Clinical trial NCT02278718
Conditions: Thermal Burns
Sponsor: MediWound Ltd
Start date: 2015-05-01; Completion date: 2022-12-01
Enrollment: 145 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:
A total of 160 patients will be randomized into NexoBrid and SOC treatment (80 patients per arm).

Age distribution will be managed as follows:

* 45 patients 0-23 months old
* 45 patients 24 months-3 years old
* 30 patients 4-11 years old
* 20 patients 12-17 years old The remaining 20 patients will be enrolled to any of the above groups, per their age during enrollment.

The study will be conducted in three stages. In Stage I, at least 24 children age 4-18 years, hospitalized in burn units, with deep partial thickness burns ranging from 1%-30% TBSA, and who meet the entrance criteria, will be enrolled. Upon completion of stage I, a safety analysis will be performed on safety parameters and the results will be evaluated by a Data Safety Monitoring Board (DSMB) as defined in the agreed charter. If the DSMB does not have any safety concerns, Stage II will commence, this time enrolling at least 26 additional children aged of 1-18 years according to the study procedures. A DSMB will be convened to assess the safety data of the first 50 patients enrolled at stages 1 \& 2. If the DSMB has not found any safety concerns, stage III will commence in which patients from the age of birth to 18 years will be included (stage III will include 110 remaining patients required to reach a total of 160 patients).

Following the enrollment of a subject to the study and prior to randomization, physicians will define one or more Target Wounds (TWs) per subject according to TWs definition. All subjects' DPT and FT burns that fit the specified criteria are intended to receive study treatment per randomized study arm and therefore, must be designated as TWs.

Prior to eschar removal treatment with NexoBrid or SOC subjects will be medicated with appropriate analgesia and undergo wound cleansing and dressing of all wounds with antibacterial solutions. Following wound cleansing and antibacterial treatments, subjects will undergo the eschar removal process as per treatment assignment (NexoBrid or SOC, following randomization). Subsequent to eschar removal, all wounds will be assessed and treated in the same manner, in accordance with post-eschar removal wound care strategy. Furthermore, subjects will undergo daily assessments (Vital signs (VS) and pain assessments) for one week and weekly assessments thereafter, until wound closure. Following wound closure, subjects will be followed up at 6 weeks, 12 weeks, and after that, at 6, 12, 18 and 24 months (for a blinded assessment of cosmesis, function and QoL evaluation).

All subjects will be invited to one additional extended follow up visit that will occur at least 30 months after wound closure confirmation for a blinded assessment of cosmesis, function and QoL evaluation.

Arms: arm 1: NexoBrid Gel is applied to the burn wound at a dose of 2g or 5g NexoBrid sterile powder mixed with 20g or 50g sterile Gel Vehicle per 180cm\^2 of TBSA for four hours. arm 2: Non surgical and Surgical Debridement
Interventions: intervention 1: NexoBrid intervention 2: Standard of Care
Intervention descriptions: intervention 1: NexoBrid is an enzymatic debriding agent for Eschar Removal. intervention 2: Surgical or Non-Surgical methods for Eschar Removal

Protocol documents:
Prot_000.pdf: 
Running Title: A multicenter, multinational, randomized, controlled, open label study, performed in children with thermal burns, 
to evaluate the efficacy and safety of NexoBrid as compared to standard of care (SOC) treatment 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 1 of 10 
 
FINAL 
 
CONFIDENTIAL 
SYNOPSIS 
Protocol Number: 
MW 2012-01-01 
Name of Investigational 
Medicinal Product 
(IMP): 
NexoBrid  
EudraCT.-No.: 
2014-003066-24 
IND 
065448 
Name of Active 
Ingredient: 
Concentrate of proteolytic enzymes enriched in bromelain 
Study Title: 
A multicenter, multinational, randomized, controlled, open label 
study, performed in children with thermal burns, to evaluate the 
efficacy and safety of NexoBrid as compared to standard of care 
(SOC) treatment 
Clinical Phase: 
3 
Study Duration: 
The total duration of the study treatment and follow up period of each 
participating 
subject 
is 
expected 
to 
be. 
at least 30 months after wound closure confirmation. Study duration 
will range from 31 months to 7 years and dependent on when the 
subject was enrolled. 
Study Population: 
Pediatric patients with thermal burn wounds defined as deep partial 
thickness and/or full thickness requiring hospitalization and who 
meet the entrance criteria will be enrolled in the study. 
Study Objective(s): 
To evaluate the safety and clinical benefit of NexoBrid in 
hospitalized children (0-18 years) with deep partial and/or full 
thickness thermal burns of 1-30% TBSA and to compare NexoBrid 
to standard of care (SOC). 
Study Design Overview: 
A total of 160 patients will be randomized into NexoBrid and SOC 
treatment (80 patients per arm)1.  
Age distribution will be managed as follows:  
o 45 patients ≥0 months and ≤23 months old 
o 45 patients ≥24 months and ≤3 years old 
o 30 patients ≥4 years and ≤11 years old 
                                                 
1 The study was completed with 145 patients (please refer to Appendix 14 – Update to study sample size due to 
COVID-19 pandemic for additional information) 


Running Title: A multicenter, multinational, randomized, controlled, open label study, performed in children with thermal burns, 
to evaluate the efficacy and safety of NexoBrid as compared to standard of care (SOC) treatment 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 2 of 10 
 
FINAL 
 
CONFIDENTIAL 
o 20 patients ≥12 years and <18 years old 
In addition, the remaining 20 patients will be enrolled to any of the 
above groups, per their age during enrollment. 
The study will be conducted in three stages. In Stage I, at least 24 
children age 4-18 years, hospitalized in burn units, with deep partial 
thickness burns ranging from 1%-30% TBSA, and who meet the 
entrance criteria, will be enrolled. Upon completion of stage I, a 
safety analysis will be performed on safety parameters and the results 
will be evaluated by a Data Safety Monitoring Board (DSMB) as 
defined in the agreed charter. If the DSMB does not have any safety 
concerns, Stage II will commence, this time enrolling at least 26 
additional children aged of 1-18 years according to the study 
procedures. A DSMB will be convened to assess the safety data of 
the first 50 patients enrolled at stages 1 & 2. If the DSMB has not 
found any safety concerns, stage III will commence in which patients 
from the age of birth to 18 years will be included (stage III will 
include 110 remaining patients required to reach a total of 160 
patients). 
Following the enrollment of a subject to the study and prior to 
randomization, physicians will define one or more Target Wounds 
(TWs) per subject according to TWs definition. All subjects’ DPT 
and FT burns that fit the specified criteria are intended to receive 
study treatment per randomized study arm and therefore, must be 
designated as TWs.  
Patients will be stratified on the basis of age groups (as applicable at 
each study stage): 0-23 months, 24 months-3yrs, 4-11yrs and 12-18 
yrs, on the basis of %TBSA, depth and center. 
Prior to eschar removal treatment with NexoBrid or SOC subjects 
will be medicated with appropriate analgesia and undergo wound 
cleansing and dressing of all wounds with antibacterial solutions. 
Following wound cleansing and antibacterial treatments, subjects 
will undergo the eschar removal process as per treatment assignment 
(NexoBrid or SOC, following randomization). Subsequent to eschar 
removal, all wounds will be assessed and treated in the same manner, 
in accordance with post-eschar removal wound care strategy. 
Furthermore, subjects will undergo daily assessments (Vital signs 
(VS) and pain assessments) from start of treatment until hospital 
discharge. Weekly follow-up assessments will be performed until 
complete wound closure. Following wound closure, subjects will be 
followed up at 6 weeks, 12 weeks, and after that, at 6, 12, 18 and 24 
months (for a blinded assessment of cosmesis, function and QoL 
evaluation). 


Running Title: A multicenter, multinational, randomized, controlled, open label study, performed in children with thermal burns, 
to evaluate the efficacy and safety of NexoBrid as compared to standard of care (SOC) treatment 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 3 of 10 
 
FINAL 
 
CONFIDENTIAL 
All subjects will be invited to one additional extended follow up visit 
that will occur at least 30 months after wound closure confirmation 
for a blinded assessment of cosmesis, function and QoL evaluation 
Dosage and route of 
administration: 
Two grams or 5 grams of NexoBrid sterile powder are mixed in 20 
grams or 50 grams of sterile Gel Vehicle to obtain NexoBrid Gel. 
NexoBrid Gel is applied to the burn wound at a dose of 2g 
NexoBrid/20g Gel per 180cm² for four hours.  
In most cases, NexoBrid is effective after a single application; 
however it may be applied for a second time to the same burn area 
based on the investigator's judgment of debridement efficacy.  
NexoBrid should not be applied more than twice to the same burn 
wound area. 
NexoBrid should not be applied to more than 15% TBSA in one 
session. 
Inclusion/ Exclusion 
Criteria: 
Inclusion Criteria- Patient level 
1. Stage 1: Males and females between 4 years to 18 years of age,  
Stage 2 (upon DSMB review): Males and females between 1 year 
to 18 years of age. 
Stage 3 (upon DSMB review): Males and females between 0 
years to 18 years of age. 
2. Thermal burns caused by fire/flame, scalds or contact. 
3. Patient total burns area  ≥ 1%  DPT and / or FT, 
4. Patient total burns area should be ≤ 30% TBSA; SPT, DPT and/or 
FT in depth,  
5. Signed written informed consent by a legal guardian can be 
obtained within 84 hours of the burn injury.  
Inclusion Criteria - Wound level 
At least one wound (a continuous burn area which can be treated in 
one session; might include several anatomical areas) in a patient 
should meet all following criteria: 
1. Wound that is ≥ 1% TBSA (DPT and/or FT) (not including face, 
perineal or genital), 
2. Wound is composed of DPT and/or FT in depth. Superficial 
partial thickness areas may be included in the wound area only if 
cannot be separated from deeper areas (e.g. surrounded by or 
mixed with DPT areas) and might interfere with the treatment of 
the deeper areas, 
3. Wound that is intended for surgical eschar removal, 
4. Wound’s blisters can be unroofed, as judged by the investigator. 


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


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


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


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


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


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


Running Title: A multicenter, multinational, randomized, controlled, open label study, performed in children with thermal burns, 
to evaluate the efficacy and safety of NexoBrid as compared to standard of care (SOC) treatment 
Protocol: MW 2012-01-01 
Version 11.01- 16 Jun 2021 
Page 10 of 10 
 
10 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Clinical Trial 
A multicenter, multinational, randomized, controlled, open label study, performed in children 
with thermal burns, to evaluate the efficacy and safety of NexoBrid as compared to standard 
of care (SoC) - (CIDS) 
Sponsor: 
MediWound, Ltd. 
42 Hayarkon Street 
North Industrial Area 
Yavne, Israel 8122745 
Trial protocol code: MW2012-01-01 
EudraCT number: 2014-003066-24 
ClinicalTrials.gov Identifier: NCT02278718 
IND No.: 065448 


CIDS - Protocol Code: MW2012-01-01 
Page 2 of 138 
Statistical Analysis Plan V02 of 31 May 2021 
Version Control Page 
Version: 
Version Date: 
Prepared / Updated by: 
Protocol Version: 
Comments: 
01 
07-Jul-2020 
Dr. Martin Scharpenberg 
Competence Center for 
Clinical Trials Bremen - 
Biometry 
Version 9.01, 
29-Jul-2019 
02 
31-May-2021 
Larissa Fertik, 
Bioforum Biostatistics 
Department 
Version 10.01, 
16-Nov-2020 
Updates following FDA 
recommendations, protocol 
ammendment, further 
clarifications and 
specifications  


CIDS - Protocol Code: MW2012-01-01 
Page 3 of 138 
Statistical Analysis Plan V02 of 31 May 2021 
1. Table of Contents
1.
Table of Contents
3 
2.
Introduction
11 
2.1. 
Background 
11 
2.2. 
Study Objective 
13 
2.3. 
References to Study Protocol 
13 
2.4. 
Amendments 
13 
2.5. 
Global Statistical Analysis 
13 
3.
Study Administrative Structure
15 
3.1. 
Sponsor 
15 
3.2. 
Study Conduct (Data Management) 
15 
3.3. 
Statistics 
16 
4.
Signatures
17 
5.
List of Abbreviations
18 
6.
General Definitions
21 
6.1. 
General Definitions of Medical Terms 
21 
6.2. 
Hardware and Software Used 
21 
6.3. 
General format and content of tables, figures and patient data listings. 
21 
6.4. 
Quality Control 
21 
6.5. 
General Traceability 
22 
7.
Details of Trial Design
23 
7.1. 
Trial Schedule 
23 
7.2. 
Criteria for Evaluation 
27 
7.2.1. 
Demographic Data and Other Baseline Characteristics 
27 


CIDS - Protocol Code: MW2012-01-01 
Page 4 of 138 
Statistical Analysis Plan V02 of 31 May 2021 
7.2.2. 
Efficacy Evaluation 
29 
7.2.2.1. 
Primary Endpoint: Time to Complete Eschar Removal 
29 
7.2.2.2. 
Secondary Endpoints 
29 
7.2.3. 
Safety Evaluation 
31 
7.2.3.1. 
Time to Reach Complete Wound Closure 
31 
7.2.3.2. 
Cosmesis and Function at 12 Months from Wound Closure 
31 
7.2.3.3. 
Cosmesis and Function at 24 Months from Wound Closure 
33 
7.2.3.4. 
Adverse Events 
33 
7.2.3.5. 
Laboratory Assessments 
34 
7.2.3.6. 
Additional Safety Endpoints 
35 
7.2.4. 
Exploratory Analyses 
36 
8.
Handling of Protocol Violations
37 
9.
Populations Analyzed
39 
9.1. 
Sample Size 
39 
9.1.1. 
Primary Endpoint: Time to Complete Eschar Removal 
39 
9.1.2. 
Secondary Endpoint: Incidence of Surgical Excision 
40 
9.1.3. 
Secondary Endpoint: Blood Loss 
41 
9.1.4. 
Secondary Endpoint: Area of Autograft in DPT Wounds 
41 
9.1.5. 
Secondary Endpoint: Incidence of Autograft in DPT Wounds 
41 
9.2. 
Safety Set 
42 
9.3. 
Full analysis Set (Intent-to-Treat population) 
42 
9.4. 
Per Protocol Set 
42 
9.5. 
Enrolled population 
42 
10.
Data Handling
43 
10.1. 
Handling of Missing Data, Outliers and Implausible Data 
43 


CIDS - Protocol Code: MW2012-01-01 
Page 5 of 138 
Statistical Analysis Plan V02 of 31 May 2021 
 
10.1.1. 
Missing Date/Time Variables 
43 
10.1.2. 
Primary Endpoint: Time to Complete Eschar Removal 
44 
10.1.3. 
Secondary Endpoints 
45 
10.1.3.1. 
Incidence of Surgical Excision 
45 
10.1.3.2. 
Blood Loss 
45 
10.1.3.3. 
Area of Autograft in DPT Wounds 
48 
10.1.3.4. 
Incidence of Autograft in DPT Wounds 
49 
10.1.4. 
Safety Endpoints 
49 
10.1.4.1. 
Time to Reach Complete Wound Closure 
49 
10.1.4.2. 
Cosmesis and Function at 12 Months from Wound Closure 
50 
10.1.4.3. 
Cosmesis and Function at 24 Months from Wound Closure 
51 
10.1.4.4. 
General Parameters of Safety 
51 
10.1.5. 
Exploratory Endpoints 
52 
10.1.5.1. 
POSAS 
52 
10.2. 
Handling of Withdrawals and Dropouts 
52 
10.3. 
Data Transformation 
53 
10.3.1. 
Demographic Data and Other Baseline Characteristics 
53 
10.3.1.1. 
Baseline Values 
53 
10.3.1.2. 
Age 
53 
10.3.1.3. 
Day to Month Conversion 
53 
10.3.1.4. 
Height 
53 
10.3.1.5. 
Weight 
54 
10.3.1.6. 
Body Mass Index (BMI) 
54 
10.3.1.7. 
Time Since Injury 
54 
10.3.2. 
Primary Endpoint: Time to Complete Eschar Removal 
54 


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10.3.3. 
Secondary Endpoints 
55 
10.3.3.1. 
Incidence of Surgical Excision 
55 
10.3.3.2. 
Blood Loss 
55 
10.3.3.2.1. Blood Loss Calculation 
55 
10.3.3.2.2. Proportion of SPT Area of Wounds Treated per Procedure 
56 
10.3.3.2.3. Proportion of DPT Area of Wounds Treated per Procedure 
56 
10.3.3.2.4. Proportion of FT Area of Wounds Treated per Procedure 
56 
10.3.3.2.5. Course of Debridement Procedure 
57 
10.3.3.3. 
Area of Autograft in DPT Wounds 
57 
10.3.3.4. 
Incidence of Autograft in DPT Wounds 
58 
10.3.4. 
Safety Endpoints 
58 
10.3.4.1. 
Time to Reach Complete Wound Closure 
58 
10.3.4.2. 
Cosmesis and Function at 12 Months from Wound Closure 
58 
10.3.4.3. 
Cosmesis and Function at 24 Months from Wound Closure 
59 
10.3.4.4. 
General Parameters of Safety 
59 
10.3.5. 
Exploratory Analyses 
67 
10.3.5.1. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
67 
10.3.5.2. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremities target wounds 
67 
10.3.5.3. 
% wound area surgically excised for eschar removal 
67 
10.3.5.4. 
Incidence of surgically harvested donor sites wounds 
68 
10.3.5.5. 
% area of surgically harvested donor site wounds 
68 
10.3.5.6. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
68 


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10.3.5.7. 
POSAS 
69 
10.3.5.8. 
Duration of hospitalization 
69 
10.3.6. 
Laboratory Values 
69 
10.4. 
Multiple Visits Per Time Point 
70 
10.5. 
Implications of COVID-19 Pandemic to the Study Data 
70 
10.5.1. 
Handling of Missing Values 
70 
10.5.2. 
Handling of Remotely Captured Data 
70 
10.5.2.1. 
Cosmesis and Function at 12 Months from Wound Closure 
71 
10.5.2.2. 
Cosmesis and Function at 24 Months from Wound Closure 
72 
10.5.2.3. 
Exploratory Analyses of MVSS and POSAS 
72 
11. 
Statistical Analysis of Target Variables 
73 
11.1. 
First Stage Analysis –12 Months Follow Up 
74 
11.1.1. 
Demographics Data and Other Baseline Characteristics 
74 
11.1.2. 
Re-Randomization Test 
76 
11.1.3. 
Primary Efficacy Analysis: Time to Complete Eschar Removal 
77 
11.1.4. 
Secondary Efficacy Analyses 
80 
11.1.4.1. 
Incidence of Surgical Excision 
80 
11.1.4.2. 
Blood Loss 
80 
11.1.4.3. 
Area of Autograft in DPT Wounds 
81 
11.1.4.4. 
Incidence of Autograft in DPT Wounds 
82 
11.1.5. 
Safety Analyses 
82 
11.1.5.1. 
Time to Reach Complete Wound Closure 
82 
11.1.5.2. 
Cosmesis and Function at 12 Months from Wound Closure 
85 
11.1.5.3. 
Cosmesis and Function at 24 Months from Wound Closure 
86 
11.1.5.4. 
Adverse Events 
86 


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11.1.5.5. 
Central Laboratory Values 
88 
11.1.5.6. 
Vital Signs 
88 
11.1.5.7. 
Pain Assessment 
89 
11.1.5.8. 
Blood Transfusions 
90 
11.1.5.9. 
Immunogenicity and PK Evaluation 
90 
11.1.5.10. Antibiotic Use 
91 
11.1.5.11. Medical History 
91 
11.1.5.12. Concomitant Medications 
91 
11.1.5.13. Hospital Readmission Rates 
91 
11.1.5.14. Change in PTT/INR 
92 
11.1.5.15. Lower Extremity Function Scale (LEFS) 
92 
11.1.5.16. Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
92 
11.1.5.17. Range of Motion (ROM) 
93 
11.1.5.18. EQ-5D (Quality of Life) 
93 
11.1.5.19. Burn Outcome Questionnaire (BOQ) 
94 
11.1.6. 
Exploratory Analyses 
94 
11.1.6.1. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
94 
11.1.6.2. 
Incidence 
of 
reduction 
in 
interstitial/compartment 
pressure 
in 
circumferential extremities target wounds 
94 
11.1.6.3. 
% wound area surgically excised for eschar removal 
95 
11.1.6.4. 
Incidence of surgically harvested donor site wounds 
95 
11.1.6.5. 
% area of surgically harvested donor site wounds 
95 
11.1.6.6. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
95 


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11.1.6.7. 
POSAS 
95 
11.1.6.8. 
MVSS (target wounds) 
96 
11.1.6.9. 
Duration of hospitalization 
96 
11.1.7. 
Pharmacokinetic Variables 
96 
11.1.8. 
Multicenter Data 
96 
11.1.9. 
Handling of Multiple Comparisons 
96 
11.1.10. Interim Analysis 
97 
11.1.11. Stratification 
97 
11.1.12. Analysis of Subgroups 
98 
11.1.12.1. Age group 0-23 months 
98 
11.1.12.2. Age group 24 months – 3 years 
99 
11.1.12.3. Age group 0 – 3 years 
99 
11.1.12.4. Age group 4 – 11 years 
99 
11.1.12.5. Age group 12 – 18 years 
99 
11.2. 
Second stage analysis – 24 months long-term follow-up (LTFU24) 
100 
11.2.1. 
Demographics Data and Other Baseline Characteristics 
100 
11.2.2. 
Primary Efficacy Analysis 
100 
11.2.3. 
Secondary Efficacy Analyses 
100 
11.2.4. 
Safety Analyses 
100 
11.2.4.1. 
Time to Reach Complete Wound Closure 
100 
11.2.4.2. 
Cosmesis and Function at 12 Months from Wound Closure 
100 
11.2.4.3. 
Cosmesis and Function at 24 Months from Wound Closure 
100 
11.2.4.4. 
Adverse Events 
101 
11.2.4.5. 
Concomitant Medications 
102 
11.2.4.6. 
Lower Extremity Function Scale (LEFS) 
102 


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11.2.4.7. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
102 
11.2.4.8. 
Range of Motion (ROM) 
102 
11.2.4.9. 
EQ-5D (Quality of Life) 
102 
11.2.5. 
Exploratory Analyses 
103 
11.2.5.1. 
POSAS 
103 
11.2.5.2. 
MVSS (target wounds) 
103 
11.2.6. 
Pharmacokinetic Variables 
104 
11.2.7. 
Multicenter Data 
104 
11.2.8. 
Handling of Multiple Comparisons 
104 
11.2.9. 
Interim Analysis 
104 
11.2.10. Stratification 
104 
11.2.11. Analysis of Subgroups 
104 
12. 
Reference List 
105 
13. 
Appendices 
110 
13.1. 
Randomization Algorithm 
110 
13.2. 
Potentially Clinically Significant Thresholds 
111 
13.2.1. 
Vital Signs 
111 
13.2.2. 
Laboratory Parameters 
115 
13.3. 
Update to Study Sample Size Due to COVID-19 Pandemic 
122 
13.4. 
Update Memo to Sites Due to COVID-19 Pandemic 
134 
 


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2. Introduction 
2.1. Background 
Eschar removal, “Debridement”, is the first stage of the comprehensive wound care process. 
This process of debridement constitutes a well-recognized and critical part of burn wound care. 
Timely and rapid debridement of eschar is essential to initiate the wound healing process and 
prevent further complications. The dead tissue, if not removed, often becomes heavily 
contaminated in 2 to 3 days and is the source of local and/or systemic infection or sepsis. The 
local inflammation and infection destroy healthy surrounding tissues and extends the original 
damage. To prevent these complications, it is imperative to evaluate the burn and remove all 
the offending eschar at the earliest possible opportunity. 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] [4] [5] [6]. 
Removal of eschar may be accomplished by surgery or by non-surgical means. The choice of 
debridement method (surgical or non-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 (operating rooms) and staff. 
The current SoC in the US relies primarily on surgical tangential excision to remove the 
offending eschar through use of sharp instruments such as scalpels and dermatomes [7] [8]. 
Non-surgical SoC are all based on maceration (in situ) of the eschar. They include collagenase 
ointment (Santyl), antimicrobial agents such as silver sulfadiazine, or various hydrogels. 
Care of Pediatric Burn Patients 
There is an unmet need for treatment modalities that can facilitate the care of children with 
burns. Patients below the age of 20 years, account for 31.9% of the total number of burn 
injuries in the USA [9]. Burns in pediatric patients exhibit the same pathophysiological 
responses as in adults but with typical pediatric characteristics. These characteristics include 
differences of relative sizes between areas, anatomy, physiology, emotional and psychological 
development, which influence the child’s response to injuries including burns. 


