Double-blind, Randomised, Vehicle-controlled, Phase III, Efficacy and Safety Study With 24-month Open-label Follow-up of Oleogel-S10 in Patients With Inherited Epidermolysis Bullosa
Phase: PHASE3
Conditions: Epidermolysis Bullosa
Sponsor: Amryt Research Limited

 
 
C O N F I D E N T I A L  
Confidentiality Statement 
The information contained in this document is the property of Amryt Research Ltd. and is therefore 
provided to you in confidence as an investigator, potential investigator, and member of regulatory 
authorities or consultant, for review by you, your staff and an applicable Independent Ethics 
Committee/Institutional Review Board. It is understood that this information will not be disclosed to 
others without written authorisation from Amryt Research Ltd., except to the extent necessary to obtain 
written informed consent from those persons to whom the drug may be administered. 
 
Study Protocol 
 
Double-blind, Randomised, Vehicle-controlled, Phase III, Efficacy 
and Safety Study with 24-month Open-label Follow-up of 
Oleogel-S10 in Patients with Inherited Epidermolysis Bullosa  
EASE Study 
 
Investigational product 
Oleogel-S10 
Indication 
Inherited epidermolysis bullosa (EB) 
Identifier 
EudraCT No. 2016-002066-32 
Study number 
BEB-13 
Development phase 
III 
Document 
Study Protocol BEB-13 
Version number 
6.0 
Status 
Final 
Release date 
18 April 2019 
 
 
 
Revision chronology 
Version 1.0 
29 September 2016 
 
Version 2.0 
30 November 2016 
 
Version 3.0 
16 February 2017 
 
Version 4.0 
20 April 2018 
 
Version 5.0 
01 October 2018 
 
 
 
Author(s) 
 
Compliance 
The study will be conducted in accordance with standards of Good 
Clinical Practice, as defined by the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) and all applicable federal and local regulations. 
Sponsor 
Amryt Research Limited 
90 Harcourt Street 
Dublin 2 
Ireland 
 
 
 

Amryt Research Ltd. 
 
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C O N F I D E N T I A L  
INVESTIGATOR’S AGREEMENT 
I have read and understood the protocol and agree with its content. 
I will conduct the study in compliance with the protocol, Good Clinical Practice, national law, 
and all applicable regulatory requirements. In addition, I will conduct the study in accordance 
with the ethical principles of the Declaration of Helsinki. 
I am familiar with the nonclinical and clinical data of the investigational drug and with its 
known and potential benefits and risks. 
I agree to assume responsibility for the proper conduct of the study at this site and I will 
ensure that all persons assisting in the study under my supervision are adequately informed 
about the protocol/amendments, the investigational product and their study-related duties 
and functions as described in the protocol. 
I will not implement any deviation from, or changes to the protocol without agreement from 
Amryt Research Ltd. and prior submission to and written approval from the responsible 
regulatory authorities and Independent Ethics Committee/Institutional Review Board of an 
amendment, except when necessary to eliminate an immediate hazard to the patients. 
I understand that either Amryt Research Ltd. or myself may terminate the study or may 
suspend enrolment at any time, if it becomes necessary to protect the patients’ best interest.  
 
 
Name 
 
 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
Place, Date 
 
Signature 
 
 
 
 
 
 
 

Amryt Research Ltd. 
 
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C O N F I D E N T I A L  
TABLE OF CONTENTS 
 
LIST OF TERMS AND ABBREVIATIONS ........................................................................... 10 
1 
SUMMARY OF CLINICAL STUDY ................................................................................ 12 
1.1 
Study Synopsis .................................................................................................. 12 
1.2 
Flow Chart of Study (Randomised, Double-blind and Open-label Follow-up) ..... 20 
2 
INTRODUCTION ............................................................................................................ 23 
2.1 
Background ........................................................................................................ 23 
2.1.1 
Epidermolysis Bullosa ......................................................................... 23 
2.1.2 
Epidermolysis Bullosa Partial Thickness Wounds ............................... 24 
2.1.3 
Treatment Options and Medical Need ................................................. 25 
2.2 
Investigational Product ....................................................................................... 26 
2.3 
Summary of Non-clinical Studies with Oleogel-S10 ............................................ 27 
2.3.1 
Non-clinical Evidence for Acceleration of Reepithelialisation in 
Inherited Epidermolysis Bullosa .......................................................... 27 
2.4 
Summary of Clinical Studies with Oleogel-S10 ................................................... 30 
2.4.1 
Split-Thickness Skin Graft Donor Sites ................................................ 30 
2.4.2 
Grade 2a Burn Wounds ....................................................................... 30 
2.4.3 
Epidermolysis Bullosa ......................................................................... 30 
2.5 
Rationale for Dose Selection .............................................................................. 31 
2.6 
Known and Potential Benefits and Risks ............................................................ 32 
2.7 
Study Rationale .................................................................................................. 32 
2.7.1 
Rationale of the Study ......................................................................... 33 
2.7.2 
Rationale of Study Design ................................................................... 33 
2.7.3 
Rationale of Primary Efficacy Endpoint – Double-blind Phase ............. 34 
2.7.4 
Rationale of Secondary Efficacy Endpoints – Double-blind Phase ...... 34 
2.7.5 
Rationale of Endpoints – Open-label Follow-up Phase ........................ 35 
3 
STUDY OBJECTIVES .................................................................................................... 35 
3.1 
Primary Objective – Double-blind Phase ............................................................ 35 
3.2 
Secondary Objectives – Double-blind Phase ...................................................... 35 
3.3 
Objectives – Open-label Follow-up Phase .......................................................... 36 
4 
INVESTIGATIONAL PLAN ............................................................................................ 36 
4.1 
Study Endpoints ................................................................................................. 36 
4.1.1 
Primary Efficacy Endpoint – Double-blind Phase ................................. 36 
4.1.2 
Secondary Endpoints – Double-blind Phase ....................................... 37 
4.1.3 
Endpoints of Open-label Follow-up Phase ........................................... 38 
4.2 
Overall Study Design .......................................................................................... 39 
4.2.1 
Double-blind Phase ............................................................................. 39 
4.2.2 
Open-label Follow-up Phase ............................................................... 40 
4.2.3 
End of Trial .......................................................................................... 40 
5 
STUDY POPULATION ................................................................................................... 42 
5.1 
Inclusion Criteria ................................................................................................ 42 
5.2 
Exclusion Criteria ............................................................................................... 42 
6 
STUDY MEDICATION .................................................................................................... 43 
6.1 
Description of the Investigational Product ........................................................... 43 
6.1.1 
Formulation, Packaging, and Labelling ................................................ 43 

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C O N F I D E N T I A L  
6.1.2 
Storage and Stability ........................................................................... 43 
6.1.3 
Drug Accountability ............................................................................. 43 
6.2 
Description of the Vehicle ................................................................................... 43 
6.3 
Standard of Care Non-adhesive Wound Dressings ............................................ 43 
7 
STUDY TREATMENT .................................................................................................... 44 
7.1 
Treatment Schedule ........................................................................................... 44 
7.1.1 
Treatment Assignment/Blinding Procedure ......................................... 45 
7.2 
Dose Interruption/Dose Modification for Adverse Events .................................... 45 
7.2.1 
Emergency Procedure for Unblinding .................................................. 45 
7.3 
Patient Discontinuation Criteria .......................................................................... 46 
7.4 
Overdose ........................................................................................................... 46 
7.5 
Concomitant Medication ..................................................................................... 47 
7.5.1 
Permitted Concomitant Medication ...................................................... 47 
7.5.2 
Non-permitted Concomitant Medication .............................................. 47 
8 
ASSESSMENTS ............................................................................................................ 48 
8.1 
Eligibility and Safety Assessments ..................................................................... 48 
8.1.1 
Eligibility Assessments ........................................................................ 48 
8.1.2 
Safety Assessments ............................................................................ 49 
8.2 
Assessment of Efficacy ...................................................................................... 50 
8.2.1 
Photography of EB Target Wound and Other Wounds ........................ 50 
8.2.2 
Total Body Wound Burden .................................................................. 51 
8.2.3 
Body Surface Area Percentage ........................................................... 51 
8.3 
Patient-reported Outcomes ................................................................................ 51 
8.3.1 
‘Itch Man Scale’ ................................................................................... 52 
8.3.2 
‘Leuven Itch Scale’ .............................................................................. 52 
8.3.3 
‘Face, Legs, Activity, Cry, Consolability’ Pain Rating Scale ................. 52 
8.3.4 
‘Wong-Baker FACES Pain Rating Scale’ ............................................. 52 
8.3.5 
Impact of Wounds on Sleep ................................................................ 52 
8.3.6 
Days Missed from School or Work ...................................................... 52 
8.3.7 
Treatment Satisfaction Questionnaire for Medication, Version 9 ......... 53 
8.3.8 
Instrument for Scoring Clinical Outcome of Research for 
Epidermolysis Bullosa (iscorEB) .......................................................... 53 
8.3.9 
EQ-5D ................................................................................................. 53 
9 
VISIT SCHEDULE .......................................................................................................... 78 
9.1 
Screening, Enrolment, and Stratified Randomisation (≤D0) ................................ 78 
9.1.1 
Screening Assessments ...................................................................... 78 
9.1.2 
Enrolment and Stratified Randomisation ............................................. 78 
9.1.3 
Rescreening ........................................................................................ 79 
9.2 
Double-blind Phase (Visits 1 to 7a) .................................................................... 87 
9.2.1 
Visit 1 (Site Visit at D0) ........................................................................ 87 
9.2.2 
Visit 2 (Site Visit, Home Visit, or Phone Call by Study Team Member 
at D7±2) .............................................................................................. 88 
9.2.3 
Visit 3 and Visit 5 (Site Visit or Home Visit by Investigator at D14±5 
and D45±7) ......................................................................................... 89 
9.2.4 
Visit 4 and Visit 6 (Site Visit at D30±7 and D60±7) .............................. 89 

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C O N F I D E N T I A L  
9.2.5 
‘Confirmation of Complete Closure’ Visit (Flexible Site Visit or Home 
Visit by Study Team Member 7 days [+2 Days] After First Complete 
Closure of the EB Target Wound in the Double-blind Phase) .............. 90 
9.3 
Unscheduled Visits ............................................................................................. 90 
9.4 
Visit 7a (Site Visit at D90±7): End of Double-blind Phase/ Premature 
Discontinuation of Double-Blind Phase .............................................................. 91 
9.5 
Open-label Follow-up Phase .............................................................................. 92 
9.5.1 
Visit 7b (in Conjunction with Visit 7a at D90±7) ................................... 92 
9.5.2 
Visit 8 (Site Visit M3±14 Days) ............................................................ 92 
9.5.3 
Visit 9 (Site Visit at M12±14 Days) ...................................................... 93 
9.5.4 
Interim Calls (M6, M9, M15, M18, and M21 [±28 Days]) ...................... 93 
9.5.5 
End of Follow-up Visit 10 (M24±14 Days)/ Premature Discontinuation 
of Follow-Up Phase ............................................................................. 94 
10 COLLECTION, STORAGE, AND SHIPMENT OF LABORATORY SAMPLES .............. 94 
11 DRUG SAFETY .............................................................................................................. 95 
11.1 
Definitions .......................................................................................................... 95 
11.1.1 
Adverse Event ..................................................................................... 95 
11.1.2 
Adverse Drug Reaction ....................................................................... 95 
11.1.3 
Unexpected Adverse Drug Reaction ................................................... 95 
11.1.4 
Serious Adverse Event or Adverse Drug Reaction .............................. 95 
11.1.5 
Suspected Unexpected Serious Adverse Reaction ............................. 96 
11.1.6 
Anticipated Adverse and Serious Adverse Events ............................... 96 
11.2 
Recording of Adverse Events and Serious Adverse Events................................ 97 
11.2.1 
Assessment of Seriousness ................................................................ 97 
11.2.2 
Assessment of Severity ....................................................................... 97 
11.2.3 
Assessment of Causality ..................................................................... 97 
11.3 
Documenting of Adverse Events and Serious Adverse Events ........................... 98 
11.4 
Immediately Reportable Information ................................................................... 98 
11.4.1 
Reporting of Serious Adverse Events .................................................. 98 
11.4.2 
Other Reportable Information .............................................................. 99 
11.5 
Independent Data Monitoring Committee ........................................................... 99 
12 STATISTICAL ANALYSIS ........................................................................................... 100 
12.1 
Statistical Methods ........................................................................................... 100 
12.1.1 
Statistical Hypothesis ........................................................................ 100 
12.1.2 
Level of Significance, Multiple Comparisons, and Multiplicity ............ 100 
12.1.3 
Determination of Sample Size ........................................................... 101 
12.2 
Definition of Study Populations ......................................................................... 101 
12.3 
Planned Analyses ............................................................................................ 101 
12.3.1 
Demographic Data and Other Baseline Characteristics ..................... 101 
12.3.2 
Unblinded Interim Analysis ................................................................ 102 
12.3.3 
Planned Analysis for Primary Endpoint ............................................. 102 
12.3.4 
Planned Analyses for Key Secondary Endpoints ............................... 103 
12.3.5 
Planned Analyses for Additional Secondary Endpoints ..................... 104 
12.3.6 
Planned Analyses for Open-label Follow-up Phase Endpoints .......... 106 
12.4 
Statistical Criteria for Study Termination ........................................................... 107 
12.5 
Handling of Missing Data ................................................................................. 107 
12.6 
Time Windows .................................................................................................. 108 

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C O N F I D E N T I A L  
13 QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 108 
13.1 
Prestudy Documentation .................................................................................. 108 
13.2 
Monitoring ........................................................................................................ 108 
13.3 
Data Management and Processing .................................................................. 109 
13.3.1 
Data Collection .................................................................................. 109 
13.3.2 
Data Management Procedures .......................................................... 109 
13.3.3 
Data Verification Procedures ............................................................. 109 
13.3.4 
Coding .............................................................................................. 109 
13.3.5 
Procedures for Analysis of Consistency and Medical Plausibility ....... 109 
13.3.6 
Data to be Recorded Directly into the Electronic Case Report Form . 109 
13.4 
Study and Site Closure ..................................................................................... 109 
13.5 
Audits and Inspections ..................................................................................... 110 
14 LEGAL AND ETHICAL REQUIREMENTS ................................................................... 110 
14.1 
Regulatory Authority Approval .......................................................................... 110 
14.2 
Independent Ethics Committee/Institutional Review Board ............................... 110 
14.3 
Patient Information and Informed Consent ....................................................... 111 
14.4 
Data Protection ................................................................................................ 111 
14.5 
Notification of Primary Care Physician.............................................................. 111 
14.6 
Investigator Reporting Requirements ............................................................... 111 
14.7 
Record Retention ............................................................................................. 111 
15 PROTOCOL AMENDMENTS ....................................................................................... 112 
16 DISCLOSURE OF INFORMATION .............................................................................. 112 
16.1 
Publication of Study Findings ........................................................................... 112 
17 COMPENSATION FOR INJURIES .............................................................................. 113 
18 REFERENCES ............................................................................................................. 114 
18.1 
Source Documents ........................................................................................... 114 
18.2 
Literature .......................................................................................................... 114 
19 APPENDICES .............................................................................................................. 118 
19.1 
Appendix 1: Declaration of Helsinki .................................................................. 118 
19.2 
Appendix 2: Anticipated Adverse Events by System Organ Class and Lowest 
Level Term ....................................................................................................... 122 
1.1.1.1 
Appendix 1 Declaration of Helsinki ................................................................... 118 
1.1.1.2 
Appendix 2 Anticipated Adverse Events by System Organ Class and Lowest 
Level Term ....................................................................................................... 122 
 
 
 

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C O N F I D E N T I A L  
LIST OF TABLES 
Table 1 
Doses of Oleogel-S10 in Previous Partial Thickness Wound Studies ................. 31 
 
LIST OF FIGURES 
Figure 1 
Wounds in Epidermolysis Bullosa by Subtype .................................................... 23 
Figure 2 
Human Skin and Depths of Cutaneous Wounds ................................................. 24 
Figure 3 
Molecular Structure of Betulin, the Active Pharmaceutical Ingredient of 
Oleogel-S10 ....................................................................................................... 26 
Figure 4 
Acceleration of Reepithelialisation due to Oleogel-S10 Versus Impaired 
Wound Healing in Inherited Epidermolysis Bullosa ............................................. 29 
Figure 5 
Composition of Oleogel-S10 ............................................................................... 31 
Figure 6 
Design of Double-blind, Randomised Treatment Phase and Open-label 
Follow-up Phase ................................................................................................ 41 
Figure 7 
Target Wound Photography with the ARANZ Silhouette® System ...................... 50 
Figure 8 
Assessment of Total Body Wound Burden based on the ‘EB Disease Activity 
and Scarring Index’ (EBDASI) ............................................................................ 54 
Figure 9 
Assessment of Body Surface Area Percentage of Total Body Surface Area 
Affected by EB Partial Thickness Wounds .......................................................... 55 
Figure 10 ‘Itch Man Scale’ .................................................................................................. 56 
Figure 11 The ‘Leuven Itch Scale’ ...................................................................................... 57 
Figure 12 ‘Face, Legs, Activity, Cry, Consolability’ (FLACC) Pain Rating Scale ................. 60 
Figure 13 ‘Wong-Baker FACES®’ Pain Rating Scale .......................................................... 61 
Figure 14 Impact of Wounds on Sleep Based on Wound Quality of Life Questionnaire ...... 62 
Figure 15 Days Missed from Work or School ..................................................................... 63 
Figure 16 Treatment Satisfaction Questionnaire for Medication, Version 9 ........................ 64 
Figure 17 iscorEB, September 2015 .................................................................................. 67 
Figure 18 EQ-5D-5L, Version 1.2 ....................................................................................... 72 
Figure 19 EQ-5D-Y, Version 2.0 ......................................................................................... 75 
Figure 20 Study Schema – Double-blind Phase ................................................................. 80 
Figure 21 Study Schema – Open-label Follow-up Phase ................................................... 82 
Figure 22 Chronology of Efficacy Assessments by Visit ..................................................... 84 
Figure 23 Example of Investigator’s Worksheet ................................................................. 86 
 
 
 

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C O N F I D E N T I A L  
LIST OF TERMS AND ABBREVIATIONS 
Term or Abbreviation 
Description 
AE 
Adverse event 
ADR 
Adverse drug reaction 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BG 
Blood glucose 
BSAP 
Body surface area percentage 
Ca 
Calcium 
CCC 
Confirmation of complete closure (of EB target wound) 
CHW 
Cui, Hung, Wang 
CI 
Confidence interval(s) 
Cl 
Chloride 
CMH 
Cochran-Mantel-Haenszel 
COL7A1 
Collagen VII 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day(s) 
DBP 
Double-blind phase 
DDEB 
Dominant dystrophic epidermolysis bullosa 
DEB 
Dystrophic epidermolysis bullosa 
DEJZ 
Dermal-epidermal junction zone 
DS 
Donor site 
EB 
Epidermolysis bullosa 
EBDASI 
Epidermolysis Bullosa Disease Activity and Scarring Index 
EBS 
Epidermolysis bullosa simplex 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDBP  
End of Double-blind Phase 
EoFU 
End of Follow-up 
EQ-5D 
EuroQol 5 Dimensions 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FLACC 
Face, Legs, Activity, Cry, Consolability 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
I 
Investigator 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 

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C O N F I D E N T I A L  
Term or Abbreviation 
Description 
iscorEB 
Instrument for Scoring Clinical Outcome of Research for 
Epidermolysis Bullosa 
JEB 
Junctional epidermolysis bullosa 
K 
Potassium 
M 
Month(s) 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MNAR 
Missing not at Random 
Na 
Sodium 
P 
Phosphate 
PP 
Per-protocol (analysis set) 
PRO 
Patient-reported outcome 
Pt 
Patient 
Q 
Quarter 
RDEB 
Recessive dystrophic epidermolysis bullosa 
SAE 
Serious adverse event 
SADR 
Serious adverse drug reaction 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SOC 
Standard of care 
STSG 
Split-thickness skin graft 
SUSAR 
Suspected unexpected serious adverse reaction 
TBSA 
Total body surface area 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
V 
Visit 
W-QoL 
Wound Quality of Life Questionnaire 
 
 

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C O N F I D E N T I A L  
1 
SUMMARY OF CLINICAL STUDY 
1.1 
Study Synopsis 
Title of study 
Double-blind, Randomised, Vehicle-controlled, Phase III, Efficacy and Safety Study with 24-month 
Open-label Follow-up of Oleogel-S10 in Patients with Inherited Epidermolysis Bullosa 
Sponsor 
Amryt Research Ltd, 90 Harcourt Street, Dublin 2, Ireland 
Coordinating investigator 
 The Royal Melbourne Hospital, Department of Dermatology, 300 Grattan St, 
Parkville VIC 3050, Australia 
Study centres 
Global multicentre study with approximately 50 study sites 
Countries 
Argentina, Australia, Austria, Belgium, Brazil, Chile, Colombia, Croatia, Czech Republic, Denmark, 
France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Romania, Russia, Serbia, 
Singapore, Spain, Switzerland, United Kingdom, United States of America and more are planned 
Phase of development 
Phase III 
Number of patients 
Planned enrolment (original study design): N=192 
Planned enrolment (following unblinded interim analysis): N = 250 
Patients will be randomised to treatment in a 1:1 ratio to receive Oleogel-S10 or vehicle 
Study objectives 
Primary objective 
• The primary objective of the double-blind phase (DBP) is to compare the efficacy of Oleogel-S10 
(treatment arm A) with vehicle (treatment arm B) in the promotion of healing of epidermolysis 
bullosa (EB) partial thickness wounds. This will be assessed as evidenced by the incidence of the 
first complete closure of the EB target wound (defined as EB partial thickness wound of 10 cm2 to 
50 cm2 in size aged ≥ 21 days and < 9 months) in patients with inherited EB (subtypes junctional 
EB [JEB], dystrophic EB [DEB], or Kindler syndrome) within 45±7 days of treatment. 
Secondary objectives – double-blind phase 
The secondary objectives of the DBP are to:  
• Compare the efficacy of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) as 
evidenced by: 
− The time to first complete closure of the EB target wound in either arm within 90±7 days of 
treatment 
− The incidence of first complete closure of the EB target wound over time 
− The relative change from baseline in EB target wound size over time 
− The relative change from baseline in total body wound burden over time 
− The relative change from baseline in percentages of total body surface area (TBSA) 
affected by EB partial thickness wounds over time 
− The incidence and severity of wound infection over time 
− The change from baseline in “background” pain before wound dressing changes and the 
change from baseline in “procedural” pain after wound dressing changes over time 
− The change from baseline in itch before wound dressing changes over time 
− The change from baseline in impact of wounds on sleep over time (in patients ≥ 14 years 
of age) 
− The number of days missed from school or from work 
− The response to treatment as assessed by patients ≥ 14 years of age, using the Treatment 
Satisfaction Questionnaire for Medication (TSQM). 

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C O N F I D E N T I A L  
• Compare the safety of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) as evidenced 
by the incidence, severity, and relatedness of adverse events (AEs), and based on laboratory 
assessments 
• Compare the tolerability of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) 
• Assess betulin exposure 
Objectives – open-label follow-up phase 
The objectives of the 24-month open-label follow-up (FU) phase are to:  
• Evaluate the safety of Oleogel-S10 as evidenced by the incidence, severity, and relatedness of 
AEs, and based on laboratory assessments 
• Evaluate local tolerability of Oleogel-S10 
• Assess betulin exposure 
• Assess the proportion of patients with complete closure of the EB target wound at Month 3 (M3) 
±14 days 
• Assess the changes from baseline of both DBP (Day 0 [D0]) and the FU (D0)/end of DBP (EDBP 
[D90±7]) in total body wound burden at M3±14 days, M12±14 days, and M24±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in percentages 
of TBSA affected by EB partial thickness wounds at M3±14 days, M12±14 days, and M24±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in “background” 
pain before wound dressing changes and the change from baseline in “procedural” pain after 
wound dressing changes at M3±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in itch before 
wound dressing changes at M3±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in impact of 
wounds on sleep (in patients ≥ 14 years of age) at M3±14 days 
• Assess the number of days missed from school or from work at M3±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in treatment 
response (in patients ≥ 14 years of age) at M3±14 days 
• Assess the changes from EDBP (D90±7) in disease severity from both the clinician and 
patient/family perspective at M12±14 days, and M24±14 days  
• Assess the changes from EDBP (D90±7) in patients’ quality of life at M12±14 days, and 
M24±14 days 
Endpoints for double-blind phase 
Primary efficacy endpoint 
• 
Proportion of patients with first complete closure of the EB target wound (defined as EB partial 
thickness wound of 10 cm2 to 50 cm2 in size aged ≥ 21 days and < 9 months) in patients with 
inherited EB (subtypes JEB, DEB, or Kindler syndrome) within 45±7 days of treatment with 
Oleogel-S10 compared to vehicle based on clinical assessment by the investigator (the wound 
will be rated as “closed” at first appearance of complete reepithelialisation without drainage) 
Key secondary (confirmatory) efficacy endpoints 
• 
Time to first complete closure of the EB target wound as evidenced by clinical assessment until 
EDBP (D90±7) 
• 
Proportion of patients with first complete closure of the EB target wound at D90±7 based on 
clinical assessment by the investigator 
• 
The incidence of wound infection between baseline (DBP D0) and D90±7 as evidenced by AEs 
and/or use of topical and/or systemic antibiotics (related to wound infection) 
• 
The maximum severity of wound infection between baseline (DBP D0) and D90±7 as evidenced 
by AEs and/or use of topical and/or systemic antibiotics (related to wound infection) 
• 
Change from baseline (DBP D0) in total body wound burden as evidenced by clinical assessment 
using Section I (assessment of the skin except for the anogenital region) of the ‘EB Disease 
Activity and Scarring Index’ (EBDASI) at D90±7 
• 
Change from baseline (DBP D0) in itching using the ‘Itch Man Scale’ in patients ≥ 4 years and up 
to 13 years of age and the ‘Leuven Itch Scale’ in patients ≥ 14 years of age before wound 
dressing changes at D90±7 

