschar removal soaking dressing is in 
place. 
Sedation administration can be repeated two hours later, before the removal of the soaking-
dressing. 
 Objective: 
The object of the analgesia is to ensure that the entire treatment course is performed in a safe 
and comfortable manner. During the treatment the patient should be free of significant pain and 
easily arousable, without interference with vital functions. 
In the majority of cases the pain can be managed without the need for deep sedation, by the 
pre-administration of oral analgesics and being prepared to administer intravenous Morphine as 
needed to control pain surge.  
If sedation is used the patient should not need intubation and it should be easily and quickly 
reversible by discontinuing administration of the sedation agent. Sedation can normally be 
discontinued after the first painful wave that lasts for 30-60 minutes from NexoBrid 
application; it should be reinitiated before and during dressing removal and wiping of the 
dissolved eschar, a process that may last for another 30 minutes. 
Attention should be given to background analgesia during the interval between these 
procedures. 
During procedures, the patient should as a minimum be monitored frequently for: 
 Blood Pressure (non-invasive)  
 Cardiac activity (ECG) 
 Respiratory rate 
 Oxygen saturation (pulse oximetry) 
Example of a medication regimen: 
Bolus intravenous analgesia/sedation using appropriate combinations of fentanyl, and 
midazolam and ketamine. Suggested initial doses are: 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Fentanyl- 2 microgram/Kg 
Midazolam- 0.06 mg/Kg (1 mg/15 Kg) 
Ketamine HCl- 0.5 mg/Kg  
Maintenance doses will typically be one-third to one-half of the initial dose at 10-20 minute 
intervals; considerable inter-patient variation should be expected.   
Intravenous continuous sedation using a syringe driver or target-controlled infusion (TCI) 
driver is a very acceptable technique, using propofol + alfentanil, propofol + remifentanil, or 
remifentanil alone.   
 
Continuum of depth sedation: Definition of general anesthesia and levels of 
sedation/analgesia*- American Society of Anesthesiologists 
 
  
Minimal 
Sedation 
Anxiolysis 
Moderate 
Sedation/ 
Analgesia 
(“Conscious 
Sedation”)  
Deep Sedation/ 
Analgesia  
General 
Anesthesia  
Responsiveness  
Normal response 
to verbal 
stimulation  
Purposeful** 
response to 
verbal or  
tactile 
stimulation  
Purposeful** 
response 
following 
repeated or 
painful 
stimulation  
Unarousable 
even with painful 
stimulus  
Airway  
Unaffected  
No intervention 
required  
Intervention may 
be required  
Intervention 
often required  
Spontaneous 
Ventilation  
Unaffected  
Adequate  
May be 
inadequate  
Frequently 
inadequate  
Cardiovascular 
Function  
Unaffected  
Usually 
maintained  
Usually 
maintained  
May be impaired  
  
 Minimal Sedation (Anxiolysis) is a drug-induced state during which patients 
respond normally to verbal commands. Although cognitive function and physical 
coordination may be impaired, airway reflexes, and ventilation and cardiovascular 
functions are unaffected.  
Moderate Sedation/Analgesia (“Conscious Sedation”) is a drug-induced 
depression of consciousness during which patients respond purposefully** to verbal 
commands, either alone or accompanied by light tactile stimulation. No interventions 
are required to maintain a patent airway, and spontaneous ventilation is adequate. 
Cardiovascular function is usually maintained.  
Deep Sedation/Analgesia is a drug-induced depression of consciousness during 
which patients cannot be easily aroused but respond purposefully** following 
repeated or painful stimulation. The ability to independently maintain ventilatory 
function may be impaired. Patients may require assistance in maintaining a patent 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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airway, and spontaneous ventilation may be inadequate. Cardiovascular function is 
usually maintained.  
General Anesthesia is a drug-induced loss of consciousness during which patients 
are not arousable, even by painful stimulation. The ability to independently maintain 
ventilation function is often impaired. Patients often require assistance in 
maintaining a patent airway, and positive pressure ventilation may be required 
because of depressed spontaneous ventilation or drug-induced depression of 
neuromuscular function. Cardiovascular function may be impaired.  
Because sedation is a continuum, it is not always possible to predict how an 
individual patient will respond. Hence, practitioners intending to produce a given 
level of sedation should be able to rescue*** patients whose level of sedation 
becomes deeper than initially intended. Individuals administering Moderate 
Sedation/Analgesia (“Conscious Sedation”) should be able to rescue*** patients 
who enter a state of Deep Sedation/Analgesia, while those administering Deep 
Sedation/Analgesia should be able to rescue*** patients who enter a state of General 
Anesthesia.  
* Monitored Anesthesia Care (“MAC”) does not describe the continuum of depth of 
sedation, rather it describes “a specific anesthesia service in which an 
anesthesiologist has been requested to participate in the care of a patient undergoing 
a diagnostic or therapeutic procedure.”  
** Reflex withdrawal from a painful stimulus is NOT considered a purposeful 
response.  
*** Rescue of a patient from a deeper level of sedation than intended is an 
intervention by a practitioner proficient in airway management and advanced life 
support. The qualified practitioner corrects adverse physiologic consequences of the 
deeper-than-intended level of sedation (such as hypoventilation, hypoxia and 
hypotension) and returns the patient to the originally intended level of sedation. It is 
not appropriate to continue the procedure at an unintended level of sedation. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 3- PHOTOGRAPHIC WOUND DOCUMENTATION 
In accordance with FDA guidance, the photography methods will be standardized in all centers with 
standard camera type and control of the distance/size (zoom), color, exposure, (lighting) and color 
bend tag (as a reference for color and size) of the acquired picture. This will be performed using 
patient ID label (see below) which will be identical in size and content (colors scale) for all patients 
and should be used as detail below. Photographs will be uploaded into a secure file sharing account. 
Photographic Documentation 
1. Each wound area is considered an independent entity and should be documented as such. 
2. Each wound site should be photographed using a standard digital camera with flash card 
memory which together with sterile photography patient ID labels, are supplied by 
MediWound.   
3. Patient ID, date and time, TW#    and assessment type (e.g. screening, pre-treatment, post- 
treatment,, weekly visits and monthly visit, etc) should be noted on each ID label, (see 
below). 
4. Each wound site should include the patient ID label.  
5. The photograph should be taken using the zoom facility while including the entire treated 
area and at least two distinctive body parts as reference points. 
6. The photograph should be taken 90 Degrees to the desired area. A small angle is 
acceptable, but any higher angle will make it more difficult to evaluate the wound from 
photos, at a later time point, if needed. Any pictures taken below 45 Degrees should be 
avoided. 
7.  In order to ensure patient confidentiality, facial photographs are not allowed. 
 
Recording Kit 
The recording kit consists of: 
1. Sterile photography patient ID labels, 
2. One digital camera, 
3. Flash cards.


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 4- POST-ESCHAR REMOVAL WOUND MANAGEMENT 
Post Eschar removal Burn Wound Bed(s) 
An ideal burn debriding agent should effectively and quickly debride the burn eschar but also 
preserve viable tissues to source and allow spontaneous healing by epithelialization. It should 
combine the non-invasiveness of the ineffective and slow non-surgical debriding means and 
the efficacy and speed of surgery. 
Following any eschar removal process, whether surgical or non surgical one, the wound is 
being assessed for eschar removal efficacy and for presence of residual viable dermis by 
experienced plastic/burn surgeon. Usually, following an effective eschar removal with 
visualization of the viable tissue bed, a more accurate burn depth diagnosis can be made. 
Macroscopically, the components of the human integument are from epidermal, dermal and 
subdermal origins. Few colors are involved in the final visual appearance of the healthy tissues: 
the brown-black of the melanin, hemoglobin's shades of reds (depending on the oxygenation 
level) and the pearly-white of the collagen. Below the skin a yellow fat add another color.  
The debrided wounds can be divided into four groups based on the debrided bed condition:  
1. Complete eschar removal revealing residual viable dermis. 
2. Complete eschar removal revealing a full thickness skin defect requiring permanent 
cover. 
3. Complete eschar removal revealing a wound bed with areas of viable dermis and areas 
of full thickness defect.    
4. Incomplete eschar removal to various degrees. 
Several means and strategies can be used to remove the eschar, each ending in a typical bed: 
Surgically debrided beds:  
Sharp dissection (using dermatomes, dermabrasion or hydro dissection such as Versajet) will 
leave a smooth bed that is composed, in the case of complete eschar removal, of transected 
structures such as dermis and blood vessels or subcutaneous fat.  This bed will readily accept 
autograft with good take if adherence and drainage are assured.  
Autolytically debrided beds:   
Slow decomposition and maceration will cause eventually the sloughing of the necrotic tissue 
but simultaneously, at the end of the second week granulation tissue will start to form and 
epithelial cell will start to epithelialize clean exposed dermis originating from the edges or the 
appendages (hair follicles, sweat and sebaceous glands). Granulation tissue will form if wound 
closure (by epithelialization, grafting or wound edges approximation) is delayed developing 
into scar. Granulation tissue will, if not infected, readily accept autograft but may contract later 
pulling with it the wound’s edges. In case of significant bacterial infection the process can 
invade surrounding healthy tissues (Invasive Infection) extending the damage. Infection 
together with other wound healing intervening factors (e.g. diabetes, hypoproteinaemia, etc) 
can cause the wound healing process to stop and become chronic. Chronic wounds may be 
highly contaminated or chronically covered with biofilm with only slowly granulation tissue 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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formation. Such wounds may behave as chronic, recalcitrant wounds, and will not heal easily 
or support graft. 
NexoBrid- Enzymatically debrided bed  
NexoBrid is an enzymatic debriding agent provided for eschar removal of the eschar. The raw 
surface that is left after this eschar removal is the Interface Layer (IL), which is comprised of 
the upper layer of healthy tissue that is made of exposed viable tissues. After wiping away the 
dissolved eschar the dermal IL has a whitish hue due to the dermal collagen matrix seeded with 
punctuated bleeding capillaries. The dissolved ends of the collagen fibres are made of 
unferruled collagen fibrils that may give a “furred” aspect to the surface. This layer preserves 
all viable components such as deep epithelial elements inside the adnexae and deep dermal 
remnants (collagen fibres, subdermal fat and blood vessels). In all but the deepest wounds, the 
presence of the dermal Interface Layer permits spontaneous healing (epithelialisation over 
dermal remnants); however, the majority of transacted blood vessels are still occluded at their 
ends. In the event that skin grafting is required (a full thickness burns or after the spontaneous 
healing potential has been exhausted or when an immediate wound closure is required) a 
graftable bed is obtained by simple scrubbing the Interface Layer with a dry swab or a sterile 
nail brush to expose the blood vessels during the graft application session. 
Wound bed assessment 
Any effective eschar removal will reveal the surface of the exposed viable tissue with its 
components and structures and the exact extent of the original damage (Figure 1). Being aware 
of the cutaneous three dimensional macroscopical structures, the form and color of the various 
components, it is rather easy to assess the depth of the debrided bed. The first step is to assess 
visually the presence or absence of epidermis which is the criterion of second degree (dermal) 
burn. Residual, none removed eschar appears opaque, yellowish-grey clearly differing from the 
pearly-white viable collagen. Bleeding vessels on the background of white collagen indicate 
that the eschar removal process reached viable tissue. Once the dermis is revealed the bleeding 
pattern that characterizes the different dermal levels clearly indicates the depth. Very fine, 
homogeneous bleeding characterizes the superficial papillary dermis (superficial, II° dermal 
burns). Deeper the burn is, the bleeding vessels are set wider and wider apart. In mid and deep 
dermal burns, only few bleeders can be seen on the background of white collagen matrix 
background. The few deep dermal capillary complexes that are situated around the adnexae 
may give the dermis a pinkish hew. When most of the dermis is removed the yellow subdermal 
fat gives the debrided bed a yellowish hew. Reaching the deepest part of the dermis, at the 
transition to the subdermal layer, one can see the yellow fat lobules protrude through the loose 
net of collagen fibers with few bleeders. This “quasi” full thickness burn behaves as a full 
thickness 
burn 
and 
only 
rarely 
will 
heal 
spontaneously.    


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Figure 1- Wound bed assessment 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Non burned skin, uninjured by NexoBrid 
b. 
Superficial dermal burn with bleeding 
c. 
Mid depth dermal burn with well preserved dermal collagen matrix 
d. 
Deep dermal burn with larger and wider spaced bleeding capillaries and a very thin dermal matrix 
e. 
Full Thickness burn 
f. 
Non dissolved eschar protected by the blister that was not removed prior to NexoBrid application 
 
Wound healing options post eschar removal 
In general, burn wound closure can be achieved by:  
Primary Intention: closure of the wound bed by graft that covers and obliterates the raw 
surface and “heals” the wound completely, similar to using sutures for bringing together the 
surgical wound’s edges. This approach requires a completely clean and viable bed with all 
cellular and non cellular components exposed for the healing process. The severed end of the 
blood vessels should be opened to allow endothelial cells to bud and connect the graft’s raw 
underside and eventually supply the graft with the necessary life giving blood. The graft 
survives the first days by “imbibition phenomenon”: graft’s nutrition by the serous exudates 
from the wound bed but its continuous survival depends on blood vessels connection and 
integration with the graft’s capillary bed. The capillary bed in the dermal papillary layer 
indirectly supplies the epidermis (that does not have any capillary bed of it own) with the 
necessary nutrients and oxygen so autograft needs a certain dermal layer to provide nutrient to 
the epidermis for survival. Graft adhesion during first days will provide good contact to the 
recipient bed, decreased danger of exudates’ collection and a better chance of take. Such graft 
stabilization and adherence is achieved by compressive dressings or using sub atmospheric 
(vacuum) external dressing over the graft that will stabilize the graft to its bed and remove 
exudates that can interfere with graft take.        
a
d
c
f 
e 
b


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
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Protocol: MW 2010-03-02 
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Autograft: grafting the raw bed with autograft that includes epidermis and a thicker or thinner 
layer of dermis. If the graft take >95% – the engrafted wound is practically closed.  
Autografting requires surgery under general anesthesia, sacrifice of healthy donor site skin area 
and surgical facilities (OR, surgical team etc.). The donor site will heal spontaneously during 
2-3 weeks by epithelialization but may be scarred and infected. Thicker the harvested dermal 
layer is better the functional and aesthetic results are but more damage is inflicted on the donor 
site, longer its healing is and higher is the likelihood to develop scars. Thicker the graft is, 
higher are the demands of the transplanted tissue from the wound’s bed and so are the risks of 
graft failure. 
Permanent Skin Substitutes: products such as Matriderm, Integra and Jalomatrix can be applied 
on the debrided bed, serving as regenerating matrix for the development of new dermis. Here 
too the debrided bed should be free of necrotic eschar and contain opened capillaries ends as 
the source for endothelial cells that will integrate, together with the native fibroblasts, into the 
artificial matrix forming the neodermis. All these products have to be engrafted sooner or later 
also with thin autograft (Matriderm immediately and Integra and Jalomatrix, 2-4 weeks later) 
that contains mainly the epidermal layer. The grafting procedure will necessitate surgical 
facilities as in a formal autografting but the donor sites heal faster (< 2 weeks) as the harvested 
graft is thinner with much less sacrificed dermis.  The cost and success rate of these products is 
a severe limiting factor.   
Allograft, xenograft and adherent biological covers: will adhere to the bed (assisted by vacuum 
dressing in the first days), preserve moisture and provide conditions for epithelialization or 
autograft for later stage, following removal of the temporary dressings.  
Epithelialization over preserved dermis: Full thickness defect greater than few cm2 should be 
closed by grafting but exposed dermis can heal by epithelialization that will close the wound 
without granulation and scar formation. When sufficient dermal elements exist, epidermal cells 
(Keratocytes) originating from the wound’s edges, the skin appendages (hair follicles, sweat 
and sebaceous glands) or Keratocytes cultures/ suspension can proliferate and propagate over 
the dermal bed creating a new epidermis.  This process requires a healthy and clean dermal bed 
and a dressing that will protect the exposed, raw dermal bed from desiccation and infection and 
provide the epithelialization process with the necessary conditions (moisture and propagation 
surfaces for the Keratocytes). There is a plethora of products that can be used for this purpose 
each with its advantages and disadvantages, each fulfilling a specific need in the healing 
process. 
Healing By Secondary Intention: As real regeneration of full thickness skin defect is 
impossible, the natural healing process of these wounds is aimed at creating first a temporary 
protection mechanism followed by a “plug” that fills the defect, replacing the missing, normal 
skin. Following a generalized inflammation-healing process of three overlapping phases of 
Inflammation, Proliferation and Modulation the granulation tissue forms, covering the wound 
bed and slowly filling the defect. Granulation tissue originates from connective tissue, 
containing fibroblasts, macrophages, white blood cells elements and endothelial cells from the 
severed blood vessels all forming a tortuous mass of new capillaries imbedded in new 
connective tissue. Keratocytes from the wound’s edge slowly strive to cover the granulation 
tissue but very often their progress is extremely slow and may be completely denied by the 
fibroblasts. The granulation tissue with all the local and systemic defense mechanisms provides 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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protection against infection. The fibroblasts deposit collagen and the fibroblasts–originating 
miofibroblasts pull-in the wound’s edges forming a scar with more or less contracture element. 
The progressive development of the granulation tissue (proliferative phase) may be controlled 
and decreased by the influence of the epithelial cells, the Keratocytes. Once the granulation 
tissue is entirely covered by the Keratocytes, its growth will decrease and the granulation tissue 
becomes a scar that will start to mature, often also to contract. Granulation tissue proliferation 
may be attenuated by topical corticosteroid ointment short (few days) treatment course 
exploiting the controlling affect of corticosteroids on inflammatory processes.  In the 
granulation tissue, the fibroblasts deposit collagen and the entire tissue undergoes modulation 
to become fibrous, hard scar filling the original defect. The scar contracts by the miofibroblast, 
pulling-in the healthy skin margin, reducing the scar’s surface but these contractures, 
especially across joints will interfere with function and cosmesis.   
Grafting granulation tissue is routinely practiced: during surgery the granulation tissue is 
forcefully scraped with a blunt edge surgical instrument (spoon, scalpel handle, metal ruler, 
etc.), removing the superficial layer with its bacterial load and opening the multitude of 
capillaries to accept the graft. In burn care healing by secondary intention with granulation 
tissue scarring and contractions is undesirable and often the scarring is more incapacitating and 
dangerous than the acute burn itself.  The lengthy (sometimes years) of the scar modulation 
process may be influenced by application of continuous pressure on the scar by made-to-
measure pressure “garment” dressings that applies a constant pressure and silicon sheets 
applied directly on the scar under the pressure garment.  
Healing by tertiary (delayed primary) intention: In some cases primary closure by wound 
edges approximation (suturing) or grafting is not feasible mainly due to local infection, 
patient’s general condition or external restrictions (surgical team, OR, other facilities or graft 
donor site availability). Another condition is when wounds closed by suturing disrupt (dehisce) 
or the grafts do not “take” to the wound bed and slough off. In most cases it is either an 
infection process of the underlining wound bed or edges or collection (blood, serum, pus). Re-
suturing or re-grafting the contaminated bed will end only with another closure failure and 
probably also with spreading the infectious process to adjacent tissues. The accepted practice is 
to leave the wound open, to treat the infection by topical and sometimes also systemic 
medications and once the infection is resolved the wound can be closed again. Formation of 
granulation tissue during the treatment course can favor graft take by providing additional 
blood supply to the graft but later may promote scar formation. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Summary of wound healing strategy in burns 
 Ideally burns wounds should be debrided and closed as soon as possible after injury. At 
present that means: immediate or very early after injury tangential excision and autografting. 
Due to diagnosis difficulties mainly of the dermal burns, the interest of avoiding the surgical 
related trauma, morbidity and the surgical needed facilities/costs with the potential (and hope) 
that the burn may heal spontaneously, the surgical treatment may be delayed. Once the eschar 
is not surgically debrided a slower, non surgical eschar removal approach is practiced. It is 
based on the best possible anti-infection care with the promotion of the eschar separation 
(sloughing) or disintegration (necrosis). This is a slow process that may lead to local and 
systemic infection and additional tissue damage. The time needed for this non surgical process 
allows also the formation of granulation tissue. The granulation tissue protects the open wound 
and offers a good bed for grafting but in many cases will form a heavy, contracted scar in few 
weeks. During this healing process an educated, cyclic (short spells of 2-3 days) of 
corticosteroid ointment will reduce the granulation tissue and will offer the bed a better 
grafting bed.  
To graft or not to graft: Full thickness defect will not heal properly without grafting and need 
always autograft or permanent skin substitute to prevent healing by secondary intention and 
scaring. Clean dermal bed that can epithelialize spontaneously can be grafted as well in order 
to close the wound immediately. Several factors should be considered when striving to close 
the wound "as soon as possible".  The true benefit to the burn patient in earlier burn wound 
closure by few days (the difference between grafted and epithelialized dermal burn) not always 
is truly advantageous. Autograft involves surgery, surgical and anaesthesia related trauma, 
donor site morbidity and the healing time of the donor site by epithelialization (≈2 weeks) is 
very similar to the epithelialization of the burn wound exposed dermis. Donor site morbidity 
includes infection, pain, additional dressing changes and scars. Grafting will not speed early 
subject mobilization as the latest normally starts much before wound closure ends and a return 
to work/normal lifestyle requires at least several weeks of recovery and rehabilitation after the 
wound is closed.  Thus, the decision to graft exposed dermis in order to shorten by few days 
wound healing should take into consideration the comprehensive well being and benefit to the 
patient. Issues such as length of treatment course and hospitalization depend on the nature of 
the dressing and wound care that in many cases allow early hospital discharge and prevent 
open wound related complications. 
Following wound closure the healed wound is dressed with a thin protective primary dressing 
or silicon sheet followed by pressure “garment” dressing modulating their modulation to a 
smooth, pale and pliable skin-like scar.   
 
Wound healing requirements 
The general prerequisites for good wound healing are based on adequate conditions and 
microenvironment for this dynamic process. 
Tissue factors 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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 Adequate blood supply: adequate arterial supply, adequate venous return, healthy capillary 
bed (example to potential problematic conditions: PVD, Varicose Veins, arterial or venous 
insufficiency, diabetes, peripheral edema of any kind, hypertension, etc.)   
 Clean wound bed: no eschar, foreign bodies or materials: all the followings can interfere 
with the healing process: necrotic eschar such as in burns, pressure sores, exposed bone, 
tendon or orthopedic implant and suturing material, foreign bodies introduced during injury, 
intradermal or subdermal hematomas or seromas. 
 No severe wound infection: < 10 5 count /cm3, purulent discharge, invasive wound infection, 
signs of cellulites, fungal infection.   
 Balanced healing dynamics: offering adequate conditions for epithelialization propagation 
and preventing overgranulation and its stagnation.    
 Systemic factors such as chronic steroid intake, anticancer drugs, malnutrition, diabetes, etc. 
 Post radiation tissue damage 
 Avoiding local medication that can interfere with the desired healing process (e.g. SSD, 
pseudoeschar formation, desiccating dressings). 
Local wound bed conditions that promote wound healing 
 The healing process is a cell-based process with different cells requiring different conditions 
besides the very general ones of blood supply and contact with the bed: 
 Moist wound surface: desiccation of the healing bed is one of the main dangers. All cells 
need moist environment for their survival. An occlusive dressing, any adherent- to-the-bed 
dressing, hydrogels (hydrating dressings) and ointment (oil based medicament) will create a 
thin moist environment underneath.    
 Three-dimensional wound bed topography: 
o Propagation surfaces: Keratocytes “prefer” to propagate and epithelialize on a 
collagen/HA, dermal surface under guiding, protective, scab like surface.   
o Contact inhibition: Fibroblasts and endothelial cells tend to develop granulation tissue in 
the direction of the wound’s open space.   
o Surface modulation of inflammation process: granular and fibrous surfaces   
macrophages, fibroblasts, etc.      
 Infection free surfaces: early treatment of any apparent infection  
 Adherent dressing will keep the undersurface moist, infection free, provide propagation 
surface and protects from mechanical insults. Usually an adherent dressing is the sign of a 
safely healing wound though desiccating, hydrophilic dressings may also desiccate a viable 
bed, deepening the damage. 
Wound-bed, Interface Layer (IL)’ Contact, Primary Dressings-Covers: Main Demands  
The primary dressing, the dressing that is in immediate contact with the IL exposed raw tissue 
has very well defined role: to protect and promote care and healing. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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The followings are the factors that are important in these aspects: 
1. 
Adheres to the Interface Layer (with its special characteristics) 
2. 
Moisture regulation 
3. 
Epithelialization enhancement 
4. 
Fibroblastic activity modulation 
5. 
Infection control 
6. 
Trans-Dressing Diagnosis of changing conditions (TDD)  
7. 
Trans-Dressing Intervention (TDI) 
1. Adherents to the Interface Layer: Dressing’s adherence is important as it provides the 
protection against microorganism contamination and propagation, serving as a mechanical 
barrier shielding the healing wound from external insults and maintaining a thin moisture 
layer over the healing bed. In general, the dressing’s adherence may be due to the 
following situations: 
a. Incorporating, ingrowths of the wound bed tissue into the dressing structure (as may be 
seen in Allografts, Xenografts, cotton gauze or some of the sponge dressings). 
b. The “dressing” is an integral structural part of the wound (a desiccated eschar, the 
desiccated, upper layer of the bed or a planned mummification of the eschar by cerium 
nitrate [Flamacerium] or iodine will preserve the original collagen fibers ties with the 
bed’s matrix. 
c. There may be a physical/chemical layer that “bonds” the dressing to the underlying bed 
(such as scab formation where the fibrin and fibrous clot will adhere and bond dry 
hydrofiber [Aquacell], cellulose [Velloderm] etc. dressings). Dressings such as some of the 
Hyluronic acid [Jaloskin], Collagen [Biobran] or DL-Lactide (Vicryl like poliglycolic acid 
[Suprathel]) dressings may adhere by their undersurface, deeper layer that serves as 
adhering layer with the bed. In these cases very often, if the bed’s viability is maintained 
(not desiccated) the epithelial or granulation tissue will grow underneath and their 
advancing fronts will separate the dressing from the healing bed.  
In some of these dressings this bonding surface can bond the dressing also to a not 
completely debrided beds. If the eschar is very thin and not too contaminated there is a 
good chance that the dressing will remain adherent and the bed, slowly healing with the 
eschar remnants, will disintegrate as the healing front progresses. This characteristic is 
very important as it allows an effective cover to a wide range of wound beds.   
Unfortunately an adherent dressing to the wound bed may also form a barrier to the 
propagating healing process. The dressings from groups a. & b. above, though they may 
effectively prevent infection will not allow propagation of the epithelialization fronts 
underneath and may also prevent the formation of granulation tissue. The dressings from 
group c. may become also occlusive and increase microorganisme spreading and infection.      
2. Moisture regulation: The optimal moisture at the wound’s surface should be delicately 
balanced between desiccation that leads to cell death and matrix changes and 
overhydration that leads to maceration. Adherent dressing may normally keep the optimal 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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moisture unless they are hydrophilic (desiccating) by nature and in this case may desiccate 
the wound. Hydrating dressing with high water content may overhydrate the wound acting 
also as occlusive dressings increasing the danger of infection and infection propagation. 
The moisture condition in the individual wound is dynamic and may change within hours. 
A “moist” highly exudating wounds that may need drainage by absorbing dressing may 
become dry, recalcitrant wound by too active desiccation or even exposure. In the case of 
burn, “weeping” surface of a dermal scald burn or a fresh, raw donor site may desiccate in 
few hours of exposure and develop a layer of neo-eschar: a layer of desiccated, newly 
“killed” dermis. This dry, adhering layer can, if not infected, serve as a biological dressing 
but at a price: death of tissue that could be instrumental in the healing process and a danger 
of contamination and infection of this new eschar.   
All vital functions of healing and proliferation, healing factors and cellular activity need 
moist environment for their function. Nevertheless, microorganism survival and 
propagation need also moisture. The dressing we use should allow us to intervene and 
correct these changing conditions.  
Dressings from the group of “hydrogels”, “gelfoams”, all occlusive dressings-films, some 
of the adhering dressings, all topical gels, creams and ointments will maintain the bed 
moist and offer good healing conditions but a continuous monitoring should be maintained 
to intervene in time to prevent too much moisture, maceration and/or infection.               
3. Epithelialization enhancement: The progression of the epithelialization process is a 
complex one, involving the inbuilt epithelial progression based on the contact inhibition 
phenomenon with the proliferation of the keratocytes from the wound’s exposed edges and 
the epithelial islands originated in the skin adnexae. The Keratocytes propagate slowly 
over the dermal matrix in a moist atmosphere. The following are conditions that the 
propagation and the entire epithelialization process may be disturbed even in presence of 
sufficient epithelial sources (epidermal wounds edges, skin adnexae or autografts):  
 Mechanical disruption: dressing change, forced scraping or wiping of the healing wound 
will peel off the friable new epithelium from its bed  
 Mechanical barrier: such as to adherent dressing 
 Infection: may destroy keratocytes  
 Eschar presence: beside being a mechanical barrier that will not allow epithlialization over 
viable bed is also  a potent source for infection 
 Actively granulating tissue: (“overgranulation”) that will stop epithelialization by forming 
a physical barrier and biological competition by the fibroblastic activity. 
 Topical medications: may be noxious to the proliferating keratocytes (i.e. SSD, Iodine 
compounds)  
 Systemic conditions: mainly malnutrition as expressed by hypoproteinaemia and 
hypoalbuminaemia or Oncological cytotoxic drugs.  
4. Fibroblastic activity modulation: The Keratocytes and Fibroblasts originate from two 
different embryonic cellular origins: ectodermis and mesodermis. In spite of a very 
intimate relation in structuring the skin and forming the Epidermis and Dermis each of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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them exerts an inhibitory effect on the other. Fibroblasts are very active cells that 
proliferate in wound beds forming the three dimensional granulation tissue (together with 
new blood vessels by endothelial cells, also from Mesodermal origin). The Keratocytes, 
proliferate and propagate along the dermal superficial plan striving to from the Epidermis. 
They exert an inhibitory effect on the granulation tissue formation, arresting its 
development as soon as they cover it with the newly formed epidermis. The Fibroblasts 
and the granulation process are more robust than the thin epidermal, Keratocytes 
unicellular epithelialization healing front. Thus, if epithelialization process will not cover 
the healing bed, modulating and arresting the formation of rich granulation tissue the 
granulation tissue can become Overgranulation, forming a barrier to the Keratocytes and 
the epithelialization process and eventually becoming a heavy, contracting and deforming 
scar.  
In view of such a situation of developing granulation tissue in front of epithelialization 
process we can intervene by providing the Keratocytes with the optimal conditions 
(moisture, propagation surfaces and protection) and trying to interfere and decrease the 
overgranulation process. This can be done by mechanically scraping the overgranulation 
tissue, chemically destroying its surface (AgNO3) or using short (2-4 days) courses of 
topical corticosteroid treatment. The later treatment will effectively inhibit the granulation 
process allowing epithelialization to propagate and exert it own inhibitory effect on the 
fibroblasts. Topical steroids in given in shorts spells of few days each for over a month 
will not exert systemic effect and may be considered as safe. A wound healing dressing 
should promote epithelialization (that controls granulation) and allow us to intervene 
medically 
or 
mechanically 
interfering 
with 
overgranulation 
and 
promoting 
epithelialization.      
5. Infection control: Adherent dressing will prevent infection and occlusive conditions may 
favor it. Some dressings may be the source or serve as a medium for microorganisme 
growth (rejected allografts or xenografts, infected collagen or HA based dermal substitutes 
such as Integra, Hyalomatrix,). The dressing’s structure may itself harbor, as a foreign 
body, microrganismes (fibrous dressings such as cotton gauzes, some of the foams, other 
absorbing materials- Hydrogels and even hydrofibres-Aquacel to a certain point). Some of 
the dressings contain antibacterial agents (mainly silver) but they are not innocent. In such 
case that the dressing itself became contaminated we may wish either to replace it or be 
able to treat it with anti bacterial agents.        
6. Trans-Dressing Diagnosis of changing conditions (TDD): Being aware to the rather fast 
dynamic process, beneficial or not, that may happen in the healing wound the dressing 
should allow the diagnosis of emerging situations that may need our intervention. Process 
such as infection, granulation, overgranulation and epithelialization should be diagnosed 
and monitored in real time. An opaque, adherent, unchanged dressing may make such a 
diagnosis difficult. Dressings that are changed frequently (every 1-3 days at most, i.e. all 
topical medications, hydrogels, etc.) make such a diagnosis (on dressing change) easy. 
Some transparent dressings allow diagnosis through them (i.e. Jaloskin) or staining of their 
external surface when exudates from the wound ooze through (i.e. Aquacel, Polymem).    
7. Trans-Dressing Intervention (TDI): Adherent dressings that can remain for days, 
preventing infection, offering optimal healing conditions and allowing diagnosis of the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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processes that take place underneath are obviously ideal. The last possible criterion for an 
optimal dressing is the possibility to treat the wound bed through the dressing without 
disrupting it. Some of the occlusive dressings (Occludress, VAC+ all vacuum assisted 
dressings) could be connected to intake ports others, absorbing dressings such as gauze 
could be soaked without disruption.    
Wound Dressings and Covers 
The effect of the dressing’s physical properties 
As previously mentioned the role of the dressing is to protect and create an optimal healing 
microenvironment. Moisture and temperature that allow gases exchange and surfaces for 
epithelial migration, function of cells such as macrophages, neutrophils and fibroblasts. 
Another alternative are all the topical medications that need replacing or renewing daily or 
every other day.  
Absorbing & Non-absorbing 
The absorption function may depend on the physical structure (filament, fibers, hydrofibres, 
foams, etc.) or specific absorbing (hydrophilic mostly) materials the impregnate the dressing 
(starch, HA, alginates, collagen to a lesser measure, etc.). The passage of the fluids (exudates, 
soaking solutions, etc.) to or from the wound surface depend on the concentration gradient 
between the wound and the dressing and the characteristics of the dressing itself (potential 
fluid capacity, hydrophilic characteristics). Once fluid completely saturates the dressing the 
absorption power is cancelled and moisture at the wound surface increases to the point of 
maceration. Dressings with high absorption power may desiccate the wound to the point of 
tissue death. In order to maintain the absorption function the dressing should always be under 
its maximal saturation. This can be done by replacing the dressing before saturation or adding 
an external dressing that will absorb, through the primary dressing the fluid access. 
a. 
Antibacterial Topical Creams and Ointments 
Topical medicaments in the form of creams and ointments are innumerable, based on various 
antiseptic and/or antibiotic in different excipients preparations (few examples: Bacitracin, 
mupirocin, silver sulfadiazine, neomycin, polymyxin, honey inhibine, HA based creams) 
Indications: prophylaxis of infection, ointment maintain moist wound environment and can be 
used as covers in wound healing process.    
Burns care involves often the more effective combination of soaking and creams/ointments 
(silver nitrate compresses, chlorhexidine gluconate, mafenide acetate cream 0.5%, povidone 
iodine, nitrafurazone, silver sulfadiazine). 
Application: once or twice a day after washing and cleansing the wound.  
Contraindications: Allergic reactions, decreased cellular activity and viability. 
Complications: Drug specific, usually without risk of systemic toxicity. Local adverse effects 
include contact dermatitis (i.e., neomycin is as high as 34%). Application of silver sulfadiazine 
has been associated with neutropenia and epithelialization inhibition. 
Special points:  Bacitracin zinc is extremely popular because of low cost, low toxicity, and low 
allergic contact dermatitis. Relatively safe; topical antibiotics have low systemic absorption. 
HA based creams have additional benefit due to the HA base. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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b. 
Solutions for Irrigation & Soakings.  
Topical medicaments solutions are routinely used for soaking and irrigation of wound over a 
primary dressing, usually gauze. They are used for initial cleansing, being effective 
antimicrobial agents and mechanically washing away contaminants particles. With 
antibacterial agents they may be used for infection control. Corticosteroid addition will control 
topical inflammation and over granulation and with hypertonic solutions they can reduce 
cellulites, edema and swelling and even be used as antiseptics. Leaving the soaked gauze to dry 
will “suck in” the superficial dissolved materials be it dirt, bacteria or dissolved eschar 
allowing its removal. If the gauze is allowed to desiccate and bond to the bed surface its 
removal will tear off the surface (“wet to dry” cleansing). The following are common solutions 
used in burn and wound care: Saline (0.9%), Hypertonic Saline (<20%), MgSO4 (<10%), 
Chlorhexidine acetate (0.5%), Chlorhexidine gluconate (0.05%-0.1%), Sulfamylon 3%-5%, 
povidone-iodine, AgNO3 (0.5%), corticosteroid solutions,  antibiotic +/-corticosteroid 
solutions, PHMB (Polyhexamethylen biguanide) solution, Prontosan® (Betain + PHMB).  
Tissue toxicity is possible, caution should be used in the management of open wounds as well 
as wound desiccation. Corticosteroid long term (weeks), continuous soaking may cause 
transient, systemic Cushingoid symptoms. 
c. 
Gauze, gauze-like: woven & non-woven, cotton-base, not-cotton-based 
Cotton or cotton-like fibrous materials are used since antiquity as dressings. The pliability, 
adherence, absorption and their capacity to serve as a matrix to many medicaments and 
materials made them the current choice in wound care. This characteristic make them serve as 
a“reinforcement” for the creation of the scab that is the natural dressing for the healing wound. 
The fibrin from the raw bed is absorbed by the dressing that remains embedded in the 
solidified fibrin, forming a strengthened scab that by its nature (it is nature’s raw bed’s 
dressing) adheres to the bed. Due to their fibrous structure they serve also as wicks for soaking, 
passing the solution and bathing the bed. They can also serve as absorbing dressings passing 
the exudates to the surface, to be reabsorbed by additional, external, absorbing dressings. 
Normally, they will not adhere to full thickness wounds unless adhere through fibrous bonds 
that in every dressing-change (daily) will damage re-epithelialized layer delaying healing. The 
problem with such dressings is that they may shed particles that some become embedded in the 
healing bed, forming later foreign body inclusion cysts.   
d. 
Impregnated Dressings including Silver Dressings 
Dressings coated or impregnated with any material that is conceived to be beneficial to any of 
the wound healing phases or factors are produced by all wound care companies. Each of these 
agents has its advantages and its potential risks and drawbacks and should be assessed 
individually. The dressings can be made of many kinds of matrixes (cotton woven or non 
woven, films of various permeabilities and geometries, foams, hydrofibres, alginates, etc.).  
The choice of the dressing should be done according to the matrix characteristics (e.g. the 
difference in the properties of cotton gauze and hydrofibres) and the impregnating medication 
(e.g. the difference between SSD and Paraffin ointment) considering the specific requirement/s 
of the wound and its healing phase.  Few examples are:   
Paraffin with or without antimicrobial medicaments, coating woven, non woven or other 
primary form of dressings (such as Jelonet, Neotulle, Aquaphor-Gauze, Paranet, Unitulle, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Bactigras etc.): It will keep it moist, will not adhere to the bed, may increase infection danger, 
should be changed every 2 days at most. 
Silver compounds of different formulations (Acticoat, Silvelon, Atrauman Ag, Biatain Ag, 
Aquacel Ag, Contreet Hydrocolloid, Mepilex, Physiotulle Ag, PolyMem Silver, Silvercel, 
Suprasorb A+Ag, Tegaderm Alginate Ag, Urgocell Silver, Urgotul Silver): Silver ions (Ag+) 
have antibacterial effects, hyper sensitivity and arginosis (staining by silver oxide) of tissues 
has been reported. 
 SSD impregnated matrixes (Allevyn Ag, Urgotul SSD):widely used as a local antimicrobial, 
not to be used in sensitive to silver or sulfa drugs, known to delay epithelialization, 
kerenicterus has been reported.   
e. 
Biological covers (autografts, allografts, xenograft, skin substitutes and equivalents) 
The biological covers have a complex three dimensional collagen or collagen-like matrix, 
saturated by mucopolisaccaride compounds such as Hyluronic Acid and usually covered by 
semi permeable layer (epidermis, silicone).  They are applied on clean, viable surfaces, initially 
adhere by fibrin bonding and serum imbibition followed by in-growth of new vessels and 
fibroblasts from the bed. When they adhere (“take”) on a clean and viable bed all provide good 
protection and healing conditions.  The ones with antigenic potential (allograft and xenograft) 
should be replaced before immune rejection occurs. 
o Autografts are the classical means for permanent wound closure. In full thickness defects 
they provide a complete closure by primary intention healing. Deep dermal defect will also 
heal in a similar way by accepting the graft as a permanent cover but dermal remnants that 
contain epidermal foci (skin appendages) may also heal by epithelialization under the graft 
forming cysts or unsightly overgrafting patches. Autograft is a costly means, requiring 
surgery and sacrifice of healthy donor site skin areas and should be reserved for permanent 
closure for full thickness defects where spontaneous healing is impossible or when a fast 
closure is so important as to abandon the somewhat slower epithelialization of the dermal 
surface. 
o Allograft (fresh or cryopreserved) is used as a temporary solution to close the wound. It 
will “take” as autograft but will be rejected by the immune reaction 7-14 days later. On a 
clean IL bed they provide good healing conditions for the dermal IL and a temporary 
closure for full thickness defect. The epithelialization process will take place under the graft 
protection with the sloughing graft exposing the healing bed. The allograft keratocyte’s 
growth factors can promote the process but infection may harm the healing process. As the 
allograft is practically occlusive it is advisable to perforate or mesh it without expanding it 
to allow for a drainage and potential treatment medication. Use of allograft does not require 
surgical facilities but the availability of allograft may pose a problem in some countries. 
Their availability may be limited to the skin bank services and their shelf life is limited to a 
week when fresh and 3-4 years when frozen. Glycerol preserved allografts have a longer 
shelf life and do not need skin bank preservation facilities but are not viable, do not “take” 
but bond to the surface by fibrin, being less effective than fresh or cryopreserved. 
o Xenograft (fresh or cryopreserved, Mediskin I) usually from porcine origin, as allografts 
they are used as a temporary cover to “close” the wound. Fresh or cryopreserved, it will 
“take” as allograft but will be rejected by the immune reaction in few days. On a clean IL 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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bed they provide good healing conditions for the dermal IL and a very temporary closure for 
full thickness defect. The epithelialization process will take place under the graft protection 
with the sloughing graft exposing the healing bed. It is more infection-prone and should be 
applied meshed and medicated with antimicrobial agents. The glycerolized xenograft has a 
better shelf life but is even less effective and more infection-prone. Use of xenograft does 
not require surgical facilities but its availability may pose a problem in some countries.  
Skin Substitutes, Biodegradable & Non-biodegradable: Collagen, Hyluronic Acid (HA), 
Synthetic (DL-Lactide)  
There are number of materials that the inflammatory and healing process can degrade thus 
avoiding removing them at the end of the healing process. The problem is always to decide 
whether we want this degradation process in addition to the normal inflammatory, healing one. 
Biological materials such as Collagen, Hyluronic acid or DL Lactide- polyglactin (the raw 
material for Vicryl sutures) are all used as films or three dimensional sponge-like structures. In 
full thickness wounds, some are designed to serve as templates for new dermis formation 
(Collagen: Integra, Matriderm, HA: Hyalomatrix) by providing a growth matrix for capillaries 
and fibroblasts to be grafted with thin autograft when their survival (“take”) is secured. Similar 
approach is shared by other products: Dermagraft (non-immunogenic neonatal fibroblast on 
polyglactin mesh), OrCel (Fibroblasts layered onto bovine collagen matrix), TransCyte 
(Shipped frozen for use on partial- and full-thickness burns, epidermal layer with dead 
fibroblasts layered onto a nylon mesh), Apligraf (dermis-like matrix from cultured 
heterogenous human foreskins and bovine collagen type 1, has epidermal and dermal 
components), Oasis (porcine, small-intestine submucosal dehydrated dressing with longer 
shelf-life, rehydrate when needed with a secondary dressing to prevent desiccation), Alloderm 
(Freeze-dried, cell-free).  
Another group is design to serve as a cover for clean, dermal wounds providing healing 
(epithelialization) conditions and disintegrating when epithelialization is completed (Collagen 
films and sponges, HA Jaloskin or DL Lactide Suprathel).  All need a clean bed to adhere to, 
with Suprathel in need of a meticulously dermabraded bed. All are sensitive to infection. 
Collagen and HA can be used to coat synthetic matrixes or fabric (Nylon-Biobrane).  Biobrane 
is common in wound care, peeling off at the end of epithelialization but is prone to desiccation 
of the bed and infection.  
f. 
Inert, synthetic materials 
The alternative to biodegradable materials are the ones that are completely inert, most are 
synthetic providing the required conditions to the wound bed but are not part of the healing 
process and peel-off, trimmed away as wound heals by the epithelializing front. Another 
alternative are all the topical medications that need replacing or renewing daily or every other 
day.  
g. 
Foams  
Synthetic (i.e. polyurethane or silicone) foams may by more or less absorbent depending on 
their structure (large or small, open or partially open cells) and the additive materials (e.g. 
starch, SSD, silver) (i.e. Allevyn, Flexzan, Lyofoam, Sof-Foam). 
They may be considered as a farther development of more simple dressings such as: 
impregnated multilayer gauze, Polyurethane or gel film coated, hydrophilic or hydrophobic, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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semiocclusive, bilaminated dressings. Foam dressings offer most of the advantages of 
medicated gauze with a better absorption and protection in most cases. Very often they adhere 
to the bed (incorporation by ingrowths of granulation tissue and/or bonding by fibrin), creating 
the required adhering, moist environment and absorbing exudates from discharging wounds 
thus reducing the need for dressing changes. Foams provide also mechanical protection but in 
many cases their permeability can be obstructed by hardened exudates transforming them to 
opaque, occlusive dressings that are prone to infection. 
h. 
Films, permeable, non permeable 
These dressings, may be completely occlusive or permeable to gas and water vapors, but are a 
barrier to bacteria and water. Films, Semiocclusive/semipermeable made of polyurethane or 
copolyester, approximately 0.2 mm thick (Bioclusive, Polyskin II, OpSite, Tegaderm).  They 
are elastic and transparent but difficult to occlude larger that few cm2 areas. They are 
commonly used as occlusive dressings, sometimes with additional medicated gauze or topical 
medication underneath as a primary dressing, creating a microenvironment over the wound that 
can contain gazes (02, 03, or vacuum etc.) or medicaments. On clean beds they may adhere 
through the bonding effect of the wound exudates and fibrin but usually are transparent 
allowing easy assessment of the wound bed. When adhering to the bed they are generally 
reserved for the definitive closure of superficial, shallow partial thickness wounds where 
comfort and ease of management are important. The dressings can be left in place for several 
days, but their occlusive nature and accumulated exudates make them extremely prone for 
infection and daily monitoring is important. 
i. 
Hydrocolloids   
These dressings are non adhesive, water and gas impermeable membranes (Comfeel, Cutinova, 
DuoDERM, Intrasite, Replicare, Hyprapad Tegagel®, Intrasite etc.). Composed mainly of 
water held in a complex network or fibres that keep the polymer gel intact. Water is released to 
keep the wound moist.  
When the inner layer comes into contact with exudates, it forms a gel providing adequate 
moisture, the liquefied gel and exudates fill the dressing that has to be changed. If the dressing 
dries it may adhere to the bed interfering with healing and may damage, tear-off new 
epithelium when removed. Obviously the occluded moist atmosphere is prone to infection 
propagation and sometime to overhydration and maceration.  Hydrocolloids can be applied 
directly to clean wound but not on eschar or tendons. Perform dressing changes every 3 to 7 
days with saline irrigation cleans colloidal layer. Hypersensitivity to materials can develop. 
j. 
Aquacel (with or without Ag.) 
Soft non-woven pad made from sodium carboxymethylcellulose fibres. These Hydrofibres 
absorb exudates and fluids from the wound becoming a gel like material. Germs thus absorbed 
are eliminated from the wound surface but the dressing itself may dry to become a dry adherent 
shell. The desiccation may dry viable surface extending the original damage but the dry shell 
allows discharge before wound is closed with epithelial cells slowly separating the dry dressing 
from its bed.   
k. 
Alginates 
Composed of calcium alginate (a seaweed component). When in contact with wound, calcium 
in the dressing is exchanged with sodium from wound fluid and this turns dressing into a gel 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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that maintains a moist wound environment. Do not use on low exudating wounds as this will 
desiccate the wound. Dressing should be changed daily to avoid desiccation. 
E.g. Kaltostat, Sorbsan Alginates are derivatives of seaweed are in the form of dry non-woven 
mats, absorbing wound exudates to become a hydrophilic gel like hydrocolloids and behave in 
a similar way (Kaltostat, Sorbsan, Algosteril, AlgiSite, Kaltostat, Sorbsan etc.).  Jellified 
alginates are not adhesive, they are easily washed away but applied on a moist, clean bed they 
may strongly adhere to become a hard shell that will protect the wound but may slow the 
healing process and be hard to remove, injuring and stripping the healing bed. It is a strong 
hemostatic that can be used on bleeding wounds (post tangential excision or graft harvesting) 
but can interfere with healing later. A secondary wet dressing may prevent desiccation. 
Soaking and irrigation of the desiccated dressing will jellify it again and ease changing. 
Hypersensitivity to materials. Thyroid abnormalities can develop. 
l. 
Hydrogels-gelfoams 
These gels are usually based on starch polymers providing ample moisture (Carrasyn, Intrasite, 
Lamin, Nu-gel, Vigilon, etc.). Hydrogels are best suited to autolyse dry necrotic wounds, but 
they also absorb exudates while maintaining the products of tissue repair and degradation, 
including growth factors and lysosomes, in contact with the wound. If the wound is clean, the 
gel only needs to be replaced once or twice a week providing good healing conditions but these 
conditions are also favorable for infection propagation (especially gram negative bacteria). 
m. 
Negative Pressure Wound Therapy 
It is still a constantly evolving technology based on an occlusive dressing connected to a 
vacuum pump, containing a fibrous or foam matrix that distribute the sub-atmospheric pressure 
onto the wound bed. There are numerous similar available systems differing mainly in price 
and nature of matrix. Used initially mainly for chronic ulcers, it is quite effective as a 
secondary dressing to secure skin graft adherence and take.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
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APPENDIX 5- WOUND MANAGEMENT; APPROVED COVERS 
General remark: the guidelines of this appendix follow the ABA White Paper guidelines with 
detailed additions of some commonly used topical treatments.  
All dressings that are films, sheet-like (including biological dressings such as autografts, 
allograft and xenografts) and even foams, hydrocolloids and gauzes can become occlusive 
(sometimes by desiccated exudates) and pose danger associated with occlusion to healing 
wounds. It is recommended to perforate or mesh (without expansion) such dressings and if 
possible, apply a negative pressure dressing (e.g. VAC, etc.) on top of them for few days to 
ensure adherence and “take”). There are many additional dressings that strive to fulfill wound 
healing goals beside the approved to be used in the study detailed below. Some of them, 
beneficial as they may, are not standard. If the PI wishes to use then in this study, MediWound 
clinical department should be approached to verify and approve their use.  
Below is a list of the approved wound care products in the study which are all legally marketed 
in the US as detailed in the ABA guidelines. 
In the study protocol, there are 2 main categorizes of wound care products: 
Skin substitute [commercial product]: A biomaterial, engineered tissue or combination of 
materials and cells or tissues that can be substituted for skin autograft or allograft in a clinical 
procedure.  
Skin replacement: A tissue or graft that permanently replaces lost skin with healthy skin. 
 