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NexoBrid is a non-surgical debridement product developed for treatment of second and third 
degree severe burns with improved safety and efficacy characteristics. 
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 [10], including two phase 3 pivotal trials, MW 2004-11-02 [11] 
and MW2010-03-02. Efficacy data generated during the NexoBrid clinical program suggest 
that the clinical benefits of NexoBrid address the unmet medical needs for both improved 
routine burn care as well as care in the event of a mass casualty incident (MCI), as 
demonstrated by the product’s specific attributes: 
1. An effective topical eschar removal agent (comparable to SoC) 
2. Enables significantly earlier eschar removal compared to SoC, allowing direct visual 
assessment of wound depth and assisting in the decision on the proper subsequent 
wound closure strategy 
3. Reduces the surgical burden (extent of excision and grafting); less traumatic than SoC 
4. Reduces blood loss associated with eschar removal 
5. Product use is not dependent on operating room facilities or surgeons (i.e., it can be 
applied at the patient’s bedside) and therefore can alleviate bottlenecks in treatment in 
an MCI situation, as demonstrated in the MCI in Romania [12] 
6. Enables avoiding of 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 [13] 
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 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.  


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3. Blood loss is minimized by reduced excisional and autografting surgery. 
2.2. Study Objective 
The objective of this study is to evaluate the safety and effectiveness of NexoBrid in 
hospitalized pediatric patients with DPT and FT thermal burns of 1-30% TBSA and to compare 
NexoBrid to SoC. The specific study objectives are: 
1. To demonstrate enzymatic eschar removal efficacy of NexoBrid by providing earlier, 
complete eschar removal, 
2. To demonstrate enzymatic eschar removal efficacy of NexoBrid by reducing patients’ 
surgical burden, eschar removal related blood loss and resulting in non-inferior final 
outcomes of cosmesis and function as compared to SoC, 
3. To assess the safety of NexoBrid compared to SoC. 
2.3. References to Study Protocol 
This Statistical Analysis Plan refers to the study protocol version10.01 of 16 November 2020. 
The trial protocol code is MW2012-01-01. 
2.4. Amendments 
The study was initiated under the trial protocol version 4. Since then, there have been six 
amendments (to versions 5, 6, 7.02, 8, 9.01 and 10.01)1. 
2.5. Global Statistical Analysis 
The CIDS MW2012-01-01 protocol is conducted as part of a Pediatric Investigational Plan in 
Europe and therefore changes in key binding elements in the Pediatric Investigational Plan are 
subject to the EMA's pediatric committee (PDCO) prior approval. The PDCO and the FDA had 
different requirements for the statistical analysis and therefore, as agreed with the FDA, the 
                                               
1 Only versions 7.02 and 9.01 were submitted under the IND 


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study conduct will be the same for the EU and US, however the SAPs will be different (Type B 
meeting minutes, May 2017). The SAPs will include the same analyses, but in a different order, 
according to each agency's requirements. This document is the non-EU version of the SAP. 


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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 
VP Clinical Affairs 
MediWound Ltd. 
 
 
Nimrod Leuw 
VP of Quality 
MediWound Ltd. 
3.2. Study Conduct (Data Management) 
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: 
Professor (emer.) Paul D. Feigin 
Director of the Israel Data Science Initiative (IDSI) 
Head of the Technion Statistics Laboratory 
Faculty of Industrial Engineering and Management 
Technion – Israel Institute of Technology 
Haifa 3200003, ISRAEL 
Larissa Fertik 
Senior Biostatistician 
Bioforum Biostatistics Department 
3 Golda Meir St., Weizmann Science Park 
Ness Ziona 7414001, Israel 




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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 
FPS-R 
Faces Pain Scale - Revised 


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abbreviation 
meaning 
FT 
Full Thickness 
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 
pCS 
Post-treatment potentially clinically significant 
PDF 
Portable Document Format 
POSAS 
Patient Observer Scar Assessment Scale 
PP 
Per Protocol 


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abbreviation 
meaning 
PRBC 
Packed Red Blood Cells 
PTT 
Prothrombin Time 
QoL 
Quality of Life 
ROM 
Range of Motion 
RTF 
Rich Text Format 
SAE  
Serious Adverse Event 
SoC 
Standard of Care 
SOC 
System Organ Class 
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. General Definitions of Medical Terms 
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: is achieved at the end of the eschar removal treatment phase. 
The Eschar Removal assessment should be more or equal to 95% and will be 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 [14]. 
Complete wound closure: defined as % of wound area epithelialized and/or closed by 
graft is >95% without drainage or dressing requirements confirmed at two consecutive 
study visits, 2 weeks apart. 
Efficacy assessment period: defined as the time period up to the 12 weeks follow-up post 
wound closure confirmation. 
6.2. Hardware and Software Used 
The statistical analysis will be performed using SAS® version 9.4. 
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). 
6.4. Quality Control 
The statistical analysis must follow the statistical analysis plan. 
The planned method of QC for all analyses is double programming. 


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6.5. General Traceability 
All generated outputs will include headers and footnotes containing the following information: 
 
Page number (Page xx of xx) 
 
Name of generating program 
 
Output run time 
 
Data base extraction date 
 
Output file name 
 
Source data set(s) 
 


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7. Details of Trial Design 
7.1. Trial Schedule 
 


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Table 1: Treatment flow chart – Study Schedule (all arms) 
* Weekly FU assessments will be performed 7±2 days post eschar removal and, thereafter on a weekly basis until wound closure. Long term FU will be 
performed 6 and 12 weeks, 6,12,18 and 24 months after last wound closure confirmation. 
#-If applicable 
Parameter 
Screening 
& Baseline 
Pre-treatment 
- Within 1 h pre 
treatment – 
Both Arms 
 
Treatment 
Daily 
Assessments 
Wound 
Management & 
Re-admission – 
surgical 
procedures 
Weekly FU* 
Hospital 
Discharge or 
premature 
discontinuation 
visit 
FU (weeks 6, 12 
months 6, 12, 18, 
24) 
NexoBrid 
(S=Soaking 
R=Removal) 
SoC (including 
additional 
procedures post 
NexoBrid) 
Signing informed 
consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Burn Description 
X 
 
 
 
 
 
 
 
 
ConMeds & AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
X 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
X 
 
 
 
 
Pain assessment 
X 
X 
4h post R 
Pre and 4h post 
X 
 
 
 
 
Photograph of TWs 
X 
X 
Post S 
Pre & Post 
 
Pre & post 
X 
 
X 
Local Lab - HbA1C,  
βhCG 
X 
 
 
 
 
 
 
 
 
Central Lab: 
Urianalysis 
 
X 
4h post R 
Pre & 4h Post 
 
 
 
 
 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Parameter 
Screening 
& Baseline 
Pre-treatment 
- Within 1 h pre 
treatment – 
Both Arms 
 
Treatment 
Daily 
Assessments 
Wound 
Management & 
Re-admission – 
surgical 
procedures 
Weekly FU* 
Hospital 
Discharge or 
premature 
discontinuation 
visit 
FU (weeks 6, 12 
months 6, 12, 18, 
24) 
NexoBrid 
(S=Soaking 
R=Removal) 
SoC (including 
additional 
procedures post 
NexoBrid) 
Central Lab: 
Biochemistry2 
 
X 
4h post R 
Pre & 4h Post  
 
 
 
 
 
Central Lab: 
Hematology 
 
X 
4h post R 
Pre & 4h Post 
 
Pre & post 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Local Lab: Wound 
culture 
 
X 
Post S 
Pre & Post 
 
 
 
 
 
Local Lab: Blood 
culture3 
 
X 
4h post R 
4h Post 
 
 
 
 
 
PK4 
 
X 
X 
 
X 
 
 
 
 
Immunogenicity5 
 
X 
 
 
 
 
X 
 
X 
Local Lab: PTT & INR 
 
X 
4h post R 
4 h post – first 
treatment only 
 
 
 
 
 
Coverage 
 
 
 
Start and end 
date, type of 
primary dressing 
 
Start and end 
date, type of 
primary dressing 
 
 
 
Pressure 
Measurement (for 
Circumferential 
 
# 
# 
#1 h pre & Post 
 
 
 
 
 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Parameter 
Screening 
& Baseline 
Pre-treatment 
- Within 1 h pre 
treatment – 
Both Arms 
 
Treatment 
Daily 
Assessments 
Wound 
Management & 
Re-admission – 
surgical 
procedures 
Weekly FU* 
Hospital 
Discharge or 
premature 
discontinuation 
visit 
FU (weeks 6, 12 
months 6, 12, 18, 
24) 
NexoBrid 
(S=Soaking 
R=Removal) 
SoC (including 
additional 
procedures post 
NexoBrid) 
extremity wounds 
monitoring) 
Cosmesis, function 
and quality of life6  
 
 
 
 
 
 
 
 
X 
Record of scar 
modulating/reconstruc
tive procedures 
 
 
 
 
 
 
 
 
X 
Range of Motion7 
 
 
 
 
 
 
 
 
X 
Blood transfusion 
# 
 
# 
# 
# 
# 
 
 
# 
Histological biopsy 
# 
 
 
# 
# 
# 
# 
# 
# 
1 Physical examination will include height and weight. Height will be taken only once, at screening.  
2  For patients weighing less than 18kg, serum chemistry will be collected at baseline only. 
3  Blood culture is to be tested only if this is clinically indicated: 
 
in patients weighing less than 18kg,  
 
and/or in patients requiring two NexoBrid applications (either because of failure of the first treatment session or because >15%TBSA) 
4 PK samples should be taken as detailed in Appendix 10 of the study protocol 
5 Immunogenicity will be performed only for NexoBrid patients weighing at screening over 18kg at baseline, weeks 4, 8 and months 6 and 24 following wounds closure.  In case that weekly visit 8 is not 
performed, this assessment should be taken on the relevant weekly/first follow up visit as close as possible to 8 weeks. 
6 Cosmesis will be evaluated in donor site scars as well 
7 Range of motion measurement of injured joints will be measured, if relevant. The measurement will be performed on the corresponding non injured joint as well, for comparison. 
 


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7.2. Criteria for Evaluation 
7.2.1. 
Demographic Data and Other Baseline Characteristics 
The following demographic data will be documented at screening/baseline: 
 
Date of birth 
 
Age Group (0 to 23 months, 24 months to 3 years, 4 to 11 years, 12 to 18 years) 
 
Gender 
 
Ethnicity 
 
Race 
 
Serum Pregnancy Test results (βHCG) 
Furthermore, at screening/baseline the inclusion and exclusion criteria will be collected and 
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) 
 
Date and time of admission 
General wound description: 
 
Wound number 
 
Anatomical location 
 
%TBSA of 2° SPT Burns (clinical assessment) 
 
%TBSA of 2° DPT Burns (clinical assessment) 
 
%TBSA of 3° FT Burns (clinical assessment) 
 
Information whether the respective wound will be designated as TW 
 
Information whether a wounded extremity is circumferential 
 
Information whether escharotomy had been performed prior to randomization 
 
Eschar description 
 
Information whether cleansing was performed 


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Statistical Analysis Plan V02 of 31 May 2021 
 
 
Information whether all superficial keratin (blister) were removed from wound 
Target wound identification (data collected per wound): 
 
Target wound number 
 
Anatomical location 
 
%TBSA of 2° SPT Burns (clinical assessment) 
 
%TBSA of 2° DPT Burns (clinical assessment) 
 
%TBSA of 3° FT Burns (clinical assessment) 
 
Information whether the wound was treated prior to enrollment 
Information needed for randomization and treatment: 
 
Total wounds TBSA % per patient (clinical assessment) 
 
Overall total area of FT burns (clinical assessment) 
 
TWs FT total area (% TBSA, out of the total burned area of the patient, clinical 
assessment) 
 
Randomization result (treatment) 
 
Date of randomization 
Physical examination: 
 
Height (cm or inch) 
 
Weight (kg or lb) 
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 


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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 FPS-R 
 
Assessment of pain (normal, abnormal-NCS, abnormal-CS) 
Local laboratory: 
 
Information whether patient is diabetic 
 
HbA1c (%) 
Information on infections as well as the medical history will be recorded. 
7.2.2. 
Efficacy Evaluation 
7.2.2.1. 
Primary Endpoint: Time to Complete Eschar Removal 
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 2.1 for target wound 
definition) in accordance with the study protocol:  
Earlier eschar removal (in days): Demonstrate superiority of NexoBrid over SoC for eschar 
removal (see definition in Section 6.1) as measured by a survival analysis of incidence of 
complete eschar removal for all TWs as a function of time in days from randomization. Eschar 
removal will be measured at the end of the debridement starting from randomization date, and 
marked as yes/no in the eCRF. 
7.2.2.2. 
Secondary Endpoints 
The following secondary endpoints will be evaluated in this study and compared between 
NexoBrid and SoC: 


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Incidence of Surgical Excision 
Reduction of surgical need for excisional eschar removal is measured by an analysis of 
incidence (yes/no response) of surgical eschar removal (tangential/ minor/ avulsion/ Versajet 
and/or dermabrasion excision). The time frame for this incidence rate is until complete eschar 
removal has been achieved. 
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 Hematocrit during the 
eschar removal procedures and the amount of units of blood transfused. Blood loss will be 
calculated using the following formula [15]: 
𝐵𝑙𝑜𝑜𝑑 𝐿𝑜𝑠𝑠 (𝑚𝐿) = 𝑅𝐵𝐶𝑉𝑏𝑒𝑓𝑜𝑟𝑒+ (𝑇𝑟𝑎𝑛𝑠𝑓𝑢𝑠𝑖𝑜𝑛 𝑅𝐵𝐶𝑉) −𝑅𝐵𝐶𝑉𝑎𝑓𝑡𝑒𝑟
𝐻𝑐𝑡𝑎𝑓𝑡𝑒𝑟[%] ∗0.01
 
RBCV (mL) = Red Blood Cell Volume (mL) = Body Weight (kg) * 80 (mL/kg) * (Hematocrit [%] 
* 0.01) 
Transfusion RBCV (mL) = [Total Volume (mL) of Whole Blood Transfused * 0.3] + [Total 
Volume (mL) of Packed Red Blood Cells Transfused * 0.8] 
The blood loss will be computed over the whole eschar removal period, using the formula 
above, i.e. the eschar removal process will be considered as one continuous procedure. 
Therefore, only the Hematocrit 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. 
Additionally, the blood loss will be summed over all procedures carried out to remove eschar, 
with the hematocrit 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 up to 24 hours from the end time of the debridement 
procedure. 
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. 


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Area of Autograft in DPT Wounds 
Reduction in the need for Autograft in deep partial thickness wounds is measured by an 
analysis of percent area of deep partial thickness wounds autografted. 
Incidence of Autograft in DPT Wounds 
Reduction in the need for Autograft in deep partial thickness wounds is also measured by an 
analysis of incidence of Autograft procedures. 
7.2.3. 
Safety Evaluation 
7.2.3.1. 
Time to Reach Complete Wound Closure 
Time to reach complete wound closure will be assessed in days, starting from randomization 
date. 
7.2.3.2. 
Cosmesis and Function at 12 Months from Wound Closure 
Cosmesis and Function assessment will be performed based on the Modified Vancouver Scar 
Scale (MVSS) at 6 and 12 weeks and at 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. 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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7.2.3.3. 
Cosmesis and Function at 24 Months from Wound Closure 
See section 7.2.3.2. 
7.2.3.4. 
Adverse Events 
For each AE the following information will be determined: 
 
AE description 
 
Type of AE (General, Local – TW related, Local – not TW related) 
 
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) 
Treatment-emergent Adverse Events (TEAEs) are defined as AEs that start during or after first 
NexoBrid or SoC treatment. TEAEs, related TEAEs, and Serious TEAEs will be summarized 
by Medical Dictionary for Regulatory Activities (MedDRA) system organ class, preferred term 
and severity. Events where the relation is considered “related”, “possibly related”, or “probably 
related” will be considered as related and events where the relation is considered ‘not related’ 
or ‘remotely related’ will be considered “not related”. Events with missing causality will be 
considered as "related" and will be included in the summary of related TEAEs. Serious AEs 
resulting in death and AEs resulting in withdrawal from the study will be listed separately. 
For randomized patients, AEs that occur between signing the informed consent document and 
receipt of study treatment will be provided in a listing. 
Except for a summary table on event level, TEAEs will be reported on a per-patient basis. This 
means that even if a patient reported the same event repeatedly (i.e., events mapped to the 
same preferred term) during the assigned study period, the event will be counted only once in 
tabulations. In the latter case the event will be assigned the worst severity and the strongest 
relationship to the study drug. The earliest date will be regarded as start date of the event and 


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the latest date will be regarded as stop date of the event. All AEs, including those occurring 
more than once will be listed. 
The same rules for counting, severity and relationship apply for PTs mapped to the same 
system organ class. 
Notes:  
 
The MedDRA version will be denoted in the footnote of tables and listings. 
 
Listings will be sorted within patients by start date of the adverse event according to 
treatment group. 
7.2.3.5. 
Laboratory Assessments 
The following tests will be performed: 
Serum chemistry, hematology and urinalysis testing will be performed at a central laboratory 
during NexoBrid eschar removal phase. Any additional procedures require hematology tests, 
as described in the protocol, will be performed using Central lab. Pregnancy testing, HbA1c, 
wound cultures, blood cultures and biopsies (if indicated) will be performed locally on-site. 
The following tests will be performed in special central laboratories: Pharmacokinetics test, 
Immunogenicity evaluation. 
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. 
HbA1C2 will be assessed at a local lab at Screening for diabetic patients as captured during 
the medical history. 
                                               
2 HbA1C will not be collected for patients weighing less than 18kg at screening 


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PTT and INR will be tested at a local lab pre treatment and post treatment. 
Pregnancy Testing: 
A serum or urine pregnancy (βHCG) test 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 Culture3: 
Test blood for microbial flora 
7.2.3.6. 
Additional Safety Endpoints 
Additional safety endpoints to be evaluated in this study are: 
 
Vital signs 
 
Pain assessment (using FPS-R and as reported as AEs) 
 
Volume of blood transfusion given during hospitalization 
 
Immunogenicity evaluation for NexoBrid patients 
 
Analgesia and anesthesia medications 
 
Days of exposure to systemic antibiotic drugs 
 
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’ 
                                               
3 Blood culture is to be tested only if this is clinically indicated in patients weighing less than 18kg, and/or 
only if it is clinically indicated in patients requiring two NexoBrid applications (either because of failure 
of the first treatment session or because >15%TBSA) 


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 
'QuickDASH' questionnaires 
 
'Range Of Motion' measurements 
 
Long-term Quality of Life using EQ5D and Burn Outcome Questionnaire (BOQ) for a 
subset of patients4 
7.2.4. 
Exploratory Analyses 
 
Incidence of surgical Escharotomy procedures on circumferential extremities target 
wounds, 
 
Incidence of reduction in interstitial/compartment pressure in circumferential extremity 
wounds, 
 
Reduction in surgical needs as measured by an analysis of % wound area surgically 
excised for eschar removal. 
 
Reduction in surgical need as measured by analysis of incidence of surgically 
harvested donor sites scars, 
 
Reduction in surgical need as measured by analysis of % area of surgically harvested 
donor site scars. 
 
Blood loss related to eschar removal assessed by changes in Hemoglobin incurred 
during the eschar removal procedures 
 
PK evaluation in NexoBrid patients 
 
Cosmesis evaluation (MVSS and POSAS) will be used to assess the quality of the 
donor site scars, 
 
Incidence of wound closure 
 
Additional Cosmesis and Function evaluation will be performed using POSAS 
measured at 12 and 24 months from wound closure.  
 
Incidence and extent of Autograft in DPT wounds 
 
Duration of hospitalization  
                                               
4 BOQ will be completed only for patient from study sites in the USA. BOQ11-18 will be completed by 
patients aged 11-18. BOQ0-5 will be completed by parents of burned children under the age of 5 years 
and BOQ5-18 will be completed by parents of burned children between the ages of 5 and 18 


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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 
 
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 
 
treatment started more than 5 days from injury, or 
 
one of the following inclusion criteria is violated: 
o Stage 1: Males and females between 4 years to 18 years of age, 
o Stage 2 (upon DSMB review): Males and females between 1 year to 18 years 
of age, 
o Stage 3 (upon DSMB review): Males and females between 0 years to 18 years,  
o Thermal burns caused by fire/flame, scalds or contact,  
o Patient total burns area ≥ 1% 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 ≥1% TBSA (DPT and/or 
FT) (this minimal wound size should not include face, perineal or genital) 
o Wound that is potentially intended for surgical eschar removal 
o Wound’s blisters can be removed/unroofed, as judged by the investigator 
 
one of the following exclusion criteria is met: 
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 calculations are taken from the protocol. 
9.1. Sample Size 
The following sample size calculations are based on the consideration of the primary endpoint 
of this study. For the secondary endpoints, the power, which can be achieved with the planned 
sample size, is determined. Updated calculations were performed to support the final sample 
size of 145 patients enrolled into the study (provided in 13.3 13.3Update to Study Sample Size 
Due to COVID-19 Pandemic). 
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. This study included 
both adults and children. Similar effects were observed among the children population 
and the adult one; 
b) The effect of NexoBrid versus standard of care was estimated together with the 
standard error of the estimate; 
c) The size of the effect to be detected in this study, MW2012-01-01, was taken as the 
previous estimate decreased by half its standard error, in order to use a conservative 
value. 
9.1.1. 
Primary Endpoint: Time to Complete Eschar Removal 
Estimated log hazard ratio from study MW2004-11-02 (SoC versus NexoBrid) = -1.39, using a 
Cox proportional hazards model with treatment as only covariate. 
Standard error = 0.28 
Target log hazard ratio = -1.39 + 0.28/2 = -1.25; target hazard ratio λ= 0.29. 
The formula for the number of events D (successful complete eschar removals) is: 
𝐷=
4(𝑧𝛼+ 𝑧𝛽)
2
(ln λ)2
 


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(Piantadosi, Clinical Trials: A Methodologic Perspective, p.169) 
zα= 1.96;  
zβ= 1.28 for 90% power. 
If the proportion of events in NexoBrid group is denoted by p1 = 0.59 
and the proportion of events in SoC group is denoted by p2 = 0.70, 
which are the observed proportions in the study MW2004-11-02, the number of patients 
required 𝑛=
2𝐷
𝑝1+𝑝2 = 42 (to the nearest even number), 21 in each group. 
In accordance with the European regulatory requests and planned age distribution, we believe 
that a sample size of 80 patients per arm will detect with a 90% power a difference on the 
primary endpoint, which is well within what would be expected, based on the results from the 
previous study. 
Based on the above calculations, we plan a study with total sample size of 160 patients; 80 
(NexoBrid) + 80 (SoC)5. 
9.1.2. 
Secondary Endpoint: Incidence of Surgical Excision 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.42; 
SoC 0.80  
Standard errors: NexoBrid 0.057; SoC 0.044  
Difference = 0.38; Standard error of difference = 0.073  
Anticipated difference: 0.38-0.073/2 ≈ 0.34  
We therefore take the anticipated proportion with surgical excision to be: NexoBrid 0.44 and 
SoC 0.78.  
Using Fisher’s exact test, the power achieved with a total sample size of 160 patients (80 in 
each group) using a two-sided significance level of 5% is 99.1%. 
                                               
5 Updated calculations were performed to support the final sample size of 145 patients enrolled into the 
study (provided in 13.3 13.3Update to Study Sample Size Due to COVID-19 Pandemic) 


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9.1.3. 
Secondary Endpoint: Blood Loss 
Estimated mean blood loss from study MW2004-11-02: NexoBrid 421.93 ml; SoC 1024.27 ml 
Standard errors: NexoBrid 129.52; SoC 240.98 
Difference: -602.33; Standard error of difference: 273.58 
Anticipated difference: -602.33 + 273.58 /2 = -465.54 
Using a two-sided two-sample t-test the power with a total sample size of 160 patients and a 
two-sided significance level of 5% is 58.8%. 
9.1.4. 
Secondary Endpoint: Area of Autograft in DPT Wounds 
The proportion of subjects with at least one DPT wound was 62.6% in the study MW2004-11-
02. Therefore, if 160 patients are enrolled to the CIDS study, we expect 100 patients to have 
at least one DPT wound and be thereby eligible for this analysis. 
Estimated difference in mean area autograft in DPT wounds from study MW2004-11-02 
(NexoBrid vs. SoC) = 13.30-23.63 = -10.33. 
Standard error = 6.02 
Target difference Δ = -10.33 + 6.02/2 ≈ -7.32. 
Using a two-sided two-sample t-test the power with a total sample size of 160 patients using a 
two-sided significance level of 5% is 23.1%. 
9.1.5. 
Secondary Endpoint: Incidence of Autograft in DPT Wounds 
Estimated log OR using GEE approach from study MW2004-11-02 (NexoBrid vs SoC): -0.676 
Standard Error: 0.40 
Anticipated log OR: -0.676+0.40/2=-0.476 
Using the normal approximation to the Wald test statistics (see for example Shih (1997)) we 
obtain a power of 53.3% with a total sample size of 160 patients using a two-sided significance 
level of 5%. 