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C O N F I D E N T I A L  
Other secondary efficacy endpoints 
• Proportion of patients with first complete closure of the EB target wound at D14±5, D30±7 and 
D60±7 based on clinical assessment by the investigator 
• Proportion of patients with first complete closure of the EB target wound at D7±2, D14±5, D30±7, 
D45±7, D60±7, and D90±7 based on patient assessment  
• Proportion of patients with first complete closure of the EB target wound at D7±2, D14±5, D30±7, 
D45±7, D60±7, and D90±7 based on blinded evaluation of photographs 
• Percentage change from baseline (DBP D0) in EB target wound size as evidenced by blinded 
evaluation of photographs taken at D7±2, D14±5, D30±7, D45±7, D60±7, and D90±7 
• Change from baseline (DBP D0) in total body wound burden as evidenced by clinical assessment 
using Section I (assessment of the skin except for the anogenital region) of the ‘EB Disease 
Activity and Scarring Index’ (EBDASI) at D30±7 and D60±7  
• Change from baseline (DBP D0) in body surface area percentage (BSAP) of TBSA affected by EB 
partial thickness wounds as evidenced by clinical assessment based on the ‘Lund and Browder’ 
chart at D30±7, D60±7, and D90±7  
• Change from baseline (DBP D0) in “background” pain using the ‘Face, Legs, Activity, Cry, 
Consolability’ (FLACC) pain rating scale in patients <4 years of age and the ‘Wong-Baker FACES® 
Pain Rating Scale’ in patients ≥ 4 years of age before wound dressing changes at D7±2, D14±5, 
D30±7, D45±7, D60±7, and D90±7 
• Change from baseline (DBP D0) in “procedural” pain using the FLACC scale in patients <4 years 
of age and the ‘Wong-Baker FACES Pain Rating Scale’ in patients ≥ 4 years of age after wound 
dressing changes at D7±2, D14±5, D30±7, D45±7, D60±7, and D90±7 
• Change from baseline (DBP D0) in itching using the ‘Itch Man Scale’ in patients ≥ 4 years and up 
to 13 years of age, and the ‘Leuven Itch Scale’ in patients ≥ 14 years of age, before wound 
dressing changes at D7±2, D30±7 and D60±7 
• Change from baseline (DBP D0) in impact of wounds on sleep (in patients ≥ 14 years of age) as 
measured by differences in 11-point Likert scales at D7±2, D30±7, D60±7, and D90±7  
• The number of days missed from school or from work due to EB as reported by patients at D0 for 
the last 14 days and cumulatively for all visits until D90±7 
• Evaluation of the treatment response (in patients ≥ 14 years of age) using the TSQM, Version 9, 
before wound dressing changes at D7±2, D30±7, D60±7, and D90±7 
Safety endpoints 
• Incidence, severity, and relatedness of AEs 
• Local tolerability as judged by the investigator 
• Safety laboratory data 
• Systemic exposure to betulin  
Endpoints for open-label follow-up phase (Oleogel-S10 for 24 months after completion of 
randomised treatment) 
• Incidence, severity, and relatedness of AEs 
• Local tolerability as judged by the investigator 
• Safety laboratory data 
• Systemic exposure to betulin  
• Proportion of patients with first complete closure of the EB target wound at M3±14 days based on 
clinical assessment by the investigator and blinded evaluation of photographs 
• Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in total body wound burden as 
evidenced by clinical assessment using Section I (assessment of the skin except for the anogenital 
region) of the EBDASI at M3±14 days, M12±14 days, and at End of Follow-up (EoFU) at 
M24±14 days  
• Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in BSAP of TBSA affected by 
EB partial thickness wounds as evidenced by clinical assessment based on the ‘Lund and 
Browder’ chart at M3±14 days, M12±14 days, and at EoFU at M24±14 days 
• Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in “background” pain using 
the FLACC scale in patients <4 years of age and the ‘Wong-Baker FACES Pain Rating Scale’ in 
patients ≥ 4 years of age before wound dressing changes at M3±14 days 

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• Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in “procedural” pain using the 
FLACC scale in patients <4 years of age and the ‘Wong-Baker FACES Pain Rating Scale’ in 
patients ≥ 4 years of age after wound dressing changes at M3±14 days 
• Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in itching using the ‘Itch Man 
Scale’ in patients ≥ 4 years and up to 13 years of age and the ‘Leuven Itch Scale’ in patients 
≥ 14 years of age before wound dressing changes at M3±14 days 
• Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in impact of wounds on sleep 
(in patients ≥ 14 years of age) as measured by differences in 11-point Likert scales at M3±14 days 
• The number of days missed from school or from work due to EB as reported by patients at M3±14 
days for the last 14 days 
• Evaluation of the treatment response (in patients ≥ 14 years of age) using the TSQM, Version 9, 
before wound dressing changes at M3±14 days 
• Changes from EDBP (D90±7) in disease severity from both clinician and patient/family perspective 
as quantified with the ‘iscorEB’ at, M12±14 days, and M24±14 days  
Changes from EDBP (D90±7) in patients’ quality of life as assessed by the 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression) with the ‘EQ-5D’ instrument at 
M12±14 days, and M24±14 days 
Study design 
This is a 2-part, Phase III study with a double-blind, randomised, vehicle-controlled phase to compare 
the efficacy, safety, and tolerability of Oleogel-S10 (treatment arm A) versus vehicle (treatment arm B) 
in patients with inherited EB (subtypes JEB, DEB, or Kindler syndrome). At the EDBP (Visit 7a on 
D90±7), patients in both treatment arms will enter the single-arm, open-label FU phase with 
Oleogel-S10 for 24 months. The randomised DBP will consist of 3 periods; the open-label FU phase 
will comprise 1 period as described below. 
Double-blind phase: 
1. Screening (up to 28 days prior to baseline) 
Study sites contact and invite patients registered in centre-specific databases. Patients who fail 
screening may be rescreened if he/she later becomes eligible, as deemed appropriate by the 
investigator. 
2. Baseline, enrolment and stratified randomisation (D0) 
The investigator will confirm eligibility for the patient on D0 corresponding to the study flow chart, 
check the eligibility criteria, select the EB target wound, and enrol the patient into the study. 
Patients will be stratified according to their EB subtype and target wound size (cm2) to the 
following groups: JEB/Kindler 10 to <20; JEB/Kindler 20 to <30; JEB/Kindler 30 to 50; DEB 10 to 
<20; DEB 20 to <30; or DEB 30 to 50 cm2. Patients will then be randomised 1:1 to receive either 
Oleogel-S10 (treatment arm A) or vehicle (treatment arm B). 
3. Intervention (90 days±7 days) 
The treatment of the EB partial thickness target wound and all areas on the patient’s body that are 
affected by EB partial thickness wounds with Oleogel-S10 and a standard of care (SOC) 
non-adhesive wound dressing (treatment arm A) or with vehicle and an SOC non-adhesive wound 
dressing (treatment arm B) will start the same day (D0).  
Safety and local tolerability will be monitored and documented continuously throughout the study. 
24-month open-label follow-up phase: 
Once the EDBP visit for the randomised DBP has been completed and the return of the 
corresponding unused study medication (Oleogel-S10 or vehicle gel) has occurred, the patient will 
enter the single-arm, open-label, 24-month FU phase. The EDBP visit at D90±7 (Visit 7a) 
corresponds to first visit (D0) of the FU phase (Visit 7b). The data of total body wound burden and 
BSAP assessment at EDBP (D90±7) will be used as baseline data of D0 of the FU phase.  
All patients will start topical Oleogel-S10 administration on D0 of the FU phase to all areas on the 
patient’s body that are affected by EB partial thickness wounds including the EB target wound. Wound 
areas will be covered with SOC non-adhesive wound dressing. This procedure will be repeated during 
all dressing changes based on the study flow chart (at least every 4 days) until the end of treatment at 
M24±14 days.  

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Study population 
Inclusion criteria 
A patient will be eligible for study participation only if all of the following criteria apply: 
1. Male and female patients age ≥ 4 years with the following subtypes of inherited EB: JEB, DEB, 
and Kindler syndrome 
Note: Children ≥ 21 days old and <4 years may be included only after confirmation by the 
Independent Data Monitoring Committee (IDMC) upon review of the safety and bioanalytical data 
at the interim safety review stage 
2. Patients with an EB target wound (i.e., EB partial thickness wound of 10 cm2 to 50 cm2 in size, 
aged ≥ 21 days and <9 months) outside of the anogenital region 
3. Patient and/or his/her legal representative has/have been informed, has/have read and understood 
the patient information/informed consent form, and has/have given written informed consent 
4. Patient and/or his/her legal representative must be able and willing to follow study procedures and 
instructions 
Exclusion criteria 
A patient will not be eligible to participate in this study if any of the following criteria apply: 
1. Patient has EB subtype EB simplex  
2. EB target wound that is ≥ 9 months old or has clinical signs of local infection 
3. Use of systemic antibiotics for wound-related infections within 7 days prior to enrolment 
4. Administration of systemic or topical steroids (except for inhaled, ophthalmic, or topical 
applications, such as budesonide suspension for oesophageal strictures [e.g., Pulmicort 
Respules® 0.25 mg/2 mL or 0.5 mg/2 mL]) within 30 days before enrolment 
5. Immunosuppressive therapy or cytotoxic chemotherapy within 60 days prior to enrolment 
6. Patient has undergone stem cell transplant or gene therapy for the treatment of inherited EB 
7. Current and/or former malignancy including basal cell carcinomas and squamous cell carcinomas 
8. Enrolment in any interventional study or treated with any investigational drug for any disease within 
4 weeks prior to study entry 
9. Factors present in the patient and/or his/her legal representative that could interfere with study 
compliance such as inability to attend scheduled study visits or compliance with home dressing 
changes 
10. Pregnant or nursing women 
11. Women of childbearing potential, including postmenarchal female adolescents, and men who are 
not willing to use an effective form of birth control with failure rates <1% per year (e.g., implant, 
injectable, combined oral contraceptive, intrauterine contraceptive device, sexual abstinence, 
vasectomy or vasectomised partner) during participation in the study (and at least 3 months 
thereafter) 
12. Patient is a member of the investigational team or his/her immediate family 
13. Patient lives in the same household as a study participant  
Treatment plan 
Investigational product 
100 g of the investigational product Oleogel-S10 consists of 10 g active pharmaceutical ingredient 
birch bark extract and 90 g sunflower oil 
Placebo/Control 
100 g of the sterile vehicle gel will consist of 85 g sunflower oil, 5 g Cera flava/yellow wax, and 10 g 
Carnauba wax 
Standard of care non-adhesive wound dressing 
Standard of care non-adhesive wound dressings are defined as modern non-adhesive wound 
dressings such as Mepitel® (Mölnlycke Health Care AB, Sweden) or PolyMem® (Ferris Mfg. Corp., 
USA) or equivalents. Silver dressings and dressings containing topical emollients (e.g. vaselinized 
gauze) are not allowed. 

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Dosage and mode of administration 
Double-blind, randomised phase: 
The study medication will be administered topically at approximately 1 mm (0.04 inch) thickness to the 
EB target wound and to all areas on the patient’s body that are affected by EB partial thickness 
wounds. Wound areas will then be covered with an SOC non-adhesive wound dressing. Alternatively, 
the study medication may be applied to the dressing first and the medication-covered dressing then 
placed on the wound. This procedure will be repeated during all dressing changes based on the study 
flow chart (at least every 4 days) until the EDBP at D90±7. The study medication should not be 
rubbed into the wounds. The study medication should not be mixed with other skin products such as 
creams, ointments, gels, or emollients or applied with such skin products at the same time. The 
investigator may implement a dose interruption if considered medically necessary for optimal 
management of the patient. Dose interruptions are not allowed for using non-permitted concomitant 
medication to treat worsening of wound status, increase in wound size, and wound infections of EB 
target wounds and other wounds matching target wound criteria. For worsening of the EB target 
wound status or EB target wound infections the patient may discontinue the DBP and enter the FU 
phase prematurely. Should any other interruptions of treatment occur, the investigator should be 
contacted immediately. Areas on the patient’s body that are not affected by EB partial thickness 
wounds are not to be treated with the study medication. If the EB target wound (or other wound 
matching target wound criteria) closes during the study, it is not necessary to apply study medication 
to the closed wound. The study medication is not intended for use on full thickness wounds (i.e., 
entire dermis, extend into the subcutis) in this study.  
Open-label follow-up: 
Open-label treatment with Oleogel-S10 during the FU phase until the end of treatment at M24±14 
days corresponds to the dosage and mode of administration as described above. 
Concomitant treatment/medication 
Permitted concomitant treatment/medication 
• Liquid antiseptics such as polyhexanide, iodine products, or octenidine dihydrochloride at each 
wound dressing change to clean the EB target wound (and other wounds matching target wound 
criteria) and/or to reduce microbial colonisation of the EB target wound (and other wounds 
matching target wound criteria) prior to study treatment 
• Bathing (e.g., with chlorhexidine, diluted bleach, or salt) prior to study treatment at each wound 
dressing change 
• Systemic antibiotics except for treatment of EB target wound (and other wounds matching target 
wound criteria) infections 
• Inhaled, ophthalmic, or topical steroids, such as budesonide suspension for oesophageal strictures 
(e.g., Pulmicort Respules® 0.25 mg/2 mL or 0.5 mg/2 mL) 
• Supportive therapy upon the investigator’s discretion 
On single EB wounds (except for the EB target wound and other wounds matching target wound 
criteria) during both the DBP and FU phase of the study: 
• Silver sulfadiazine 
• Topical antibiotics 
• Topical steroids 
Non-permitted concomitant treatment/medication 
The following medication will not be permitted during the study until M3±14 days of the open-label FU: 
• Systemic steroids (except for inhaled, ophthalmic, or topical applications, such as budesonide 
suspension for oesophageal strictures [e.g., Pulmicort Respules® 0.25 mg/2 mL or 0.5 mg/2 mL]) 
• Immunosuppressive therapy or cytotoxic chemotherapy 
• Systemic antibiotics to treat EB target wound (and other wounds matching target wound criteria) 
infections 
On areas on the patient’s body that are affected by EB wounds, the following medication will not be 
permitted during the DBP of the study: 
• Skin products such as creams (including barrier creams), ointments (and dressings containing 
topical emollients e.g. vaselinized gauze), gels, or emollients 

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On the EB target wound (and other wounds matching target wound criteria), the following medication 
will not be permitted until complete closure and confirmed epithelialisation during both the DBP and 
FU phase of the study: 
• Silver dressings  
• Silver sulfadiazine 
• Topical antibiotics 
Topical steroids 
Duration of patient participation in the study 
Each patient will participate for 90±7 days in the randomised DBP (approx. 3 months). Each patient in 
the open-label FU phase will receive Oleogel-S10 treatment for 24 months. The total study duration 
(DBP and open-label FU phase) will be approximately 27 months.  
Timelines of randomised, double-blind phase 
• Estimated date of first patient enrolled: Quarter (Q)1/2017 
• Estimated date of last patient enrolled: Q3/2019 
• Estimated date of last patient EDBP: Q4/2019 
Timelines of open-label, follow-up phase 
• Estimated date of last patient EoFU treatment: Q4/2021 
Number of visits (DBP) 
• Six visits at the study site at D0, D14±5, D30±7, D45±7, D60±7, and D90±7 (EDBP) (for visits at 
D14±5 and at D45±7; alternatively, it is possible that the investigator visits patients at home) 
• Two additional study site visits or study team member visits at home at D7±2 and 7 days (+2 days) 
after first clinical assessment of complete target wound closure for confirmation of complete 
closure (of the EB target wound). D7±2 can also be a phone call instead of a site or home visit.  
Number of visits (open-label, follow-up phase) 
• Three visits at the study site at M3±14 days, M12±14 days, and M24±14 days (EoFU).  
• Five interim phone calls at M6±28 days, M9±28 days, M15±28 days, M18±28 days, M21±28 days. 
A site visit may be scheduled instead of an interim phone call to facilitate dispensing of study 
medication. 
Patient discontinuation criteria 
Patients and/or his/her legal representatives will have the right to withdraw from the study at any time 
for any reason without prejudice to their future medical care.  
The investigator will also be able to withdraw patients from the study for the following reasons: 
• Worsening of the EB target wound status or EB target wound infection as assessed by the 
investigator 
• Patient is non-compliant with the study procedures or medications in the opinion of the investigator 
• Progression of a medical condition, which in the opinion of the investigator should preclude further 
participation of the patient in the study 
• Administration of non-permitted concomitant medication(s) 
• Investigator’s decision that a change of therapy is in the patient’s best interest 
• Occurrence of an AE, which makes discontinuation desirable or necessary in the investigator’s 
and/or the patient’s opinion 
If a patient discontinues the DBP or the FU prematurely due to an AE/serious AE (SAE), every 
effort will be made to follow the patient until the resolution of the AE/SAE. If a patient discontinues 
the DBP prematurely due to worsening of the EB target wound status or due to EB target wound 
infection, the investigator may decide whether the patient enters the FU prematurely or 
discontinues the study completely. 
• Pregnancy as evidenced by a positive pregnancy test 
If a patient or the partner of a male patient becomes pregnant during the study, during the FU 
phase, or 30 days within the last application of study medication, the sponsor must be informed 
within 24 hours. The investigator will be asked to complete a pregnancy report provided by the 
sponsor. The investigator will be asked to obtain data on the course of the pregnancy, including 
perinatal and neonatal outcome up to 28 days after delivery. 

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Independent Data Monitoring Committee  
An IDMC will be established to review and evaluate primary efficacy and safety data during the DBP 
of the study. The board will consist of independent experts who will not be involved in the study. The 
safety review will be performed blinded and is to ensure safety for participants, and to advise for 
continuation, modification or discontinuation of individual patients and/or of the study. Following an 
unblinded interim safety review, the IDMC will be able to confirm if the study can be expanded to 
allow the inclusion of children with EB to all ages (i.e., ≥ 21 days and < 4 years). 
The unblinded interim analysis for sample size re-estimation will take place when approximately 50% 
of patients have completed D45±7. Depending on the results of the sample size re-estimation, the 
IDMC will recommend to continue with the initial sample size, increase the sample size, or stop the 
study for futility. 
Statistical methods 
Sample size of the study 
The assumed true control rate for the primary endpoint of first complete closure of the EB target 
wound is 27%. Based on the use of a two-sided test of equality of binomial proportions at the 
alpha=0.05 level of significance, a total sample size of 182 subjects (91 subjects per arm) will provide 
80% power to detect an improvement of 20 percentage points (i.e., a true Oleogel-S10 rate of 47%). 
A total of 192 patients are planned to be enrolled into the study and treated to account for an 
estimated drop-out rate of 5%. 
Following the unblinded interim analysis, the IDMC recommended to have a sample increase of 48 
patients (24 per arm) to have a total of 230 subjects.  A total of 250 patients are planned to be 
enrolled into the study and treated to account for drop-outs. 
Confirmatory statistical testing 
The primary efficacy endpoint and the key secondary efficacy endpoints will be tested in a 
confirmatory way, following the hierarchical testing principle. 

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AE = Adverse event; ALT = Alanine aminotransferase; AP = A kaline phosphatase; AST = Aspartate aminotransferase; BSAP = Body surface area percentage; Ca = Calcium; CCC = Confirmation 
of complete closure (of EB target wound); Cl = Chloride; D = Day; d = days; EB = Epidermolysis bullosa; EBDASI = EB Disease Activity and Scarring Index; EDBP = End of Double-blind Phase; 
EoFU = End of Follow-up; EQ-5D = EuroQol 5 Dimensions; FLACC = Face, Legs, Activity, Cry, Consolability; GGT = Gamma-glutamyl transpeptidase; K = Potassium; Na = Sodium; 
P = Phosphate; SAE = Serious adverse event; W-QoL = Wound Quality of Life Questionnaire; y = Year(s) 
 
A. 
A site visit can be scheduled instead of an interim phone call to facilitate dispensing and return of study medication. 
B. 
D7±2 visit can also be a phone call instead of a site or home visit.  
C. 
CCC visit: Confirmation of Complete Closure of the EB target wound 7 days (+2 days) after first clinical assessment of complete closure of the EB target wound in the Double-blind phase. 
D. 
Alternatively, the investigator may visit the patient at home on D14±5d, and D45±7d. 
E. 
The first day of the open-label follow-up phase (FU [D0]) occurs at visit EDBP (D90±7d).  
F. 
An optional informed consent form for collection blood samples for betulin analysis and an optional consent form for genetic testing to determine EB subtype will be provided to the patient at 
screening. If the patient consents to the optional collection of blood samples for betulin analysis, written consent should be obtained at the baseline visit, if not already provided at the 
screening visit. Written informed consent for optional genetic testing can be obtained at any visit during the study. 
G. 
If not obtained at screening. 
H. 
Optional genetic testing procedures can be carried out at any visit, if the patient has provided consent. 
I. 
Assessment will be performed if patient has site visit or home visit at D7±2. If the patient has phone call, the assessment will not be performed. 
J. 
“Background” pain will be measured before dressing change; “procedural” pain will be measured after dressing change using either the FLACC scale or the Wong-Baker FACES. 
K. 
iscorEB should only be completed if available in the local language. 
L. 
Assessment of wound status and wound size should be in comparison to baseline (DBP) and not the previous visit. Worsening of wound status, increase in wound size, re-opening of wounds 
and wound infections should be reported as AEs.  
M. 
Investigator to confirm closure of target wound from assessment of target wound photography. 
N. 
If haematology and biochemistry parameters have been determined within 4 weeks prior to baseline, they may be used as baseline values. (Note: The blood draw must occur prior to study 
medication exposure.) 
O. 
Betulin analyses from safety laboratory blood samples do not require additional consent. 
P. 
Betulin levels are not required at M12 visit. 
Q. 
In women of childbearing potential/postmenarchal female adolescent patients only. 
R. 
If a pregnancy test has been performed within 14 days prior to baseline it does not need to be repeated at baseline. 
S. 
No additional voluntary sample is required if blood sample for safety laboratory test is to be taken at the same visit. Blood samples for safety laboratory tests can be used for betulin analysis. 
T. 
Study medication and wound dressing changes performed at home except for site visits. 
U. 
If the EB target wound (or other wound matching target wound criteria) is confirmed as closed, it is not necessary to continue to apply study medication. The area may be dressed to protect 
the skin. Study medication will continue to be applied to any other EB partial thickness wounds.  
 

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subtypes is skin blistering with associated recurrent and persistent wounds (Schwieger-Briel, 
Chakkittakandiyil et al. 2015). 
2.1.2 
Epidermolysis Bullosa Partial Thickness Wounds 
Human skin consists of 3 layers comprising epidermis, dermis, and subcutis (see Figure 2). 
The epidermis serves as a barrier to infection. The dermis underneath contains the skin 
appendages, sensory nerve receptors, nails, and blood vessels. A thin sheet of fibres called 
the basement membrane separates epidermis and dermis. Basal keratinocytes of the 
stratum basale that continuously regenerate the epidermis are located above the basement 
membrane. Keratinocytes mature, differentiate, and progress through the layers of the 
epidermis in a life cycle lasting approximately 3 to 4 weeks before being shed as 
corneocytes. Keratinocytes are of paramount importance for the reepithelialisation of partial 
thickness wounds (Doughty 2012). 
Figure 2 
Human Skin and Depths of Cutaneous Wounds 
 
Source: (Vogt and Ipaktchi 2013) 
Wounds of the skin are classified into partial or full thickness wounds based on the depth of 
skin layers involved (see Figure 2). Partial thickness wounds involve loss of the epidermis 
and extend into the dermis. The basement membrane is lost, but skin appendages remain. 
Keratinocytes and epidermal stem cells in these dermal appendages are able to regenerate 
the epidermis within 1 to 3 weeks with minimal or no scarring. Full thickness wounds involve 
the entire dermis, extend into the subcutis and are not able to heal spontaneously within 
3 weeks.  
Partial thickness wounds are very painful, because sensory nerve endings are abundant in 
the remaining dermal tissue of the wound bed. In addition, there is an increased risk of 
infection due to the compromised skin barrier.  
Many wounds in EB might be classified as partial thickness wounds, as the level of skin 
cleavage in the major 4 EB subtypes extends at maximum into the dermis. The total body 
wound burden of EB partial thickness wounds has a decisive effect on the quality of life, as it 
relates to pain, itching, and the complexity of wound care.  
Fine and colleagues assessed pain in children with EB and reported that only 12 to 14% of 
children with EBS, JEB, and DDEB and 5% of children with RDEB were pain-free (Fine, 
Johnson et al. 2004).  
Danial et al. evaluated the prevalence of itch among children and adults with EB. Itch was 
rated as the most bothersome EB complication. Overall, 87% of participants reported itch to 

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be present at rest. The average itch frequency increased with self-reported EB severity and 
was highest in RDEB patients and lowest in EBS patients (p=0.01). EB patients with 
≥ 3 wound locations had a significantly higher frequency of pruritus than patients with 
< 3 wounds (p<0.001). Pruritus was strongest in healing wounds (p<0.001), skin around 
wounds (p<0.001), dry skin (p=0.001), and infected wounds (p=0.002) (Danial, Adeduntan et 
al. 2015). 
Repeated infections, constant trauma and comorbidities such as compromised nutrition and 
anaemia are reasons for developing chronic wounds (Denyer and Pillay 2012). Infected and 
chronic wounds belong to the most frequent complications in the generalised intermediate 
and severe forms of EB (El Hachem, Zambruno et al. 2014). The most commonly isolated 
microorganisms in wound cultures from EB patients encompass Staphylococcus sp., 
Streptococcus sp., diphtheroids, P. aeruginosa, and Candida sp.; the presence of 
≥ 4 bacterial groups is associated with significant delayed wound healing (Brandling-Bennett 
and Morel 2010). 
Health care professionals and patients with EB were asked for their perception of disease 
severity as basis for the development of the ’Instrument for Scoring Clinical Outcome of 
Research for Epidermolysis Bullosa’ (iscorEB). ‘Skin’ was the category most commonly listed 
by health care professionals with ‘affected body surface area’, ‘frequency of infections’, and 
‘chronic wounds’ being the most frequent items. Comparably, ‘pain’ and the ‘extent and 
healing of wounds’ were the most common items listed by patients (Schwieger-Briel, 
Chakkittakandiyil et al. 2015). 
In summary, disease burden of EB across all subtypes closely relates to the total body 
surface area (TBSA) of EB partial thickness wounds with complications such as infections 
and symptoms such as pain and itching.  
2.1.3 
Treatment Options and Medical Need 
In spite of the progress in aetiopathogenetic research of EB, there is still no cure or effective 
treatment for this group of potentially severe and fatal diseases (Uitto, McGrath et al. 2010, 
Hunefeld, Mezger et al. 2013). While there is a broad research effort searching for the best 
molecular strategies to ameliorate or treat EB (Hunefeld, Mezger et al. 2013), the knowledge 
on symptomatic and preventive wound care in EB is still limited by the paucity of scientific 
evidence with most recommendations based on expert opinion (Pope, Lara-Corrales et al. 
2012). 
Wound management in EB primarily depends on the subtype of the disease and on the age 
of the patient. The nutritional status, the general state of health, the current condition of the 
skin, the availability of wound dressings, optional involvement of nursing care at home, and 
the domestic environment also play important roles. The general principles of wound care 
are similar across all EB subtypes, but might differ markedly regarding intensity and effort 
(Diem and Sailer 2012). 
There is no standard wound care in EB. Wound dressings are changed about every second 
day. Adherent wound dressings are soaked with lukewarm water in a bath or during a 
shower and with damp compresses, respectively. Creams or ointments are administered on 
those wounds that tend to adhere to the wound dressings. In case wounds are still not clean 
after taking a bath or a shower, small amounts of antiseptics are used before creams, 
ointments, and wound dressings are administered.  
In moist wounds, rather searing creams are preferred. In dry, crusty wounds, greasing or 
moist creams are recommended. Infected, malodorous wounds are treated with antimicrobial 
creams for a maximum of 2 to 4 weeks. Antiseptic baths or antibiotic ointments might be 
used instead. Wounds that are difficult to be dressed might be treated with ointments 
containing zinc to dry out opened blisters. If a cream or an ointment is necessary, it might be 
administered directly to the wound or to the wound dressing that is applied to the wound 
(Diem and Sailer 2012).  