Temporary Wound Coverage  
Temporary skin substitutes are used when the wound is too extensive to be closed in one stage 
because there is not enough donor skin available, because the patient is too ill to undergo the 
creation of another wound that results when skin is harvested from a donor site, because there 
is a question regarding the viability of the recipient bed, or because of a concern regarding 
potential infectious complications. The gold standard temporary skin substitute is cadaver 
allograft. Other temporary skin substitutes are used to provide transient wound coverage and 
to create a physiologically homeostatic environment such as- Skin Xenografts—also termed 
heterografts. 
Biobrane® is a silicone membrane pressed onto a flexible nylon fabric which has been coated 
with porcine dermal collagen. Used as a temporary wound cover, it is considered a dressing by 
the FDA and CPT Editorial Panel.  
Transcyte®, a related product, is not a dressing. It is classified as a temporary skin substitute 
and is composed of Biobrane® and cultured newborn human fibroblasts, which secrete growth 
factors and matrix proteins onto the wound surface. TransCyte® must be applied to a clean 
wound bed and monitored closely because it is prone to infection. It can be used in ways 
similar to Allograft and Xenograft.  
Permanent Wound Coverage  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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A full-thickness skin graft contains all components of the skin: epidermis, dermis, hair 
follicles and nerve endings. The most important advantage of full-thickness grafts is decreased 
scar formation; however, because there is no dermis to regenerate epithelial coverage, the 
donor site of a full-thickness skin graft must be closed either with primary direct closure or 
with a split-thickness skin graft; local advancement of skin flaps is a rarely used option. Full-
thickness grafts are thus usually used to cover small, functionally and cosmetically important 
areas (such as eyelids and digits).  
The split-thickness skin graft is the most common method used to achieve permanent wound 
coverage. It includes the entire epidermis but the dermal layer is split by the dermatome blade. 
With thicker split-thickness grafts, more dermis is transferred with the skin graft (such as 
15/1000 of inch or greater). This reduces the risk of scar formation at the recipient site, but it 
takes longer for the donor site to heal. Furthermore, the thicker the graft, the more likely the 
donor site will heal with a scar and the less likely the donor site may be reharvested for further 
grafts. 
There are a number of commercially available products to facilitate permanent wound 
coverage. Acellular human dermal allograft (Alloderm®) is devoid of epidermis and must 
be covered by a thin split-thickness autograft at the time of the initial operation; however, it 
replaces a portion of the missing dermis on the newly covered wound, thus reducing 
postoperative scarring. Another permanent wound coverage product is a dermal regenerative 
template (Integra®) constructed with bovine collagen and shark chondroitin sulfate with a 
silicone surface layer. This is applied to an excised wound bed that is well vascularized and 
free from infection, and provides wound coverage much like other skin substitutes; however, 
after the template becomes vascularized, it forms a neodermis (usually within 10 days to three 
weeks) and when the silicone layer is removed, an epidermal autograft (< 0.008 inch thickness) 
can be applied. This intermingling of autograft on a biosynthetic neodermis is permanent, 
unlike the wound coverage provided by temporary skin substitutes. This approach may be 
lifesaving and provides quality skin coverage.  
Cultured epidermal autograft (CEA; Epicel®), also referred to as “test tube” skin, was 
introduced by Rhinewald & Green in 1975 and is often employed to provide permanent skin 
coverage for patients with extensive burns.  
 
All of the above surgical or non surgical agents and covers are routinely used in the US, 
specified in the protocol and are allowed to be used in the proposed study based on the 
investigator’s medical judgment for the specific wound condition or patient. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 6- REGULATORY AND ETHICAL ISSUES 
Compliance with Regulations Applicable to Clinical Trials 
The study will be conducted according to the laws, regulations and administrative provisions 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use, as applicable by national legislation and EU Directives and 
US 21 CFR Part 11, 50, 54, 56, 312. 
This clinical trial will be registered on the “clinicaltrials.gov” clinical trial registry website as 
required by 42 USC 282(j) and the State of Maine’s PL 205, c. 392, §1. 
Informed Consent 
The principles of Informed Consent, conducted in accordance with Declaration of Helsinki and 
its updates, current Good Clinical Practice (GCP), the provisions of ICH (International 
Conference on Harmonisation); US Code of Federal Regulations (Title 21, CFR Part 50,) 
and/or EU Directives; local country regulations and the sponsor's Standard Operating 
Procedures (SOPs) will be followed. A subject is not allowed to enter a clinical study until 
he/she has been properly informed, has been given time to contemplate participation, and has 
freely given his/her consent by signing and dating the Ethics Committee/Institutional Review 
Board (EC/IRB) approved informed consent form.  This must be done prior to performing any 
study related procedures. 
The proposed consent form and any other documents relevant to the consent process must be 
submitted to the EC/IRB, together with the protocol, and must be approved prior to study start. 
A copy of the fully signed and dated Informed Consent Form and any other documents relevant 
to the consent process will be given to the subject and the original will be maintained at the 
site. 
Subject Confidentiality 
All subject data will be identified only by a subject identification number, subject initials (may 
be dummy) and date of birth.  
The investigator should keep the initials given in the “Subject Identification Log”. After 
obtaining subject’s consent, the investigator will permit the study monitor, independent auditor 
or regulatory agency personnel to review that portion of the subject’s medical record that is 
directly related to the study. This shall include all study relevant documentation including 
subject medical history to verify eligibility, laboratory tests results, admission/discharge 
summaries for hospital admissions occurring while the subject is on study, and autopsy reports 
for deaths occurring during the study (if applicable). 
Good Clinical Practice 
The study described in this protocol will be carried out according to the local regulatory 
requirements (FDA, EU, other) and ICH accepted standards of Good Clinical Practice. 
Ethics Committee (EC) / Institutional Review Board (IRB) 
The study must have unconditional approval in writing, by an appropriate Ethics 
Committee/Institutional Review Board (EC/IRB). A copy of the Letter of Approval from the 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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EC/IRB, which contains specific identification of the documents approved, must be received 
by local Sponsor prior to site activation. 
Any amendments to the protocol or subsequent changes to the informed consent form as a 
result of changes to the protocol and/or investigator brochure that is approved by MediWound, 
must also be approved by the EC/IRB and documentation of this approval provided to 
MediWound. Records of the EC/IRB review and approval of all documents pertaining to this 
study must be kept on file by the investigator and are subject to the sponsor’s audit and/or 
regulatory authority inspection, during or after completion of the study.  
Serious adverse events (SAEs) must also be reported to the EC/IRB by the investigator or the 
sponsor according to local regulations. 
The investigator must submit a periodic status reports to their EC/IRB as required, as well as 
notification of completion of the study and a final report where applicable. A copy of all 
reports submitted to the EC/IRB must be sent to the sponsor. 
Protocol Amendments 
Protocol amendments must be prepared by sponsor or designee and approved by the sponsor, 
Competent Authorities (if applicable), Central EC/IRB and/or each respective site’s EC/IRB (if 
applicable), prior to implementation.  
Changes to the protocol can only be made by an approved protocol amendment. In case of 
urgent safety amendment ICH GCP guideline, should be followed. 
For clinical trial sites located in EU Member States, the procedures outlined in Directive 
2001/20/EC, Article 10(a), are applicable. 
Declaration of the End of the Clinical Trial 
For clinical trial sites located in EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC, Article 10(c) and for those 
countries outside EU local regulations will be followed. 
Liability And Insurance (If Applicable)  
A Certificate of Clinical Trials Insurance will be provided to the study centers by MediWound 
Ltd. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 7- STUDY ADMINISTRATIVE PROCEDURES 
This study will be conducted, recorded and reported according to ICH E6 requirements 
“Guideline for Good Clinical Practice” and its other implementing directives and guidelines.  
Study Site Initiation 
After the investigator files were updated with the following documents, the site may begin 
patient recruitment:  
1. CV and Medical License of the Principal Investigator, 
2. A signed and dated Investigator Protocol Agreement, 
3. A Financial Disclosure form, 
4. Signed Agreement between MediWound and the trial site, 
5. The laboratory certification or proficiency ratings, the normal ranges for laboratory 
determinations required by the protocol and the curriculum vitae of the laboratory director, 
6. A copy of competent authority written notification of protocol approval (EU sites), study-
specific informed consent form and any advertisements, notices or bulletins to be used in 
this study, 
7. A copy of the ethics committee/IRB approval,  
8. The ethics committee name, address and a list of ethics committee members including 
occupations and institutional affiliations, 
9. Signed Investigator Brochure receipt. 
 
Informed Consent 
Protection of clinical trial subjects will be performed as follows: 
A clinical trial may be undertaken only if the following elements are fulfilled: 
1. The study may be initiated only if the ethics committee and the competent authority come to 
a conclusion that the anticipated therapeutic benefit justifies the foreseeable risks and 
inconveniences.  
a. Prior to signing the informed consent, the trial subject had a discussion with the 
investigator or a member of the investigating team concerning the objectives, risks and 
inconveniences of the trial and the conditions and has been informed of his right to 
withdraw from the study at any time. 
b. Neither minor nor patients not being able to consent on their own are not included in the 
study However, legal representative may be involved in the Inform Consent procedure 
and sign the form if this is pre approved by the local IRB/EC and only for subjects with 
temporary medical conditions related to the injury, subjects who might be under the 
influence of pain medication, sedation, etc (see Section ‎8.1.1).   
c. The rights of the subject to physical and mental integrity, to privacy and to protection of 
the data concerning him are safeguarded. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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d. If the subject is unable to write, an oral consent in the presence of at least one witness 
may be given in exceptional cases, as provided in national legislation. 
e. Provision has been made for insurance or indemnity to cover the liability of the 
investigator and the sponsor. 
f. The medical care given to, and medical decisions made on behalf of, subjects shall be the 
responsibility of an appropriately qualified physician. The subjects shall be provided with 
a contact where he may obtain further information. 
2. In addition to the above restrictions the following elements are to be fulfilled in clinical 
trials on minors and incapacitated adults: 
a. The subject should receive information regarding the trial, the risks and benefits, from an 
experienced staff, 
b. The investigator should consider explicit wish of the subject who is capable of forming 
an opinion, to refuse participation or to be withdrawn from the clinical trial at any time, 
c. No incentives or financial inducements will be given except compensation, 
d. The study should relate directly to the clinical condition from which the subject 
concerned suffers, 
e. The study is designed to minimize pain, discomfort, fear and any other foreseeable risk, 
being based on common, routinely practiced thermal burns SOC strategies and 
techniques 
f. The ethics committee, with expertise in the relevant disease and the patient population 
concerned or after taking advice in clinical, ethical and psychosocial problems in the 
field in the subject’s population involved, has endorsed the protocol, 
g. The interests of the patient always prevail over those of science and society. 
 
3. The following issues should be included in the Informed Consent discussion and the written 
Informed Consent Form: 
a. A statement that the study involves research, 
b. Discussion with the subject should include: an explanation of the purposes of the 
 
research and the expected duration of the subject's participation, a description of the 
procedures to be followed and identification of any procedures that are experimental, 
c. The trial treatment(s) and the probability for random assignment to each treatment, 
d. Disclosure of any available alternative procedures or courses of treatment that might be 
advantageous to the subject, 
e. A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and that notes the possibility that the regulatory 
authorities, the institutional ethics committee or MediWound or designee may inspect the 
records, 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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f. A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is normally entitled, 
g. The subject’s responsibilities,  
h. A statement that the particular treatment or procedure may involve risks to the subject (or 
the embryo or fetus if the subject is, or may become, pregnant) that are currently 
unforeseeable, 
i. Anticipated circumstances under which the subject's participation may be terminated by 
the investigator without regard to the subject's consent,  
j. Any additional costs to the subject that may result from participation in the research,  
k. A statement that significant new findings developed during the course of the research, 
which may relate to the subject's willingness to continue participation, will be provided 
to the subject, 
l. The approximate number of subjects involved in the study, 
m. The person(s) to contact for further information regarding the trial and the rights of trial 
subjects. 
 
The Principal Investigator or designee is responsible for obtaining written informed consent 
from potential subjects prior to entry into the study. The investigator must keep each subject's 
signed consent form on file.  A copy of the signed document must be given to the subject. 
Competent Authority (CA)1 and the Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) 
This study must be approved by the CA (EU sites) and the ethics committee prior to patient 
enrollment.MediWound will obtain a EudraCT number before submitting an application to the 
CA. Each member state CA shall be provided with a list of CAs to which application was 
made, with a copy of their decisions as soon as it is available. 
The investigator must maintain an accurate and complete record of all submissions made to the 
CA including a list of all reports and documents submitted. The investigator agrees to promptly 
report to the ethics committee all unanticipated problems involving risks to human subjects or 
others.  
MediWound will inform the CA and the ethics committee of any new information relating to 
the conduct of the trial or the development of the IP where it is likely to affect the safety of 
subjects. Any safety measures taken should be reported to the authorities. Periodic status 
reports must be submitted at least yearly to the IRB/IEC.  
MediWound Ltd. shall notify the competent authorities of the member states concerned and the 
ethics committees that the clinical trial has ended within 90 days of the end of trial. If the trial 
                                                 
1 Relevant for sites located in the EU. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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has been terminated earlier than expected, notification should be made within 15 days and 
reasons clearly explained. 
Electronic Case Report Forms (eCRFs) 
No data will be directly entered into the e-CRF without source documentation. 
The CRF is an integral part of the study and subsequent reports. The Case Report Form 
provided by MediWound Ltd. must be used to capture all study data recorded in the subject’s 
medical record. The CRF must be kept current to reflect subject status during the course of the 
study. Only a subject identification number and subject initials will be used to identify the 
subject. The investigator must keep a separate log of subject names and medical record 
numbers (or other personal identifiers). 
The protocol will use an Internet-Based Remote Data Entry System, primarily to collect 
clinical trial data at the investigational sites.  The system will comply with 21 CFR Part 11 and 
ICH E6. The system will be used to enter, modify, maintain, archive, retrieve, and transmit 
data. Paper source documents are to be retained to enable a reconstruction and evaluation of 
the trial. No original observations will be entered directly into the computerized system. Source 
documents include the hospital patient files and study worksheets provided by the Sponsor. 
Data will be recorded in the study worksheets as appropriate in order to complete and/or clarify 
source data. 
The design of a computerized system complies with all applicable regulatory requirements for 
record keeping and record retention in clinical trials (21 CFR Part 11 and ICH E6 Good 
Clinical Practice) to the same degree of confidence as is provided with paper systems. Clinical 
investigators must retain either the original or a certified copy of all source documents sent to a 
sponsor or contract research organization, including query resolution correspondence. The 
system is designed so that changes to any record do not obscure the original information.  The 
audit record clearly indicates that a change was made and clearly provides a means to locate 
and read the prior information. All changes to the data have an electronic audit trail, in 
accordance with 21 CFR 11.10(e). Electronic signatures will be used in conformance with 21 
CFR Part 11. 
Corrections are made in source documents by crossing out the error with a single line, making 
the correct entry in close proximity to the data field, then initialing and dating the strike-
through and the new entry. 
Maintenance of Study Files 
All essential documents listed in ICH Guideline CPMP/ICH/135/95 should be filed in an 
organized way that will facilitate management of the clinical trial and audit.  
Agreements between the involved parties, all Institutional Review Board correspondence 
including notification of protocol and consent form approval and all annual reports along with 
the final report to the IRB must be retained.   
Study records including patient source documents, Case Report Forms, all test results and 
signed informed consent forms must be kept on file by the investigator.   


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Other documents pertaining to the conduct of the study including laboratory normal values, 
laboratory certification, monitor logs and telephone reports and all written correspondence 
must also be kept as part of the permanent record. 
Storage conditions: Essential documents should be maintained in a legible condition and so 
that they can be promptly retrieved. Any change in the ownership and location of the 
documentation should be documented in order to allow tracking of stored records. 
The investigator should make the sponsor aware of the storage arrangements for the 
documents. If the investigator for any reason cannot keep the study records, MediWound Ltd. 
should be notified in writing so that alternative arrangements can be agreed upon. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending applications or at least 2 years elapsed 
since the formal discontinuation of clinical development of the investigational product. It is the 
responsibility of the MediWound Ltd. to inform the investigator/ institution as to when these 
documents no longer need to be retained. 
These regulations are described in: Detailed Guidelines on Trial Master File and Archiving – 
July, 2006. 
Monitoring Procedures 
Investigational sites will be monitored periodically to assure satisfactory patient enrollment, 
data recording and protocol adherence. The frequency of monitoring may vary depending on 
enrollment rate and the quantity of data collection.  The investigator and staff are expected to 
cooperate with the study monitor and provide to study monitor all relevant study 
documentation.  It is essential that the investigator and study coordinator set aside a sufficient 
amount of time for these visits to permit an adequate review of the study's progress and of 
completed Case Report Forms. 
Changes in Study Personnel  
The ‘Authorization Signature Log’ which is a list of appropriate qualified persons to whom the 
Principal Investigator has delegated significant trial-related duties, should be updated if there is 
a change or addition of any personnel initially listed. CVs and other relevant documents 
evidencing qualifications should be provided to MediWound Ltd. 
On-Site Inspections/Audits 
In accordance with section 1.29 in ICH E6 inspections may be requested and coordinated by 
the European Medicines Agency or the FDA. Inspections may take place at various times: 
before, during and/or after the conduct of the clinical trial. The investigator and staff are 
requested to cooperate with all such audits. The investigator must notify MediWound Ltd. of 
any expected inspection as soon as possible. A representative or designee of MediWound, Ltd. 
Clinical Research Department, may also conduct similar auditing procedures. 
Disclosure and Publication of Information 
All proprietary information including: MediWound Ltd. operations, patent applications, 
formulas, manufacturing processes, basic scientific data and formulation information provided 
to the investigator or the methodologies used in this study, as well as proprietary information 
obtained during the course of the study are confidential and will remain the sole property of 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 141 of 173 
 
 
  
 
 
FINAL 
CONFIDENTIAL 
MediWound Ltd.  The investigator agrees not to disclose any proprietary information supplied 
by MediWound Ltd. in any way without prior written permission. 
Individual patient data obtained during this study are confidential and will not be disclosed to 
third parties with the following exceptions: 
When the data is needed by a patient's personal physician or other medical personnel 
responsible for the patient's welfare, 
For data inspection and verification by MediWound Ltd. or designee, European Medicine 
Agency inspectors or by the Institutional Review Board (IRB). 
Any manuscript or abstract produced by an investigator must be provided to MediWound Ltd. 
for review 45 days prior to submission. Individual patient identity must not be divulged in any 
publication. 
Protocol Changes or Amendments 
The investigator also agrees not to make any changes in the study protocol or its conduct 
except when necessary to prevent immediate hazards to human life.   
Substantial amendments in protocol may be made only by written amendment by the 
MediWound Ltd. Substantial amendment to the conduct of the clinical trial may arise from 
changes in the protocol that have impact on safety or physical or mental integrity of the 
subjects, the scientific value of the trial, conduct or management of the trial or the quality or 
safety of any IP used in the trial. The Ethics committee and the competent authority must 
approve protocol amendments prior to implementation.  Documentation of IRB/IEC approval 
for such amendments must be kept on file by the investigator and forwarded to MediWound 
Ltd. 
Notification to the ethics committee/IRBs and the competent authorities (EU sites) on non-
substantial amendments should follow the local regulatory policies. Such amendments should 
be recorded and be available for inspection. 
These regulations are described in: Detailed Guidance for the request for authorization of a 
clinical trial on a medicinal product for human use to the competent authorities, notification 
and substantial amendments and declaration of the end of the trial – April, 2002. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 142 of 173 
 
 
  
 
 
 
142 
APPENDIX 8- BIOPSY & HISTOLOGIC ASSESSMENT METHOD 
Burn Wound Infection - Biopsy & Histologic Assessment Method  
1. Using a scalpel, a 500 mg lenticular sample of eschar and underlying, unburned 
subcutaneous tissue is harvested from the area of the burn wound showing the most marked 
changes characteristic of infection.   
2. If local anesthetic is required, it should be injected around the planned margin of the biopsy 
to minimize distortion of the architecture of the biopsied tissue.   
3. One-half of the specimen is sent to the quantitative microbiology laboratory for culture and 
antibiotic sensitivity determinations, and the other half of the specimen is processed for 
histologic examination by a frozen section technique (requiring 45 minutes) or a rapid 
section technique (requiring 3.5 to 4.0 hours).   
4. If the frozen section technique is utilized, the tissue should be subsequently processed by 
rapid section technique for definitive examination, since the frozen section method is 
associated with a 3.6% false-negative rate which can be corrected by careful examination of 
permanent sections. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 143 of 173 
 
 
  
 
 
 
143 
APPENDIX 9- PAIN MEASUREMENT SCALE 
Pain scores will be measured using a Visual Analogue Scale (VAS) for the adult population at 
the required timelines. VAS is a measurement instrument that tries to measure a characteristic 
or attitude that is believed to range across a continuum of values and cannot easily be directly 
measured.  
As illustrated in Figure 2, the patient marks on the line (100 mm line), the point that they feel 
represents their perception of their current state. The VAS score is determined by measuring in 
millimeters from the left end of the line to the point that the patient marks. 
Figure 2- Visual Analogue Scale 
 
 
 
No Pain 
Worst Pain Ever 
No Pain 
Worst Pain Ever 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 144 of 173 
 
 
  
 
 
 
144 
APPENDIX 10- PROCEDURES FOR SPECIFIC BLOOD TESTS 
Immunogenicity blood Samples 
Serum samples for antibodies to NexoBrid will be obtained prior to application (time 0), and at 
the following time points:  
 At day 28±7 days (week 4 visit) from start of treatment, 
 At day 56±14 days (week 8 visit) from start of treatment. 
 At the 6 months FU visit 
 At the 24 months FU visit  
 
The blood sampling should be taken after an overnight fast (at least 8 hours if possible) at 
about the same time of the day (± 2 hours and before noon) due to potential daily fluctuations 
in the levels of immunological responses. The serum samples will be kept at (-) 20oC until 
delivery for analysis.  
Sample preparation procedures are as follows: 
1. For each immunogenicity sample at each time point, draw 3 ml whole blood into a 5 ml pre-
labeled tube and check the label for subject number, time point, and type of test. 
2. Place the tube in the refrigerator at 2-8oC for 0.5hrs - 2 hours for clotting. Important Note: Do 
not leave the serum with the clot longer than 2 hours in the refrigerator or at room 
temperature.  
3. Centrifuge the sample at a minimum of 1100 g for 10 minutes, at ambient temperature for red 
blood cells sedimentation.  
4. Divide the serum equally (the upper liquid layer, approximately 1.5 ml) into four pre-labeled 
1 ml conical bottom cryotubes resulting in at least 0.3 ml serum each. Check the subject 
number, time point, and type of test and fill DATE and TIME, 2 cryotubes will be used for 
analysis and 2 for backup.  
5. Store the cryotubes at (-) 20 ± 5 oC or below until shipped for analysis at Covance.  
6. The shipment of samples will be in (-) 20 ± 5 oC or below.  
If possible, storage and shipment are preferred in (-) 70o±10°C conditions.  
7. The set of 2 samples for analysis should be shipped to Covance first. The samples should be 
sent at the end of the study. Please contact your CRA when shipment is required.  
8. The second set of samples (backup) should be dispatched to Covance in a subsequent and 
separate shipment, after confirmation that the first set has been received, but only if asked by 
the lab. 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 145 of 173 
 
 
  
 
 
 
145 
Procedures for Pharmacokinetic Samples 
PK evaluation will be performed for a subset of 32 NexoBrid patients:  
1. 16 patients with total wounds area of  <=15% TBSA  will be tested for PK 
2. 16 patients with total wounds area of  >15% TBSA  will be tested for PK 
PK samples will be obtained prior to application (time 0), and at the following time points:  
 
In subjects requiring a single application:  
o 
Before treatment (time zero), 0.5 hours ± 10 minutes,  2 hours ± 10 minutes, 4 hours ± 
10 minutes, 12 hours ± 30 minutes, 24 hours ± 30 minutes , 48 hours ± 30 minutes and 
72 hours ± 30 minutes after NexoBrid application. 
 