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9.2. Safety Set 
The safety set includes all patients who received a treatment and analysis is focused on the 
treatment actually performed. 
9.3. Full analysis Set (Intent-to-Treat population) 
The full analysis set (FAS) includes all patients who were randomized into the trial. The 
analysis is focused on the planned treatment. The analysis of the ITT population (FAS) 
provides the primary and secondary efficacy and the comparative safety analyses. 
9.4. 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. The PP analysis will 
include patients in the treatment group according to treatment received. 
9.5. Enrolled population 
The enrolled population consists of all subjects who passed through the screening processes 
and signed informed consent. 


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10. Data Handling 
10.1. Handling of Missing Data, Outliers and Implausible Data 
10.1.1. Missing Date/Time Variables 
If time data is missing (e.g. for ICF or injury), i.e. a date variable is given but without the time, 
the time is set to 12 pm (middle of the day). 
In case 12 weeks follow-up date is missing (needed for the definition of the efficacy 
assessment period), it will be imputed by adding 42 days to the 6 weeks follow-up date. In 
case 6 weeks follow-up date is missing, it will be imputed by adding 12 weeks (84 days) to the 
wound closure confirmation date. In case wound closure confirmation date is missing, it will be 
imputed by subtracting 90 days from the 6 months follow-up date. In case 6 months follow-up 
date is missing, it will be imputed by subtracting 270 days from the 12 months follow-up date. 
In case 12 months follow-up date is missing, it will be imputed by subtracting 450 days from 
the 18 months follow-up date. If the wound closure confirmation date and all further follow-up 
dates are missing, it will be imputed by the study termination date. 
In case the 12 months follow-up date is missing (needed for the definition of the stages of the 
analyses, see Section 11), it will be imputed by adding 12 months to the wound closure 
confirmation date. If the wound closure confirmation date is missing, the 12 months follow-up 
date will be imputed by adding half the difference (in days, rounded to the next highest whole 
number) between the 6 months follow-up date and the 18 months follow-up date to the 6 
months follow-up date. If the 6 months follow-up date is not missing (and the 18 months follow-
up date is missing), the 12 months follow-up date will be imputed by adding 180 days to the 6 
months follow-up date. If the 18 months follow-up date is not missing (and the 6 months follow-
up date is missing), the 12 months follow-up date will be imputed by subtracting 180 days from 
the 18 months follow-up date. If the wound closure confirmation date and all further follow-up 
dates are missing, the 12 months follow-up date will be imputed by the study termination date. 
In case the 24 months follow-up date is missing, it will be imputed by the study termination 
date. 


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In case the end date of an adverse event or a concomitant medication is missing, it will be 
imputed by the maximum of the end date of the analysis stage, respectively the study 
termination date. 
A missing start date of an ongoing concomitant medication or adverse event will be imputed 
by the date of informed consent. 
10.1.2. Primary Endpoint: Time to Complete Eschar Removal 
The main analysis of the primary endpoint time to complete eschar removal will compute 
missing values as censored at the date of the last non-missing eschar removal assessment 
(typically last debridement procedure). If no eschar removal assessment after baseline is 
available, the subject will be censored with time 0. 
In addition, three sensitivity analyses will be performed: 
1. For the first sensitivity analysis, subjects with no available eschar removal assessment 
will be censored with Median Time, estimated using the Kaplan-Meier method based 
on subjects from both treatment groups having a non-missing value on this endpoint 
(including subjects censored at the date of the last non-missing eschar removal 
assessment). 
2. For the second sensitivity analysis, subjects with no available eschar removal 
assessment will be censored as follows (a worst case scenario):  
 
For NexoBrid – with the maximal time obtained for subjects randomized to 
NexoBrid group (including subjects censored at the date of the last non-missing 
eschar removal assessment) 
 
For SoC – with the Median Time, estimated using the Kaplan-Meier method 
based on subjects from SoC group having a non-missing value on this endpoint 
(including subjects censored at the date of the last non-missing eschar removal 
assessment) 
3. For the third sensitivity analysis, subjects with no available eschar removal assessment 
will be censored as follows (a best case scenario): 
 
For NexoBrid – with the Median Time, estimated using the Kaplan-Meier 
method based on subjects from NexoBrid group having a non-missing value on 


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this endpoint (including subjects censored at the date of the last non-missing 
eschar removal assessment) 
 
For SoC – with the maximal time obtained for subjects randomized to SoC 
group (including subjects censored at the date of the last non-missing eschar 
removal assessment) 
10.1.3. Secondary Endpoints 
10.1.3.1. 
Incidence of Surgical Excision 
Little or no missing data are expected for the secondary endpoint incidence of surgical 
excision. 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 "success" (i.e. no surgical excision performed). 
Note: The main analysis specified in the protocol was the complete case analysis. However, 
in previous discussions concerning the study MW2010-03-02, FDA suggested to use all 
subjects for the main analysis of this endpoint. Therefore, in the previous study, the main 
analysis included all subjects with those having a missing value assumed to have "failed", i.e. 
to have received surgery. This approach was also adopted here. 
10.1.3.2. 
Blood Loss 
As defined in Section 10.3.3.2.1, the measure of blood loss per patient will be computed using 
two different methods: 
 
Method 1: treating the whole eschar removal process as one continuous procedure 
 
Method 2: summing the blood loss computed per procedure over all procedures carried 
out to remove eschar 
Missing blood loss values will be imputed separately for each method. The procedures can be 
described as follows: 
1. Test for normality: 


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 
For Method 1: The measure of blood loss defined in Section 10.3.3.2.1 will be 
computed for each patient. 
 
For Method 2: The measure of blood loss defined in Section 7.2.2.210.3.3.2.1 
will be computed for each procedure and aggregated to patient level. 
An ANOVA model (on a patient level) incorporating the stratification factors treatment 
center, %TBSA, proportion of the FT area and age will be used to detect differences 
between both treatment groups. The normality of the data will be tested on residuals of 
this model using the Shapiro-Wilk test. If the normal distribution hypothesis is not 
rejected at the 5% significance level, then the ANOVA model will constitute the main 
analysis model. In case the normal distribution hypothesis is rejected at the 5% 
significance level, then a stratified Wilcoxon test, using the same stratification variables 
as outlined for the ANOVA, will be used. 
2. Imputation: 
If the normality condition is satisfied, the following will be performed:  
 
For Method 1: Fit a linear regression model with target variable blood loss on a 
patient level (as computed in Section 10.3.3.2.1) and independent variables 
age, wound area, depth of wound (categorized as all DPT / mixed / all FT) and 
course of debridement procedure (as defined in Section 10.3.3.2.5) to the 
subset containing patients with complete data in those variables for both 
treatment groups separately. 
 
For Method 2: Fit a linear regression model with target variable blood loss on a 
procedure level (as computed in Section 10.3.3.2) and independent variables 
age, size of wounds treated in this procedure (wound area), proportion of area 
SPT of wounds treated in this procedure (as defined in Section 10.3.3.2.2), 
proportion of area DPT of wounds treated in this procedure (as defined in 
Section 10.3.3.2.3), proportion of area FT of wounds treated in this procedure 
(as defined in Section 10.3.3.2.4) and type of procedure (surgical/non-surgical) 
to the subset containing patients with complete data in those variables for both 
treatment groups separately. This model will treat all the procedures as 
independent. 


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Impute the missing entries of the incomplete data sets m = 25 times as follows. Draw 
a set of regression coefficients from their sampling distribution obtained from fitting the 
respective linear models outlined above. Sample a variance as the quotient between 
the residual variance from the linear model fitted to the data and a random variable 
which is chi-square distributed with corresponding degrees of freedom (a different 
distribution for the regression coefficients and variance will be obtained in the different 
treatment groups). With these sampled coefficients calculate the predicted blood loss 
values for the missing blood loss values 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 sampled standard 
deviation. The imputation outlined above will be performed using PROC MI in SAS. 
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 m=25 multiply imputed datasets will be used. The 
predictive mean matching method is implemented in the SAS procedure PROC MI.  
 
For Method 1: The random seed will be 12467. 
 
For Method 2: The random seed will be 1732. On the imputed datasets the 
blood loss on a patient level will be calculated. 
3. Analysis: Analyze each of the m complete datasets with an ANOVA or the stratified 
Wilcoxon test according to the test result in step 1 using the re-randomization test 
outlined in Section 11.1.2. An estimated treatment difference,  (NexoBrid versus SoC), 
from the analysis model and a two-sided p-value, p, from the permutation test (as 
described in Section 11.1.2) will be obtained for each imputed dataset. In case the 
analysis is performed with the stratified Wilcoxon test, Hodges-Lehmann (HL) estimate 
for treatment difference will be used (options ALIGN=STRATA WILCOXON HL in SAS 
NPAR1WAY procedure). 
4. Pooling: Integrate the m analysis results into a final result, as follows. A “working 
standard error”, s, of the estimated treatment difference for each imputed dataset will 
be obtained by s = (1-p/2) if >0, or s = (p/2) if <0, where  is the inverse 
of the standard normal cumulative distribution function. Then Rubin’s rules will be used 
to combine the set of values of  and s (using PROC MIANALYZE in SAS) - to give an 
overall estimate of  and its standard error. 


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5. The p-values (p1, …, pm) will be combined using the Licht-Rubin formula (as described 
in Section 4.1 of [16]), as follows: 
1) Compute 𝑧𝑖= Φ−1(1 −𝑝𝑖) for each i 
2) Compute the mean: 𝑧̅ =
1
𝑚∑
𝑧𝑖
𝑚
𝑖=1
 
3) Compute the between variance: B =
1
𝑚−1 ∑
(𝑧𝑖−𝑧̅)2
𝑖=1
 
4) Compute the total variance: T = 1 + (1 + 𝑚−1)B 
5) Compute the relative variance increase due to non-response: 
r = (1 + 𝑚−1)B 
6) Compute the degrees of freedom: ν = (𝑚−1)(1 + 𝑟−1)2 
7) The final p-value is then: Pr[tν > z̅/√T] where 𝑡ν is the t-distribution with ν 
degrees of freedom. 
Analyses with both blood loss values will be conducted. However, 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. 
10.1.3.3. 
Area of Autograft in DPT Wounds 
Very few cases of missing data are expected to be observed in the secondary endpoint of 
percentage of wound area autografted in DPT wounds. Any missing data for percent area 
autografted will be imputed using the multiple imputation method. The procedure can be 
described as follows: 
1. Imputation: The imputation model will be built on a subject level by multiple linear 
regression of known percent area autografted on center, total area of TWs, %TBSA, 
number of TWs (1,2,3-4,≥5), age and sex, and will be carried out separately within each 
treatment group. Once the model is estimated, the imputed values will be obtained from 
the value predicted by the model plus a residual term that will be drawn at random from 
the estimated residuals. The random seed will be 141421. Twenty five (m=25) imputed 
datasets will be created. 
2. Analysis: Each of the m complete datasets will be analyzed using a linear regression 
model. The explanatory variables in the model will include treatment, center, age, 
%TBSA, proportion of the FT area of a patient and number of TWs (1,2,3-4,≥5). An 


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estimated treatment difference,  (NexoBrid versus SoC), from the analysis model and 
a two-sided p-value, p, from the permutation test (as described in Section 11.1.2) will 
be obtained for each imputed dataset. 
3. Pooling: The m analysis results will be integrated into a final result – an overall estimate 
of , its standard error, and the final p-value, as described in Section 10.1.3.2 (items 4 
and 5). 
10.1.3.4. 
Incidence of Autograft in DPT Wounds 
Little or no missing data are expected for the secondary endpoint incidence of Autograft 
performed in deep partial thickness wounds. The main analysis (on a target wound level) will 
include only DPT target wounds from all randomized patients, with those having a missing 
value assumed to have "failed", i.e. to have received autograft. Two sensitivity analyses will 
be performed. First, in each treatment group, only DPT target wounds with documented 
Autograft will be counted and this number divided by the total number of DPT target wounds 
from randomized subjects with non-missing endpoint (i.e. wounds with missing values will be 
excluded, a complete case analysis). A second analysis will include DPT target wounds from 
all randomized patients and count all wounds with missing data (for this endpoint) as "success" 
(i.e. no autograft performed). 
Note: The main analysis specified in the protocol was the complete case analysis. However, 
for the same reasons as detailed for the secondary endpoint incidence of surgical excision 
(see 10.1.3.1), the main analysis will be based on DPT target wounds from all randomized 
subjects. 
10.1.4. Safety Endpoints 
10.1.4.1. 
Time to Reach Complete Wound Closure 
The analyses of the safety endpoint time to complete wound closure on a target wound level 
will compute missing values as censored at the date of the last non-missing wound closure 
assessment. If no wound closure assessment after baseline is available, the target wound will 
be censored with time 0. 
For additional analyses on a subject level, if a subject has a wound which did not reach 
complete closure, the time will be censored at last date of wound closure assessment. If a 


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subject has a wound with no wound assessment available after baseline, the subject will be 
censored with time 0. 
Note: the additional analysis on a subject level had been added per FDA recommendation. 
10.1.4.2. 
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 assumed that the 6 weeks 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 11.1.11) at that time point. If no non-
missing value in that stratum is present, the missing values will be imputed by the 6 weeks 
mean MVSS value of all patients who belong to the same treatment group. For missing MVSS 
values at later time points (12 and 24 months) the following imputation method will be used: 
For each time point (6 and 12 weeks, and 6 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 11.1.11) 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 12 weeks measurement but not the 6 months or 12 months measurement the 12 months 
measurement is imputed from the 12 weeks measurement; and for those who have the MVSS 
measurement at 6 weeks but not at 12 weeks, 6 months or 12 months the 12 months 
measurement will be imputed from the 6 weeks 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 (6 and 12 weeks, 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 11.1.11) 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 


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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 predictive 
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 [17], [18]). 
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). 
10.1.4.3. 
Cosmesis and Function at 24 Months from Wound Closure 
See 10.1.4.2. 
10.1.4.4. 
General Parameters of Safety 
Lower Extremity Functional Scale 
The calculation of the total score will be made if less than or equal to 10% of the items were 
left blank. If more than 10% of items are missing the score cannot be calculated. In the event 
of missing items, the total score will be adjusted by dividing the total by the proportion of 
completed items. 
Disabilities of the Arm, Shoulder and Hand (Quick-DASH) 
The calculation of the total score will be made if less than or equal to 10% of the items were 
left blank. If more than 10% of items are missing the score cannot be calculated. 


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Range of Motion (ROM) (at 12 and 24 months) 
In case of missing data of ROM, LOCF will be used for imputation. If a subject has no ROM 
measurement at all, it will be excluded from the general linear model analysis of the ROM. 
EQ-5D (Quality of Life) 
Missing EQ-5D values will not be imputed, but form a separate category in the analysis of this 
endpoint. 
10.1.5. Exploratory Endpoints 
10.1.5.1. 
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. If 
for a wound an item of the observer scale is missing the respective value will be imputed by 
the mean value of the other items from the observer scale of that wound. Analogously, if for a 
wound an item of the patient scale is missing the respective value will be imputed by the mean 
value of the other items from the patient scale of that wound. 
If more than one value is missing within a scale for one wound, the respective scale and the 
overall POSAS value for that wound (see Section 10.3.5.7) will not be calculated and regarded 
as missing value. 
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. 
Subjects with premature study discontinuation before end of the efficacy assessment period 
(i.e. before the 12 weeks follow-up post wound closure confirmation) lead to problems for 
analyses which include data from re-admissions. If a subject discontinued study participation 
during the efficacy assessment period, it is not known whether the subject had a(nother) re-
admission and data are missing. Consequently, the corresponding variables will be set to 
missing for all those subjects except for “Lost-to-follow-ups” who completed the eschar 


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removal treatment. The exception is done under assumption that subjects who are lost to follow 
up would have come back for re-admission if this had been necessary (Without this exception 
a lot of information would have been lost in MW2010 since the percentage of subjects with re-
admission is higher for “Lost-to-follow-ups” then for the rest of the population). 
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. 
Baseline Values 
Baseline value of a variable is defined as the last available measurement of this variable before 
treatment (screening/pre-treatment data). 
10.3.1.2. 
Age 
Age at entry will be computed from the date of birth to the informed consent (IC) date by the 
following formula: 
𝐴𝑔𝑒 (𝑖𝑛 𝑦𝑒𝑎𝑟𝑠) = (𝐼𝐶 𝑑𝑎𝑡𝑒 − 𝑡ℎ𝑒 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑏𝑖𝑟𝑡ℎ)/365.25. 
10.3.1.3. 
Day to Month Conversion 
1 𝑚𝑜𝑛𝑡ℎ =  30.4375 𝑑𝑎𝑦𝑠 
10.3.1.4. 
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 
ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚) = 2.54 × ℎ𝑒𝑖𝑔ℎ𝑡(𝑖𝑛𝑐ℎ) 
ℎ𝑒𝑖𝑔ℎ𝑡(𝑖𝑛𝑐ℎ) = 0.3937 × ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚) 
Hence, height data for each patient will be available in inch as well as in cm. 


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10.3.1.5. 
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 
𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) = 0.4536 × 𝑤𝑒𝑖𝑔ℎ𝑡(𝑙𝑏) 
𝑤𝑒𝑖𝑔ℎ𝑡(𝑙𝑏) = 2.2046 × 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) 
Hence, weight data for each patient will be available in lb as well as in kg. 
10.3.1.6. 
Body Mass Index (BMI) 
A patient's BMI will be calculated using the following formula: 
𝐵𝑀𝐼(𝑘𝑔/𝑚2) = 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)
ℎ𝑒𝑖𝑔ℎ𝑡(𝑚)2 
10.3.1.7. 
Time Since Injury 
The time since injury will be computed as the time in hours between injury and randomization. 
10.3.2. Primary Endpoint: Time to Complete Eschar Removal 
Information about date will be transformed to time in days from randomization. Time until 
complete eschar removal will be calculated as the time (in days) 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). 
Furthermore, for a sensitivity analysis, time to complete eschar removal will be computed as 
above but in days from ICF. 
For each patient the number of TWs (1, 2, 3-4, ≥5) will be computed and used as an 
explanatory variable in the analysis of this endpoint. 
For each patient the proportion of FT area burned will be computed. 


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10.3.3. Secondary Endpoints 
10.3.3.1. 
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. The time frame for this analysis is the time until 
complete eschar removal has been achieved. 
Furthermore, for each target wound a binary (yes/no) variable will be computed, indicating 
whether this wound needed surgical excision for eschar removal. 
10.3.3.2. 
Blood Loss 
10.3.3.2.1. Blood Loss Calculation 
Blood loss will be calculated using the following formula [15], [48]: 
𝐵𝑙𝑜𝑜𝑑 𝐿𝑜𝑠𝑠 (𝑚𝐿) = 𝑅𝐵𝐶𝑉𝑏𝑒𝑓𝑜𝑟𝑒+ (𝑇𝑟𝑎𝑛𝑠𝑓𝑢𝑠𝑖𝑜𝑛 𝑅𝐵𝐶𝑉) −𝑅𝐵𝐶𝑉𝑎𝑓𝑡𝑒𝑟
𝐻𝑐𝑡𝑎𝑓𝑡𝑒𝑟[%] ∗0.01
 
RBCV (mL) = Red Blood Cell Volume (mL) = Body Weight (kg) * 80 (mL/kg) * (Hematocrit [%] 
* 0.01) 
Transfusion RBCV (mL) = [Total Volume (mL) of Whole Blood Transfused * 0.3] + [Total 
Volume (mL) of Packed Red Blood Cells Transfused * 0.8]  
The blood loss will be computed over the whole eschar removal period, using the formula 
above, i.e. the eschar removal process will be considered as one continuous procedure. 
Therefore, only the Hematocrit 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. 
Additionally, the blood loss will be summed over all procedures carried out to remove eschar, 
with the hematocrit 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 up to 24 hours from the end time of the debridement 
procedure. 
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. 


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10.3.3.2.2. Proportion of SPT Area of Wounds Treated per Procedure 
For the multiple imputation outlined in Section 10.1.3.2 information on the proportion of the 
SPT area of wounds treated per procedure will be computed using the following formula: 
𝑃𝑟𝑜𝑝(𝑆𝑃𝑇) = ∑%𝑆𝑃𝑇(𝑊𝑖) ∗%𝑇𝐵𝑆𝐴(𝑊𝑖)
𝑖
∑%𝑇𝐵𝑆𝐴(𝑊𝑖)
𝑖
, 
where both sums range over all target wounds treated in a debridement procedure, %𝑆𝑃𝑇(𝑊𝑖) 
is the percent area of SPT of target wound 𝑖 before start of first treatment and %𝑇𝐵𝑆𝐴(𝑊𝑖) is 
the area of the target wound 𝑖 before start of first treatment. 𝑃𝑟𝑜𝑝(𝑆𝑃𝑇) will be computed for 
each procedure in each patient separately. 
10.3.3.2.3. Proportion of DPT Area of Wounds Treated per Procedure 
For the multiple imputation outlined in Section 10.1.3.2 information on the proportion of the 
DPT area of wounds treated per procedure will be computed using the following formula: 
𝑃𝑟𝑜𝑝(𝐷𝑃𝑇) = ∑%𝐷𝑃𝑇(𝑊𝑖) ∗%𝑇𝐵𝑆𝐴(𝑊𝑖)
𝑖
∑%𝑇𝐵𝑆𝐴(𝑊𝑖)
𝑖
, 
where both sums range over all target wounds treated in a debridement procedure, %𝐷𝑃𝑇(𝑊𝑖) 
is the percent area of DPT of target wound 𝑖 before start of first treatment and %𝑇𝐵𝑆𝐴(𝑊𝑖) is 
the area of the target wound 𝑖 before start of first treatment. 𝑃𝑟𝑜𝑝(𝐷𝑃𝑇) will be computed for 
each procedure in each patient separately. 
10.3.3.2.4. Proportion of FT Area of Wounds Treated per Procedure 
For the multiple imputation outlined in Section 10.1.3.2 information on the proportion of the FT 
area of wounds treated per procedure will be computed using the following formula: 
𝑃𝑟𝑜𝑝(𝐹𝑇) = ∑%𝐹𝑇(𝑊𝑖) ∗%𝑇𝐵𝑆𝐴(𝑊𝑖)
𝑖
∑%𝑇𝐵𝑆𝐴(𝑊𝑖)
𝑖
, 
where both sums range over all target wounds treated in a debridement procedure, %𝐹𝑇(𝑊𝑖) 
is the percent area of FT of target wound 𝑖 before start of first treatment and %𝑇𝐵𝑆𝐴(𝑊𝑖) is the 
area of the target wound 𝑖 before start of first treatment. 𝑃𝑟𝑜𝑝(𝐹𝑇) will be computed for each 
procedure in each patient separately. 