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Care of the skin currently not affected by superficial wounds is of major importance, 
particularly in dry skin (Diem and Sailer 2012). The use of topical emollients including 
moisturisers for skin care is widely recommended (Denyer and Pillay 2012, El Hachem, 
Zambruno et al. 2014). Equal parts of liquid paraffin and white soft paraffin are also used for 
(periwound) skin care (Denyer and Pillay 2012). Overall, greasy ointments (e.g., Vaseline®) 
are used most frequently, particularly for the management of pruritus. EB patients who used 
creams (p=0.05) or lotions (p=0.04) reported to experience less pruritus than those who used 
them less often (Danial, Adeduntan et al. 2014).  
A wide range of oral medications is used for the treatment of pruritus including antihistamines 
(e.g., hydroxyzine, cetirizine, diphenhydramine), corticosteroids, antiepileptics (e.g., 
gabapentin), tricyclic antidepressants (e.g., doxepin, amitriptyline), serotonin 5-HT3 receptor 
antagonists (e.g., ondansetron), and benzodiazepines. For the treatment of severe 
recalcitrant itch, even thalidomide and cyclosporine are used. However, pruritus in EB is not 
mediated by histamine. Therefore, antihistamines are of limited value and are rather 
administered because of their sedating effect (Denyer and Pillay 2012).  
Pain is relieved by the administration of non-steroidal anti-inflammatory analgesics and 
opioids depending on individual needs and the severity, chronicity and location of discomfort 
(Pillay 2008). 
In summary, current treatment of EB is primarily preventive including protection from 
mechanical forces by avoiding friction, early treatment of lesions to prevent superinfections, 
and protection of the wound with adequate non-adhesive dressings to enable wound healing. 
Supportive care relieves itch and pain (Denyer and Pillay 2012, Pope, Lara-Corrales et al. 
2012).  
The acceleration of wound healing would meet an important medical need, as it would 
reduce pain, itch, and the risk of wound infection. 
2.2 
Investigational Product 
Oleogel-S10 is a wound gel containing 10 g/100 g extract (as dry extract, refined) from 
Betulae cortex (birch bark) from Betula pendula Roth, Betula pubescens Ehrh, as well as 
hybrids of both species (5-10:1), quantified to 72% (w/w) to 88% (w/w) betulin (see Figure 3), 
extraction solvent n-heptane, and refined sunflower oil 90 g/100 g. Additional specified 
components of birch bark extract are betulinic acid, lupeol, oleanolic acid, and erythrodiol. 
Figure 3 
Molecular Structure of Betulin, the Active Pharmaceutical Ingredient of 
Oleogel-S10 
 
Amryt Pharma Figure 
Betulin = 3β,28-Dihydroxylup-20(29)-ene, Chemical Abstracts Service (CAS) number 473-98-3 
Molecular formula: C30H50O2; Molecular weight: 442.72 g/mol 
Oleogel-S10 is a “preparation for treatment of wounds and ulcers” according to the 
Anatomical Therapeutic Chemical (Classification System [Anatomical Therapeutic Chemical 
code D03AX13 Betulae cortex]). It was approved under the trade name Episalvan® on 
14 January 2016 in the European Union (EU/1/15/1069) for the treatment of partial thickness 

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wounds in adults after having demonstrated efficacy and safety in split-thickness skin graft 
(STSG) donor site (DS) wounds and in Grade 2a burn wounds.  
2.3 
Summary of Non-clinical Studies with Oleogel-S10 
Woelfle and colleagues demonstrated that birch bark extract promotes the differentiation of 
keratinocytes, a process required for the reepithelialisation and maintenance of the skin 
barrier (Woelfle, Laszczyk et al. 2010). Ebeling and colleagues have shown in human 
primary keratinocytes that birch bark extract and betulin modulate various mediators involved 
in the inflammatory phase of the wound healing process. Birch bark extract increased the cell 
migration of primary human keratinocytes and accelerated wound closure in an ex vivo 
porcine wound healing model (Ebeling, Naumann et al. 2014).  
Wardecki et al. investigated the impact of birch bark extract, betulin, and lupeol on primary 
human keratinocytes and fibroblasts from non-diabetic and diabetic donors in vitro. They 
have demonstrated an upregulation of chemokines, proinflammatory cytokines, and 
mediators important in wound healing and a shape change of the actin cytoskeleton in both 
keratinocytes and fibroblasts (Wardecki, Werner et al. 2016).  
Furthermore, for triterpenes present in birch bark extract, namely betulin, betulinic acid and 
oleanolic acid, antiviral, antibacterial, antimycotic, anti-inflammatory, and antitumoral effects 
have been described (Galgon, Wohlrab et al. 2005, Alakurtti, Makela et al. 2006, Lee, Nam 
et al. 2006, Suksamrarn, Panseeta et al. 2006). 
2.3.1 
Non-clinical Evidence for Acceleration of Reepithelialisation in 
Inherited Epidermolysis Bullosa  
The pathogenesis of blistering differs by EB subtype and the mechanisms of impaired wound 
healing are not fully delineated in all subtypes. Oleogel-S10 counteracts mechanisms of 
delayed wound healing downstream and it is assumed that these effects are relevant for all 
EB subtypes. Hemidesmosome protein complexes are not only involved in stable adhesion, 
but also regulate signal pathways in migrating cells (Tsuruta, Hashimoto et al. 2011). 
Collagen VII (COL7A1) for example is a functionally important adhesion molecule of the 
dermal-epidermal junction zone (DEJZ). Epidermal keratinocytes and dermal fibroblasts both 
synthesise and secrete collagen VII to form anchoring fibrils that attach the epidermis 
strongly to the dermis. In DEB, the COL7A1 gene is mutated resulting in reduced or absent 
collagen VII synthesis.  
Nystrom et al. investigated the role of COL7A1 in wound healing using 2 different mouse 
models of genetic skin fragility. They have shown that COL7A1 was a critical player in 
physiological wound healing based on 2 interconnected mechanisms: First, COL7A1 was 
required for reepithelialisation through organisation of laminin-332 at the dermal-epidermal 
junction. The loss of COL7A1 perturbed laminin-332 organisation during wound healing, 
which in turn abrogated strictly polarised expression of integrin α6β4 in basal keratinocytes 
and negatively influenced the laminin-332/integrin α6β4 signalling axis guiding keratinocyte 
migration. Second, COL7A1 supported dermal fibroblast migration and regulated their 
cytokine production in the granulation tissue. These findings were validated in human 
wounds (Nystrom, Velati et al. 2013). Since laminin-332 and integrin α6β4 are either absent 
or markedly reduced in JEB due to mutations of LAMA3, LAMB3, LAMC2, ITGB4, and ITGA6 
genes, wound healing could be delayed for the same reason in this disorder. In fact, it has 
clinically been described that patients with generalised severe JEB heal slowly and it has 
been suggested that the deficiency of laminin-332 was the reason (Fine 2010, Boeira, Souza 
et al. 2013). 
Oleogel-S10 accelerates the reepithelialisation of wounds, which is thought to be due to an 
enhancement of keratinocyte proliferation and migration as well as keratinocyte 
differentiation. Hence, Oleogel-S10 induces different pathways of keratinocyte proliferation, 

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migration, and differentiation compared with the genetically altered pathways in inherited EB 
(see Figure 4) (Ebeling, Naumann et al. 2014). 
Therefore, different EB subtypes can be assumed to respond equally to treatment, although 
wound healing may be impaired at different stages. The structural integrity of the skin is 
compromised at different proteins depending on the EB subtype. However, reepithelialisation 
and keratinocyte migration, where birch bark extract is thought to be active, are not directly 
affected by these mutations. 
 

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Figure 4 
Acceleration of Reepithelialisation due to Oleogel-S10 Versus Impaired Wound Healing in Inherited Epidermolysis Bullosa 
 
 
Amryt Pharma Figure 
BP Ag = bullous pemphigoid antigen; DEB = dystrophic EB; DEJZ= dermo‑epidermal junction zone; EB = epidermolysis bullosa; EBS = EB simplex; KS = Kindler Syndrome; 
IFN‑γ = interferon‑gamma; IL‑8 = interleukin‑8; IP‑10 = IFN‑γ inducible protein 10; JEB = junctional EB; MAPK = mitogen‑activated protein kinase; Rac1 = Ras‑related C3 
botulinum toxin substrate; RANTES = Regulated on Activation, Normal T Cell Expressed and Secreted (chemokine); RhoA = Ras homolog gene family, member A; STAT3 = Signal 
Transducer and Activator of Transcription 3 (transcription factor); TE = birch bark extract 
Source: (Fine, Eady et al. 1999, Boeira, Souza et al. 2013, Ebeling, Naumann et al. 2014) 

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2.4 
Summary of Clinical Studies with Oleogel-S10 
2.4.1 
Split-Thickness Skin Graft Donor Sites 
Two blindly evaluated, randomised, controlled, phase III studies (EudraCT nos. 
2012-003390-26 and 2012-000777-23) investigated the intra-individual difference in time to 
wound closure in STSG donor sites of 219 adult patients.  
Donor site wounds were divided into 2 equal halves and were randomised 1:1 to 
Oleogel-S10 plus non-adhesive wound dressing or to the same non-adhesive wound 
dressing only, as standard of care (SOC) control (mostly used was Mepilex®). Wounds were 
treated until complete closure of both wound halves, for a maximum of 28 days. Wound 
dressings were changed every 3 to 4 days. Oleogel-S10 accelerated wound healing 
compared with SOC (p<0.0001) (Barret, Podmelle et al. 2017). 
2.4.2 
Grade 2a Burn Wounds 
An open, blindly evaluated, prospective, intrapatient controlled, randomised, phase III study 
(EudraCT No. 2012-000362-38) investigated the efficacy and tolerability of Oleogel-S10 in 
accelerating the healing of Grade 2a burn wounds. The target wound was divided into 
2 halves of similar size; 1 half was treated with Oleogel-S10 and covered with fatty gauze 
dressing, the other half was treated with Octenilin® Wound Gel and was also covered with 
fatty gauze dressing, as a SOC control.  
Overall, 61 adult patients were enrolled into the study. In blinded assessment of wound 
photographs, earlier healing was demonstrated for the wound halves that had been treated 
with Oleogel-S10 compared to those treated with SOC control (p<0.0001) (Frew, 
Rennekamff et al. 2018. 
2.4.3 
Epidermolysis Bullosa 
Case Studies 
Oleogel-S10 has been successfully used for the treatment of chronic wounds in a case 
series of 4 patients with different subtypes of EB: Of those, a 57-year-old male with DEB 
presented with a chronic wound on the scrotal area present for 3 months. Within 6 days of 
treatment, the wound size decreased from 9.48 cm2 to 0.65 cm2. In a 3-year old girl with JEB, 
the size of a chronic abdominal wound decreased within 2 days of treatment from 13.63 cm2 
to 9.58 cm2. A 4-year old boy with EBS had chronic wounds on the upper back and lower 
abdomen that completely healed within 3 months of treatment with Oleogel-S10. 
Open-label, Prospective, Controlled, Blindly Evaluated, Phase II Study 
An open-label, prospective, controlled, blindly evaluated, phase II study at the University 
Medical Centre Freiburg, Germany compared - intra-individually - the efficacy and tolerability 
of Oleogel-S10, versus non-adhesive wound dressing only, in accelerating the 
epithelialisation of skin lesions in patients with inherited EB during a treatment period of 
28 days. 
The primary efficacy variable of the study was the progress of reepithelialisation from 
baseline to either Day 14 in ‘recent wounds’ or Day 28 in ‘chronic wounds’; with the half of 
the wound treated with Oleogel-S10 and non-adhesive wound dressing compared to the 
other half of the wound covered with non-adhesive wound dressing only (intra-individual 
comparison).  
Overall, 10 patients were enrolled into the study; 9 patients had RDEB and 1 patient DDEB 
localised. As 2 patients received 2 consecutive cycles of treatment, 12 wounds were treated 
with study medication.  

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Based on blinded analysis of wound photographs, Oleogel-S10 and non-adhesive wound 
dressing accelerated the reepithelialisation of wounds in inherited EB compared to 
non-adhesive wound dressing only (Schwieger-Briel, Kiritsi et al. 2017). 
2.5 
Rationale for Dose Selection 
Oleogel-S10 has a unique composition. The active pharmaceutical ingredient birch bark 
extract is a white powder consisting of 80% betulin and other closely related triterpene 
compounds, namely betulinic acid, lupeol, oleanolic acid, and erythrodiol. Triterpenes are 
able to gel oil, enabling a formulation that consists only of an oil and the active 
pharmaceutical ingredient without any supplemental ingredients (see Figure 5). 
Figure 5 
Composition of Oleogel-S10 
 
Amryt Pharma Figure 
The active pharmaceutical ingredient concentration of 10% weight per weight provides 
optimum physical properties of the formulation, being a thick gel that allows for good 
coverage of the wound. The 10% concentration was used in the clinical development 
programme in partial thickness wounds, as early clinical studies in other skin conditions 
showed good safety and tolerability of the formulation with poor systemic absorption.  
In all phase II and phase III partial thickness wound studies, Oleogel-S10 has been applied 
at doses of 100 to 115 mg/cm2 in wound sizes ≥ 10 cm2 up to ≥ 40 cm2 every 1 to 4 days 
(see Table 1). 
Table 1 Doses of Oleogel-S10 in Previous Partial Thickness Wound Studies 
Study 
Phase 
Indication 
Dose 
Wound Size 
Frequency of Treatment 
BSH-10 
II 
STSG DS 
115 mg/cm2 
≥ 10 cm2 
Variable (mean 2.3 days) 
BEB-10 
II 
EB 
115 mg/cm2 
≥ 10 cm2 
Every 24 to 48 h 
BBW-11 
III 
Burns Grade 2a 
100 mg/cm2 
≥ 40 cm2 
At least every 2 days 
BSH-12 
III 
STSG DS 
100 mg/cm2 
≥ 15 cm2 
At least every 3 to 4 days 
BSG-12 
III 
STSG DS 
100 mg/cm2 
≥ 15 cm2 
At least every 3 to 4 days 
EB = Epidermolysis bullosa; STSG DS = Split-thickness skin graft donor site 
Patients in this EB Phase III study will be allowed to apply study medication at least every 
4 days, since efficacy and safety has been shown in all studies. No cases of Oleogel-S10 
overdose have been reported. The maximum exposure achieved in nonclinical studies is 
1100 ng/mL. Nonclinical safety and toxicology studies have not demonstrated any 
dose-limiting toxicities. Since Oleogel-S10 is administered topically, overdose is considered 
unlikely. Patients in this clinical trial will be closely monitored for any adverse events, and 
treatment will be terminated if felt appropriate. Based upon the pharmacological properties of 
Oleogel-S10, no additional specific measures are advised.  

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There is no standard wound care in EB as described in Section 2.1.3 Treatment Options and 
Medical Need. Wound management in EB depends on several factors including the subtype 
of the disease, the age of the patient, the current condition of the skin, the availability of 
wound dressings, an optional involvement of nursing care at home, and the domestic 
environment (Diem and Sailer 2012). 
EB patients usually need to plan their wound dressing changes, because they require 
external support (e.g., nursing care or relatives), large amounts of wound care products, 
drugs (anaesthetics or analgesics), a convenient and clear environment, and time.  
The study burden will be decreased markedly for patients and caregivers, if patients are 
allowed to keep their usual schedule of dressing changes.  
2.6 
Known and Potential Benefits and Risks 
Skin blistering with associated recurrent and persistent wounds is the hallmark of most EB 
subtypes. Self-reported perception of disease severity closely relates to the body surface 
area affected by EB wounds, the frequency of infected and chronic wounds, and pain 
(Schwieger-Briel, Chakkittakandiyil et al. 2015). Only 5 to 14% of all paediatric EB patients 
reported to be pain-free (Fine, Johnson et al. 2004). Itch was present in 87% among children 
and adults with EB. It increased with increasing number of wounds (p<0.001) and was strong 
in infected wounds (p=0.002) (Danial, Adeduntan et al. 2015). Infected and chronic wounds 
belong to the most frequent complications in the generalised intermediate and severe forms 
of EB (El Hachem, Zambruno et al. 2014). 
The knowledge on wound care in EB is still limited by the paucity of scientific evidence with 
most recommendations based on expert opinion (Pope, Lara-Corrales et al. 2012). Current 
treatment of EB is primarily preventive including protection from mechanical forces, early 
treatment of lesions to prevent superinfections, and protection of the wound with adequate 
non-adhesive dressings to enable wound healing (Denyer and Pillay 2012, Pope, Lara-
Corrales et al. 2012). 
The acceleration of wound healing would meet an important medical need, as it would 
reduce disease burden by decreasing the risk of wound infection and relieving pain and itch. 
Oleogel-S10 is authorised in the European Union for treatment of partial thickness wounds in 
adults under the brand name Episalvan since January 2016 (EU/1/15/1069). It was safe and 
well tolerated throughout the clinical development programme in partial thickness wounds. 
The most common adverse events (AEs) related to Oleogel-S10 concerned 25 of 
280 patients (9%), comprising pain of skin (2.9%) and pruritus (1.4%). Intensive non-clinical 
in vitro and in vivo experiments in different species of different ages and different routes of 
administration up to long-term chronic use raise no concerns for conducting clinical trials. No 
adverse effects have been observed in single and repeated dose experiments, in safety 
pharmacology tests, and in the genotoxic evaluation. Oleogel-S10 can be considered as safe 
when applied to the (abraded) skin based on the results of all toxicological experiments. 
Oleogel-S10 has successfully been used for the treatment of EB wounds in 4 patients with 
different subtypes of EB as well as in a phase II study with 10 patients suffering from RDEB 
or DDEB. It has been shown to accelerate the reepithelialisation of partial thickness wounds 
in patients with Grade 2a burns and STSG donor sites.  
In conclusion, the benefits of Oleogel-S10 outweigh its risks for an administration in patients 
with EB. 
2.7 
Study Rationale 
The purpose of this double-blind, randomised, vehicle-controlled, phase III study is to 
compare the efficacy, safety, and tolerability of Oleogel-S10 (treatment arm A) with vehicle 
(treatment arm B) in patients with inherited EB (subtypes JEB, DEB, or Kindler syndrome). In 

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addition, the long-term effect of Oleogel-S10 will be assessed during an open-label, 24-
month follow-up (FU). 
2.7.1 
Rationale of the Study 
The proven safety and efficacy of an authorised product in partial thickness wounds on the 
one hand and the proof of principle as well as the high medical need in EB on the other hand 
are the rationales for initiating this study.  
Oleogel-S10 is authorised in the European Union for the treatment of partial thickness 
wounds in adults under the brand name Episalvan since January 2016 (EU/1/15/1069). 
Oleogel-S10 was safe and well tolerated throughout the clinical development programme in 
partial thickness wounds. Non-clinical in vitro and in vivo experiments with Oleogel-S10 have 
not raised any safety concerns. 
Oleogel-S10 accelerated wound healing compared with SOC in STSG donor site wounds, 
(p<0.0001) (see Section 2.4.1 Split-Thickness Skin Graft Donor Sites) and in Grade 2a burn 
wounds (p<0.0001) (see Section 2.4.2 Grade 2a Burn Wounds).  
Oleogel-S10 has been successfully used for the treatment of chronic wounds in a case 
series of 4 patients with different subtypes of EB and accelerated the reepithelialisation of 
wounds in inherited EB compared to non-adhesive wound dressing only (see Section 2.4.3 
Epidermolysis Bullosa).  
The acceleration of wound healing would meet an important medical need, as it would 
reduce pain, itch, and the risk of wound infection (see Section 2.1.3 Treatment Options and 
Medical Need). 
2.7.2 
Rationale of Study Design 
Although skin blistering with associated recurrent and persistent wounds is the hallmark of 
EB, there are different clinical subtypes presenting with diverse symptoms and variable 
clinical severity, ranging from mild to debilitating, life-limiting disease. Only few intervention 
studies have been initiated in EB due to factors well recognised in other orphan diseases 
such as small number of patients and multiple complications making the patient a 
less-than-ideal candidate for research studies (Schwieger-Briel, Chakkittakandiyil et al. 
2015). EBS patients will not be included in the study. This subtype of EB has the mildest 
form of the disease with the shortest wound healing cycle times, and hence would be the 
least likely to derive a substantial treatment benefit. Therefore, inclusion of these patients is 
likely to dilute the overall treatment effect. Exclusion of these patients will help to ensure that 
healing rates in the control arm of the study will not be too high and thus avoid a reduction in 
statistical power while increasing the likelihood of demonstrating a statistically significant 
treatment effect in other treatment groups. 
A vehicle-controlled study allows for a parallel-group design with randomisation and blinding 
thereby reducing allocation bias and balancing confounding variables.  
A 2-arm parallel-group design with vehicle gel control was chosen, because many EB 
patients apply creams or ointments on those wounds that tend to adhere to wound dressings 
(Diem and Sailer 2012). The use of topical emollients including moisturisers for skin care is 
widely recommended for EB patients (Denyer and Pillay 2012, El Hachem, Zambruno et al. 
2014). Equal parts of liquid paraffin and white soft paraffin are also used for (periwound) skin 
care (Denyer and Pillay 2012). Overall, greasy ointments (e.g., Vaseline®) are used most 
frequently, particularly for the management of pruritus (Danial, Adeduntan et al. 2014). The 
use of a sunflower oil gel as vehicle control provides patients in the control arm also with 
such a greasy ointment. As no well-defined SOC cream or ointment exists, the use of this 
vehicle control will not only provide a standard SOC for EB treatment, but also a comparison 
of vehicle versus Oleogel-S10 (both share sunflower oil as the main ingredient) and a control 
group suited for a double-blind study design.  

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2.7.3 
Rationale of Primary Efficacy Endpoint – Double-blind Phase 
The primary efficacy endpoint of the double-blind phase (DBP) will be the proportion of 
patients with first complete closure of the EB target wound (defined as EB partial thickness 
wound of 10 cm2 to 50 cm2 in size aged ≥ 21 days and <9 months) in patients with inherited 
EB (subtypes JEB, DEB, or Kindler syndrome) within 45±7 days of treatment with 
Oleogel-S10 compared to vehicle based on clinical assessment by the investigator. The 
wound will be rated as “closed” at first appearance of complete reepithelialisation without 
drainage. 
There are no published data on either the natural history of the disease process in EB or the 
expected response to SOC. Therefore, an EB partial thickness wound aged ≥ 21 days is 
considered to be delayed in wound healing. Partial thickness wounds normally heal within 
1 to 3 weeks (Doughty 2012). In burn victims, partial thickness wound aged ≥ 21 days are 
covered with STSGs to avoid complications of delayed wound healing such as scarring.  
There is no guidance on the specified time of an ‘acute’ EB wound becoming ‘chronic’, 
although the consensus meetings on the development of the ’Instrument for Scoring Clinical 
Outcome of Research for Epidermolysis Bullosa’ (iscorEB) defined wounds in EB to be 
chronic, if they are present for longer than 6 weeks (Schwieger-Briel, Chakkittakandiyil et al. 
2015). Younger and particularly smaller wounds <10 cm2 are more dynamic and tend to heal 
on their own. In chronic wounds, multiple factors such as nutritional deficiencies, an infection, 
or repeated trauma contribute to the delay of healing.  
Oleogel-S10 accelerates the reepithelialisation of wounds due to an enhancement of 
keratinocyte differentiation and migration. Hence, its mechanism of action would target those 
wounds that are delayed in wound healing being prone to become a chronic wound. These 
wounds are of high clinical relevance and a major source of complications in patients with 
EB.  
The assessment for the primary endpoint follows the US Food and Drug Administration 
(FDA) Guidance for Industry ‘Chronic Cutaneous Ulcer and Burn Wounds – Developing 
Products for Treatment’.  
2.7.4 
Rationale of Secondary Efficacy Endpoints – Double-blind Phase 
One of the key secondary (confirmatory) efficacy endpoints of the DBP will be to compare 
the efficacy of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) as evidenced by 
the time to first complete closure of the EB target wound (defined as EB partial thickness 
wound of 10 cm2 to 50 cm2 in size aged ≥ 21 days and <9 months) in patients with inherited 
EB (subtypes JEB, DEB, or Kindler syndrome) in either treatment arm as evidenced by 
clinical assessment until D90±7. The time taken to achieve complete wound healing is a 
clinically important endpoint for the assessment of the potential benefit of a wound healing 
treatment in EB. More rapid wound healing results in fewer symptoms related to open 
wounds (e.g., pain and itching), and would be expected to decrease the likelihood of wound 
infection. 
The assessment for this key secondary (confirmatory) endpoint follows the US FDA 
Guidance for Industry ‘Chronic Cutaneous Ulcer and Burn Wounds – Developing Products 
for Treatment’.  
Further secondary efficacy endpoints of the DBP will include: time to first complete closure of 
the EB target wound as evidenced by blinded evaluation of photographs taken until D90±7; 
proportion of patients with first complete closure of the EB target wound within D14±5, 
D30±7, D60±7 and D90±7 based on clinical assessment by the investigator; and proportion 
of patients with complete closure of the EB target wound at D7±2, D14±5, D30±7, D45±7, 
D60±7, and D90±7 based on blinded evaluation of photographs.  
In addition, further secondary efficacy endpoints have been determined to demonstrate the 
impact of accelerated healing such as the difference in EB target wound size reduction, the 

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change in total body wound burden, the change in percentage of TBSA affected by EB partial 
thickness wounds, the difference in wound infection rates, the change in impact of wounds 
on sleep, the change in “background” and “procedural” pain, the change in itch, and the 
evaluation of the response to treatment.  
2.7.5 
Rationale of Endpoints – Open-label Follow-up Phase 
The primary rationale of the open-label FU phase is to obtain long-term safety data and real-
world data on severity and quality of life; apart from that the rationales of the other 
assessments in particular at the first visit at Month 3 (M3)±14 days are comparable to those 
in the DBP. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective – Double-blind Phase 
The primary objective of the DBP is to compare the efficacy of Oleogel-S10 (treatment 
arm A) with vehicle (treatment arm B) in the promotion of healing of EB partial thickness 
wounds. This will be assessed as evidenced by the incidence of the first complete closure of 
the EB target wound (defined as EB partial thickness wound of 10 cm2 to 50 cm2 in size aged 
≥ 21 days and <9 months) in patients with inherited EB (subtypes JEB, DEB, or Kindler 
syndrome) within 45±7 days of treatment. 
3.2 
Secondary Objectives – Double-blind Phase 
The secondary objectives of the DBP are to:  
• Compare the efficacy of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) as 
evidenced by: 
− The time to first complete closure of the EB target wound in either arm within 90±7 
days of treatment 
− The incidence of first complete closure of the EB target wound over time 
− The relative change from baseline in EB target wound size over time 
− The relative change from baseline in total body wound burden over time 
− The relative change from baseline in percentages of TBSA affected by EB partial 
thickness wounds over time 
− The incidence and severity of wound infection over time  
− The change from baseline in “background” pain before wound dressing changes and 
the change from baseline in “procedural” pain after wound dressing changes over time 
− The change from baseline in itch before wound dressing changes over time 
− The change from baseline in impact of wounds on sleep over time (in patients 
≥ 14 years of age)  
− The number of days missed from school or from work 
− 
The response to treatment as assessed by patients ≥ 14 years of age using the 
Treatment Satisfaction Questionnaire for Medication (TSQM). 
• Compare the safety of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) as 
evidenced by the incidence, severity, and relatedness of AEs, and based on laboratory 
assessments 
• Compare the tolerability of Oleogel-S10 (treatment arm A) with vehicle (treatment arm B) 

