A Phase III Efficacy and Safety Study of Beremagene Geperpavec (B-VEC, Previously "KB103") for the Treatment of Dystrophic Epidermolysis Bullosa (DEB)
Phase: PHASE3
Conditions: Dystrophic Epidermolysis Bullosa, Recessive Dystrophic Epidermolysis Bullosa, Dominant Dystrophic Epidermolysis Bullosa
Sponsor: Krystal Biotech, Inc.

 
 
The GEM-3 Study 
B-VEC-03 
A Phase III Efficacy and Safety Study of Beremagene Geperpavec (B-VEC, 
previously KB103) for the Treatment of Dystrophic Epidermolysis Bullosa 
(DEB) 
Status: 
Final 
Protocol Version: 
1.4 
Version Date 
21-APR-2021 
IND Number: 
018100 
Investigational Product: 
B-VEC 
Phase of Development: 
Phase III 
 
 
 
 
 
CONFIDENTIAL MATERIAL 
This material is the property of Krystal Biotech, Inc. and it must not be disclosed or used without written 
authorization from Krystal Biotech, Inc 
 

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Sponsor Approval 
Sponsor Endorsement 
This protocol has been approved by Krystal Biotech, Inc. 
Sponsor’s Authorized Officer:  
 
Suma Krishnan, M.S., M.B.A. 
 
Chief Operating Officer 
 
Krystal Biotech, Inc. 
 
2100 Wharton Street, Suite 310 
 
Pittsburgh, PA 15203 
 
 
 
_____________________________________  
 
_______________ 
Signature 
 
 
 
 
 
 
Date  
 

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Investigator’s Acknowledgement 
Principal Investigator’s Agreement 
I have read the Phase III Protocol: 
GEM-3: A Phase III Efficacy and Safety Study of Beremagene Geperpavec (B-VEC, previously 
“KB103”) for the treatment of Dystrophic Epidermolysis Bullosa (DEB) 
I have fully discussed the objectives of this trial and the contents of this protocol with the Sponsor’s 
representative. 
I understand that the information in this protocol is confidential and should not be disclosed, other than 
to those directly involved in the execution or the review of the study, without written authorization from 
Krystal Biotech, Inc. It is permissible to provide the information contained within to a subject to obtain 
their consent to participate.  
I agree to conduct the study as outlined herein and in accordance with International Conference on 
Harmonization (ICH) guidelines on Good Clinical Practice (GCP), with applicable Food and Drug 
Administration (FDA) regulations set forth in 21 CFR Parts 50, 54, and 312, and all other applicable 
regulatory requirements. 
I understand that failure to comply with the protocol requirements may lead to termination of my role as 
an Investigator for this study.  
I understand that Krystal Biotech, Inc may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated in writing. If I should decide to withdraw 
from execution of the study, I will communicate my intention immediately in writing to Krystal Biotech, 
Inc.  
 
Principal Investigator Name: ____________________________________ 
 
____________________________________ 
 
 
_____________________ 
Signature 
 
 
 
 
 
 
Date  

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Protocol History 
Protocol History  
Version and Date of Protocol  
Comments 
Version 1.0 (05-MAY-2020) 
Original Version Submitted to FDA 
Version 1.1 (29-JUN-2020) 
Updated Version Submitted to FDA 
Version 1.2 (20-OCT-2020) 
Urine collection, phlebotomy and dressing viral 
shedding collection minimized 
Version 1.3 (10-DEC-2020) 
Matched Wounds capped at one (1) pair and 
Secondary Unmatched Wounds capped at four (4). 
Version 1.4 (21-APR-2021) 
Updated statistical plan and additional details on 
study assessments  

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Key Changes in the Protocol 
Major changes to the protocol are summarized below. Minor administrative changes involving 
formatting, grammar, syntax, punctuation, and other editorial changes are not summarized in the 
table below.  
Change and Rationale  
Affected Sections 
Statistical analysis for primary and key secondary endpoint 
measurement will be analyzed using the McNemar Test, adjusted 
per FDA agreement. Furthermore, the primary endpoint is defined 
as wounds that meet any of the following conditions: 
• 
Healed on Week 22 and Week 24, or 
• 
Healed on Week 24 and Week 26.  
The secondary key endpoint is defined as wounds that meet any of 
the following conditions: 
• 
Healed on Week 8 and Week 10, or 
• 
Healed on Week 10 and Week 12.  
Only wounds that are healed for at least two (2) consecutive weeks 
are counted as positive responses. 
Synopsis; Section 2.2; Section 
6.2; Section 8.1; Section 8.2; 
and Section 8.7  
The protocol has been amended to add clarification around the 
assessment of the Primary Wounds, such that only the originally 
selected area at the Week 1 Visit, will be assessed at the Week 8, 
10, 12, 22, 24 and 26 Visits. The neighboring wounds which have 
received treatment during the study will not be included in this 
assessment.  
Section 2.2; Section 4.2; 
Section 5.1; Section 6.2; 
Section 8.1; Section 8.2; and 
Section 8.7 
Per Agency’s recommendation, a McNemar Test has been used for 
sample size calculation. In the Phase I/II study, the response rates 
for Weeks 8 through 12 were from 70-100% for wounds randomized 
to B-VEC and 0-33% for wounds randomized to placebo, 
respectively. Therefore, the sample size has been revised to 24 
subjects assuming a response rate of 75% among wounds 
randomized to B-VEC and a response rate of 25% among wounds 
randomized to placebo. With 90% power and a two-sided Type 1 
error rate of 5%, 24 subjects (i.e., 24 wound pairs) are required.  
 