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10.3.3.2.5. Course of Debridement Procedure 
For the multiple imputation outlined in Section 10.1.3.2 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: 
 
"NexoBrid" or "NexoBrid - Nonsurgical Procedure" or "NexoBrid - Nonsurgical 
Procedure - Surgical Procedure" or "NexoBrid - Surgical Procedure" 
 
"Nonsurgical Procedure" 
 
"Nonsurgical Procedure - Surgical Procedure" 
 
"Surgical Procedure - Nonsurgical Procedure - Surgical Procedure" 
 
“Surgical Procedure” 
10.3.3.3. 
Area of Autograft in DPT Wounds 
For each DPT target wound, percent area wound autografted will be calculated as the sum of 
areas autografted in all autografting procedures of the specific wound, as collected on CRF 
wound management page (field "% area wound grafted clin. ass."). Treated DPT target wounds 
that had not been autografted will receive the value of 0. 
For the purpose of the Main analysis, percent area wound autografted will be calculated on a 
subject level. 
For each subject with at least one DPT target wound, the percent area wound autografted in 
DPT wounds will be calculated as follows: 
𝑇𝐵𝑆𝐴 𝐴𝑢𝑡𝑜𝑔𝑟𝑎𝑓𝑡 𝑖𝑛 𝐷𝑃𝑇= ∑𝑇𝐵𝑆𝐴𝑖∗%𝐴𝑢𝑡𝑜𝑔𝑟𝑎𝑓𝑡𝑖
𝑖
∑𝑇𝐵𝑆𝐴𝑖
𝑖
 
where 𝑇𝐵𝑆𝐴𝑖 is the % TBSA of the 𝑖th DPT target wound (the original TW assessment defined 
in the treatment visit), %𝐴𝑢𝑡𝑜𝑔𝑟𝑎𝑓𝑡𝑖 is the corresponding percent area autografted of that 
wound and the sum is taken over all DPT target wounds of a patient. 
This is a weighted average of the % area autografted over all DPT target wounds for that 
patient, and is equivalent to the formula:  
𝑇𝐵𝑆𝐴 𝐴𝑢𝑡𝑜𝑔𝑟𝑎𝑓𝑡 𝑖𝑛 𝐷𝑃𝑇= ∑𝑎𝑟𝑒𝑎𝐴𝑢𝑡𝑜𝑔𝑟𝑎𝑓𝑡𝑒𝑑𝑖
𝑖
∑𝑇𝐵𝑆𝐴𝑖
𝑖
∗100% 
where 𝑎𝑟𝑒𝑎𝐴𝑢𝑡𝑜𝑔𝑟𝑎𝑓𝑡𝑒𝑑𝑖 is the area autografted in the 𝑖th DPT target wound. 


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Patients with only FT wounds and having no DPT wounds will be excluded from this analysis. 
10.3.3.4. 
Incidence of Autograft in DPT Wounds 
For each DPT TW a binary (yes/no) variable will be defined, indicating whether this wound 
needed autografting. 
10.3.4. Safety Endpoints 
10.3.4.1. 
Time to Reach Complete Wound Closure 
Information about date will be transformed to time in days from randomization. Missing values 
will be addressed as described in Section 10.1.4.1. 
For the purpose of the main analysis, time until complete wound closure (for definition see 
Section 6.1), will be defined as the time (in days) until complete wound closure has been 
achieved at a wound level. The definition of complete wound closure demands that the wound 
closure is to be confirmed at two consecutive study visits, 2 weeks, i.e. 14 (± 2 days), apart. 
A wound is only to be regarded as closed in this analysis if the wound was closed at a wound 
closure assessment and this was confirmed at an additional assessment within 12-16 days 
from the initial closure assessment. In case wound closure is not confirmed in the pre-defined 
time frame the wound is considered not completely closed at the first closure assessment. 
Additionally, for the SoC group, a variable for time to wound closure will be calculated as 
above, but in the non-inferiority comparison, a 7 days non-inferiority margin will be added. 
For additional analyses on a subject level, time to complete wound closure of all target wounds 
(last healing wound) will be computed, i.e. the time from randomization (in days) to subject's 
last wound closure. 
For supportive analyses, the time to reach 100% wound closure will be computed on a wound 
level and on a subject level, where the complete wound closure is defined as 100% of wound 
area epithelialized and/or closed by graft without drainage or dressing requirements 
confirmed at two consecutive study visits, 2 weeks apart. 
10.3.4.2. 
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 


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wound. The patient MVSS score will be the average of the MVSS over all TWs. To note, in 
case the individual item score is missing, the TW score and the patient score will be defined 
as missing. 
10.3.4.3. 
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. To note, in 
case the individual item score is missing, the TW score and the patient score will be defined 
as missing. 
10.3.4.4. 
General Parameters of Safety 
Volume of Blood Transfusions Given 
The volume of blood transfusions given during hospitalization (including readmissions) will be 
according to the volume (in milliliters) of whole blood and packed red blood cells transfused, 
presented separately, as collected on eCRF. In addition, Transfusion RBC Volume (in 
milliliters) will be calculated using the following formula [15], [48]: 
𝑇𝑟𝑎𝑛𝑠𝑓𝑢𝑠𝑖𝑜𝑛 𝑅𝐵𝐶 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿)
= [𝑇𝑜𝑡𝑎𝑙 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿) 𝑜𝑓 𝑊ℎ𝑜𝑙𝑒 𝐵𝑙𝑜𝑜𝑑 𝑇𝑟𝑎𝑛𝑠𝑓𝑢𝑠𝑒𝑑× 0.3]
+ [𝑇𝑜𝑡𝑎𝑙 𝑉𝑜𝑙𝑢𝑚𝑒 (𝑚𝐿) 𝑜𝑓 𝑃𝑎𝑐𝑘𝑒𝑑 𝑅𝑒𝑑 𝐵𝑙𝑜𝑜𝑑 𝐶𝑒𝑙𝑙𝑠 𝑇𝑟𝑎𝑛𝑠𝑓𝑢𝑠𝑒𝑑× 0.8] 
For subjects who discontinued study participation during the efficacy assessment period, it is 
not known whether a(nother) transfusion occurred and relevant data are missing. 
Consequently, the variable is set to missing for all those subjects except for “Lost-to-follow-
ups” who completed the eschar removal treatment. The exception is done under the 
assumption that subjects who are lost to follow up would have come back for readmission if 
this had been necessary (see also safety endpoint “rates of hospital readmission”). 
Analgesia and Anesthesia 
Relevant analgesia and anesthesia medications will be presented in the concomitant 
medications tables. 


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Antibiotic Use 
The number of days of exposure to systemic antibiotic drugs will be calculated for each patient. 
This will be done overall and also for antibiotic use due to AE involvement (as indicated in the 
eCRF) and for prophylactic antibiotic use (as indicated in the eCRF) separately. 
Only records with ATC level 2 equal to “ANTIBACTERIALS FOR SYSTEMIC USE" are used. 
In case of a missing start date for a medication marked as pre-existing, the start date is imputed 
by the date of informed consent. In case of a missing stop date for a medication ongoing at 
study termination, the stop date is imputed by the study termination date. No other imputation 
is planned, i.e. if the start or stop date for antibiotics is missing, the days of antibiotic use will 
be counted as missing for the respective subject. 
The calculation of the number of days only considers days between randomization and wound 
closure confirmation. Each day is only counted once; the actual frequency is not considered. 
Values for subjects with premature study discontinuation prior to the end of the efficacy 
assessment period are set to missing. 
Rates of Hospital Readmission 
For each patient a binary (yes/no) variable will be computed indicating whether this patient had 
a hospital readmission or not. Additionally, for each hospital readmission, a binary (yes/no) 
variable will be collected 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 the sponsor 
in order to decide whether they are to be classified as planned or unplanned. 
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 (overall, planned, and unplanned) 
will be calculated per treatment arm. 
For subjects who discontinued study participation during the efficacy assessment period, it is 
not known whether a(nother) readmission occurred and relevant data are missing. 


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Consequently, the variable is set to missing for all those subjects except for “Lost-to-follow-
ups” who completed the eschar removal treatment. The exception is done under the 
assumption that subjects who are lost to follow up would have come back for readmission if 
this had been necessary (Without this exception a lot of information would have been lost in 
MW2010 since the percentage of subjects with re-admission is higher for “Lost-to-follow-ups” 
then for the rest of the population). 
Change in PTT/INR 
Change in PTT/INR will be computed as PTT/INR on 4h ± 15 min post first application 
(NexoBrid arm) respectively to 4h post first SoC treatment (SoC arm) minus PTT/INR pre the 
respective procedure for each patient. 
For the classification of normal and abnormal PTT/INR values (low or high), the reference limits 
of the local labs will be used. If INR reference ranges will not be available for specific sites, 
common normal range of 0.8-1.2 will be used for these sites [19]. 
In addition, for each subject, for each parameter (INR/PTT) a variable will be computed, 
indicating whether the 4 hour post first treatment measurement was post treatment potentially 
clinically significant high (pCS high) or post treatment potentially clinically significant low (pCS 
low). 
For the definition of pCS high and pCS low, see Section 13.2.2. 
Lower Extremity Function Scale (LEFS) 
The LEFS will be assessed at the following time points: at 6, 12 weeks and months 6, 12, 
18 and 24 after wound closure. It 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 
𝐿𝐸𝐹𝑆= ∑𝑎𝑖
20
𝑖=1
−20, 
where ai is the answer to item i (coded 1 to 5). As indicated in Section 10.1.4.4, the calculation 
of the total score will be made if less than or equal to 10% of the items were left blank. If 
more than 10% of items are missing the score cannot be calculated. In the event of missing 


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items, the total score will be adjusted by dividing the total by the proportion of completed 
items, as follows: 
𝐿𝐸𝐹𝑆= ∑
𝑎𝑖
𝑘
𝑖=1
𝑘/20 −20 
where k is the number of completed items and 𝑎𝑖 are the non-missing values. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH will be assessed at the following time points: at 6, 12 weeks and months 
6, 12, 18 and 24 after wound closure. It consists of 11 items which are scored 1-5. As 
indicated in Section 10.1.4.4, the calculation of the total score will be made if less than or 
equal to 10% of the items were left blank. If more than 10% of items are missing the score 
cannot be calculated. Hence, 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: 
𝑄𝑢𝑖𝑐𝑘𝐷𝐴𝑆𝐻= (𝑠𝑢𝑚 𝑜𝑓 𝑛 𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒𝑠
𝑛
−1) ∗25. 
Range of Motion (ROM) 
For each visit (12 months FU and 24 months FU), a binary (yes/no) variable will be calculated, 
indicating whether the range of motion assessment for that patient was abnormal or not. The 
range of motion assessment will be considered abnormal, if the measurement of at least one 
joint under consideration does not lie within the normal ranges of motion given in appendix 13 
of the study protocol at the respective time point. For handling of missing data see 
Section 10.1.4.4. 
EQ-5D (Quality of Life) 
EQ-5D-Y consists of 5 items with 3 possible answers each. It will be evaluated per the EQ-5D-
Y user guide [20]. Note that for children aged 2 – 11 years, the parent/caregiver will complete 
a proxy version of the EQ-5D for the patient, children aged 12-18 will complete the 


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questionnaire themselves. EQ-5D will not be assessed for children younger than 2 years 
(based on age of first FU visit). 
For each item, relative and absolute frequencies of the answers will be computed in total and 
per age group, defined in the stratification variables (see Section 11.1.11). The table will be 
presented by treatment arm and overall. The analysis will be done per age at randomization. 
Furthermore, summary statistics of the EQ VAS will be computed in total and per age group. 
The table will be presented by treatment arm and overall. 
The EQ-5D states will be converted to a single summary index using the USA value set from 
[21]. For subjects with incomplete questionnaires, the summary index will be a missing value. 
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 
Systemic infections reported as AEs will be presented in the AEs tables. 
Adverse Events 
Counts and frequencies of subjects reporting treatment emergent adverse events (TEAEs), 
related TEAEs, and serious TEAEs per treatment arm will be computed per system organ class 
(SOC) and preferred term (PT). This will be done separately by: 
 
Severity (mild / moderate / severe AEs) 
 
Relatedness (not related or remotely related / possibly related or probably related or 
related AEs) 


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 
Time of onset (during the treatment session / within 24 hours after treatment / 24 – 72 
hours after treatment / more than 72 hours up to the end of the first week after treatment 
/ during week 2 to week 4 after treatment / more than 4 weeks after treatment) 
Note: During the treatment session is defined as the time frame from start date/time of first 
eschar removal procedure to end date/time of last eschar removal procedure. 
All serious adverse events will be listed for the enrolled population. 
For more details see Section 11.1.5.4. 
For each of the two stages of analysis (see Section 11 for details), the safety data gathered in 
that stage will be analyzed separately. That is, in the first stage analysis (acute + 12M follow-
up), all AEs reported until the 12 months follow-up will be analyzed separately for the following 
sub-periods: 1) until the 12 weeks follow-up, 2) between the 12 weeks follow-up and the 12 
months follow-up (including AEs from the first sub-period that are still ongoing), 3) combined 
until the 12 months follow-up. In the second stage analysis (24 months follow-up), all AEs 
reported between the 12 months follow-up and the 24 months follow-up (including AEs from 
the first stage that are still ongoing) will be analyzed. Furthermore, a combined analysis, 
including all reported AEs, will be provided at the end of the trial. 
Central Laboratory Values 
For all analyses involving data from the central laboratory only samples taken within the 
allowed time range are considered  
 
Pre procedure: Within 12 hours before start of the procedure until up to 15 min after 
start. 
 
Post procedure: Within 24 hours after end of the procedure 
Samples not taken in the allowed time range are excluded from the analysis.  
Imputation of data from the central laboratory is only done for planned missing values. Version 
10.01 of the study protocol specifies some planned missing laboratory samples. On the one 
hand, a laboratory sample before the additional application of NexoBrid is not required. On the 
other hand, a laboratory sample before a nonsurgical procedure is only prescribed for the first 
eschar removal procedure and a laboratory sample after a nonsurgical procedure is only 


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required for the last eschar removal procedure. To enable analysis of pre-post differences on 
procedure level, the planned missing values are imputed as follows: 
1. Planned missing measurements before an additional application / a non-surgical 
procedure 
Values of a sample taken after the previous eschar removal procedure are used if the 
laboratory sample was taken within 12 hours before start of the eschar removal 
procedure. 
2. Planned missing measurements after a non-surgical procedure 
Values of a sample taken before the subsequent eschar removal procedure are used 
if the laboratory sample was taken within 24 hours after end of the nonsurgical 
procedure. 
For each subject, each laboratory parameter and each time point of measurement a variable 
will be defined, indicating whether this measurement was post treatment potentially clinically 
significant high (pCS high) or post treatment potentially clinically significant low (pCS low). 
From this, for each subject and each laboratory parameter, an indication whether this subject 
experienced any pCS high measurement post baseline in this parameter and/or whether this 
subject experienced any pCS low measurement post baseline in this parameter will be 
produced. 
For the definition of pCS high and pCS low, see Section 13.2.2. 
Vital Signs 
Body temperatures given in °F will be transformed to °C using the following formula: 
𝑇𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒[°𝐶] = 5
9 (𝑇𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒[°𝐹] −32) 
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 
𝐷𝑖𝑓𝑓𝑑= 𝑉𝑆𝑑−𝑉𝑆𝑑−1 
where 𝑉𝑆𝑑 is the vital sign assessment at day d (daily follow-up) and d is varied from 2 to 7.  


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Note: Vital sign assessments will only be recorded while a subject is hospitalized. It may 
however be the case that certain subjects will be discharged during the first week, making 
some of the measurements not available. The respective subjects will be excluded from all 
vital sign analysis referring to time points after hospital discharge. 
Additionally, for each subject, each vital sign and each time point of measurement  a variable 
will be defined, indicating whether this measurement was post treatment potentially clinically 
significant high (pCS high) or post treatment potentially clinically significant low (pCS low) 
(based on definitions in Section 13.2.1). Baseline categories (pCS low, pCS high and not pCS) 
will be created using the reference values from Section 13.2.1 without the increase/decrease 
criteria. 
In addition, for each subject and each vital sign an indication whether the subject experienced 
any pCS high and/or any pCS low result post baseline (within the first 7 days) in this vital sign 
will be produced. 
For subjects discharged before day 7, this indication will be calculated only taking into account 
the time during hospitalization. 
Pain Assessment 
Pain assessments will only be recorded while a subject is hospitalized. It may however be the 
case that certain subjects will be discharged during the first week, making some of the 
measurements not available. The respective subjects will be excluded from all pain analysis 
referring to time points after hospital discharge. 
For each eschar removal procedure and each daily follow-up pain assessment the change in 
pain from baseline will be calculated as  
𝐷𝑖𝑓𝑓𝑑= 𝑃𝑎𝑖𝑛𝑑−𝑃𝑎𝑖𝑛𝐵𝑎𝑠𝑒 
where 𝑃𝑎𝑖𝑛𝑑 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. The pain value captured pre first procedure will be considered as baseline. If this 
is missing, the pain assessed at screening will be used. 
In addition, for each patient, an indication will be produced whether: 


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 
The patient experienced any post treatment abnormal (NCS) pain assessment 
according to investigator’s assessment 
 
The patient experienced any post treatment abnormal (CS) pain assessment according 
to investigator’s assessment 
For subjects discharged before day 7, this indication will be calculated only taking into account 
the time during hospitalization. 
10.3.5. Exploratory Analyses 
10.3.5.1. 
Incidence of surgical Escharotomy procedures on circumferential 
extremities target wounds 
For each circumferential extremity 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 with at least one circumferential extremities target wound will be computed 
indicating whether this patient had at least one circumferential extremities target wound which 
was escharotomized. 
10.3.5.2. 
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 (+15 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 during the procedure. 
10.3.5.3. 
% wound area surgically excised for eschar removal 
% of wound area surgically excised for eschar removal, Atotal, will be calculated per patient 
using the following formula: 
𝐴𝑡𝑜𝑡𝑎𝑙= ∑(𝑎𝑖∗%𝑇𝐵𝑆𝐴𝑖)
𝑖
∑%𝑇𝐵𝑆𝐴𝑖
𝑖
 
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. The sums refer to all TWs of a patient. 


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For TWs that were treated for eschar removal with NexoBrid and/or non-surgical procedures 
only, the 𝑎𝑖 will receive the value of 0. 
For TWs that were treated for eschar removal with at least one surgical procedure and no 
corresponding % area excised is available, the value of 𝑎𝑖 will be set to missing. Consequently, 
for subjects having such TWs, 𝐴𝑡𝑜𝑡𝑎𝑙 will be set to missing. 
10.3.5.4. 
Incidence of surgically harvested donor sites wounds 
For each patient, the number of donor site wounds will be calculated. 
Not all donor sites are numbered during wound management and re-admissions. Therefore, 
Donor sites will be identified in SDTM domain PR and duplicates for donor sites already 
numbered will be deleted. For donor sites not already numbered but only described by the 
anatomical location, only one entry per procedure date and anatomical location will be kept. 
The remaining entries are all considered as separate donor sites and numbered under 
consideration of already numbered donor sites. That means, even if the anatomical location is 
equal, entries with no donor site number are considered as separate donor sites if the 
procedure date differs. 
10.3.5.5. 
% 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. 
10.3.5.6. 
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. 


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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: 
𝑃𝑂𝑆𝐴𝑆𝑃= ∑𝑝𝑖
6
𝑖=1
, 
where pi is the score the patient assigned to item i. The total score of the observer scale will 
be computed analogously as: 
𝑃𝑂𝑆𝐴𝑆𝑂= ∑𝑜𝑖
6
𝑖=1
, 
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: 
𝑃𝑂𝑆𝐴𝑆𝑡𝑜𝑡= 𝑃𝑂𝑆𝐴𝑆𝑃+ 𝑃𝑂𝑆𝐴𝑆𝑂. 
For each patient the mean over all TWs will be computed separately for 𝑃𝑂𝑆𝐴𝑆𝑡𝑜𝑡, 𝑃𝑂𝑆𝐴𝑆𝑃 and 
𝑃𝑂𝑆𝐴𝑆𝑂. 
The POSAS will be computed for TWs at the long-term follow up visits. 
10.3.5.8. 
Duration of hospitalization 
Duration of acute hospitalization will be computed as the difference in days between hospital 
admission and hospital discharge (initial hospitalization only). Subjects without a discharge 
date will be censored at the date of death (if applicable) or date of last known assessment 
performed during initial hospitalization period. 
10.3.6. Laboratory Values 
The following transformations will be applied to the central laboratory data obtained pre and 
post the eschar removal procedures: 


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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 
(difference between post-procedure value and pre-procedure value). 
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), long-term follow-up at 6 and 12 weeks and 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. 
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. 
10.5. Implications of COVID-19 Pandemic to the Study Data 
This section describes how deviations related to COVID-19 pandemic will be handled. 
10.5.1. 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. 
10.5.2. Handling of Remotely Captured Data 
Due to COVID-19 restrictions, the sponsor has submitted a protocol memo (see SAP 
Section 13.4), dated 09 Apr 2020, to sites allowing them to perform long-term follow-up visits 


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remotely. All visits could have been performed remotely, but at the time of COVID-19 outbreak 
almost all patients had already been post 12 weeks FU visit, so it is expected a large portion 
of remote assessments starting from the 6 months FU visit and onwards. 
Apart from MVSS and POSAS assessments, all endpoints, allowed to be evaluated remotely 
during long-term follow-up visits, are self-reported. Therefore, no influence of remote study 
visits is expected. For MVSS and POSAS assessments, the possible influence of remotely 
captured data will be addressed as described in the following sub-sections. 
10.5.2.1. 
Cosmesis and Function at 12 Months from Wound Closure 
For the purpose of the main analysis, all values (both on-site and remotely collected) will be 
used, with missing values imputed as described in SAP Section 10.1.4.2. 
For the purpose of the sensitivity analysis, to explore the possible influence of remotely 
captured data, the following procedure will be applied:  
1. For a time point t=12 months take a subset of subjects in each treatment group who 
have on-site evaluations 𝑋12𝑚 or remote evaluations 𝑌12𝑚 (at least 10 subjects with 
on-site evaluations at 12 months, and at least 10 subjects with remote evaluations at 
12 months in each treatment group), and also have on-site evaluations for all previous 
time points (6 weeks, 12 weeks and 6 months). In case such a subset cannot be 
obtained due to absence of sufficient on-site values at time point 6 months, a subset 
with on-site evaluations for time points 6 weeks and 12 weeks will be considered. 
Denote the set of relevant previous time points as (𝑡−1, … ,1). 
2. Separately for each treatment group, regress 𝑌12𝑚 on 𝑥𝑡−1 = (1, 𝑋𝑡−1, … , 𝑋1) and all 
stratification variables (S) (see Section 11.1.11), where 𝑌12𝑚 are the remote 
evaluations at 12 months (from a subset of subjects obtained at the first step), 𝑥𝑡−1 are 
the on-site evaluations at previous times (for subjects with 𝑌12𝑚) and “1” is to indicate 
regression with intercept. For each regression: 
a. Obtain the estimate of residual variance, denote by σ𝑅
2
̂. 
b. Obtain a prediction formula 𝑌12𝑚
̂ = 𝐻(𝑥𝑡−1, 𝑆) to predict 𝑌12𝑚 given 𝑥𝑡−1 and S. 
c. Apply this formula to the (𝑥𝑡−1, 𝑆) of the subjects who had on-site evaluations 𝑋12𝑚 
(from a subset of subjects obtained at the first step). For each such subject there 
will be both 𝑋12𝑚 and 𝑌12𝑚
̂. 