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• Assess betulin exposure 
3.3 
Objectives – Open-label Follow-up Phase 
The objectives of the 24-month, open-label FU phase are to:  
• Evaluate the safety of Oleogel-S10 as evidenced by the incidence, severity, and 
relatedness of AEs, and based on laboratory assessments 
• Evaluate local tolerability of Oleogel-S10 
• Assess betulin exposure 
• Assess the proportion of patients with first complete closure of the EB target wound at 
M3±14 days 
• Assess the changes from baseline of both DBP (Day [D] 0) and FU (D0)/end of DBP 
(EDBP, D90±7) in total body wound burden at M3±14 days, M12±14 days, and M24±14 
days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in 
percentages of TBSA affected by EB partial thickness wounds at M3±14 days, 
M12±14 days, and M24±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in 
“background” pain before wound dressing changes and the change from baseline in 
“procedural” pain after wound dressing changes at M3±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in itch 
before wound dressing changes at M3±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in 
impact of wounds on sleep (in patients ≥ 14 years of age) at M3±14 days 
• Assess the number of days missed from school or from work at M3±14 days 
• Assess the changes from baseline of both DBP (D0) and FU (D0)/EDBP (D90±7) in 
treatment response (in patients ≥ 14 years of age) at M3±14 days 
• Assess the changes from EDBP (D90±7) in disease severity from both the clinician and 
patient/family perspective at M12±14 days, and M24±14 days 
• Assess the changes from EDBP (D90±7) in patients’ quality of life at M12±14 days, and 
M24±14 days 
4 
INVESTIGATIONAL PLAN 
All references to “the investigator” throughout this document refer to “the investigator or a 
delegated sub-investigator”. 
4.1 
Study Endpoints 
4.1.1 
Primary Efficacy Endpoint – Double-blind Phase 
The primary efficacy endpoint of the DBP is: 
• 
Proportion of patients with first complete closure of the EB target wound (defined as EB 
partial thickness wound of 10 cm2 to 50 cm2 in size aged ≥ 21 days and <9 months) in 
patients with inherited EB (subtypes JEB, DEB, or Kindler syndrome) within 45±7 days of 
treatment with Oleogel-S10 compared to vehicle based on clinical assessment by the 
investigator (the wound will be rated as “closed” at first appearance of complete 
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4.1.2 
Secondary Endpoints – Double-blind Phase 
The key secondary (confirmatory) efficacy endpoints are: 
• 
Time to first complete closure of the EB target wound as evidenced by clinical 
assessment until EDBP (D90±7) 
• 
Proportion of patients with first complete closure of the EB target wound at D90±7 based 
on clinical assessment by the investigator 
• 
The incidence of wound infection between baseline (DBP D0) and D90±7 as evidenced 
by AEs and/or use of topical and/or systemic antibiotics (related to wound infection) 
• 
The maximum severity of wound infection between baseline (DBP D0) and D90±7 as 
evidenced by AEs and/or use of topical and/or systemic antibiotics (related to wound 
infection) 
• 
Change from baseline (DBP D0) in total body wound burden as evidenced by clinical 
assessment using Section I (assessment of the skin except for the anogenital region) of 
the ‘EB Disease Activity and Scarring Index’ (EBDASI) (Loh, Kim et al. 2014) at D90±7 
• 
Change from baseline (DBP D0) in itching using the ‘Itch Man Scale’ (Morris, Murphy et 
al. 2012) in patients ≥ 4 years and up to 13 years of age and the ‘Leuven Itch Scale’ in 
patients ≥ 14 years of age, before wound dressing changes at D90±7 
 
 
Other secondary efficacy endpoints of the DBP are: 
• 
Proportion of patients with first complete closure of the EB target wound at D14±5, D30±7 
and D60±7 based on clinical assessment by the investigator 
• 
Proportion of patients with first complete closure of the EB target wound at D7±2, D14±5, 
D30±7, D45±7, D60±7, and D90±7 based on patient assessment  
• 
Proportion of patients with first complete closure of the EB target wound at D7±2, D14±5, 
D30±7, D45±7, D60±7, and D90±7 based on blinded evaluation of photographs 
• 
Percentage change from baseline (DBP D0) in EB target wound size as evidenced by 
blinded evaluation of photographs taken at D7±2, D14±5, D30±7, D45±7, D60±7, and 
D90±7 
• 
Change from baseline (DBP D0) in total body wound burden as evidenced by clinical 
assessment using Section I (assessment of the skin except for the anogenital region) of 
the ‘EB Disease Activity and Scarring Index’ (EBDASI) (Loh, Kim et al. 2014) at D30±7 
and D60±7 
• 
Change from baseline (DBP D0) in body surface area percentage (BSAP) of TBSA 
affected by EB partial thickness wounds as evidenced by clinical assessment based on 
the ‘Lund and Browder’ chart (Miminas 2007) at D30±7, D60±7, and D90±7 
• 
Change from baseline (DBP D0) in “background” pain using the ‘Face, Legs, Activity, 
Cry, Consolability’ (FLACC) pain rating scale (Merkel, Voepel-Lewis et al. 1997) in 
patients <4 years of age and the ‘Wong-Baker FACES® Pain Rating Scale’ (Wong-Baker 
2015) in patients ≥ 4 years of age before wound dressing changes at D7±2, D14±5, 
D30±7, D45±7, D60±7, and D90±7 
• 
Change from baseline (DBP D0) in “procedural” pain using the FLACC scale (Merkel, 
Voepel-Lewis et al. 1997) in patients <4 years of age and the ‘Wong-Baker FACES Pain 
Rating Scale’ (Wong-Baker 2015) in patients ≥ 4 years of age after wound dressing 
changes at D7±2, D14±5, D30±7, D45±7, D60±7, and D90±7 

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• 
Change from baseline (DBP D0) in itching using the ‘Itch Man Scale’ (Morris, Murphy et 
al. 2012) in patients ≥ 4 years and up to 13 years of age and the ‘Leuven Itch Scale’ in 
patients ≥ 14 years of age before wound dressing changes at D7±2, D30±7 and D60±7 
• 
Change from baseline (DBP D0) in impact of wounds on sleep (in patients ≥ 14 years of 
age) as measured by differences in 11-point Likert scales at D7±2, D30±7, D60±7, and 
D90±7 (Blome, Baade et al. 2014) 
• 
The number of days missed from school or from work due to EB as reported by patients 
at D0 for the last 14 days and cumulatively for all visits until D90±7 
• 
Evaluation of the treatment response (in patients ≥ 14 years of age) using the TSQM, 
Version 9, before wound dressing changes at D7±2, D30±7, D60±7, and D90±7 
(Bharmal, Payne et al. 2009).  
The safety endpoints of the DBP are: 
• 
Incidence, severity, and relatedness of AEs 
• 
Local tolerability as judged by the investigator 
• 
Safety laboratory data 
• 
Systemic exposure to betulin  
4.1.3 
Endpoints of Open-label Follow-up Phase 
• 
Incidence, severity, and relatedness of AEs 
• 
Local tolerability as judged by the investigator 
• 
Safety laboratory data 
• 
Systemic exposure to betulin  
• 
Proportion of patients with first complete closure of the EB target wound at M3±14 days 
based on clinical assessment by the investigator and blinded evaluation of photographs 
• 
Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in total body wound 
burden as evidenced by clinical assessment using Section I (assessment of the skin 
except for the anogenital region) of the EBDASI (Loh, Kim et al. 2014) at M3±14 days, 
M12±14 days, and at End of Follow-up (EoFU) at M24±14 days  
• 
Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in BSAP of TBSA 
affected by EB partial thickness wounds as evidenced by clinical assessment based on 
the ‘Lund and Browder’ chart (Miminas 2007) at M3±14 days, M12±14 days, and at EoFU 
at M24±14 days 
• 
Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in “background” pain 
using the FLACC scale (Merkel, Voepel-Lewis et al. 1997) in patients <4 years of age 
and the ‘Wong-Baker FACES® Pain Rating Scale’ (Wong-Baker 2015) in patients 
≥ 4 years of age before wound dressing changes at M3±14 days 
• 
Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in “procedural” pain 
using the FLACC scale (Merkel, Voepel-Lewis et al. 1997) in patients <4 years of age 
and the ‘Wong-Baker FACES® Pain Rating Scale’ (Wong-Baker 2015) in patients 
≥ 4 years of age after wound dressing changes at M3±14 days 
• 
Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in itching using the 
‘Itch Man Scale’ (Morris, Murphy et al. 2012) in patients ≥ 4 years and up to 13 years of 
age and the ‘Leuven Itch Scale’ in patients ≥ 14 years of age before wound dressing 
changes at M3±14 days 

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• 
Changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in impact of wounds 
on sleep (in patients ≥ 14 years of age) as measured by differences in 11-point Likert 
scales at M3±14 days (Blome, Baade et al. 2014) 
• 
The number of days missed from school or from work due to EB as reported by patients 
at M3±14 days for the last 14 days 
• 
Evaluation of the treatment response (in patients ≥ 14 years of age) using the TSQM, 
Version 9 before wound dressing changes at M3±14 days (Bharmal, Payne et al. 2009) 
• 
Changes from EDBP (D90±7) in disease severity from both clinician and patient/family 
perspective as quantified with the ‘iscorEB’ at M12±14 days, and M24±14 days 
• 
Changes from EDBP (D90±7) in patients’ quality of life as assessed by the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression) with the 
‘EQ-5D’ instrument at M12±14 days, and M24±14 days 
4.2 
Overall Study Design 
This is a 2-part, phase III study with a double-blind, randomised, vehicle-controlled phase to 
compare the efficacy, safety, and tolerability of Oleogel-S10 (treatment arm A) versus vehicle 
(treatment arm B) in patients with inherited EB (subtypes JEB, DEB, or Kindler syndrome). At 
the EDBP (Visit 7a on D90±7), patients in both treatment arms will enter the single-arm, 
open-label FU phase with Oleogel-S10. Each patient will participate for 90±7 days in the 
randomised DBP. Each patient in the open-label FU phase will receive Oleogel-S10 
treatment for 24 months. The total study duration (DBP and open-label FU phase) will be 
approximately 27 months. 
4.2.1 
Double-blind Phase 
The randomised DBP will consist of 3 periods (see Figure 6):  
1. 
Screening (up to 28 days prior to baseline) 
Study sites contact and invite patients registered in centre-specific databases. Patients 
who fail screening may be rescreened if he/she later becomes eligible, as deemed 
appropriate by the investigator. 
2. 
Baseline, enrolment, and stratified randomisation (D0) 
The investigator will confirm eligibility for the patient on D0 corresponding to the study 
flow chart, check the eligibility criteria, and enrol the patient into the study. The EB target 
wound will be selected based on the ‘Investigator’s Worksheet’ displayed in Figure 23. 
Patients will be stratified according to their EB subtype and target wound size (cm2) to 
the following groups: JEB/Kindler 10 to <20; JEB/Kindler 20 to <30; JEB/Kindler 30 to 
50; DEB 10 to <20; DEB 20 to <30; or DEB 30 to 50 cm2. Patients will then be 
randomised 1:1 to receive either Oleogel-S10 (treatment arm A) or vehicle (treatment 
arm B) (see Section 9.1 Baseline, Enrolment, and Stratified Randomisation [D0]). 
3. 
Intervention (90 days±7 days) 
The treatment of the EB partial thickness target wound and all areas on a patient’s body 
that are affected by EB partial thickness wounds with Oleogel-S10 and SOC 
non-adhesive wound dressing (treatment arm A) or with vehicle and SOC non-adhesive 
wound dressing (treatment arm B) as described in Section 7.1 Treatment Schedule will 
start the same day (D0). 
Each patient will participate for 90±7 days in the DBP of the study.  

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4.2.2 
Open-label Follow-up Phase 
Once the EDBP visit for the randomised DBP has been completed and the return of the 
corresponding unused study medication has occurred, the patient will enter the single-arm, 
open-label, 24-month FU phase. The EDBP visit at D90±7 (Visit 7a) corresponds to the first 
visit (D0) of the FU phase (Visit 7b). The data of total body wound burden and BSAP 
assessment at EDBP (D90±7) will be used as baseline data of D0 of the FU (see Section 9.5 
Open-label Follow-up Phase).  
All patients will start with topical Oleogel-S10 administration on D0 of the FU phase to all 
areas on the patient’s body that are affected by EB partial thickness wounds as described in 
Section 7.1 Treatment Schedule. Wound areas will be covered with SOC non-adhesive 
wound dressings. This procedure will be repeated during all dressing changes based on the 
study flow chart (at least every 4 days) until the end of treatment at M24±14 days. The 
investigator may implement a dose interruption if considered medically necessary for optimal 
management of the patient. 
Patients who participate in the FU phase will receive Oleogel-S10 treatment for 24 months. 
After the EoFU visit, it is intended that patients will receive Oleogel-S10 on a named-patient 
basis, where feasible as per local regulation, until approval of the investigational product. 
4.2.3 
End of Trial 
The End of Trial is defined as completion of the last visit or assessment for the last subject. 
 

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Figure 6 
Design of Double-blind, Randomised Treatment Phase and Open-label Follow-up Phase 
 
Amryt Pharma Figure 
DEB = Dystrophic EB; EB = Epidermolysis bullosa; JEB = Junctional EB; SOC = Standard of care 
 

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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
A patient will be eligible for study participation only if all of the following criteria apply: 
1. Male and female patients aged ≥ 4 years with the following subtypes of inherited EB: 
JEB, DEB, and Kindler syndrome  
Note: Children ≥ 21 days old and <4 years may be included only after confirmation by the 
Independent Data Monitoring Committee (IDMC) upon review of the safety and 
bioanalytical data at the interim safety review stage  
2. 
Patients with an EB target wound (i.e., EB partial thickness wound of 10 cm2 to 50 cm2 in 
size, aged ≥ 21 days and <9 months) outside of the anogenital region) 
3. 
Patient and/or his/her legal representative has/have been informed, has/have read and 
understood the patient information/informed consent form, and has/have given written 
informed consent 
4. 
Patient and/or his/her legal representative must be able and willing to follow study 
procedures and instructions 
5.2 
Exclusion Criteria 
A patient will not be eligible to participate in this study if any of the following criteria apply: 
1. 
Patient has EB subtype EBS 
2. 
EB target wound that is ≥ 9 months old or has clinical signs of local infection 
3. 
Use of systemic antibiotics for wound-related infections within 7 days prior to enrolment 
4. 
Administration of systemic or topical steroids (except for inhaled, ophthalmic, or topical 
applications, such as budesonide suspension for oesophageal strictures [e.g., Pulmicort 
Respules® 0.25 mg/2 mL or 0.5 mg/2 mL]) within 30 days before enrolment 
5. 
Immunosuppressive therapy or cytotoxic chemotherapy within 60 days prior to enrolment 
6. 
Patient has undergone stem cell transplant or gene therapy for the treatment of inherited 
EB 
7. 
Current and/or former malignancy including basal cell carcinomas and squamous cell 
carcinomas 
8. 
Enrolment in any interventional study or treated with any investigational drug for any 
disease within 4 weeks prior to study entry 
9. 
Factors present in the patient and/or his/her legal representative that could interfere with 
study compliance such as inability to attend scheduled study visits or compliance with 
home dressing changes 
10. Pregnant or nursing women 
11. Women of childbearing potential, including postmenarchal female adolescents, and men 
who are not willing to use an effective form of birth control with failure rates <1% per 
year (e.g., implant, injectable, combined oral contraceptive, intrauterine contraceptive 
device, sexual abstinence, vasectomy or vasectomised partner) during participation in 
the study (and at least 3 months thereafter) 
12. Patient is a member of the investigational team or his/her immediate family 
13. Patient lives in the same household as a study participant 
 
 

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6 
STUDY MEDICATION 
6.1 
Description of the Investigational Product 
6.1.1 
Formulation, Packaging, and Labelling 
The investigational product, Oleogel-S10, is a colourless to slightly yellowish, opalescent gel 
packed in white collapsible aluminium tubes containing 23.4 g gel each. Tamper-evident 
aluminium membranes close the tubes, which are fitted with white polypropylene screw caps. 
The single-use tubes are packed in cardboard boxes. The investigational product will be 
packed and labelled according to applicable regulatory requirements. 
Please refer to Section 2.2 Investigational Product for the composition of Oleogel-S10. 
6.1.2 
Storage and Stability 
Oleogel-S10 gel is stable for 24 months if stored below 30°C (refer to ‘Investigational 
Medicinal Product Manual’ for more details). 
6.1.3 
Drug Accountability 
A sufficient number of single-use Oleogel-S10 or vehicle tubes will be provided to sites at 
appropriate intervals depending on the phase of the study and accrual of patients. The 
investigator, or the person designated by the investigator, will be responsible for dispensing 
study medication to the patients. The site may ship study medication to a patient’s home 
using a courier if permitted by local regulations. 
At each site, the investigator, or the person designated by the investigator, will be 
responsible for keeping accurate records of study medication accountability comprising the 
receipt of study medication, the dispensing of study medication, and the return of all used 
and unused study medication throughout the study. The drug accountability form should be 
kept up to date and will be reviewed periodically by the study monitor. 
Patients will be asked to keep all used and unused tubes and return them to the site during 
the scheduled visits. For drug accountability, the number of used and unused tubes will be 
counted and used kits will be weighed. The data on frequency of dressing changes during 
the study will be used to support drug accountability. All unused tubes will be redispensed to 
the patient after drug accountability is completed by the site study team member. 
For estimations of drug compliance, treatment interruptions will be recorded on the electronic 
Case Report Form (eCRF) and compliance will be calculated as (treatment end date – 
treatment start date +1 – treatment interruptions in days) / (treatment end date – treatment 
start date +1). The compliance calculation will be adjusted for variations in drug application 
due to changes in wounds and difference in frequencies of dressing changes.  
6.2 
Description of the Vehicle 
For clarification, please note that the term “vehicle” describes the control/placebo throughout 
this protocol. 
The sterile vehicle gel matches Oleogel-S10 in texture and visual appearance. 100 g of the 
vehicle gel will consist of 85 g sunflower oil, 5 g Cera flava/yellow wax, and 10 g Carnauba 
wax. 
6.3 
Standard of Care Non-adhesive Wound Dressings 
Standard of care non-adhesive wound dressings are defined as modern non-adhesive 
wound dressings or equivalents. Please refer to the ‘International Consensus Best Practice 

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Guidelines for Skin and Wound Care in Epidermolysis Bullosa’ for recommended wound 
dressings in different subtypes and wounds of EB (Denyer and Pillay 2012).  
Standard of care varies across geographic regions and between sites. In addition, patients 
have individual preferences strongly rooted in their personal experience. Therefore, it will 
probably not be feasible to standardise wound care completely in this study. Hence, patients 
will be allowed to continue using their SOC non-adhesive wound dressings except for silver 
dressings and dressings containing topical emollients (e.g. vaselinized gauze). However, it is 
recommended to reduce the diversity of wound dressings as much as possible, e.g., by using 
a small number of products, such as Mepitel® (Mölnlycke Health Care AB, Sweden) or 
PolyMem® (Ferris Mfg. Corp., USA) only.  
7 
STUDY TREATMENT 
7.1 
Treatment Schedule 
The investigator will explain to the patient and/or to his/her legal representative that the wound 
dressings will have to be changed and the study medication will have to be applied at least 
every 4 days. The patient can keep his/her usual schedule of wound dressing changes; for 
example every day, every second, third, or fourth day as long as he/she does not wait longer 
than 4 days until the next wound dressing change. The patient will be asked to keep a regular 
schedule of wound dressing changes (i.e., not to change intervals between wound dressing 
changes) and to report this schedule to the investigator. 
The patient will be allowed to apply the study medication directly to the wound or to the area of 
the wound dressing that will be used to cover the wound so that the study medication is in direct 
contact with the wound, based on personal preference.  
Both the EB target wound and all areas on the patient’s body that are affected by EB partial 
thickness wounds will be treated with study medication. The study medication should not be 
rubbed into the wounds. The study medication should not be mixed with other skin products 
such as creams, ointments, gels, or emollients, or applied with such skin products at the 
same time. If the EB target wound (or other wound matching target wound criteria), is 
confirmed as closed, it is not necessary to continue to apply study medication to the closed 
wound. The patient may dress the wound to protect the area, if required.  
Products and dressings that are permitted or not permitted for use in conjunction with the 
study medication during the DBP and the open-label FU are described in Section 7.5.1 
Permitted Concomitant Medication and Section 7.5.2 Non-permitted Concomitant 
Medication. 
Areas on the patient’s body that are not affected by EB partial thickness wounds are not to 
be treated with study medication. The study medication is not intended for use on full 
thickness wounds in this study. 
The study medication (Oleogel-S10 or vehicle gel) will be administered topically at 
approximately 1 mm (0.04 inch) thickness to the EB target wound and to all areas on the 
patient’s body that are affected by EB partial thickness wounds. Wound areas will then be 
covered with an SOC non-adhesive wound dressing. Alternatively, the study medication may 
be applied to the dressing first and the medication-covered dressing then placed on the 
wound so that the study medication is in direct contact with the wound. This procedure will be 
repeated during all dressing changes based on the study flow chart (at least every 4 days) 
until EDBP (D90±7).  
The open-label treatment with Oleogel-S10 during the FU phase corresponds to the 
treatment described for the DBP of the study, but lasts until the end of treatment at 
M24±14 days. 

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7.1.1 
Treatment Assignment/Blinding Procedure 
Patients will be stratified according to their EB subtype and size of target wound (cm2) to the 
following groups: JEB/Kindler 10 to <20; JEB/Kindler 20 to <30; JEB/Kindler 30 to 50; DEB 
10 to <20; DEB 20 to <30; or DEB 30 to 50 cm2. Patients will then be randomised 1:1 to 
receive either Oleogel-S10 (treatment arm A) or vehicle gel (treatment arm B). Investigators 
and patients both will be blinded for treatment allocation. 
Once a randomisation number has been assigned, that number must not be used again for 
any other patient (e.g., when the patient is withdrawn from the study, that patient’s 
randomisation number must not be reused for any other patient). 
An independent unblinded biostatistics team in a separate location will maintain the 
randomisation scheme key and will only distribute this to approved personnel. This key will 
remain unavailable to all other individuals until after DBP completion and subsequent locking 
of the study database for the DBP. 
For the purpose of the interim analysis for sample size re-estimation and the unblinded 
interim safety review to confirm if the study can be expanded to allow the inclusion of 
children with EB to all ages (i.e., ≥ 21 days and <4 years), the independent unblinded 
biostatistics team will provide the unblinded results to the approved IDMC members. 
During the FU phase, all patients will be treated with Oleogel-S10. Both the investigator and 
the patient will know the treatment. 
7.2 
Dose Interruption/Dose Modification for Adverse Events 
No treatment-limiting toxicities have been reported in studies of Oleogel-S10 across several 
indications, including EB; therefore, dose interruptions due to toxicity are not expected. The 
investigator may implement a dose interruption if considered medically necessary for optimal 
management of the patient. Dose interruptions are not allowed for using non-permitted 
concomitant medication (see Section 7.5.2) to treat worsening of wound status, increase in 
wound size, and wound infections of EB target wounds and other wounds matching target 
wound criteria (see Section 8.1.2). For worsening of the EB target wound status or EB target 
wound infections the patient may discontinue the DBP and enter the FU phase prematurely 
(see Section 7.3). Should any other interruptions of treatment occur, the investigator should 
be contacted immediately.  
7.2.1 
Emergency Procedure for Unblinding 
Patients should not be unblinded except in an emergency when it is necessary to know the 
treatment assignment. For example, unblinding may be indicated if: 
• There is a medical emergency in a study patient where knowledge of the blinded 
treatment is necessary to make medical decisions 
• There is need to know the treatment assignment in order to treat an AE 
• There is a situation in which a child in a patient’s household accidentally ingests the study 
medication 
• In the event of a suspected unexpected serious adverse reaction (SUSAR) needing 
expedited reporting (following the study safety plan) 
• Request by the external IDMC 
Unblinding is performed in the electronic system iMedidata Balance. This system records the 
date and time and reason for unblinding, as well as the person requesting the code break. 
The system also notifies the sponsor in a blinded fashion of a code break. Patients who are 
unblinded by the investigator will not remain in the study. 