In subjects requiring two planned applications of NexoBrid: 
o 
1st treatment: before treatment (time 0), 0.5 hours ± 10 minutes, 2 and 4 hours ± 10 
minutes after the first NexoBrid application. 
o 
2nd treatment: time 0, 0.5 hours ± 10 minutes, 2 and 4 hours ± 10 minutes, 12 hours ± 
30 minutes, 24 hours ± 30 minutes, 48 and 72 hours ± 30 minutes after the second 
NexoBrid application. 
Please carefully follow the procedure below for handling the PK blood samples: 
1. For each PK sample at each time point, draw 2 ml whole blood into a 5 ml pre-labeled tube and 
check the label for subject number, time point, and type of test. 
2. Place the tube at room temperature for approximately 30 minutes for clotting.  
3. Store the sample at refrigeration (2-8 ºC) for approximately 120 minutes. 
4. Following the refrigeration period, Centrifuge the sample for approximately 20 minutes at 2800 
to 3000 x g at a temperature of 2-8 ºC. 
5. Divide the serum equally (the upper liquid layer) into pre-labeled 1 ml conical bottom cryotubes. 
Check the subject number, time point, and type of test and fill DATE and TIME. 
6. Store the cryotubes in (-) 20 ± 5 ºC or below until shipment for analysis at Quintiles. The 
shipment of samples will be in (-) 20 ± 5 ºC or below.  
7. If possible, storage and shipment are preferred in (-) 80 ± 10°C conditions.  
8. The samples should be shipped to Quintiles after 4 patients completed the 48hrs test, but no 
more than 7 months post first sample was drawn (in that case you may send samples of less than 
4 patients). Please contact your CRA when shipment is required. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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146 
APPENDIX 11- BURN PATIENTS: POTENTIAL ADVERSE EVENTS 
Cardiovascular 
Hypotension 
(decrease of either 
systolic or diastolic 
for >/= 2hrs) 
Pressor or inotrope 
requirement for 
normotension 
Sinus tachycardia 
Dysrhythmia 
Hypertension 
Pulmonary 
Tachypnea 
Pulmonary edema 
Pneumonia 
Pneumothorax 
Pleural Effusions 
Atelectasis 
Pulmonary 
Infiltrates 
Inhalation injury 
and/or airway (req. 
intubation) 
Respiratory failure 
Neurological 
Mental status 
changes 
Sedation 
Confusion/delirium 
Substance 
withdrawal 
GI 
Nausea 
Vomiting (>/= 
2/shift or >/= 
6/day) 
Diarrhea (>/= 
2/shift or >/= 
6/day) 
Constipation 
Ileus during bum 
shock 
Renal 
Acute renal failure 
(BUN >/= 24; Cr 
>/= 1.19) 
Renal failure 
 
Urinary tract infections 
Urinary tract infection, 
early 
Urinary retention 
Fluctuation in UOP during 
burn resuscitation 
«1mllkg/hr for 2 hrs) 
Blood 
Anemia (chronic or acute) 
(based on hemoglobin 
gm/dL) 
Thrombocytopenia (plt </= 
145,000) 
Thrombocytosis (plt >/= 
350) 
C-Reactive Protein (>/=30) 
Mild 
coagulopathy 
as 
evidenced by ele PT/PTT 
(PT> 12.3, PTT>36.5) 
Asymptomatic electrolyte 
imbalance 
(see 
norm 
ranges) 
Hyperglycemia 
(glycosuria, insulin drip) 
Leukocytosis 
WBC 
2: 
highest normal range 
Leukopenia WBC ~lowest 
normal range 
Other hematologic 
Coagulopathy 
ODE III/DDDP 
Mise 
Pain from primary injury 
Pruritis 
Microbial colonization of 
burn wounds 
Wound infection 
Other infection 
 
Excision and grafting of burn injury 
Graft loss «/= to 10% ofthe extent 
grafted) 
Hands 
Sepsis / septicemia 
Line infection 
Compartment syndrome (extremity) 
Hypothermia «37.2C for 2hrs) 
Hyperthermia (>/=39.5C) 
Amputation of extremities/digits 
from deep burn 
Cellulitis 
Traumatic injury 
Graft site contracture requiring 
release or revision 
Death 
Multiple organ failure / multi-system 
organ failure 
Permanent neuro/vascular deficit not 
r/t sev of inj 
Unplanned surgical intervention 
Autografting to donor site for failure 
to heal 
Repeat autografting to same body site 
(>10% org grafted) 
Auto Graft/regraft 
CSS regraft 
Intubation due to declining 
respiratory status not related to 
edema or inhalation injury 
Acute Respiratory Distress Syndrome 
(ARDS) 
Abdominal Compartment Syndrome 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 147 of 173 
 
 
  
 
 
 
147 
APPENDIX 12- COSMESIS, FUNCTION AND QUALITY OF LIFE QUESTIONNAIRES  
Modified Vancouver Scar Scale (MVSS) 
The six parameters listed below are evaluated on a point system (please tick the correct 
answer): 
1. Pigmentation 
□ (0) Normal 
□ (1) Hypopigmented 
□ (2) Mixed 
□ (3) Hyperpigmented 
2. Pliability  
□ (0) Normal 
□ (1) Supple- flexible with minimal resistance 
□ (2) Yielding- giving way to pressure 
□ (3) Firm- inflexible, not easily moved, resistant to manual pressure 
□ (4) Banding- rope- like tissue that blanches with extension of the scar 
□ (5) Contracture- permanent shortening of scar, producing deformity or distortion 
3. Height  
□ (0) Flat 
□ (1) <2mm 
□ (2) 2 to 5mm 
□ (3) >5mm 
4. Vascularity  
□ (0) Normal 
□ (1) Pink 
□ (2) Red 
□ (3) Purple 
5. Pain 
□ (0) None 
□ (1) Occasional 
□ (2) Requiring medication 
6. Pruritus 
□ (0) None 
□ (1) Occasional 
□ (2) Requiring medication 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 148 of 173 
 
 
  
 
 
 
148 
 
Patient and Observer Scar Assessment Scale (POSAS) 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 149 of 173 
 
 
  
 
 
 
149 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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150 
EQ-5D (QoL) 
EQ-5D is a standardized measure of health status developed in order to provide a simple, generic 
measure of health for clinical and economic appraisal. Applicable to a wide range of health conditions 
and treatments, it provides a simple descriptive profile and a single index value for health status that can 
be used in the clinical and economic evaluation of health care as well as in population health surveys. 
EQ-5D is designed for self-completion by respondents and is ideally suited for use in postal surveys, in 
clinics, and in face-to-face interviews. 
EQ-5D essentially consists of 2 pages - the EQ-5D descriptive system (Figure 3) and the EQ visual 
analogue scale (EQ VAS) (Figure 4). The EQ-5D descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has 3 levels: no problems, some problems, severe problems. The respondent is asked to indicate his/her 
health 
state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 
dimensions. This decision results in a 1-digit number expressing the level selected for that dimension.  
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale where the 
endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’.  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 151 of 173 
 
 
  
 
 
 
151 
Figure 3- EQ-5D Descriptive system 
 
EQ-5D (UK English version) 
By placing a tick in one box in each group below, please indicate which statements best describe your 
own health state today. 
 
Mobility 
I have no problems in walking about  
 
 
� 
I have some problems in walking about  
 
 
� 
I am confined to bed   
 
 
 
� 
 
Self-Care 
I have no problems with self-care  
 
 
� 
I have some problems washing or dressing myself  
 
� 
I am unable to wash or dress myself  
 
 
� 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities  
� 
I have some problems with performing my usual activities  
� 
I am unable to perform my usual activities   
 
� 
 
Pain/Discomfort 
I have no pain or discomfort  
 
 
 
� 
I have moderate pain or discomfort  
 
 
� 
I have extreme pain or discomfort  
 
 
� 
 
Anxiety/Depression 
I am not anxious or depressed  
 
 
 
� 
I am moderately anxious or depressed  
 
 
� 
I am extremely anxious or depressed  
 
 
� 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 152 of 173 
 
 
  
 
 
 
152 
To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
WE WOULD LIKE YOU TO INDICATE 
ON THIS SCALE HOW GOOD OR BAD 
YOUR OWN HEALTH IS TODAY, IN 
YOUR OPINION. PLEASE DO THIS BY 
DRAWING A LINE FROM THE BOX 
BELOW TO WHICHEVER POINT ON THE 
SCALE INDICATES HOW GOOD OR BAD 
YOUR HEALTH STATE IS TODAY. 
To help people say how good or bad a health 
state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can 
imagine is marked 100 and the worst state you 
can imagine is marked 0. 
WE WOULD LIKE YOU TO INDICATE 
ON THIS SCALE HOW GOOD OR BAD 
YOUR OWN HEALTH IS TODAY, IN 
YOUR OPINION. PLEASE DO THIS BY 
DRAWING A LINE FROM THE BOX 
BELOW TO WHICHEVER POINT ON THE 
SCALE INDICATES HOW GOOD OR BAD 
YOUR HEALTH STATE IS TODAY. 
 
Figure 4- EQ visual analogue scale (EQ VAS) 
 
Your 
own 
health 
state


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 153 of 173 
 
 
  
 
 
 
153 
Burn Specific Health Scale-Brief 
 
 
extreme(ly)  
quite a bit 
moderate(ly) 
a little bit 
None (not at all) 
1. Bathing independently 
 
 
 
 
 
2. Dressing by yourself 
 
 
 
 
 
3. Getting in and out of a chair 
 
 
 
 
 
4. Signing your name 
 
 
 
 
 
5. Eating with utensils 
 
 
 
 
 
6. Tying shoelaces, bows, etc 
 
 
 
 
 
7. Picking up coins from a flat surface 
 
 
 
 
 
8. Unlocking a door 
 
 
 
 
 
9. Working in your old job performing your old duties 
 
 
 
 
 
10. I am troubled by feelings of loneliness 
 
 
 
 
 
11. I often feel sad or blue 
 
 
 
 
 
12. At times, I think I have had an emotional problem 
 
 
 
 
 
13. I am not interested in doing things with my friends 
 
 
 
 
 
14. I don’t enjoy visiting people 
 
 
 
 
 
15. I have no one to talk to about my problems 
 
 
 
 
 
16. I have feelings of being trapped or caught 
 
 
 
 
 
17. My injury has put me further away from my family 
 
 
 
 
 
18. I would rather be alone than with my family 
 
 
 
 
 
19. I don’t like the way my family acts around me 
 
 
 
 
 
20.My family would be better off without me 
 
 
 
 
 
21. I feel frustrated because I cannot be sexually aroused as well as I 
d
 
 
 
 
 
22. I am simply not interested in sex any more 
 
 
 
 
 
23. I no longer hug, hold or kiss 
 
 
 
 
 
24. Sometimes, I would like to forget that my appearance has changed 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 154 of 173 
 
 
  
 
 
 
154 
25. I feel that my burn is unattractive to others 
 
 
 
 
 
26. My general appearance really bothers me 
 
 
 
 
 
27. The appearance of my scars bothers me 
 
 
 
 
 
28. Being out in the sun bothers me 
 
 
 
 
 
29. Hot weather bothers me 
 
 
 
 
 
30. I can’t get out and do things in hot weather 
 
 
 
 
 
31. It bothers me that I can’t get out in the sun 
 
 
 
 
 
32. My skin is more sensitive than before 
 
 
 
 
 
33. Taking care of my skin is a bother 
 
 
 
 
 
34. There are things that I’ve been told to do for my burn that I dislike 
d i
 
 
 
 
 
35. I wish that I didn’t have to do so many things to take care of my burn 
 
 
 
 
 
36. I have a hard time doing all the things I’ve been told to take care of my 
b
 
 
 
 
 
37. Taking care of my burn makes it hard to do other things that are 
i
 
 
 
 
 
38. My burn interferes with my work 
 
 
 
 
 
39. Being burned has affected my ability to work 
 
 
 
 
 
40. My burn has caused problems with my working 
 
 
 
 
 
.. 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 155 of 173 
 
 
  
 
 
 
155 
QuickDASH 
QuickDASH outcome measure for burns in the upper extremities. The Disabilities of the Arm, 
Shoulder and Hand (DASH) Outcome Measure is a 30-item, self-report questionnaire designed 
to measure physical function and symptoms in patients with any or several musculoskeletal 
disorders of the upper limb. The questionnaire was designed to help describe the disability 
experienced by people with upper-limb disorders and also to monitor changes in symptoms and 
function over time. Testing has shown that the DASH performs well in both these roles. 
It gives clinicians and researchers the advantage of having a single, reliable instrument that can 
be used to assess any or all joints in the upper extremity. 
The DASH Outcome Measure contains two optional, four-item modules intended to measure 
symptoms and function in athletes, performing artists and other workers whose jobs require a 
high degree of physical performance. Because they may be having difficulties only at high 
performance levels–which are beyond the scope of the 30-item DASH Outcome Measure–
clinicians may find the modules, which are scored separately from the DASH, useful in 
assessing these special patients.  
The DASH Outcome Measure was jointly developed by the Institute for Work & Health and 
the American Academy of Orthopaedic Surgeons (AAOS). The project was supported by the 
American Association for Hand Surgery, the American Orthopaedic Society for Sports 
Medicine, the American Shoulder & Elbow Surgeons, the American Society for Surgery of the 
Hand, the Arthroscopy Association of North America and the American Society of Plastic and 
Reconstructive Surgeons. 
The QuickDASH is a shortened version of the DASH Outcome Measure. Instead of 30 items, 
the QuickDASH uses 11 items to measure physical function and symptoms in persons with any 
or multiple musculoskeletal disorders of the upper limb. Like the DASH, the QuickDASH also 
has two four-item optional modules that are scored separately. The QuickDASH was found to 
be valid and repeatable in patients with upper limb burns and supports the use of the 
QuickDASH in this population to help assess change in functional level [100-101]. 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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156 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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Lower Extremity Functional Scale test (Binkley et al, 2011) 
The Lower Extremity Functional Scale (LEFS) is a questionnaire containing 20 questions 
about a person’s ability to perform everyday tasks. The LEFS can be used by clinicians as a 
measure of patients' initial function, ongoing progress and outcome, as well as to set functional 
goals. The LEFS can be used to evaluate the functional impairment of a patient with a disorder 
of one or both lower extremities. It can be used to monitor the patient over time and to evaluate 
the effectiveness of an intervention.  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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158 
 
 
 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 13- ASA CLASSIFICATION SYSTEM 
The ASA physical status classification system is a system for assessing the fitness of patients 
before surgery. These are: 
ASA Physical Status 1 - A normal healthy patient 
ASA Physical Status 2 - A patient with mild systemic disease 
ASA Physical Status 3 - A patient with severe systemic disease 
ASA Physical Status 4 - A patient with severe systemic disease that is a constant threat to life 
ASA Physical Status 5 - A moribund patient who is not expected to survive without the 
operation 
ASA Physical Status 6 - A declared brain-dead patient whose organs are being removed for 
donor purposes 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 160 of 173 
 
 
  
 
 
 
160 
APPENDIX 14- RANGE OF MOTION 
In this study, passive ROM will be measured in which the motion is being created by the 
patient contracting the muscles around the joint. A goniometer will be used in this study to 
measure joint angles (joint range of motion).  
Instructions for using a goniometer 
1. Align the fulcrum of the device with the joint to be measured 
2. Align the stationary arm of the device with the limb being measured 
3. Hold the arms of the goniometer in place while the joint is moved through its range of 
motion. 
The degree between the endpoints represents the entire range of motion. 
Important tips: 
1. Stabilize the stationary of the body. This is the part of the body that is proximal (closer to the 
midline of the body) to the joint you are testing. It is important that the patient does not move 
his body while moving the joint; this step isolates the joint movement for a more accurate 
measurement. 
2. Look at the reading on the goniometer before moving it from the patient’s body. Ensure that 
you take an accurate reading of the degree of motion on the geometer, and that you 
consistently use the same stationary and movable landmarks on the body when measuring, to 
ensure consistency. Be sure to record the range of motion for the joint. 
Range of Motion measurements 
16.1.1.1 Shoulder Joint 
The shoulder joint has the following normal ranges of movement: Flexion, Extension, 
Adduction, Abduction and Medial Rotation. Flexion, Extension, Adduction and Abduction will 
be measured: 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 161 of 173 
 
 
  
 
 
 
161 
Shoulder normal ranges: 
Movement 
Degree 
Description 
Flexion (Vertical) 
180° 
Raise arm straight forward 
Extension 
(Vertical) 
60° 
Raise arm straight backward 
Abduction 
90° 
Bring arm up sideways 
Adduction 
45° 
Bring arm toward the midline of the 
body 
 
Elbow joint 
The elbow joint has the following normal ranges of movement: Flexion, Extension, Pronation 
and Supination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elbow normal ranges: 
Movement 
Degree 
Description 
Flexion 
150° 
Bring lower arm to the biceps 
Extension 
180° 
Straighten out lower arm 
Pronation 
90° 
Turn lower arm so palm faces down 
Supination 
90° 
Turn lower arm so palm of hand faces 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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up 
Wrist joint 
The wrist joint has the following normal ranges of movement: Flexion, Extension, Adduction, 
Abduction and Circumduction. Flexion, Extension, Adduction and Abduction will be 
measured: 
 
 
 
 
 
 
 
Wrist normal ranges: 
Movement 
Degree 
Description 
Flexion 
80-90° 
Bend wrist so palm nears lower arm 
Extension 
70° 
Bend wrist in opposite direction 
Abduction 
20° 
Bend wrist so thumb nears radius 
Adduction 
30-50° 
Bend wrist so pinky finger nears ulna 
 
Palm and Fingers 
Normal ranges of the palm & fingers joints will include the following joints (see Figure 5):  
 The fingers IP joints;  
o Distal Interphalangeal (DIP) joints 
o Proximal Interphalangeal (PIP) joints 
  The thumb joints; 
o Proximal Interphalangeal (PIP) joint 
o Metacarpophalangeal (MTP) joint 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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163 
 
 
 
 
 
 
 
 
 
Figure 5- Hand fingers joints 
 
Joints normal ranges: 
Movement 
Degree 
Description 
Thumb IP 
Hyperextension/Flexion 
0/80 
Thumb MTP 
Hyperextension/Flexion 
0/55 
Finger DIP joints 
Extension/Flexion  
0/60  
Finger PIP joints 
Extension/Flexion  
0/100 
Finger MCP joints (see 
Figure 6) 
Hyperextension/Flexion 
10/90 
 
 
 
 
 
 
 
 
 
Figure 6- Finger MCP hyperextension (a) and flexion (b) 
 
a 
b 
MTP 
j i
MTP
PIP 
jointsPIP 
DIP jointsDIP 
joints
 
 
 
a 
b 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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164 
Knee joint 
The knee joint has the following normal ranges of movement: Flexion and Extension. 
 
 
 
 
 
 
Knee normal ranges: 
Movement 
Degree 
Description 
Flexion 
130° 
Touch calf to hamstring 
Extension 
15° 
Straighten out knee as much as 
possible 
 
Ankle joint 
The ankle joint has the following normal ranges of movement: Plantar Flexion, Dorsi Flexion, 
Inversion and Eversion. Dorsi and Plantar flexion will be measured in this study: 
 
 
 
 
 
 
 
Knee normal ranges: 
Movement 
Degree 
Description 
Flexion 
45° 
Bend ankle so toes point up 
Extension 
20° 
Bend ankle so toes point down 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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APPENDIX 15- BLINDED ASSESSOR MEMO- SAMPLE 
In accordance with study protocol, for patients who are randomized to one of the topical arms, 
NexoBrid or Gel Vehicle, eschar removal assessment will be done by assessor blinded to the 
treatment arm. This assessor will evaluate eschar removal in all study arm (but will be blinded 
only to the topical arms) and for all procedures until complete eschar removal.  
In addition, weekly evaluations of wound closure and long term cosmesis and function will be 
done by a second assessor blinded to all treatment arms.  
The following procedures and assessments will be performed by the blinded assessors at the 
following time-points:  
First blinded assessor:  
Eschar Removal assessment- For the topical arms (NexoBrid/Gel Vehicle), eschar removal 
assessment will be performed immediately following removal of the soaking dressing (6 hours 
after start of 1st and 2nd treatment and after any additional procedure until complete eschar 
removal. The assessment will include photograph, wound depth assessment and clinical 
assessment of the extent of eschar removal.  
Eschar removal in the SOC arm will be evaluated by the same assessor, but he will not be 
blinded to the SOC arm.  
Second blinded assessor (blinded to all treatment arms): 
Weekly follow up visits and wound closure confirmation visit-  
The following procedures will be performed by the blinded assessor: 
o All wounds should be photographed.   
o Clinical assessment of % of target wound area epithelialized and/or closed by graft and 
assessment of % donor site epithelialized, 
o Assessment of the percent ‘take’ of any graft should be recorded 2-7 days post-grafting 
procedure. A photograph should be taken at the time of assessment  
Long term follow up visits-  
The following procedures will be performed by the blinded assessor: 
o 
All wounds should be photographed.   
o 
The following questionnaires will be filled by the blinded assessor: 
 
Patient and Observer Scar Assessment Scale (POSAS) 
 
A modified Vancouver Scar Scale (MVSS) 
o 
Range of Motion measurements (injured and non-injured joints) 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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166 
In order to maintain the blinding, the sponsor would like your site to implement measures, as 
best as possible, to ensure that the blinded assessors will not be aware of the treatment 
assignments for the duration of the study.  
The first blinded assessor (eschar removal assessor) should not be involved with product 
application. The second blinded assessor (wound closure and long term assessor) should not be 
involved with any eschar removal procedure, PK and Immunogenicity blood sampling should 
not be taken at the same time of the blinded assessment. 
The topical (NexoBrid/Gel Vehicle) treatment allocation will not be accessible through the 
subject’s electronic case report forms. Paper source documents that could unblind the assessor 
will be kept in a separate folder, appropriately labeled. The blinded assessor should not review 
subject’s data that will include randomization reports, PK and Immunogenicity blood 
collection, drug accountability records, and any other data that could unblind the assessor for 
the topical arms. In addition, all Investigational Products (used and unused) should be stored, 
dispensed, and administered out of the sight of the blinded assessor.  
Treatment allocation to the SOC group cannot be reconciled from all eCRFs and SD. The 
weekly and long term follow up set of source documents worksheets are in separated sections 
and not reviling the treatment arm. 
The second blinded assessor who evaluates the weekly and long term effects of the treatment 
should not review other sections of source worksheets and will not access to eCRFs. 
The Sponsor's medical team will be blinded to the topical arms treatment, and can provide 
support blindly when needed during the eschar removal treatment.  
You are being required to sign this memo to acknowledge and certify that you will make all 
attempts to comply with these requirements. 
Acknowledgement (To be signed at the start of the study): 
 I acknowledge that I fully understand my role in maintaining the blind and assure that I will 
not access subject’s data except for the information relevant to the conduct the blinded 
assessments listed above. 
 
Eschar removal assessor:  
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 Wound closure, cosmesis and function assessor: 
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 
 
Certification (To be signed at completion of study):  


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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167 
I certify and confirm that I did not review subject’s data except for the information relevant to 
the conduct of the blinded assessments. 
 
Eschar removal assessor:  
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 
 Wound closure, cosmesis and function assessor: 
Printed Name of Blinded Assessor      
 
Signature            
Date_____________  
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
Page 168 of 173 
 
 
  
 
 
 
168 
APPENDIX 16- TREATMENT DIAGRAM 
 
 
 


Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
Version 11- 23 June 2016 
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Gel 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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Running Title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care 
Protocol: MW 2010-03-02 
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SAP_005.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Clinical Trial 
 
A multicenter, multinational, randomized, controlled, assessor blinded study, performed in 
subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid compared to Gel 
Vehicle and compared to Standard of Care (DETECT) 
 
 
 
Sponsor: 
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Trial protocol code: MW2010-03-02 
EudraCT number: 2014-001672-55 
IND No.: 65,448 
 
 
Competence Center for Clinical Trials Bremen - Biometry 
Author: Dr. Martin Scharpenberg 
Version of 29 November 2018, Version V03 – (final) 
 


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1. Table of Contents 
1. 
Table of Contents 
2 
2. 
Introduction 
13 
2.1. 
Background 
13 
2.2. 
Study Objective 
17 
2.3. 
References to Study Protocol 
17 
2.4. 
Amendments 
18 
3. 
Study Administrative Structure 
19 
3.1. 
Sponsor 
19 
3.2. 
Study Conduct 
19 
3.3. 
Statistics 
20 
4. 
Signatures 
21 
5. 
List of Abbreviations 
22 
6. 
General Definitions 
25 
6.1. 
Hardware and software used 
25 
6.2. 
Reporting standards and language 
25 
6.3. 
General format and content of tables, figures and patient data listings. 
25 
6.4. 
Quality control 
25 
7. 
Details of Trial Design 
26 
7.1. 
General Information of Trial Design 
26 
7.1.1. 
Study medication 
27 
7.1.1.1. 
Topical arms 
27 
7.1.1.1.1. NexoBrid 
27 
7.1.1.1.2. Gel Vehicle 
27 


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7.1.1.2. 
Standard of Care 
27 
7.1.2. 
Intended dosage and duration of treatment 
28 
7.1.2.1. 
NexoBrid 
28 
7.1.2.2. 
Gel Vehicle 
28 
7.1.2.3. 
Standard of Care 
28 
7.1.3. 
Study population and choice of study invitee 
29 
7.1.3.1. 
Inclusion Criteria - Patient level 
29 
7.1.3.2. 
Inclusion Criteria - Wound level 
29 
7.1.3.3. 
Exclusion Criteria - Patient level 
29 
7.1.4. 
Drop-out criteria 
31 
7.1.4.1. 
Stopping rules (apply for NexoBrid or Gel Vehicle arms only) 
31 
7.1.5. 
Concomitant medication and treatment 
33 
7.2. 
Trial schedule 
34 
7.3. 
Criteria for evaluation 
39 
7.3.1. 
Demographic data and other baseline characteristics 
39 
7.3.2. 
Efficacy evaluation 
42 
7.3.2.1. 
Primary target variable 
42 
7.3.2.2. 
Secondary target variables 
42 
7.3.3. 
Safety evaluation 
43 
7.3.3.1. 
Time to complete wound closure 
43 
7.3.3.2. 
Cosmesis and function at 12 months from wound closure confirmation 43 
7.3.3.3. 
Cosmesis and function at 24 months from wound closure confirmation 46 
7.3.3.4. 
Adverse Events 
46 
7.3.3.5. 
Laboratory assessments and vital signs 
47 
7.3.3.6. 
Additional safety endpoints 
49 


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7.3.4. 
Exploratory analyses 
50 
8. 
Handling of protocol violations 
52 
9. 
Populations Analyzed 
54 
9.1. 
Sample Size 
54 
9.1.1. 
Primary Endpoint: Incidence of complete eschar removal (NexoBrid vs. Gel) 54 
9.2. 
Secondary Endpoint: Incidence of surgical excision 
55 
9.3. 
Secondary Endpoint: Time to complete eschar removal 
55 
9.3.1. 
Summary of sample size 
56 
9.4. 
Safety Set 
56 
9.5. 
Full analysis Set (Intent-to-Treat population) 
56 
9.6. 
Per Protocol Set 
56 
9.7. 
Enrolled population 
56 
10. 
Data Handling 
57 
10.1. 
Handling of Missing Data, Outliers and Implausible Data 
57 
10.1.1. 
Primary Endpoint: Incidence of complete eschar removal 
57 
Secondary Endpoints 
58 
10.1.1.1. 
Secondary Endpoint: Incidence of surgical excision 
58 
10.1.1.2. 
Secondary Endpoint: Time to complete eschar removal 
58 
10.1.1.3. 
Secondary Endpoint: Blood loss 
58 
10.1.2. 
Safety Endpoints 
61 
10.1.2.1. 
Safety Endpoint: Time to reach complete wound closure 
61 
10.1.2.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 61 
10.1.2.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 62 


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10.2. 
Handling of Withdrawals and Dropouts 
62 
10.3. 
Data Transformation 
62 
10.3.1. 
Demographic data and other baseline characteristics 
63 
10.3.1.1. 
Age 
63 
10.3.1.2. 
Height 
63 
10.3.1.3. 
Weight 
63 
10.3.1.4. 
Time since injury 
63 
10.3.1.5. 
Early grafted wounds 
63 
10.3.1.1. 
Late grafted wounds 
63 
10.3.1.2. 
Wounds at least partially found in the anatomical area of the hand 
64 
10.3.2. 
Primary Endpoint: Incidence of complete eschar removal in the topical arms 64 
10.3.3. 
Secondary Endpoints 
64 
10.3.3.1. 
Secondary Endpoint: Incidence of surgical excision 
64 
10.3.3.2. 
Secondary Endpoint: Time to complete eschar removal 
65 
10.3.3.3. 
Secondary Endpoint: Blood loss 
66 
10.3.3.3.1. Blood loss for main analysis 
66 
10.3.3.3.2. Proportion of SPT area of wounds treated per procedure 
67 
10.3.3.3.3. Proportion of DPT area of wounds treated per procedure 
67 
10.3.3.3.4. Proportion of FT area of wounds treated per procedure 
67 
10.3.3.3.5. Course of debridement procedure 
67 
10.3.4. 
Safety Endpoints 
68 
10.3.4.1. 
Safety Endpoint: Time to reach complete wound closure 
68 
10.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 68 


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10.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 68 
10.3.4.4. 
General Parameters of safety 
69 
10.3.5. 
Exploratory Analyses 
75 
10.3.5.1. 
%SPT area 
75 
10.3.5.2. 
%TBSA 
75 
10.3.5.3. 
Application data 
75 
10.3.5.4. 
Maintenance of complete wound closure 
75 
10.3.5.5. 
% wound area surgically excised for eschar removal 
76 
10.3.5.6. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremities target wounds 
76 
10.3.5.7. 
POSAS 
76 
10.3.5.8. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
77 
10.3.5.9. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremity wounds 
77 
10.3.5.10. Incidence of surgically harvested donor sites wounds 
77 
10.3.5.11. % area of surgically harvested donor site wounds 
77 
10.3.5.12. Blood loss using changes in hematocrit following eschar removal 
procedures 
77 
10.3.5.13. Blood loss using changes in hemoglobin following eschar removal 
procedures 
78 
10.3.5.14. Blood loss comparing NexoBrid procedures to surgical procedures 
78 
10.3.5.15. Autograft related parameters 
78 
10.3.5.16. Duration of hospitalization 
78 
10.3.5.17. Time to reach 100% wound closure 
79 


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10.3.6. 
Laboratory values 
79 
10.4. 
Multiple visits per time point 
79 
11. 
Statistical Analysis of Target Variables 
80 
11.1. 
First stage analysis – end of efficacy assessment period (EAP) 
82 
11.1.1. 
Demographics and Other Baseline Characteristics 
82 
11.1.2. 
Primary Efficacy variable 
84 
11.1.3. 
Secondary Efficacy variables 
85 
11.1.3.1. 
Incidence of surgical excision 
85 
11.1.3.2. 
Time to complete eschar removal 
86 
11.1.3.3. 
Blood loss 
88 
11.1.4. 
Safety variables 
89 
11.1.4.1. 
Safety Endpoint: Time to wound closure 
89 
11.1.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 91 
11.1.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 91 
11.1.4.4. 
Adverse Events 
91 
11.1.4.5. 
Vital Signs 
92 
11.1.4.6. 
Pain Assessment 
92 
11.1.4.7. 
Extend of exposure to study drug 
93 
11.1.4.8. 
Medical history and concomitant diseases 
93 
11.1.4.9. 
Concomitant medication 
93 
11.1.4.10. Central laboratory values 
93 
11.1.4.11. Blood transfusions 
94 
11.1.4.12. Maintenance of complete wound closure 
94 


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11.1.4.13. Incidence of QT prolongation 
94 
11.1.4.14. Analgesia, anesthesia and antibiotic use 
94 
11.1.4.15. Hospital readmission rates 
95 
11.1.4.16. INR/PTT change 
95 
11.1.4.17. Blood glucose change 
96 
11.1.5. 
Exploratory Analyses 
96 
11.1.5.1. 
% wound area surgically excised for eschar removal 
96 
11.1.5.2. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
96 
11.1.5.3. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremities target wounds 
97 
11.1.5.4. 
Incidence of surgically harvested donor site wounds 
97 
11.1.5.5. 
% area of surgically harvested donor site wounds 
97 
11.1.5.6. 
Blood loss using changes in hematocrit following eschar removal 
procedures 
98 
11.1.5.7. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
98 
11.1.5.8. 
Blood loss in NexoBrid procedures vs. surgical procedures 
98 
11.1.5.9. 
Autograft related parameters 
98 
11.1.5.10. Duration of hospitalization 
99 
11.1.6. 
Pharmacokinetic Variables 
99 
11.1.7. 
Multicenter Data 
100 
11.1.8. 
Handling of Multiple Comparisons 
100 
11.1.9. 
Interim analysis 
100 
11.1.10. Stratification 
100 
11.1.11. Analysis of Subgroups 
101 


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11.1.11.1. Target wounds in the anatomical area of the hand 
101 
11.1.11.2. Patients with < 25% SPT area 
101 
11.1.11.3. Patients with ≥ 25% SPT area 
102 
11.1.11.4. Total TBSA ≤ 15% 
102 
11.1.11.5. Total TBSA > 15% 
102 
11.1.11.6. All target wounds full thickness 
102 
11.1.11.7. Mixed target wounds – full thickness and deep partial thickness 
102 
11.1.11.8. All target wounds are deep partial thickness 
102 
11.1.11.9. Wounds that are entirely full thickness 
102 
11.2. 
Second stage analysis – 12 month short-term follow-up (STFU12) 
103 
11.2.1. 
Demographics and Other Baseline Characteristics 
103 
11.2.2. 
Primary Efficacy variable 
103 
11.2.3. 
Secondary Efficacy variables 
103 
11.2.4. 
Safety variables 
103 
11.2.4.1. 
Safety Endpoint: Time to wound closure 
103 
11.2.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 103 
11.2.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 104 
11.2.4.4. 
Adverse Events 
104 
11.2.4.5. 
Concomitant medication 
105 
11.2.4.6. 
Lower Extremity Function Scale (LEFS) 
105 
11.2.4.7. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
105 
11.2.4.8. 
Range of Motion (ROM) 
105 
11.2.4.9. 
EQ-5D (Quality of Life) 
105 


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11.2.4.10. Burn Specific Health Scale – Brief (BSHS-B) 
106 
11.2.5. 
Exploratory Analyses 
106 
11.2.5.1. 
POSAS 
106 
11.2.5.2. 
MVSS (target wounds) 
106 
11.2.5.3. 
MVSS (donor site scars) 
107 
11.2.6. 
Pharmacokinetic Variables 
107 
11.2.7. 
Multicenter Data 
107 
11.2.8. 
Handling of Multiple Comparisons 
107 
11.2.9. 
Interim analysis 
107 
11.2.10. Stratification 
107 
11.2.11. Analysis of Subgroups 
107 
11.2.11.1. Total TBSA ≤ 15% 
107 
11.2.11.2. Total TBSA > 15% 
108 
11.2.11.3. All target wounds full thickness 
108 
11.2.11.4. Mixed target wounds – full thickness and deep partial thickness 
108 
11.2.11.5. All target wounds are deep partial thickness 
108 
11.3. 
Third stage analysis – 24 month long-term safety follow-up (LTSFU24) 
109 
11.3.1. 
Demographics and Other Baseline Characteristics 
109 
11.3.2. 
Primary Efficacy variable 
109 
11.3.3. 
Secondary Efficacy variables 
109 
11.3.4. 
Safety variables 
109 
11.3.4.1. 
Safety Endpoint: Time to wound closure 
109 
11.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound closure
 109 


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11.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound closure
 109 
11.3.4.4. 
Adverse Events 
110 
11.3.4.5. 
Concomitant medication 
111 
11.3.4.6. 
Immunogenicity evaluation 
111 
11.3.4.7. 
Lower Extremity Function Scale (LEFS) 
111 
11.3.4.8. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
111 
11.3.4.9. 
Range of Motion (ROM) 
111 
11.3.4.10. EQ-5D (Quality of Life) 
112 
11.3.4.11. Burn Specific Health Scale – Brief (BSHS-B) 
112 
11.3.5. 
Exploratory Analyses 
112 
11.3.5.1. 
POSAS 
112 
11.3.5.1. 
MVSS (target wounds) 
113 
11.3.5.2. 
MVSS (donor site scars) 
113 
11.3.6. 
Pharmacokinetic Variables 
113 
11.3.7. 
Multicenter Data 
113 
11.3.8. 
Handling of Multiple Comparisons 
113 
11.3.9. 
Interim analysis 
113 
11.3.10. Stratification 
113 
11.3.11. Analysis of Subgroups 
114 
11.3.11.1. Total TBSA ≤ 15% 
114 
11.3.11.2. Total TBSA > 15% 
114 
11.3.11.3. All target wounds full thickness 
114 
11.3.11.4. Mixed target wounds – full thickness and deep partial thickness 
114 
11.3.11.5. All target wounds are deep partial thickness 
114 


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12. 
Reference List 
115 
13. 
Appendices 
118 
13.1. 
Definitions 
118 
13.1.1. 
General Definitions 
118 
13.1.2. 
Levels of Sedation 
118 
13.2. 
Lay-out and list of tables 
121 
13.3. 
Lay-out and list of figures 
128 
13.4. 
Lay-out and content of individual patient data listings (case wise listing) 
130 
13.4.1. 
List of AEs and SAEs 
131 
13.5. 
Details of the Amendments 
132 
13.5.1. 
Summary of Amendment of version 8 to version 9 
132 
13.5.1. 
Summary of Amendment of version 9 to version 11 
133 
 


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2. Introduction 
2.1. Background 
Optimal treatment of burn injuries requires understanding of and response to the profound 
local and systemic reactions following thermal injury.  
The treatment strategy should be planned and executed on the basis of a timely (early) 
assessment of the extent of tissue damage and remaining viable tissue available for the 
healing process. Only when the eschar is removed and the wound bed revealed, can the true 
damage be observed and assessed, and the appropriate wound closure modality prescribed 
[1] [2] [3]. 
As soon as the burn eschar is formed, it induces, within hours, a cascade of local and systemic 
pathologic changes. Dead eschar becomes heavily contaminated in two to three days, creating 
a source for local and systemic infection and sepsis [1] [4] [5] [2] [6]. Local inflammatory 
responses may lead to additional destruction of healthy surrounding tissue, extending the 
original damage. If not otherwise removed, inflammatory and autolytic processes slowly 
decompose and destroy the eschar, which will slough in approximately two weeks. The long 
inflammation based spontaneous sloughing period allows the simultaneous formation of 
advanced granulation tissue, later evolving into a heavy and deforming scar.  
Delaying the removal of the eschar increases the incidence and severity of systemic and local 
complications, especially in more extensive burns [1] [2] [4] [5] [6] [7] [8] [9] [10]. The 
decomposing eschar is a source of strong local and (if the burn is extensive) systemic 
mediators that induce inflammatory reaction and that may cause burn wound progression into 
potentially viable tissue [2] [5] [7] [9] [11]. 
Moreover, the eschar is non-resilient and forms a cocoon-like constricting shell around circular 
body parts. With increasing tissue edema, this increases the interstitial/compartment pressure, 
seriously compromising the viability of the still barely surviving skin by stretching it and 
compressing blood supply to other vital structures. An early diagnosis and response to these 
events releasing surgical escharotomy, is important and should be executed emergently. In 
this case too, delay in diagnosis and reluctance to perform surgical escharotomy may delay 


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this procedure especially in cases where experienced burn surgeons are not readily and 
immediately available [4] [12].  
To prevent eschar-related complications and to initiate the healing process, it is imperative to 
remove all of the offending eschar at the earliest possible opportunity. Eschar removal, 
“Debridement”, is the first stage of the comprehensive wound care process. There is no benefit 
in the presence of the eschar on the burn. Thus, the decision is not whether or not to remove 
an eschar but when and how. Therefore, delay or avoidance of eschar removal should have a 
specific reason.  
Estimation of burn size and depth is essential for a diagnosis-based treatment strategy, but 
cannot be accurately performed in most instances unless and until the opaque eschar has 
been completely removed.  
Immediate (within 24 hours post-burn) eschar removal may improve the potential for survival 
of the Zone of Stasis, reverse the Zone of Hyperemia and may attenuate, or avoid many of the 
systemic reactions [1] [9] [5] [2] [6] [13]. Delayed eschar removal (within the first three days) 
may not provide all the benefits of immunological and inflammatory modulation, but will reduce 
the burn bacterial load and its outcomes [4] [12] [14] [15]. Delaying eschar removal up to the 
seventh day will forfeit the local and systemic benefits, but may still prevent healing by 
secondary intention potentiating better long-term results (especially in terms of scarring) [2] [5] 
[6] [16].  
In current standard of care, removal of the eschar may be accomplished by surgery. Usually 
with tangential excision followed by split thickness autografting (TE&STSG) of the acute 
exposed debrided wound, or by non-surgical topical care that includes daily dressing changes, 
bathing, scraping, wet to dry dressing, macerating activity of bacteria, etc., until the eschar 
sloughs, leaving a clean wound bed for subsequent non-surgical or surgical wound closure 
treatment. This combination of debridement followed by surgical or non-surgical wound closure 
treatment is the basis of all burn wound care modalities.  
The choice of debridement method (non-surgical or surgical) depends on many variables such 
as the burn depth, anatomical site and size (expressed as % TBSA of the burn wound), the 
patient’s general condition, available donor site for autograft harvesting as well as the 
availability of surgical facilities and staff. Tangential excision should be carried down into the 
healthy intact tissue to make sure that no trace of the eschar remains. It is estimated that up 


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to 30–50% of healthy tissue (mainly dermis), which is essential for the spontaneous 
epithelialization potential of the wound, may be sacrificed in this procedure, thus usually 
necessitating autografting. These surgical procedures are traumatic, often long and difficult, 
require skilled personnel and sophisticated medical resources and are usually accompanied 
by bleeding [1] [2] [12] [16] [17] and heat loss [18]. The surgically excised raw wound bed 
should be covered immediately, i.e., in most cases autografted. Thus, the excision is followed 
by harvesting of autografts from intact, non-injured skin areas, skin graft transplantation, and 
care of the donor sites in addition to the original burn injury. These surgical procedures are 
performed under general anesthesia that requires pre- and post-surgical fasting and recovery. 
In most centers, caution and post surgery intensive care dictate that only a limited percentage 
of the affected areas (~15%TBSA) will be surgically debrided at one time in order to limit 
inflicting excessive stress on the patient. Thus, the decision to surgically debride a burn is not 
taken lightly. Reluctance, hesitation and doubts due to uncertain diagnosis delay the decision 
to perform surgery, extending the time to start and finish of the debridement from the optimal 
few hours to several days.  
In partial, mixed thickness, and intermediate depth wounds, and with difficult to diagnose depth 
“indeterminate” wounds, early surgical debridement will usually be avoided and a more 
conservative debridement approach using topical medications will be pursued. Such 
conservative non-surgical debridement lasts for days until the eschar decomposes or until a 
decision is taken to excise the offending, remaining eschar. The non-surgical debridement 
process involves the combined activity of topical medications, contaminant microorganisms, 
autolytic tissue processes and the inflammatory process with frequent dressing changes, 
showering, mechanical scraping of loose debris etc. The infectious-inflammatory processes 
are slow (lasting between 10-14 days) and may involve significant systemic and local 
complications. Using topical anti-bacterial or anti-inflammatory medicaments may reduce the 
infectious-inflammatory processes but will also delay eschar separation (sloughing). Locally, 
all these processes prolong the removal of the eschar and lead to additional tissue damage 
due to the death of the Zones of Stasis and Hyperemia which deepen, transforming partial 
thickness damage into a full thickness injury. The long debridement time with sustained 
inflammatory processes can lead to the formation of granulation tissue that will develop into 
heavy scars.  