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d. Estimate the mean Bias μ𝐵
̂ using the mean of the differences 𝐷12𝑚= 𝑋12𝑚−𝑌12𝑚
̂ 
for those subjects. 
e. Estimate the variance of the Bias σ𝐵
2
̂ by the estimate of the variance (σ𝐷
2
̂) of the 
differences 𝐷12𝑚= 𝑋12𝑚−𝑌12𝑚
̂ plus σ𝑅
2
̂. That is σ𝐵
2
̂ = σ𝐷
2
̂ + σ𝑅
2
̂. 
3. For the sensitivity analysis of MVSS at 12 months: 
a. Take the remote evaluations 𝑌12𝑚 and add to each a random normal variate with 
mean μ𝐵
̂ and variance σ𝐵
2
̂ (for the appropriate treatment group). This will provide 
a "correction" to remote evaluations, as if they were observed during an on-site 
visit. 
b. Repeat step a for each previous time point separately to get the "corrected" 
remote evaluations. All these "corrections" (biases) would be sampled from the 
same fixed distribution with mean μ𝐵
̂ and variance σ𝐵
2
̂, estimated at step 2 above. 
c. Impute missing MVSS values at 12 months, applying the imputation procedure 
from SAP Section 10.1.4.2 on observed on-site evaluations and "corrected" 
remote evaluations. 
10.5.2.2. 
Cosmesis and Function at 24 Months from Wound Closure 
For the purpose of the main analysis, all values (both on-site and remotely collected) will be 
used, with missing values imputed as described in SAP Section 10.1.4.2. 
For the purpose of the sensitivity analysis, to explore the possible influence of remotely 
captured data, the following procedure will be applied:  
1. Repeat step 3a from the above section (10.5.2.1) for additional follow-up time points 
18 months and 24 months, to get the "corrected" remote evaluations. 
2. Impute missing MVSS values at 24 months, applying the imputation procedure from 
SAP Section 10.1.4.2 on observed on-site evaluations and "corrected" remote 
evaluations from all previous time points (for time points up to 12 months previously 
"corrected" remote evaluations can be used). 
10.5.2.3. 
Exploratory Analyses of MVSS and POSAS 
For the purpose of exploratory analyses of MVSS (see SAP Sections 11.1.6.8 and 11.2.5.2) 
and POSAS (see SAP Sections 11.1.6.7 and 11.2.5.1) all observed values (both on-site and 
remotely collected) will be used.  


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11. Statistical Analysis of Target Variables 
The analysis is planned to be carried out in two stages, as described below. 
1. The first analysis will be performed at the end of the 12 months follow up period. This 
analysis will be the only inductive analysis of the trial and will include statistical tests 
for the primary and secondary endpoints as described above, as well as 12 months 
safety endpoints. At this time-point, data will be available for all patients on the primary 
and secondary end-points, as well as the 12 months safety endpoints. Missing values 
for early 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. 
The 24 months data, although captured in the eCRF for a few of the subjects at the 
stage of end of the 12 months follow up period, will not be included, revealed or 
analyzed during these analyses. 
 
2. The second and final analysis covers the data of the full 24 months safety follow up. It 
will be conducted after the last patient has reached the 24 months assessment, 12 
months after first stage of analysis. At this analysis, all accumulated safety endpoints 
at the 24 months follow up will be evaluated. 
Long term follow up assessments of Cosmesis (MVSS and POSAS), quality of life (EQ5D and 
BOQ) and functionality (LEFS, QuickDASH and ROM) will be performed by a “blinded 
assessor”. The assessor signs a “blinded assessor memo” which describes the procedures 
required to maintain the investigator blinded from the treatment arm. The blinded assessor will 
remain blinded throughout the whole duration of the trial. 
The data sets for analysis will be 100% source document verified 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 2 stages of analyses. 
All variables not mentioned explicitly in the following will be analyzed descriptively (as part of 
the case-wise listing). 


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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. 
11.1. First Stage Analysis –12 Months Follow Up 
11.1.1. Demographics Data and Other Baseline Characteristics 
For all considerations regarding the demographics and other baseline characteristics the full 
analysis set will be used. 
The following demographic and baseline information will be tabulated: 
 
Age Group 
 
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 


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 
Systolic and diastolic blood pressure (mmHg) 
 
Assessment of vital signs (normal, abnormal-NCS, abnormal-CS) 
 
Pain assessment: 
 
FPS-R 
 
Assessment of pain (normal, abnormal-NCS, abnormal-CS) 
 
Local laboratory: 
 
Diabetes status (yes/no) 
 
HbA1c (%) 
 
Burn history (on a patient level): 
 
Time since injury to randomization (hours) 
 
Etiology of injury (Fire/Flame, Scald, Contact) 
 
Place of injury (Outdoors, Indoors, Car, Other) 
 
General wound description (on a wound level): 
 
Anatomical location (face, head, neck, etc.) 
 
%TBSA of 2° SPT Burns (clinical assessment) 
 
%TBSA of 2° DPT Burns (clinical assessment) 
 
%TBSA of 3° FT Burns (clinical assessment) 
 
Information whether escharotomy 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 (assessments at screening): 
 
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, assessments at screening): 
 
Total wounds %TBSA 
 
TWs DPT total area (%TBSA) (clinical assessment) 
 
TWs FT total area (%TBSA) (clinical assessment) 


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 
Overall TWs depth per patient (all full thickness, mixed, all deep partial 
thickness) (clinical assessment) 
 
Overall TW area (SPT+DPT+FT) (clinical assessment) 
 
Criteria for inclusion (met/not met) 
 
Counts of patients/wound per strata (%TBSA cut point 15%, % FT burns cut point 20 
%, center) 
All the above baseline information will be presented using descriptive statistics by treatment 
group and in total. 
If any of the baseline factors gender, 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, 3-4, ≥5) are found to be significantly different between the treatment 
groups at the 15% level (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. 
Furthermore, a table for the disposition of patients will be produced. 
11.1.2. Re-Randomization Test 
Treatment allocation will be performed in this trial by minimization, therefore the p-values 
reported in this trial for the main analyses of the primary and secondary endpoints, performed 
on the FAS, will be based on the re-randomization test. To note, all other analyses (sensitivity, 
supportive, additional), including analyses on PP population, will be performed without the re-
randomization test. 
The re-randomization test is advocated by Proschan et al (Biometrics 2011; 67:1135-41) for 
trials that employ minimization, and belongs to the class of tests that are based on permuting 
the treatment allocations of the patients. 
The test works as follows. Suppose the analysis for an endpoint is performed as described in 
Sections 11.1.3 or 11.1.4 below and a p-value for the estimated treatment difference is p*. We 
now return to the list of patients in the same order as they entered the trial and re-apply the 
minimization procedure to their treatment allocation, as described in Appendix 13.1. Because 


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the procedure involves random allocations at various junctures during the trial, the next time 
we apply the procedure it will in general yield a different set of treatment allocations for the 
patients. Having obtained these new treatment allocations, we then re-analyze the data as if 
these had been the true treatment allocations, and obtain a new p-value p1 and corresponding 
test statistic s1 for the test of the treatment difference. We repeat this step a large number of 
times (in this trial we will use 8000 repeats) and obtain a set of 8000 pairs of p-values and test 
statistics (p1, s1), (p2, s2), …, (p8000, s8000). If exactly n of these 8000 p-values are less than or 
equal to the value p* (obtained on the real data) with the test statistic in the direction of 
advantage to NexoBrid, then the re-randomization test p-value is assigned the value 2*n/8000. 
The random seed for the re-randomization will be 48920. 
Following teleconference with the FDA on April 2017, it was decided that the form of the 
minimization used for treatment allocation in the trial will be modified from strict minimization 
(without a random element) to minimization with a random element. The re-randomization test 
can naturally accommodate this modification. When re-allocating treatments for this re-
randomization analysis, those patients allocated treatment in the trial using strict minimization 
will be re-allocated treatment using strict minimization, while those patients who entered later 
and were allocated treatment using minimization with a random element will be re-allocated 
treatment using minimization with a random element. 
The minimum and maximum numbers of patients allocated to each treatment group over the 
8000 re-randomized samples will be reported. 
11.1.3. Primary Efficacy Analysis: Time to Complete Eschar Removal 
The primary efficacy variable will be analyzed using the FAS. Missing data for the main primary 
analysis and for the three sensitivity analyses will be handled by the methods described in 
Section 10.1.2. In addition, the primary analysis will be repeated for the PP collective as 
sensitivity analysis. 
Time until complete eschar removal will be defined as the time until complete eschar removal 
has been achieved for all TWs. This will be measured as time from the randomization date 
(days). 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 


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will be estimated for each treatment group with a 95% confidence interval. Furthermore, 
descriptive statistics for time to complete eschar removal will be presented. The treatment 
groups will be compared using a Cox regression model. The comparison will be adjusted for 
clinical center, age, %TBSA, proportion of the FT area of a patient and number of TWs (1,2,3-
4, ≥5) 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. 
This coefficient will be tested (on actual sample allocation, without the re-randomization test) 
to be nonzero. Additionally, a log likelihood test comparing the model fit of a model with all time 
by covariate interactions added with a model without these interactions will be computed. The 
proportionality assumption will be rejected if one of these tests yields a significant result at the 
10% level. In this case, we will use a generalized Wilcoxon-Gehan test. The 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 agegroup ftgroup 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 (0 for censor and 1 for 
complete ER event) and agegroup, ftgroup, numtw, tbsagroup, and centergroup are the 
variables, which the model is adjusted for. Agegroup, ftgroup, tbsagroup and centergroup are 
the stratification levels defined in Section 11.1.11 and numtw is the number of target wounds 
(1, 2, 3-4, ≥5). 
Supportive analyses will include adjustment for other baseline variables that are imbalanced, 
based on the analyses described in Section 11.1.1. 


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The comparison between treatments will also be conducted on the time to complete eschar 
removal measured from the date of ICF as an additional analysis. 
As an additional analysis, time to complete eschar removal will be analyzed on a target 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. The proportional hazards assumption will be checked in the same way as in the patient 
level analysis. I.e. a Cox regression model will be fitted with covariates treatment, center, age, 
%TBSA, proportion of the FT area of a patient, number of TWs (1,2,3-4, ≥5) and a variable 
representing the interaction between time since randomization and treatment group. The latter 
coefficient will be tested to be nonzero. Additionally, a log likelihood test comparing the model 
fit of a model with all time by covariate interactions added with a model without these 
interactions will be computed. The proportionality assumption will be rejected if one of these 
tests yields a significant result at the 10% level. 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. [22]. The parametric frailty model will be implemented using the following SAS-code: 
PROC PHREG DATA=burn_data;  
CLASS Subject_id treatment_group centergroup numtw;  
MODEL time*status(0) = treatment_group centergroup age tbsa pctFT numtw;  
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 complete 
eschar removal on a wound level, status is an indicator whether the wound has achieved 
complete eschar removal or not (censoring indicator, 0 for censor and 1 for complete ER 
event), treatment_group gives the treatment group, centergroup is the stratification factor 
defined in Section 11.1.11, age is the patient’s age, TBSA is the overall percent TBSA of a 
patient, pctFT is the proportion of the FT area of a patient, numtw is the number of TWs (1,2,3-
4, ≥5) of the patient 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 


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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 to display the distribution of time to complete 
eschar removal (on a wound level) under the two treatments. 
11.1.4. Secondary Efficacy Analyses 
The secondary endpoints will be analyzed as described below. 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. 
11.1.4.1. 
Incidence of Surgical Excision 
This is a binary yes/no variable and the proportion of patients who need excision will be 
compared using logistic regression. Missing data for the main analysis and for the two 
sensitivity analyses will be handled by the methods described in Section 10.1.3.1. The 
explanatory variables in the model will include treatment, center, age, %TBSA, proportion of 
the FT area of a 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 a 95% confidence interval 
and the level of statistical significance. 
As sensitivity analysis, the procedure outlined above will be repeated using the PP instead of 
the FAS as analysis population. 
A supportive analysis will be performed adjusting for other baseline variables that are 
imbalanced, based on the analyses described in Section 11.1.1. 
As an additional analysis, the incidence of surgical excision will be compared on a wound level 
using a mixed logistic regression model with a random effect for patient. 
11.1.4.2. 
Blood Loss 
As defined in Section 10.3.3.2.1, the measure of blood loss per patient will be computed using 
two different methods: 
 
Method 1: treating the whole eschar removal process as one continuous procedure  


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 
Method 2: summing the blood loss computed per procedure over all procedures carried 
out to remove eschar 
Descriptive statistics of the blood loss values will be provided by treatment group. 
The imputation of missing values, involving the multiple imputations procedure, and further 
statistical analysis are detailed in Section 10.1.3.2. An overall estimate of the treatment 
difference with its standard error will be reported, together with the final combined p-value. 
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. 
As sensitivity analysis, the analysis outlined above will be repeated using the PP instead of the 
FAS as analysis population. 
A supportive analysis will be performed adjusting for other baseline variables that are 
imbalanced, based on the analyses described in Section 11.1.1. 
Note: No wound level analysis of this endpoint is possible, since blood loss cannot be attributed 
to single target wounds. 
11.1.4.3. 
Area of Autograft in DPT Wounds 
For the purpose of the main analysis, the mean percent area of autograft in DPT wounds will 
be compared on a subject level between NexoBrid and SoC. This analysis will be restricted to 
subjects having at least one DPT target wound. Descriptive statistics of the observed values 
on a subject level (including the number of missing values) will be provided by treatment group. 
The imputation of missing values, involving the multiple imputations procedure, and further 
statistical analysis are detailed in Section 10.1.3.3. An overall estimate of the treatment 
difference with its standard error will be reported, together with the final combined p-value. 
As sensitivity analysis, the main analysis outlined above will be repeated using the PP instead 
of the FAS as analysis population, also restricted to subjects having at least one DPT target 
wound. 
Supportive analyses on a subject level will include adjustments for additional baseline 
variables which are found to be imbalanced, based on the analyses described in 
Section 11.1.1. 


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As an additional analysis, the percent area autografted in DPT target wounds will be analyzed 
on a target wound level. This analysis will be restricted to DPT target wounds only.  Descriptive 
statistics will be provided on a target wound level for each treatment group. The differences in 
the distribution of percent area autografted in DPT wounds between the treatment groups will 
be tested using a mixed linear regression model with patient as the random effect that accounts 
for within-subject correlation between target wounds. 
11.1.4.4. 
Incidence of Autograft in DPT Wounds 
This is a binary yes/no variable and the proportion of Deep Partial Thickness TWs that were 
autografted will be compared (on a wound level). Missing data for the main analysis and for 
the two sensitivity analyses will be handled by the methods described in Section 10.1.3.4. The 
comparison of NexoBrid versus SoC will be conducted using logistic regression within the 
generalized estimating equations (GEE) framework that accounts for within-subject correlation 
between target wounds. The explanatory variables in the model will include treatment, center, 
age, %TBSA (wound level), proportion of the FT area of a patient and number of TWs (1,2,3-
4, ≥5). The odds ratio of requiring Autograft for NexoBrid versus SoC will be estimated from 
the model, as well as 95% confidence intervals and the level of statistical significance. 
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 baseline variables which are found to be 
imbalanced, based on the analyses described in Section 11.1.1. 
These analyses will only take into account DPT target wounds. 
11.1.5. Safety Analyses 
All safety variables except for the first safety endpoint “time to reach complete wound closure”, 
which will be evaluated using the FAS, will be evaluated on the safety set. 
11.1.5.1. 
Time to Reach Complete Wound Closure 
For the purpose of the main analysis, 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 


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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 Cox regression model will be fitted with covariates 
treatment, center, age, %TBSA, proportion of the FT area of a patient, number of TWs (1,2,3-
4, ≥5) and a variable representing the interaction between time since randomization and 
treatment group. The latter coefficient will be tested to be nonzero. Additionally, a log likelihood 
test comparing the model fit of a model with all time by covariate interactions added with a 
model without these interactions will be computed. The proportionality assumption will be 
rejected if one of these tests yields a significant result at the 10% level. 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. [22]. The parametric frailty model will be implemented using the 
following SAS-code: 
PROC PHREG DATA=burn_data;  
CLASS Subject_id treatment_group centergroup numtw;  
MODEL time*status(0) = treatment_group centergroup age tbsa pctFT numtw;  
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, 
centergroup is the stratification factor defined in Section 11.1.11, age is the patient’s age, tbsa 
is the overall percent TBSA of a patient, pctFT is the proportion of the FT area of a patient, 
numtw is the number of TWs (1,2,3-4, ≥5) of the patient 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. 


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In case the proportional hazards assumption is rejected and the parametric frailty model is 
used, the underlying proportional hazards assumption (conditional on the frailty term) will be 
checked by adding a variable representing the interaction between time since randomization 
and treatment group to the model. In case the coefficient of the latter term is significantly 
different from zero (at the 5% level) a further sensitivity analysis using an accelerated failure 
time (AFT) model with shared frailty will be performed. This model will be implemented using 
the following SAS-code:  
PROC NLMIXED DATA=burn_data; 
BOUNDS gamma>0; 
linp = b0 + b1*treatment_group + b2*age1 + b3*age2 + b4*age3 + b5*tbsa1 + 
b6*ft1+ b7*number_tw2+ b8*number_tw3 + b9*number_tw4 + b10*US + b11*EEU + 
b12*WEU + 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, age1-age3 are indicator variables for a subject being in age group A1 – A3 respectively 
(per age groups defined in Section 11.1.11), ft1is an indicator for a subject with proportion of 
the FT area <20% out of the total burned area (group C1, defined in Section 11.1.11), TBSA1 
is an indicator for a subject with overall %TBSA in (1% to 15%), inclusive (group B1, defined 
in Section 11.1.11), 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 3-4 target wounds 
(patient level), number_tw4 is an indicator variable for the subject having ≥5 target wounds 
(patient level), US, EEU and WEU are indicator variables for the individual being in region US, 
EEU and WEU (patient level) and burn_data is a SAS data set containing the required 
information. 
Kaplan-Meier curves will be presented graphically to display the distribution of time to complete 
wound closure under the two treatments. 


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If any of the baseline factors are found to be significantly different between the treatment 
groups (based on the analyses described in Section 11.1.1), then the factor will be included as 
an extra adjusting covariate in a supportive analysis of time to complete wound closure. 
As an additional analysis, the time to complete wound closure will be analyzed on a subject 
level. Kaplan-Meier curves will be presented graphically to display the distribution of time to 
complete eschar removal under the two treatments on a subject level. Median time to complete 
eschar removal will be estimated for each treatment group with a 95% confidence interval. 
Furthermore, descriptive statistics for time to complete eschar removal will be presented. The 
treatment groups will be compared using either a Cox regression model (if the proportional 
hazards assumption appears to hold), or a generalized Wilcoxon-Gehan test (if the 
proportional hazards assumption does not hold), as described in Section 11.1.3 for the main 
analysis of the primary efficacy endpoint. 
As supportive analyses, the time to reach 100% wound closure will be analyzed on a wound 
level (similar to the main analysis outlined above) and on a subject level (similar to the 
additional analysis outlined above). 
11.1.5.2. 
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. Descriptive 
statistics of MVSS score at 12 months will be provided by treatment group, for both observed 
and imputed data (for handling of missing data see Section 10.1.4.2.) The treatment groups 
will be compared using a linear model with imputed MVSS score at 12 months as the 
dependent variable. The explanatory variables in the model will include treatment, and the 
following variables: treatment center, age, %TBSA, proportion of the FT area of a patient and 
number of TWs (1,2,3-4, ≥5). The coefficient corresponding to the treatment group will be 
estimated and will represent the estimated mean difference in MVSS score at 12 months 
between NexoBrid and SoC adjusted for any imbalance in the stratification factors. The results 
of the regression analysis will be provided. 
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: 


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𝐻0: Δ ≥1.9     𝑣𝑠.     𝐻1: Δ < 1.9  
Where Δ 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. 
The main analysis will be performed as described above using both on-site and remotely 
collected evaluations, with missing values imputed as described in SAP Section 10.1.4.2. 
In addition, a sensitivity analysis will be performed (similar to the main analysis described 
above) to explore the possible influence of remotely captured data. For this sensitivity analysis, 
the remote evaluations will be "corrected", as described in SAP Section 10.5.2.1, and missing 
values at 12 months will be imputed applying the imputation procedure from SAP 
Section 10.1.4.2 on observed on-site evaluations and "corrected" remote evaluations. 
 
11.1.5.3. 
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 second stage analysis (see 11.2.4.3). 
11.1.5.4. 
Adverse Events 
In this analysis, only the treatment emergent adverse events occurring until the 12 months 
follow-up visit will be analyzed. 
All adverse events will be listed. Furthermore, the following tables will be produced separately 
for the following sub-periods: 1) until the 12 weeks follow-up, 2) between the 12 weeks follow-
up and the 12 months follow-up (including AEs from the first sub-period that are still ongoing), 
3) combined until the 12 months follow-up: 
 
Summary of Treatment Emergent Adverse Events (TEAEs) on a subject level  and on 
an event level 
 
Summary of TEAEs by System Organ Class (SOC), and Preferred Term (PT) 
separately for: 
o All TEAEs 


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o Treatment related TEAEs 
o General and local, not TW-related TEAEs 
o Local, TW-related TEAEs 
 
Summary of Special Interest TEAEs by PT (for sub-period 1), separately for: 
o TEAEs with PTs associated with fever (Pyrexia, Body Temperature Increased, 
Hyperthermia) 
o TEAEs associated with target wound infections (only if Local, TW-related: 
relevant preferred terms will be reviewed after finalization of coding and can 
include for example preferred terms as: Wound Infection Bacterial, 
Staphylococcal 
Skin 
Infection, 
Wound 
Infection, 
Wound 
Infection 
Staphylococcal if reported as local TW-related) 
o TEAEs associated with target wound pain (relevant preferred terms will be 
reviewed after finalization of coding) 
 
Summary of TEAEs by SOC, PT, and time of onset (for sub-period 1) separately for: 
o All TEAEs 
o General and 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. 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 and local, not TW-related Treatment related TEAEs 
o Local, TW-related Treatment related TEAEs 
o All TESAEs 
o Treatment related TESAEs 


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11.1.5.5. 
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 presented 
by treatment group using descriptive statistics. In addition, laboratory measurements obtained 
prior the first eschar removal procedure and after the last eschar removal procedure, as well 
as the corresponding pre-post difference, will be presented by treatment group using 
descriptive statistics. 
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, as well as at the last eschar removal procedure, for each laboratory value 
separately. 
Shift tables for central laboratory values indicating shifts from baseline to post every type of 
eschar removal procedure (first application, additional application, surgical procedure, 
additional surgical procedure, and nonsurgical procedure), as well as to post last eschar 
removal procedure, will be produced. 
Furthermore, shift tables indicating shifts from baseline (low/normal/high) to any abnormal 
(low/high) value will be presented. 
Additional tables will indicate shifts from baseline (low/normal/high) to any post treatment 
potentially clinically significant result. A listing of subjects experiencing such shifts will be 
provided. 
The denominator for the shift tables will be the patients that had both pre and post results for 
the respective procedure. 
The above tables will be presented for biochemistry parameters, hematology parameters and 
urine analysis parameters (where applicable) separately, and for parameters with numeric 
values only. 
11.1.5.6. 
Vital Signs 
All vital signs (body temperature, heart rate, respiratory rate, systolic blood pressure, diastolic 
blood pressure) will be presented by treatment group using descriptive statistics. 


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The analyses will be done for the vital signs assessments at baseline, at the first 7 daily 
assessments as well as for the pre-post differences of the daily vital signs assessments 
described in Section 10.3.4.4 separately. 
Note: Vital sign assessments will only be recorded while a subject is hospitalized. It may 
however be the case that certain subjects will be discharged during the first week, making 
some of the measurements not available. The respective subjects will be excluded from all 
vital sign analysis referring to time points after hospital discharge. 
Furthermore, for the vital signs assessment at baseline and at the first 7 daily assessments 
the information whether the overall vital signs investigator's assessment was normal, abnormal 
(NCS) or abnormal (CS) is given in the eCRF. For these overall vital signs investigator's 
assessment classifications, a shift table will be produced indicating shifts from baseline to each 
of the daily assessments from day 1 to day 7 and to the last daily assessment within the first 7 
days. 
Additionally, for individual vital signs parameters a shift table will be produced indicating shifts 
from baseline to post treatment potentially clinically significant (pCS) results at each of the 
daily assessments from day 1 to day 7 and at the last daily assessment within the first 7 days. 
Furthermore, a shift table indicating shifts from baseline to any post treatment potentially 
clinically significant result within the first 7 daily assessments will be provided. A subject listing 
of patients experiencing such shifts will be provided. As additional analysis, this shift analysis 
will be repeated excluding subjects with hospital discharge before day 7. 
11.1.5.7. 
Pain Assessment 
The pain assessment score (FPS-R) will be analyzed descriptively by treatment group with 
counts and percentages and compared between groups using a chi square test (or Fisher’s 
exact test in case of small estimated cell counts). Additionally, the pain score will be evaluated 
as a metric variable and presented using numeric descriptive statistics by treatment group. 
The analyses will be done for the pain assessments at screening, pre and post eschar removal 
procedures as well as at the first 7 daily assessments separately. Changes from baseline per 
time point as calculated in Section 10.3.4.4, will be presented by treatment group using 
descriptive statistics. 