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There will be an unblinded interim analysis for the purpose of a sample size re-estimation 
performed by the Unblinded Biostatistician and evaluated by the IDMC. Details of the 
unblinded sample size re-estimation will be described in the Statistical Analysis Plan (SAP). 
The sample size re-estimation will be performed when approximately 50% of patients have 
completed D45±7. The final unblinding of the study will not take place until all patients have 
completed the study, all queries have been resolved, and the database is locked. 
7.3 
Patient Discontinuation Criteria 
Patients and/or his/her legal representatives will have the right to withdraw from the study at 
any time for any reason without prejudice to their future medical care.  
The investigator will also be able to withdraw patients from the study for the following 
reasons: 
• Worsening of the EB target wound status or EB target wound infection as assessed by the 
investigator 
• Patient is non-compliant with the study procedures or medications in the opinion of the 
investigator 
• Progression of a medical condition, which in the opinion of the investigator should 
preclude further participation of the patient in the study 
• Administration of non-permitted concomitant medication(s) 
• Investigator’s decision that a change of therapy is in the patient’s best interest 
• Occurrence of an AE, which makes discontinuation desirable or necessary in the 
investigator’s and/or the patient’s opinion 
If a patient discontinues the DBP or the FU phase prematurely due to an AE/serious AE 
(SAE), every effort will be made to follow the patient until the resolution of the AE/SAE. If 
a patient discontinues the DBP prematurely due to worsening of the EB target wound 
status or due to EB target wound infection, the investigator may decide whether the 
patient enters the FU phase prematurely or discontinues the study completely. 
• Pregnancy as evidenced by a positive pregnancy test 
If a patient or the partner of a male patient becomes pregnant during the study, during the 
FU phase, or 30 days within the last application of study medication, the sponsor must be 
informed within 24 hours. The investigator will be asked to complete a pregnancy report 
provided by the sponsor. The investigator will be asked to obtain data on the course of the 
pregnancy, including perinatal and neonatal outcome up to 28 days after delivery (see 
Section 11.4.2 Other Reportable Information). 
If a patient discontinues the study prematurely during the DBP, the EDBP (D90±7) visit 
assessment should be performed (see Section 9.4 Visit 7a [Site Visit at D90±7] End of 
Double-blind Phase). In case the patient discontinues the FU phase prematurely, the 
assessments scheduled for the EoFU visit should be performed (see Section 9.5.5 End of 
Follow-up Visit 10 [M24±14 Days]).  
All data collected before premature discontinuation of the study will be used for analysis. 
Patients who drop out will not be replaced.  
7.4 
Overdose 
No cases of Oleogel-S10 overdose have been reported. The maximum exposure achieved in 
nonclinical studies is 1100 ng/mL. Nonclinical safety and toxicology studies have not 
demonstrated any dose-limiting toxicities. Since Oleogel-S10 is administered topically, 
overdose is considered unlikely. Patients in this clinical trial will be closely monitored for any 
adverse events, and treatment will be terminated if felt appropriate. Based upon the 

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pharmacological properties of Oleogel-S10, no additional specific measures are advised. 
Standard medical care should be used to monitor patients with an assumed or documented 
overdose with Oleogel-S10. 
7.5 
Concomitant Medication 
7.5.1 
Permitted Concomitant Medication 
The following medication will be permitted during both phases of the study (DBP and 
open-label FU phase): 
• Liquid antiseptics such as polyhexanide, iodine products, or octenidine dihydrochloride at 
each wound dressing change to clean the EB target wound (and other wounds matching 
target wound criteria) and/or to reduce microbial colonisation of the EB target wound (and 
other wounds matching target wound criteria) prior to study treatment 
• Bathing (e.g., with chlorhexidine, diluted bleach, or salt) prior to study treatment at each 
wound dressing change (Denyer and Pillay 2012) 
• Systemic antibiotics except for treatment of EB target wound (and other wounds matching 
target wound criteria) infections 
• Inhaled, ophthalmic, or topical steroids, such as budesonide suspension for oesophageal 
strictures (e.g., Pulmicort Respules® 0.25 mg/2 mL or 0.5 mg/2 mL) 
• Supportive therapy upon the investigator’s discretion 
On single EB wounds (except for the EB target wound and other wounds matching target 
wound criteria), the following medication will be permitted during both the DBP and FU phase 
of the study: 
• Silver sulfadiazine 
• Topical antibiotics 
• Topical steroids 
7.5.2 
Non-permitted Concomitant Medication 
The following medication will not be permitted during the study until M3±14 days of the 
open-label FU: 
• Systemic steroids (except for inhaled, ophthalmic, or topical applications, such as 
budesonide 
suspension 
for 
oesophageal 
strictures 
[e.g., 
Pulmicort 
Respules® 
0.25 mg/2 mL or 0.5 mg/2 mL]) 
• Immunosuppressive therapy or cytotoxic chemotherapy 
• Systemic antibiotics to treat EB target wound (and other wounds matching target wound 
criteria) infections 
On areas on the patient’s body that are affected by EB wounds, the following medication will 
not be permitted during the DBP of the study: 
• Skin products such as creams (including barrier creams), ointments (and dressings 
containing topical emollients e.g. vaselinized gauze), gels, or emollients 
On the EB target wound (and other wounds matching target wound criteria), the following 
medication will not be permitted until complete closure and confirmed epithelialisation during 
both the DBP and FU phase of the study: 
• Silver dressings 
• Silver sulfadiazine 

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• Topical antibiotics 
• Topical steroids 
8 
ASSESSMENTS 
Please refer to Section 1.2 Flow Chart of Study (Randomised, Double-blind and Open-label 
Follow-up) for a tabular overview of assessments by visit.  
8.1 
Eligibility and Safety Assessments 
8.1.1 
Eligibility Assessments 
Informed Consent 
The investigator will obtain written informed consent from the patient and/or his/her legal 
representative(s) before he/she will initiate any study-specific procedure. For this study in 
patients <18 years, in addition to information sheets and consent/assent forms for patients 
(according to applicable local regulations), parent/legal guardian information sheets and 
consent forms will also be prepared. 
The following criteria will be assessed for eligibility prior to enrolment: 
Inclusion/Exclusion 
The investigator will assess the patient’s eligibility as outlined in Section 5.1 Inclusion Criteria 
and Section 5.2 Exclusion Criteria including confirmation of a negative urine pregnancy test 
in women of childbearing potential and postmenarchal female adolescents. 
Demographics 
Age, gender, ethnic origin, Fitzpatrick skin type (Fitzpatrick 1988), height, and weight will be 
recorded at baseline. 
Medical History/Current Medical Conditions 
The investigator will ask the patient and/or his/her legal representative(s) for the patient’s 
general and disease-specific medical history and current medical conditions. The investigator 
will record the EB subtype as well as the date and method of diagnosis (e.g., genetic 
analysis, immunofluorescence mapping, transmission electron microscopy). If genetic 
confirmation of EB subtype is not available for the patient, the patient will be asked to 
consent to additional testing for genetic confirmation of EB subtype. Consent to the additional 
genetic testing is optional, and written informed consent can be given at any visit during the 
study.  
Physical Examination 
The investigator will do a complete physical examination of the patient and will document all 
clinically relevant findings including systemic manifestations of EB.  
Selection of Target Wound 
The investigator will select 1 EB target wound based on the ‘Investigator’s Worksheet’ 
displayed in Figure 23. Target wounds must be EB partial thickness wounds of 10 cm2 to 
50 cm2 in size and must be aged ≥ 21 days and < 9 months. Wounds in the anogenital region 
should not be chosen as target wounds, however, wounds close to this region may be 
selected provided it is possible to apply dressings in accordance with Section 7.1 and there 
are no privacy concerns regarding these wounds. 
In the event of several EB partial thickness wounds match the target wound criteria, the 
wound of the largest size, maximum depth and longest duration should be chosen as the 
target wound, based on the investigator’s clinical judgement. The target wound and all other 
wounds that match target wound criteria must be mapped for size, location and duration in a 

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body chart and appropriately photo-documented until complete closure or until M3±14 days 
of the open-label FU phase. Information regarding size and location of all wounds that match 
the target wound criteria will be captured in the database. 
8.1.2 
Safety Assessments 
Concomitant Medication 
During the DBP and open-label FU phase, all concomitant medications will be recorded. 
Adverse Events 
Adverse events occurring before the first administration of study medication will be recorded 
in the Medical History/Current Medical Conditions section of the eCRF. AEs occurring during 
the treatment period of the DBP and the FU phase until 4 weeks after the last administration 
of study medication (Oleogel-S10 or vehicle) will be recorded in the AE section of the eCRF. 
During the screening period (<D0) and at baseline (D0 of the DBP) before study medication 
administration, AEs related to study procedures should also be reported. For reporting of 
AEs, please refer to Section 11.2 Recording of Adverse Events and Serious Adverse Events. 
Worsening of wound status, increase in wound size, re-opening of wounds and wound 
infections should be reported as AEs. Assessment of wound status and wound size should 
be in comparison to baseline (DBP) and not the previous visit. It should be ensured that 
clinical signs are present for wound infections, i.e., mere colonisation of the wound with 
proliferating bacteria without a host response is not to be reported as AE. 
Serious Adverse Events 
Serious AEs will be recorded in the SAE section of the eCRF during screening, at baseline, 
during the DBP, and the 24-month, open-label FU phase. For reporting of SAEs, please refer 
to Section 11.4 Immediately Reportable Information. 
Local Tolerability 
Local tolerability will be judged by the investigator continuously throughout the study. 
Vital Signs 
Vital signs (heart rate, respiratory rate, and body temperature) will be recorded at baseline, at 
D90±7 of the DBP, and at M24±14 days of the open-label FU. 
Electrocardiogram  
An electrocardiogram (ECG) will be performed at baseline, at D90±7, and at M24±14 days, 
where available. The ECG recordings are to be reviewed by the investigator and classified as 
“normal’ or ‘abnormal”. Abnormal ECGs must in addition be classified as “abnormal, clinically 
significant” or “abnormal, not clinically significant”. The reason(s) for ‘abnormal’ findings 
should be documented. Abnormal, clinically significant findings occurring after first 
administration of study medication should be reported as an AE (unless already pre-existing 
at baseline with the same severity).  
Laboratory Assessments 
Laboratory safety assessments comprise: haematology (full blood count with white blood cell 
differential); biochemistry panels (sodium [Na], potassium [K], calcium [Ca], chloride [Cl], 
phosphate [P], blood glucose [BG]) including renal (urea, creatinine) and hepatic function 
tests 
(serum 
total 
protein, 
albumin, 
alanine 
aminotransferase 
[ALT], 
aspartate 
aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], and alkaline phosphatase 
[AP]); and betulin levels. Laboratory safety assessments samples are to be taken at 
baseline, at D90±7, M12 ±14 days and at M24±14 days. If haematology and biochemistry 
parameters have been determined within 4 weeks prior to enrolment, they may be used as 
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safe blood sampling by age group, i.e. smaller volumes should be taken in younger children 
according to the local laboratory policy. 
Blood tests for Betulin Analysis 
As well as the mandatory safety laboratory samples, patients will be asked to provide written 
informed consent for collecting additional optional blood samples up to M24±14 days of the 
open-label FU. Betulin levels will be analysed in dried blood spots that will be sent to the 
central laboratory (Nuvisan GmbH, Germany).  
Pregnancy Tests 
Urine pregnancy tests will be conducted in women of childbearing potential/postmenarchal 
female adolescent patients using test strips provided by Amryt Research Ltd. at DBP 
baseline (D0) and EDBP (D90±7), and M3±14 days, M12±14 days, and M24±14 days of the 
open-label FU. If a pregnancy test has been performed within 14 days prior to baseline it 
does not need to be repeated at baseline. 
8.2 
Assessment of Efficacy 
A training programme will be provided to site study team members for all efficacy 
assessments.  
Assessment of wound status should be in comparison to baseline (DBP) and not the 
previous visit.   
 
8.2.1 
Photography of EB Target Wound and Other Wounds 
The investigator or delegated site study team member will photo-document the EB target 
wound and all other wounds that match target wound criteria with the ARANZ Silhouette® 
system for blinded efficacy assessment by 3 independent experts.  
The Silhouette® system consists of the SilhouetteStar™ point of care imaging device (see 
Figure 7 a) that captures the wound image using 3-D laser technology (see Figure 7 b). In 
addition, it provides the SilhouetteConnect™ software, which creates a 3-D model of the 
wound based on photo-data, derives measurements of the model, and records standardised 
notes (see Figure 7 c).  
Figure 7 
Target Wound Photography with the ARANZ Silhouette® System 
 
Source: ARANZ Medical Ltd., Christchurch 8140, New Zealand 
The ARANZ Silhouette® system measures accurately, precisely, and reliably, provides high 
quality imaging, and a standardised documentation. The Silhouette® system is compliant with 
all major accreditation marks. Regulatory clearance includes an FDA Class 1 approval (US) 
along with CE Mark (Europe), Health Canada – Therapeutic Products Directorate (Canada), 
and Therapeutic Goods Administration approval (Australia). 
The investigator and authorised site study team members will receive both the ARANZ 
Silhouette® system and a standardised training before start of the study. The ‘Photo 

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Documentation Manual’ will provide a detailed description of the ARANZ Silhouette® system, 
instructions for use, and a standard operating procedure of target wound photography.  
During screening, the investigator will select the EB target wound as described in the 
‘Investigator’s Worksheet’ (see Figure 23). Before start of treatment, he/she will select 
2 appropriate anatomical landmarks on either side of the EB target wound. He/she will 
document the landmarks used. The investigator or delegated site study team member will 
take a baseline reference image with these landmarks. He/she will create a separate image 
of the EB target wound with tracings. At future visits, the investigator or delegated site study 
team member will always refer to the baseline reference image to ensure that the correct 
wound is assessed. All other wounds that match target wound criteria will be 
photo-documented similarly.  
The baseline reference image(s) of the target wound and of other wounds that match target 
wound criteria will be uploaded to the wound documentation report and the results will be 
recorded in the eCRF as described in the ‘Photo Documentation Manual’. Photo compilations 
by visit will be prepared for the blinded expert landmark analysis (i.e., presence of complete 
wound closure and EB target wound size). Details on the blinded expert assessments of the 
target wound and of other wounds that match the target wound criteria will be determined in 
a separate plan and results analysed per the SAP. 
8.2.2 
Total Body Wound Burden 
An investigator will assess the change in total body wound burden clinically using Section I 
(assessment of the skin except for the anogenital region) of the EBDASI (see Figure 8) (Loh, 
Kim et al. 2014).  
The EBDASI is a reliable and valid instrument for inherited EB of all ages and subtypes, 
which scores activity response to therapy separately from damage. It consists of 5 sections, 
namely Section I ‘Skin’, Section II ‘Scalp’, Section III ‘Mucous Membranes’, Section IV ‘Nail 
Disease’, and Section V ‘Other Surfaces and SCC [squamous cell carcinoma]’. Since this 
study will investigate medication for cutaneous use, Section I will be used only.  
8.2.3 
Body Surface Area Percentage 
An investigator will assess the change in BSAP of TBSA affected by EB partial thickness 
wounds clinically using a matrix based on the ‘Lund and Browder’ chart (see Figure 9) 
(Miminas 2007).  
There are 3 approaches to assess BSAP, the ‘Rule of Nines’, the ‘Rule of Palms’, and the 
‘Lund and Browder’ chart. The ‘Lund and Browder’ chart is regarded as the most accurate 
and is widely used in the management of burn patients. It consists of 2 drawings of the 
anterior and posterior part of the human body. The BSAP of the respective regions appear 
either on the drawings or on a corresponding table providing the BSAP by age. The matrix 
that has been prepared for the evaluation of the change in BSAP affected by EB partial 
thickness wounds in this study is based on these regional weighing factors by age to account 
for the different proportions of children to be included in this study.  
While Section I of the EBDASI measures the total body wound burden consisting of erosions, 
blisters, and crusting, the matrix based on the ‘Lund and Browder’ chart measures the BSAP 
of EB partial thickness wounds only.  
8.3 
Patient-reported Outcomes 
Amryt Research Ltd. evaluated Patient-reported Outcome (PRO) instruments based on the 
target patient population, the clinical study objectives and design, the PRO instrument’s 
conceptual framework, and the PRO instrument’s measurement properties as recommended 
in the 2009 FDA guidance for industry ‘Patient-reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims’. Since a Health-related Quality of Life 

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instrument evaluating age-appropriate concepts for EB was not available and content validity 
was lacking in the majority of Health-related Quality of Life measures (Mordin, Clark et al. 
2012), the concepts ‘pain’, ‘itch’, ‘impact of wounds on sleep’, and the patient’s satisfaction 
with treatment will be assessed with concept-specific PRO instruments instead.  
Standardised training for PROs will be provided to ensure consistent instructions are given to 
patients, and to provide sites with standardised guidance in reviewing data and answering 
questions about the scales. If a legal representative completes the assessments, the 
investigator should make sure, that preferably the same legal representative completes the 
assessments each time to limit variability. 
8.3.1 
‘Itch Man Scale’ 
In patients ≥ 4 years and up to 13 years of age, itching will be assessed using the ‘Itch Man 
Scale’ (see Figure 10) (Morris, Murphy et al. 2012). The ‘Itch Man Scale’ is the only measure 
that specifically assesses itching in children. Blakeney and Marvin developed it in 2000 
based on a child’s drawing showing his distress with itching. The ‘Itch Man Scale’ is a 
validated itch assessment tool.  
8.3.2 
‘Leuven Itch Scale’ 
In patients ≥ 14 years of age, itch will be evaluated using the ‘Leuven Itch Scale’ (see Figure 
11) (Haest, Casaer et al. 2011). The ‘Leuven Itch Scale’ is an instrument measuring all 
dimensions of the itch experience including symptom occurrence (frequency, duration, 
severity, and circumstances), symptom distress, symptom management, symptom location, 
sensory perception of the symptom, and consequences of the symptom. Snauwaert et al 
demonstrated that the ‘Leuven Itch Scale’ was an appropriate instrument to measure itch in 
EB (Snauwaert, Yuen et al. 2014). 
8.3.3 
‘Face, Legs, Activity, Cry, Consolability’ Pain Rating Scale 
In patients <4 years of age, the investigator or delegated site study team member will use the 
FLACC scale for assessing “background” pain before wound dressing change and 
“procedural” pain after wound dressing change (see Figure 12) (Merkel, Voepel-Lewis et al. 
1997). 
The FLACC pain rating scale is a valid and reliable tool for quantifying pain behaviours in 
children who may not be able to verbalise the presence or severity of pain. It was found to 
have high interrater reliability.  
8.3.4 
‘Wong-Baker FACES Pain Rating Scale’ 
In patients ≥ 4 years of age, ‘Wong-Baker FACES Pain Rating Scale’ will be used for 
assessing “background” pain before wound dressing change and “procedural” pain after 
wound dressing change (see Figure 13) (Wong-Baker 2015). 
Wong and Baker have developed the ‘Wong-Baker FACES Pain Rating Scale’ in the early 
1980s, because children had considerable difficulty using any scales with numbers, 
unfamiliar words, or colours. It is reliable and valid.  
8.3.5 
Impact of Wounds on Sleep 
In patients ≥ 14 years of age, the site study team member will ask before wound dressing 
change: “Have the wounds affected your sleep within the last 7 days” using an 11-point Likert 
scale (‘Not at all’ = 0, ‘Very much’ = 10) (see Figure 14) (Blome, Baade et al. 2014).  
8.3.6 
Days Missed from School or Work 
A site study team member will ask the patient (in patients ≥ 14 years of age) or a parent (in 
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due to EB in the last 14 days (D0) or since the last visit if it was performed within less than 14 
days (days missed to attend study visits will not be counted) (see Figure 15).  
8.3.7 
Treatment Satisfaction Questionnaire for Medication, Version 9 
A site study team member will ask the patient (in patients ≥ 14 years of age) whether he/she 
was satisfied with the treatment using the abbreviated TSQM, Version 9 (see Figure 16) 
(Bharmal, Payne et al. 2009).  
8.3.8 
Instrument for Scoring Clinical Outcome of Research for 
Epidermolysis Bullosa (iscorEB) 
The iscorEB is a combined score that contains clinician- and patient-derived items. This 
instrument was proposed by Schwieger-Briel et. al. (2015) and the combined scores allow to 
differentiate between EB subtypes and degrees of severity (Schwieger-Briel et al. 2015). 
For the clinical items five domains are evaluated (skin involvement, mucosal involvement, 
internal organ involvement, laboratory abnormalities, and complications/procedures). Each 
item contains several questions that will be used to obtain an item “score”, that will allow the 
calculation of a “total clinical score” by adding all individual item scores. The maximum total 
clinical score is a value of 114. 
For the patient items seven domains are evaluated (pain, itch, essential functions, sleeping, 
daily activities, mood and impact). Each item contains questions that will be used to obtain 
an item “score”, that will allow the calculation of a “total patient score” by adding all individual 
item scores. The maximum total patient score is a value of 120.Clinical and patient total 
scores and item scores will be recorded and derived in the eCRF. 
8.3.9 
EQ-5D 
EuroQol 5 Dimensions (EQ-5D) is a standardized instrument developed by the EuroQol 
Group (euroqol.org) as a measure of health-related quality of life that can be used in a wide 
range of health conditions and treatments. For this trial the EQ-5D-5L and EQ-5D-Y with 5 
levels of severity will be assessed as applicable depending on the patient’s age (Herdman et 
al 2013, Wille et al 2010). 
Both questionnaires assess several dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) with a multiple choice question (five possible choices for 
the EQ-5D-5L, or three possible choices for the EQ-5D-Y). An overall score between 0 (worst 
possible) and 100 (best possible) is also recorded to describe how good or bad the health of 
the patient is on the day of the assessment. 
All questions to assess individual dimensions and the overall score will be recorded in the 
eCRF. 
 

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Figure 8 
Assessment of Total Body Wound Burden based on the ‘EB Disease 
Activity and Scarring Index’ (EBDASI) 
Source: (Loh, Kim et al. 2014) 
 

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Figure 9 
Assessment of Body Surface Area Percentage of Total Body Surface 
Area Affected by EB Partial Thickness Wounds 
 
Source: (Miminas 2007) 
 

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Figure 10 
‘Itch Man Scale’ 
 
Source: (Morris, Murphy et al. 2012) 
 

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Figure 11 The ‘Leuven Itch Scale’ 
 

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Source: (Haest, Casaer et al. 2011) 
 

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Figure 12 
‘Face, Legs, Activity, Cry, Consolability’ (FLACC) Pain Rating Scale 
 
Source: (Merkel, Voepel-Lewis et al. 1997) 
 

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Figure 13 
‘Wong-Baker FACES®’ Pain Rating Scale 
 
Source: (Wong-Baker 2015) 
 

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Figure 14 
Impact of Wounds on Sleep Based on Wound Quality of Life 
Questionnaire 
 
 
Source: (Blome, Baade et al. 2014) 
 
 

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Figure 15 
Days Missed from Work or School 
 

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Figure 16 Treatment Satisfaction Questionnaire for Medication, Version 9 
 
 

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Source: (Bharmal, Payne et al. 2009) 
 

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Figure 17 
iscorEB, September 2015 
 
 

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Figure 18 
EQ-5D-5L, Version 1.2 
 

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Figure 19 
EQ-5D-Y, Version 2.0 
 

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9 
VISIT SCHEDULE 
The visit schedule is summarised in Section 1.2 Flow Chart of Study (Randomised, 
Double-blind and Open-label Follow-up). Figure 20 displays the assessments by visit during 
the randomised DBP and Figure 21 shows the assessments by visit during the open-label 
FU. The proposed chronology of efficacy assessments by visit is summarised in Figure 22.  
The calculation of all study days is based on D0, which is defined as the day of the first 
application of study medication for the randomised DBP and the day of the first application of 
study medication for the open-label FU phase. 
9.1 
Screening, Enrolment, and Stratified Randomisation (≤D0) 
During screening, study sites might contact patients who are registered in centre-specific 
databases to inform them about the study and to invite them for screening. If applicable 
informed consent may be obtained. During screening, the optional informed consent for 
collection of blood samples for betulin analysis and the optional consent for genetic testing to 
determine EB subtype will be discussed with the patient.  
At baseline on D0 of the DBP, if the informed consent has not been collected at screening, 
the investigator will have to obtain written informed consent from the patient or legal study 
representative(s) before any study-related procedure will be initiated. If the patient consents 
to the optional collection of blood samples for betulin analysis, written consent will also be 
obtained at the baseline visit, if not already provided at the screening visit. Written informed 
consent for optional genetic testing can be obtained at any visit during the study. 
All patients who sign the study-specific informed consent form will be recorded on the 
Screening Log. The patients will be identified by a code of letters and numbers during 
screening. Only those patients who will have met all eligibility criteria will be assigned a 
patient number (please refer to Section 7.1.1 Treatment Assignment/Blinding Procedure), 
and will be documented on the enrolment log.  
The patient number is a 1-letter, 6-digit number. The letter identifies the study, the first 
4 digits identify the study site, and the last 2 digits identify the patients in the sequence they 
enter the study (assigned by the investigator at the study site). If a patient is screened, but 
not enrolled into the study, the reason for screening failure will be recorded. 
9.1.1 
Screening Assessments 
During the screening visit, the following will be completed: 
• Confirmation of patient eligibility using the inclusion criteria (see Section 5.1 Inclusion 
Criteria) and exclusion criteria (see Section 5.2 Exclusion Criteria) 
• A blood sample will be taken for haematology (full blood count with white blood cell 
differential), biochemistry panels (Na, K, Ca, Cl, P, BG) including renal (urea, creatinine), 
and hepatic function tests (serum total protein, albumin, ALT, AST, GGT, and AP), and 
betulin levels. This sample can alternatively be taken at baseline (D0). 
• A urine pregnancy test in all women of childbearing potential including postmenarchal 
female adolescents 
9.1.2 
Enrolment and Stratified Randomisation 
If the patient meets all eligibility criteria, the investigator will stratify the patient according to 
his/her EB subtype and target wound size (cm2) to the following groups: JEB/Kindler 10 to 
<20; JEB/Kindler 20 to <30; JEB/Kindler 30 to 50; DEB 10 to <20; DEB 20 to <30; or DEB 30 
to 50 cm2. The site will proceed with the centralised randomisation procedure as described in 
Section 7.1.1 Treatment Assignment/Blinding Procedure.  

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9.1.3 
Rescreening 
If the patient is a screen failure, the patient can be rescreened if he/she later becomes 
eligible, as deemed appropriate by the investigator. The patient must be reconsented, and all 
screening procedures must be repeated. The patient will receive a new patient number in the 
database.  
 

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Figure 20 Study Schema – Double-blind Phase 
Amryt Pharma Figure 
* D7±2 may be a phone call instead of a site or home visit. If the patient has a phone call the photography, patient-reported outcomes, and voluntary blood sample will not be 
performed. 