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This excerpt of literature emphasizes that timely eschar removal is, for the last 40 years, the 
goal of burn wound care initiation. Physicians today are forced to choose between or combine 
two sub optimal alternatives of eschar removal; (i) the fast and efficient surgery (TE&STSG) 
with its diagnosis-dependent often prolonged initiation, non-selective, traumatic and 
demanding results or (ii) the inefficient non-surgical prolonged debridement means with their 
associated sequelae. The lack of fast and effective non-surgical eschar removal means has 
left surgery as the available SOC for deep burns.  
An optimal treatment solution would be a non-surgical, selective means for removing 
exclusively the eschar without harming the non-injured tissues immediately or nearly 
immediately after patients’ admission and stabilization, independently of the burn depth 
diagnosis. Such early removal of the eschar will enable the physician accurate visual diagnosis 
of the exposed burn wound bed. The clean exposed bed can be treated by the most 
appropriate wound closure strategies tailored for each patient and wound area in order to 
achieve optimal long-term results with minimal trauma and cost to the patient.  
The development of NexoBrid as a product for enzymatic debridement of burns started several 
decades ago. 
The safety and efficacy of NexoBrid (for burn eschar debridement) has been extensively 
investigated in 7 clinical studies [19], including a phase 3 pivotal trial (MW 2004-11-02) [20]. 
Efficacy data generated during NexoBrid clinical program demonstrated the following direct 
beneficial effects of removal of burn eschar by NexoBrid: 
1. Effective eschar removal by NexoBrid: NexoBrid removes the necrotic tissue without 
surgery, which is an imperative first step in burn care. Non-surgical effective 
debridement facilitates debridement in children, aged and of difficult skin areas (hands, 
feet, joints etc.) 
2. Selective eschar removal: NexoBrid removes the eschar in a minimally invasive 
manner that leaves the surrounding uninjured and viable tissues unharmed and thus 
allows maximization of spontaneous healing and reduces the incidence and extent of 
skin grafting [21]. 
3. Early and fast debridement: NexoBrid allows earlier initiation and successful 
completion of the eschar removal process compared to SOC, enabling preservation of 
the underlying tissue from secondary ischemia, and allowing the healthcare provider to 


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directly visually assess the burn wound bed earlier to prescribe proper subsequent 
treatment. 
4. Avoiding escharotomy surgery and its sequelae: Early application of NexoBrid may 
reduce the elevated interstitial pressure in circumferential burns and alleviate burn-
induced compartment syndrome, thus reducing the need for eschar incision. 
Indirect beneficial effects: 
1. Reduction of incidence and extent of surgery (excision and grafting) by NexoBrid 
eschar removal treatment.  
2. Autografting can be reduced by selective debridement with increased preservation of 
uninjured dermis and potential for spontaneous epithelialization. In choosing the 
approach of epithelialization over preserved dermis, autografting is reserved to close 
full thickness wounds. In addition to the benefit of reduced surgery, decreased 
autografting reduces sacrifice of the subject’s healthy uninjured skin and accompanying 
morbidity.  
3. Blood loss is minimized by reduced excisional and autografting surgery. 
2.2. Study Objective 
1. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing 
complete eschar removal as compared with Gel Vehicle,  
2. To demonstrate the efficacy of enzymatic eschar removal with NexoBrid by providing earlier 
complete eschar removal, reduction in patients’ surgical burden and its related blood loss as 
compared to SOC,  
3. To assess the safety of NexoBrid compared to SOC, including demonstration that treatment 
with NexoBrid does not cause an unacceptable level of harm on wound closure outcome and 
long-term outcomes of cosmesis and function  
2.3. References to Study Protocol 
This Statistical Analysis plan refers to the study protocol version 11 of 23 June 2016. The trial 
protocol code is MW2010-03-02. 


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2.4. Amendments 
The study was initiated under the trial protocol version 08. Since then, there have been two 
amendments (to version 9 and version 11). Details of the Amendments are provided in 
Appendix 13.5. 


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3. Study Administrative Structure 
3.1. Sponsor 
Sponsor: 
MediWound, Ltd 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
 
Represented by: 
Prof. Lior Rosenberg 
Chief Medical Officer 
MediWound Ltd. 
 
 
Keren David Zarbiv 
Director Clinical Affairs 
MediWound Ltd. 
 
 
Nimrod Leuw 
Director of QA/QC 
MediWound Ltd. 
3.2. Study Conduct 
Study Conduct (CRO): 
Dr. Marco Schwarzer 
GCP-Service International Ltd. & Co. KG 
Anne-Conway-Str. 2 
28359 Bremen 
 
 


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3.3. Statistics 
Statisticians: 
Prof. Dr. Dr. h.c. Jürgen Timm 
Dr. Martin Scharpenberg 
Competence Center for Clinical Trials Bremen 
University of Bremen 
Linzer Str. 4 
28359 Bremen 
Germany 




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5. List of Abbreviations 
abbreviation 
meaning 
ABA 
American Burn Association 
ABL 
Actual Blood loss 
AE 
Adverse Event 
AFT 
Accelerated Failure Time 
ATC 
Anatomical Therapeutical Chemical Classification 
BICS 
Burn-induced Compartment Syndrome 
BMI 
Body Mass Index 
BSHS-B 
Burn Specific Health Scale - Brief 
CS 
Clinically Significant 
DDD 
Defined Daily Dose 
DPT 
Deep Partial Thickness 
DSMB 
Data Safety Monitoring Board 
EAP 
Efficacy Assessment Period 
EAR 
Extremities at Risk 
EBV 
Estimated Blood Volume 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
ER 
Eschar Removal 
FAS 
Full Analysis Set 
FDA 
Food and Drug Agency 
FT 
Full Thickness 


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abbreviation 
meaning 
FU 
Follow up 
Hb 
Hemoglobin 
HD 
Hospital Discharge 
HEENT 
Head, Eyes, Ears, Nose and Throat 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
INR 
International Normalized Ratio 
ITT 
Intention to Treat 
KKSB 
Competence Center for Clinical Trials Bremen 
LEFS 
Lower Extremity Function Scale 
LOCF 
Last Observation Carried Forward 
LTFU24 
24 months Long-Term follow up period 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MVSS 
Modified Vancouver Scar Scale 
NCS 
Not Clinically Significant 
PDF 
Portable Document Format 
POSAS 
Patient Observer Scar Assessment Scale 
PP 
Per Protocol 
PRBC 
Packed Red Blood Cells 
PTT 
Prothrombin Time 


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abbreviation 
meaning 
ROM 
Range of Motion 
RTF 
Rich Text Format 
SAE  
Serious Adverse Event 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
SPT 
Superficial Partial Thickness 
SSD 
Silver Sulphadiazine 
STFU12 
12 months Short-Term Follow up period 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBSA 
Total Body Surface Area 
TW 
Target Wound 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell (Count) 
 
 


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6. General Definitions 
6.1. Hardware and software used 
The statistical analysis will be performed using SAS® version 9.4. The statistical report will be 
created with Microsoft Office running on hardware of Competence Center for Clinical Trials 
Bremen (KKSB). 
6.2. Reporting standards and language 
The language of the statistical report is English. This statistical analysis report is written as 
specified in the standard operating procedure (SOP) SR01 StatisticalReport of the KKSB and 
in accordance with the ICH E3 guideline (structure and content of clinical study reports). 
6.3. General format and content of tables, figures and patient data 
listings. 
Tables, figures and listings of subjects will be created in SAS® version 9.4 and be converted 
in rich text format (RTF) or portable document format (PDF). Appendix 13 contains a detailed 
description of contents and layout of the result representation. 
6.4. Quality control 
The statistical analysis plan follows the SOPs ST01 to ST06 of the KKSB. The statistical 
analysis must follow the statistical analysis plan. 
The implementation of the analysis for the primary endpoint, the secondary endpoints, the 
safety endpoint “time to wound closure” as well as the 12 months and 24 months MVSS 
assessment will be repeated by a second statistician independent from the implementation of 
the main statistician. Possible differences will be discussed together with the quality control 
and the responsible statistician (see Section 3.3). 


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7. Details of Trial Design 
7.1. General Information of Trial Design 
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. 
One hundred and seventy five subjects (175 subjects) are planned to be randomized to the 
study in a 3:3:1 ratio (NexoBrid: SOC: Gel Vehicle). The study will be conducted at sites in the 
US and out of the US.  
Following the enrollment of a patient to the study and prior to randomization, physicians will 
identify one or more TWs per patient according to the TW definitions described in Section 1.1 
of the protocol. 
All subjects’ DPT and FT burns that comply with the specified entrance criteria under 
Section 7.1.3 are intended to receive study treatment per the randomized study arm and 
therefore, must be designated as TWs. This will further allow an evaluation of the subject 
systemic safety by allowing treatment of the subject’s entire deep burns as per the randomized 
study arm. After reviewing the entrance criteria, prior to randomization, eligible subjects will be 
stratified into different groups in order to standardize and minimize bias between study groups 
in terms of efficacy and safety outcomes that are expected to be correlated to the patient total 
burn area and its depth. Please refer to Section 13.7.1 of the protocol for full description of the 
randomization procedure. 
Following the stratification, patients will be randomized as per their stratification group (see 
Section 11.1.10) 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 (please refer to Appendix 2- Pain Management Procedures of the protocol) and 
undergo wound cleansing and dressing of all wounds with antibacterial solutions (as specified 


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in Section 8.1 of the protocol). Following wound cleansing and antibacterial treatments, 
subjects will undergo the eschar removal process as per treatment assignment (NexoBrid, 
SOC or Gel Vehicle, following randomization) as further described in APPENDIX 16- Treatment 
Diagram of the protocol. 
Subsequent to complete eschar removal, all wounds will be assessed and treated 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 complete wounds and donor sites closure. Following 
wound closure confirmation visit, subjects will be followed up at 1, 3, 6, 12, 18 and 24 months 
post last wound closure confirmation for long-term outcomes evaluation. 
7.1.1. 
Study medication 
7.1.1.1. 
Topical arms 
7.1.1.1.1. NexoBrid 
NexoBrid is presented as lyophilised Bromelain powder and gel vehicle for preparation of a gel 
for cutaneous use, including concentrate of proteolytic enzymes enriched in Bromelain as the 
active component. Following mixing of the powder with the gel vehicle, each gram of the 
prepared product contains 0.09 g partially purified Bromelain. Partially purified Bromelain is a 
mixture of enzymes extracted from the stem of Ananas comosus (pineapple plant).  
7.1.1.1.2. Gel Vehicle 
The same Gel Vehicle used in the preparation of NexoBrid will be used as negative control. 
7.1.1.2. 
Standard of Care 
SOC arm will include surgical and/or non-surgical eschar removal procedures.  
Surgical procedures will include tangential/ minor/ avulsion/ Versajet/ dermabrasion excisions. 
Non-surgical procedures will include the application of collagenase ointment (e.g. Santyl), 
antimicrobial solutions (e.g. Dakin’s Solution, Sulfa-Nystatin Solution), ointments/creams (e.g. 
Bacitracin, Polysporin, Silvadene) and/or Silver dressings (e.g. Mepilex Ag, Aquacel Ag, 
Acticoat). 


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The need of either non-surgical or surgical procedures will be determined by the burn 
specialists and can be repeated as needed until complete debridement is achieved. 
7.1.2. 
Intended dosage and duration of treatment 
7.1.2.1. 
NexoBrid 
Two grams or five grams of NexoBrid sterile powder are mixed in 20 grams or 50 grams of 
sterile Gel Vehicle (ratio of 1:10), respectively to obtain sterile NexoBrid Gel. NexoBrid Gel is 
applied to the burn wound at a dose of 2 g NexoBrid sterile powder mixed with 20g sterile Gel 
Vehicle per 1% of TBSA (~ surface of an adult palm) for four hours (or 5 g NexoBrid sterile 
powder mixed with 50g sterile Gel Vehicle per 2.5% of TBSA). The NexoBrid powder and the 
Gel Vehicle are to be mixed at the patient bedside ≤ 15 min prior to use.  
NexoBrid should not be applied to more than 15% TBSA in one session.  
NexoBrid may be applied for a second time to the same burn area, if eschar removal from the 
target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. NexoBrid may only be applied twice to the same burn 
wound area. 
7.1.2.2. 
Gel Vehicle 
Twenty (20) grams or 50 grams of sterile Gel Vehicle will be applied on the burn skin. Gel 
Vehicle is applied to the burn wound at a dose of 20 grams sterile Gel per 1% of TBSA (~ 
surface of an adult palm) or 50 grams per 2.5% TBSA for four hours.  
Gel Vehicle should not be applied to more than 15% TBSA in one session.  
Gel Vehicle may be applied for a second time to the same burn area, if eschar removal from 
the target wound after the first application is not complete but at least 50% of the eschar was 
removed during the first application. The Gel Vehicle may only be applied twice to the same 
burn wound area. 
7.1.2.3. 
Standard of Care 
No more information on intended dosage or duration of treatment was specified in the protocol 
for the Standard of Care arm than that already given in Section 7.1.1.2.  


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7.1.3. 
Study population and choice of study invitee 
7.1.3.1. 
Inclusion Criteria - Patient level 
1. Males and females; ≥ 18 years of age,  
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.  
7.1.3.2. 
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 include face, perineal or genital),1  
All planned target wounds (TWs) should meet the following criteria:  
2. SPT areas 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.  
7.1.3.3. 
Exclusion Criteria - Patient level 
1. Patients who are unable to follow study procedures and follow up period,  
2. Modified Baux index2 ≥ 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) as described in section 11.8 of the protocol,  
                                               
1 All these wounds which are in line with this criteria should be defined as target wounds (TWs) and 
treated per randomization   
2 Modified Baux score will be calculated based on the %TBSA affected by burns, age of the patient and 
the presence of smoke inhalation injury; Age + Percent Burn + 17 * (Inhalation Injury, 1 = yes, 0 = no). 


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7. The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate (AgNO3),  
8. Patients with pre-enrollment wounds which are covered by eschar heavily saturated 
with iodine or by SSD pseudoeschar (e.g. pseudoeschar as a result of >12 h 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 burns area of up to 15% TBSA or BMI 
greater than 34.0 kg/m2 in patients with burns area of more than 15% %TBSA,  
15. ASA greater than 2 (Appendix 13- ASA classification system of study protocol),  
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, severe edema and/or lymphedema, regional lymph nodes dissection, 
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 Enrollment in 
any investigational drug trial within 4 weeks prior to screening,  
23. Current (within 12 months prior to screening) severe alcohol or drug use disorder (see 
definition in section 1.1 of study protocol),  


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24. Prisoners and incarcerated,  
25. Patients who might depend on the clinical study site or investigator.  
7.1.4. 
Drop-out criteria 
After screening and prior to treatment any changes in the patient's medical condition should 
be assessed. The patient should be excluded from treatment if these changes represent 
deterioration in his/her condition which may affect the patient's safety and/or suitability for the 
study (e.g. exclusion criteria).  
Throughout the course of a subject's participation in the study, he/she may be removed from 
the study as follows:  
· 
Whenever it is necessary to safeguard his/her welfare as judged by the Principle 
Investigator,  
· 
Participation in another investigational drug trial,  
· 
Subjects who express a desire to withdraw from the study,  
· 
Subjects with EAR identified post randomization but prior to treatment.  
The reason for any subject withdrawal from the study should be recorded in the eCRFs and 
the occurrence should be reported to the sponsor. Early termination visit should include final 
assessments as in the Hospital Discharge visit, as applicable (please refer to Section 8.7 of 
the study protocol).  
Discontinued subjects will not be replaced.  
When a subject is removed from the study treatment, he/she will receive treatment according 
to the standard of care as appropriate in the investigative site and will be followed up according 
to the study schedule, in accordance with patient’s availability. 
7.1.4.1. 
Stopping rules (apply for NexoBrid or Gel Vehicle arms only) 
Treatment (eschar removal) should be stopped following a safety concerns raised by the 
treating physician or if a patient expresses his desire to withdraw from the study. In addition, 
in the following situations: 


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Burn Induced Compartment Syndrome (BICS) Monitoring and Diagnosis 
All circumferential wounds should be closely monitored during treatment for signs of 
improvement or deterioration that may require escharotomy. If clinical assessment and SpO2 
monitoring are possible, they will be done continuously and recorded in the eCRFs every 2 
hours. If such assessment is not practical, direct pressure will be measured every 2 hours from 
start of the eschar removal. The eschar removal process shall be discontinued (escharotomy 
may be performed at the discretion of the physician in any of the following cases: 
· 
Increasing interstitial/compartment pressure >30 mmHg  
· 
Difference of >20 mmHg of diastolic pressure between the opposite uninjured extremity  
· 
Decreased SpO2 reading during treatment with difference of >6% compared to a non 
injured extremity or deterioration of clinical signs  
· 
Deterioration of any of the 5 “P” signs: Pain, Paralysis, Pulselessness, Pallor, 
Paraesthesia  
Since in such cases the eschar removal procedure will not be completed as planned, such 
patients (if any) will still be part of the full analysis set (FAS, see Definition in Appendix 13.1.1) 
and any missing data usually collected during eschar removal (e.g. time to end of eschar 
removal, etc.) will be handled as missing data according to the protocol.  
In case of 3 consecutive cases where there is a need to disrupt the dressing and perform a 
surgical escharotomy, enrollment will be halted and a DSMB shall be convened to:  
· 
assess the severity of the phenomenon in a closed session  
· 
Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences  
As discussed above, increased interstitial/compartment pressure is a common medical 
condition in circumferential deep burns and its detection and resolution is part of daily standard 
of care. The only difference in the treatment of the patients in the study is during the eschar 
removal stage as dictated by randomization. 
Coagulopathy during or within 24 hours of eschar removal 
It is evident that during the first 48 hours post injury there is deterioration in coagulation 
parameters in burn patients [22]. In addition, some burn patients are treated with 


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anticoagulants after admission (in some burn centers all patients are treated with 
anticoagulants). Due to these facts, any stopping rule concerning coagulopathy after topical 
debriding agent application must take these factors into consideration.  
Enrollment will be halted and a DSMB will convene if 3 subjects develop the following signs 
which have been defined as life threatening coagulopathy in trauma patients:  
INR>2 or a PTT>2 times the normal range [23], in cases where the patient is not receiving 
anticoagulants that can explain the coagulopathy.  
A DSMB shall be convened to assess in a closed session the following:  
· 
The relationship between coagulopathy and the treatment arm  
· 
The severity of the phenomenon  
· 
Recommend on appropriate corrective measures, as applicable to prevent such 
reoccurrences  
DSMB investigation will consider patients’ medical history, including any anticoagulants given 
to the patient prior to start of treatment. 
Post treatment diagnosed infection (until complete wound closure) 
Following the eschar removal treatment, in case 3 subjects develop infections listed in Section 
11.9 of the study protocol and are assessed as related to the treatment arm (possibly, probably 
or related as defined in section 12.1 of the study protocol), enrollment will be halted and a 
DSMB will convene in close session to investigate cases reported and their relatedness and 
severity.  
In all the above 3 described cases, enrollment may continue in accordance with DSMB 
conclusions. 
7.1.5. 
Concomitant medication and treatment 
Concomitant medications will be recorded throughout the study, starting from signing on ICF 
and will include those prescribed for common burn management practice. Any record should 
include dose, frequency, route, start and stop date and indication.  


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Unit of blood transfused (whole blood or blood packed cells) with the appropriate volume will 
be captured for the entire patient’s duration in the study and recorded in the concomitant 
medications form. Any analgesia and anesthesia administered per subject will be recorded in 
the eCRFs. Incidence & number of procedures for wound care requiring anesthesia will be 
analyzed. 
7.2. Trial schedule 
The healing and care of the burn wound may be divided into the three distinctive phases:  
1. Eschar removal treatment phase (until complete eschar removal)  
2. Wound management (until complete wound closure)  
3. Scar modulation and maturation  
These phases are common to the care of all wounds and are well defined in acute wounds 
such as burns.  
In this study, these phases and their treatment strategy are equal for all arms, NexoBrid, SOC, 
and Gel Vehicle, following the ABA white paper recommendations [24]. 
The total duration of the study treatment and follow up period of each participating subject is 
expected to be 25 months: following the Eschar removal procedure, each subject will be 
followed up weekly (Weeks 1, 2, 3 and 4 etc.) until complete wound closure is achieved and 2 
weeks later for wound closure confirmation, for each of the subject's TWs. Long-term follow-
up visits will be performed at 1, 3, 6, 12, 18 and 24 months post last wound closure confirmation 
visit (for details see Table 1). 
 


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Table 1: Treatment flow chart - all arms3 
#- If applicable  
* Weekly FU assessments will be performed every 7± 2 days from start of treatment until complete wound closure. Long-term FU will be performed 1,3,6,12,18 and 24 M after 
last wound closure confirmation.  
**First treatment session will include any procedure for eschar removal: the NexoBrid/ /Gel Vehicle/Surgical or non-surgical procedure, as per randomization arm  
** Procedure can be either surgical or non-surgical. A whole period of continuous dressing changes (from first coverage application to last coverage application) is considered 
as one non-surgical procedure, assessments should not be repeated for each dressing change; Pre procedures assessments refer only to surgical procedures. Post procedures 
assessments refer to any surgical procedures and for non-surgical procedure only if it is the last procedure 
Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
Inform Consent signing 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Burn History5 
X 
 
 
 
 
 
 
 
 
ConMeds & AEs 
X 
X 
X 
X 
X 
 
X 
X 
X 
Physical examination6 
X 
 
 
 
 
 
X 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
Post S 
Post  
X 
 
 
 
 
Pain assessment 
X 
X 
4h post R  
Pre and 4h post  
X 
 
 
 
 
Photograph of TWs 
X7 
X 
Post S 
Pre & Post  
 
Pre & Post  
 
X 
X 
                                               
3 This table differs from the corresponding table in the protocol. Minor corrections were performed. 
4Wound Management will include any, post complete eschar removal additional excisions, Autografts, and donor site data if relevant. 
5 Data captured will include burn etiology, mechanism of injury, place of injury, treatments prior to admission and general description of the burn wound (anatomical locations 
and description of the eschar (such as: white, moist, dry, gray, charcoal, etc.), % TBSA assessments and depth 
6 Physical examination will include height and weight. Height will be taken only once, at screening. 
7 Photos should be taken after cleansing 


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Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
Clinical assessment of the 
burn8 
X 
X 
Post S 
Post  
 
Post  
 
X 
 
Local lab - HbA1C, WBC, 
βhCG 
X 
 
 
 
 
 
 
 
 
Central lab hematology/ 
biochemistry tests & 
Urinalysis 
 
X 
4 h Post R  
Pre & 4 h Post  
 
 
 
 
 
Central lab Hematology 
 
 
 
 
 
1h pre & 4 h post 
 
 
 
Cleansing including at 
least 2h soaking) 
X 
# 
 
 
 
 
 
 
 
Fluid balance9 
X 
X 
X 
X 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Local lab Wound culture 
 
X 
Post S 
Pre &Post  
 
 
 
 
 
Local lab Blood culture 
 
X 
4h Post R  
4 h Post 
 
 
 
 
 
12-Lead ECG (if feasible) 
 
60, 40, 20 
min pre 
treatment 
During: 0.5, 2,4h from 
start of first application 
only 
During: 0.5, 2, 4h  
from start of first 
treatment only 
12, 24, 48h 
 
 
week 1 
 
                                               
8Clinical assessments will include % TBSA per depth, % eschar removed, % excised, % autografted, % wound epithelialization (TW and donor site, if relevant), % graft take as 
relevant. 
9 Daily fluid balance will be monitored for 7 days from injury or until hospital discharge, whichever comes first for patients with catheter.  


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Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
PK (for a subset of 32 
NexoBrid Pts) 
 
X 
During:0.5, 2, 4h from 
start of first application 
 
12,24,48, 72h 
 
 
 
 
Immunogenicity 
assessment 
(NexoBrid patients only) 
 
X 
 
 
 
 
 
weeks 
4,810 
Long-term FU:  
6, 24 
Local lab PTT & INR  
 
X 
4 h post R - first 
application only 
4 h post- first 
treatment only 
24,48h 
 
 
 
 
Circumferential extremity 
wounds monitoring11 
X 
X 
during and post R (4 
hours from start) 
1h pre & post  
 
 
 
 
 
Eschar Removal treatment 
 
 
X 
X 
 
 
 
 
 
Coverage 
 
 
 
Start and end date , 
type of primary 
dressing 
 
Type of primary 
dressing& 
frequency 
 
 
 
                                               
10 In case that 8 weekly visit is not performed, this assessment should be taken on the relevant weekly/first visit as close as possible to 8 weeks. 
11 The Extremities At Risk (EAR) burns prone to develop BICS will be identified at screening and excluded. Monitoring for the development of EAR in circumferential extremity 
wounds at the above specified timelines will be done. During each topical application (NexoBrid or gel Vehicle), clinical assessment and SpO2 monitoring will be done 
continuously. If such assessment is not practical, direct pressure will be measured every 2 hours from start of eschar removal. Direct pressure will be measured before and 
after each eschar removal procedure and additional surgical procedures  


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Parameter 
Screening 
tests 
Baseline within 
1 h Pre First 
treatment 
session - All 
arms 
Topical arms (NexoBrid or 
Gel Vehicle): (refer to first 
and second application). 
S=Soaking, R=Removal 
SOC procedures** 
(including additional 
procedures in the topical 
arms) 
Daily 
assessments 
Wound 
Management & Re-
admissions4- 
surgical procedures 
assessment 
HD or premature 
discontinuation visit 
Weekly 
FU* 
Long-Term  FU 
(1, 3, 6,12,18 & 
24 months)* 
Wound closure 
confirmation12 
 
 
 
 
 
 
 
X 
Long-term FU:  
1, 3 
Cosmesis, Function and 
Quality Of Life13 
 
 
 
 
 
 
 
 
X 
Scar-modulating 
procedures and scar 
 
 
 
 
 
# 
 
 
# 
Blood transfusion (units & 
volume) 
# 
# 
# 
# 
# 
# 
# 
# 
# 
Histological biopsy 
# 
# 
# 
# 
# 
 
# 
# 
# 
 
 
                                               
12 Wound closure should be confirmed 2weeks after the initial wound closure assessment for each TW. 
13Cosmesis will be evaluated in donor site scars as well 


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7.3. Criteria for evaluation 
7.3.1. 
Demographic data and other baseline characteristics 
The following demographic data will be documented at screening/baseline: 
· 
Date of birth 
· 
Gender 
· 
Ethnicity 
· 
Race 
· 
Serum Pregnancy Test (βHCG) 
Furthermore, at screening the inclusion and exclusion criteria will be collected. 
At baseline the following parameters will be documented. 
Burn history / description: 
· 
Date and time of injury 
· 
Etiology of injury (Fire/Flame, Scald, Contact) 
· 
Place of injury (Outdoors, Indoors, Car, Other) 
· 
Information whether patient was transferred from another facility 
· 
Date and time of primary admission 
· 
Date and time of current admission 
General wound description: 
· 
Wound number 
· 
Anatomical location 
· 
%TBSA of 2° SPT Burns 
· 
%TBSA of 2° DPT Burns 
· 
%TBSA of 3° FT Burns 
· 
Information whether the respective wound will be designated as TW 
· 
Information whether a wounded extremity is circumferential 
· 
Extremities at risk 


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· 
Information whether eschartomy had been performed prior to randomization 
· 
Eschar description 
· 
Information whether cleansing was performed 
· 
Information whether all superficial keratin (blister) were removed from wound 
Target wound identification: 
· 
Target wound number 
· 
Anatomical location 
· 
%TBSA of 2° SPT Burns 
· 
%TBSA of 2° DPT Burns 
· 
%TBSA of 3° FT Burns 
· 
Information whether the wound was treated prior to enrollment 
Information needed for randomization: 
· 
Total wounds TBSA % per patient 
· 
TWs DPT total area (% TBSA) 
· 
TWs FT total area (% TBSA) 
· 
Overall TWs depth per patient 
· 
Overall TW area (SPT + DPT + FT) 
· 
Randomization result (treatment) 
· 
Date of randomization 
Circumferential extremity wounds: 
· 
Information whether any treated TWs were circumferential extremity wounds 
· 
Target wound number 
· 
Information whether pressure measurement was done 
· 
Interstitial pressure (mmHg) 
· 
Date and time of measurement 
Physical examination: 
· 
Height (cm or inch) 
· 
Weight (kg or lb) 
· 
BMI 


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Furthermore, for each of the following body systems 4 categories are documented 
(normal, abnormal-NCS [not clinically significant], abnormal-CS [clinically significant], 
not done). In case of abnormal findings, they have to be documented. If abnormality is 
present for another body system, this has to be documented, too. Reasons for the 
category "not done" have to be documented. 
· 
Head, eyes, ears, nose and throat (HEENT) 
· 
Respiratory system 
· 
Cardiovascular system 
· 
Abdomen 
· 
Musculoskeletal / Extremities 
· 
Neurological 
· 
Lymph Nodes 
Vital signs: 
· 
Temperature (incl. unit and method of measurement) 
· 
Heart rate (beats/min) 
· 
Respiratory rate (breaths/min) 
· 
Systolic and diastolic blood pressure (mmHg) 
· 
Assessment of vital signs (normal, abnormal-NCS, abnormal-CS) 
Pain assessment: 
· 
Pain measured via visual analogue scale (VAS, mm from the left point of the scale) 
· 
Assessment of pain (normal, abnormal-NCS, abnormal-CS) 
Local laboratory: 
· 
Leukocyte count (WBC) 
· 
Assessment of leukocyte count (normal, abnormal-NCS, abnormal-CS) 
· 
Information whether patient is diabetic 
· 
HbA1c (%) 
Information on infections as well as the medical history will be recorded. 


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7.3.2. 
Efficacy evaluation 
7.3.2.1. 
Primary target variable 
The following primary endpoint will be evaluated at a ‘per patient’ level i.e., on the full set of 
target wounds treated for each patient (please refer to protocol Section 1.1 for target wound 
definition) in accordance with the study protocol:  
Incidence of complete eschar removal (see definition in Appendix 13.1.1) in the topical 
arms (NexoBrid and Gel Vehicle): Incidence of complete eschar removal (ER) will be based 
on the assessment of the blinded assessor at the end of the topical agent soaking period. In 
cases where 2 applications are performed, complete ER will be based on the assessment at 
the end of the topical agent soaking period following the 2nd application. 
7.3.2.2. 
Secondary target variables 
The following secondary endpoints will be evaluated in this study: 
Reduction in surgical needs 
Reduction of surgical need for excisional eschar removal is measured by an analysis of 
incidence of surgical eschar removal (tangential/ minor/ avulsion/ Versajet and/or 
dermabrasion excision). 
Earlier eschar removal 
The time when complete eschar removal has been achieved will be assessed for each patient 
on the entire eschar removal period. For definition of complete eschar removal, see 
Appendix 13.1.1. 
Blood loss 
Blood loss incurred during the eschar removal procedures will be evaluated. Actual blood loss 
will be measured by considering the estimated blood loss, changes in Hemoglobin during the 
eschar removal procedures and the amount of units of blood transfused. Blood loss (Actual 
Blood Loss, ABL) will be calculated using the following formula [25]: 


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 !" = #!$ % &'()*+,-* . '(/+0*-1
&'()*+,-* 2 '(/+0*-1 3
4
2 $56 2 7
8 $9: 
EBV= Estimated blood volume is assumed 70 cm3/Kg  
(Hbbefore- Hbafter)= Changes in Hb following each eschar removal procedure  
VWB= Volume [mL] of whole blood transfused 
VPC= Volume [mL] of packed red blood cells transfused. 
The ABL will be summed over all procedures carried out to remove eschar, with the Hb 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during all debridement 
procedures and 4 hrs later i.e. the before-after periods that are spanned by these Hb 
measurements. 
Additionally, ABL will also be computed using the formula above, but over the whole eschar 
removal period (not procedure wise) i.e. the eschar removal process will be considered as one 
continuous procedure. Therefore, only the Hemoglobin value before the first eschar removal 
procedure and after the last procedure will be used and all blood transfusions performed 
between these measurements will be included. 
Analyses with both blood loss values will be conducted. However, some missing values are 
expected. The analysis with less missing values will be regarded as more reliable and is 
therefore considered the main analysis. The other analysis is considered supportive. 
7.3.3. 
Safety evaluation 
7.3.3.1. 
Time to complete wound closure 
Time to reach complete wound closure (definition see Appendix 13.1.1) as assessed by the 
blinded assessor and marked in the eCRFs will be assessed in days, starting from 
randomization date. 
7.3.3.2. 
Cosmesis and function at 12 months from wound closure confirmation 
Cosmesis and Function assessment will be performed based on the Modified Vancouver Scar 
Scale (MVSS) at 1, 3, 6, 12, 18 and 24 months after the wound closure confirmation visit by a 


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burn wound specialist who is masked to randomized wound treatment and to the other 
outcome assessments of the same wound. Table 2 gives an overview of the MVSS. 
 