Synopsis; Section 3.0; and 
Section 8.3 
 
 
 
 
 
 

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Protocol Synopsis 
Title 
GEM-3: A Phase III Double Blinded, Placebo-Controlled, Efficacy and 
Safety Study of Beremagene Geperpavec (B-VEC, previously 
“KB103”) for the treatment of Dystrophic Epidermolysis Bullosa (DEB) 
Study Number 
B-VEC-03 
Number of Subjects 
Approximately 24 subjects 
Study Phase 
Phase III study 
Number of Centers 
3 centers 
Study Objectives 
The primary objective is to determine whether administration of B-
VEC in addition to standard of care improves wound healing as 
compared to placebo in children, adolescents, and adults with 
Dystrophic Epidermolysis Bullosa (DEB). 
Study Design 
GEM-3 is a multi-center, intra-subject randomized, placebo-
controlled, double blinded, Phase III study of B-VEC for the topical 
treatment of DEB wounds. Each subject will serve as their own control.  
Definition of Unit Dose: Unit dose varies by wound area 
Wound Area* 
Unit Dose 
<20 cm2 
4×108 PFU/wound 
20 to 40 cm2 
8×108 PFU/wound 
40 to 60 cm2 
1.2×109 PFU/wound 
* Wound area determined by the Investigator using the validated 
Canfield photography quantitation at Week 1. Subsequent 
Secondary Wounds not selected at Week 1, will have the wound 
area determined during selection.  
Definitions: 
Weekly Treatment:  1 unit-dose of B-VEC or placebo 
Treatment Cycle:  Weekly Treatment until complete wound closure 
of wounds selected at baseline and any new surrounding wounds 
(neighboring wounds) during the treatment phase. 
Maximum Weekly Dose per subject:   
Age  
Maximum Weekly Dose 
≥ 6 months to < 3 years  1.6×109 PFU/week 
≥ 3 years to < 6 years 
2.4×109 PFU/week 
≥ 6 years 
3.2×109 PFU/week 
Matched Wounds: Two matched wounds similar in size, located in 
similar anatomical regions, and have similar appearance.  
Two matched wounds in a 1:1 ratio per subject will be selected to 
evaluate the primary and secondary endpoints. The matched wounds 
will be randomized, such that one wound will receive Weekly 

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Treatment of B-VEC and one wound will receive Weekly Treatment of 
placebo for a Treatment Cycle. 
Study Design 
(continued) 
Remaining Weekly Dose: The difference between Maximum Weekly 
Dose per subject per week and the sum total of the B-VEC Dose(s) 
applied to the Primary Wound Pair per subject per week. The 
Remaining Weekly Dose will be used to treat Secondary Wounds. Up 
to four (4) Secondary Wounds may be selected.  
For example: If a subject 7 years of age, presents with the primary 
wound pair < 20cm2 then the Remaining Weekly Dose during a weekly 
visit = Difference of (3.2×109 PFU – (4×108 PFU)) = 2.8×109 
PFU/subject/week. The Remaining Weekly Dose will be applied to 
secondary wounds for monitoring safety and efficacy. 
Re-dosing regimen 
During the study, if a neighboring wound near the primary wound 
opens up, (approximately 2-3 cm from the original wound) that wound 
may receive treatment at the discretion of the Investigator. When a 
matched primary wound and its neighboring wound/s close 
completely, as determined by the Investigator during a weekly visit, 
then no treatment will occur. Weekly treatment on that wound will 
resume when the originally selected wound or its neighboring wound/s 
is determined to be open by the Investigator at a weekly visit.  
The re-dosing regimen will be followed throughout the study. 
Secondary Wounds 
The Remaining Weekly Dose calculated during a weekly visit will be 
applied to a maximum of four (4) additional wounds (“Secondary 
Wounds”). Secondary Wound(s) will receive a Weekly Treatment of 
B-VEC for the Treatment Cycle. The number of Secondary Wounds 
treated will depend on wound area of the Secondary Wound(s). The 
total dose applied to Secondary Wounds is not to exceed the 
Remaining Weekly Dose. During the study, if a neighboring wound 
near the Secondary wound opens up, (approximately 2-3 cm from the 
original wound) that wound may receive treatment. When the 
secondary wound and the neighboring wound close completely, as 
determined by the Investigator during a weekly visit, then that 
particular wound will stop receiving treatment. For Secondary 
Wounds, avoid selecting wounds that are in close proximity to the 
Primary Wound Pair.  
Primary Endpoint 
Wound Healing 
The primary endpoint is the proportion of DEB primary wound sites 
with complete wound healing of the originally selected baseline wound 
in B-VEC versus placebo treated intra-subject wound sites at Weeks 
22 and 24 or Weeks 24 and 26, as determined by the Investigator, to 
evaluate durability and repeat dosing. The complete wound healing is 
defined as 100% wound closure of the exact original wound surface 
area selected at baseline, specified as skin re-epithelialization without 
drainage.  