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AEs = Adverse event(s); BSAP = Body surface area percentage; CCC = Confirmation of complete closure (of EB target wound); D = Day; EB = Epidermolysis Bullosa; 
EBDASI = Epidermolysis Bullosa Disease Activity and Scarring Index; EDBP = End of Double-blind Phase; EQ-5D = EuroQol 5 Dimensions; FLACC = ‘Face, Legs, Activity, Cry, 
Consolability’; iscorEB = Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa; SAEs = Serious adverse events; SOC = Standard of care; 
TSQM = Treatment Satisfaction Questionnaire for Medication; V = Visit; W-QoL = Wound Quality of Life Questionnaire. 
Sources: BSAP affected by EB partial thickness wounds based on the ‘Lund and Browder’ chart (Miminas 2007); EBDASI (Loh, Kim et al. 2014); EQ-5D (Herdman et al 2013, Wille 
et al 2010); FLACC (Merkel, Voepel-Lewis et al. 1997); iscorEB (Schwieger-Briel et al 2015); ‘Itch Man’ Scale (Morris, Murphy et al. 2012); ‘Leuven Itch Scale’ (Haest, Casaer et al. 
2011); Treatment Satisfaction Questionnaire for Medication (Bharmal, Payne et al. 2009); ‘Wong-Baker FACES®’ (Wong-Baker 2015); ‘W-QoL’ (Blome, Baade et al. 2014) 

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Figure 21 Study Schema – Open-label Follow-up Phase 
 

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* Urine pregnancy test only  
in women of childbearing potential/postmenarchal female adolescent patients 
Amryt Pharma Figure 
AEs = Adverse event(s); BSAP = Body surface area percentage; D = day; d = Days; EB = Epidermolysis bullosa; EBDASI = Epidermolysis Bullosa Disease Activity and Scarring 
Index; EQ-5D = EuroQol 5 Dimensions; EoFU = End of Follow-up; FLACC = ‘Face, Legs, Activity, Cry, Consolability’; iscorEB = Instrument for Scoring Clinical Outcome of 
Research for Epidermolysis Bullosa; SAEs = Serious adverse event(s); SOC = Standard of care; TSQM = Treatment Satisfaction Questionnaire for Medication; V = Visit; 
W-QoL = Wound Quality of Life Questionnaire 
Sources:  
BSAP affected by EB partial thickness wounds based on the ‘Lund and Browder’ chart (Miminas 2007); EBDASI (Loh, Kim et al. 2014); EQ-5D (Herdman et al 
2013, Wille et al 2010); FLACC (Merkel, Voepel-Lewis et al. 1997); iscorEB (Schwieger-Briel et al 2015); ‘Itch Man’ Scale (Morris, Murphy et al. 2012); ‘Leuven Itch Scale’ (Haest, 
Casaer et al. 2011); Treatment Satisfaction Questionnaire for Medication (Bharmal, Payne et al. 2009); ‘Wong-Baker FACES®’ (Wong-Baker 2015); ‘W-QoL’ (Blome, Baade et al. 
2014) 
 

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Figure 22 Chronology of Efficacy Assessments by Visit 
 

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Amryt Pharma Figure  
* D7±2 may be a phone call instead of a site or home visit. If the patient has a phone call efficacy assessment will not be performed 
BSAP = Body surface area percentage; CCC = Confirmation of complete closure (of the EB target wound); D = Day; d = Days; EB = Epidermolysis Bullosa; 
EBDASI = Epidermolysis Bullosa Disease Activity and Scarring Index; EDBP = End of Double-blind Phase; EQ-5D = EuroQol 5 Dimensions; FLACC = ‘Face, Legs, Activity, Cry, 
Consolability’; FU = Follow-up; I = Investigator; iscorEB = Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa; M = Month; Pt = Patient; 
TSQM = Treatment Satisfaction Questionnaire for Medication; W-QoL = Wound Quality of Life Questionnaire 
Sources:  
BSAP affected by EB partial thickness wounds based on the ‘Lund and Browder’ chart (Miminas 2007); EBDASI (Loh, Kim et al. 2014); EQ-5D (Herdman et al 
2013, Wille et al 2010); FLACC (Merkel, Voepel-Lewis et al. 1997); iscorEB (Schwieger-Briel et al 2015); ‘Itch Man’ Scale (Morris, Murphy et al. 2012); ‘Leuven Itch Scale’ (Haest, 
Casaer et al. 2011); Treatment Satisfaction Questionnaire for Medication (Bharmal, Payne et al. 2009); ‘Wong-Baker FACES®’ (Wong-Baker 2015); Wound-QoL’ (Blome, Baade et 
al. 2014) 

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Figure 23 Example of Investigator’s Worksheet 
  
 
 

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9.2 
Double-blind Phase (Visits 1 to 7a) 
9.2.1 
Visit 1 (Site Visit at D0) 
The following assessments will be completed and treatment with study medication will be 
initiated as follows: 
Before wound dressing change 
• Demographic data (age, gender, ethnic origin, Fitzpatrick skin type, height, weight), 
medical history and current medical conditions, and EB subtype as evidenced by date and 
method of diagnosis (e.g., genetic analysis, immunofluorescence mapping, transmission 
electron microscopy) 
• A physical examination and selection of the EB target wound as described in the 
‘Investigator’s Worksheet’ (see Figure 23) 
• Vital signs: heart rate, respiratory rate, and body temperature 
• ECG 
• A record of concomitant medication 
• Enquire about any AEs/SAEs and record them on the Medical History/Current Medical 
Conditions section in the eCRF 
• Patients ≥ 4 years and up to 13 years of age to will be asked to assess itch using the ‘Itch 
Man Scale’ (Morris, Murphy et al. 2012). Patients ≥ 14 years of age will use the ‘Leuven 
Itch Scale’ Version 2.0 (see Section 8.3.1 ‘Itch Man Scale’ and Figure 10 as well as 
Section 8.3.2 ‘Leuven Itch Scale’ and Figure 11). 
• The investigator or delegated site study team member will assess “background” pain 
using the FLACC scale (Merkel, Voepel-Lewis et al. 1997) in patients <4 years of age (see 
Section 8.3.3 ‘Face, Legs, Activity, Cry, Consolability’ Pain Rating Scale and Figure 12). 
In patients ≥ 4 years of age the ‘Wong-Baker FACES Pain Rating Scale’ (Wong-Baker 
2015) will be used (see Section 8.3.4 Wong-Baker FACES Pain Rating Scale and Figure 
13). 
• Patients ≥ 14 years of age will be asked “whether the wounds have affected their sleep 
within the last 7 days” using an 11-point Likert scale (Blome, Baade et al. 2014). 
• Patients ≥ 14 years of age or a parent of patients <14 years of age will be asked “how 
many days have been missed from school or from work due to EB in the last 14 days”. 
• A blood sample will be taken for haematology (full blood count with white blood cell 
differential), biochemistry panels (Na, K, Ca, Cl, P, BG) including renal (urea, creatinine), 
and hepatic function tests (serum total protein, albumin, ALT, AST, GGT, and AP), and 
betulin levels at baseline. If haematology and biochemistry parameters have been 
determined within 4 weeks prior to this visit, they might be used as baseline values 
instead. If blood samples for haematology and biochemistry parameters are not taken at 
this visit, and if the patient consents, a blood sample will be taken for betulin analysis. 
Note: Blood sampling needs to occur prior to study medication exposure. 
• A urine pregnancy test in all women of childbearing potential including postmenarchal 
female adolescents. If performed within 14 days prior to baseline it does not need to be 
repeated. 
After removal of wound dressings 
• An investigator will assess total body wound burden using Section I of the EBDASI (see 
Figure 8) (Loh, Kim et al. 2014).  
• The investigator will assess the BSAP of TBSA affected by EB partial thickness wounds 
based on the ‘Lund and Browder’ chart (see Figure 9) (Miminas 2007).  
• An investigator or delegated site study team member will photo-document the target 
wound and all other wounds that match target wound criteria with the ARANZ Silhouette® 

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system as described in Section 8.2.1 Photography of EB Target Wound and Other 
Wounds. 
• The patient will be randomised to receive Oleogel-S10 or the vehicle as described in 
Section 7.1.1 Treatment Assignment/Blinding Procedure. The study medication will be 
dispensed to the patient or the patient’s parent/legal guardian. 
• The investigator or delegated site study team member will apply the assigned treatment 
and train the patient or the patient’s parent/legal guardian in the application of the study 
medication. 
• The patient or the patient’s parent/legal guardian will be asked how frequently he/she 
plans to change wound dressings in the following weeks.  
After wound dressing change 
• In patients <4 years of age, “procedural” pain during wound dressing change will be 
assessed by the site study team member using the FLACC scale (Merkel, Voepel-Lewis 
et al. 1997). Patients ≥ 4 years of age will be asked to assess “procedural pain” during 
wound dressing change using the ‘Wong-Baker FACES Pain Rating Scale’ (Wong-Baker 
2015). 
• The patient or the patient’s parent/legal guardian will be instructed to call the site if he/she 
observes closure of the target wound at any time during the study. If a patient or the 
patient’s parent/legal guardian observes target wound closure, the next visit should be 
arranged for as early as possible within the visit window.  
9.2.2 
Visit 2 (Site Visit, Home Visit, or Phone Call by Study Team Member 
at D7±2) 
The patient will visit the site or a site study team member (e.g., study nurse) will visit the 
patient at home on D7±2. Alternatively, the patient will receive a phone call from a site study 
team member on D7±2 for: 
Before wound dressing change 
• The record of AEs and/or SAEs.  
• The record of concomitant medication. 
• The evaluation of itch as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessments of “background” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0).* 
• The evaluation of impact of wounds on sleep (in patients ≥ 14 years of age) as described 
in Section 9.2.1 Visit 1 (Site Visit at D0).* 
• The assessment of treatment response (in patients ≥ 14 years of age) using the TSQM as 
described in Section 8.3.7 Treatment Satisfaction Questionnaire for Medication, 
Version 9.* 
• If the patient consents, a blood sample will be taken for betulin analysis. Note: Blood draw 
needs to occur prior to study medication exposure.*  
After removal of wound dressings 
• The assessment of first closure of the EB target wound from the patient’s point of view. 
• Photography of the EB target wound and all other wounds that match target wound criteria 
with the ARANZ Silhouette® system as described in Section 8.2.1 Photography of EB 
Target Wound and Other Wounds*. 
• Observation of and, if wished by the patient, assistance in wound dressing change and 
the application of study medication.* 
• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 

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After wound dressing change 
• The assessment of “procedural” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0).* 
* Assessment will be performed if patient has site visit or home visit. If the patient has phone 
call, the assessment will not be performed. 
9.2.3 
Visit 3 and Visit 5 (Site Visit or Home Visit by Investigator at D14±5 
and D45±7) 
The patient will visit the site at D14±5 and D45±7. Alternatively, the investigator may visit the 
patient at home at D14±5 and D45±7. 
Before wound dressing change 
• The record of AEs and/or SAEs.  
• The record of concomitant medication. 
• The assessment of “background” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0). 
• The assessment of “how many days have been missed from school or from work due to 
EB in the last 14 days” as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• If the patient consents, a blood sample will be taken for betulin analysis. Note: Blood draw 
needs to occur prior to study medication exposure.  
After removal of wound dressings 
• The assessment of first closure of the EB target wound from the patient’s point of view. 
• The clinical assessment of the target wound for closure (performed by an investigator). 
• Photography of the target wound and all other wounds that match target wound criteria 
with the ARANZ Silhouette® system as described in Section 8.2.1 Photography of EB 
Target Wound and Other Wounds. 
• Observation of and, if wished by the patient, assistance in wound dressing change and 
the application of study medication. 
• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 
After wound dressing change 
• The assessments of “procedural” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0). 
• Study medication will be reviewed. All used and unused medication will be returned and 
the unused tubes will be redispensed. Additional study medication will be dispensed as 
required. For drug accountability, the number of used and unused tubes will be counted 
and used kits will be weighed. 
9.2.4 
Visit 4 and Visit 6 (Site Visit at D30±7 and D60±7) 
The patient will visit the site at D30±7 and at D60±7. 
Before wound dressing change 
• The record of AEs and/or SAEs. 
• The record of concomitant medication. 
• The evaluation of itch as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessments of “background” pain and “procedural” pain as described in 
Section 9.2.1 Visit 1 (Site Visit at D0). 
• The evaluation of impact of wounds on sleep (in patients ≥ 14 years of age) as described 
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• The assessment of “how many days have been missed from school or from work due to 
EB in the last 14 days” as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessment of treatment response (in patients ≥ 14 years of age) using the TSQM as 
described in Section 8.3.7 Treatment Satisfaction Questionnaire for Medication, Version 9. 
• If the patient consents, a blood sample will be taken for betulin analysis. Note: Blood 
sampling needs to occur prior to study medication exposure. 
After removal of wound dressings 
• The assessment of first closure of the EB target wound from the patient’s point of view. 
• The assessment of total body wound burden as described in Section 9.2.1 Visit 1 (Site 
Visit at D0). 
• The assessment of BSAP of TBSA affected by EB partial thickness wounds as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The clinical assessment of the target wound for closure (performed by an investigator). 
• Photography of the target wound and all other wounds that match target wound criteria 
with the ARANZ Silhouette® system as described in Section 8.2.1 Photography of EB 
Target Wound and Other Wounds. 
• Observation of and, if wished by the patient, assistance in wound dressing change and 
the application of study medication. 
• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 
After wound dressing change 
• The assessment of “procedural” pain as described in Section 9.2.1 Visit 1 (Site Visit at D0) 
• Study medication will be reviewed. All used and unused medication will be returned and 
the unused tubes will be redispensed. Additional study medication will be dispensed as 
required. For drug accountability, the number of used and unused tubes will be counted 
and used kits will be weighed. 
9.2.5 
‘Confirmation of Complete Closure’ Visit (Flexible Site Visit or Home 
Visit by Study Team Member 7 days [+2 Days] After First Complete 
Closure of the EB Target Wound in the Double-blind Phase) 
A site study team member (e.g., study nurse) will visit the patient at home 7 days (+2 days) 
after first clinical assessment of complete closure of the EB target wound (based on clinical 
assessment by an investigator at a scheduled visit) for confirmation of complete closure 
(CCC) of EB target wound. Alternatively, the patient will visit the site 7 days (+2 days) after 
first clinical assessment of complete closure of the EB target wound for CCC. Adverse 
events/SAEs, local tolerability, and concomitant medication will be recorded. If the patient 
consents, a blood sample will be taken for betulin analysis. Note: Blood draw needs to occur 
prior to study medication exposure. The target wound will be photo-documented with the 
ARANZ Silhouette® system as described in Section 8.2.1 Photography of EB Target Wound 
and Other Wounds. Photographs will be reviewed by the investigator. Wound dressings will 
be changed, and the study medication will continue to be applied to any remaining EB 
wounds matching target wound criteria. It is not necessary to continue to apply study 
medication to the closed wound. 
9.3 
Unscheduled Visits 
Unscheduled visits should be performed whenever necessary (e.g., in case of AEs or SAEs). 
Evaluations and/or assessments should be performed as deemed appropriate by the 
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The results of all examinations during an unscheduled visit should be documented in the 
patient’s file and should be recorded in the eCRF. If a patient discontinues the study 
prematurely during the DBP, the EDBP (D90±7) visit assessments should be performed (see 
Section 9.4 Visit 7a [Site Visit at D90±7] End of Double-blind Phase). If a patient discontinues 
the FU phase prematurely, the assessments scheduled for the EoFU (M24±14 Days) visit 
should be performed (see Section 9.5.5 End of Follow-up Visit 10 [M24±14 Days]).  
9.4 
Visit 7a (Site Visit at D90±7): End of Double-blind Phase/ 
Premature Discontinuation of Double-Blind Phase 
The patient will visit the site for the EDBP visit at D90±7. The EDBP visit should also be 
performed at any time if the patient is prematurely discontinued from the DBP of the study. 
Before wound dressing change 
• The record of AEs and/or SAEs.  
• The record of concomitant medication. 
• A physical examination will be performed. 
• Vital signs such as heart rate, respiratory rate, and body temperature will be recorded. 
• ECG. 
• A urine pregnancy test in all women of childbearing potential including postmenarchal 
female adolescents. 
• The evaluation of itch as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessments of “background” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0). 
• The evaluation of impact of wounds on sleep (in patients ≥ 14 years of age) as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessment of “how many days have been missed from school or from work due to 
EB in the last 14 days” as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessment of treatment response (in patients ≥ 14 years of age) using the TSQM as 
described in Section 8.3.7 Treatment Satisfaction Questionnaire for Medication, Version 9. 
• The assessment of disease severity from both clinician and patient/family perspective 
using the iscorEB (only when available in the local language) as described in Section 
8.3.8. 
• The assessment of health-related quality of life using the EQ-5D instrument as described 
in Section 8.3.9. 
• A blood sample will be taken for haematology (full blood count with white blood cell 
differential), biochemistry panels (Na, K, Ca, Cl, P, BG) including renal (urea, creatinine), 
and hepatic function tests (serum total protein, albumin, ALT, AST, GGT, and AP), and 
betulin levels.  
• All used and unused study medication will be returned. For drug accountability, the 
number of used and unused tubes will be counted and used kits will be weighed. 
After removal of wound dressings 
• The assessment of first closure of the EB target wound from the patient’s point of view. 
• The assessment of total body wound burden as described in Section 9.2.1 Visit 1 (Site 
Visit at D0). 
• The assessment of BSAP of TBSA affected by EB partial thickness wounds as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The clinical assessment of the target wound for closure (performed by an investigator). 
• Photography of the target wound and all other wounds that match target wound criteria 
with the ARANZ Silhouette® system as described in Section 8.2.1 Photography of EB 
Target Wound and Other Wounds. 

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• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 
Once the EDBP visit is complete and all study medication is returned, the patient will enter 
the single-arm, open-label FU phase. Visit 7b will performed as part of the same visit as 
Visit 7a and open-label study medication will be applied in Visit 7b (see Section 9.5.1 Visit 7b 
[in Conjunction with Visit 7a at D90±7]).  
9.5 
Open-label Follow-up Phase 
The patients will be asked to call the study site if any AEs or unexpected events occur 
between the site visits or site calls.  
9.5.1 
Visit 7b (in Conjunction with Visit 7a at D90±7) 
The EDBP visit at D90±7 corresponds to the D0 of the open-label FU. The data of EB total 
body wound burden and BSAP assessment at EDBP (D90±7) will be used as baseline data 
of D0 of the FU.  
Following completion of the EDBP visit (Visit 7a), the patient will continue to D0 of the 
open-label FU: 
After removal of wound dressings 
• The open-label FU study medication will be dispensed to the patient.  
• Observation of and, if wished by the patient, assistance in wound dressing change. The 
open-label phase study medication will be applied. 
After wound dressing change 
• The assessment of “procedural” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0). 
9.5.2 
Visit 8 (Site Visit M3±14 Days) 
The patient will come in for a site visit at M3±14 days for: 
Before wound dressing change 
• The record of AEs and/or SAEs.  
• The record of concomitant medication. 
• A urine pregnancy test in all women of childbearing potential including postmenarchal 
female adolescents. 
• The evaluation of itch as described in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The assessment of “background” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0). 
• The evaluation of impact of wounds on sleep (in patients ≥ 14 years of age) as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The evaluation of days missed from school or from work as described in Section 9.2.1 
Visit 1 (Site Visit at D0). 
• The assessment of treatment response (in patients ≥ 14 years of age) using the TSQM as 
described in Section 8.3.7 Treatment Satisfaction Questionnaire for Medication, Version 9. 
• If the patient consents, a blood sample for betulin analysis. Note: Blood sampling needs to 
occur prior to study medication exposure. 
After removal of wound dressings 
• The assessment of total body wound burden as described in Section 9.2.1 Visit 1 (Site 
Visit at D0). 
• The assessment of BSAP of TBSA affected by EB partial thickness wounds as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 

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• The clinical assessment of the target wound for closure (performed by an investigator). 
• Photography of the target wound and all other wounds that match target wound criteria 
with the ARANZ Silhouette® system as described in Section 8.2.1 Photography of EB 
Target Wound and Other Wounds. 
• Observation of and, if wished by the patient, assistance in wound dressing change and 
the application of study medication. 
• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 
After wound dressing change 
• The assessment of “procedural” pain as described in Section 9.2.1 Visit 1 (Site Visit at 
D0). 
• Study medication will be reviewed. All used and unused medication will be returned and 
counted. The unused tubes will be redispensed. Additional study medication will be 
dispensed as required. 
9.5.3 
Visit 9 (Site Visit at M12±14 Days) 
The patient will come in for a site visit at M12±14 days.  
Before wound dressing change 
• The record of AEs and/or SAEs.  
• The record of concomitant medication. 
• The assessment of disease severity from both clinician and patient/family perspective 
using the iscorEB (only when available in the local language) as described in Section 9.4. 
• The assessment of health-related quality of life using the EQ-5D instrument as described 
in Section 9.4. 
• A urine pregnancy test in all women of childbearing potential including postmenarchal 
female adolescents.  
• A blood sample will be taken for haematology (full blood count with white blood cell 
differential), biochemistry panels (Na, K, Ca, Cl, P, BG) including renal (urea, creatinine), 
and hepatic function tests (serum total protein, albumin, ALT, AST, GGT, and AP). Betulin 
levels are not required at this visit. 
After removal of wound dressings 
• The assessment of total body wound burden as described in Section 9.2.1 Visit 1 (Site 
Visit at D0). 
• The assessment of BSAP of TBSA affected by EB partial thickness wounds as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 
• Observation of and, if wished by the patient, assistance in wound dressing change and 
the application of study medication. 
• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 
After wound dressing change 
• Study medication will be reviewed. All used and unused medication will be returned and 
counted. The unused tubes will be redispensed. Additional study medication will be 
dispensed as required. 
9.5.4 
Interim Calls (M6, M9, M15, M18, and M21 [±28 Days]) 
Interim phone calls will be conducted by the study team at M6±28 days, M9±28 days, 
M15±28 days, M18±28 days, and M21±28 days to encourage continuous study participation 
and to conduct safety/tolerability assessments. The patient will also be asked about 
frequency of wound dressing change, method of study medication application, and type of 

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dressing used since the last visit/call. If required, patients may be asked to visit the site for 
further evaluations. A site visit may be scheduled instead of an interim phone call to facilitate 
dispensing and return of study medication. If the patient attends the site for study medication 
dispensing, he/she is not required to change wound dressings and apply study medication at 
the visit.  
9.5.5 
End of Follow-up Visit 10 (M24±14 Days)/ Premature Discontinuation 
of Follow-Up Phase 
The patient will come in for the EoFU visit at M24±14 days. The EoFU visit should also be 
performed at any time if the patient is prematurely discontinued from the Open-label 
Follow-Up Phase of the study. 
Before wound dressing change 
• The record of AEs and/or SAEs.  
• The record of concomitant medication. 
• A physical examination will be performed. 
• Vital signs such as heart rate, respiratory rate, and body temperature will be recorded. 
• ECG. 
• The assessment of disease severity from both clinician and patient/family perspective 
using the iscorEB (only when available in the local language) as described in Section 9.4. 
• The assessment of health-related quality of life using the EQ-5D instrument as described 
in Section 9.4. 
• A urine pregnancy test in all women of childbearing potential including postmenarchal 
female adolescents. 
• A blood sample will be taken for haematology (full blood count with white blood cell 
differential), biochemistry panels (Na, K, Ca, Cl, P, BG) including renal (urea, creatinine), 
and hepatic function tests (serum total protein, albumin, ALT, AST, GGT, and AP), and 
betulin levels. 
After removal of wound dressings 
• The assessment of total body wound burden as described in Section 9.2.1 Visit 1 (Site 
Visit at D0). 
• The assessment of BSAP of TBSA affected by EB partial thickness wounds as described 
in Section 9.2.1 Visit 1 (Site Visit at D0). 
• The record of frequency of wound dressing change, method of study medication 
application, and type of dressing used since the last visit. 
• All used and unused medication will be returned and counted. 
 
10 
COLLECTION, STORAGE, AND SHIPMENT OF 
LABORATORY SAMPLES 
The safety laboratory tests including haematology and biochemistry panels will be performed 
at the local hospital laboratories. If safety laboratory data within 4 weeks prior to enrolment is 
available, it should be documented in the eCRF as baseline data.  
Amryt Research Ltd. will provide urine pregnancy test strips to the sites for conducting urine 
pregnancy tests in women of childbearing potential.  
Dried blood spots from blood samples will be sent to the central laboratory (Nuvisan GmbH, 
Germany) for betulin analysis. All samples will be kept for up to 2 years after the study is 
completed. 

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If the investigator takes a wound swab for a suspected EB wound infection, the result should 
be documented in the eCRF.  
11 
DRUG SAFETY 
The investigator is responsible for the detection and documentation of events meeting the 
definition of an AE or a SAE as provided in Section 11.1 Definitions. This includes the 
evaluation of its seriousness, its severity, and the causal relationship to the investigational 
product and/or concomitant therapy (see Section 11.2 Recording of Adverse Events and 
Serious Adverse Events). 
At each visit, the patient will be asked whether any AEs have occurred. A diagnosis of the 
event based on signs, symptoms, and/or other clinical information should be established if 
possible. The diagnosis should be recorded as an AE and/or SAE in the corresponding 
section of the eCRF rather than the individual symptoms. If no diagnosis is known and 
neither clinical signs nor symptoms are present, the abnormal finding should be recorded. 
The patient should be observed and monitored carefully until the AE has resolved, the 
condition will have stabilised, or its cause will have been identified completely. The 
investigator will be responsible to ensure that FU will include any supplemental investigations 
that may be indicated to elucidate the nature and/or the cause of the event. 
11.1 
Definitions 
The definitions of this section follow the tripartite harmonised International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Guidelines E6 ‘Good Clinical Practice (GCP)’ and E2A ‘Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting’.  
11.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the medicinal 
product, whether or not considered related to the medicinal product. 
11.1.2 
Adverse Drug Reaction 
Adverse drug reactions (ADRs) are all noxious and unintended responses to a medicinal 
product related to any dose. The phrase ‘responses to a medicinal product’ means that a 
causal relationship between a medicinal product and an AE is at least a reasonable 
possibility (i.e., the relationship cannot be ruled out). 
All AEs judged by the reporting investigator or the sponsor as having a reasonable causal 
relationship to the study medication qualify as ADRs. 
11.1.3 
Unexpected Adverse Drug Reaction 
If the nature or severity of the ADR is not consistent with the ‘Reference Safety Information’ 
described in the ‘Investigator’s Brochure’ (see Section 18.1 Source Documents), it is an 
unexpected ADR. 
11.1.4 
Serious Adverse Event or Adverse Drug Reaction 
Special medical or administrative criteria are needed to define reactions that, either due to 
their nature (‘serious’) or due to the significant, unexpected information they provide, justify 
expedited reporting. 

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Please refer to Section 11.2.2 Assessment of Severity for the difference between the terms 
‘serious’ and ‘severe’.  
An SAE or serious ADR (SADR) is any untoward medical occurrence or effect that at any 
dose: 
• Results in death (death is an outcome, the condition leading to death is the SAE) 
• Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
Medical and scientific judgement should be exercised in deciding whether an AE is serious in 
other situations. Important AEs may not be immediately life-threatening, result in death or 
hospitalisation, but may jeopardise the patient or may require intervention to prevent 1 of the 
other outcomes listed above. These should also be considered serious.  
Serious AEs related to the underlying disease will not be expedited as SAEs for the study 
medication. 
11.1.5 
Suspected Unexpected Serious Adverse Reaction 
A SUSAR is a suspected adverse reaction related to the study medication that is both 
unexpected and serious.  
The nature or severity of the unexpected ADR is not consistent with the ‘Reference Safety 
Information’ described in the ‘Investigator’s Brochure’ (see Section 18.1 Source Documents). 
If the investigator or the Medical Monitor judges an SAE not previously documented in the 
‘Investigator’s Brochure’ (see Section 18.1 Source Documents) to be related to study 
medication, the event will qualify as SUSAR and will be subject to expedited regulatory 
reporting. 
11.1.6 
Anticipated Adverse and Serious Adverse Events 
Patients participating in this study are suffering from EB, which can be associated with 
significant multiorgan involvement.  
Anticipated Adverse Events 
Refer to Appendix 19.2 in Section 19 Appendices for an overview of ‘anticipated AEs’ by 
system organ class and lowest level term coded using Version 19.0 of the Medical Dictionary 
for Regulatory Activities (MedDRA).  
Anticipated Serious Adverse Events 
In EB patients, often in-patient hospitalisation for routine multidisciplinary care is necessary. 
Hospitalisation per se will not be considered as criterion for expedited reporting except for 
hospitalisation or prolongation of hospitalisation judged by the investigator to be 
unanticipated with regard to disease course. 

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11.2 
Recording of Adverse Events and Serious Adverse Events 
11.2.1 
Assessment of Seriousness 
See Section 11.1.4 Serious Adverse Event or Adverse Drug Reaction for the definition of 
SAEs and SADRs. 
11.2.2 
Assessment of Severity 
The severity of AEs will be evaluated according to the Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.03 (see Section 18.1 Source Documents). 
The terms ‘severe’ and ‘serious’ are not synonymous:  
• Severity: The term ‘severe’ is often used to describe the intensity of a specific event (as 
in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  
• Seriousness: The term ‘serious’ is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a patient's life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
If an AE term is not listed in the CTCAE classification, the severity of the event should be 
assessed as follows: 
• Grade 1 (mild): The AE is noticeable to the patient but does not interfere with routine 
activity. 
• Grade 2 (moderate): The AE interferes with routine activity but responds to symptomatic 
therapy or rest. 
• Grade 3 (severe): The AE significantly limits the patient's ability to perform routine 
activities despite symptomatic therapy. 
• Grade 4 (life-threatening): The patient is at immediate risk of death. 
• Grade 5 (death): Death related to the AE. 
11.2.3 
Assessment of Causality 
Careful medical judgement is necessary to determine if there is a causal relationship 
between an AE and the investigational product: 
• Certain: A clinical event, including laboratory test abnormality occurring in a plausible 
time relationship to drug administration, which cannot be explained by concurrent disease 
or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should 
be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, using a satisfactory rechallenge procedure if necessary. 
• Probable: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfil this definition. 
• Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug withdrawal may be lacking or 
unclear. 
• Unlikely: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration, which makes a causal relationship improbable, and in 
which other drugs, chemicals, or underlying disease provide plausible explanations. 