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Table 2: Modified Vancouver Scar Scale (MVSS) 
Pigmentation 
Pliability 
Height 
Vascularity 
Pain 
Pruritus 
(0) Normal 
(0) Normal 
(0) Flat 
(0) Normal 
(0) None 
(0) None 
(1) Hypopigmentation 
(1) Supple-flexible with minimal resistance 
(1) <2mm 
(1) Pink 
(1) Occasional 
(1) Occasional 
(2) Mixed 
(2) Yielding- giving way to pressure 
(2) 2-5 mm 
(2) Red 
(2) Requiring 
medication 
(2) Requiring 
medication 
(3) Hyperpigmentation 
(3) Firm- inflexible, not easily moved, 
resistance to manual pressure 
(3) >5mm 
(3) Purple 
 
 
 
(4) Banding-rope-like tissue that blanches 
with extension of the scar 
 
 
 
 
(5) Contracutre-perment shortening of scar, 
producing deformity or distortion  
 
 
 
 
 
 


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7.3.3.3. 
Cosmesis and function at 24 months from wound closure confirmation 
See section 7.3.3.2. 
7.3.3.4. 
Adverse Events 
For each AE the following information will be determined: 
· 
AE description 
· 
AE is an infection (yes, no, unknown) 
· 
onset date and time 
· 
outcome date and time 
· 
outcome (resolved, resolved with sequelae, not resolved, death) 
· 
intensity (mild, moderate, severe) 
· 
action taken regarding study drug (yes, no) 
· 
relation to study drug (not related, remotely related, possibly related, probably related, 
related) 
· 
treatment required (none, medication, surgery, hospitalization, other) 
· 
seriousness (serious, not serious) 
The following definitions to assess the relationship between an adverse event and the study 
drug is used: 
· 
Not Related: The event is clearly related to other factors such as a patient's clinical 
state, therapeutic interventions or concomitant medications.  
· 
Remotely Related: The event was most likely produced by other factors such as a 
patient's clinical state, therapeutic interventions or concomitant medications and does 
not follow a known response pattern to the study drug.  
· 
Possibly Related: The event has a reasonable temporal relationship to study Drug 
administration and follows a known response pattern to the study Drug. However, a 
potential alternate etiology may be responsible for the event. The effect of Drug 
withdrawal is unclear. Rechallenge information is unclear or lacking.  
· 
Probably Related: The event follows a reasonable temporal sequence from the time of 
Drug administration and follows a known response pattern to the study Drug and cannot 
be reasonably explained by other factors. There is a reasonable response to withdrawal 
of the Drug. Re-challenge information is not available or advisable.  
· 
Related: The event follows a temporal sequence from the time of Drug administration 
and follows a known response pattern to the study Drug and either occurs immediately 


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following study Drug administration, or improves on stopping the Drug, or reappears 
on repeat exposure. 
For the assessment of the intensity of the AE the following definitions should be used: 
· 
Mild Adverse Events: A mild adverse event is one that the symptoms are barely 
noticeable to a patient. It does not influence performance or prevent a patient from 
carrying on with normal life activities.  
· 
Moderate Adverse Events: A moderate adverse event is one that the symptoms make 
a patient uncomfortable and causes some impairment to normal life activities. 
Treatment for symptom(s) may be required.  
· 
Severe Adverse Events: A severe adverse event is one that the symptoms cause 
severe discomfort to a patient and severely limits the patient's normal daily activities. 
Treatment for symptom(s) is given. Note that serious and severe are not synonymous. 
A serious adverse event must fulfill the requirements listed in the definition below. 
A serious adverse event is an adverse event that is:  
· 
fatal 
· 
life-threatening  
· 
results in persistent or significant disability/incapacity  
· 
requires or prolongs inpatient unexpected hospitalization  
· 
is a congenital anomaly or birth defect or  
· 
is a medically important event. 
7.3.3.5. 
Laboratory assessments and vital signs 
The following tests described below are performed. Any abnormal findings must be assessed 
for clinical significance – Abnormal NCS or Abnormal CS:  
Serum chemistry, hematology and urinalysis testing will be performed at a central laboratory 
during the eschar removal phase. Any additional procedures during the wound management 
phase require hematology tests, as described in the protocol, and will be performed using 
Central lab. Pregnancy testing, HbA1c, leukocyte count (at Screening, in addition to central 
lab hematology), wound cultures, blood cultures, PTT/INR and biopsies will be performed 
locally on-site.  
The following tests are performed in special laboratories: Pharmacokinetics test, 
Immunogenicity evaluation and evaluation of QT prolongation (using multiple ECG tests).  
Serum Chemistry:  


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Urea, Creatinine, Glucose, Total Bilirubin, Cholesterol, Triglycerides, Uric Acid, Total Protein, 
Albumin, Globulin, Calcium (Ca++), Phosphorous, Sodium (Na+), Potassium (K+), Chloride 
(Cl-), Alkaline Phosphatase, SGOT (ASAT), SGPT (ALAT), LDH.  
Hematology:  
Hemoglobin, Hematocrit, RBC, MCV, MCH, MCHC, Platelets, Leukocyte count (WBC) with 
differential count (absolute numbers). 
HbA1c will be assessed at a local lab at Screening for diabetic patients as captured during the 
medical history.  
PTT and INR will be tested at a local lab pre treatment and 4 hours after start of eschar 
removal.  
Pregnancy Testing:  
A serum pregnancy (βHCG) will be performed at a local lab for women of child bearing 
potential.  
Urinalysis:  
pH, Ketone, Specific gravity, Protein, Glucose, Bilirubin, Microscopic examination.  
Qualitative Wound Culture:  
Test burn wound for microbial flora (swab).  
Blood Culture:  
Test blood for microbial flora.  
Diagnosis of Invasive Burn Wound Infection is based on Quantitative (Histological) Wound 
Culture Biopsy:  
Infection should be assessed clinically by symptoms and signs that include local burn wound 
signs purulent drainage, erythema, warmth, exudation, odor, pain, and systemic signs that may 
or may not be related to the burn wound, such as fever, and leukocytosis as well as wound 
size and time to wound healing. Histological Biopsy may be performed to rule out suspicion of 
a clinical invasive burn wound infection (please refer to Appendix 8- Biopsy & Histologic 
Assessment Method) [26].  
Clinical Invasive Burn Wound Infection will be defined when an Invasive Burn Wound Infection 
is diagnosed by quantitative bacterial count of >105 organisms per gram of tissue and 
histological signs of bacterial invasion of healthy tissues will define a positive invasive burn 


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wound infection. At least one of the following histological signs of invasive burn wound infection 
is required:  
· 
Microorganisms presence in viable unburned tissue  
· 
Small vessel thrombosis and ischemic necrosis of unburned tissue  
· 
Inflammation evident in unburned tissue  
· 
Hemorrhage in uninjured tissue  
· 
Evidence of microbial proliferation  
· 
Variable migration of microorganisms along hair follicle and sweat glands  
· 
Dense growth of nonviable-viable tissue interface (subeschar space)  
· 
Intracellular viral inclusion  
· 
Light microscopy  
· 
Type A Cowdry bodies: herpes simplex virus-1  
· 
Owl's eye inclusion bodies: cytomegalovirus  
· 
Electron microscopy  
· 
Intracellular virions  
Vital signs (temperature, pulse, blood pressure and respiration rate) will be completed 24 
hours prior to start of treatment and once daily from start of eschar removal until hospital 
discharge. 
7.3.3.6. 
Additional safety endpoints 
Additional safety endpoints to be evaluated in this study are: 
· 
pain assessment (using VAS and as reported as AEs) 
· 
units (and volume) of blood transfusion given during hospitalization 
· 
Immunogenicity evaluation for NexoBrid patients 
· 
Incidence of increased interstitial/compartment syndrome 
· 
Incidence of QT prolongation 
· 
Extent of analgesia, anaesthesia and antibiotic use 
· 
Rates 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) 
· 
Long-term functionality evaluation of the extremities using the ‘Lower Extremity 
Functional Scale’ 
· 
'QuickDASH' questionnaires 


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· 
'Range Of Motion' measurements 
· 
Long-term Quality of Life using EQ5D and Burn Specific Health Scale- Brief (BSHS-B) 
7.3.4. 
Exploratory analyses 
1. Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal (and % TBSA excised of the treated TW) (tangential/ minor/ 
avulsion/ Versajet and/or dermabrasion excision),  
2. Additional Cosmesis and Function evaluation will be performed using the Patient and 
Observer Scar Assessment Scale (POSAS) version 2.0 at 1, 3, 6, 12, 18 and 24 months 
after the wound closure confirmation visit by a burn wound specialist who is masked to 
randomized wound treatment and to the other outcome assessments of the same wound. 
POSAS version 2.0 was published in 2005 in Plast. Reconstr. Surg. 116: 514-522 by van 
de Kar et al. The POSAS consists of two parts: a Patient Scale and an Observer Scale. 
Both scales contain six items that are scored numerically and make up a ‘Total Score’ of 
the Patient and Observer Scale. The POSAS has been developed for all types of scars 
and has been tested in linear scars, burn scars and keloids and was found to be validated 
and reliable [27].  
Each item of both scales has a 10-point score, with 10 indicating the worst imaginable scar 
or sensation. The lowest score is ‘1’, and corresponds to the situation of normal skin 
(normal pigmentation, no itching etc). The score goes up to the worst imaginable. The Total 
Score can be simply calculated by summing up the scores of each of the six items. The 
Total Score will therefore range from 6 to 60 (observer and patient) and 12-120 in total. 
POSAS will be evaluated for all measurement times mentioned above,  
3. Additional Cosmesis and Function evaluation will be performed using the Modified 
Vancouver Scar Assessment Scale (MVSS) measurements obtained at 1, 3, 6 and 18 
months, 
4. Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds,  
5. Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds (measured immediately following eschar removal),  
6. Reduction in surgical need as measured by analysis of incidence of surgically harvested 
donor sites wounds,  
7. Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site wounds,  


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8. Blood loss following eschar removal procedures using changes in Hematocrit following 
eschar removal procedures,  
9. Cosmesis MVSS and POSAS will be used to assess the quality of the donor sites scars,  
10. PK evaluation for a subset of NexoBrid patients (as described in section 11.21 of the 
protocol)  
11. Autograft related parameters.  
11.1. 
Efficacy and safety analyses for early and late grafted wounds (for definition see 
Appendix 13.1.1) 
11.2. 
Total number of target wound grafting procedures  
11.3. 
Incidence of repeated/additional grafting procedures  
11.4. 
Area of repeat grafting  
12. Duration of hospitalization  


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8. Handling of protocol violations 
Before database lock and statistical analysis, possible protocol violations will be discussed by 
data management, sponsor, PI and his/her proxy and the statisticians and classified as minor 
or major violations. The list with all protocol violations will be prepared by the data 
management. 
A protocol violation will be classified as major if 
· 
the treatment differs from the planned treatment (randomization arm), or 
· 
the documentation of a primary observation was not done or is different from the study 
protocol: i.e. assessment was not done by a blinded assessor (assessment by blinded 
assessor from photos is acceptable), or 
· 
there was drug misuse (this may include application time deviated in 25% or more, 
deviation of more than 20% in the TBSA area treated in one session at a time, if 
relevant, error in drug preparation (e.g. 2g mixed in 50g), storage temperature below -
2°C - 8°C or >24h at room temperature and used without any stability confirmation by 
sponsor), or 
· 
the first blinded assessor was unblinded, or 
· 
treatment started more than 5 days from injury, or 
· 
one of the following inclusion criteria is violated: 
o Males and females; ≥ 18 years of age,  
o Thermal burns caused by fire/flame, scalds or contact,  
o Patient total burns area ≥ 3% DPT and / or FT,  
o Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or FT in depth,  
o Informed consent can be obtained within 84 hours of the burn injury 
o At least one wound (a continuous burn area) that is ≥0.5% TBSA (DPT and/or 
FT) (this minimal wound size should not include face, perineal or genital) 
o Wound’s blisters can be removed/unroofed, as judged by the investigator 
· 
one of the following exclusion criteria is met: 
o Patients with burned charred fingers, 3rd degree in depth and possibly devoid 
of circulation 
o Patients with abraded wound/s that cannot be treated by an enzymatic debrider 
application (NexoBrid) 
o Patients with electrical or chemical burns 
o The following pre-enrollment dressings: a. Flammacerium, b. Silver Nitrate 
(AgNO3) 


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o 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 h SSD treatment), 
o Patients with pre-enrollment escharotomy 
o Enrollment in any investigational drug trial within 4 weeks prior to screening 
In all other cases protocol violations will be classified as minor. 
 


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9. Populations Analyzed 
The following sample size calculation is taken from the protocol. 
9.1. Sample Size 
The following sample size calculations are based on the consideration of the primary and two 
secondary endpoints for this study.  
Estimated effects of NexoBrid from study MW2004-11-02 were used to design the study with 
adequate statistical power using the following steps.  
(a) Sample size calculations were based on study MW2004-11-02;  
(b) The effect of NexoBrid versus standard of care was estimated together with the standard 
error of the estimate; the effect of NexoBrid versus gel was estimated based on study 
MW2002-04-01, previous phase II study, which included 35 patients treated with gel vehicle.  
The size of the effect to be detected in this study, MW2010-03-02, was taken as the previous 
estimate decreased by half its standard error, in order to use a conservative value. 
9.1.1. 
Primary Endpoint: Incidence of complete eschar removal 
(NexoBrid vs. Gel) 
Estimated proportion achieving complete eschar removal (for further definition and explanation 
see section 7.3.2.1) in all TWs from study MW2004-11-02 (analyzed as post hoc): NexoBrid 
0.595  
Standard error = 0.057  
Anticipated proportion achieving complete eschar removal using NexoBrid: 0.595-0.057/2 = 
0.5665  
Estimated proportion achieving complete eschar removal using Gel vehicle in a previous 
Phase II study, MW2002-04-01: 0 (0 out of 35 patients).  
Anticipated proportion achieving complete eschar removal using gel: 0.0 or 0.10. (0.0 is the 
point estimate; 0.10 is the 97.5 upper confidence limit).  
Because numbers of complete eschar removals are anticipated to be low in the gel group, we 
calculate sample size using Fisher’s exact test. We used the computer program nQuery 
Advisor version 7.0 to calculate power for a two-sided significance level of 5%, and thereby 


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found the following sample size combination that led to approximately 90% power for detecting 
a statistically significant difference at the 5% level, under the assumption of a 10% rate in the 
Gel Vehicle group (see above).  
For 90% overall power, number in NexoBrid group = 65 and in Gel vehicle group 13. 
Total sample size = 78. 
9.2. Secondary Endpoint: Incidence of surgical excision 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.22; 
SOC 0.62  
Standard errors: NexoBrid 0.048; SOC 0.054  
Difference = 0.40; Standard error of difference = 0.072  
Anticipated difference: 0.40-0.072/2 ≈ 0.36  
We therefore take the anticipated proportion with complete excision to be: NexoBrid 0.24 and 
SOC 0.60.  
Using Fisher’s exact test, the sample size needed to achieve 90% power using a two-sided 
significance level of 5% is 86: 43 in the NexoBrid group and 43 in the SOC group. 
9.3. Secondary Endpoint: Time to complete eschar removal 
The logrank comparison between NexoBrid and SOC in the previous trial yielded an estimated 
log hazard ratio of -1.37 (hazard ratio of 0.254) with a standard error of 0.28. 
Therefore, target log hazard ratio (log HR) is -1.37 +0.28/2 = -1.23 (hazard ratio = 0.29). 
The formula for the number of events (successful complete eschar removals) is: 
 =
4!"# + "$%
&
(log ')*&  
where zα = 1.96 two-sided significance level of 5%; and zβ = 1.28 for 90% power; For 90% 
overall power, number of events = 28. 
Proportions of events: p1 = 0.595 in NexoBrid and p2 = 0.728 in SOC. 
Total number of patients required , =
&-
./0.1 = 44 (to the nearest even number), 22 in each of 
the NexoBrid and SOC groups. 


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9.3.1. 
Summary of sample size 
Although the maximum sample size from the above calculations is a total of 121 patients (65 
in the NexoBrid group, 13 in the Gel vehicle group and 43 in the SOC group (to match NexoBrid 
numbers)), we propose entering larger numbers to provide an extra margin of assurance in 
achieving positive results on the efficacy outcomes, and adequate information on safety 
outcomes to allow better benefit vs. risk assessment.  
Therefore, we plan a study with total sample size of 175 patients; 75 (NexoBrid) + 75 
(SOC) + 25 (Gel Vehicle). 
9.4. Safety Set 
The safety set includes all patients who received a treatment and analysis is focused on the 
treatment actually performed. 
9.5. Full analysis Set (Intent-to-Treat population) 
The full analysis set (FAS) includes all patients who are randomized into the trial. The analysis 
is focused on the planned treatment. 
9.6. Per Protocol Set 
The per protocol (PP) set includes all subjects who do not have major protocol violations (cf. 
section 8). Analysis of the PP population is for supportive purposes, whereas the analysis of 
the ITT population (FAS) provides the primary and secondary efficacy and the comparative 
safety analyses. The PP analysis will include patients in the treatment group according to 
treatment received. 
9.7. Enrolled population 
The enrolled population consists of all subjects who passed through the screening processes 
and signed inform consent. 


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10. Data Handling 
10.1. Handling of Missing Data, Outliers and Implausible Data 
Missing data in the primary and secondary outcomes is the main concern. 
10.1.1. Primary Endpoint: Incidence of complete eschar removal 
Little or no missing data are expected for the primary endpoint, since the outcome is assessed 
only several hours after the start of treatment for both NexoBrid and Gel Vehicle groups. The 
primary analysis of complete eschar removal will include patients with missing endpoint data 
in the analysis. Such patients will be counted as having failed on this endpoint, i.e. as not 
having achieved complete eschar removal. 
Three sensitivity analyses will be conducted for this endpoint. A first analysis will count all 
patients with missing data (for this endpoint) as positive (i.e. complete eschar removal) and a 
second analysis will be a complete-case analysis. In each treatment group, only patients with 
documented total eschar removal (at the end of the eschar removal soaking period) will be 
counted and this number divided by the total number of complete cases. The third sensitivity 
analysis will be a tipping point analysis, in which the effect of missing data on the conclusion 
will be investigated. This analysis will be conducted as follows: 
1. Impute the entries of the incomplete data sets m = 100 times from Bernoulli 
distributions. For the imputations of the Gel Vehicle group, the event probability 2 is 
chosen as the observed incidence of complete eschar removal in the Gel group (without 
missing data). For the NexoBrid group the event probability will be 2 = 2356 7 8, where 
8 is a shift parameter (see below). The random seeds for the imputations will be 
14983,…,15082. 
2. For each of the 100 imputed data sets compute Fishers exact test and calculate the 
proportion of tests that reject the null-hypothesis. 
3. Repeat steps 1. and 2. for 8 = 9: 9;9<: … as long as 2356 7 8 is still non-negative. 
The analysis outlined here allows investigating for which assumed success probability for the 
patients with missing data in the NexoBrid group, the conclusion of the analysis remains stable. 


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Secondary Endpoints 
10.1.1.1. 
Secondary Endpoint: Incidence of surgical excision 
The same procedure as for the primary endpoint will be applied for this endpoint, i.e. the main 
analysis will include all randomized patients, with those having a missing value assumed to 
have "failed", i.e. to have received surgery. Two sensitivity analyses will be performed. First, 
in each treatment group, only patients with documented surgical excision will be counted and 
this number divided by the total number of randomized subjects with non-missing endpoint. A 
second analysis will include all randomized patients and count all patients with missing data 
(for this endpoint) as positive (i.e. no surgical excision performed). 
10.1.1.2. 
Secondary Endpoint: Time to complete eschar removal 
The analysis of the secondary endpoint time to eschar removal will compute missing values 
as censored at the date of the last non-missing eschar removal assessment (typically last 
debridement procedure). 
10.1.1.3. 
Secondary Endpoint: Blood loss 
Missing blood loss values for some eschar removal procedures may occur within a certain 
patient. A regression model containing main prognostic factors (wound area, depth of wound 
and type of procedure) for blood loss of eschar removal procedures will be computed on a 
procedure level treating all procedures as independent. On this basis a multiple imputation will 
be calculated. The procedure can be described as follows: 
1. Test for normality: The Shapiro-Wilk test will be performed on the dataset of non-
missing values in each treatment group. The result of these tests will determine the 
type of the analysis on the imputed data sets (step 3). If the normal distribution 
hypothesis is not rejected at the 0.5% significance level in either group, then differences 
in distribution between NexoBrid and SOC will be tested using a t-test. If the normal 
distribution hypothesis is rejected either in the NexoBrid group or in the SOC group, 
then the differences in distribution between the treatment groups will be tested using a 
Mann-Whitney test. 
2. Imputation: Fit a linear regression model with target variable blood loss on a procedure 
level (as computed in Section 10.3.3.3) and dependent variables size of wounds 
treated in this procedure (wound area), proportion of area SPT of wounds treated in 
this procedure (as defined in Section 10.3.3.3.2), proportion of area DPT of wounds 
treated in this procedure (as defined in Section 10.3.3.3.3), proportion of area FT of 
wounds treated in this procedure (as defined in Section 10.3.3.3.4) and type of 


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procedure (surgical/non-surgical) to the subset containing patients with complete data 
in those variables for both treatment groups separately. Impute the missing entries of 
the incomplete data sets m = 25 times as follows: Draw a set of regression coefficient 
from their sampling distribution obtained from fitting the respective linear models 
outlined above (a different distribution for the regression coefficients will be obtained in 
the different treatment groups). With these sampled coefficients calculate the predicted 
blood loss values for the procedures with missing blood loss using the covariate 
information. To these predicted blood loss values add the realizations of a normally 
distributed random variable with zero mean and standard deviation equal to the 
residual standard deviation from the linear model fitted to the complete data set. The 
random seeds for these 25 imputations will be (11468, 11469, 11470, ..., 11492). On 
the imputed datasets calculate the blood loss on a patient level.  
If the normality condition is not satisfied, then the multiple imputation method known as 
predictive mean matching will be used. Random draws from the five nearest neighbors 
for each missing value, and five multiply imputed datasets will be used. Multiple 
imputation may indeed be used with the Mann-Whitney Test, combining the Mann-
Whitney test statistics across multiply imputed datasets, as described in the paper by 
Mogg and Mehotra, Statistics in Medicine 2007; 26:484-497 [1]. The predictive mean 
matching method is implemented in the SAS procedure PROC MI. The random seed 
for the imputations of blood loss values will be 11468. 
3. Analysis: Analyze each of the m complete data sets with a t-test or the Mann-Whitney 
test according to the test result in step 1. This step results in m estimates of the effect 
and m estimates of the standard deviation.  
4. Pooling: Integrate the m analysis results into a final result with the SAS procedure 
PROC MIANALYZE according to Rubin’s combination rules for multiple imputation to 
obtain the final estimates of mean and variance [28]. 
For the additional analysis of blood loss which treats the whole eschar removal process as 
one continuous procedure (see section 7.3.2.2) the multiple imputation will be performed 
on a patient level. The procedure can be described as follows: 
1. Test for normality: The Shapiro-Wilk test will be performed on the dataset of non-
missing values in each treatment group. The result of these tests will determine the 
type of the analysis on the imputed data sets (step 3.). If the normal distribution 
hypothesis is not rejected at the 0.5% significance level in either group, then 
differences in distribution between NexoBrid and SOC will be tested using a t-test. 
If the normal distribution hypothesis is rejected either in the NexoBrid group or in 


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the SOC group, then the differences in distribution between the treatment groups 
will be tested using a Mann-Whitney test. 
2. Imputation: Fit a linear regression model with target variable blood loss on a patient 
level (as computed in Section 10.3.3.3) and dependent variables wound area, depth 
of wound (categorized as described in Section 11.1.10) and course of debridement 
procedure (as defined in Section 10.3.3.3.5) to the subset containing patients with 
complete data in those variables for both treatment groups separately. Impute the 
missing entries of the incomplete data sets m = 25 times as follows: Draw a set of 
regression coefficient from their sampling distribution obtained from fitting the 
respective linear models outlined above (a different distribution for the regression 
coefficients will be obtained in the different treatment groups). With these sampled 
coefficients calculate the predicted blood loss values for the procedures with 
missing blood loss using the covariate information. To this predicted blood loss 
values add the realization of a normally distributed random variable with zero mean 
and standard deviation equal to the residual standard deviation from the linear 
model fitted to the complete data set. The random seeds for these 25 imputations 
will be (12467, 12468, 12469, ..., 12491). On the imputed datasets calculate the 
blood loss on a patient level. 
If the normality condition is not satisfied, then the multiple imputation method known 
as predictive mean matching will be used. Random draws from the five nearest 
neighbors for each missing value, and five multiply imputed datasets will be used. 
Multiple imputation may indeed be used with the Mann-Whitney Test, combining 
the Mann-Whitney test statistics across multiply imputed datasets, as described in 
the paper by Mogg and Mehotra, Statistics in Medicine 2007; 26:484-497 [1]. The 
predictive mean matching method is implemented in the SAS procedure PROC MI. 
The random seed for the imputations of blood loss values will be 12467. 
3. Analysis: Analyze each of the m complete data sets with a t-test or the Mann-
Whitney test according to the test result in step 1. This step results in m estimates 
of the effect and m estimates of the standard deviation.  
4. Pooling: Integrate the m analysis results into a final result with the SAS procedure 
PROC MIANALYZE according to Rubin’s combination rules for multiple imputation 
to obtain the final estimates of mean and variance [28]. 


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10.1.2. Safety Endpoints 
10.1.2.1. 
Safety Endpoint: Time to reach complete wound closure 
The analysis of the safety endpoint time to complete wound closure will compute missing 
values as censored at the date of the last non-missing wound closure assessment. 
10.1.2.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
A higher ratio of missing values is expected in the case of later MVSS values, especially for 
24 months. It is expected that the 1 months MVSS value exists. If this is not the case the 
missing MVSS value will be replaced by the mean MVSS value of all patients who belong to 
the same treatment group and the same stratum (see Section 11.1.10) at that time point. For 
missing MVSS values at later time points (3, 6, 12, 18 and 24 months) the following imputation 
method will be used: 
For each time point (1, 3, 6 and 12 months) and each treatment arm separately, a linear 
regression model with target variable MVSS at 12 months and explanatory variables MVSS at 
the respective time point and all stratification variables (see Section 11.1.10) is fitted to the 
data of patients having both MVSS values. Missing MVSS values at 12 months are then 
imputed with the prediction of the linear regression model, which has the last non-missing 
MVSS value before the 12 months measurement for the individual as explanatory variable (i.e. 
for patients who have the 6 months MVSS measurement but not the 12 months measurement, 
the 12 months measurement is imputed from the 6 months measurements; for those who have 
the 3 months measurement but not the 6 months or 12 months measurement the 12 months 
measurement is imputed from the 3 months measurement; and for those who have the MVSS 
measurement at 1 month but not at 3 months, 6 months or 12 months the 12 months 
measurement will be imputed from the 1 month measurement). To this prediction, the 
realization of a normally distributed random variable with zero mean and standard deviation 
equal to the residual standard deviation from the linear model is added. The random seed for 
this imputation is 45318. 
Similarly, for each time point (1, 3, 6, 12 and 18 months) and each treatment arm separately, 
a linear regression model with target variable MVSS at 24 months and explanatory variables 
MVSS at the respective time point and all stratification variables (see Section 11.1.10) is fitted 
to the data of patients having both MVSS values. Missing MVSS values at 24 months are then 
imputed with the prediction of the linear regression model, which has the last non-missing 
MVSS value before the 24 months measurement for the individual as explanatory variable. To 


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this prediction, the realization of a normally distributed random variable with zero mean and 
standard deviation equal to the residual standard deviation from the linear model is added. The 
random seed for this imputation is 45448. 
Using this imputation method deviates from the handling of missing data specified in the 
protocol. There, simple LOCF was intended. However, LOCF is not considered a suitable 
imputation method for the MVSS values as early MVSS values are not considered 
representative for late MVSS measurements in the same individual. Furthermore, LOCF is 
heavily criticized in the statistics community since it may lead to biased results even when the 
missing occurs completely at random (see [29], [30]). 
Additionally, best case – worst case imputations will be used as a supporting sensitivity 
analysis. One using the worst case MVSS value of 9 (observed maximum MVSS value in the 
SOC group in the previous study MW2004-11-02) for all missing MVSS data and one using 
the best case value of 0 (observed minimum MVSS value in the SOC group in the previous 
study MW2004-11-02). 
10.1.2.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
See 10.1.2.2. 
10.2. Handling of Withdrawals and Dropouts 
Withdrawn subjects will be evaluated in the FAS and safety set. Missing values are imputed 
as mentioned in Section 10.1. 
10.3. Data Transformation 
For all continuous variables, mean, standard deviation, minimum, maximum, median, 25% 
quantile and 75% quantile will be calculated per treatment group and overall. 
For all categorical variables counts and frequencies of categories will be calculated per 
treatment group and overall. 


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10.3.1. Demographic data and other baseline characteristics 
10.3.1.1. 
Age 
Age will be calculated as the difference in years (rounded down) between date of birth and the 
date of the baseline physical examination. 
10.3.1.2. 
Height 
A patient's height is either given in cm or inch. Height in inch will be transformed to height in 
cm and vice versa using the formulae 
 !"# $(%&) = 2.54 ×  !"# $("'% ) 
 !"# $("'% ) = 0.3937 ×  !"# $(%&) 
Hence, height data for each patient will be available in inch as well as in cm. 
10.3.1.3. 
Weight 
A patient's weight is either given in kg or lb. Weight in lb will be transformed to weight in kg 
and vice versa using the formulae 
*!"# $(+#) = 0.4536 × *!"# $(,-) 
*!"# $(,-) = 2.2046 × *!"# $(+#) 
Hence, weight data for each patient will be available in lb as well as in kg. 
10.3.1.4. 
Time since injury 
The time since injury will be computed as the time in hours between injury and first treatment. 
10.3.1.5. 
Early grafted wounds 
For each target wound, a binary (yes/no) variable will be computed indicating whether it was 
early autografted (for definition see Appendix 13.1.1). 
For each patient a binary (yes/no) variable will be computed indicating whether the patient had 
at least one early grafted target wound. 
10.3.1.1. 
Late grafted wounds 
For each target wound, a binary (yes/no) variable will be computed indicating whether it was 
late autografted (for definition see Appendix 13.1.1). 
For each patient a binary (yes/no) variable will be computed indicating whether the patient had 
at least one late grafted target wound. 


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10.3.1.2. 
Wounds at least partially found in the anatomical area of the hand 
For each target wound, a binary (yes/no) variable will be computed indicating whether it was 
at least partially found in the anatomical area of the hand. 
For each patient a binary (yes/no) variable will be computed indicating whether the patient had 
at least one target wound which was at least partially found in the anatomical area of the hand. 
10.3.2. Primary Endpoint: Incidence of complete eschar removal in the 
topical arms 
Information on whether complete eschar removal was obtained after the application of 
NexoBrid or Gel vehicle per target wound will be combined to a single binary variable (yes/no) 
indicating whether complete eschar removal was achieved for all target wounds of a patient at 
the end of the eschar removal treatment (after the 2 hrs soaking). The eschar removal 
treatment may contain one or two topical removal procedures. Complete eschar removal is 
judged after the last topical procedure in a patient. 
Furthermore, for all patients with at least one early grafted target wound (for definition see 
Appendix 13.1.1), a binary (yes/no) variable will be computed indicating whether complete 
eschar removal has been achieved in all early grafted wounds of the patient at the end of the 
eschar removal treatment (after the 2 hrs soaking). 
Additionally, for all patients with at least one late grafted target wound (for definition see 
Appendix 13.1.1), a binary (yes/no) variable will be computed indicating whether complete 
eschar removal has been achieved in all late grafted wounds of the patient at the end of the 
eschar removal treatment (after the 2 hrs soaking). 
Furthermore, for patients who had at least one target wound that is found, at least partially, in 
the anatomical area of the hand, a binary (yes/no) variable will be computed, indicating whether 
complete eschar removal has been achieved in all target wound that are found, at least 
partially, in the anatomical area of the hand. 
10.3.3. Secondary Endpoints 
10.3.3.1. 
Secondary Endpoint: Incidence of surgical excision 
For each patient a binary (yes/no) variable will be computed, indicating whether this patient 
needed surgical excision for eschar removal. 


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Furthermore, for patients with at least one early grafted target wound, a binary (yes/no) variable 
will be computed, indicating whether this patient needed surgical excision in an early grafted 
target wound. Similarly, for patients with at least one late grafted target wound, a binary 
(yes/no) variable will be computed, indicating whether this patient needed surgical excision in 
a late grafted target wound. 
Additionally, for patients who had at least one target wound that is found, at least partially, in 
the anatomical area of the hand, a binary (yes/no) variable will be computed, indicating whether 
this patient needed surgical excision in a target wound that is found, at least partially, in the 
anatomical area of the hand. 
For each patient the number of TWs will be computed and used as an explanatory variable in 
the analysis of this secondary endpoint. 
10.3.3.2. 
Secondary Endpoint: Time to complete eschar removal 
Information about date will be transformed to time in hours from randomization. Time until 
complete eschar removal will be calculated as the time (in hours) until complete eschar 
removal has been achieved for a TW. From these times, time to reach complete eschar 
removal at a patient level, i.e. for all TW's of an individual patient will be calculated. For 
wounds/patients that do not reach complete eschar removal, their time will be censored at the 
last non-missing eschar removal assessment (typically the last debridement procedure). 
For further analysis, for patients with at least one early grafted target wound, time to complete 
eschar removal will also be calculated as above, but taking into account only early grafted 
wounds. Additionally, for patients with at least one late grafted target wound, time to complete 
eschar removal will also be calculated as above, but taking into account only late grafted 
wounds. 
Additionally, for patients who had at least one target wound that is found, at least partially, in 
the anatomical area of the hand, time to complete eschar removal will also be calculated as 
above, but taking into account only target wounds that are found, at least partially, in the 
anatomical area of the hand. 
For an additional analysis, time to complete eschar removal will be computed as above but in 
hours from injury. 
Furthermore, time to complete eschar removal will be computed as above but in hours from 
ICF. 


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The patients’ age will be categorized into two categories: “younger than 35 years” and “35 
years or older”. The number 35 years is found to be the median age of the adult population in 
the previous study MW2004-11-02. 
10.3.3.3. 
Secondary Endpoint: Blood loss 
10.3.3.3.1. Blood loss for main analysis 
For each patient and each procedure carried out to remove eschar the estimated blood volume 
(EBV) will be calculated as  
/18 = 70 %&:
+# ; *!"# $(+#) 
Furthermore, the total volume of whole blood and packed red blood cells (PRBC) transfused 
(in milliliters) will be calculated per procedure (transfusions given during the procedure and 4 
hours ± 15 minutes later) and denoted by VWB and VPC in the following. 
From these quantities, the blood loss (Actual Blood Loss, ABL) will be calculated using the 
following formula [25]: 
<1> = /18 ; ?@-ABCDEB F @-GCHBEI
?@-ABCDEB J @-GCHBEI 2
K
J 8LM J 5
3 8NO 
The factor of 5/3 is derived from chapter 5 of Transfusion Medicine, 4th Edition [31] and 
compensates for the fact that equal volumes of whole blood and packed red blood cells are 
not comparable. 
The ABL will be summed over all procedures carried out to remove eschar, with the Hb 
measured immediately before each procedure and 4 hours after its completion. The amount 
of blood transfused will be summed over all transfusions carried out during the debridement 
procedure and 4 hrs later i.e. the before-after periods that are spanned by these Hb 
measurements. 
Additionally, blood loss will be computed considering the whole debridement process as one 
continuous procedure. For this value, the formula for ABL given above will also be used. 
However, the ABL will be computed using the Hb measured immediately before the first 
procedure and 4 hours after completion of the last procedures. The amount of whole blood 
and packed red blood cells (PRBC) transfused will be calculated as before, but incorporating 
all such transfusions in the time frame spanned by the Hb measurements used for the 
calculation (pre first procedure to 4 hrs post last procedure (in which complete debridement 
was achieved). 


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Analyses with both blood loss values will be conducted. However, some missing values are 
expected. The analysis with less missing values will be regarded as more reliable and is 
therefore considered the main analysis. The other analysis is considered supportive. 
10.3.3.3.2. Proportion of SPT area of wounds treated per procedure 
For the multiple imputation outlined in Section 10.1.1.3 information on the proportion of the 
SPT area of wounds treated per procedure will be computed using the following formula: 
PQRS(TPU) = V WTPU(XY) ; WU1T<(XY)
Y
V WU1T<(XY)
Y
Z 
where both sums range over all target wounds treated in a debridement procedure, WTPU(XY) 
is the percent area of SPT of target wound " and WU1T<(XY) is the area of the target wound 
". PQRS(TPU) will be computed for each procedure in each patient separately. 
10.3.3.3.3. Proportion of DPT area of wounds treated per procedure 
For the multiple imputation outlined in Section 10.1.1.3 information on the proportion of the 
DPT area of wounds treated per procedure will be computed using the following formula: 
PQRS([PU) = V W[PU(XY) ; WU1T<(XY)
Y
V WU1T<(XY)
Y
Z 
where both sums range over all target wounds treated in a debridement procedure, W[PU(XY) 
is the percent area of DPT of target wound " and WU1T<(XY) is the area of the target wound 
". PQRS([PU) will be computed for each procedure in each patient separately. 
10.3.3.3.4. Proportion of FT area of wounds treated per procedure 
For the multiple imputation outlined in Section 10.1.1.3 information on the proportion of the FT 
area of wounds treated per procedure will be computed using the following formula: 
PQRS(\U) = V W[PU(XY) ; WU1T<(XY)
Y
V WU1T<(XY)
Y
Z 
where both sums range over all target wounds treated in a debridement procedure, W\U(XY) 
is the percent area of FT of target wound " and WU1T<(XY) is the area of the target wound ". 
PQRS(\U) will be computed for each procedure in each patient separately. 
10.3.3.3.5. Course of debridement procedure 
For the multiple imputation outlined in Section 10.1.1.3 for each patient a categorical variable 
describing the course of the debridement process will be calculated. The different levels of the 
variable are defined as: 


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· 
Only non-surgical SOC debridement  
· 
Non-surgical SOC debridement followed by surgical debridement 
· 
Only surgical debridement 
· 
Only NexoBrid debridement 
· 
NexoBrid debridement followed by non-surgical SOC debridement followed by surgical 
debridement 
· 
NexoBrid debridement follow by surgical debridement 
· 
Only Gel Vehicle debridement 
· 
Gel Vehicle debridement followed by non-surgical SOC debridement followed by 
surgical debridement 
· 
Gel Vehicle debridement followed by surgical debridement 
10.3.4. Safety Endpoints 
10.3.4.1. 
Safety Endpoint: Time to reach complete wound closure 
Information about date will be transformed to time in days from randomization. Time until 
complete wound closure (for definition see Appendix 13.1.1), will be defined as the time (in 
days) until complete wound closure has been achieved at a wound level. For wounds, which 
do not reach complete wound closure, the time will be censored at last date of wound closure 
assessment. 
10.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
MVSS sub scores at 12 months for pigmentation, pliability, height, vascularity, pain and pruritus 
will be added up to obtain the overall MVSS score (range 0 to 18) at 12 months per target 
wound. The patient MVSS score will be the average of the MVSS over all TWs. Additionally, 
the average MVSS score for donor site scars will be calculated per patient. 
10.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
MVSS sub scores at 24 months for pigmentation, pliability, height, vascularity, pain and pruritus 
will be added up to obtain the overall MVSS score (range 0 to 18) at 24 months per target 
wound. The patient MVSS score will be the average of the MVSS over all TWs. Additionally, 
the average MVSS score for donor site scars will be calculated per patient. 