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Note: Pain assessments will only be recorded while a subject is hospitalized. It may however 
be the case that certain subjects will be discharged during the first week, making some of the 
measurements not available. The respective subjects will be excluded from all pain analysis 
referring to time points after hospital discharge. 
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 pain assessment by displaying shifts from baseline by 
treatment group. 
Furthermore, a shift table indicating shifts from baseline to any abnormal (NCS) or any 
abnormal (CS) result will be provided. As additional analysis, this shift analysis will be repeated 
excluding subjects with hospital discharge before day 7. 
The Pain scale (FPS-R) was validated only for children above the age of 4. The analyses 
described above will be therefore done for the children above the age of 4 and below the age 
of 4 separately. 
11.1.5.8. 
Blood Transfusions 
The volume of blood transfusions in milliliters (as calculated in Section 10.3.4.4) will be 
presented by treatment group using descriptive statistics. The mean volume of blood 
transfusions between treatment groups will be compared by a one-way analysis of variance. 
The volume of blood transfusions will be presented overall (during hospitalization), 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. 
The volume of blood transfusions will be analyzed as described above separately for calculated 
transfusion RBC volume, for the volume of packed red blood cells transfused and the volume 
of whole blood transfused. 
11.1.5.9. 
Immunogenicity and PK Evaluation 
The immunogenicity and PK evaluation will be done separately and is described in a separate 
document. 


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11.1.5.10. 
Antibiotic Use 
The number of days of exposure to systemic antibiotic drugs will be presented by treatment 
group using descriptive statistics and compared between groups with a one-way analysis of 
variance. This analysis will be conducted for overall systemic 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. 
11.1.5.11. 
Medical History 
Medical history events will be classified using the MedDRA dictionary. They will be tabulated 
with reference to system organ class, preferred term and frequency of occurrence. The system 
organ classes will be sorted alphabetically, the preferred terms within the system organ classes 
will be displayed in decreasing order of incidence in the NexoBrid group. 
11.1.5.12. 
Concomitant Medications 
In this analysis, only the concomitant medications administered during the first phase (until the 
12 months follow-up for each patient) will be analyzed. The number of patients involved will be 
tabulated with overall numbers and with reference to ATC coding using the Level 2 and Level 
4 codes. The summary tables will be produced separately for the following sub-periods: 1) until 
the 12 weeks follow-up, 2) between the 12 weeks follow-up and the 12 months follow-up 
(including CM with a start date before the 12 weeks follow up but an end date after that or still 
ongoing), 3) combined until the 12 months follow-up. 
11.1.5.13. 
Hospital Readmission Rates 
Hospital admission rates will be analyzed on a patient level by displaying counts and 
percentages by treatment group. 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). 
Furthermore, the number of planned hospital readmissions per patient will be analyzed by 
displaying counts and percentages by treatment group. 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). 


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Additionally, the number of unplanned hospital readmissions per patient will be analyzed by 
displaying counts and percentages by treatment group. 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). 
Hospital readmission will also be analyzed on a readmission level. Counts and percentages of 
planned/unplanned readmissions will be displayed by treatment group. 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). 
11.1.5.14. 
Change in PTT/INR 
Change in INR/PTT will be evaluated at 4h post first treatment. For the classification of normal 
and abnormal INR/PTT values, the reference limits of the local labs will be used (see also 
Section 10.3.4.4).  
The following tables will be produced for INR and PTT: 
 
Shift tables indicating shifts from baseline (low/normal/high) to post first treatment 
(low/normal/high) as well as a listing of subjects experiencing shifts from low/normal to 
high 
 
Shift tables indicating shifts from baseline to post first treatment potentially clinically 
significant result as well as a listing of subjects experiencing such shifts. For the 
definition of pCS high and pCS low, see Section 13.2.2. 
Only subjects with non-missing pre and post values will be considered for the analysis. 
11.1.5.15. 
Lower Extremity Function Scale (LEFS) 
The analysis of LEFS is restricted to subjects with at least one TW with lower extremity 
involvement. The LEFS scores at 12 months follow up assessment will be presented by 
treatment group using descriptive statistics. The mean LEFS scores between treatment groups 
will be compared by a one-way analysis of variance. 
11.1.5.16. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The analysis of QuickDASH is restricted to subjects with at least one TW with arm, shoulder 
or hand involvement. The QuickDASH scores at 12 months follow up assessment will be 


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presented by treatment group using descriptive statistics. The mean QuickDASH scores 
between treatment groups will be compared by a one-way analysis of variance. 
11.1.5.17. 
Range of Motion (ROM) 
The ROM will be evaluated using a variable with 2 levels (all measurements normal / at least 
one abnormal finding). Summary tables will be provided giving sample size, absolute and 
relative frequency and 95% CI (Confidence Interval) for the proportion with a normal score, 
separately for each study treatment group. 
A logistic regression model will be applied for testing the statistical significance of the difference 
in ROM measurements between NexoBrid and SoC treatments at 12 months. Adjustment will 
be made for any imbalance between the groups in treatment center, overall treated %TBSA 
and % of FT per patient. 
Only subjects with joint injury will be regarded for this analysis. A footnote to the results will 
indicate this. 
11.1.5.18. 
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, Looking after myself, Doing usual activities, Having pain or discomfort, 
Feeling worried, sad or unhappy) the count and percentages of each possible answer will be 
presented per age group (the analysis will be done per age at randomization) and per treatment 
group. 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 presented by treatment group 
using descriptive statistics. The mean EQ VAS values between treatment groups will be 
compared by a one-way analysis of variance. 
Additionally, the single summary index will be analyzed analogously as the EQ VAS. 
The linear regression model with the single summary index as target variable will be applied 
for testing the statistical significance of the difference in scores between NexoBrid and SoC 
treatments at 12 months. Adjustment will be made for any imbalance between the groups in 
treatment center and overall treated %TBSA. 


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11.1.5.19. 
Burn Outcome Questionnaire (BOQ) 
The BOQ will be analyzed separately. Its analysis will be detailed in a separate document. 
11.1.6. Exploratory Analyses 
11.1.6.1. 
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. The proportion of circumferential extremities target wounds that 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. 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). The reference count will be the number of 
subjects with at least one circumferential extremities target wound. 
11.1.6.2. 
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. 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). 


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11.1.6.3. 
% wound area surgically excised for eschar removal 
The % wound area surgically excised for eschar removal per patient (computed as in 
section 10.3.5.3) will be presented by treatment group using descriptive statistics and 
compared between groups with a one-way analysis of variance. 
11.1.6.4. 
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. 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). 
11.1.6.5. 
% area of surgically harvested donor site wounds 
The % wound area of surgically harvested donor site wounds per patient (computed as in 
section 10.3.5.5) will be presented by treatment group using descriptive statistics and 
compared between groups with a one-way analysis of variance. 
11.1.6.6. 
Blood loss using changes in hemoglobin following eschar removal 
procedures 
The measure of blood loss defined in Section 10.3.5.6 will be computed for each patient, 
presented by treatment group using descriptive statistics and compared between groups with 
a one-way analysis of variance. 
11.1.6.7. 
POSAS 
The POSAS will be evaluated on a subject level. The POSAS based on target wounds will be 
calculated as outlined in Section 10.3.5.7 and will be presented by treatment group using 
descriptive statistics. The mean POSAS values between treatment groups will be compared 
by a one-way analysis of variance. 
The analysis will be repeated for the patient scale and for the observer scale separately. 
The analyses will be conducted for the POSAS assessments (both on-site and remotely 
collected) of 6 and 12 weeks and 6 and 12 months. 
In addition, the analysis will be repeated excluding subjects with remotely collected data. 


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11.1.6.8. 
MVSS (target wounds) 
The MVSS for target wounds (analyzed on a subject level) at 6 and 12 weeks and 6 months 
(both on-site and remotely collected) will be calculated as outlined in Section 10.3.4.2 and will 
be presented by treatment group using descriptive statistics. The mean MVSS values between 
treatment groups will be compared by a one-way analysis of variance.  
In addition, the analysis will be repeated excluding subjects with remotely collected data. 
11.1.6.9. 
Duration of hospitalization 
The duration of hospitalization will be analyzed descriptively with Kaplan-Meier plots and 
compared between groups with a log rank test. 
11.1.7. Pharmacokinetic Variables 
Pharmacokinetic variables will be analyzed separately. The analysis is described in a separate 
document. 
11.1.8. Multicenter Data 
Randomization will be stratified by center as detailed in the Section 15.7.2 of the protocol. 
The analyses of the primary and secondary endpoints of this trial will adjust for possible center 
effects by including the grouped center as covariate in the analyses. The grouping will be done 
using the geographical regions: US (United States), EEU (Eastern Europe), WEU (Western 
Europe) and India. 
11.1.9. 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: time to complete eschar removal 
2. Secondary: Incidence of surgical excision 
3. Secondary: Blood loss 
4. Secondary: Area of Autograft in DPT wounds 


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5. Secondary: Incidence of Autograft in DPT wounds 
11.1.10. Interim Analysis 
No interim analyses will be performed. 
11.1.11. Stratification 
The following factors are used to stratify the study design: 
A. Age group: 
A1: 0 to 23 month 
A2: 24 months to 3 years 
A3: 4 to 11 years 
A4: 12 to 18 years 
B. Overall total area of burns measured by % of TBSA 
B1: (1% to 15%), inclusive 
B2: (> 15% to ≤ 30%) 
C. The proportion of the FT area out of the total burned area of a patient 
C1: < 20% of the burned area defined as FT 
C2: ≥ 20% of the burned area defined as FT 
D. Clinical center, so as to address possible differences in SoC procedures between sites (if 
any), to allow comparison of the results within center and to reduce the likelihood of a center 
including patients in only one arm of the study. 
D1, D2,…,Dm (m being the number of participating clinical centers). 
Using this stratification, patients will be randomized in a 1:1 ratio (NexoBrid: SoC). 


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11.1.12. 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. 
11.1.12.1. 
Age group 0-23 months 
A subgroup analysis will be performed on the subject aged 0-23 months. 
The primary endpoint time to eschar removal will be analyzed with Kaplan-Meier curves to 
display the distribution of time to complete eschar removal under the two treatments. Time to 
complete eschar removal will be compared between treatment groups by a log rank test. 
For the secondary endpoint “incidence of surgical excision” counts and percentages of patients 
needing surgical excision will be presented. The treatment groups will be compared using a 
chi square test (of Fisher’s exact test in case of small expected cell counts). 
For the secondary endpoint “blood loss” descriptive statistics will be presented by treatment 
group. Treatment groups will be compared using a t-test. 
For the secondary endpoint “area of Autograft in DPT wounds” descriptive statistics (on a 
subject level) will be presented by treatment group. Treatment groups will be compared using 
at-test. 
For the secondary endpoint “incidence of Autograft in DPT wounds” counts and percentages 
on a target wound level will be presented by treatment group. The treatment groups will be 
compared using a logistic regression within the generalized estimating equations (GEE) 
framework that accounts for within-subject correlation between target wounds. 
The analysis of Adverse Events for the sub-period until the 12 weeks follow-up, (see 
Section 11.1.5.4) will be repeated, as deemed relevant, on the subgroup of patients aged 0-
23 months. 
The analyses of PTT/INR (see Section 11.1.5.14) will be repeated on the subgroup of patients 
aged 0-23 months. 
The analyses of central laboratory parameters (see Section 11.1.5.5) will be repeated, as 
deemed relevant, on the subgroup of patients aged 0-23 months. The following parameters 
will be analyzed: 


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 
Biochemistry: Creatinine, Glucose, Total Bilirubin, Albumin, Calcium (Ca++), Sodium 
(Na+), Potassium (K+), Alkaline Phosphatase, SGOT (ASAT), SGPT (ALAT), LDH. 
 
Hematology: 
Hemoglobin, 
Hematocrit, 
Platelets, 
Total 
WBC, 
Neutrophils, 
Lymphocytes. 
11.1.12.2. 
Age group 24 months – 3 years 
The same analyses as outlined in Section 11.1.12.1 will be performed but on the subgroup of 
patients aged 24 months – 3 years. 
11.1.12.3. 
Age group 0 – 3 years 
The same analyses as outlined in Section 11.1.12.1 will be performed but on the subgroup of 
patients aged 0 – 3 years. 
11.1.12.4. 
Age group 4 – 11 years 
The same analyses as outlined in Section 11.1.12.1 will be performed but on the subgroup of 
patients aged 4 – 11 years. 
11.1.12.5. 
Age group 12 – 18 years 
The same analyses as outlined in Section 11.1.12.1 will be performed but on the subgroup of 
patients aged 12 – 18 years 
 
 


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11.2. Second stage analysis – 24 months long-term follow-up (LTFU24) 
11.2.1. Demographics Data and Other Baseline Characteristics 
Not applicable for this stage of analysis since all information on demographics data and other 
baseline characteristics was already analyzed in the first stage analysis (see 11.1.1). 
11.2.2. Primary Efficacy Analysis 
Not applicable for this stage of analysis since all information on the primary efficacy variable 
was already analyzed in the first stage analysis (see 11.1.3). 
11.2.3. Secondary Efficacy Analyses 
Not applicable for this stage of analysis since all information on the secondary efficacy 
variables was already analyzed in the first stage analysis (see 11.1.4). 
11.2.4. Safety Analyses 
11.2.4.1. 
Time to Reach Complete Wound Closure 
Not applicable for this stage of analysis since all information on this endpoint was already 
analyzed in the first stage analysis (see 11.1.5.1). 
11.2.4.2. 
Cosmesis and Function at 12 Months from Wound Closure 
Not applicable for this stage of analysis since this endpoint was already analyzed in the first 
stage analysis (see 11.1.5.2). 
11.2.4.3. 
Cosmesis and Function at 24 Months from Wound Closure 
The MVSS score for a patient will be calculated as described in Section 10.3.4.2. Descriptive 
statistics of MVSS score at 24 months will be provided by treatment group, for both observed 
and imputed data (for handling of missing data see Section 10.1.4.2). The treatment groups 
will be compared using a linear model with imputed MVSS score at 24 months as the 
dependent variable. The explanatory variables in the model will include treatment, and the 
following variables: treatment center, age, %TBSA, proportion of the FT area of a patient and 


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number of TWs (1,2,3-4, ≥5). The coefficient corresponding to the treatment group will be 
estimated and will represent the estimated mean difference in MVSS score at 24 months 
between NexoBrid and SoC adjusted for any imbalance in the stratification factors. The results 
of the regression analysis will be provided. 
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: 
𝐻0:Δ ≥1.9     𝑣𝑠.     𝐻1:Δ < 1.9  
Where Δ 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. 
The main analysis will be performed as described above using both on-site and remotely 
collected evaluations, with missing values imputed as described in SAP Section 10.1.4.2. 
In addition, a sensitivity analysis will be performed (similar to the main analysis described 
above) to explore the possible influence of remotely captured data. For this sensitivity analysis, 
the remote evaluations will be "corrected", as described in SAP Section 10.5.2.2, and missing 
values at 24 months will be imputed applying the imputation procedure from SAP 
Section 10.1.4.2 on observed on-site evaluations and "corrected" remote evaluations. 
11.2.4.4. 
Adverse Events 
The analyses of Adverse Events described in Section 11.1.5.4 will be repeated, as deemed 
relevant, on the following additional sub-periods: 
o adverse events occurring after the 12 months follow up (including AEs from the 
first stage that are still ongoing); 
o adverse events occurring during the entire study period 


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11.2.4.5. 
Concomitant Medications 
In this analysis, only the concomitant medications 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 overall 
numbers and with reference to ATC coding using the Level 2 and Level 4 codes. 
11.2.4.6. 
Lower Extremity Function Scale (LEFS) 
The LEFS scores at 24 months follow up assessment will be presented by treatment group 
using descriptive statistics. The mean LEFS scores between treatment groups will be 
compared by a one-way analysis of variance. 
11.2.4.7. 
Disabilities of the Arm, Shoulder and Hand (QuickDASH) 
The QuickDASH scores at 24 months follow up assessment will be presented by treatment 
group using descriptive statistics. The mean QuickDASH scores between treatment groups 
will be compared by a one-way analysis of variance. 
11.2.4.8. 
Range of Motion (ROM) 
The ROM will be evaluated using a variable with 2 levels (all measurements normal / at least 
one abnormal finding). Summary tables will be provided giving sample size, absolute and 
relative frequency and 95% CI (Confidence Interval) for the proportion with a normal score, 
separately for each study treatment group. 
A logistic regression model will be applied for testing the statistical significance of the difference 
in ROM measurements between NexoBrid and SoC treatments at 24 months. Adjustment will 
be made for any imbalance between the groups in treatment center, overall treated %TBSA 
and % of FT per patient. 
Only subjects with joint injury will be regarded for this analysis. A footnote to the results will 
indicate this. 
11.2.4.9. 
EQ-5D (Quality of Life) 
The 24 months follow up assessment of the EQ-5D will be analyzed as follows. 


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The EQ-5D consists of 5 items with 3 possible answers each and an EQ visual analogue scale. 
For each item (Mobility, Looking after myself, Doing usual activities, Having pain or discomfort, 
Feeling worried, sad or unhappy) the count and percentages of each possible answer will be 
presented per age group (the analysis will be done per age at randomization) and per treatment 
group. 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 presented by treatment group 
using descriptive statistics. The mean EQ VAS values between treatment groups will be 
compared by a one-way analysis of variance. 
Additionally, the single summary index will be analyzed analogously as the EQ VAS. 
The linear regression model with the single summary index as target variable will be applied 
for testing the statistical significance of the difference in scores between NexoBrid and SoC 
treatments at 24 months. Adjustment will be made for any imbalance between the groups in 
treatment center and overall treated %TBSA. 
11.2.5. Exploratory Analyses 
11.2.5.1. 
POSAS 
The POSAS will be evaluated on a subject level. The POSAS for target wounds will be 
calculated as outlined in Section 10.3.5.7 and will be presented by treatment group using 
descriptive statistics. The mean POSAS values between treatment groups will be compared 
by a one-way analysis of variance. 
The analysis will be repeated for the patient scale and for the observer scale separately. 
The analyses will be conducted for the POSAS assessments (both on-site and remotely 
collected) of 18 and 24 months. 
In addition, the analysis will be repeated excluding subjects with remotely collected data. 
11.2.5.2. 
MVSS (target wounds) 
The MVSS for target wounds (analyzed on a subject level) at 18 months (both on-site and 
remotely collected) will be calculated as outlined in Section 10.3.4.2 and will be presented by 


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treatment group using descriptive statistic. The mean MVSS values between treatment groups 
will be compared by a one-way analysis of variance. 
In addition, the analysis will be repeated excluding subjects with remotely collected data. 
11.2.6. Pharmacokinetic Variables 
Not applicable. All pharmacokinetic data was already analyzed in the first stage analysis (see 
Section 11.1.7). 
11.2.7. Multicenter Data 
See Section 11.1.8. 
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 11.1.11. 
11.2.11. Analysis of Subgroups 
No subgroup analyses are planned in this stage. 
 
 


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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]  J. Barret and D. Herndon, "Modulation of inflammatory and catabolic responses in 
severely burned children by early burn wound excision in the first 24 hours," Arch Surg, 
vol. 138, no. 2, pp. 127-32, Feb 2003.  
[3]  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.  
[4]  Y. Ong, M. Samuel and C. Song, "Meta-analysis of early excision of burns," Burns, vol. 
32, no. 2, pp. 145-50, 2006.  
[5]  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.  
[6]  D. Young, "Burn and Electrical Injury," Second ed. Plastic Surgery, vol. 1, pp. 811-833, 
2006.  
[7]  S. Hindocha, "Burns eschar debridement: A review.," Journal of Wound Technology, vol. 
21, pp. 16-19, 07 2013.  
[8]  S.-J. Edmondson, I. Jumabhoy and A. Murray, "Time to start putting down the knife: A 
systematic review of burns excision tools of randomised and non-randomised trials," 
Burns, vol. 44, 02 2018.  
[9]  American Burn Association, "National Burn Repository® Version 12.0," 2016. 
[10] 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.  


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[11] 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.  
[12] Shoham et al, "The Use of Rapid Enzymatic Debridement in the 2015 Romanian Burn 
Mass Casualty Incident: Ground Breaking Experience," in SAWC Spring meeting, San 
Diego, 2017.  
[13] S. Fischer et al., "Feasibility and safety of enzymatic debridement for the prevention of 
operative escharotomy in circumferential deep burns of the distal upper extremity," 
Surgery, vol. 165, no. 6, pp. 1100-1105, June 2019.  
[14] American Burn Association, "American Burn Association Consensus Statements," 
Journal of Burn Care & Research, July 2013.  
[15] D. Hart, S. Wolf, R. Beauford, S. Lal, D. Chinkens and D. Herndon, "Determinants of 
blood loss during primary burn excision," Surgery, vol. 130, no. 2, pp. 396-402, Aug 2001. 
[16] C. Licht, New methods for generating significance levels from multiply-imputed data, 
2011.  
[17] G. Molenberghs and M. G. Kenward, Missing Data in Clinical Studies, John Wiley & Sons, 
Ltd , 2008.  
[18] C. Mallinckrodt, „Missing Data in Clinical Trails,“ in Handbook of Missing Data 
Methodology, CRC Press, 2015, pp. 499-522. 
[19] M. Levine and W. K. D. Shao, "Monitoring of international normalized ratios: comparison 
of community nurses with family physicians," Can Fam Physician, vol. 58, no. 8, p. e465‐
e471, 2012.  
[20] M. van Reen, B. Janssen, M. Oppe, S. Kreimeier and W. Greiner, "EQ-5D-Y user guide," 
August 2014. [Online]. Available: https://euroqol.org/wp-content/uploads/2019/10/EQ-
5D-Y-User-Guide.pdf. [Accessed 22 April 2020]. 