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Secondary Endpoints 
Key Secondary Endpoint 
• 
Proportion of the selected primary wound sites with 
complete wound healing of the exact wound surface area 
selected at baseline (as defined in the primary endpoint) in 
B-VEC-treated versus placebo at Weeks 8 and 10 or Weeks 
10 and 12 (as determined by the Investigator) to evaluate 
durability. 
Secondary Endpoint 
• 
The mean change in pain severity using a VAS score per 
primary wound site associated with wound dressing 
changes at Weeks 22, 24 and 26 for each treated versus 
placebo wound, for ages 6 and above on the primary wound 
pair. For ages below 6 years, the Face Legs Activity Cry and 
Consolability-Revised (FLACC-R) scale will be used. 
Exploratory Endpoints 
• 
Relative time to wound closure from baseline. 
• 
Duration of closure, as defined by the time from complete 
wound closure to the reopening of the Primary Wounds.  
• 
The mean change in Quality of Life in addition to Skindex 
score as compared to baseline at Week 26. 
Safety Endpoint 
• 
The safety and tolerability of B-VEC based on the 
assessment of adverse events, physical examinations, vital 
signs, and clinical laboratory test results. 
Subject 
Population 
Inclusion Criteria 
1. The 
subject 
or 
legally 
appointed 
and 
authorized 
representative must have read, understood and signed an 
Institutional Review Board/Ethics Committee (IRB/EC) 
approved Informed Consent or Assent Form and must be able 
to and willing to follow study procedures and instructions. 
2. Age ≥ 6 months and older at the time of Informed Consent. 
3. Clinical diagnosis of the Dystrophic Epidermolysis Bullosa. 
4. Confirmation of DEB diagnosis (either DDEB or RDEB) by 
genetic testing including COL7A1. 
5. Two (2) cutaneous wounds meeting the following criteria: 
a. Location: similar in size, located in similar anatomical 
regions, and have similar appearance (Refer to Section 
5.8 for more details). 
b. Appearance: clean with adequate granulation 
tissue, excellent vascularization, and do not 
appear infected. 
6. Subjects and caregivers who, in the opinion of the 
Investigator, are able to understand the study, co-operate with 
the study procedures, and are willing to return to the clinic for 
all the required visits. 
7. Male or Female of childbearing potential must use a reliable 
birth control method throughout the duration of the study and 
for 3 months post the last treatment. Refer to Section 4.5.1 for 
more details. 
8. Negative Pregnancy test on Visit 1 (Week 1), if applicable.  

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Exclusion Criteria 
1. Medical instability limiting ability to travel to the Investigative 
Center. 
2. Diseases or conditions that could interfere with the 
assessment of safety and efficacy of the study treatment and 
compliance of the subject with study visits/procedures, as 
determined by the Investigator. 
3. Current evidence or a history of squamous cell carcinoma in 
the area that will undergo treatment. 
4. Subject’s actively receiving chemotherapy or immunotherapy 
at Visit 1 (Week 1) 
5. Active drug or alcohol addiction as determined by the 
Investigator. 
6. Hypersensitivity to local anesthesia (lidocaine/prilocaine 
cream). 
7. Participation in an interventional clinical trial within the past 
three (3) months (not including B-VEC administration). 
8. Receipt of a skin graft in the past three (3) months. 
9. Pregnant or nursing women. 
 