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10.3.4.4. 
General Parameters of safety 
Volume of blood transfusions given 
The volume of blood transfusions given during hospitalization will be computed for each patient 
as 8LM J
]
: 8NO, where VWB and VPC are the volume (in milliliters) of whole blood and packed 
red blood cells transfused. As in the calculation of blood loss in Section 10.3.3.3.1, the factor 
of 5/3 is derived from chapter 5 of Transfusion Medicine, 4th Edition [31] and compensates for 
the fact that equal volumes of whole blood and packed red blood cells are not comparable. 
The volume of blood transfused will be calculated overall, as well as separately for volumes 
transfused before start of treatment, during the ER period, within 1 week after the ER period 
and later than 1 week after the ER period for each patient. 
Extent of analgesia, anesthesia and antibiotic use 
The numbers and percentages of patients per each level of sedation (see definitions in 
Appendix 13.1.2) per procedure (in topical arms: 1st and second topical application, surgical 
rescue procedures and non-surgical rescue procedures; in SOC arms: surgical procedures 
and non-surgical procedures) will be calculated. 
The number of days of exposure to antibiotic drugs will be calculated for each patient. This will 
be done overall, for antibiotic use due to AE involvement (as indicated in the eCRF) and for 
prophylactic antibiotic use (as indicated in the eCRF) separately. 
Incidence of increased interstitial/compartment syndrome 
For each patient in the topical arms a binary (yes/no) variable is indicating whether the patient 
developed a burn-induced compartment syndrome (BICS) during the eschar removal 
procedure is given in the data. 
Incidence of QT prolongation 
Incidence of QT prolongation will be analyzed separately. The analysis and all needed 
transformations are described in a separate document. 
Rates of hospital readmission 
For each hospital readmission, a binary (yes/no) variable will be computed indicating whether 
this readmission was planned or not. A readmission will be considered as being planned when 


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the reason for readmission was indicated as “planned wound management” or “scar 
modulation” in the eCRF. Readmissions for which the reason was given as “AE” in the eCRF 
are considered as being unplanned. Hospital readmission for which the reason is given as 
“other” will be reviewed by blinded personnel of the sponsor in order to decide whether they 
are to be classified as planned or unplanned. 
For each patient a binary (yes/no) variable will be computed indicating whether this patient had 
a hospital readmission or not. Furthermore, a variable giving the number of planned hospital 
readmissions and a variable giving the number of unplanned readmissions will be computed 
for each patient. 
Relative and absolute frequencies of hospital readmission will be calculated per treatment arm. 
Change in PTT/INR 
Change in PTT/INR will be computed as change from pre Eschar Removal procedure to 4h ± 
15 min post first application (Topical arms) respectively to 4h post first SOC treatment (SOC 
arm) for each patient. Additionally, change from baseline PTT/INR will be computed for the 
first and second daily assessment post treatment (24h & 48h after start of debridement). 
The proportion of patients with a change to > upper limit of normal range PTT/INR (patients 
with normal PTT/INR at baseline and PTT/INR > upper limit of normal range at the respective 
time point) will be computed per treatment arm and time point of measurement (4h post 
treatment, 24 h, 48h). Reference count is the number of patients with normal PTT/INR values 
at baseline. For the classification of normal and abnormal PTT/INR values, the reference limits 
of the local labs will be used. 
Change in blood glucose 
Change in blood glucose will be computed as change in blood glucose value from pre first 
topical procedure to 4h post first topical procedure (4h after removal of topical) and from 
post first topical to post second topical (if available) and from pre surgical procedure to 
post surgical procedure for each patient. In case non-surgical procedure was the only one 
performed for a SOC patient, the change in blood glucose value will be computed as 
change from pre to post procedure. Furthermore, a binary (yes/no) variable will be 
computed indicating whether there was a change to above upper limit of normal (the upper 
reference limit of the central lab) from baseline to 4h post treatment for each debridement 
procedure. This is the case if the blood glucose level at baseline was below the upper limit 


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of the normal range as given in the data base and was above the upper limit at 4h post 
treatment. From this for each patient a binary variable will be computed indicating whether 
there was a change in blood glucose to > upper limit of normal range at any of the 
debridement procedures. 
Lower Extremity Function Scale (LEFS) 
The LEFS consists of 20 items which can each be answered on a scale of 0 to 4. In the 
database the answers will be coded as 1 to 5. Therefore, the total LEFS for a patient will be 
computed as 
 !"# = $ %&
'(
&)*
+ 20, 
where ai is the answer to item i (coded 1 to 5). 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH consists of 11 items which are scored 1-5. At least 10 of the 11 items must 
be completed for a score to be calculated. The assigned values for all completed responses 
are simply summed and averaged, producing a score out of five. This value is then transformed 
to a score out of 100 by subtracting one and multiplying by 25. Hence, the QuickDASH score 
for a single patient is calculated by: 
-./1345#6 = 78.9:;<:>:?@A;>8@8
>
+ BC D 2EF 
Range of Motion (ROM) 
For each visit (12 months FU and 24 months FU), a binary (yes/no) variable is given in the 
eCRF, indicating whether the range of motion assessment for that patient was abnormal or 
not. Furthermore, for each visit (12 months FU and 24 months FU) a binary (yes/no) variable 
will be computed, indicating whether there was at least one abnormal (NCS) ROM assessment 
for that patient. Finally, for each visit (12 months FU and 24 months FU) a binary (yes/no) 
variable will be computed, indicating whether there was at least one abnormal (CS) ROM 
assessment for that patient. 


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EQ-5D (Quality of Life) 
EQ-5D consists of 5 items with 3 possible answers each. It will be evaluated per the EQ-5D-
3L user guide [32]. 
For each item relative and absolute frequencies of the answers will be computed in total and 
per age group defined in the EQ-5D-3L user guide per treatment arm and overall. Furthermore, 
summary statistics of the EQ VAS will be computed in total and per age group defined in the 
EQ-5D-3L user guide per treatment arm and overall. 
The EQ-5D states will be converted to a single summary index as described in the EQ-5D-3L 
user guide. 
Burn Specific Health Scale – Brief (BSHS-B) 
The Burn Specific Health Scale – Brief (BSHS-B) consists of 40 item which can each be scored 
with 0 – 4. In the dataset the scores will be coded as 1- 5. The 40 items can be aggregated to 
9 domains. The domains are: 
· 
Heat sensitivity (questions 28-32 of the eCRF) 
· 
Affect (questions 10-16 of the eCRF) 
· 
Hand Function (questions 4-8 of the eCRF) 
· 
Treatment Regimens (questions 33-37 of the eCRF) 
· 
Work (questions 9, 38-40 of the eCRF) 
· 
Sexuality (questions 21-23 of the eCRF) 
· 
Interpersonal Relationships (questions 17-20 of the eCRF) 
· 
Simple Abilities (questions 1-3 of the eCRF) 
· 
Body Image (questions 24-27 of the eCRF) 
For each domain a domain specific sub score is computed using the following formula: 
#1;?@G4;9%/>H = B
> $
G#1;?@& + BH,
I
&)*
 
where > is the number of items of the domain and #1;?@& is the score of the /th item as 
coded in the data set (i.e. the domain score is the mean of the item scores as coded in the 
BSHS-B). 
An overall BSHS-B score is computed as the mean of the domain specific sub scores. 


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Immunogenicity evaluation 
The immunogenicity evaluation will be done in a separate analysis and is described in a 
separate document. 
Pyrexia and hypothermia 
Pyrexia (and related terms) and hypothermia reported as AEs will be presented in the AEs 
tables. 
Systemic Infection 
For each patient a binary (yes/no) variable will be computed indicating whether the patient 
developed a systemic infection during the study. For data captured with the eCRF version from 
13 Oct 2016 the information, whether an AE is a systemic infection, is directly available in the 
AE description. For data captured before that, a medical person appointed by the sponsor will 
review all MedDRA Preferred Terms belonging to the MedDRA SOC of “Infections and 
Infestations”, as well as all other Preferred Terms reported in the study, and all reported terms 
of AEs including the word “infection”, to decide which AEs meet the definition of systemic 
infection. 
Systemic adverse events 
Counts and frequencies of systemic adverse events (marked as “general” in the eCRF) per 
treatment will be computed. This will be done separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (before treatment / during the treatment session / during the first week 
after treatment / during week 2 to week 4 after treatment / during week 5 to week 8 
after treatment / more than 8 weeks after treatment) 
For each of the tree stages of analysis (see Section 11 for details), the safety data gathered in 
that stage will be analyzed separately. That is, in the acute stage analysis, all AEs reported 
until the 3 months follow-up will be analyzed. In the second stage analysis (12 months follow-
up), all AEs reported between the 3 months follow-up and the 12 months follow-up (including 


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AEs from first stage that are still ongoing) will be analyzed. Analogously, in the third stage 
analysis (24 months follow-up), all AEs reported between 12 months follow-up and the 24 
months follow-up (including AEs from the first or second stage that are still ongoing) will be 
analyzed. 
Local adverse events 
Local adverse events are classified as being local – TW related or local – not TW related in 
the eCRF. Per each of these categories, counts and frequencies of adverse events per 
treatment group will be computed. This will be done separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (before treatment / during the treatment session / during the first week 
after treatment / during week 2 to week 4 after treatment / during week 5 to week 8 
after treatment / more than 8 weeks after treatment) 
For each of the tree stages of analysis (see Section 11 for details), the safety data gathered in 
that stage will be analyzed separately. That is, in the acute stage analysis, all AEs reported 
until the 3 months follow-up will be analyzed. In the second stage analysis (12 months follow-
up), all AEs reported between the 3 months follow-up and the 12 months follow-up (including 
AEs from the first stage that are still ongoing) will be analyzed. Analogously, in the third stage 
analysis (24 months follow-up), all AEs reported between 12 months follow-up and the 24 
months follow-up (including AEs from the first or second stage that are still ongoing) will be 
analyzed. 
Vital signs 
Body temperatures given in °F will be transformed to °C using the following formula: 
J@9A@?%K.?@[°L] = E
M GJ@9A@?%K.?@[°"] + N2H 
Differences in the vital signs assessments (body temperature, heart rate, respiratory rate, 
systolic blood pressure, diastolic blood pressure) between daily visits will be calculated by 
4/<<O = P#OQ* + P#O 


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where P#O is the vital sign assessment at day d (daily follow-up) and d is varied from 2 to 7. 
Furthermore, pre-post differences for vital signs assessments per procedure will be calculated 
in the same way, using the screening assessment as pre first procedure and the post first 
procedure measurement as pre second procedure measurement if needed. 
Pain assessment 
For each eschar removal procedure and each daily follow-up pain assessment the change in 
pain from baseline will be calculated as  
 !""# = $%!&'()* + $%!&# 
where $%!&# is the pain assessment at the respective time point. For the calculation of the 
difference in pain for the eschar removal procedures the pain assessment post that procedure 
will be used. 
10.3.5. Exploratory Analyses 
10.3.5.1. 
%SPT area 
For each patient the % SPT area (the area of SPT as a percentage of the total area of all TWs) 
will be calculated. From this a binary variable will be computed indicating whether % SPT area 
is < 25% or ≥ 25%. Cumulative and absolute frequencies for each category will be computed. 
10.3.5.2. 
%TBSA 
A binary variable indicating whether total %TBSA of all TWs is ≤ 15% or > 15% will be 
calculated per patient. For this variable cumulative and absolute frequencies for each category 
will be computed. 
10.3.5.3. 
Application data 
For the patients of the NexoBrid and the gel vehicle arm the number of applications (0, 1, 2) 
will be determined. Cumulative and absolute frequencies will be computed for each category. 
Furthermore, for each patient the amount of NexoBrid gel each patient in the NexoBrid 
treatment arm has been exposed to, will be calculated. 
10.3.5.4. 
Maintenance of complete wound closure 
For each follow-up visit the information of complete wound closure for each TW will be 
aggregated to a binary variable indicating maintenance of complete wound closure on a patient 
level (i.e. complete wound closure for each TWs of a patient). Cumulative and absolute 
frequencies will be computed for each category. 


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10.3.5.5. 
% wound area surgically excised for eschar removal 
% of wound area surgically excised for eschar removal, Atotal, will be calculated using the 
following formula: 
,-.-(/ =01 2%3 4 5678,39
3
1 5678,3
3
 
where %TBSAi is the area of TW i (in % TBSA) and ai denotes the % of wound area surgically 
excised for eschar removal of TW i. 
10.3.5.6. 
Incidence of reduction in interstitial/compartment pressure in 
circumferential extremities target wounds 
Interstitial/compartment pressure in circumferential extremities target wounds is measured 
within 1 hour (+30 min) prior to start of each eschar removal procedure and post-eschar 
removal. For each circumferential target wound and each eschar removal procedure a binary 
(yes/no) variable will be computed indicating whether reduction in interstitial/compartment 
pressure in that wound was present. 
10.3.5.7. 
POSAS 
The Patient Observer Scar Assessment Scale (POSAS) consists of two parts: a patient scale 
and an observer scale. Both scales contain six items that are scored numerically with 1-10. 
For each wound of a patient the total score of the patient scale will be computed as: 
$:8,8; = < >3
?
3@A
B 
where pi is the score the patient assigned to item i. The total score of the observer scale will 
be computed analogously as: 
$:8,8C = < D3
?
3@A
B 
where oi is the score the observer assigned to item i. 
A total score for the POSAS is then obtained by summing the patient scale score and the 
observer scale score: 
$:8,8-.- = $:8,8; E $:8,8CF 
For each patient the mean of $:8,8-.- over all TWs will be computed. Analogously the mean 
of $:8,8-.- over all donor site scars will be computed. 


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Additional to the quantitative scoring of the items they are also score qualitatively (for each 
item different categories are available). Absolute and relative frequencies of the categories for 
each item will be computed over all patients per treatment arm. 
The POSAS will be computed for TWs and donor site scars at the long-term follow up visits. 
10.3.5.8. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
For each circumferential extremities target wound a binary (yes/no) variable will be computed, 
indicating whether this wound was escharotomized. Furthermore, a binary (yes/no) variable 
for each patient will be computed indicating whether this patient had at least one 
circumferential extremities target wound which was escharotomized. 
10.3.5.9. 
Incidence of reduction in interstitial/compartment pressure in 
circumferential extremity wounds 
For circumferential extremity wounds the reduction in interstitial/compartment pressure will be 
computed as 
$GHII#3JJ = $GHIIK()* + $GHIIL.)- 
where Pressbase is the interstitial/compartment pressure at baseline and Presspost is the 
interstitial/compartment pressure after eschar removal. This will be done for each topical 
eschar removal procedure. Furthermore, for each circumferential extremity wound and each 
topical eschar removal procedure a binary (yes/no) variable will be computed indicating 
whether interstitial/compartment was reduced during the procedure. 
10.3.5.10. 
Incidence of surgically harvested donor sites wounds 
For each patient, the number of donor sites wounds will be calculated. 
10.3.5.11. 
% area of surgically harvested donor site wounds 
For each autograft procedure the % TBSA of the donor site is captured. These values will be 
summed up over all autograft procedures for each patient giving the % area of surgically 
harvested donor site wounds. 
10.3.5.12. 
Blood loss using changes in hematocrit following eschar removal 
procedures 
For each debridement procedure, the change in hematocrit will be calculated as the difference 
of the hematocrit value before the procedure and the hematocrit value 4 hours post the 
procedure. This difference in hematocrit values will be summed for each patient. 


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Furthermore, for each patient, the difference of the hematocrit value prior to the first 
debridement procedure and the hematocrit value 4 hours post the last debridement procedure 
will be calculated. 
10.3.5.13. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
For each debridement procedure, the change in hemoglobin will be calculated as the difference 
of the hemoglobin value before the procedure and the hemoglobin value 4 hours post the 
procedure. This difference in hemoglobin values will be summed for each patient. 
Furthermore, for each patient, the difference of the hemoglobin value prior to the first 
debridement procedure and the hemoglobin value 4 hours post the last debridement procedure 
will be calculated. 
10.3.5.14. 
Blood loss comparing NexoBrid procedures to surgical procedures 
For a comparison of blood loss between NexoBrid procedures and surgical procedures, the 
blood loss per eschar removal procedure will be calculated as outlined in Section 10.3.3.3.1. 
10.3.5.15. 
Autograft related parameters 
The total number of grafting procedures per patient and per target wound will be computed. 
Procedure will be based on the date in the eCRFs per patient and per wound.  
Furthermore, a binary (yes/no) variable will be computed indicating whether more than one 
autografting procedure was performed on a wound level as well as on a patient level. 
The area of repeat autografting for each wound will be calculated as follows: 
,GH%M*L*(- = < ,GH%3
N
3@O
B 
where n is the total number of autografting procedures for the specific wound and Areai is the 
area autograft in the i-th grafting procedure for that wound. 
The area of repeat autografting on a patient level is calculated as the sum over the areas of 
repeat grafting over all TWs of that patient. 
10.3.5.16. 
Duration of hospitalization 
Duration of acute hospitalization will be computed as the difference in days between hospital 
admission and hospital discharge (initial hospitalization only). 


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10.3.5.17. 
Time to reach 100% wound closure 
Information about date will be transformed to time in days from randomization. Time until 100% 
wound closure will be defined as the time (in days) until 100% wound closure has been 
achieved at a wound level. For wounds that do not reach 100% wound closure, the time will 
be censored at last date of wound closure assessment. In case one or more wounds do not 
reach complete wound closure, the time to wound closure at a patient level will be censored 
at the minimum of all wound wise censoring times. 
10.3.6. Laboratory values 
The following transformations will be applied to the central laboratory data obtained pre and 
post the eschar removal procedures: 
Laboratory findings that are given in various units will be transformed to standard units. 
Laboratory values will be categorized as “abnormal (low)”, “normal” and “abnormal (high)” 
based on the reference limits of the labs. 
Pre-post differences of laboratory values for each eschar removal procedure will be calculated. 
Absolute and relative frequencies of “abnormal (low)”, “normal” and “abnormal (high)” findings 
will be calculated per laboratory value, eschar removal procedure and treatment arm. 
10.4. Multiple visits per time point 
Study visit time-points are scheduled at screening, pre eschar removal, eschar removal 
(treatment), post-treatment, hospital discharge, follow-up (weekly until wound closure, wound 
closure confirmation, three monthly visits post wound closure), long-term follow-up at 6, 12, 18 
months and 24 months post wound closure confirmation and re-admission to hospital/day care 
(if done). One visit is expected for each time-point. The following approach is used if there are 
multiple visits per patient per time-point.  
For all endpoints, if a subject has more than one visit with data at a time-point, the later non-
missing evaluation will be used for analyses. 


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11. Statistical Analysis of Target Variables 
The analysis is planned to be carried out in three stages, as described below. 
1. The first analysis will be performed at the end of the Efficacy Assessment Period (EAP). 
This analysis will be the only inductive analysis of the trial and will include statistical 
tests for the primary and secondary endpoints as described below, as well for short-
term safety endpoints (including time to wound closure). The analysis will be 
conducted, when 3 months had passed from the last patient reaching complete wound 
closure, in accordance with FDA guidance for industry Chronic Cutaneous Ulcer and 
Burn Wounds — Developing Products for Treatment “Trial subjects generally should 
remain in the study for follow-up evaluation at least 3 months following complete wound 
closure. The purpose for this follow-up period is to help distinguish actual wound 
healing from transient wound coverage”. At this time-point, data will be available for all 
patients on the primary end-point (proportion with complete eschar removal), the three 
secondary endpoints (proportion undergoing surgery, time to complete eschar removal, 
and blood loss) and short-term safety endpoints (including time to wound closure). 
Missing values for early drop outs etc. will be handled as described in Sections 10.1 
and 10.2. The complete data set documented so far will be locked and analyzed as 
described above. In the analysis of adverse events and concomitant medication, for 
each patient only the data until the 3 months follow up will be analyzed in this stage. 
Data obtained after the 3 months follow up will be analyzed in the second and third 
stage of analysis. MVSS data, although captured in the eCRF for a few of the subjects 
at the stage of EAP, will not be included, revealed or analyzed during the EAP analyses.  
 
2. The second analysis will be performed for the 12 months follow up period (STFU12) 
and will be started after the last patient has reached the 12m assessment. At this 
analysis, all accumulated safety data at the 12m follow-up will be analyzed, particularly 
the 12m MVSS assessment for cosmesis and function. The complete data set 
documented so far will be locked and analyzed as described below. In the analysis of 
adverse events for each patient only the data obtained after the 3 months follow up and 
until the 12 months follow up (including AEs and concomitant medications from the first 
stage that are ongoing) will be analyzed in this stage. 
 
3. The third and final analysis covers the data of the long-term safety follow up 
(LTSFU24). It will be conducted after the last patient has reached the 24 months 


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assessment at last 12 months after (STFU12) analysis (stage 2). At this analysis, all 
accumulated safety endpoints at the 24m follow-up will be analyzed, particularly the 
24m MVSS assessment for cosmesis and function. The complete data set 
documented during the trial will be locked and analyzed as described below (hard 
lock). In the analysis of adverse events for each patient only the data obtained after 
the 12 months follow up (including AEs and concomitant medications from the first or 
second stage that are still ongoing) will be analyzed in this stage. 
Two “blinded assessors” are appointed in each clinical site during the site initiation visit. The 
assessor signs a “blinded assessor memo” which describes the procedures required to 
maintain the investigator blinded from the treatment arm. The first blinded assessor is 
responsible for the eschar removal assessment of the topical arms and is not involved with 
product application. All patients will complete the eschar removal treatment by the time of the 
first planned analyses of the acute stage and thus, there is no risk of unblinding of the first 
blinded assessor. The second blinded assessor is responsible for the wound closure and long-
term assessments and is not involved with any eschar removal procedures. The second 
blinded assessor will remain blinded throughout the whole duration of the trial including after 
the acute and the first long-term (12 months) analysis results are available. To assure that 
patients’ treatment codes will not be revealed during the EAP analyses, all patients’ 
identification numbers will be Pseudonyms by data management before analysis is being 
performed and presented. 
The data sets for analysis will be 100% SDVd and signed by the site investigator. Therefore, 
data changes are prevented during the further conduct of the study. Data management quality 
control actions will ensure that data used in the analysis is not changed afterwards see the 
Data Management Plan for further details. 
For a better overview of this SAP, the statistical analysis of target variables described below 
will be displayed separately for these 3 stages of analyses. 
All variables not mentioned explicitly in the following will be analyzed descriptively (as part of 
the case wise listing). 
Unless otherwise specified, all statistical tests will be conducted against a two-sided 
alternative hypothesis, employing a significance level of 0.05. 


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11.1. First stage analysis – end of efficacy assessment period (EAP) 
11.1.1. Demographics and Other Baseline Characteristics 
For all considerations regarding the demographics and other baseline characteristics the full 
analysis set will be used. 
The demographic and baseline information concerning 
· 
Age 
· 
Gender 
· 
Ethnicity 
· 
Race 
· 
Height (cm) 
· 
Weight (kg) 
· 
BMI 
· 
Physical examinations (categorized as normal, abnormal-NCS, abnormal-CS, not 
done): 
· 
Head, eyes, ears, nose and throat (HEENT) 
· 
Respiratory system 
· 
Cardiovascular system 
· 
Abdomen 
· 
Musculoskeletal / Extremities 
· 
Neurological 
· 
Lymph Nodes 
· 
Vital signs: 
· 
Temperature 
· 
Heart rate 
· 
Respiratory rate 
· 
Systolic and diastolic blood pressure (mmHg) 
· 
Assessment of vital signs (normal, abnormal-NCS, abnormal-CS) 
· 
Pain assessment: 
· 
VAS (mm) 
· 
Assessment of pain (normal, abnormal-NCS, abnormal-CS) 
· 
Local laboratory: 
· 
Leukocyte count (WBC) 


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· 
Assessment of leukocyte count (normal, abnormal-NCS, abnormal-CS) 
· 
Diabetes status (yes/no) 
· 
HbA1c (%) 
· 
Infections (yes/no for infections in last week before baseline) 
· 
Relevant medical history (regarded as categorical variable) 
· 
Burn history (on a patient level): 
· 
Time since injury 
· 
Etiology of injury (Fire/Flame, Scald, Contact) 
· 
Place of injury (Outdoors, Indoors, Car, Other) 
· 
Information whether patient was transferred from another facility 
· 
General wound description (on a wound level): 
· 
Anatomical location (face, head, neck, etc.) 
· 
%TBSA of 2° SPT Burns 
· 
%TBSA of 2° DPT Burns 
· 
%TBSA of 3° FT Burns 
· 
Indicator (yes/no) of circumferential extremity involvement 
· 
Extremities at risk (not relevant, pain, paralysis, etc.) 
· 
Information whether eschartomy had been performed prior to randomization 
· 
Eschar description (white, moist, dry, etc.) 
· 
Information whether cleansing was performed 
· 
Information whether all superficial keratin (blister) were removed from wound 
· 
Target wound description: 
· 
General wound description (see above; on a wound level; for target wounds 
only) 
· 
Information whether the wound was treated prior to enrollment (TWs) 
· 
Treatment of TWs prior to enrollment (SSD, Iodine, etc.) 
· 
Target wound description (on a patient level): 
· 
Total wounds %TBSA 
· 
TWs DPT total area (%TBSA) 
· 
TWs FT total area (%TBSA) 
· 
Over TWs depth per patient (all full thickness, mixed, all deep partial thickness) 
· 
Overall TW area (SPT+DPT+FT) 
· 
%SPT area classified as <25% or ≥25% of TWs area 
· 
Number of circumferential extremity wounds per patient 


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· 
Interstitial pressure (mmHg) for circumferential extremity wounds (on a wound level) 
· 
Criteria for inclusion (met/not met) 
· 
Counts of patients/wound per strata (%TBSA cut point 15%, depth cases 1-3, center) 
will be analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles in case of numeric values and counts and 
percentages in case of categorical items to describe the study population. The analysis will be 
done by treatment group and in total. 
The descriptive results for all variables will be tabulated. Exemplary tables are presented in 
Section 13.2. Histograms will be produced for each continuous variable, bar plots for 
categorical variables. Figures can be seen in Section 13.3. 
If any of the baseline factors, gender, age, percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%), time from injury to randomization or 
number of TWs (1, 2, ≥3) are found to be significantly different between the treatment groups 
(Chi-squared tests (or in case of small estimated cell counts Fisher’s exact test) for categorical 
variables and one-way analysis of variance for continuous variables) then the factor will be 
included as an extra adjusting covariate in the supportive analysis models for the primary and 
secondary efficacy endpoints and the comparative analyses of safety endpoints. 
11.1.2. Primary Efficacy variable 
The primary efficacy variable will be analyzed using the FAS. 
The proportions of patients who reached complete eschar removal at the end of the topical 
agent soaking period will be compared using logistic regression. The primary analysis will be 
based on the binary variable (yes/no): ‘has complete eschar removal been achieved in all TWs’ 
and will compare NexoBrid with the Gel Vehicle (for further definition and explanation of 
complete eschar removal see Section 1.1 of the protocol and Section 10.3.2 of this SAP). For 
handling of missing data see Section 10.1.1. The statistical test will be based on Fisher’s exact 
test because of the small numbers expected in the Gel vehicle group. The odds ratio of 
achieving complete eschar removal for NexoBrid versus Gel Vehicle and its 95% confidence 
interval will be estimated using exact distribution methods and will be displayed as shown in 
Table 6. Bar plots will be shown for the proportions of patients who reached complete eschar 
removal. 
Note: The primary analysis method is Fisher’s exact test. 


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If numerically possible, the comparison will supportively be adjusted for the stratification factor 
wound depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness) by including 
the factor in a logistic regression model together with the treatment variable (NexoBrid vs. Gel 
Vehicle). Similarly, if convergence of the estimation procedure can be obtained, then, in two 
other supportive analyses, the factor “Total %TBSA per patient” and the factor treatment center 
group (see Section 13.8.5 of the protocol as well as Section 11.1.7 of this SAP) will be included 
in a logistic regression model with the treatment variable. Statistical inference will be based 
upon exact distribution methods using the “exact” statement in the SAS procedure PROC 
LOGISTIC. The estimated regression coefficients of the regression analyses will be presented 
as displayed in Table 7. 
The odds ratio of achieving complete eschar removal for NexoBrid versus Gel Vehicle will be 
estimated from these supportive models, as well as 95% confidence intervals and the level of 
statistical significance. The results will be displayed as shown in Table 6. 
The primary efficacy analysis will be repeated on a wound level as an additional analysis using 
a mixed logistic regression model with a random effect for patient. 
Furthermore, as an additional sensitivity analysis, the primary analysis will be repeated using 
the PP as analysis population. 
If any of the baseline factors, gender, age, percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%), time from injury to randomization or 
number of TWs (1, 2, ≥3) are found to be significantly different between the treatment groups, 
then, if possible, the factor will be included as an extra adjusting covariate in a supportive 
analysis of the primary endpoint. 
11.1.3. Secondary Efficacy variables 
The secondary endpoints will be analyzed as described below and will compare efficacy in the 
NexoBrid group with the SOC group. Missing data will be handled by the methods described 
in Section 10.1. All secondary endpoints will be analyzed using the FAS. Sensitivity analyses 
will include analyzing the endpoints using the PP as analysis population. 
11.1.3.1. 
Incidence of surgical excision 
This is a binary yes/no variable and the proportion of patients who need excision for eschar 
removal will be compared using logistic regression. The explanatory variables in the model will 
include treatment, and the following variables: overall TW depth (all TWs full thickness, mixed 
TWs, all TWs deep partial thickness), “Total %TBSA per patient” and number of TWs (1, 2, 


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≥3). The odds ratio of requiring surgery for NexoBrid versus SOC will be estimated from the 
model, as well as 95% confidence intervals and the level of statistical significance. The results 
will be displayed as shown in Table 6 and Table 7. Bar plots will be shown for the proportions 
of patients who needed excision for eschar removal. 
If numerically possible, as a supportive analysis, the variable treatment center will be added 
into the logistic regression model and the analysis repeated. 
As a sensitivity analysis, the logistic regression outlined above will be repeated using the PP 
as analysis population. 
If any of the baseline factors, gender, age, percent SPT area (the area of SPT as a percentage 
of the total area of all TWs, classified as <25% or ≥25%), time from injury to randomization or 
number of TWs (1, 2, ≥3) are found to be significantly different between the treatment groups, 
then the factor will be included as an extra adjusting covariate in the logistic regression model 
described above as additional analysis. 
As supportive analysis, the incidence of surgical excision for eschar removal will be compared 
between NexoBrid and Gel Vehicle using the same explanatory variables as in the main 
analysis of this endpoint. 
A further supportive analysis will repeat the analysis (NexoBrid versus SOC) as described 
above, but on a wound level. I.e. a mixed logistic regression model with explanatory variables 
treatment, TW depth, %TBSA per wound and number of TWs and a random effect for patient 
will be performed. 
11.1.3.2. 
Time to complete eschar removal 
Time until complete eschar removal will be defined as the time until complete eschar removal 
has been achieved at a patient level, i.e. for all TW’s of an individual patient. This will be 
measured as time from the randomization date (hours). For patients who do not reach 
complete eschar removal, their time will be censored at the last non-missing eschar removal 
assessment (typically the last debridement procedure). Kaplan-Meier curves will be presented 
graphically (see Figure 3) and in a table (see Table 8) to display the distribution of time to 
complete eschar removal under the two treatments (NexoBrid vs. SOC). Median time to 
complete eschar removal will be estimated for each treatment group with a 95% confidence 
interval. Additionally, time to complete eschar removal will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4. The treatment groups will be compared using a Cox 
regression model. The comparison will be adjusted for the explanatory variables overall TW 


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depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness), “Total %TBSA per 
patient”, center group (as defined in Section 11.1.10) and number of TWs (1, 2, ≥3), by 
including each of them in the Cox regression model together with the treatment variable 
(NexoBrid vs. SOC). The results of the regression analysis will be displayed as in Table 7. The 
treatment groups will be compared by testing the null hypothesis of no difference, comparing 
the ratio of the estimated treatment coefficient to its standard error to a standard normal 
distribution. 
The Cox Regression analysis outlined above will be performed if the proportional hazards 
assumption appears to hold. This will be checked by including in the regression model a 
variable representing the interaction between time since randomization and treatment group. 
If the coefficient for this time variable is non-significant at the 5% significance level, then the 
Cox Regression analysis will be adopted. If the time-treatment group interaction is significant, 
then a generalized Wilcoxon-Gehan test will be performed using the Wilcoxon option (also 
provided by default) in the SAS procedure PROC LIFETEST using the following SAS Code: 
PROC LIFETEST DATA=burn_data; 
TIME time*status(0); 
STRATA depthgroup numtw tbsagroup centergroup / GROUP = treatment_group; 
RUN;  
Here burn_data is the data set containing all necessary information. The variable time is the 
time to complete eschar removal, status is a censoring variable and depthgroup, numtw, 
tbsagroup, and centergroup are the variables, which is adjusted for. Depthgroup, tbsagroup 
and centergroup are the stratification levels defined in Section 11.1.10 and numtw is the 
number of target wounds (1, 2, ≥3). 
As sensitivity analysis the procedure outlined above will be repeated using the PP instead of 
the FAS as analysis population. 
Supportive analyses will include adjustment for other baseline variables that are imbalanced 
(i.e. gender, age, percent SPT area [the area of SPT as a percentage of the total area of all 
TWs, classified as <25% or ≥25%], time from injury to randomization or number of TWs (1, 2, 
≥3)), and investigating interactions between those variables and the treatment groups. In case 
the proportional hazards assumption could not be rejected, this will be done by including each 
of the imbalanced baseline variable as well as the interaction between that variable and the 
treatment group in a separate cox regression analysis. The results of these analyses will be 
presented as in Table 7. In case the proportional hazards assumption does not hold, the 
adjustment for the baseline variables will be done using the following SAS code: 


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PROC LIFETEST DATA=burn_data; 
TIME time*status(0); 
STRATA depthgroup numtw tbsagroup centergroup gender agegroup sptgroup / 
GROUP = treatment_group; 
RUN;  
Here burn_data is the data set containing all necessary information. The variable time is the 
time to complete eschar removal, status is a censoring variable and depthgroup, numtw, 
tbsagroup, centergroup, gender, agegroup and sptgroup are the variables, which is adjusted 
for. Agegroup is the categorical age variable computed in Section 10.1.1.2, depthgroup, 
tbsagroup and centergroup are the stratification levels defined in Section 11.1.10 and numtw 
is the number of target wounds (1, 2, ≥3). 
Another supportive analysis will be the comparison of treatments based on the time of 
complete eschar removal measured from the date of ICF using the same methods as for the 
time measured from randomization. 
Another supportive analysis will be the comparison of treatments based on the time of 
complete eschar removal measured from the date of injury using the same methods as for the 
time measured from randomization. 
As an additional analysis, time to complete eschar removal will be compared between 
NexoBrid and Gel Vehicle using the same explanatory variables as for the main analysis of 
this endpoint. 
11.1.3.3. 
Blood loss 
In Section 10.3.3.3 two blood loss estimates are defined. Analyses with both blood loss 
estimates will be conducted. However, some missing values are expected. The analysis with 
less missing values will be regarded as more reliable and is therefore considered the main 
analysis. The other analysis is considered supportive. Both analyses will be conducted as 
follows: 
The measure of blood loss defined in Section 10.3.3.3 will be computed for each patient, and 
the distribution in the NexoBrid group will be compared with that in the SOC group. Means, 
standard deviations, medians, and interquartile ranges will be calculated and presented as in 
Table 4. Furthermore, the blood loss will be described graphically by histograms. The normality 
of the data will be tested on each treatment group using the Shapiro-Wilk test. If the normal 
distribution hypothesis is not rejected at the 0.5% significance level in either group, then 
differences in distribution between NexoBrid and SOC will be tested using a t-test. If the normal 
distribution hypothesis is rejected either in the NexoBrid group or in the SOC group, then the 


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differences in distribution between the treatment groups will be tested using a Mann-Whitney 
test. The test results will be presented as in Table 7. 
As sensitivity analysis, the procedure outlined above will be repeated using the PP instead of 
the FAS as analysis population. 
Supportive analyses will include adjustments for the covariates overall TW depth (all TWs full 
thickness, mixed TWs, all TWs deep partial thickness), “Total %TBSA per patient”, center 
group (as defined in Section 11.1.10), number of TWs (1, 2, ≥3) and number of debridement 
procedures. This will be done by including these variables in a regression model for blood loss 
together with treatment group. 
If any of the baseline factors, gender, age, or percent SPT area (the area of SPT as a 
percentage of the total area of all TWs, classified as <25% or ≥25%), time from injury to 
randomization are found to be significantly different between the treatment groups, then the 
factor will be included as an extra adjusting covariate in a supportive analysis of blood loss (as 
described in the preceding paragraph). 
As an additional analysis, blood loss will be compared between NexoBrid and Gel Vehicle 
without covariate adjustment (similar to the main analysis of this endpoint). 
11.1.4. Safety variables 
All safety variables except for the first safety endpoint “time to wound closure” will be evaluated 
on the safety set. 
11.1.4.1. 
Safety Endpoint: Time to wound closure 
This safety endpoint will be analyzed using the FAS. A sensitivity analysis will be done by 
repeating the analysis outlined below with the PP as analysis population. 
Time to reach complete wound closure will be compared between the NexoBrid and SOC at a 
wound level using a method of survival analysis with clustered data that is based on 
appropriate assumptions. By “clustered data”, we refer to the multiple target wounds that can 
occur in a patient. As stated in the protocol, a non-inferiority margin will be incorporated into 
the analysis that will represent a 7-day advantage to the SOC group. This will be done by 
adding 7 days to the wound closure times in the SOC group. After that, the proportional 
hazards assumption will be checked in the same way as in the analysis of the timely eschar 
removal endpoint. I.e. a marginal cox regression model with a robust sandwich estimator (see 
below for further details) will be performed including the variables treatment, TW depth (on a 
wound level), %TBSA (on a wound level) and number of TWs (1, 2, ≥3) as well as a variable 


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representing the interaction between time since randomization and treatment group. If the 
coefficient for this time variable is non-significant at the 5% significance level, then the 
proportional hazards assumption will be considered appropriate. In this case we will use a 
marginal Cox regression analysis with a robust sandwich estimator. If not, then we will use an 
accelerated failure time (AFT) model with shared frailty. Note that this deviates from the 
previously planned parametric frailty model implemented in the SAS procedure PHREG. The 
latter one assumes proportional hazards and is therefore not suitable here. 
Either method can be implemented in SAS (see [33] for details). The marginal Cox regression 
model is implemented in the PHREG procedure and the robust variance option is implemented 
by specifying the COVS(AGGREGATE) option. This induces the use of the robust variance 
method of Binder et. al. [34]. The accelerated failure time model with shared frailty will be 
implemented using the following SAS-code:  
PROC NLMIXED DATA=burn_data; 
BOUNDS gamma>0; 
linp = b0 + b1*treatment_group + b2*spt + b3*dpt + b4*ft + b5*tbsa + 
b6*number_tw2+ b7*number_tw3 + b8*center2 + b9*center3 + b10*center4 + 
b11*center5 + z; 
alpha = exp(-linp); 
G_t = 1/(1+alpha*time**gamma); 
g = alpha*gamma*time**(gamma-1)/(1+alpha*time**gamma)**2; 
ll = (censor=0)*log(g) + (censor=1)*log(G_t); 
model time~general(ll); 
RANDOM z ~ normal(0,sigma) subject=subject_id; 
RUN; 
where subject_ID is a unique identification number for each patient, time is the time to wound 
closure on a wound level. Censor is a censoring indicator, treatment_group gives the treatment 
group, spt gives the % area SPT (on a wound level), dpt gives the % area DPT (on a wound 
level), ft gives the % area FT (on a wound level), TBSA gives the %TBSA (on a wound level), 
number_tw2 is an indicator variable for the subject having 2 target wounds (patient level), 
number_tw3 is an indicator variable for the subject having ≥3 target wounds (patient level), 
center2,…,center5 are indicator variables for the individual being in center group 2,…,5 
(patient level) and burn_data is a SAS data set containing the required information. 
The SAS code presented above calculates the treatment effect in an accelerated failure time 
model with shared frailty assuming a log-logistic distribution of the data. The commonly used 
Weibull-distribution is not applicable in this case, because the AFT model is equivalent to a 
proportional hazards model. 