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[21] J. W. Shaw, J. A. Johnson and S. J. Coons, "US Valuation of the EQ-5D Health States - 
Development and Testing of the D1 Valuation Model," Medical Care, vol. 43, no. 3, March 
2005.  
[22] D. Binder, "Fitting Cox’s proportional hazards models from survey data," Biometrika, vol. 
79, pp. 139-147, 1992.  
[23] T. K. Mattoo, "Definition and diagnosis of hypertension in children and adolescents 
(UpToDate)," [Online]. Available: https://www.uptodate.com/contents/definition-and- 
diagnosis-of-hypertension-in-children-and-adolescents?search=blood%20pressure 
%20children&source=search_result&selectedTitle=1~150&usage_type=default 
&display_rank=1. [Accessed 1 June 2020]. 
[24] N. Nishimura and N. Hiranuma, "Respiratory changes after major burn injury," Crit Care 
Med, vol. 10, no. 1, pp. 25-28, 1982.  
[25] Mayo Clinic, "Hypothermia.," [Online]. Available: https://www.mayoclinic.org/diseases- 
conditions/hypothermia/symptoms-causes/syc-20352682. [Accessed 17 April 2020]. 
[26] E. Mann-Salinas, M. Baun, J. Meininger and e. al., "Novel predictors of sepsis outperform 
the American Burn Association sepsis criteria in the burn intensive care unit patient," J 
Burn Care Res, vol. 34, no. 1, pp. 31-43, 2013.  
[27] D. Greenhalgh, J. Saffle, J. 4. Holmes and e. al., "American Burn Association consensus 
conference to define sepsis and infection in burns," J Burn Care Res, vol. 28, no. 6, pp. 
776-790, 2007.  
[28] National Cancer Institute (NCI), "Common Terminology Criteria for Adverse Events 
(CTCAE) 
version 
5.0," 
2017. 
[Online]. 
Available: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_ 
Quick_Reference_5x7.pdf. [Accessed 31 May 2020]. 
[29] R. Bellomo, C. Ronco, J. Kellum, R. Mehta and P. Palevsky, "Acute Dialysis Quality 
Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, 
fluid therapy and information technology needs: the Second International Consensus 


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Conference of the Acute Dialysis Quality Initiative (ADQI) G," Crit Care, vol. 8, no. 4, pp. 
R204-R212, 2004.  
[30] P. Thornton, C. Stanley, D. De Leon and e. al., "Recommendations from the Pediatric 
Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in 
Neonates, Infants, and Children," J Pediatr, vol. 167, no. 2, pp. 238-245, 2015.  
[31] C. Holm, F. Hörbrand, M. Mayr, G. von Donnersmarck und W. Mühlbauer, „Acute 
hyperglycaemia following thermal injury: friend or foe?,“ Resuscitation. , Bd. 60, Nr. 1, pp. 
71-77, 2004.  
[32] A. Laird, P. Miller, P. Kilgo, J. Meredith and M. Chang, "Relationship of early 
hyperglycemia to mortality in trauma patients," J Trauma, vol. 56, no. 5, pp. 1058-1062, 
2004.  
[33] G. Mecott, A. Al-Mousawi, G. Gauglitz, D. Herndon and M. Jeschke, "The role of 
hyperglycemia in burned patients: evidence-based studies," Shock, vol. 33, no. 1, pp. 5-
13, 2010.  
[34] M. Jeschke, R. Micak, C. Finnerty and D. Herndon, "Changes in liver function and size 
after a severe thermal injury," Shock, vol. 28, no. 2, pp. 172-77, 2007.  
[35] O. Aguayo-Becerra, C. Torres-Garibay, M. Macías-Amezcua and e. al., "Serum albumin 
level as a risk factor for mortality in burn patients," Clinics (Sao Paulo), vol. 68, no. 7, pp. 
940-945, 2013.  
[36] M. Çakırca, İ. Sözen, G. Tozlu Bindal, M. Baydar und A. Yastı, „Relationship between the 
albumin level and the anesthesia method and the effect on clinical course in patients with 
major burns,“ Ulus Travma Acil Cerrahi Derg, Bd. 25, Nr. 1, pp. 55-59, 2019.  
[37] G. Liumbruno, F. Bennardello, A. Lattanzio, P. Piccoli and G. Rossettias, "Italian Society 
of Transfusion Medicine and Immunohaematology (SIMTI). Recommendations for the 
use of albumin and immunoglobulins," Blood Transfus, vol. 7, no. 3, pp. 216-234, 2009.  
[38] G. Lindner and G. Funk, "Hypernatremia in critically ill patients," J Crit Care, vol. 28, no. 
2, p. 216.e11‐216.e2.16E20, 2013.  


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[39] P. Hébert, G. Wells, M. Blajchman and e. al., "A multicenter, randomized, controlled 
clinical trial of transfusion requirements in critical care," N Engl J Med, vol. 340, no. 6, pp. 
409-17, 1999.  
[40] T. Palmieri, "Burn injury and blood transfusion," Curr Opin Anaesthesiol, vol. 32, no. 2, 
pp. 247-251, 2019.  
[41] J. Teruya, "Red blood cell transfusion in infants and children: Indications (UpToDate)," 
[Online]. 
Available: 
https://www.uptodate.com/contents/red-blood-cell-transfusion-in-
infants-and-children-indications. [Accessed 31 March 2020]. 
[42] ,. E. Demidowicz, J. Moppert, A. Nowacka, J. Styczynski and M. Wysocki, "Essential 
thrombocythemia and reactive thrombocytosis in children," EC Paediatrics, vol. 2, no. 2, 
pp. 107-115, 2016.  
[43] R. Dinsdale, A. Devi, P. Hampson and e. al., "Changes in novel haematological 
parameters following thermal injury: A prospective observational cohort study," Sci Rep, 
vol. 7:3211, 2017.  
[44] S. Sevitt, "Eosinophil and other leucocyte changes in burned patients, with special 
reference to adreno-cortical activity," Br Med J, vol. 1, no. 4713, pp. 976-983, 1951.  
[45] N. Cosgriff, E. Moore, A. Sauaia, M. Kenny-Moynihan, J. Burch and B. Galloway, 
"Predicting life-threatening coagulopathy in the massively transfused trauma patient: 
hypothermia and acidoses revisited," J Trauma, vol. 42, no. 5, pp. 857-862, 1997.  
[46] J. McCullogh, Transfusion Medicine, 4th Edition ed., Chincester, West Sussex: John 
Wiley & Sons, 2017.  
[47] 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.  
[48] G.D. Warden, J.R. Saffle and M. Kravitz, "A Two-stage Technique for Excision and 
Grafting of Burn Wounds," J Trauma, vol. 22, no. 2, pp. 98-103, Feb 1982. 
 


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13. Appendices 
13.1. Randomization Algorithm 
Treatment allocation is performed using the method of minimization with stratification by the 
factors A, B, C and D described in Section 11.1.11 above: age group (A), overall %TBSA of all 
TW wounds (B), overall % of FT area (C) and clinical center (D). 
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, Ci and Di, respectively, where i is corresponding to the value of each 
factor, which is i = 1, 2, 3, 4 for factor A, i = 1, 2 for factors B and C and i = 1,..., m for factor D, 
with m being the number of participating clinical centers.  
For example: a patient, of 25 months of age with overall total area of burns of 4% - 9% and a 
proportion of the FT area of ≥20% is to be recruited in the 5th clinical center. This would lead 
to (A2, B1, C2, D5).  
The different treatment groups are denoted by j where j=1 corresponds to the NexoBrid group, 
j=2 to the SoC group. The numbers of patients in each stratum A, B, C, D receiving the j-th 
treatment and having the i-th factor are denoted by Aij, Bij, Cij and Dij.  
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, 
Cij and Dij. In our example the new patient has the factors A2, B1, C2, D5, hence the numbers 
of patients for each of these factors in treatment group j=1 which is the NexoBrid treatment are 
A21, B11, C21, and D51 respectively and the score N1 can be calculated as N1 = A21 + B11 
+ C21+D51. The score for the SoC treatment N2 can be calculated similarly: N2 = A22 + B12 
+C22+D52. To determine which treatment has to be allocated to the next patient, these two 
scores are compared. 
The trial started with the following method of treatment allocation. Since a 1:1 randomization 
is used in this trial, the patient is allocated to the treatment group with the smallest value among 
these two score values (strict minimization). Thus, the allocation decision is based on min (N1, 


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N2). If N1 equals N2, then simple randomization between the treatments is used with 
probabilities p1=p2=0.5 for each treatment.  
On 19th May 2017 it was decided to modify the method of treatment allocation in the following 
manner. The strict minimization method (described above) assigned the treatment to a patient 
so as to reduce the imbalance between the treatment groups at any stage. Only if allocating 
to either treatment yielded the same level of imbalance would the treatment be assigned at 
random (with a probability of 0.5). A modification is that the algorithm would henceforth assign 
with probability 0.9 the treatment that reduces the imbalance and with probability 0.1 the 
treatment that increases the imbalance (minimization with a random element). As before, if 
both treatment allocations lead to the same imbalance, randomization with probability 0.5 will 
be used. Thus, using the same notation as above, if N1 < N2 then treatment 1 is allocated with 
probability 0.9 and treatment 2 with probability 0.1. Conversely, if N1 > N2 then treatment 2 is 
allocated with probability 0.9 and treatment 1 with probablitiy 0.1. If N1 = N2, then treatment 1 
is allocated with proability 0.5 and treatment 2 with probability 0.5. 
13.2. Potentially Clinically Significant Thresholds 
13.2.1. Vital Signs 
The burn injury and any treatments administered before study treatment may affect body 
systems and their regulatory functions, including heart rate, blood pressure, fluid balance, and 
temperature. Therefore, measurements of vital signs might be abnormal prior to study 
treatment administration. In addition, only a few hours elapse between baseline and the 
following time point when vital signs are measured. 
In order to capture significant changes in vital signs that might be related to treatment, 
potentially clinically significant (PCS) thresholds for vital signs were defined using both the 
numerical value of the parameter and a clinically significant change from baseline.  


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Vital Sign 
(unit) 
Criterion 
value 
Explanation 
Systolic 
Blood 
Pressure 
(mmHg) 
Low PCS: < 
age defined 
threshold 
and 
decrease 
>10% 
Low PCS is based on PALS Guidelines depending upon age: 
Term neonates (0 to 28 days): The systolic BP is < 60 mmHg 
Infants (1 to 12 months): Systolic BP is < 70 mmHg 
Children 1 to 10 years (5th BP percentile): Systolic BP is < 70 
mmHg + (age in years x 2) 
Children > 10 years: Systolic BP is < 90 mmHg 
High PCS:≥  
20% above 
the 
95th 
percentile 
for 
age/gender 
and 
increase 
>10% 
High PCS is based on the normal blood pressure levels for 
boys and girls by age and height percentile. The 95th percentile 
is taken for the 50th height percentile [23]. 
95th percentile SBP for Girls (mmHg): 
1y-103 
2y-106 
3y-108 
4y-109 
5y-110 
6y-111 
7y-112 
8y-113 
9y-114 
10y-116 
11y-118 
12y-122 
13y-124 


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14y-125 
15y-126 
16y-127 
17y-127 
 
95th percentile SBP for Boys (mmHg): 
1y-103 
2y-106 
3y-107 
4y-108 
5y-109 
6y-111 
7y-112 
8y-114 
9y-115 
10y-116 
11y-118 
12y-121 
13y-125 
14y-130 
15y-132 
16y-134 
17y-135 
The increase from baseline for High PCS is used to capture 
significant changes, since elevated blood pressure might be 


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present prior to study treatment due to effects of the burn injury 
and any pre-study treatments.  
Respiratory 
Rate 
(breaths/mi
n) 
Low 
PCS: 
<age 
defined 
threshold 
and 
decrease 
>10% 
Low Respiratory Rate PCS is based on PALS Guidelines 
depending upon age: 
Infant, 30 
Toddler, 24 
Preschooler, 22 
School-aged, 18 
Adolescent, 12 
Respiration can be compromised following burn injury [24].  
High PCS: 
> 
age 
defined 
threshold 
and 
increase 
>10% 
High Respiratory Rate PCS is based on PALS Guidelines 
depending upon age: 
Infant, 60 
Toddler, 40 
Preschooler, 34 
School-aged, 30 
Adolescent, 16 
Temperatur
e (°C) 
Low 
PCS: 
<36 
and 
decrease 
>0.5 
Temperature <36°C was used in the NexoBrid protocols (eg, 
CIDS) to define hypothermia.  
A temperature of 35°C is commonly used in the definition of 
hypothermia [25], which is lower than the PCS threshold and 
therefore encompassed by it. 
Temperature <36°C was found to be useful as a predictor for 
sepsis [26] 


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High PCS: 
>39 
and 
increase 
>0.5 
Burn patients are very often hyperthermic.  
Pyrexia was defined as >39°C in the NexoBrid protocols (eg, 
CIDS).  
Temperature >39°C was found to be useful as a predictor for 
sepsis [27] 
Heart 
rate 
(beats/min) 
Low PCS: < 
lower 
threshold 
for 
age 
while 
awake and 
decrease 
>10% 
Normal Pulse Rate according to PALS will be defined 
depending upon age, while awake:  
Newborns up to 3 months old, 85–205  
Age 3 months to 2 years old, 100–190  
Ages 2 to 10, 60–140  
Children aged 10 years and above, 60–100  
High PCS: 
> 
upper 
threshold 
for 
age 
while 
awake and 
increase 
>10% 
Normal Pulse Rate according to PALS will be defined 
depending upon age, while awake: 
Newborns up to 3 months old, 85–205  
Age 3 months to 2 years old, 100–190  
Ages 2 to 10, 60–140  
Children aged 10 years and above, 60–100  
13.2.2. Laboratory Parameters 
Burn injury affects almost all body systems. Therefore, a wide range of laboratory parameters 
may be affected, which may be abnormal prior to study treatment. In addition, only a few hours 
elapse between baseline and the following time point when laboratory parameters are 
measured. 


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For these reasons, in order to capture significant changes in laboratory parameters that might 
be related to treatment, PCS thresholds for laboratory parameters were defined using both the 
numerical value of the parameter and a clinically significant change from baseline.  
Many of the PCS definitions for laboratory values below are based on Grade 2 definitions from 
the CTCAE version 5.0 [28]. As in the CTCAE, multiplication of the baseline value is used to 
define high PCS for several parameters in order to capture significant changes from baseline, 
as the lab result may be abnormal at baseline. 
Test (unit) 
Criterion 
value 
Explanation 
Serum Chemistry 
Creatinine 
(umol/L) 
High 
PCS: 
>1.5x ULN 
if 
Baseline 
≤ ULN  
or 
>1.5x Baseline 
value 
if 
Baseline 
> ULN. 
Acute kidney injury is a common complication in burn patients. 
Early kidney damage in the burn patient might be due to 
hypovolemia, inflammatory processes, tissue destruction and 
release of denaturated proteins, iatrogenic causes (eg, 
nephrotoxic agents), and/or cardiac dysfunction. 
The High PCS definition is based on the definition of Stage 1 
acute kidney injury and on the lower limit of the CTCAE Grade 
2 definition [28]. 
The approach of using multiplication of baseline value when 
baseline is already elevated is used in the CTCAE Grade 2 
definition and in the RIFLE risk definition in the Acute Dialysis 
Quality Initiative (ADQI) criteria for the definition and 
classification of AKI [29].  
Glucose 
(mmol/L) 
Low 
PCS: 
<3.00 mmol/L  
Low PCS is based on the upper limit of CTCAE definition of 
Grade 2 hypoglycemia [28] [30] 
High 
PCS: 
>11.10 mmol/
L and increase 
≥2.78 mmol/L 
Hyperglycemia is common in burn patients [31]. High glucose 
values >200 mg/dL (>11.10 mmol/L) are related to higher 
rates of infection and mortality among burn and trauma 
patients [32] [33]. In addition, glucose >200 mg/dL is one of 


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Statistical Analysis Plan V02 of 31 May 2021 
 
 
the triggers for the definition of sepsis according to the 
American Burn Association [27] 
Total 
Bilirubin 
(umol/L) 
High 
PCS: 
>1.5x ULN 
if 
Baseline 
≤ 
ULN  
or 
>1.5x Baseline 
value 
if 
Baseline 
> ULN  
Based on the lower limit of the CTCAE Grade 2 definition [28]. 
Alkaline 
Phosphatase 
(U/L) 
High 
PCS: 
>2.5x Age/ 
Gender ULN if 
Baseline 
≤ ULN  
or 
>2.5x Baseline 
value 
if 
Baseline 
> Age/Gender 
ULN  
Based on the lower limit of the CTCAE Grade 2 definition [28], 
and age normal range U/L of study laboratory:  
7-365 days: 50-270 
1-2y: 50-270 
3-12y: 60-415 
13-15y male: 60-500, 13-15y female: 60-350 
16-19y male: 30-225, 16-19y female: 30-165 
SGPT 
(ALT) 
(U/L) 
High 
PCS: 
>3x ULN 
if 
Baseline 
≤ 
ULN  
or 
>3.0x Baseline 
value 
if 
Based on the lower limit of the CTCAE Grade 2 definition [28]. 
Alanine 
aminotransferase 
(ALT) 
levels 
can 
increase 
immediately after burn injuries [34] and therefore might be 
increased already at baseline. 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Baseline 
> ULN 
SGOT 
(AST) 
U/L 
High 
PCS: 
>3x ULN 
if 
Baseline 
≤ ULN  
or 
>3.0x Baseline 
value, 
if 
Baseline 
> 
ULN 
Based on the lower limit of the CTCAE Grade 2 definition. 
Aspartate aminotransferase (AST) levels can increase 
immediately after burn injuries [34] and therefore might be 
increased already at baseline. 
Albumin (g/L) 
Low 
PCS: 
≤25 g/L 
and 
Decrease 
≥10% 
Hypoalbuminemia 
is 
common 
in 
burn 
patients. 
Hypoalbuminemia might occur in burn patients due to protein 
loss, an inflammatory process that affects plasma protein 
synthesis in the liver, and/or higher vascular permeability in 
burn wounds that causes exudation with protein loss.  
The CTCAE definition of Grade 2 hypoalbuminemia is albumin 
levels between 2 to 3 g/dL (20-30 g/L) [28].  
Since the lower limit of normal laboratory ranges of the study 
is around 3g/dL (7days-2y: 3-5g/dL, 3-199y: 3.2-5g/dL), PCS 
value lower than normal was taken. 
In the literature, morbidity corresponds to albumin <20 to 25 
g/L [35] [36].  
Oncotic activity remains physiologically adequate at albumin 
≥2 g/dL. An albumin level ≤20 g/L is commonly agreed by 
practitioners to trigger administration of intravenous albumin 
[37]. 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Calcium (Ca++), 
(mmol/L) 
Low 
PCS: 
<2 mmol/L and 
decrease 
≥10%  
Please refer to corrected calcium below 
High 
PCS: 
>2.9 mmol/L 
and 
increase 
≥10% 
Please refer to corrected calcium below 
Corrected 
Calcium (Ca++), 
(mmol/L) 
Low 
PCS: 
<1.75 mmol/L 
and decrease 
≥10% 
Low calcium levels are seen in burn patients and might be due 
to extracellular-intracellular shifts, calcium accumulation in 
erythrocytes, increased urinary excretion, and/or calcium loss 
in tissue exudates. 
Calcium levels are related to albumin levels, which are 
frequently decreased in burn patients.  
Low PCS is based on the upper limit of CTCAE definition of 
Grade 3 hypocalcemia [28].  
High 
PCS: 
>2.9 mmol/L 
and 
increase 
≥10% 
High PCS is based on the lower limit of CTCAE definition of 
Grade 2 hypercalcemia [28]. 
Sodium 
(Na+) 
(mmol/L) 
Low 
PCS: 
≤129 
and 
decrease >4 
Low PCS is based on the upper limit of CTCAE definition of 
Grade 2 hyponatremia [28]. 
High 
PCS: 
>150 
and 
increase ≥5 
High PCS is based on the lower limit CTCAE definition of 
Grade 2 hypernatremia [28].  
Studies have shown increased morbidity and mortality for 
patients with hypernatremia defined as >150 meq/L (mmol/L) 
[38]. 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Potassium (K+) 
(mmol/L) 
Low PCS: <3 
and decrease 
≥10% 
Low PCS is based on the upper limit of CTCAE definition of 
Grade 3 hypokalemia [28]. 
Since the normal laboratory ranges of the study are between 
3.5-5.5mmol/L (0-2y 3.8-5.5mmol/L, 3-12y 3.5-5.5mmol/L, 13-
199y 3.5-5.3mmol/L), PCS value lower than normal 
corresponding to Grade 3 was taken. 
High 
PCS: 
>6.0 
and 
increase ≥10% 
High PCS is based on the lower limit of CTCAE definition of 
Grade 3 hyperkalemia [28]. 
Since the normal laboratory ranges of the study are between 
3.5-5.5mmol/L (0-2y 3.8-5.5mmol/L, 3-12y 3.5-5.5mmol/L, 13-
199y 3.5-5.3mmol/L), PCS value higher than normal 
corresponding to Grade 3 was taken. 
Hematology 
Hemoglobin 
(g/L) 
Low 
PCS: 
<80  
and 
decrease 
≥10% 
Low PCS was set to be in line with the limit at which blood 
transfusion is recommended [39]. According to current clinical 
recommendations for burn patients, blood transfusion is 
administered when hemoglobin is below 7.0 to 8.0 g/dl (70-80 
g/L) [40].  
For most patients, restrictive RBC transfusion strategy (ie, 
Hgb of 7 g/dL (70g/L) as the transfusion threshold) rather than 
more liberal transfusion strategies is recommended. Slightly 
higher limit was taken as PCS since higher Hgb levels may be 
appropriate in certain conditions [41] 
Platelets 
(109/L) 
Low 
PCS: 
<75 and 
decrease 
≥10% 
Low PCS is based on the upper limit of CTCAE Grade 2 
definition [28]. 


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Statistical Analysis Plan V02 of 31 May 2021 
 
High 
PCS: 
>600 and 
increase >10% 
Platelet levels greater than the upper limit of normal but below 
700 are regarded as mild thrombocytosis and do not require 
treatment. Platelet levels >700 are defined as moderate 
thrombocytosis 
[42] 
Increased platelet turnover might be seen in burn patients due 
to a fall in platelet count followed by an increase in platelet 
production and a rebound thrombocytosis [43] 
Total 
Leukocyte 
(109/L) 
Low PCS: < 
=20% 
age 
related 
lower 
threshold  
The Low PCS is based on the normal limits of total leukocytes 
depending upon age;  
60-179days: 5-18 
180days-1y: 5-17,  
2-5y: 5-16,  
6-11y: 4.5-13.5,  
12-17y: 4.5-13 
High PCS: ≥ 
20% 
age 
related 
threshold  
The high PCS is based on the normal limits of total leukocytes 
depending upon age;  
60-179days: 5-18 
180days-1y: 5-17,  
2-5y: 5-16,  
6-11y: 4.5-13.5,  
12-17y: 4.5-13 
Neutrophil 
(109/L) 
Low PCS: <1.5  Low PCS is based on the common definition of neutropenia 
and the upper limit of CTCAE Grade 2 definition [28]. 
High 
PCS: 
≥20% 
upper 
limit of normal 
White 
Cell 
Neutrophil count might increase following burn trauma, 
surgical procedures, or stress [44]  


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Statistical Analysis Plan V02 of 31 May 2021 
 
Count 
upon 
age group and 
increase 
≥ 
10% 
from 
baseline 
Normal White Cell Count upon age group: 
90-179days: 1-8.5 
180-364days: 1.5-8.5 
1-199y: 1.8-8  
Coagulation 
International 
Normalized 
Ratio 
(INR) 
ratio 
High PCS >1.5 
if Baseline is 
≤1.2 
>1.5x Baseline 
if Baseline is 
>1.2 
A common normal range of INR was set to be up to 1.2, since 
normal ranges for local labs were not available for all sites. 
The PCS is based on the lower limit of the CTCAE Grade 2 
definition [28]. 
Activated 
Partial 
Thromboplastin 
Time 
(PTT) 
(sec)  
>1.5x ULN if 
Baseline 
< ULN 
>1.5 
x 
Baseline 
if 
Baseline 
> ULN 
Derived from the lower limit of CTCAE Grade 2 definition [28]. 
This limit was used in the DETECT protocol to define a 
significant increase [45]  
 
13.3. Update to Study Sample Size Due to COVID-19 Pandemic 
According to the study protocol version 9.01 dated 29 July 2019, 160 patients were to be 
enrolled into the study according to the defined age group distribution. Prior to the outbreak of 
COVID-19 pandemic and until March 2020, 145 patients were enrolled into the study. 
The COVID-19 pandemic significantly affected all study sites’ ability to enroll additional 
patients. There was a great uncertainty regarding when restrictions would be lifted and study 
sites would be able to resume enrollment. Therefore, MediWound explored whether the 
recruitment to the study can be completed at this stage, with 145/160 (91%) of patients 


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Statistical Analysis Plan V02 of 31 May 2021 
 
enrolled, in line with FDA guidance document: “Statistical Considerations for Clinical Trials 
During the COVID-19 Public Health Emergency”, issued on 17 June 2020. 
The original sample size and statistical power calculations for this study were based on effects 
reached during the first Phase 3 study (MW2004-11-02) which was completed in 2009. Since 
then MediWound had also completed the recruitment and the 12 month follow up of 175 adult 
patients randomized to the Phase 3 study MW2010-03-02 (DETECT). Power calculations were 
performed also using data from this latest phase 3 study.  
The updated sample size calculations, presented below, confirmed that based on a sample 
size of 145 patients, the study is sufficiently powered to meet the primary and main secondary 
and safety endpoints as originally planned.  Thus, the study provides all required data to 
evaluate NexoBrid’s safety and efficacy in pediatric patients while enabling the early availability 
of the product to address an unmet need in the pediatric population. These power calculations 
were submitted to the pediatric committee (PDCO) within the EMA and to the FDA to support 
MediWound’s request for early completion of enrollment. 
The request for early study completion was endorsed by the study’s DSMB, relying on the 
confirmation that study endpoints can be met with the sample size of 145 patients and pending 
FDA and EMA approval.  
The request for early completion of enrollment was accepted by both the FDA and the PDCO 
(EMA) and therefore the enrollment of patients into the study was completed with a total of 145 
patients, with the following age distribution:  
 
45 patients ≥0 months and ≤23 months old  
 
30 patients ≥24 months and ≤3 years old 
 
50 patients ≥4 years and ≤11 years old 
 
20 patients ≥12 years and <18 years old 
 
Power calculations for MW2012-01-01 study considering a reduced sample size of 145 
patients 
Sample sizes needed to achieve a power of 90% for the statistical tests in the analysis of 
MW2012-01-01 (CIDS) are estimated. The calculations are based on the 12 months’ data of 


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Statistical Analysis Plan V02 of 31 May 2021 
 
the DETECT study (MW2010-03-02), as well as on data from the previous study MW2004-11-
02. 
Note, that the power calculated for each test does only refer to the power of that specific test. 
When conducting multiple tests in a hierarchical testing procedure, endpoints which are 
positioned at later points of the hierarchy, might not be tested if earlier tests do not reject the 
corresponding null hypotheses. Therefore, the power of the tests in a hierarchical testing 
procedure also depends on the other endpoints and will be lower. 
 