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• Conditional/Unclassified: A clinical event, including laboratory test abnormality, reported 
as an adverse reaction, about which more data are essential for a proper assessment or 
the additional data are under examination. 
• Unclassifiable: A report suggesting an adverse reaction, which cannot be judged 
because information is insufficient or contradictory, and which cannot be supplemented or 
verified. 
11.3 
Documenting of Adverse Events and Serious Adverse Events 
All information regarding AEs and SAEs, whether reported by the patient/parent/legal 
guardian or observed by the investigator, must be documented in the patient’s medical 
record and recorded in the AE/SAE section of the eCRF. For SAEs, the paper SAE form in 
the investigator site file must also be completed (see Section 11.4.1 Reporting of Serious 
Adverse Events). 
The investigator is responsible for recording and reporting AEs observed from the first dose 
of study medication (DBP D0) to the last dose of study medication at M24±14 days.  
All AEs occurring during screening (i.e., after obtaining the patient’s written consent, but 
before starting study medication) should be recorded in the Medical History/Current Medical 
Conditions section of the eCRF, except those resulting from a protocol-mandated procedure, 
which should be reported in the AE/SAE section of the eCRF. 
All patients will be followed-up for AEs/SAEs for up to 30 days after their last dose of study 
medication or until the AE/SAE resolves, whichever is the earlier. The Medical Monitor can 
specify a longer period of follow-up to protect the patient’s safety. 
If an investigator learns of an SAE to be reasonably related to study medication any time 
after study medication dosing has stopped, he/she should promptly notify the sponsor. 
11.4 
Immediately Reportable Information 
11.4.1 
Reporting of Serious Adverse Events 
All SAEs should be reported immediately (i.e., within 24 hours of learning that the event 
meets the definition of an SAE). The investigator should complete the paper SAE report form 
in the investigator site file, assess the causality and send the initial SAE report within 
24 hours to the Pharmacovigilance Department. 
Contact details are provided below: 
Safety and Pharmacovigilance Department 
Fax: 
+ 1 877 464 7787 
Email: 
INCDrugSafety@INCResearch.com 
If the SAE is fatal or life-threatening and is considered at least possibly related to the study 
medication, the completed SAE form should be sent to the Safety and Pharmacovigilance 
Department immediately. 
The minimum information required for the initial SAE report is: 
• Patient number 
• Description of the event 
• Investigational drug information (start date) 
• Reporter information 

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• Causality assessment 
If relevant information is missing at the time of the initial SAE report, the reporter should 
provide it in a follow-up SAE report(s) upon availability. The follow-up report should contain 
new, updated, or corrected information. It should further describe whether the event has 
resolved or continues, if and how it was treated including documentation of all supportive 
actions taken, and whether the blind was broken or not.  
11.4.2 
Other Reportable Information 
If a patient is confirmed to be pregnant during the study or during FU, the continued use of 
the investigational product must be re-evaluated immediately. Administration of the 
investigational product should be discontinued unless the investigator decides, following 
discussion with the sponsor, that the potential benefit to the patient justifies the potential risk 
to the foetus. 
Any pregnancy or fathering of a child, which occurs for up to 30 days within the last 
application of study medication should immediately be reported within 24 hours of 
awareness. While not considered an adverse event or serious adverse event, pregnancies 
require monitoring and follow up. For data analysis purposes pregnancies will be reported as 
AE in the eCRF. The investigator will be asked to complete a pregnancy report provided in 
the investigator site file. In addition, the investigator should provide follow-up information 
regarding the course of the pregnancy in the middle of pregnancy, at the time of the 
expected date of delivery and at 28 days/ 4 weeks after delivery of newborns for any 
potential congenital anomalies. Three follow-up attempts should be made to obtain missing 
information for the pregnancy cases and pregnancy outcome. Spontaneous abortions should 
always be reported as SAEs. This management is done regardless of whether the patient 
has discontinued participation in the study. 
Pregnancy and pregnancy outcome of female partners of male trial subjects need to be 
reported in the same way. The Pregnancy Report Form will be used to report the pregnancy 
information for the partner of a male subject. A pregnancy informed consent form (ICF) 
and/or a pregnancy partner ICF may be required per regional /local regulation before any 
collection of information related to pregnant progress and outcome can be performed. 
Pregnancy cases will be captured in the safety database; a narrative will be prepared. If the 
pregnant female’s partner is a participant of the clinical trial, the male partner’s study subject 
number and all relevant treatment information should be captured in the case file. For 
pregnancy case that results in a live birth, the outcome should be captured within the 
maternal or paternal case. If a serious adverse event is reported for the newborn, including 
congenital anomalies, a separate child case should be created and parent case should be 
cross referenced. Pregnancies will be considered finalized once all fields on the pregnancy 
notification and pregnancy outcome reports are properly completed. If a pregnancy is 
ongoing or a new pregnancy report is received after database lock, the responsibility for 
follow-up/processing is transferred to Amryt Research Ltd. 
 
11.5 
Independent Data Monitoring Committee 
An IDMC will be established to review and evaluate efficacy and safety data during the DBP 
of the study. The IDMC will consist of independent experts who will not be involved in the 
study. The safety reviews will be performed blinded and are to ensure safety for participants 
and to advise for continuation, modification, or discontinuation of individual patients and/or of 
the study. Following an unblinded interim safety review, the IDMC will be able to confirm if 
the study can be expanded to allow the inclusion of children with EB to all ages (i.e., ≥ 21 
days and <4 years). 

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The unblinded interim analysis for sample size re-estimation will take place when 
approximately 50% of patients have completed D45±7. Depending on the results of the 
sample size re-estimation, the IDMC will recommend to continue with the initial sample size, 
increase the sample size, or stop the study for futility.  
12 
STATISTICAL ANALYSIS 
12.1 
Statistical Methods 
The first full statistical analyses of the study will be performed after all data up to the EDBP 
visit (D90±7) has been entered and cleaned (including AE, local tolerability and concomitant 
medication data with date of onset until day of EDBP visit [D90±7]), a database lock of these 
data has been performed and unblinding has been done. The statistical analysis of the FU 
will be performed after database closure of the FU and will be reported separately. An 
unblinded interim analysis will also be performed as outlined in Section 12.3.2 Unblinded 
Interim Analysis. 
12.1.1 
Statistical Hypothesis 
This study is a double-blind, randomised, vehicle-controlled design intended to show 
superiority of Oleogel-S10 versus vehicle. 
The primary endpoint analysis will be performed as follows: 
The proportions of patients with first complete closure of the EB target wound within 
45±7 days based on clinical assessment by the investigator in the Oleogel-S10 and vehicle 
treatment groups will be compared using the Cochran-Mantel-Haenszel (CMH) test, stratified 
by EB subtype and target wound size class. 
The final statistical analysis of the primary endpoint will be performed based on the Cui, 
Hung, Wang (CHW) approach using a weighted statistic (Cui, Hung et al. 1999) (refer to 
sample size re-estimation plan for details, and also to Section 12.3.2 Unblinded Interim 
Analysis). 
12.1.2 
Level of Significance, Multiple Comparisons, and Multiplicity 
The testing approach of the study is that the primary efficacy endpoint will be tested at the 
5% significance level (two-sided). At the final analysis, in case the primary efficacy analysis 
is statistically significant, the confirmatory testing approach will continue hierarchically (in the 
order specified in Section 12.3.4) with the statistical testing of the key secondary endpoints at 
the two-sided 5% significance level. 
The analysis of the remaining secondary and open-label endpoints will be considered as 
non-confirmatory and descriptive only. 
If the primary efficacy endpoint is significant the study will claim the superiority of Oleogel-
S10 compared to vehicle. If the primary efficacy endpoint does not show significance at the 
5% level, then the study will have failed to show the superiority of Oleogel-S10 compared to 
vehicle. 
The CHW weighted statistics for consideration of sample size re-estimation does not require 
an adjustment of the significance level in case the interim analysis is for sample size re-
estimation only and will not allow for early stopping due to early efficacy.  
An unblinded interim analysis with a sample size re-estimation will be performed (see 
Section 12.3.2 Unblinded Interim Analysis). 

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12.1.3 
Determination of Sample Size 
The assumed true control rate for the primary endpoint of first complete closure of the EB 
target wound is 27%. Based on the use of a two-sided test of equality of binomial proportions 
at the alpha=0.05 level of significance, a total sample size of 182 subjects (91 subjects per 
arm) will provide 80% power to detect an improvement of 20 percentage points (i.e., a true 
Oleogel-S10 rate of 47%. A total of 192 patients are planned to be enrolled into the study and 
treated to account for a drop-out rate of 5%, as drop-out rates in studies with EB patients are 
reported to be small (Paller, Browning et al. 2016). 
Following the unblinded interim analysis, the IDMC recommended to have a sample increase 
of 48 patients (24 per arm) to have a total of 230 subjects.  A total of 250 patients are 
planned to be enrolled into the study and treated to account for drop-out patients. 
12.2 
Definition of Study Populations 
The statistical analysis will be based on the following study populations: 
• 
The safety analysis set (SAF) will include all patients treated at least once with study 
medication. The SAF will be used for all safety analyses.   In the SAF, subjects will be 
analysed based on the treatment that was received (if different from the randomized 
treatment). 
• 
All patients from the SAF constitute the full analysis set (FAS).  The FAS will be used for 
all efficacy analyses.   In the FAS, subjects will be analysed based on the randomized 
treatment (if different from the received treatment). 
• 
All patients from the FAS will be assigned to a completer analysis set, if they have not 
discontinued the study early irrespective of the reason for discontinuation. 
• 
Patients who reasonably adhered to all relevant protocol conditions (i.e., who will have 
met the eligibility criteria and will have received planned study medication) without 
relevant protocol deviations constitute the per-protocol (PP) analysis set.  
The data obtained will be used to check whether the study protocol was adhered to (e.g., 
inclusion and exclusion criteria, time windows, concomitant medication). Case-by-case 
decisions regarding exclusions of patients from the PP analysis will be made prior to final 
unblinding in a blind data review meeting. 
Patients who are randomised but not treated, will not be assigned to any of these analysis 
sets.  
Within the SAF, the patients will be analysed ‘as treated’, i.e., the patients will be assigned to 
the treatment regimen they will be treated with.  
Within the FAS and completer analysis set, the patients will be analysed using the 
intent-to-treat principle, i.e., the patients will be assigned to the treatment regimen to which 
they have been randomised. 
The FAS will be used as primary population for all efficacy analyses. In addition, the primary 
efficacy endpoints and some secondary endpoints will be analysed using the PP and the 
completer analysis set, serving as supportive analyses. Safety analyses will be conducted 
using the SAF. 
12.3 
Planned Analyses 
12.3.1 
Demographic Data and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarised in total and by 
treatment arm by means of summary statistics (number of patients, mean, standard 
deviation, minimum, median, maximum) for continuous variables and by absolute and 

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relative frequencies for categorical variables. Baseline characteristics are defined as all 
results of the examinations performed prior to the first Oleogel-S10 or vehicle administration. 
12.3.2 
Unblinded Interim Analysis 
An unblinded interim analysis will be performed at the time when approximately 50% of 
patients have completed D45±7. The unblinded interim analysis will include an unblinded 
sample size re-estimation using the CHW approach and the conditional power will be 
computed to check for futility (Cui, Hung et al. 1999, Mehta and Pocock 2011). 
Depending on the results of the sample size re-estimation, the IDMC may give the following 
recommendations regarding the sample size and the continuation of the study: 
• Initially estimated sample size is sufficient. Do not increase sample size.  
• Increase sample size (to not more than 169 evaluable patients per treatment group, which 
corresponds to an additional 156 evaluable patients)) to provide a statistical power of 
80%.  
• Stop for futility. 
The initial sample size will not be decreased for any reason. Discussion of various potential 
scenarios and assumptions at the unblinded interim analysis influencing the re-estimation of 
the sample size will be provided in the ‘sample size re-estimation plan’. 
12.3.3 
Planned Analysis for Primary Endpoint 
The confirmatory testing of the primary endpoint will be performed using the CMH test on the 
FAS. After the unblinded interim analysis, if it is decided that the sample size needs to be 
increased then the final statistical analysis of the primary endpoint will be performed based 
on the CHW. 
The FAS will be used as primary population for all efficacy analyses. The first complete 
closure of the target wound within 45±7 days (i.e., at Visit 5 on day 45±7 or at an earlier visit) 
will be considered as a failure (wound not closed) or as a success (wound closed) based on 
the clinical assessment of the investigator as recorded in the eCRF. 
For the analysis of the primary efficacy endpoint, missing data for patients in the Oleogel-S10 
or vehicle group with regard to wound closure will be considered as failures. 
The following supportive and sensitivity analyses for primary efficacy will be performed: 
- The primary efficacy analysis will be repeated on the PP and the completer analysis set. 
- A CMH test on the FAS will be performed to evaluate the first complete wound closure 
based on the clinical assessment by the investigator and confirmed by a second observation 
after 7 days [+2 days] at the CCC visit. That is, the first wound closure will only be 
considered as a success if both the clinical assessment and the second observation assess 
the wound as closed.  
- A Fisher’s exact test and Pearson’s chi-square test for comparison between treatment 
groups on the FAS without consideration of any stratification will be performed for the overall 
difference in proportions of first wound closure as clinically assessed by the investigator 
within D45±7, and 95% confidence intervals (CIs) for the difference between the proportions 
will be provided.  
- Further potential risk factors will be investigated by a logistic regression model with 
consideration of EB subtypes, target wound size class, and additional baseline factors on the 
FAS. 
- In a sensitivity analysis, the primary efficacy analysis will be repeated on the FAS by 
investigating the effect of “worst-case” imputation for missing values: a patient in the 
Oleogel-S10 group with missing data will be defined as a failure, while a patient in the vehicle 
group with missing data will be defined as a success. 

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- If the primary efficacy analysis significantly favours the Oleogel-S10 group, a sensitivity 
analysis based on multiple imputation (MI) will be conducted using the tipping point approach 
to assess the departures from missing at random (MAR) to missing not at random (MNAR) 
assumptions.  
For this analysis only monotone missing patterns will be considered, since it is assumed that 
at the time of database lock only discontinued subjects will have missing values for the 
primary efficacy assessment. Monotone missing patterns will be imputed with a discriminant 
function. 
The distribution of missing responses in the Oleogel S-10 group will be assumed to be worse 
than for the vehicle group.  Variations in the assumptions for the MI will be examined to 
adjust the imputed values until the statistical significance is lost (i.e., the p-value is greater 
than 0.05). 
- The CMH test will be repeated with considering ‘complete closure’ as patient’s status 
exactly on D45±7 instead of the first occurrence of complete closure within D45±7. 
- The CMH test, Fisher’s exact test and the chi square test without consideration of strata will 
be repeated on PP and in the subset of completers. 
- The primary efficacy analysis using the FAS will be repeated stratified by the type of wound 
dressing material used (non-adhesive or fatty gauze). 
12.3.4 
Planned Analyses for Key Secondary Endpoints 
After the superiority of the primary efficacy endpoint has been shown at the 5% significance 
level, the following key secondary (confirmatory) efficacy endpoints will be tested 
hierarchically to ensure an overall significance level of 5%: 
1) Time to first complete closure of the EB target wound as evidenced by clinical assessment 
until the end of the double-blind phase (EDBP) at 90±7 days of treatment using the 
non-stratified log-rank test. 
The non-stratified log-rank test will be repeated on PP and on the subset of completed 
patients, also, serving as supportive analyses. 
Additionally, the stratified log-rank test with consideration of EB subtypes as strata will be 
performed on FAS. Further potential risk factors will be investigated by a Cox regression 
model on FAS with adjusting for EB subtypes, target wound size class, and additional 
baseline factors. 
2) Proportion of patients with first complete closure of the EB target wound within D90±7 
based on clinical assessment by the investigator. 
This analysis will be performed similarly as the primary endpoint. 
3) The incidence of wound infection between baseline (DBP D0) and D90±7 as evidenced by 
AEs and/or use of topical and/or systemic antibiotics (related to wound infection). 
Incidence rates of wound infection between treatments will be compared using a CMH test 
considering the strata of EB subtype and target wound size class. 
4) The maximum severity of wound infection between baseline (DBP D0) and D90±7 as 
evidenced by AEs and/or use of topical and/or systemic antibiotics (related to wound 
infection).  
Maximum severity will be compared between treatments using a 2-sided Wilcoxon Rank 
Sum test stratified by EB subtype and target wound size class (van Elteren test). 
5) Change from baseline (DBP D0) in total body wound burden as evidenced by clinical 
assessment using Section I (assessment of the skin except for the anogenital region) of the 
‘EB Disease Activity and Scarring Index’ (EBDASI) at D90±7. 

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The changes from baseline will be calculated for the overall score as well as for the separate 
subscores (total activity score and total damage score) and will be analysed using an 
ANCOVA with treatment group, EB subtype, and target wound size class as fixed effects and 
EBDASI score (overall or subscore as appropriate) at baseline as a covariate. The 95% CIs 
for the difference in least squares means between treatment groups will be calculated. 
For confirmatory testing, only the change from baseline in the overall score will be tested and 
if significant, the hierarchy will continue with the next key secondary endpoint. 
6) Change from baseline (DBP D0) in itching using the ‘Itch Man Scale’ in patients ≥ 4 years 
and up to 13 years of age and the ‘Leuven Itch Scale’ in patients ≥ 14 years of age before 
wound dressing changes at D90±7. 
The changes from baseline between treatments will be compared using a 2-sided Wilcoxon 
Rank Sum test stratified by EB subtype and target wound size class (van Elteren test). 
For confirmatory testing, the hierarchy will test both the ‘Itch Man Scale’ and the ‘Leuven Itch 
Scale’ separately. 
All confirmatory testing of the key secondary endpoints will be performed on the FAS 
12.3.5 
Planned Analyses for Additional Secondary Endpoints 
The following additional secondary efficacy endpoints will be analysed on FAS as described 
below: 
• 
The proportion of patients with first complete closure of the EB target wound at D14±5, 
D30±7 and D60±7 based on clinical assessment by the investigator will be analysed in a 
similar way as the primary endpoint considering the first complete closure of EB target 
wound at D45±7.  
• 
The proportion of patients with first complete closure of the EB target wound at D7±2, 
D14±5, D30±7, D45±7, D60±7 and D90±7 based on patient assessment will be analysed 
in a similar way as the primary endpoint.  
• 
The proportion of patients with first complete closure of the EB target wound at D7±2, 
D14±5, D30±7, D45±7, D60±7, and D90±7 based on blinded evaluation of photographs 
will be analysed in a similar way as the primary endpoint. A sensitivity analysis will be 
performed using the assessment of all photographs of EB partial thickness wounds. 
• 
The percentage change from DBP baseline (D0) in EB target wound size as evidenced 
by blinded evaluation of photographs taken at D7±2, D14±5, D30±7, D45±7, D60±7, and 
D90±7 is calculated as ([wound size at visit x – wound size at baseline] / wound size at 
baseline) *100%. This will be analysed for each visit using analysis of covariance 
(ANCOVA) including treatment group and EB subtype as fixed effects and size of target 
wound at baseline as a covariate. The 95% CIs for the difference in least squares means 
between treatment groups will be calculated. Additionally, treatments will be compared 
using a 2-sided Wilcoxon Rank Sum test stratified by EB subtype (van Elteren test). A 
sensitivity analysis will be performed using the assessment of all photographs of EB 
partial thickness wounds. 
• 
The change from baseline (DBP D0) in total body wound burden will be evaluated by 
clinical assessment using Section I of the EBDASI at D30±7 and D60±7. The changes for 
each visit from baseline will be calculated for the overall score as well as for the separate 
subscores (total activity score and total damage score) and will be analysed using an 
ANCOVA with treatment group, EB subtype, and target wound size class as fixed effects 
and EBDASI score (overall or subscore as appropriate) at baseline as a covariate. The 
95% CIs for the difference in least squares means between treatment groups will be 
calculated. 

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• 
The change from baseline (DBP D0) in BSAP of TBSA affected by EB partial thickness 
wounds will be evaluated by clinical assessment based on the ‘Lund and Browder’ chart 
at D30±7, D60±7, and D90±7, calculated for overall as well as for the individual clinician 
item domains. Each score will be analysed for each visit using an ANCOVA with 
treatment group, EB subtype, and target wound size class as fixed effects, and the 
respective baseline score as a covariate. The 95% CIs for the difference in least squares 
means between treatment groups will be calculated. 
• 
The change from baseline (DBP D0) in “background” pain will be evaluated using the 
FLACC scale in patients <4 years of age and the ‘Wong-Baker FACES Pain Rating 
Scale’ in patients ≥ 4 years of age before wound dressing changes at D7±2, D14±5, 
D30±7, D45±7, D60±7, and D90±7. Treatments will be compared using a 2-sided 
Wilcoxon Rank Sum test stratified by EB subtype and target wound size class (van 
Elteren test).  
• 
The change from baseline (DBP D0) in “procedural” pain will be evaluated using the 
FLACC scale in patients <4 years of age and the ‘Wong-Baker FACES Pain Rating 
Scale’ in patients ≥ 4 years of age after wound dressing changes at D7±2, D14±5, 
D30±7, D45±7, D60±7, and D90±7. Treatments will be compared using a 2-sided 
Wilcoxon Rank Sum test stratified by EB subtype and target wound size class (van 
Elteren test). 
• 
The change from baseline (DBP D0) in itching will be evaluated using the ‘Itch Man 
Scale’ or the ‘Leuven Itch Scale’ before wound dressing changes at D7±2, D30±7 and 
D60±7. Treatments will be compared using a 2-sided Wilcoxon Rank Sum test stratified 
by EB subtype and target wound size class (van Elteren test). 
• 
The change from baseline (D0) in the impact of wounds on sleep (in patients ≥ 14 years 
of age) will be evaluated using 11-point Likert scales at D7±2, D30±7, D60±7, and 
D90±7. This will be analysed using an ANCOVA with treatment group and EB subtype as 
fixed effects and size of target wound at baseline as a covariate. The 95% CIs for the 
difference in least squares means between treatment groups will be calculated.  
• 
The number of days missed from school or from work will be evaluated. All days missed 
form school or from work will be added up for the entire DBP (D0 to D90±7). Treatment 
groups will be compared descriptively. Baseline data will be summarised; no change from 
baseline will be calculated. 
• 
The treatment response (in patients ≥ 14 years of age) will be evaluated using the TSQM, 
Version 9 before wound dressing changes at D7±2, D30±7, D60±7, and D90±7. This will 
be analysed using an ANCOVA with treatment group and EB subtype as fixed effects, 
and size of target wound at baseline as a covariate. The 95% CIs for the difference in 
least squares means between treatment groups will be calculated.  
In a blind data review meeting prior to final unblinding, the amount of available data 
regarding photography and PROs will be evaluated for D7±2 to decide if statistical analysis 
will be performed for that time point. 
Safety endpoints will be analysed on the SAF as described below: 
• 
Incidence, severity, and relatedness of AEs: Adverse events will be summarised and 
provided as data listings. Verbatim terms will be mapped to preferred terms and organ 
systems using the current MedDRA version. For each preferred term, the number of 
events as well as frequency counts and percentages will be calculated. Separate 
analyses will be conducted using severity, seriousness, and relationship to study 
medication. 
• 
Vital signs and clinical laboratory values (including betulin) will be summarised 
descriptively. Changes from baseline (DBP D0) to EDBP (D90±7) will be presented. For 

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clinical laboratory variables, shift tables will be used to evaluate categorical changes by 
examining the proportion of patients whose test values are outside the normal ranges. 
• 
Local tolerability as judged by the investigator will be summarised descriptively. 
12.3.6 
Planned Analyses for Open-label Follow-up Phase Endpoints 
Changes from baseline analyses will be performed using the baseline for the DBP (i.e., DBP 
[D0]) and repeated using the baseline for the open-label FU phase (i.e., FU [D0]/EDBP 
[D90±7]). Day 0 of the FU is the same day as EDBP (D90±7). 
• 
Incidence, severity, and relatedness of AEs: Adverse events will be summarised and 
provided as data listings. Verbatim terms will be mapped to preferred terms and organ 
systems using the current MedDRA version. For each preferred term, the number of 
events as well as frequency counts and percentages will be calculated. Separate 
analyses will be conducted using severity, seriousness, and relationship to study 
medication. 
• 
Vital signs and clinical laboratory values (including betulin) will be summarised 
descriptively. Changes from DBP baseline (D0) to EoFU at M24±14 days and from 
FU phase baseline (FU [D0]/EDBP [D90±7]) to EoFU at M24±14 days will be presented. 
For clinical laboratory variables shift tables will be used to evaluate categorical changes 
by examining the proportion of patients whose test values are outside the normal ranges. 
• 
Local tolerability as judged by the investigator will be summarised descriptively. 
• 
The proportion of patients with complete closure of the EB target wound at M3±14 days 
based on clinical assessment by the investigator and blinded evaluation of photographs 
will be analysed in a similar way as the primary endpoint with treatment group referring to 
the group in the DBP. A sensitivity analysis will be performed using the assessment of all 
photographs of EB partial thickness wounds. 
• 
The changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in total body 
wound burden will be evaluated by clinical assessment using Section I of the EBDASI at 
M3±14 days, M12±14 days, and at EoFU at M24±14 days. The change from baseline in 
total body wound burden as well as clinician items domains will be analysed for each visit 
using an ANCOVA with treatment, EB subtypes, and target wound size class as fixed 
effect terms and the respective baseline score as covariate. The 95% CIs for the 
difference in least squares means between treatment groups referring to the group in the 
DBP will be calculated.  
• 
The changes from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in BSAP of 
TBSA affected by EB partial thickness wounds will be evaluated by clinical assessment 
based on the ‘Lund and Browder’ chart at M3±14 days, M12±14 days, and at EoFU at 
M24±14 days. The change from baseline in BSAP as well as clinician items domains will 
be analysed for each visit using an ANCOVA with treatment, EB subtypes, and target 
wound size class as fixed effect terms, and the respective baseline value of BSAP or of 
the item domains as covariate. The 95% CIs for the difference in least squares means 
between treatment groups referring to the group in the DBP will be calculated. 
• 
The change from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in “background” 
pain will be evaluated using the FLACC scale in patients <4 years of age and the 
‘Wong-Baker FACES Pain Rating Scale’ in patients ≥ 4 years of age before wound 
dressing changes at M3±14 days. Treatment groups referring to the group in the DBP will 
be compared using a 2-sided Wilcoxon Rank Sum test stratified by EB subtype and 
target wound size class (van Elteren test).  
• 
The change from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in “procedural” 
pain will be evaluated using the FLACC scale in patients <4 years of age and the 
‘Wong-Baker FACES Pain Rating Scale’ in patients ≥ 4 years of age after wound 

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dressing changes at M3±14 days. Treatment groups referring to the group in the DBP will 
be compared using a 2-sided Wilcoxon Rank Sum test stratified by EB subtype and 
target wound size class (van Elteren test). 
• 
The change from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in itching will be 
evaluated using the ‘Itch Man Scale’ or the ‘Leuven Itch Scale’ before wound dressing 
changes at M3±14 days. Treatment groups referring to the group in the DBP will be 
compared using a 2-sided Wilcoxon Rank Sum test stratified by EB subtype and target 
wound size class (van Elteren test). 
• 
The change from baseline (both DBP [D0] and FU [D0]/EDBP [D90±7]) in the impact of 
wounds on sleep (in patients ≥ 14 years of age) will be evaluated using 11-point Likert 
scales at M3±14 days. This will be analysed using an ANCOVA with treatment group 
referring to the group in the DBP and EB subtype as fixed effects and size of target 
wound at baseline as a covariate. The 95% CIs for the difference in least squares means 
between treatment groups will be calculated.  
• 
The number of days missed from school or from work will be evaluated. Days missed 
from school or from work will be added up for the 14-days preceding M3±14 days. Data 
for 14-day periods preceding DBP D0, D90±7 and M3±14 days will be compared taking 
into account the treatment received during the DBP.  
• 
The treatment response (in patients ≥ 14 years of age) will be evaluated using the TSQM, 
Version 9 before wound dressing changes at M3±14 days. This will be analysed using an 
ANCOVA with treatment group referring to the group in the DBP and EB subtype as fixed 
effects and size of target wound at baseline as a covariate. The 95% CIs for the 
difference in least squares means between treatment groups will be calculated. 
• 
Changes from EDBP (D90±7) in disease severity from both clinician and patient/family 
perspective as quantified with the ‘iScorEB’ at  M12±14 days, and M24±14 days. 
Changes from baseline will be obtained for the clinician and patient total scores only, 
separately. If the assessment is not performed at D90±7 (due to patient discontinuation 
or if the patient is already ahead of day 90 of treatment) baseline values and all changes 
from baseline will be set to “missing”. If baseline values are available but one or more 
assessments are missing after baseline, the changes from baseline will be obtained with 
the last observation carried forward. 
• 
Changes from EDBP (D90±7) in patients’ quality of life as assessed by the 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression) with the ‘EQ-
5D’ instrument at  M12±14 days, and M24±14 days. Changes from baseline will be 
obtained only for the overall score. If the assessment is not performed at D90±7 (due to 
patient discontinuation or if the patient is already ahead of day 90 of treatment) baseline 
values and all changes from baseline will be set to “missing”. If baseline values are 
available but one or more assessments are missing after baseline, the changes from 
baseline will be obtained with the last observation carried forward. 
12.4 
Statistical Criteria for Study Termination 
The criteria for early termination of the study due to futility will be described in the ‘sample 
size re-estimation plan.’ 
12.5 
Handling of Missing Data 
Care will be taken during the conduct of this study to minimise the amount of missing data. 
The last observation will be carried forward to visits that are not conducted due to an early 
discontinuation to allow for analyses on change from/percentage change from baseline 
endpoints.  