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The presented methods include information on all the target wounds of each patient and 
account for any within-patient correlation. Missing information due to incomplete follow-up is 
incorporated naturally into such analyses as censored observations.  
Kaplan-Meier curves will be presented graphically (see Figure 3) and in a table (see Table 8) 
to display the distribution of time to complete wound closure under the two treatments. 
If any of the baseline factors, gender, age, or percent SPT area (the area of SPT as a 
percentage of the total area of all TWs, classified as <25% or ≥25%) are found to be 
significantly different between the treatment groups, then the factor will be included as an extra 
adjusting covariate in a supportive analysis of time to complete wound closure. 
Furthermore, time to reach 100% wound closure will be analyzed as outlined above as an 
additional analysis. 
11.1.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
Not applicable for this stage of analysis since the relevant information for all patients is not 
available yet. This endpoint will be analyzed in the second stage analysis (see 11.2.4.2). 
11.1.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
Not applicable for this stage of analysis since the relevant information for all patients is not 
available yet. This endpoint will be analyzed in the third stage analysis (see 11.3.4.3). 
11.1.4.4. 
Adverse Events 
In this analysis, only the adverse events occurring in the acute phase (until the 3 months follow-
up for each patient) will be analyzed. 
All adverse events will be listed (see Table 14). 
Adverse events are classified as being general, local – TW related or local – not TW related in 
the eCRF. Per each of these categories, the AEs will be listed as given in Table 9 and Table 
10. The listing will be presented separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 


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· 
Time of onset (before start of treatment / during the treatment session / during the first 
week after treatment / during week 2 to week 4 after treatment / during week 5 to week 
8 after treatment / more than 8 weeks after treatment) 
SAEs will be analyzed in the same way as AEs. 
11.1.4.5. 
Vital Signs 
All vital signs (body temperature, heart rate, respiratory rate, systolic blood pressure, diastolic 
blood pressure) will be analyzed descriptively with number of subjects, number of missing 
values, mean, standard deviation, min, max, median and quartiles as shown in Table 4 and 
compared between groups with a one way analysis of variance. A graphical representation of 
the data will be done using histograms. 
The analyses will be done for the vital signs assessments at screening, post eschar removal 
procedures, at the first 7 daily assessments as well as for the pre-post differences per 
procedure and the pre-post differences of the daily vital signs assessments described in 
Section 10.3.4.4 separately. 
Furthermore, for the vital signs assessment at screening, post eschar removal procedures and 
at the first 7 daily assessments the information whether the overall vital signs assessment was 
normal, abnormal (NCS) or abnormal (CS) is given in the eCRF. These classifications will be 
analyzed separately for each time point of vital signs assessment by displaying counts and 
percentages by treatment group (see Table 5). The proportion of normal / abnormal (NCS) and 
abnormal (CS) assessments will be compared between treatment groups using a chi square 
test (or Fisher’s exact test in case of small estimated cell counts). Bar plots of the proportions 
of patients with normal / abnormal (NCS) and abnormal (CS) assessments will be shown. 
11.1.4.6. 
Pain Assessment 
The pain assessment score will be analyzed descriptively with number of units, number of 
missing values, mean, standard deviation, min, max, median and quartiles as shown in Table 
4 and compared between groups with a one way analysis of variance. A graphical 
representation of the data will be done using histograms. Furthermore, a plot of the mean pain 
(and the mean change in pain from baseline) over time will be presented. 
The analyses will be done for the pain assessments at screening, pre and post eschar removal 
procedures, at the first 7 daily assessments as well as for the pre-post differences of the daily 
vital sings assessments (difference to baseline) described in Section 10.3.4.4 separately. 


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Furthermore, for the pain assessment at screening, pre and post eschar removal procedures 
and at the first 7 daily assessments the information whether the pain assessment was normal, 
abnormal (NCS) or abnormal (CS) is given in the eCRF. These classifications will be analyzed 
separately for each time point of vital signs assessment by displaying counts and percentages 
by treatment group (see Table 5). The proportion of normal / abnormal (NCS) and abnormal 
(CS) assessments will be compared between treatment groups using a chi square test (or 
Fisher’s exact test in case of small estimated cell counts). 
11.1.4.7. 
Extend of exposure to study drug 
Counts and percentages of patients having one respectively two applications will be presented 
as shown in Table 5 for the NexoBrid and the Gel Vehicle arm. A chi-squared test (or in case 
of small estimated cell counts Fisher’s exact test) will be used to test for any differences in the 
application data between the two treatment groups. Bar plots of the extend of exposure will be 
shown. 
Furthermore, numbers of patients in the NexoBrid arm being exposed to different grams of 
NexoBrid powder will be displayed. 
11.1.4.8. 
Medical history and concomitant diseases 
The concomitant diseases will be classified using the MedDRA dictionary. They will be 
tabulated with reference to system organ class and frequency of occurrence (see Table 9). A 
similar analysis will be conducted but on the level of preferred terms instead of system organ 
class. Concomitant diseases include all active conditions at start of trial (as documented in the 
medical history). The analysis of medical history conditions will be done and displayed 
separately for previous and ongoing diseases. 
11.1.4.9. 
Concomitant medication 
In this analysis, only the concomitant medication administered during the acute phase (until 
the 3 months follow-up for each patient) will be analyzed. The number of concomitant 
medication and patients involved will be tabulated with reference to ATC coding (see Table 
11). 
11.1.4.10. 
Central laboratory values 
Laboratory measurements obtained prior and after each eschar removal procedure as well as 
pre-post differences in laboratory values for each eschar removal procedure will be analyzed 
descriptively with number of subjects, number of missing values, mean, standard deviation, 
min, max, median and quartiles as presented in Table 4. 


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As described in Section 10.3.6, laboratory values will be categorized as “abnormal (low)”, 
“normal” and “abnormal (high)” based on the reference limits of the labs. This categorization 
will be analyzed by displaying counts and percentages of each category by treatment group 
and by procedure (see Table 5) for each laboratory value separately. 
11.1.4.11. 
Blood transfusions 
The volume of blood transfusions in milliliters (as calculated in Section 10.3.4.4) will be 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as presented in Table 4. The mean volume of blood 
transfusions between treatment groups will be compared by a one-way analysis of variance. 
Histograms will be provided to illustrate the distribution of the volume of blood transfusions in 
the treatment groups. 
The volume of blood transfusions will be presented overall, as well as separately for volumes 
transfused before start of treatment, during the ER period, within 1 week after the ER period 
and later than 1 week after the ER period. 
11.1.4.12. 
Maintenance of complete wound closure 
This is a binary (yes/no) variable (on a wound level). Maintenance of complete wound closure 
will be analyzed by displaying counts and percentages of wounds maintaining complete wound 
closure by treatment group (see Table 5). The proportion of wounds maintaining complete 
wound closure will be compared between treatment groups using a chi square test (or Fisher’s 
exact test in case of small estimated cell counts). Bar plots of the proportions of wounds 
maintaining complete wound closure will be shown. 
The analysis will be conducted for the information present at month 1 and month 3 after wound 
closure. 
11.1.4.13. 
Incidence of QT prolongation 
Incidence of QT prolongation will be analyzed separately. See separate document for the 
description of the analysis. 
11.1.4.14. 
Analgesia, anesthesia and antibiotic use 
For an analysis of the level of sedation, the number and percentage of patients per each level 
of sedation and each eschar removal procedure (in topical arms: 1st and second topical 
application, surgical rescue procedures and non-surgical rescue procedures; in SOC arms: 
surgical procedures and non-surgical procedures) will be tabulated. 


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The number of days of exposure to antibiotic drugs will be analyzed descriptively with number 
of units, number of missing values, mean, standard deviation, min, max, median and quartiles 
as shown in Table 4 and compared between groups with a one way analysis of variance. This 
analysis will be conducted for overall antibiotic use, for antibiotic use due to AE involvement 
(as indicated in the eCRF) and for prophylactic antibiotic use (as indicated in the eCRF) 
separately. 
11.1.4.15. 
Hospital readmission rates 
Hospital admission rates will be analyzed on a patient level by displaying counts and 
percentages by treatment group (see Table 5). The proportion of patients needing readmission 
to a hospital will be compared between treatment groups using a chi square test (or Fisher’s 
exact test in case of small estimated cell counts) and presented graphically using bar plots. 
Furthermore, the number of planned hospital readmissions per patient will be analyzed by 
displaying counts and percentages by treatment group (see Table 5). The number of planned 
hospital readmissions per patient will be compared between treatment groups using a chi 
square test (or Fisher’s exact test in case of small estimated cell counts) and presented 
graphically using bar plots. 
Additionally, the number of unplanned hospital readmissions per patient will be analyzed by 
displaying counts and percentages by treatment group (see Table 5). The number of 
unplanned hospital readmissions per patient will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts) and presented 
graphically using bar plots. 
Hospital readmission will also be analyzed on a readmission level. Counts and percentages of 
planned/unplanned readmissions will be displayed by treatment group (see Table 5). The 
proportion of planned/unplanned readmissions to hospitals will be compared between 
treatment groups using a chi square test (or Fisher’s exact test in case of small estimated cell 
counts) and presented graphically using bar plots 
11.1.4.16. 
INR/PTT change 
Change in INR/PTT will be evaluated at 4h post first treatment as well as on the first and 
second daily assessment post treatment separately. This is a binary (yes/no) variable 
indicating whether the patient experienced a change of INR/PTT to > normal range (reference 
limits of the local laboratories). Rates of patients with this event will be analyzed by displaying 
counts and percentages by treatment group (see Table 5) in each time point separately (4h 
post, 24h and 48h). Reference count is the number of patients with normal PTT/INR values at 


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baseline. For the classification of normal and abnormal PTT/INR values, the reference limits 
of the local labs will be used. The proportion of patients with change of INR/PTT to > normal 
range will be compared between treatment groups using a chi square test (or Fisher’s exact 
test in case of small estimated cell counts). 
INR/PTT values will be classified as normal, abnormal (NCS) and abnormal (CS) based in the 
eCRF. These will be analyzed by displaying counts and percentages by treatment group (see 
Table 5) for each time point separately (4h post, 24h and 48h). 
11.1.4.17. 
Blood glucose change 
This is a binary (yes/no) variable indicating whether the patient experienced a change of blood 
glucose to > upper limit of normal range. Rates of patients with this event will be analyzed by 
displaying counts and percentages by treatment group (see Table 5) per eschar removal 
procedure. Furthermore, bar plots will be displayed. The proportion of patients with change of 
blood glucose to > upper limit of normal range will be compared between treatment groups 
using a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
Furthermore, the change in blood glucose from baseline to 4h post treatment per patient will 
be analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as shown in Table 4 and compared between groups 
with a one way analysis of variance. A graphical representation of the data will be done using 
histograms. 
11.1.5. Exploratory Analyses 
11.1.5.1. 
% wound area surgically excised for eschar removal 
The % wound area surgically excised for eschar removal per patient (computed as in 
section 10.3.5.5) will be analyzed descriptively with number of units, number of missing values, 
mean, standard deviation, min, max, median and quartiles as shown in Table 4 and compared 
between groups with a one way analysis of variance. A graphical representation of the data 
will be done using histograms. 
11.1.5.2. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
Two analyses will be done for this exploratory endpoint. The number and percentage of 
circumferential extremities target wounds that went through escharotomy will be presented by 
treatment group (see Table 5). The proportion of circumferential extremities target wounds that 


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went through escharotomy will be compared between treatment groups using a chi square test 
(or Fisher’s exact test in case of small estimated cell counts). 
The number and percentage of patients having at least one circumferential extremities target 
wound, which went through escharotomy, will be presented by treatment group (see Table 5). 
Furthermore, bar plots will be displayed. The proportion of patients having at least one 
circumferential extremities target wound which went through escharotomy will be compared 
between treatment groups using a chi square test (or Fisher’s exact test in case of small 
estimated cell counts). 
11.1.5.3. 
Incidence of reduction in interstitial/compartment pressure in 
circumferential extremities target wounds 
This is a binary (yes/no) variable indicating whether the patient experienced reduction in 
interstitial/compartment pressure in circumferential extremities target wounds for each target 
wound and each procedure separately. Rates of patients with this event will be analyzed by 
displaying counts and percentages by treatment group (see Table 5). Furthermore, bar plots 
will be displayed. The proportion of patients with reduction in interstitial/compartment pressure 
in circumferential extremities target wounds will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
11.1.5.4. 
Incidence of surgically harvested donor site wounds 
This is a counting variable, giving the number of donor site wounds per patient. Rates of 
patients with different numbers of donor site wounds will be analyzed by displaying counts and 
percentages by treatment group (see Table 5). Furthermore, bar plots will be displayed (see 
Figure 2). The number of donor site wounds will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
11.1.5.5. 
% area of surgically harvested donor site wounds 
The % wound area of surgically harvested donor site wounds per patient (computed as in 
section 10.3.5.11) will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as shown in Table 4 and 
compared between groups with a one way analysis of variance. A graphical representation of 
the data will be done using histograms. 


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11.1.5.6. 
Blood loss using changes in hematocrit following eschar removal 
procedures 
The measure of blood loss defined in Section 10.3.5.12 will be computed for each patient, 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as shown in Table 4 and compared between groups 
with a one way analysis of variance. A graphical representation of the data will be done using 
histograms. 
11.1.5.7. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
The measure of blood loss defined in Section 10.3.5.13 will be computed for each patient, 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as shown in Table 4 and compared between groups 
with a one way analysis of variance. A graphical representation of the data will be done using 
histograms. 
11.1.5.8. 
Blood loss in NexoBrid procedures vs. surgical procedures 
The measure of blood loss defined in Section 10.3.3.3.1 will be computed for each procedure, 
and analyzed descriptively with number of procedures, number of missing values, mean, 
standard deviation, min, max, median and quartiles as shown in Table 4 and compared 
between NexoBrid procedures and surgical procedures with a one way analysis of variance. 
A graphical representation of the data will be done using histograms. 
11.1.5.9. 
Autograft related parameters 
Total number of autografting procedures 
The total number of autografting procedures (per patient) will be analyzed by displaying counts 
and percentages by treatment group (see Table 5). Furthermore, bar plots will be displayed. 
The distribution of the total number of autografting procedures will compared between 
treatment groups using a chi square test (or Fisher’s exact test in case of small estimated cell 
counts). 
This analysis will be repeated on a wound level. 
Incidence of repeated autografting 
This is a binary (yes/no) variable indicating whether the patient had more than one autograft 
procedure during the study (based on different dates on the same TW). Rates of patients with 


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more than one autograft procedure will be analyzed by displaying counts and percentages by 
treatment group (see Table 5). Furthermore, bar plots will be displayed. The proportion of 
patients with repeated autograft procedures will be compared between treatment groups using 
a chi square test (or Fisher’s exact test in case of small estimated cell counts). 
This analysis will be repeated on a wound level. 
Area of repeated autografting 
The area of repeated autografting per patient will be analyzed descriptively with number of 
units, number of missing values, mean, standard deviation, min, max, median and quartiles as 
shown in Table 4 and compared between groups with a one way analysis of variance. A 
graphical representation of the data will be done using histograms. 
This analysis will be repeated on a wound level. 
Early autografted wounds 
A subgroup analysis will be performed on the subgroup of target wounds that are early grafted 
(for a definition see Appendix 13.1.1). The primary endpoint, the secondary endpoints 
“incidence of surgical excision” and “time to complete eschar removal”, as well as the safety 
endpoint “time to complete wound closure” will be analyzed while only taking wounds that are 
early grafted into account. 
Late autografted wounds 
A subgroup analysis will be performed on the subgroup of target wounds that are late grafted 
(for a definition see Appendix 13.1.1). The primary endpoint, the secondary endpoints 
“incidence of surgical excision” and “time to complete eschar removal”, as well as the safety 
endpoint “time to complete wound closure” will be analyzed while only taking wounds that are 
late grafted into account. 
11.1.5.10. 
Duration of hospitalization 
The duration of hospitalization will be analyzed descriptively with Kaplan-Meier plots (see 
Figure 3) and compared between groups with a log rank test. 
11.1.6. Pharmacokinetic Variables 
Pharmacokinetic variables will be analyzed separately. The analysis is described in a separate 
document. 


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11.1.7. Multicenter Data 
Randomization will be stratified by center group as detailed in the Section 13.7.2 of the 
protocol. 
The analyses of the primary and secondary endpoints of this trial will adjust for possible effects 
of the variable center by including it as covariate in the analyses. 
11.1.8. Handling of Multiple Comparisons 
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. The primary and secondary endpoints of 
efficacy will be tested in a hierarchy, so as to preserve the nominal significance levels:  
1. Primary 
2. Incidence of surgery 
3. Time to complete eschar removal 
4. Blood loss. 
11.1.9. Interim analysis 
No interim analyses will be performed. 
11.1.10. Stratification 
The following factors are used to stratify the study design: 
 
A. Total TBSA % per patient  
A1: Total TBSA <=15%  
A2: Total TBSA >15%  
 
B. Overall depth per patient  
B1: All TWs are full thickness;  
B2: Mixed TWs – full thickness and deep partial thickness  
B3: All TWs are deep partial thickness.  
 


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C. Center Group, to address possible differences in SOC procedures between sites (if 
any), to allow comparison of the results within group of centers and to reduce the 
likelihood of a group of centers including patients in only one arm of the study (5 groups 
of centers were formed based on similarity of SOC practice).  
 
These factors are accounted for in the analyses of the primary and secondary endpoints by 
including them as adjusting variables. 
11.1.11. Analysis of Subgroups 
The following subgroup analyses were pre planned and will be conducted to explore efficacy 
and safety within certain pre-defined subgroups of the population. All analyses presented here 
are of exploratory nature. 
11.1.11.1. 
Target wounds in the anatomical area of the hand 
A subgroup analysis will be performed on the subgroup of target wounds that are found, at 
least partly, in the anatomical area of the hand. The primary and secondary endpoints will be 
analyzed while only taking wounds that are found, at least partly, in the anatomical area of the 
hand into account. 
11.1.11.2. 
Patients with < 25% SPT area 
Patients will be classified as having < 25 % or ≥ 25% SPT area as a percentage of the area of 
all TWs. 
For the subgroup of patients with < 25 % SPT area descriptive statistics (counts and 
percentages) of patients achieving complete eschar removal will be displayed for patients 
treated with NexoBrid or Gel Vehicle as shown in Table 5. The two groups will be compared 
using Fisher’s exact test. The results will further be described by a bar plot (see Figure 2). 
For the secondary endpoint “surgical excision performed” counts and percentages of patients 
needing surgical excision will be presented (see Table 5). The treatment groups will be 
compared using a chi square test (of Fisher’s exact test in case of small expected cell counts). 
The secondary endpoint “time to complete eschar removal” Kaplan-Meier estimates will be 
presented graphically and in a table (see Figure 3 and Table 8). Time to complete eschar 
removal will be compared between treatment groups by a log rank test. 
For the secondary endpoint “blood loss” the number of subjects, number of missing values, 
means, standard deviations, medians, quartiles, minimums and maximums will be calculated 


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and presented as in Table 4. Furthermore, the blood loss will be described graphically by 
histograms (see Figure 1). Treatment groups will be compared using a t-test. 
The safety endpoint “time to reach complete wound closure” will be analyzed by presenting 
Kaplan-Meier estimates graphically and in a table (see Figure 3 and Table 8). Time to complete 
wound closure will be compared between treatment groups by a log rank test. 
11.1.11.3. 
Patients with ≥ 25% SPT area 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with ≥ 
25% SPT area. 
11.1.11.4. 
Total TBSA ≤ 15% 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
total TBSA <=15%. 
11.1.11.5. 
Total TBSA > 15% 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
total TBSA > 15%. 
11.1.11.6. 
All target wounds full thickness 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
all target wounds classified as full thickness wounds. 
11.1.11.7. 
Mixed target wounds – full thickness and deep partial thickness 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
mixed thickness target wounds (full thickness and deep partial thickness). 
11.1.11.8. 
All target wounds are deep partial thickness 
The same analysis as in Section 11.1.11.2 will be done but on the subgroup of patients with 
all target wounds classified as deep partial thickness wounds. 
11.1.11.9. 
Wounds that are entirely full thickness 
The same analysis as in Section 11.1.11.1 will be performed but on the subgroup of wounds 
that are entirely full thickness wounds. 
 
 


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11.2. Second stage analysis – 12 month short-term follow-up (STFU12) 
11.2.1. Demographics and Other Baseline Characteristics 
Not applicable for this stage of analysis since all information on demographics and other 
baseline characteristics was already analyzed in the first stage analysis (see 11.1.1). 
11.2.2. Primary Efficacy variable 
Not applicable for this stage of analysis since all information on the primary efficacy variable 
was already analyzed in the first stage analysis (see 11.1.2). 
11.2.3. Secondary Efficacy variables 
Not applicable for this stage of analysis since all information on the secondary efficacy 
variables was already analyzed in the first stage analysis (see 11.1.3). 
11.2.4. Safety variables 
11.2.4.1. 
Safety Endpoint: Time to wound closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the first stage analysis (see 11.1.4.1). 
11.2.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
The MVSS score for a patient will be calculated as described in Section 10.3.4.2. The mean 
and standard error of this MVSS score (for the target wounds) at 12 months will be 
estimated for each treatment group and presented as shown in Table 4. The treatment 
groups will be compared using a linear model with MVSS score as the dependent variable. 
The explanatory variables in the model will include treatment, and the following variables: 
overall TW depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness), “Total 
%TBSA per patient” and number of TWs (1, 2, ≥3). The coefficient corresponding to the 
treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 
factors. The results of the regression analysis will be presented as in Table 7. 


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A clinically meaningful difference will be incorporated into the analysis that will represent 
a 1.9 or more units advantage to the SOC group, so that the analysis will show whether 
the NexoBrid group is estimated to have on average a MVSS score that is not worse by 
more than 1.9 units than the score for the SOC group. That is, the following hypothesis are 
about to be tested: 
  : ! " 1.9#####$%.#####&': ! < 1.9# 
Where ! is the mean difference in MVSS score between NexoBrid and SOC adjusted for 
any imbalance in the stratification factors. These hypotheses will be tested by comparing 
the 95% confidence interval for the coefficient of the treatment group from the linear model 
outlined above to the clinically meaningful difference 1.9. The null hypothesis will be 
rejected if the upper bound of this interval is smaller than 1.9. 
For handling of missing data see Section 10.1.2.2.  
11.2.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
Not applicable for this stage of analysis since the relevant information for all patients is not 
available yet. This endpoint will be analyzed in the third stage analysis (see 11.3.4.3).  
11.2.4.4. 
Adverse Events 
In this analysis, only the adverse events occurring after the 3 months follow up and until the 
12 months follow up (including AEs from the first stage that are still ongoing) will be analyzed. 
All adverse events will be listed (see Table 14). 
Adverse events are classified as being general, local – TW related or local – not TW related in 
the eCRF. Per each of these categories, the AEs will be listed as given in Table 9 and Table 
10. The listing will be presented separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (until 3 months follow up [i.e. AEs from first stage that are still ongoing] / 
between 3 months follow up and 12 months follow up) 
SAEs will be analyzed in the same way as AEs. 


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11.2.4.5. 
Concomitant medication 
In this analysis, only the concomitant medications given after the 3 months follow up and until 
the 12 months follow up (including CM with a start date before the 3 months follow up but an 
end date after that or still ongoing at 12 months) will be analyzed. 
The number of concomitant medication and patients involved will be tabulated with reference 
to ATC coding (see Table 12). 
11.2.4.6. 
Lower Extremity Function Scale (LEFS) 
The LEFS scores of the 12 months follow up assessment will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4. The mean LEFS scores between treatment groups will be 
compared by a one-way analysis of variance. Histograms will be provided to illustrate the 
distribution of LEFS values. 
11.2.4.7. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH scores of the 12 months follow up assessment will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4. The mean QuickDASH scores between treatment 
groups will be compared by a one-way analysis of variance. Histograms will be provided to 
illustrate the distribution of QuickDASH values. 
11.2.4.8. 
Range of Motion (ROM) 
The 12 months range of motion will be evaluated using 3 binary (yes/no) variables. The 
variables indicate whether all ROM were normal, whether there was at least one abnormal 
(NCS) finding and whether there was at least one abnormal (CS) finding. This information is 
present per patient and per visit. Rates of patients with this event will be analyzed by displaying 
counts and percentages by treatment group (see Table 5) per variable (all normal / at least 
one abnormal (NCS) / at least one normal (CS)) and per visit. Furthermore, bar plots will be 
displayed. The proportion of patients with all normal / at least one abnormal (NCS) / at least 
one normal (CS) range of motion will be compared between treatment groups using a chi 
square test (or Fisher’s exact test in case of small estimated cell counts). 
11.2.4.9. 
EQ-5D (Quality of Life) 
The 12 months follow up assessment of the EQ-5D will be analyzed as follows. 
The EQ-5D consists of 5 items with 3 possible answers each and an EQ visual analogue scale. 
For each item (Mobility, Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression) the 


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count and percentages of each possible answer will be presented per age group and per 
treatment group as in Tables 3 and 4 of the EQ-5D-3L user guide [32]. Furthermore, bar plots 
will be provided. The difference between treatment groups will be tested using a chi square 
test (or Fishers’ exact test in case of small expected cell counts). 
The values of the EQ visual analogue scale (EQ VAS) will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 3 of the EQ-5D-3L user guide [32]. The mean EQ VAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of EQ VAS values. 
11.2.4.10. 
Burn Specific Health Scale – Brief (BSHS-B) 
The 12 months follow up assessment of the BSHS-B will be analyzed as follows. 
Each domain specific sub score and the overall BSHS-B score will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4.The mean (sub-) score values between treatment groups 
will be compared by a one-way analysis of variance. Histograms will be provided to illustrate 
the distribution of (sub-) score values. 
11.2.5. Exploratory Analyses 
11.2.5.1. 
POSAS 
The POSAS for target wounds will be calculated as outlined in Section 10.3.5.7 and will be 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as presented in Table 4. The mean POSAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of POSAS in the treatment groups. 
The analysis will be repeated for the patient scale and for the observer scale separately. 
The analysis will be repeated for donor site scars. 
The analyses will be conducted for the POSAS assessments of 1, 3, 6 and 12 months. 
11.2.5.2. 
MVSS (target wounds) 
The MVSS for target wounds at 1, 3, and 6 months will be calculated as outlined in 
Section 10.3.4.2 and will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 


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of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.2.5.3. 
MVSS (donor site scars) 
The MVSS for donor site scars at 1, 3, 6 and 12 months will be calculated as outlined in 
Section 10.3.4.2 and will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.2.6. Pharmacokinetic Variables 
Not applicable. All pharmacokinetic data was already analyzed in the first stage analysis (see 
Section 11.1.6). 
11.2.7. Multicenter Data 
See Section 11.1.7. 
11.2.8. Handling of Multiple Comparisons 
Not applicable. All testing done during this second stage analysis is exploratory in nature. So 
no adjustment for multiplicity is needed. 
11.2.9. Interim analysis 
No interim analyses will be performed. 
11.2.10. Stratification 
See Section 11.1.10. 
11.2.11. Analysis of Subgroups 
11.2.11.1. 
Total TBSA ≤ 15% 
A subgroup analysis will be done for the patients with Total TBSA ≤ 15%. 


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The 12 months MVSS will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.2.11.2. 
Total TBSA > 15% 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
total TBSA > 15%. 
11.2.11.3. 
All target wounds full thickness 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
all target wounds classified as full thickness wounds. 
11.2.11.4. 
Mixed target wounds – full thickness and deep partial thickness 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
mixed thickness target wounds (full thickness and deep partial thickness). 
11.2.11.5. 
All target wounds are deep partial thickness 
The same analysis as in Section 11.2.11.1 will be done but on the subgroup of patients with 
all target wounds classified as deep partial thickness wounds. 
 
 


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11.3. Third stage analysis – 24 month long-term safety follow-up 
(LTSFU24) 
11.3.1. Demographics and Other Baseline Characteristics 
Not applicable for this stage of analysis since all information on demographics and other 
baseline characteristics was already analyzed in the first stage analysis (see 11.1.1). 
11.3.2. Primary Efficacy variable 
Not applicable for this stage of analysis since all information on the primary efficacy variable 
was already analyzed in the first stage analysis (see 11.1.2). 
11.3.3. Secondary Efficacy variables 
Not applicable for this stage of analysis since all information on the secondary efficacy 
variables was already analyzed in the first stage analysis (see 11.1.3). 
11.3.4. Safety variables 
11.3.4.1. 
Safety Endpoint: Time to wound closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the first stage analysis (see 11.1.4.1). 
11.3.4.2. 
Safety Endpoint: Cosmesis and function at 12 months from wound 
closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the second stage analysis (see 11.2.4.2). 
11.3.4.3. 
Safety Endpoint: Cosmesis and function at 24 months from wound 
closure 
The MVSS score for a patient will be calculated as described in Section 10.3.4.3. The mean 
and standard error of this MVSS score (for the target wounds) at 24 months will be 
estimated for each treatment group and presented as shown in Table 4. The treatment 
groups will be compared using a linear model with MVSS score as the dependent variable. 
The explanatory variables in the model will include treatment, and the following variables: 
overall TW depth (all TWs full thickness, mixed TWs, all TWs deep partial thickness), “Total 


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%TBSA per patient” and number of TWs (1, 2, ≥3). The coefficient corresponding to the 
treatment group will be estimated and will represent the estimated mean difference in 
MVSS score between NexoBrid and SOC adjusted for any imbalance in the stratification 
factors. The results of the regression analysis will be presented as in Table 7. 
A clinically meaningful difference will be incorporated into the analysis that will represent 
a 1.9 or more units advantage to the SOC group, so that the analysis will show whether 
the NexoBrid group is estimated to have on average a MVSS score that is not worse by 
more than 1.9 units than the score for the SOC group. That is, the following hypothesis are 
about to be tested: 
 !: " # 1.9$$$$$%&.$$$$$ ': " < 1.9$ 
Where " is the mean difference in MVSS score between NexoBrid and SOC adjusted for 
any imbalance in the stratification factors. These hypotheses will be tested by comparing 
the 95% confidence interval for the coefficient of the treatment group from the linear model 
outlined above to the clinically meaningful difference 1.9. The null hypothesis will be 
rejected if the upper bound of this interval is smaller than 1.9. 
For handling of missing data, see Section 10.1.2.2.  
11.3.4.4. 
Adverse Events 
In this analysis, only the adverse events occurring after the 12 months follow up will be 
analyzed. 
All adverse events will be listed (see Table 14). 
Adverse events are classified as being general, local – TW related or local – not TW related in 
the eCRF. Per each of these categories, the AEs will be listed as given in Table 9 and Table 
10. The listing will be presented separately by: 
· 
System organ class 
· 
Preferred term 
· 
Severity (mild / moderate / severe AEs) 
· 
Relatedness (not related / remotely related / possibly related / probably related / related 
AEs) 
· 
Time of onset (until 3 months follow up [i.e. AEs from first stage that are still ongoing] / 
between 3 months follow up and 12 months follow up [i.e. AEs from second stage that 
are still ongoing] / after 12 months follow up) 


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SAEs will be analyzed in the same way as AEs. 
11.3.4.5. 
Concomitant medication 
In this analysis, only the concomitant medications (CM) given after the 12 months follow up 
(including CM with a start date before the 12 months follow up but an end date after that or still 
ongoing) will be analyzed. 
The number of concomitant medication and patients involved will be tabulated with reference 
to ATC coding (see Table 13). The tabulation will be done by treatment group. 
11.3.4.6. 
Immunogenicity evaluation 
The immunogenicity evaluation will be done separately and is described in a separate 
document. 
11.3.4.7. 
Lower Extremity Function Scale (LEFS) 
The LEFS scores of the 24 months follow up assessment will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4. The mean LEFS scores between treatment groups will be 
compared by a one-way analysis of variance. Histograms will be provided to illustrate the 
distribution of LEFS values. 
11.3.4.8. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH scores of the 24 months follow up assessment will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4. The mean QuickDASH scores between treatment 
groups will be compared by a one-way analysis of variance. Histograms will be provided to 
illustrate the distribution of QuickDASH values. 
11.3.4.9. 
Range of Motion (ROM) 
The 24 months range of motion will be evaluated using 3 binary (yes/no) variables. The 
variables indicate whether all ROM were normal, whether there was at least one abnormal 
(NCS) finding and whether there was at least one abnormal (CS) finding. This information is 
present per patient and per visit. Rates of patients with this event will be analyzed by displaying 
counts and percentages by treatment group (see Table 5) per variable (all normal / at least 
one abnormal (NCS) / at least one normal (CS)) and per visit. Furthermore, bar plots will be 
displayed. The proportion of patients with all normal / at least one abnormal (NCS) / at least 
one normal (CS) range of motion will be compared between treatment groups using a chi 
square test (or Fisher’s exact test in case of small estimated cell counts). 


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11.3.4.10. 
EQ-5D (Quality of Life) 
The 24 months follow up assessment of the EQ-5D will be analyzed as follows. 
The EQ-5D consists of 5 items with 3 possible answers each and an EQ visual analogue scale. 
For each item (Mobility, Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression) the 
count and percentages of each possible answer will be presented per age group and per 
treatment group as in Tables 3 and 4 of the EQ-5D-3L user guide [32]. Furthermore, bar plots 
will be provided. The difference between treatment groups will be tested using a chi square 
test (or Fishers’ exact test in case of small expected cell counts). 
The values of the EQ visual analogue scale (EQ VAS) will be analyzed descriptively with 
number of units, number of missing values, mean, standard deviation, min, max, median and 
quartiles as presented in Table 4 of the EQ-5D-3L user guide [32]. The mean EQ VAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of EQ VAS values. 
11.3.4.11. 
Burn Specific Health Scale – Brief (BSHS-B) 
The 24 months follow up assessment of the BSHS-B will be analyzed as follows. 
Each domain specific sub score and the overall BSHS-B score will be analyzed descriptively 
with number of units, number of missing values, mean, standard deviation, min, max, median 
and quartiles as presented in Table 4. The mean (sub-) score values between treatment groups 
will be compared by a one-way analysis of variance. Histograms will be provided to illustrate 
the distribution of (sub-) score values. 
11.3.5. Exploratory Analyses 
11.3.5.1. 
POSAS 
The POSAS for target wounds will be calculated as outlined in Section 10.3.5.7 and will be 
analyzed descriptively with number of units, number of missing values, mean, standard 
deviation, min, max, median and quartiles as presented in Table 4. The mean POSAS values 
between treatment groups will be compared by a one-way analysis of variance. Histograms 
will be provided to illustrate the distribution of POSAS in the treatment groups. 
The analysis will be repeated for the patient scale and for the observer scale separately. 
The analysis will be repeated for donor site scars. 
The analyses will be conducted for the POSAS assessments of 18 and 24 months. 


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11.3.5.1. 
MVSS (target wounds) 
The MVSS for target wounds at 18 and 24 months will be calculated as outlined in 
Section 10.3.4.2 and will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups 
11.3.5.2. 
MVSS (donor site scars) 
The MVSS for donor site scars at 18 and 24 months will be calculated as outlined in 
Section 10.3.4.3 and will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.3.6. Pharmacokinetic Variables 
Not applicable. All pharmacokinetic data was already analyzed in the first stage analysis (see 
Section 11.1.6). 
11.3.7. Multicenter Data 
See Section 11.1.7. 
11.3.8. Handling of Multiple Comparisons 
Not applicable. All testing done during this second stage analysis is exploratory in nature. So 
no adjustment for multiplicity is needed. 
11.3.9. Interim analysis 
No interim analyses will be performed. 
11.3.10. Stratification 
See Section 11.1.10. 


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11.3.11. Analysis of Subgroups 
11.3.11.1. 
Total TBSA ≤ 15% 
A subgroup analysis will be done for the patients with Total TBSA ≤ 15%. 
The 24 months MVSS will be analyzed descriptively with number of units, number of missing 
values, mean, standard deviation, min, max, median and quartiles as presented in Table 4. 
The mean MVSS values between treatment groups will be compared by a one-way analysis 
of variance. Histograms will be provided to illustrate the distribution of MVSS in the treatment 
groups. 
11.3.11.2. 
Total TBSA > 15% 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
total TBSA > 15%. 
11.3.11.3. 
All target wounds full thickness 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
all target wounds classified as full thickness wounds. 
11.3.11.4. 
Mixed target wounds – full thickness and deep partial thickness 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
mixed thickness target wounds (full thickness and deep partial thickness). 
11.3.11.5. 
All target wounds are deep partial thickness 
The same analysis as in Section 11.3.11.1 will be done but on the subgroup of patients with 
all target wounds classified as deep partial thickness wounds. 


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12. Reference List 
 
[1]  B. Atiyeh, G. S.W. and S. Hayek, "State of the art in burn treatment," World J Surg, vol. 
29, no. 2, pp. 131-48, 2005.  
[2]  D. Young, "Burn and Electrical Injury," Second ed. Plastic Surgery, vol. 1, pp. 811-833, 
2006.  
[3]  C. Cordani, "La Peau En Chirurgie Plastique," La Faculte De Medicine De Marseille, p. 
212, 2007.  
[4]  J. Barret et al., "Total Burn Wound Excision Of Massive Paediatric Burns in The First 24 
Hours Post-Injury," Annals of Burns and Fire Disasters, vol. 12, no. 1, pp. 25-27, 1999.  
[5]  Salisbury, "Thermal burns," Plastic surgery, pp. 787-830, 1990.  
[6]  B. Press, "Thermal and electrical injuries," Plastic Surgery, pp. 675-730, 1991.  
[7]  Bessey, „Wound care,“ in Total Burn Care, Saunders elsevier, 2007.  
[8]  W. ChiaChi Kao, "Acute Burns," Plastic and Reconstructive Surgery, vol. 105, no. 7, pp. 
2482-2493, 2000.  
[9]  A. Papp et al., "The progression of burn depth in experimental burns: a histological and 
methodological study," Burns, vol. 30, no. 7, pp. 684-90, 2004.  
[10] Barrett, "Effects of burn wound excision on bacterial colonization and invasion," p. 744, 
2002.  
[11] Pham, „Evaluation of the burn wound management decisions“.Total wound care.  
[12] J. Barret and D. Herndon, "Effects of burn wound excision on bacterial colonization and 
invasion," Plast Reconstr Surg, vol. 111, no. 2, pp. 744-50, 2003.  
[13] D. Heimbach et al., "Burn depth: a review," World J Surg, vol. 16, no. 1, pp. 10-5, 1992.  
[14] E. Sherwood, "The systemic inflammatory response syndrome," Total Burn Care, 2007.  
[15] G. Kramer, T. Lund and O. Beckum, "athophysiology of burn shock and burn edema," 
Total Burn Care, pp. 93-106.  