Time to Complete Eschar Removal 
Estimate based on study MW2004-11-02 
 
The sample size calculation based on the results of study MW2004-11-02 assumes that the 
proportional hazards assumption will be judged appropriate and consequently a Cox model 
will be used for the primary analysis: 
Estimated log hazard ratio from study MW2004-11-02 (NexoBrid versus SoC) = -1.39, using a 
Cox proportional hazards model with treatment as only covariate. 
Standard error = 0.28 
Target log hazard ratio = -1.39 + 0.28/2 = -1.25; target hazard ratio = 0.29. 
The formula for total number of events D is: 


2
2
ln
)
z
z
(
4
D





 
(Piantadosi, Clinical Trials: A Methodologic Perspective, p.169) 
z = 1.96;  
z = 1.28 for 90% power. 
If the proportion of events in group 1 is denoted by p1 = 0.59 
and the proportion of events in group 2 is denoted by p2 = 0.70 
which are the observed proportions in the study MW2004-11-02, the number of patients 
required per group is n = 
2𝐷
𝑝1+𝑝2 = 42 (to the nearest even number), 21 in each group. 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Estimate based on study MW2010-03-02 
Since the proportional hazards assumption was rejected in study MW2010-03-02 trial, the 
sample size calculation based in this study assumes that this will also be the case in the CIDS 
study and consequently a generalized Wilcoxon-Gehan test will be used in the analysis. Based 
on the data from MW2010-03-02, simulations were conducted, using the generalized 
Wilcoxon-Gehan-Test for the primary analysis, resulting in a total sample size of 94 (47 per 
group) needed to achieve a power of 90%. 
 
% Wound Area Surgically Excised for Eschar Removal 
Estimate based on study MW2004-11-02 
Estimated difference in mean percent wound excised from study MW2004-11-02 (NexoBrid 
vs. SoC) = 15.1 – 59.6 = –44.5. 
Standard error = 5.3 
Target difference  = –44.5 + 5.3/2 = –41.85. 
The formula for the number of patients per group n is: 
2
2
2)
z
z(2
n






 
where  
z = 1.96;  
z = 1.28 for a power of 90%; 
 = the estimated common standard deviation of percent area of wound excised = 34.  
For 90% power, number per group = 14 
Estimate based on study MW2010-03-02 
Estimated mean % area surgically excised from study MW2010-03-02: NexoBrid 3.66; SoC 
58.74  
Standard errors: NexoBrid 2.09; SoC 5.78  
Difference: -55.08; Standard error of difference = 5.89 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Target difference Δ = -55.08 + 5.89/2 ≈ -52.13. 
Using a two-sided two-sample t-test with a two-sided significance level of 5%, the total sample 
size required to achieve a power of 90% is 24 (12 per group). 
 
Incidence of Surgical Excision 
Estimate based on study MW2004-11-02 
 
Estimated proportions having surgical excision from study MW2004-11-02: NexoBrid 0.42; 
SoC 0.80  
Standard errors: NexoBrid 0.057; SoC 0.044  
Difference = 0.38; Standard error of difference = 0.073 
Anticipated difference: 0.38-0.073/2 ≈ 0.34  
We therefore take the anticipated proportion with surgical excision to be: NexoBrid 0.44 and 
SoC 0.78.  
Using Fisher’s exact test with a two-sided significance level of 5%, the total sample size 
required to achieve a power of 90% is 96 (48 per group). 
Estimate based on study MW2010-03-02 
Estimated proportions having surgical excision from study MW2010-03-02: NexoBrid 0.04; 
SoC 0.72  
Standard errors: NexoBrid 0.023; SOC 0.052  
Difference = 0.68; Standard error of difference = 0.057 
Anticipated difference: 0.68-0.057/2 ≈ 0.652  
We therefore take the anticipated proportion with surgical excision to be: NexoBrid 0.05 and 
SOC 0.70.  
Using Fisher’s exact test with a two-sided significance level of 5%, the total sample size 
required to achieve a power of 90% is 26 (13 per group). 
 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Incidence of Autograft in DPT Wounds (wound level analysis) 
Estimate based on study MW2004-11-02 
Only subjects with at least one DPT target wound will be eligible for this analysis. The expected 
proportion of subjects with at least one DPT target wound estimated from study MW2004-11-
02 is 62.6%. 
Estimated log OR using GEE approach from study MW2004-11-02 (NexoBrid vs SoC): -0.676 
Standard Error: 0.40 
Anticipated log OR: -0.676+0.40/2=-0.476 
Using the normal approximation to the Wald test statistics (see for example Shih (1997)) we 
obtain that a total sample size of 1150 patients (720 evaluable) is needed to achieve a power 
of 90% using a two-sided significance level of 5%. This means that a sample size of 575 
subjects per arm would be required to obtain the minimum number of evaluable subjects for 
90% power in this endpoint. 
Estimate based on study MW2010-03-02 
Only subjects with at least one DPT target wound will be eligible for this analysis. The expected 
proportion of subjects with at least one DPT target wound estimated from study MW2010-03-
02 is 58%. 
Estimated log OR using GEE approach from study MW2010-03-02 (NexoBrid vs SoC): -0.5078 
Standard Error: 0.4988 
Anticipated log OR: -0.5078+0.4988/2=-0.5078 
Using the normal approximation to the Wald test statistics (see for example Shih (1997)) we 
obtain that a total sample size of 5880 patients (3410 evaluable) is needed to achieve a power 
of 90% using a two-sided significance level of 5%. This means that a sample size of 2940 
subjects per arm would be required to obtain the minimum number of evaluable subjects for 
90% power in this endpoint. 
 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Area of Autograft in DPT Wounds (wound level analysis) 
Estimate based on study MW2004-11-02 
Only subjects with at least one DPT target wound will be eligible for this analysis. The expected 
proportion of subjects with at least one DPT target wound estimated from study MW2004-11-
02 is 62.6%. 
Estimated difference in mean area Autograft in DPT wounds using GEE approach from study 
MW2004-11-02 (NexoBrid vs SoC): -11.41 
Standard Error: 4.89 
Anticipated difference: -11.41+4.89/2=-8.97 
Using the normal approximation to the Wald test statistics (see for example Shih (1997)) we 
obtain that a total sample size of 486 patients (304 evaluable) is needed to achieve a power 
of 90% using a two-sided significance level of 5%. This means that a sample size of 243 
subjects per arm would be required to obtain the minimum number of evaluable subjects for 
90% power in this endpoint. 
Estimate based on study MW2010-03-02 
Only subjects with at least one DPT target wound will be eligible for this analysis. The expected 
proportion of subjects with at least one DPT target wound estimated from study MW2010-03-
02 is 58%. 
Estimated difference in mean area Autograft in DPT wounds using GEE approach from study 
MW2010-03-02 (NexoBrid vs SoC): -9.39 
Standard Error: 6.28 
Anticipated difference: -9.39+6.28/2=-6.25 
Using the normal approximation to the Wald test statistics (see for example Shih (1997)) we 
obtain that a total sample size of 1590 patients (922 evaluable) is needed to achieve a power 
of 90% using a two-sided significance level of 5%. This means that a sample size of 795 
subjects per arm would be required to obtain the minimum number of evaluable subjects for 
90% power in this endpoint. 
 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Blood Loss 
Estimate based on study MW2004-11-02 
Estimated mean blood loss from study MW2004-11-02: NexoBrid 421.93 ml; SoC 1024.27 ml 
Standard errors: NexoBrid 129.52; SoC 240.98 
Difference: -602.33; Standard error of difference: 273.58 
Anticipated difference: -602.33 + 267.75 /2 = -468.47 
Using a two-sided two-sample t-test with a two-sided significance level of 5%, the total number 
of evaluable patients needed to achieve a power of 90% is 346 (173 per group). Incorporating 
a rate of missing values of 30%, a total of 494 patients (247 per group) needs to be enrolled 
to achieve a power of 90%. 
Estimate based on study MW2010-03-02 
Note: In the MW2010-03-02 study, a different formula for the calculation of blood loss, than will 
be applied to the CIDS study, was used. However, both formulas try to estimate the same 
quantity and are therefore considered comparable. 
Estimated mean blood loss from study MW2010-03-02: NexoBrid 14.17 ml; SoC 814.51 ml  
Standard errors: NexoBrid 66.15; SOC 167.74  
Difference: -800.34; Standard error of difference: 156.08  
Anticipated difference: -800.34 + 156.08 /2 = -722.30  
Using a two-sided two-sample t-test with a two-sided significance level of 5%, the total number 
of evaluable patients needed to achieve a power of 90% is 56 (28 per group). Incorporating a  
rate of missing values of 30%, a total of 80 patients (40 per group) needs to be enrolled to 
achieve a power of 90%. 
 
Time to Complete Wound Closure 
In the following, a non-inferiority margin of 7 days is already implemented by adding 7 days to 
the wound closure times of the SoC group. 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Estimate based on study MW2004-11-02 
Estimated log hazard ratio from study MW2004-11-02 (NexoBrid versus SoC) = 0.49, using a 
Cox proportional hazards model with shared frailty adjusted for center, age, %TBSA area of 
the wound and number of TWs (1,2,3-4, ≥5). 
Standard error = 0.63 
Target log hazard ratio = 0.49 - 0.63/2 = 0.18; target hazard ratio λ = 1.2. 
The formula for total number of events D is: 


2
2
ln
)
z
z
(
4
D





 
(Piantadosi, Clinical Trials: A Methodologic Perspective, p.169) 
z = 1.96;  
z = 1.28 for 90% power. 
If the proportion of events in NexoBrid group is denoted by p1 = 0.64 
and the proportion of events in SoC group is denoted by p2 = 0.56, 
which are the observed proportions in the study MW2004-11-02, the number of subjects to be 
enrolled to achieve a power of 90% for the non-inferiority test is n = 
2𝐷
𝑝1+𝑝2= 2164 (1082 in each 
group). 
Estimate based on study MW2010-03-02 
Estimated log hazard ratio from study MW2010-03-02 (NexoBrid versus SoC) = 1.56, using a 
Cox proportional hazards model with shared frailty adjusted for center, age, %TBSA, 
proportion of the FT area of a patient and number of TWs (1,2,3-4, ≥5). 
Standard error = 0.41 
Target log hazard ratio = 1.56 - 0.41/2 = 1.36; target hazard ratio λ = 3.90. 
The formula for total number of events D is: 


2
2
ln
)
z
z
(
4
D





 
(Piantadosi, Clinical Trials: A Methodologic Perspective, p.169) 
z = 1.96;  


CIDS - Protocol Code: MW2012-01-01 
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Statistical Analysis Plan V02 of 31 May 2021 
 
z = 1.28 for 90% power. 
If the proportion of events in NexoBrid group is denoted by p1 = 0.62 
and the proportion of events in SoC group is denoted by p2 = 0.73, 
which are the observed proportions in the study MW2010-03-02, the number of subjects to be 
enrolled to achieve a power of 90% for the non-inferiority test is n = 
2𝐷
𝑝1+𝑝2= 34 (17 in each 
group). 
 
Cosmesis and Function: MVSS at 12 months 
Estimate based on study MW2004-11-02 
Estimated difference in MVSS at 24 months from previous study (NexoBrid vs. SoC) = 3.32 – 
3.83 = –0.51. 
Standard error = 0.50 
Target difference  = –0.51 + 0.50/2 = –0.26. 
The formula for the number of patients per group n is: 


2
0
2
2
d
q
)
z
z
(
2
n







 
where  
z = 1.96;  
z = 1.28 for a power of 0.9; 
 = the estimated common standard deviation= 2.33 (taken from previous study); 
d0 = clinical equivalence level = 1.9; 
q = proportion who are retained in follow-up to 12 months = 0.7 (assuming 30% loss to follow-
up over 1 year) 
For 90% overall power, the required sample size per group is 35 (70 overall). 
Estimate based on study MW2010-03-02 
Estimated mean MVSS at 12 months from study MW2010-03-02: NexoBrid 3.70; SoC 5.08 


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Statistical Analysis Plan V02 of 31 May 2021 
 
Standard errors: NexoBrid 0.24; SoC 0.38  
Difference: -1.38; Standard error of difference: 0.44 
Anticipated difference: -1.38 + 0.44 /2 = -1.16  
The non-inferiority margin employed for this analysis is 1.9 score points. 
Using a one-sided two-sample t-test with a significance level of 2.5%, 36 evaluable subjects 
are needed (18 in each group) to achieve a power of 90%. Using a conservative rate of missing  
values of 30%, the total sample sizes needed to achieve a power of 90% in the analysis is 52 
(26 per group). 
Note: In the analysis missing data will be imputed, leading to more evaluable subjects, 
increasing the power. 
 
Cosmesis and Function: MVSS at 24 months 
Estimate based on study MW2004-11-02 
Estimated difference in MVSS at 24 months from previous study (NexoBrid vs. SoC) = 3.32 – 
3.83 = –0.51. 
Standard error = 0.50 
Target difference  = –0.51 + 0.50/2 = –0.26. 
The formula for the number of patients per group n is: 


2
0
2
2
d
q
)
z
z
(
2
n







 
where  
z = 1.96;  
z = 1.28 for a power of 0.9; 
 = the estimated common standard deviation= 2.33 (taken from previous study); 
d0 = clinical equivalence level = 1.9; 
q = proportion who are retained in follow-up to 24 months = 0.5 (assuming 50% loss to follow-
up over 2 years) 


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For 90% overall power, the required sample size per group is 49 (98 overall). 
Estimate based on study MW2010-03-02 
Since at this time the 24 months MVSS data of the MW2010-03-02 study is not yet available, 
the 12 months data will be used for the calculation. 
Estimated mean MVSS at 12 months from study MW2010-03-02: NexoBrid 3.70; SoC 5.08 
Standard errors: NexoBrid 0.24; SoC 0.38  
Difference: -1.38; Standard error of difference: 0.44 
Anticipated difference: -1.38 + 0.44 /2 = -1.16  
The non-inferiority margin employed for this analysis is 1.9 score points. 
Using a one-sided two-sample t-test with a significance level of 2.5%, 36 evaluable subjects 
are needed (18 in each group) to achieve a power of 90%. Using a conservative rate of missing  
values of 50%, the total sample sizes needed to achieve a power of 90% in the analysis is 72 
(36 per group). 
 
 


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13.4. Update Memo to Sites Due to COVID-19 Pandemic 
DATE: 
09 April 2020 
TO: 
Investigators and Study Coordinators 
FROM: 
CIDS (MW2012-01-01) Study Team 
RE: 
COVID-19 Update 
Protocol:  
A multicenter, multinational, randomized, controlled, open label study, performed in 
children with thermal burns, to evaluate the efficacy and safety of NexoBrid as 
compared to standard of care (SOC) treatment 
Purpose:  
Guidance for Protocol Modifications and Documentation During COVID-19 Pandemic 
_________________________________________________________________________ 
Dear CIDS Investigators and Site Study Teams, 
The global situation with regard to COVID-19 is rapidly evolving and we appreciate that you are 
adapting your activities to ensure the safety of your team and study patients. We empathize the 
challenges faced by you as well as  your patients. 
The purpose of this document is to provide guidance for you to consider with regards to study conduct 
knowing the current situation impacts your patients and study staff, also in line with the FDA and EMA 
special guidance documents on the conduct of clinical trials of medicinal products during COVID-19 
pandemic issued in March 2020. We stress that these points are for study guidance only, and that the 
institutional and local government directives on operational measures that may already be in place 
should be prioritized.  
You must immediately submit a copy of this protocol memo to your respective local Institutional 
Review Board/Ethics Committee. In parallel, MediWound will ensure regulatory agencies are notified 
of protocol modifications.  
The following guidance and modifications should be taken into consideration: 
- 
Enrollment of new patients: 
As of today, the recruitment remains open for patients in the age of 2-4 years old. We encourage 
sites to only screen patients that can comply with the required study procedures through the 
end of the study with a few modifications described below. 
Potential patients should be screened per your hospital protocol for potential signs and/or 
symptoms of COVID-19 to avoid risk for both health care providers and the patient. If a COVID-
19 diagnosis is suspected, the patient should be excluded due to exclusion criteria #16; “Any 
known conditions that would preclude safe participation in the study or add further risk to the 
basic acute burn trauma”. 
- 
Follow-up of Enrolled Study Subjects:  
We will rely heavily on the investigator’s best judgement and their institutional policies to 
implement and conduct study procedures as conditions vary across countries.  We consider 
completion of the study visits important to the safety of the patients and they should be 


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encouraged to continue study participation, as long as the patient’s safety, welfare and rights 
are best served by continuing, as determined by the investigator.  
The following are some points by study visit for the investigator to consider: 
 
If an onsite visit is not feasible and cannot be rescheduled, to assure the safety of trial 
participants and continued investigator oversight, one or more of the following alternative 
follow-up methods can be implemented to conduct Long-Term Follow-up Visits.  These 
methods include:  
o Patient interview via telephone- at a minimum to collect adverse events and 
concomitant medication information; however, if possible, this should be 
combined with a wound assessment via photo/video.   
Additional options: 
o Telemedicine 
o HIPAA compliant Telecommunication (US only) 
o Wound assessment via photograph and/or videos that are taken by the patient and 
provided to the site.  Note: In these cases, a specific photograph label does not 
need to be utilized. The patient should be reminded not to send any photographs 
of faces or tattoos to protect patient health information (PHI).  If photographs are 
transmitted by the patient and they contain PHI, they should not be made 
available to the sponsor.   
If a follow-up visit is conducted remotely via one of the methods listed above, the reason should 
be thoroughly documented in the source documents.  Additionally, any assessments that were 
completed remotely should also be clearly documented within the study source documents. 
 
For patients that have been discharged from the hospital and have not yet reached wound 
closure confirmation-  
All wound assessments included in the weekly follow-up visits and the wound closure 
confirmation can be performed via photograph and/or videos that are taken by the 
patient/parent and provided to the site, as described above.   
 
For patients that are in the long term follow-up stage, post wound closure confirmation: 
o If a Long Term Follow-Up visit will be completed remotely, cosmesis assessments 
such as POSAS and MVSS should be completed to the best of the blinded assessor’s 
ability through patient and parent interview and photo/video assessment.  A live 
video is preferred as the assessor can request the patient or family member to 
pinch/press the scars to assess pliability and vascularity while moving the camera 
around the area of the scar.  Additionally, through live video, the height of the 
scars can be measured by a patient or family member with a ruler while moving 
the camera to a tangential angle in order to be able to see exactly where to 
measure and the height on the ruler.  Note:  Only a designated blinded assessor 
should complete POSAS and MVSS wound assessments.   
o Additionally, if a Long Term Follow-Up visit will be completed remotely, the 
patient/parent should be mailed or emailed a copy of the applicable self-
completed questionnaires (EQ5D-Y, BOQ (for USA sites), POSAS (patient scale), 
Lower Extremity Function Scale, and QuickDASH) and patient diary.  These should 
be completed by the patient/parent, initialed and dated, and returned back to the 


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site by mail or email. If it is not possible for the patient/parent to complete the 
questionnaires and return them, the questionnaires can be read to the 
patient/parent and responses can be documented by site personnel. If the 
questionnaires were not self ccompleted, it should be clearly documented in the 
patient source documents. 
o If a patient is unable to return back to the site or complete a visit via 
telecommunication then the missed visit shall be documented in the source 
documents and the reason clearly noted to be due to COVID-19. 
o Immunogenicity sample collection cannot be performed remotely. Therefore, once 
the situation normalizes, any patient previously identified for immunogenicity 
screen should arrive to the site on the earliest possible day for collection of the 
immunogenicity blood sample.  
o A table of the approved alternative methods for remote assessments is attached to 
this memo (Table 1).    
After COVID-19 hospital restrictions have been lifted, sites should continue to complete all remaining 
study visits and assessments per the approved study protocol. 
- 
Notification of Study Subjects: 
Trial participants should be kept informed of changes to the study that could impact them. 
A patient memo clarifying the possible changes during the COVID-19 pandemic is provided to 
your site together with this memo and should be submitted to your IRB/EC and provided to all 
patients’ parents. This memo will inform the parents that they may be asked to complete follow-
up visits remotely via telemedicine/telecommunicatio or phone interview and they may be asked 
to provide photos of their child’s wounds and complete questionnaires at home.   
This memo should also be provided to parents of new patients that are enrolled during the 
COVID-19 pandemic, as an addendum to the approved Informed Consent Form, so that they are 
aware of the changes that may occur in follow up procedures until the situation normalizes and 
on-site follow up visits are possible. 
- 
Study Monitoring Procedures: 
Many sites/institutions are no longer allowing onsite routine monitoring visits. If this is the case 
at your site, or there is a change to your current situation, please inform your CRA. The onsite 
monitoring visit can be re-scheduled and replaced by an offsite monitoring visit as needed.  
 
Thank you for your continuous support with the study.  We understand the inconvenience associated 
with this situation and realize that we cannot anticipate all site-specific issues. As always, please do 
not hesitate to reach out to any one of us if you have any questions. Please contact your CRA, or 
MediWound PM, Aya Ben Yaakov (email: ayaby@mediwound.com), with any questions you may have.  
We will respond promptly by email or telephone as you would prefer. 
We will alao provide further communications as new information arises.  
Please file this communication in your Investigator Site File or appropriate site regulatory binders.  
Sincerely, 
The CIDS MW2012-01-01 Study Team    


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Table 1 - Optional Methods for Completion of Remote Long Term Follow-up Visits, During COVID-19 Pandemic 
Assessment 
 
Method of Contact 
Comments 
Photo sent by Patient 
Phone conversation 
Video 
call/Telemedcine 
Wound photographs 
X 
N/A 
N/A 
Photos/Videos that will be sent by the patients will not include photo 
label.  
Documentatio
n 
Adverse events 
X 
Photo Assessment- Local TW 
related only 
X 
X 
Any SAEs should be reported within 24 hours of knowledge of the 
event.   
Concomitant 
Medication 
review 
N/A 
X 
X 
  
Scar modulation procedures 
N/A 
X 
X 
  
POSAS Observer Scale 
X 
X 
Video method preferred, if available  
MVSS 
X 
X 
Video method, if available  
ROM 
N/A 
N/A 
N/A 
Can be completed during an on-site visit only. 
Patient 
questionnaires 
POSAS Patient Scale 
X 
Photocopy sent back to site 
X 
Subject interview 
X 
Subject interview 
It is preferred to have questionnaires sent to subject via mail/email, 
completed, and returned to site, if possible. 
QOL (EQ5D,BOQ) 
X 
Photocopy sent back to site 
X 
Subject interview 
X 
Subject interview 
It is preferred to have questionnaires sent to subject via mail/email, 
completed, and returned to site, if possible. 
LEFS/ QuickDASH 
X 
Photocopy sent back to site 
X 
Subject interview 
X 
Subject interview 
It is preferred to have questionnaires sent to subject via mail/email, 
completed, and returned to site, if possible. 
Subject Diary 
X 
Photocopy sent back to site 
X 
Subject interview 
X 
Subject interview 
It is preferred to have questionnaires sent to subject via mail/email, 
completed, and returned to site, if possible. 
Immunogenicity 
N/A 
N/A 
N/A 
Can be taken during an on-site visit only. May be performed in delay 


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