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With respect to missing data related to the analysis of the primary efficacy endpoint, details 
on how to handle missing data are described in Section 12.3.3. 
Withdrawn patients will not be replaced but will be evaluated according to their last visit. If no 
assessment is available after start of therapy, the missing data will not be replaced. 
12.6 
Time Windows 
Data as evaluated during regular visits will be analysed in accordance to the respective visit. 
Time window violations will not be considered, with the exception of analyses using the PP; a 
blind data review meeting will be performed prior to data base lock and final unblinding of the 
study and it may be decided to exclude single visits from the PP analyses due to time 
window violation. For time to event analyses, the exact visit dates and D0 will be taken for 
calculating the time to event. 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Prestudy Documentation 
Prior to enrolment of patients at a study site, specific regulatory documents must be 
available, such as Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
approval and curricula vitae of investigators and study staff. Amryt Research Ltd. will inform 
the investigator which documents need to be provided according to the applicable regulatory 
requirements. 
13.2 
Monitoring 
Amryt Research Ltd. will appoint qualified and appropriately trained persons to monitor the 
study and the FU. Monitors will periodically contact the site and perform site visits in 
accordance with applicable regulations, GCP, and Amryt Research Ltd. approved 
procedures. Study objectives, study design, and enrolment rate will determine the extent, 
nature, and frequency of site visits. 
The monitor will contact the site before start of the study to discuss the protocol and data 
collection procedures with the site study team members. 
During site visits, the monitor will: 
• Check and assess the progress of the study 
• Review study data collected 
• Perform source data verification 
• Identify any issues and address their resolution 
Aim of the site visits is to verify that: 
• The data are authentic, accurate, and complete 
• The safety and rights of patients are being protected 
• The study is conducted in accordance with the approved protocol (and any subsequent 
amendment), GCP, and all applicable regulatory requirements 
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues. 
At study closure, the monitor will conduct all activities as indicated in Section 13.4 Study and 
Site Closure. 

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13.3 
Data Management and Processing 
Amryt Research Ltd. is responsible for data quality control. Each study site is responsible for 
the data documentation and for the maintenance of patient files. 
13.3.1 
Data Collection 
The investigator or an authorised delegate from the study staff will have to complete an 
eCRF for each patient enrolled including patients who discontinue prematurely. If a patient 
withdraws from the study, the reason should be noted in the eCRF if possible. If a patient is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the eCRFs and in all required reports. 
13.3.2 
Data Management Procedures 
A separate ‘Data Management Plan’ will detail data management vendors, systems, and 
processes. 
13.3.3 
Data Verification Procedures 
Data will be checked systematically according to a prespecified ‘Data Validation Plan’ after 
they will have been entered into the study database. Queries will be created for errors or 
missing data and clarified by the study monitor at the investigational site.  
13.3.4 
Coding 
A medical doctor will code all AEs and concomitant diseases according to MedDRA and all 
concomitant or previous medication based on the World Health Organization Drug 
Dictionary. 
13.3.5 
Procedures for Analysis of Consistency and Medical Plausibility 
A blind data review meeting will be conducted as soon as all data of the study has been 
entered into the eCRF and the database has been confirmed as ‘clean’. After resolution of all 
remaining queries, the SAP will be finalised and the database will be locked. All changes to 
the data will be kept in an audit trail. 
A separate database will be open for long-term follow-up data and the upload of target 
wound photographs for the evaluation by blinded experts. This database will be locked as 
soon as data of the FU has been entered and confirmed as ‘clean’. 
13.3.6 
Data to be Recorded Directly into the Electronic Case Report Form 
The eCRF will serve as source document for the following data that will only be recorded for 
the study:  
• Ethnic origin 
• Fitzpatrick skin type 
• Wound photographs 
13.4 
Study and Site Closure 
Upon completion of the study or premature study (site) closure, the monitor and the 
investigator will be responsible for 
• Return of all study data to Amryt Research Ltd.  

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• Data clarification and/or resolution 
• Accounting, reconciliation, and return of used and unused study medication 
• Review of study site records for completeness 
• Return of all study specific equipment to Amryt Research Ltd. 
Amryt Research Ltd. reserves the right to suspend or prematurely discontinue this study at 
either a single site or at all sites at any time for any reason. Amryt Research Ltd. will inform 
the investigator(s), the IECs/IRBs, and the regulatory authorities if the study will be 
suspended or stopped prematurely.  
13.5 
Audits and Inspections 
Amryt Research Ltd. or its designee may conduct a quality assurance audit of this study to 
evaluate compliance with the protocol and the principles of GCP. The investigator agrees to 
allow the auditor direct access to all relevant documents and to allocate his/her time and the 
time of his/her staff to the auditor to discuss findings and any relevant issues. 
Regulatory agencies may conduct a regulatory inspection of this study. If a regulatory 
authority requests an inspection, the investigator must inform Amryt Research Ltd. 
immediately about this request. The investigator agrees to allow the inspector(s) direct 
access to all relevant documents and to allocate his/her time and the time of his/her staff to 
the inspector(s) to discuss findings and any relevant issues. 
14 
LEGAL AND ETHICAL REQUIREMENTS 
This study will be conducted in accordance with the harmonised tripartite ICH Guidelines for 
GCP and all applicable laws and regulations, including the Declaration of Helsinki, 
June 1964, as modified by the 64th World Medical Association General Assembly, Fortaleza, 
Brazil, October 2013 (see Appendix 19.1, Section 19 Appendices). 
14.1 
Regulatory Authority Approval 
Documents required for the application of this study will be submitted to the responsible 
competent authority according to the applicable country-specific laws and regulations. The 
study will not start until the competent authority authorises the study. 
14.2 
Independent Ethics Committee/Institutional Review Board 
This protocol, any amendments if applicable, any material provided to the patient (such as 
patient information, informed consent form and patient questionnaires) as well as additional 
documents, which may be required by national regulations and the IEC/IRB, will be 
submitted to the competent IEC/IRB for review and approval.  
Written approval from the IEC/IRB must be obtained before starting the study, and must be 
documented in a letter specifying the date on which the IEC/IRB met and granted the 
approval. The IEC/IRB approval letter must identify all documents approved by listing the 
study number, study title, study sites/investigators, date and version of study protocol, and 
date and version of patient information/informed consent form. A list of IEC/IRB members 
should be attached to the approval letter. 
Any subsequent modifications made to the protocol or to any other documents that must be 
reviewed by the IEC/IRB must also be submitted to the IEC/IRB in accordance with local 
procedures and regulatory requirements. 

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14.3 
Patient Information and Informed Consent 
The investigator will explain the aims, methods, objectives and potential risks and benefits of 
the study to the patient and will obtain written informed consent from him/her before he/she 
will initiate any study-specific procedure. The patient will have sufficient time to ask and 
resolve any questions pertaining to participation in the study, and to consider study 
participation. In the event that a patient will be unable to read or will only be able to provide 
verbal informed consent, the patient’s legal representative may act on the patient’s behalf. 
For this study in patients less than 18 years, in addition to information sheets and 
consent/assent forms for patients (according to applicable local regulations), parent/legal 
guardian information sheets and consent forms will also be prepared. 
The investigator will also explain to the patient that he/she will be free to refuse entering the 
study or to withdraw from it at any time for any reason. Neither the refusal to give consent 
nor the withdrawal of consent will result in discrimination of the patient, in particular regarding 
his/her subsequent medical treatment.  
The patient will be asked to review, sign, and date the informed consent form. He/she will 
receive a copy of the signed informed consent form, including the investigator’s signature. 
The investigator will retain the original document. 
The eCRF for this study will contain a section for documenting informed patient consent, 
which needs to be completed appropriately. The consent form will be reviewed and updated, 
if the risk/benefit assessment changes or if amendments to the protocol affect the patient’s 
participation in the study. All patients (including those already being treated) will be informed 
about the new information. Patients are only allowed to further participate in the study if they 
agree to sign the amended form, indicating that they reconsent to participate in the study.  
14.4 
Data Protection 
Medical information about individual patients obtained in the course of this study is 
confidential and may not be disclosed to third parties, except authorised monitors, auditors, 
or inspectors. Confidentiality will be ensured by the use of patient numbers for the 
identification of each patient; these patient numbers will also be used for patient data in the 
patient files and eCRFs. The investigator should keep a patient enrolment log showing 
codes, names, and addresses and should maintain documents, e.g., patient’s written 
consent forms, in strict confidence. 
14.5 
Notification of Primary Care Physician 
The investigator should notify the patient’s primary care physician of the patient’s 
participation in the study, if applicable and agreed by the patient. 
14.6 
Investigator Reporting Requirements 
The investigator will ensure that site study team members will promptly bring AEs/SAEs to 
his/her attention. He/she will report all AEs/SAEs as described in Section 11.3 Documenting 
of Adverse Events and Serious Adverse Events and Section 11.4 Immediately Reportable 
Information. The investigator will inform his/her IEC/IRB of any SAE in accordance with the 
local reporting requirements. 
14.7 
Record Retention 
Upon closure of the study, the investigator/study site will maintain a copy of all study records 
in a safe and designated location at the study site in accordance with applicable regulatory 
requirements. Amryt Research Ltd. will inform the investigator/study site of the time for 
retaining these records to comply with applicable regulatory requirements. 
Essential documents as defined in the ICH E6 Guideline of GCP must be retained until: 

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• 2 years after the last approval of a marketing application in an ICH region 
• There are no pending or contemplated marketing applications in an ICH region 
• 2 years will have elapsed since the formal discontinuation of clinical development of the 
investigational product 
• Longer if required by the applicable regulatory requirement(s)/the sponsor 
Unless other Union law (outside of the EU) requires archiving for a longer period, the 
sponsor and the investigator will archive the content of the clinical trial master file for at least 
25 years after the completion or discontinuation of the study. The medical files of patients will 
be archived in accordance with local regulations.  
15 
PROTOCOL AMENDMENTS 
All protocol amendments must be submitted to the competent IECs/IRBs and Regulatory 
Agencies for information and/or approval in accordance with local requirements. If applicable, 
approval must be awaited before changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to patients. 
16 
DISCLOSURE OF INFORMATION 
All data and records generated during the study except for patient medical records and all 
inventions discovered in the course of conducting the study, whether patentable, or not, are 
the sole and exclusive property of Amryt Research Ltd. 
The investigator and site study team members will keep strictly confidential any information 
provided by Amryt Research Ltd. related to this study and all data and records generated in 
the course of conducting the study. They will not use the information, data or records for any 
other purpose than conducting the study without prior written approval of Amryt Research 
Ltd. 
Amryt Research Ltd. will prepare an integrated clinical study report in accordance with the 
harmonised tripartite ICH E3 Guideline ‘Structure and Content of Clinical Study Reports’ after 
completion of the study. 
16.1 
Publication of Study Findings 
Negative and positive results of this study will be presented at scientific meetings and/or will 
be published in a peer reviewed scientific or medical journal. By signing the clinical study 
agreement, the investigator agrees that the results of the clinical study may be used for 
publication. 
The first publication or disclosure shall be a complete, joint multicentre publication or 
disclosure. Authorship will be discussed with all parties involved, depending on such 
considerations as recruitment. A premature publication or disclosure of partial results is not 
possible. 
The investigator(s) may use the scientific data generated during the study for 
non-commercial purposes, e.g., for scientific publications of any kind only after prior written 
consent of Amryt Research Ltd. The investigator(s) will allow Amryt Research Ltd. to review 
the proposed publication or disclosure prior to submission for publication, presenting, using 
for instructional purposes or otherwise disclosing the results of the study. 
If Amryt Research Ltd. supposes the proposed publication or disclosure to risk Amryt’s ability 
to patent any invention related to the study, the publication or disclosure will be modified or 
delayed to allow Amryt Research Ltd. to file a patent application.  

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17 
COMPENSATION FOR INJURIES 
Insurance coverage for damages emerging from the study and involving study patients 
treated with the study medication will be provided according to applicable legal requirements. 
The investigator must inform the patient accordingly and must point out that the patient 
should seek the investigator’s consent before undergoing other medical treatment, whenever 
possible. The investigator will advise patients that they must inform the investigator 
immediately of any injury that might have been caused by study participation. 
 
 

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18 
REFERENCES 
18.1 
Source Documents 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 (June 14, 2010). 
US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute.  
https://www.eortc.be/services/doc/ctc/CTCAE 4.03 2010-06-14 QuickReference 5x7.pdf  
Investigator’s Brochure “Oleogel-S10 gel, Birch bark extract for treatment of epidermolysis 
bullosa”, current version. 
18.2 
Literature 
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Bharmal, M., K. Payne, M. J. Atkinson, M. P. Desrosiers, D. E. Morisky and E. Gemmen 
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Blome, C., K. Baade, E. S. Debus, P. Price and M. Augustin (2014). "The "Wound-QoL": a 
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R. P. d. A. Rêgo and I. Follador (2013). "Inherited epidermolysis bullosa: clinical and 
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Brandling-Bennett, H. A. and K. D. Morel (2010). "Common Wound Colonizers in Patients 
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Bruckner-Tuderman, L. (2010). Dystrophic Epidermolysis Bullosa: Pathogenesis and Clinical 
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Bruckner-Tuderman, L. and C. Has (2012). "Molecular heterogeneity of blistering disorders: 
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Danial, C., R. Adeduntan, E. S. Gorell, A. W. Lucky, A. S. Paller, A. L. Bruckner, E. Pope, K. 
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Denyer, J. and E. Pillay. (2012). "Best practice guidelines for skin and wound care in 
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Diem, S. and B. Sailer (2012). [Wundversorgung & Verbandwechsel für alle DEB und JEB-
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El Hachem, M., G. Zambruno, E. Bourdon-Lanoy, A. Ciasulli, C. Buisson, S. Hadj-Rabia, A. 
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Tadini, G. Salvatori, C. De Ranieri, S. Leclerc-Mercier and C. Bodemer (2014). "Multicentre 
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Fine, J. (2016). "Epidemiology of inherited epidermolysis bullosa based on incidence and 
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Fine, J. D. (2010). "Inherited epidermolysis bullosa." Orphanet J Rare Dis 5: 12. 
Fine, J. D., L. Bruckner-Tuderman, R. A. Eady, E. A. Bauer, J. W. Bauer, C. Has, A. 
Heagerty, H. Hintner, A. Hovnanian, M. F. Jonkman, I. Leigh, M. P. Marinkovich, A. E. 
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Fine, J. D., R. A. Eady, E. A. Bauer, J. W. Bauer, L. Bruckner-Tuderman and A. Heagerty 
(1999). Epidermolysis bullosa: clinical, epidemiologic, and laboratory advances and the 
findings of the National Epidermolysis Bullosa Registry. Baltimore, The Johns Hopkins 
University Press. 
Fine, J. D., L. B. Johnson, M. Weiner and C. Suchindran (2004). "Assessment of mobility, 
activities and pain in different subtypes of epidermolysis bullosa." Clin Exp Dermatol 29(2): 
122-127. 
Fine, J. D., L. B. Johnson, M. Weiner and C. Suchindran (2008). "Cause-specific risks of 
childhood death in inherited epidermolysis bullosa." J Pediatr 152(2): 276-280. 
Fitzpatrick, T. B. (1988). "The validity and practicality of sun-reactive skin types I through VI." 
Arch Dermatol 124(6): 869-871. 
Frew, Q., Rennekampff, H., Dziewulski, P., Moiemen, N., BBW-11 Study Group 1, Zahn, T.,  
Hartmann, B. "Betulin wound gel accelerated healing of superficialpartial thickness burns: 
Results of a randomized, intra-individually controlled, phase III trial with 12-months follow-
up." Burns 2018  
Galgon, T., W. Wohlrab and B. Drager (2005). "Betulinic acid induces apoptosis in skin 
cancer cells and differentiation in normal human keratinocytes." Exp Dermatol 14(10): 736-
743. 
Haest, C., M. P. Casaer, A. Daems, B. De Vos, E. Vermeersch, M. A. Morren, W. Van 
Steenbergen, J. L. Ceuppens and P. Moons (2011). "Measurement of itching: validation of 
the Leuven Itch Scale." Burns 37(6): 939-950. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P et al. Development and preliminary 
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2013 
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Hunefeld, C., M. Mezger, J. S. Kern, A. Nystrom, L. Bruckner-Tuderman, I. Muller, R. 
Handgretinger and M. Rocken (2013). "One goal, different strategies--molecular and cellular 
approaches for the treatment of inherited skin fragility disorders." Exp Dermatol 22(3): 162-
167. 
Lee, H. K., G. W. Nam, S. H. Kim and S. H. Lee (2006). "Phytocomponents of triterpenoids, 
oleanolic acid and ursolic acid, regulated differently the processing of epidermal 
keratinocytes via PPAR-alpha pathway." Exp Dermatol 15(1): 66-73. 
Loh, C. C., J. Kim, J. C. Su, B. S. Daniel, S. S. Venugopal, L. M. Rhodes, L. R. Intong, M. G. 
Law and D. F. Murrell (2014). "Development, reliability, and validity of a novel Epidermolysis 
Bullosa Disease Activity and Scarring Index (EBDASI)." J Am Acad Dermatol 70(1): 89-
97.e81-13. 
Mehta, C. R. and S. J. Pocock (2011). "Adaptive increase in sample size when interim results 
are promising: a practical guide with examples." Stat Med 30(28): 3267-3284. 
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behavioral scale for scoring postoperative pain in young children." Pediatr Nurs 23(3): 293-
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Miminas, D. A. (2007). "A critical evaluation of the Lund and Browder chart." Wounds UK 
3(3). 
Mordin, M., M. Clark, L. Doward and M. K. William (2012). Pediatric Patient-Reported 
Outcomes Assessment: A Case Study in Epidermolysis Bullosa. ISPOR 15th Annual 
European Congress. 
Morris, V., L. M. Murphy, M. Rosenberg, L. Rosenberg, C. E. Holzer, 3rd and W. J. Meyer, 
3rd (2012). "Itch assessment scale for the pediatric burn survivor." J Burn Care Res 33(3): 
419-424. 
Nystrom, A., D. Velati, V. R. Mittapalli, A. Fritsch, J. S. Kern and L. Bruckner-Tuderman 
(2013). "Collagen VII plays a dual role in wound healing." J Clin Invest 123(8): 3498-3509. 
Paller, A., J. Browning, R. Aslam, S. Bayliss, A. Lugo-Somolinos, R. Sidbury, E. Cantor, A. 
Reha, W. Lenon, L. Reklis, R. Nardi, J. Gault and J. Barth (2016). Efficacy and Safety of SD-
101 Cream in Patients with Epidermolysis Bullosa: Results From a Phase 2b Study. 
American Academy of Dermatology, 74th Annual Meeting. Washington, DC. 
Pillay, E. (2008). "Epidermolysis bullosa. Part 1: causes, presentation and complications." Br 
J Nurs 17(5): 292-296. 
Pope, E., I. Lara-Corrales, J. Mellerio, A. Martinez, G. Schultz, R. Burrell, L. Goodman, P. 
Coutts, J. Wagner, U. Allen and G. Sibbald (2012). "A consensus approach to wound care in 
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19 
APPENDICES 
19.1 
Appendix 1: Declaration of Helsinki 
 
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research 
Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best-proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 

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information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent.  
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens.  
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation.  
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed.  
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm.  
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a 

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non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol.  
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts 
of interest, incentives for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the research 
study.  
In clinical trials, the protocol must also describe appropriate arrangements for post trial 
provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final 
report to the committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, poststudy 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 

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information needs of individual potential subjects as well as to the methods used to deliver 
the information.  
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed.  
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The 
potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group. 
In such circumstances, the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon 
as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations, the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best-proven intervention(s), except in the following circumstances:  
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or  

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Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best-proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention  
And the patients who receive any intervention less effective than the best-proven one, 
placebo or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best-proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
Post-trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject.  
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, 
re-establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, 
new information must be recorded and, where appropriate, made publicly available. 
 
19.2 
Appendix 2: Anticipated Adverse Events by System Organ 
Class and Lowest Level Term 
System Organ Class 
Lowest Level Term 
Blood and lymphatic system disorders 
Anaemia 
Cardiac disorders 
Cardiac insufficiency 
 
Cardiomyopathy 
 
Congenital cardiovascular anomaly 
Investigations 
Ejection fraction decreased 
 
Urine analysis abnormal 
 
Blood calcium abnormal 
 
Blood phosphate abnormal 
 
Inflammatory marker increased 
 
Carnitine decreased 
 
Total protein low 

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C O N F I D E N T I A L  
System Organ Class 
Lowest Level Term 
 
Selenium low 
 
Iron abnormal not otherwise specified (NOS) 
 
Thyroid function test abnormal 
 
Zinc low 
 
Body mass index decreased 
 
Oxygen consumption increased 
 
Loss of weight 
 
Full blood count abnormal  
 
Urine electrolytes abnormal 
 
Abnormal liver function tests 
 
C-reactive protein abnormal 
 
Abnormal serum protein electrophoresis 
 
Urine albumin/creatinine ratio abnormal 
 
Autoantibody 
positive 
(incl. 
antinuclear 
antibodies [ANAs], antineutrophil cytoplasmic 
antibodies 
[ANCAs], 
antibasement 
membrane antibodies) 
Gastrointestinal disorders 
Ankyloglossia acquired 
 
Ankyloglossia congenital 
 
Tooth abnormal 
 
Gingivitis/periodontitis 
 
Anal fissure 
 
Painful defaecation/constipation 
 
Colitis 
 
Diarrhoea 
 
Gastrointestinal bleeding 
 
Gastroesophageal reflux 
 
Odynophagia 
 
Oesophageal mucosal blister 
 
Oesophageal diverticulitis 
 
Oesophageal disorder 
 
Oesophageal pain 
Gastrointestinal disorders (continued) 
Oesophageal perforation 
 
Pyloric stenosis 
 
Tooth lost 
 
Stricture and stenosis of oesophagus 
 
Oral mucosa blistering 
 
Dental decay 
 
Vomiting 
 
Dysphagia 
 
Fatty liver 
Eye disorders 
Blister on macula of eye 
 
Blepharitis 
 
Blindness 
 
Corneal erosion 
 
Scleritis with corneal involvement 
 
Corneal scar 
 
Ectropion 
 
Eye dryness 
 
Eyelid function disorder 
 
Visual impairment 

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C O N F I D E N T I A L  
System Organ Class 
Lowest Level Term 
 
Keratitis 
 
Keratoconjunctivitis 
 
Lacrimal duct obstruction 
 
Symblepharon 
Ear and labyrinth disorders 
Acquired stenosis of external ear canal 
 
Hearing loss 
 
Hearing impaired 
Infections and infestations 
Otitis externa 
 
Infection susceptibility increased 
 
Otitis media 
 
Gastroenteritis 
 
Infection respiratory 
 
Skin infection 
 
Bacteraemia/sepsis 
Endocrine disorders 
Delayed puberty 
 
Pubertal failure 
Congenital, familial and genetic disorders 
Microstomia 
 
Finger hypoplasia 
 
Muscular dystrophy 
 
Syndactyly/webbing 
General disorders and administration site conditions 
Application site pain 
 
Pain 
 
Pyrexia 
 
Multiorgan failure 
 
Loss of energy 
General disorders and administration site conditions 
Deformity 
(continued) 
Growth delay 
 
Asthenia 
 
Delayed healing of wound 
 
Healing delayed 
 
Wound healing delayed 
Metabolism and nutrition disorders 
Iron deficiency 
 
Vitamin deficiency 
 
Appetite lost 
 
Dehydration 
 
Malnutrition 
Musculoskeletal and connective tissue disorders 
Ainhum 
 
Contracture 
 
Juvenile idiopathic arthritis 
 
Limb/hand/foot deformity 
 
Myasthenia 
 
Multiple fractures 
 
Osteopenia 
 
Osteoporosis 
 
Mobility decreased 
Neoplasms benign, malignant and unspecified (incl. 
cysts and polyps) 
Basal cell carcinoma 
 
Epidermoid carcinoma 
 
Skin cancer 
 
Squamous cell carcinoma 
 
Atypical melanocytic hyperplasia (‘EB-nevi’) 

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C O N F I D E N T I A L  
System Organ Class 
Lowest Level Term 
Psychiatric disorders 
Sleep disturbance 
 
Parasomnia 
 
Depression 
 
Anxiety 
 
Phobia 
Renal and urinary disorders 
Bladder dysfunction 
 
Bladder hypertrophy 
 
Dysuria 
 
Glomerulonephritis 
 
Nephrotic syndrome 
 
Hydronephrosis 
 
Renal failure 
 
Abnormal kidney function 
 
Urethral stenosis 
 
Urinary retention 
 
Urogenital disorder 
 
Urogenital infection bacterial 
Reproductive system and breast disorders 
Sexual dysfunction 
Reproductive system and breast disorders 
Sexual problem 
(continued) 
Dyspareunia 
 
Vaginal inflammation 
Respiratory, thoracic and mediastinal disorders 
Oropharyngeal pain 
 
Nose bleed 
 
Bronchitis 
 
Respiratory distress 
 
Stridor 
Skin and subcutaneous tissue disorders 
Alopecia totalis 
 
Diffuse alopecia 
 
Nail dystrophy/loss 
 
Cheilitis 
 
Keratoderma 
 
Pruritus 
 
Rash 
 
Rash erythematous 
 
Skin atrophy 
 
Poikiloderma 
Injury, poisoning and procedural complications 
Wound 
 
Wound oozing 
 
Wound haemorrhage 
 
Scarring 
Vascular disorders 
Bleeding 
Surgical and medical procedures 
Dental treatment 
 
Dilatation of oesophagus 
 
Hand operation 
 
Foot surgery 
 
Tracheostomy 
 
Gastrostomy tube insertion 
 
Iron infusion 
 
Blood transfusion 
 
Skin cancer surgery 
 
IV antibiotic treatment 

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C O N F I D E N T I A L  
System Organ Class 
Lowest Level Term 
 
Dressing changes 
 
Barium meal 
 
Endoscopy 
 
Sedation/anaesthesia for imaging/medical 
procedures