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[16] W. Xiao-Wu et al., "Effects of delayed wound excision and grafting in severely burned 
children," Arch Surg, vol. 137, no. 9, pp. 1049-54, 2002.  
[17] Y. Ong, M. Samuel and C. Song, "Meta-analysis of early excision of burns," Burns, vol. 
32, no. 2, pp. 145-50, 2006.  
[18] M. Muller, D. Gahankari and D. Herndon, "Operative wound management," Total Burn 
Care, pp. 177-195, 2007.  
[19] L. Rosenberg, Y. Shoham, Y. Krieger, G. Rubin, F. Sander, J. Koller, K. David, D. Egosi, 
R. Ahuja and A. Singer, "Minimally invasive burn care: a review of seven clinical studies 
of rapid and selective debridement using a bromelain-based debriding enzyme 
(Nexobrid®)," Ann Burns Fire Disasters, vol. 28, no. 4, pp. 264-274, 2015.  
[20] L. Rosenberg, Y. Krieger, A. Bogdanov-Berezovski, E. Silberstein, Y. Shoham and A. 
Singer, "A novel rapid and selective enzymatic debridement," Burns, vol. 40, pp. 466-47, 
2014.  
[21] A. Singer, S. McClain, B. Taira, J. Rooney, N. Steinhauff and L. Rosenberg, "Rapid and 
selective enzymatic debridement of porcine comb burns with bromelain-derived Debrase: 
acute-phase preservation of noninjured tissue and zone of stasis," J Burn Care Res, vol. 
31, no. 2, pp. 304-9, 2010.  
[22] R. Lu et al., "Major burn injury is not associated with acute traumatic coagulopathy," J 
Trauma Acute Care Surg, vol. 74, no. 6, pp. 1474-9, 2013.  
[23] N. Cosgriff et al., "Predicting life-threatening coagulopathy in the massively transfused 
trauma patient: hypothermia and acidoses revisited," J Trauma, vol. 42, no. 5, pp. 857-
61, 1997.  
[24] R. Kagan, D. Arenholtz, W. Hickerson, J. Holmes, R. Korentager, J. Kraatz and G. 
Kotoski, "American Burn Association white paper Surgical Management of the Burn 
Wound and Use of Skin Substitutes," 2009.  
[25] T. McCullough et al., "Estimated blood loss underestimates calculated blood loss during 
radical retropubic prostatectomy," Urol Int, vol. 72, no. 1, pp. 13-6, 2004.  
[26] W. McManus, C. Goodwin, A. J. Madson and B. J. Pruitt, "Burn wound infection," J 
Trauma, vol. 21, no. 9, pp. 753-6, 1981.  


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[27] A. van de Kar, L. Corion, M. Smeulders, L. Draaijers, C. van der Horst and P. van Zuijlen, 
"Reliable and feasible evaluation of linear scars by the Patient and Observer Scar 
Assessment Scale," Plast. Reconstr. Surg., vol. 116, no. 2, pp. 514-522, 2005.  
[28] D. Rubin, "Multiple Imputation for Nonresponse in Surveys," 1987.  
[29] G. Molenberghs and M. G. Kenward, Missing Data in Clinical Studies, John Wiley & Sons, 
Ltd , 2008.  
[30] C. Mallinckrodt, „Missing Data in Clinical Trails,“ in Handbook of Missing Data 
Methodology, CRC Press, 2015, pp. 499-522. 
[31] J. McCullogh, Transfusion Medicine, 4th Edition ed., Chincester, West Sussex: John 
Wiley & Sons, 2017.  
[32] M. van Reen and M. Oppe, "EQ-5D-3L user guide," April 2015. [Online]. Available: 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-3L_UserGuide_2015.pdf. 
[Accessed 02 March 2018]. 
[33] L. Gharibvand and L. Liu, "Analysis of survival data with clustered events," SAS Global 
Forum 2009, p. 237, 2009.  
[34] D. Binder, "Fitting Cox’s proportional hazards models from survey data," Biometrika, vol. 
79, pp. 139-147, 1992.  
[35] R. J. Stephens, R. E. Langley, P. Mulvenna, M. Nankivell, A. Vail and P. M. K. B, "Interim 
results in clinical trials: Do we need to keep all interim randomised clinical trial results 
confidential?," Lung Cancer, no. 85, pp. 116-118, 2015.  
[36] R. J. Lilford, D. Braunholtz, S. Edwards and A. Stevens, "Monitoring clinical trials - interim 
data should be publicly available," BMJ, no. 323, pp. 441-2, 2001.  
 
 


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13. Appendices 
13.1. Definitions 
13.1.1. General Definitions 
Full analysis Set (FAS): The full analysis set includes all patients who are randomized into 
the trial. The analysis is focused on the planned treatment 
Complete eschar removal: Complete eschar removal is achieved at the end of the eschar 
removal treatment phase. This stage will be determined by a designated blinded assessor and 
clearly marked as the end of the eschar removal process and the initiation of specific treatment 
aimed to close the viable debrided bed by grafting or epithelialization. 
Complete wound closure: Defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits, 2 weeks apart, determined by a 
blinded assessor. 
Early grafted wounds: Early autografted wounds were defined as wounds autografted within 
7 days or less from injury date. 
Late grafted wounds: Late autografted wounds were defined as wounds autografted more 
than 7 after injury date. 
13.1.2. Levels of Sedation 
For the analysis of levels of sedation, the definition of general anesthesia and levels of 
sedation/analgesia of the American Society of Anesthesiologists (see Table 3) is used.


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Table 3: Continuum of depth sedation: Definition of general anesthesia and levels of sedation/analgesia*- American Society of 
Anesthesiologists 
 
Minimal Sedation 
Anxiolysis 
Moderate Sedation/ 
Analgesia (“Conscious 
Sedation”) 
Deep Sedation/ 
Analgesia 
General Anesthesia 
Responsiveness 
Normal response to 
verbal stimulation 
Purposeful** response to 
verbal or tactile 
stimulation 
Purposeful** response 
following repeated or 
painful stimulation 
Unarousable even with 
painful stimulus 
Airway 
Unaffected 
No intervention required 
Intervention may be 
required 
Intervention often 
required 
Spontaneous 
Ventilation 
Unaffected 
Adequate 
May be inadequate 
Frequently inadequate 
Cardiovascular 
function 
Unaffected 
Usually maintained 
Usually maintained 
May be impaired 
 
 


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Minimal Sedation (Anxiolysis) is a drug-induced state during which patients respond 
normally to verbal commands. Although cognitive function and physical coordination may be 
impaired, airway reflexes, and ventilation and cardiovascular functions are unaffected.  
Moderate Sedation/Analgesia (“Conscious Sedation”) is a drug-induced depression of 
consciousness during which patients respond purposefully** to verbal commands, either alone 
or accompanied by light tactile stimulation. No interventions are required to maintain a patent 
airway, and spontaneous ventilation is adequate. Cardiovascular function is usually 
maintained.  
Deep Sedation/Analgesia is a drug-induced depression of consciousness during which 
patients cannot be easily aroused but respond purposefully** following repeated or painful 
stimulation. The ability to independently maintain ventilatory function may be impaired. 
Patients may require assistance in maintaining a patent airway, and spontaneous ventilation 
may be inadequate. Cardiovascular function is usually maintained.  
General Anesthesia is a drug-induced loss of consciousness during which patients are not 
arousable, even by painful stimulation. The ability to independently maintain ventilation 
function is often impaired. Patients often require assistance in maintaining a patent airway, and 
positive pressure ventilation may be required because of depressed spontaneous ventilation 
or drug-induced depression of neuromuscular function. Cardiovascular function may be 
impaired.  
* Monitored Anesthesia Care (“MAC”) does not describe the continuum of depth of sedation, 
rather it describes “a specific anesthesia service in which an anesthesiologist has been 
requested to participate in the care of a patient undergoing a diagnostic or therapeutic 
procedure.”  
** Reflex withdrawal from a painful stimulus is NOT considered a purposeful response.  
 
 


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13.2. Lay-out and list of tables 
For continuous variables, descriptive statistics will be presented as follows: 
Table 4: Descriptive statistics of continuous variables per treatment. 
Treatment 
Variable 
N 
Missing 
Mean 
Std Dev 
Min 
Q1 
Median 
Q3 
Max 
NexoBrid 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
Gel Vehicle 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
Table 5: Counts and (column) percentages of categorical variables per treatment. 
Treatment 
Variable 
Total 
Category 1 
Category 2 
… 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
NexoBrid 
 
 
 
SOC 
 
 
 
Gel Vehicle 
 
 
 
Total 
 
 
 
 
Table 6: Confidence interval and test result for odds ratios 
Comparison 
Odds ratio 
Test 
p-value 
Lower 95 % 
confidence 
bound 
Upper 95 % 
confidence 
bound 
 
 
 
 
 
 
 


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Table 7: Presentation of test results and confidence intervals 
 
Estimate 
Std Err 
Test 
Value of 
the test 
statistic 
p-value 
Lower 95 
% 
confidence 
bound 
Upper 95 
% 
confidence 
bound 
Variable 
 
 
 
 
 
 
 
 
Table 8: Table for Kaplan-Meier estimates per treatment 
Time in 
days/hours 
NexoBrid 
SOC 
Case 
Censoring 
At risk 
% 
Case 
Censoring 
At risk 
% 
0 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 


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Table 9: Counts and percentages of Medical History Conditions or Adverse Events by MedDRA System Organ Class. 
System Organ Class 
SOC 
NexoBrid 
Gel Vehicle 
Total 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
Infections and infestations 
 
 
 
 
 
 
Neoplasmsm benign, malignant and 
unspecified (incl. cysts and polyps) 
 
 
 
 
 
 
Blood and lymphatic system disorders 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Social Circumstances 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 


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Table 10: Counts and percentages of Adverse Events by categories of a categorical variable 
Variable 
SOC 
NexoBrid 
Gel Vehicle 
Total 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
Category 1 
 
 
 
 
 
 
Category 2 
 
 
 
 
 
 
Category 3 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 


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Table 11: Counts and percentages of concomitant medication with reference to ATC coding (1st stage analysis). 
ATC code 
Contents 
Concomitant 
medication  
Number of 
Patients 
Indication 
 
 
 
 
AE 
Prophylactic 
Pre-existing 
condition 
Other 
 
 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
A 
Alimentary tract and metabolism 
 
 
 
 
 
 
 
B 
Blood and blood forming organs 
 
 
 
 
 
 
 
C 
Cardiovascular system 
 
 
 
 
 
 
 
D 
Dermatologicals 
 
 
 
 
 
 
 
G 
Genito-urinary 
system 
and 
sex 
hormones 
 
 
 
 
 
 
 
H 
System 
hormonal 
preparations, 
excluding sex hormones and insulins 
 
 
 
 
 
 
 
J 
Antiinfectives for systemic use 
 
 
 
 
 
 
 
L 
Antineoplastic and immunomodulating 
agents 
 
 
 
 
 
 
 
M 
Musculo-skeletal system 
 
 
 
 
 
 
 
N 
Nervous system 
 
 
 
 
 
 
 
P 
Antiparasitic products, insecticides and 
repellents 
 
 
 
 
 
 
 
R 
Respiratory system 
 
 
 
 
 
 
 
S 
Sensory organs 
 
 
 
 
 
 
 
V 
Various 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 


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Table 12: Counts and percentages of concomitant medication with reference to ATC coding (2nd stage analysis) 
ATC 
code 
Contents 
Concomitant 
medication  
Number of 
Patients 
Indication 
Start time 
 
 
 
 
AE 
Prophylactic 
Pre-existing 
condition 
Other 
Before 3m 
FU 
After 3m FU 
 
 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
A 
Alimentary 
tract 
and 
metabolism 
 
 
 
 
 
 
 
 
 
B 
Blood and blood forming 
organs 
 
 
 
 
 
 
 
 
 
C 
Cardiovascular system 
 
 
 
 
 
 
 
 
 
D 
Dermatologicals 
 
 
 
 
 
 
 
 
 
G 
Genito-urinary system and 
sex hormones 
 
 
 
 
 
 
 
 
 
H 
System 
hormonal 
preparations, 
excluding 
sex hormones and insulins 
 
 
 
 
 
 
 
 
 
J 
Antiinfectives for systemic 
use 
 
 
 
 
 
 
 
 
 
L 
Antineoplastic 
and 
immunomodulating agents 
 
 
 
 
 
 
 
 
 
M 
Musculo-skeletal system 
 
 
 
 
 
 
 
 
 
N 
Nervous system 
 
 
 
 
 
 
 
 
 
P 
Antiparasitic 
products, 
insecticides and repellents 
 
 
 
 
 
 
 
 
 
R 
Respiratory system 
 
 
 
 
 
 
 
 
 
S 
Sensory organs 
 
 
 
 
 
 
 
 
 
V 
Various 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 


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Table 13: Counts and percentages of concomitant medication with reference to ATC coding (3rd stage analysis) 
ATC 
code 
Contents 
Concomitant 
medication  
Number of 
Patients 
Indication 
Start time 
 
 
 
 
AE 
Prophylactic 
Pre-existing 
condition 
Other 
1st 
stage 
2nd 
stage 
3rd 
stage 
 
 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
A 
Alimentary 
tract 
and 
metabolism 
 
 
 
 
 
 
 
 
 
B 
Blood and blood forming 
organs 
 
 
 
 
 
 
 
 
 
C 
Cardiovascular system 
 
 
 
 
 
 
 
 
 
D 
Dermatologicals 
 
 
 
 
 
 
 
 
 
G 
Genito-urinary system and 
sex hormones 
 
 
 
 
 
 
 
 
 
H 
System 
hormonal 
preparations, 
excluding 
sex hormones and insulins 
 
 
 
 
 
 
 
 
 
J 
Antiinfectives for systemic 
use 
 
 
 
 
 
 
 
 
 
L 
Antineoplastic 
and 
immunomodulating agents 
 
 
 
 
 
 
 
 
 
M 
Musculo-skeletal system 
 
 
 
 
 
 
 
 
 
N 
Nervous system 
 
 
 
 
 
 
 
 
 
P 
Antiparasitic 
products, 
insecticides and repellents 
 
 
 
 
 
 
 
 
 
R 
Respiratory system 
 
 
 
 
 
 
 
 
 
S 
Sensory organs 
 
 
 
 
 
 
 
 
 
V 
Various 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 


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13.3. Lay-out and list of figures 
 
Figure 1: Histogram of continuous variable per treatment 


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Figure 2: Bar plot for categorical variable by treatment 
 
Figure 3: Kaplan Meier plot for time to event data 


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13.4. Lay-out and content of individual patient data listings (case wise 
listing) 
The case wise listing will not be done by the KKSB and also not form a part of the statistical 
report. Therefore, in this SAP no lay-out and content is given. The statistical report will refer to 
the clinical report for the case wise listing.


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13.4.1. List of AEs and SAEs 
Table 14: Table for listing of all AEs and SAEs. 
AE 
Subject Id 
Start date 
Duration 
in days 
Number 
of AE 
Description 
of AE 
Severity 
grade 
Relationship 
Outcome 
Study 
treatment 
Therapy 
of AE 
SAE 
1 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
.... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.5. Details of the Amendments 
13.5.1. Summary of Amendment of version 8 to version 9 
Study title: A multicenter, multinational, randomized, controlled, assessor blinded study, 
performed in subjects with thermal burns, to evaluate the efficacy and safety of NexoBrid 
compared to Gel Vehicle and compared to Standard of Care   
 
Study plan code: MW 2010-03-02 
IND No.:  
65,448 
EudraCT No.: 
2014-001672-55 
 
Amendment summary- protocol MW2010-03-02, version 09, 12 Aug 2015 
The following changes were performed in protocol version 9: 
1. Pages 40 and 100-102, Randomization and Stratification 
a. Changes: Stratifications levels were revised; stratification per %TBSA was 
removed and stratification per depth was revised and SPT proportion was 
removed from the stratification levels. In addition, randomization will be 
performed per blocked randomization method rather by minimization 
b. Justifications: Per FDA comments sent to the Sponsor on May 2015, 
stratification levels were reduced and will be performed in the amended 
protocol per patient’s wounds depth and per clinical center. In addition, FDA 
suggestion to perform “simple randomization” was implemented. 
2. Pages 102-104, Data Handling 
a. Changes: Missing data section was slightly revised for the efficacy & safety 
endpoints 
b. Justifications: The above changes were performed in accordance with FDA 
comments sent on May 2015. 
3. Pages 78 and 93-05 Analysis of endpoints 
a. Changes: Planned analysis of the primary, secondary & safety endpoints was 
slightly revised per FDA suggested comments (e.g. limiting the planned 
analysis to only the terms expected to have the greatest impact, pre- define a 
plan in the protocol for checking assumptions and determining which analysis 
will be used, etc) 
b. Justifications: The above revisions were implemented per FDA suggested 
comments sent on May 2015. 


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13.5.1. Summary of Amendment of version 9 to version 11 
The below table summarizes the changes to Protocol MW2010-03-02, version 9 (submitted to the FDA on August 18, 2015, 
SN0087) as was implemented in protocol, version 11.  
Line 
Section in 
version 11 
Suggested Change 
Justification 
1.  
Definition 
(section 1) 
Additions to the definition of ‘Circumferential extremity wounds’ (see in 
BOLD): “Circumferential extremity wounds: Limb DPT and/or FT burns 
which encircle ≥ 80% of the limb circumference” and “Extremities at Risk 
(EAR) are circumferential DPT and/or FT burns that may develop BICS 
during the first 3 days post injury with at least one of the following…” 
Details were added for clarity and standardization among 
sites 
Definition for ‘Increased interstitial pressure syndrome’ was revised to 
be in line with the Burn-induced compartment syndrome (BICS)- the 
common medical term 
BICS is a medical event described in the protocol which 
is being monitored by the treating physicians in 
anatomical areas of the extremities  
Additions to the definition of Target Wounds 
Details were added for clarity and standardization among 
sites. Minimal size of target wound was reduced to 0.5% 
TBSA (see further justification in line 12 below) 


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Line 
Section in 
version 11 
Suggested Change 
Justification 
Addition of definition for substance use disorder in accordance with the 
DSM-5 
This definition was added to support exclusion # 24 (see 
line #13 below)- to better describe alcohol abuse  
Addition of assessment of complete wound closure and complete eschar 
removal- by a blinded assessor 
This addition is in line with the protocol and former 
discussions with the agency. Added in this section for 
clarity and consistency with the study protocol.  
2.  
Synopsis  
(section 2) 
The following changes were performed: 
Changes to entrance criteria (see lines #10-13 below), additional safety 
outcome measures (line #8), Study Treatments and Dosage (line #9) 
and additional exploratory endpoints (line #5). All these changes are 
further detailed below. 
In accordance with changes performed in the body of the 
protocol, similar changes are described in the synopsis 
section. Please refer to more details in the relevant lines 
below. 
3.  
Introduction 
(Section 3) 
Addition of Pharmacokinetic profile section from the recently completed 
study MW2008-09-03- Section 3.2.3 
Information could be added following recent completion 
of study MW2008-09-03  
Minor additions to section 3.3.2 -  under extremities wounds  
Additional medical information was added to this section 
4.  
General 
safety 
Endpoints 
(section 6.1.3) 
Addition of the following parameters to the general safety endpoints: 
“Number and volume of blood transfusions received throughout the 
hospital admission, Extent of analgesia, anaesthesia and antibiotic use, 
Rates of hospital readmission, Change in INR/PTT and incidence of 
change to > upper limit of normal (after treatment), Change in blood 
The proposed changes were added in an attempt to 
harmonize the protocol and meet both the FDA and 
CHMP requirements 


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glucose and incidence of change to above upper limit of normal (after 
treatment)”. 
5.  
Exploratory 
Endpoints 
(section 6.1.4) 
1. Description of planned autograft analyses were added: efficacy and 
safety analyses for early and late grafted wounds, total number of 
target wound grafting procedures, incidence of repeat/additional 
grafting procedures & area of repeat grafting 
2. Duration of hospitalization- added as additional exploratory EP 
The proposed changes were added in an attempt to 
harmonize the protocol and meet both the FDA and 
CHMP requirements 
6.  
Assessment 
of 
clinical 
measures 
(section 6.3.1.1) 
Under Extent of eschar removal assessment using topical agent; 
NexoBrid or Gel Vehicle, the following was added: “For the purpose of 
standardization, if feasible, the same blinded assessor should be 
assigned to assess eschar removal in all patients, and in all study arms”. 
This change was added to further improve the 
standardization of the eschar removal assessment 
among the sites  
7.  
Non 
surgical 
eschar removal 
(section 6.3.1.3) 
The following clarification was added (in BOLD): “Wounds will be 
assessed by a burn specialist as in common daily practice, following 
any dressing change” 
This change was added to further improve the 
standardization of the eschar removal assessment 
among the sites 
8.  
Main safety 
measures 
(6.3.2) 
The following was added: “This assessor should not be involved in 
any eschar removal procedure and should not be aware whether 
the patient was assigned to the topical arms or to the SOC arm. For 
the purpose of standardization, if feasible, the same blinded 
assessor should be assigned to assess wound closure, cosmesis 
This change was added to further improve the 
standardization of the wound closure and cosmesis and 
function assessment among the sites 


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and function (as described below) in all patients, and all study 
arms. The blinded assessor will sign the "blinded assessor memo".  
9.  
Study 
Treatments and 
Dosage (6.4) 
 
The following instruction was added: "NexoBrid/Gel vehicle should not 
be applied to more than 15% TBSA (±3% TBSA) in one session". 
 
This instruction was added to instruct how to use the 
study drug in patients with targets wounds of more than 
15% TBSA that may be included to the study following the 
change in Inclusion No 4  
10.  
Inclusion 
Criteria- patient 
level 
(section 
7.1.1) 
Inclusion No. 1- upper age of 70 was deleted: “Males and females; ≥ 
18  years of age” 
The change was implemented in accordance with the 
FDA request (letter from May 14, 2015) 
Inclusion No. 4- %TBSA was revised to be maximum of 30% TBSA: 
“Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or 
FT in depth”  
The change was implemented in accordance with the 
agreed changes discussed with the FDA (Type C TC, 
May 25, 2016) 
Inclusion No. 5 was revised as following: “Informed consent can be 
obtained within 84 hours of the burn injury”  
 
Patients will need to sign on ICF before start of treatment 
which will be no later than 84 hrs from injury (section 8.2 
in the protocol, version 11) instead of within 48 hrs. This 
will allow larger flexibility for signing consent form based 
on feedback received from clinical sites participating in 
the study. Start of treatment limitation was changed as 


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well. In protocol version 9, the allowed window to start 
treatment was 72 hrs from injury. This window was 
expanded to be 84 hrs from injury. 
11.  
Inclusion 
criteria- 
wound 
level 
(section 
7.1.2) 
Addition of inclusion Criterion: “SPT areas that cannot be demarcated 
from DPT and FT areas should be less than 50% of the % TBSA of the 
TW”. In addition, clarification was added regarding the minimum criteria 
for patient to be enrolled in a wound level. 
To increase standardization of treated wounds and to 
avoid treating wounds with large superficial areas  
12.  
Inclusion 
criteria- 
wound 
level 
(section 
7.1.2) 
Minimal wound size was reduced from 1% TBSA (FT and/or DPT) to 
0.5% TBSA. 
To avoid having patients with 3% TBSA DPT and/or FT 
wounds that most of them small and could not be defined 
as TWs, the minimum size of TW was reduced.  
13.  
Exclusion 
Criteria (section 
7.1.3) 
Exclusion #5: Blast injury was removed and inserted as part of exclusion 
#18 
As blast injury considered as an additional risk in burn 
patients, this was added to Exclusion 18 which exclude 
patients with “Any conditions that would preclude safe 
participation in the study or adding further risk to the basic 
acute burn trauma” 


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Deletion of Exclusion #6: “Patients with DPT and/or FT facial burn 
wounds from flame, flash, explosion > 0.5%  TBSA (scald and contact 
burns are allowed)” 
This exclusion was originally written in order to avoid 
inclusion of subjects with diagnosis of smoke inhalation 
injury however this  concern is being addressed by 
Exclusion criterion # 12 (see below)  
Clarification added to exclusion #7 (in BOLD): “Patients with 
circumferential (≥ 80% of the limb circumference) DPT and/or FT 
burns defined as Extremities at Risk (EAR)” 
A more accurate  definition  of circumferential injury was 
inserted into this criterion  to avoid confusion 
Exclusion criterion #12: “Any signs or history that may indicate smoke 
inhalation” was revised to be “Diagnosis of smoke inhalation injury” 
This criterion was modified to avoid exclusion of patients 
with signs which do not necessarily indicate smoke 
inhalation injury  
Exclusion criterion #14- lower limit of HbA1c for poorly controlled 
diabetes mellitus was increased from 9% to 11% 
This change does not add any safety risk, as assessed 
medically 
Exclusion #15 was revised- BMI exclusion will be based on the extent of 
burn area- patients with up to 15%TBSA will be excluded if BMI above 
39 and patients with %TBSA above 15% will be excluded if BMI above 
34.  
This revision was performed following feedback from the 
US clinical sites relate to the common US population. This 
change will not add any additional safety concern 


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Exclusion criteria #17-19- Medical conditions in injured subjects that 
should be excluded from the study were better defined (see in bold): 
1. 
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), 
2. 
Pre-existing diseases which interfere with circulation (severe 
peripheral vascular disease, severe edema and/or lymphedema, 
regional lymph nodes dissection, significant varicose veins). 
Obesity was deleted from this criterion as being addressed in 
exclusion # 14 
3. 
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) 
To avoid exclusion of patients with condition that will not 
preclude safe participation 
Exclusion criterion #24- clarification regarding alcohol and drug abuse- 
this definition was revised in the protocol, section 1 (see line 1 above):  
Substance use disorder: describes a problematic pattern of using 
alcohol or another substance that results in impairment in daily life 
To avoid exclusion of patients who used drugs/drink 
alcohol but are not abused and can sign consent and 
could comply with study procedures 


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or noticeable distress. The DSM-5 states that in order for a person 
to be diagnosed with a severe disorder due to a substance, they 
must display 6 or more of the 11 symptoms within 12-months. 
These 11 symptoms are now defined in the protocol and should be 
assessed by the sites.  
14.  
Subject 
withdrawal 
criteria (7.2) 
Addition of criteria for subject’s removal from the study- “Withdrawal of 
subjects with EAR identified post randomization but prior to 
treatment” 
This addition will allow exclusion of subjects with BICS 
diagnosed after randomization and before start of 
treatment  
15.  
BICS monitoring 
& 
diagnosis 
(section 7.2.1.1) 
· Clarification was added- all circumferential wounds should be 
closely monitored during treatment. 
· Escharotomy "will" be performed was replaced with "may"  
· Minor wording changes for clarity 
· This was added to avoid deviations and ensure close 
monitoring 
of 
circumferential 
wounds 
during 
treatment 
· Following feedback from the study PIs- SOC does not 
necessarily include escharotomy following BICS 
diagnosis as defined in the study protocol hence, 
escharotomy is at the discretion of the PI.  
16.  
Post 
treatment 
diagnosed 
infection 
(section 7.2.1.3) 
Timeframe for diagnosed infection, that may be consider as a stopping 
rule, was added - until complete wound closure 
 
The timeframe was added for clarity of standardization 
Section 8- Study conduct  


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17.  
Screening 
and 
Baseline 
Procedures 
(section 8.1.1) 
Burn description (size and depth) as well as photographs were deleted 
before cleansing and will be captured only after cleansing 
Screening wound assessments will be performed only 
once after initial cleansing of wounds. Pre cleansing is 
usually done pre signing informed consent and therefore 
this assessment was deleted.  
18.  
Screening 
and 
Baseline 
Procedures 
(section 8.1.1) 
The use of schematic drawing to mark TWs location was added to the 
protocol  
This drawing is being used by the sites and the relevant 
documentation was added to the study protocol  
19.  
Assessment 
within 
24hrs 
prior to eschar 
removal (section 
8.1.3) 
Assessments and procedures previously requested within 24 hrs prior 
to start of eschar removal were moved and will be performed within 1 hr 
prior to start of treatment (8.2.1) 
All procedures before treatment will be performed at the 
same time and will prevent repeated blood tests for the 
subjects 
20.  
Treatment 
procedure- 
Eschar Removal 
(Section 8.2) 
Start of treatment was change from 72 to 84 hrs from injury 
To allow a wider time frame for treatment preparations 
(screening, ICF signing, pre treatment procedures, 
cleansing) 


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21.  
SOC & Topical 
arms- eschar 
removal 
procedures 
(sections 8.2.2 
& 8.2.3) 
Most of the changes in these sections are only editorial ones. Additional 
changes are described below 
Editorial changes were performed in order to have the 
procedures written in chronological order and with similar 
structure in both arms. 
22.  
SOC & Topical 
arms- eschar 
removal 
procedures 
(sections 8.2.2 
& 8.2.3) 
Pre procedure assessments will be done only when the additional 
procedure is surgical 
The need to perform pre assessments for additional 
topical procedure or additional SOC that is non-surgical 
were deleted, since the assessment are done post the 
previous procedure (topical or surgical) as described in 
the protocol 
23.  
sections 
8.2.2.1.4, 
8.2.2.2.3, 
8.2.3.2 & 8.4  
Addition of clarification footnote with regard to complete eschar removal 
assessment  
 
Assessment of complete eschar removal was further 
specified to improve standardization across centers.  
 
 


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24.  
Post first 
procedure (SOC 
and topical 
arms) 8.2.2.1.4 
& 8.2.3.1.6 
PTT/INR: 
· Will not be taken after surgical procedure if it is not the first 
procedure.  
· Will be taken 4 hours post treatment instead of 4 hours from start of 
treatment 
 
· To avoid duplications with 24 and 48 hours 
assessments 
· In order to reduce time points of taking blood from the 
patients, PTT/INR will be taken at the same time point 
of the safety central lab tests 
25.  
Post first & post 
second 
application 
assessments – 
8.2.3.1.6 & 
8.2.3.2.2 
Assessments post topical procedure will be collected 4 hours post 
removal of topical agent instead of 4 hours post soaking (2 hours earlier) 
This change will result in similar time point as in the SOC 
arm 
26.  
Post first 
procedure 
(8.2.2.1.4) & 
Post additional 
procedure 
(8.2.2.2.3) 
Post non-surgical assessments - Will be taken only if the non-surgical 
procedure is the last procedure – i.e. resulted in complete eschar 
removal 
If non surgical procedure is not the last it will be followed 
by a surgical procedure and assessments will be done pre 
surgical procedure.  


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27.  
General 
assessment & 
Wound 
management 
procedure 
(sections 8.3 & 
8.5) 
Coverage used as wound management will be captured until wound 
closure 
This information is important to be captured during the 
study, until wound closure 
28.  
General 
assessment 
(section 8.3) 
Additional time point for PK was added- 72 hours from start of treatment 
This point was added based on PK profile information 
collected to date  
29.  
Follow-up 
Assessments 
(section 8.6) 
Addition of clarification footnote with regard to complete wound closure 
assessment  
 
Assessment of complete wound closure was further 
specified to improve standardization across centers. 
30.  
Follow-up 
Assessments 
(section 8.6) 
Weekly FU visits will be continued until donor sites will be closed 
This assessment will provide additional safety data in 
patient level (i.e. closure of all wounds, including the 
donor sites, if relevant) 


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31.  
Hospital 
Discharge 
(section 8.7) 
The following assessments at Hospital Discharge (HD) were deleted:  
1. The target wounds and donor sites should be labeled and 
photographed, 
2. Assessment of % of wound area epithelialized and/or closed by 
graft,  
3. Assessment of % of donor site area epithelialized, 
4. Type of cover/dressing applied on TWs and donor sites should be 
recorded 
These changes were applied to avoid duplicate 
assessments of in both weekly FU visits and HD visit 
which is being performed in parallel to the weekly FU 
visits 
32.  
Follow-up 
assessments: 
wound closure 
confirmation 
(Section 8.8) 
Extent of wound closure will be documented in the confirmation visit 
This assessment was added In order to collect additional 
exploratory information 
33.  
Table 3, section 
9 
Changes performed in accordance with changes in flow of treatment  
 
34.  
Primary 
endpoint 11.1 
The assessment of the Incidence of complete eschar removal was 
clarified  
The wording was changed to stress that the assessment 
that is considered for the primary endpoint is the one done 
by  the blinded assessor and at a specific pre defined time 
point 


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35.  
Safety 
EPs- 
Time 
to 
complete wound 
closure (section 
11.3.1) 
NI margin for time to wound closure reduced to 7 days instead of 7.4 
days 
The 
proposed 
change 
was 
added 
following 
re 
assessments and taking into consideration additional 
clinical data.  
36.  
Safety 
EPs- 
Cosmesis 
& 
function at 12 
and 24 months 
(sections 11.3.2 
and 11.3.3) 
NI margin for MVSS was reduced to 1.9 
The 
proposed 
change 
was 
added 
following 
re 
assessments and further discussion with PIs.  
37.  
General 
safety 
parameters 
(section 11.3.4) 
The following were added: “Number and volume of blood 
transfusions received throughout the hospital admission, Extent of 
analgesia, anaesthesia and antibiotic use (i.e. total dose per kg 
body weight), Rates 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)” 
See line #4 above 


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38.  
Exploratory EPs 
(section 11.4)  
1. Description of planned autograft analyses were added: efficacy 
and safety analyses for early and late grafted wounds, total 
number of target wound grafting procedures, incidence of 
repeat/additional grafting procedures & area of repeat grafting 
2. Duration of hospitalization- added as additional exploratory EP.  
See line #5 above 
39.  
Additional 
analyses 
(section 11.5 & 
13.3.4.2) 
Additional analyses were added for eschar removal and wound closure  
The proposed change was added in attempt to 
harmonize the protocol and meet both the FDA and 
CHMP requirements  
40.  
Subgroup 
analyses 
(section 11.6 & 
13.3.5) 
The following sub groups were added: 
· 
Sub group analysis on entirely FT wounds 
· 
Sub group analysis on patients classified as having <25% or 
>=25% SPT area as a percentage of the area of all TWs 
· 
Sub group analysis per % TBSA  
The first 2 subgroup analyses were added in order to test 
for possible effects of wounds depth on the study results.  
The subgroup analysis per %TBSA was implemented in 
accordance with the agreed changes discussed with the 
FDA (Type C TC, May 25, 2016). See also appendix #1 
for the rational to include sub group analysis per %TBSA 
as additional analysis and not to include it in the main 
analysis (primary analysis) as discussed with the FDA 
during the TC.  


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41.  
EAR and BICS- 
Monitoring 
and 
Diagnosis 
(section 11.8) 
Revision to EAR & BICS section was performed and clarification of 
monitoring methods on each time point was added to this section 
Main reason for change is to reduce complexity in 
following protocol procedures and reduce sites’ potential 
deviations 
42.  
Immunogenicity 
evaluation 
(section 11.11) 
Week 1 test was deleted. Immunogenicity evaluation will now be 
performed based on weeks 4, 8 and 6 & 24 months visits 
The ELISA method is specific for anti NexoBrid IgG. 
Circulating anti NexoBrid IgG are not expected  one week 
after treatment and hence, this time-point was deleted  
43.  
Graft loss and 
Graft 
take 
(section 11.16)  
Added definition for graft take 
Definition was added to further allow standardization 
44.  
Pharmacokinetic 
evaluation 
(section 11.21) & 
Appendix 
10- 
Procedures 
for 
specific 
blood 
tests 
PK timelines were revised as follows:  
In subjects requiring a single application:  
Before treatment (time zero), 0.5 hours ± 10 minutes,  2 hours ± 10 minutes, 
4 hours ± 10 minutes, 12 hours ± 30 minutes, 24 hours ± 30 minutes , 48 hours 
± 30 minutes and 72 hours ± 30 minutes after NexoBrid application. 
In subjects requiring two planned applications of NexoBrid: 
1st treatment: before treatment (time 0), 0.5 hours ± 10 minutes, 2 and 4 
hours ± 10 minutes after the first NexoBrid application. 
Based on the available PK data from study MW2008-09-
03, new sampling paradigm is proposed for the Phase 3 
MW2010-03-02 study to support PK analysis after the 
first and second  applications  


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2nd treatment: time 0, 30 ± 5 minutes, 2 hours ± 10 minutes, 4 hours ± 10 
minutes, 12 hours ± 30 minutes , 24 hours ± 30 minutes, 48 and 72 hours ± 30 
minutes after the second NexoBrid application 
 
45.  
Pharmacokinetic 
evaluation 
(section 11.21) & 
Appendix 
10- 
Procedures 
The subset of patients tested for PK was modified: 
1. 16 subjects with total wounds area of  <=15% TBSA  
2. 16 subjects with total wounds area to be treated of  >15% TBSA   
 
 
This addition of PK samples in  patients with more than 
15% TBSA will provide PK information in patients with 
maximal permissible TBSA and data for second 
application  
46.  
Safety endpoint- 
Time to wound 
closure (section 
13.3.3.1) 
An addition to the planned Cox regression model 
This change was performed in accordance with the FDA 
request (letters from 14 May 2015 & 03 Nov 15) 
47.  
Stratification 
(13.7.2) 
Stratification factor of TBSA was added. Stratification levels of the factor 
Center was reduced by grouping centers into 5 groups. 
Stratification by TBSA was added due to the change in 
inclusion No 4 to include patients with TBSA of more than 
15%.  
Stratification by centre was changed to "group of centers, 
5 groups rather 30 centers to allow balance in the 
randomization. 


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48.  
Missing 
data 
(13.8.4) 
The analysis of the safety endpoint time to complete wound closure will 
compute missing values as censored. 
This change was performed in accordance with the FDA 
request (letters from 14 May 2015 & 03 Nov 15) 
49.  
Section 13 
Changes performed in sections 13.3.3.3 (general safety parameters), 
13.3.4 (exploratory), 13.3.4.2 (additional analyses) and 13.3.5 
(subgroup analyses) as described in lines 24-27 above 
Changes performed as described above 
Section 14- Quality assurance 
50.  
DSMB  
(section 14.4)  
Addition of special cases for DSMB convention- 
1.After randomization of 10 NexoBrid patients suffering from deep burns 
of more than 15% TBSA (TWs area) and were treated with 2 repeated 
applications of  NexoBrid 
2. After randomization of 25 NexoBrid patients suffering from deep 
burns of more than 15% TBSA (TWs area) and were treated with 2 
repeated applications of  NexoBrid 
This change is part of the risk mitigation plan suggested 
to support the inclusion and treatment of patients up to 
30% TBSA as was discussed with the FDA during the 
Type C meeting held on May 25, 2016 
 
DSMB  
(section 14.4) 
Timing of the routine meeting was clarified, Review of narratives by the 
DSMB was added 
The proposed changes were added in attempt to better 
clarify the DSMB role 


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51.  
Appendix 
3- 
Photographic 
wound 
documentation 
 
Details were added to the instructions in this appendix, in accordance 
with the study photograph guideline.  
Detailed instructions were added in order to ensure 
standardized digital images