 

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Study Treatment, 
Duration and 
Assessments 
Study Treatment 
Week 1 
- 
Following randomization of the matched primary wound pair, wounds will 
receive one Weekly Treatment in a double-blinded manner. 
- 
The Remaining Weekly Dose will be calculated and applied to a maximum of 
four (4) additional wounds (“Secondary Wounds”). Secondary Wound(s) will 
receive a Weekly Treatment of B-VEC. The number of Secondary Wound(s) 
treated will depend on wound area of the Secondary Wound(s). The total dose 
applied to Secondary Wound(s) is not to exceed the Remaining Weekly Dose.  
Week 2 through 26  
- 
Subjects will return to the clinical site for assessment of all wounds by the 
Investigator.  
- 
The Primary Wound Pair will receive one Weekly Treatment in a double-
blinded manner. However, if one of the wounds in a matched Primary Wound 
Pair closes completely and there are no open neighboring wounds, as 
determined by the Investigator during a weekly visit, then that particular wound 
and its neighboring wound/s will not receive Weekly Treatment that week. 
Once that particular wound, or its neighboring wound/s, is determined to be 
open by the Investigator at a weekly visit, Weekly Treatment will continue. If 
the originally selected primary wound closes, its neighboring wound/s may 
continue to receive treatment.  
- 
If a Secondary Wound is closed completely, as well as its neighboring 
wound/s, as determined by an Investigator, during a weekly visit, then that 
particular wound and its neighboring wound/s will not receive Weekly 
Treatment that week. If the originally selected secondary wound closes, its 
neighboring wound/s may continue to receive treatment. The total dose 
applied to secondary wounds is not to exceed the Remaining Weekly Dose.  
- 
Subjects will come to clinic for assessment even if the originally selected 
wounds are closed. 
Safety Follow-up/Early Termination  
- 
Subjects will return to the clinical site 30 days following the last dose of B-
VEC.  
- 
Subjects may roll into an Open Label Extension (OLE) Protocol. If subjects do 
not participate in the OLE Protocol, they will be asked to roll over into a Long-
Term Follow-up Protocol (All subjects enrolled in the study who received at 
least a Weekly Treatment). 
Assessments  
- 
Safety measures include adverse events, physical examinations, vital signs, and
clinical laboratory tests. All safety analyses results will be performed using the 
safety population. A summary of safety results will be presented for each 
treatment group. 

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Statistical 
Analyses 
Continuous variables will be summarized in tables and will include the number of 
subjects, mean, standard deviation (SD), percent of coefficient of variance (CV%), 
median, minimum, and maximum. Categorical variables will be presented in tables as 
frequencies and percentages. A statistical analysis plan (SAP) will provide additional 
details on the approach to the analysis and data displays. 
Sample Size Estimation  
In the Phase I/II study, the response rates for Weeks 8 through 12 were from 70-100% 
for wounds randomized to B-VEC and 0-33% for wounds randomized to placebo, 
respectively. Assuming a response rate of 75% among wounds randomized to B-VEC 
and a response rate of 25% among wounds randomized to placebo, with a 90% power 
and a two-sided Type 1 error rate of 5%, 24 subjects (i.e., 24 wound pairs) are required.  
Analysis Populations 
Safety Population: 
This population is defined as all subjects who were administered with either B-VEC or 
placebo. Safety population will be used for all the safety analyses. 
Intent-to-Treat Population: 
The intent-to-treat (ITT) population includes subjects whose primary wounds were 
randomized with or without either B-VEC or Placebo administration. ITT population will 
be used for all the primary and secondary efficacy sensitivity analyses and baseline 
summaries. 
Modified Intent-to-Treat Population: 
The modified intent-to-treat (mITT) population includes subjects whose primary 
wounds were randomized and received B-VEC treatment with at least one post 
baseline primary endpoint assessment. mITT population will be used for all the primary 
and secondary efficacy analyses. 
Per Protocol Population: 
The per-protocol (PP) population includes all the safety population subjects who 
completed the study without major protocol deviations. PP population will be used for 
all the primary and secondary efficacy sensitivity analyses. 
Missing Values and Imputations 
Multiple imputation method will be used to handle missing data for primary efficacy 
analysis. For all the exploratory endpoints, the missing values will not be imputed. 
 

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Statistical 
Analyses 
(continued) 
Efficacy Analyses: 
The study has a complete randomized-block design in which each subject serves as a 
block to receive all of the treatment conditions.  In this study, each subject provides 
one pair of matched target wounds with one wound being treated with B-VEC and the 
other wound with placebo in the primary wound pair. Efficacy measurements are taken 
multiple times (or repeatedly) over the on-treatment period from each subject. Efficacy 
measures collected pre-dosing at Visit 1 (Week 1) will be considered as the baseline 
measurement in this study. 
Analysis of Primary Efficacy Endpoint: 
The primary endpoint of the proportion of DEB primary wound sites with complete 
wound healing of the exact wound surface area selected at baseline will be 
analyzed using the McNemar Test.  
The primary endpoint is defined as wounds that meet any of the following 
conditions: 
• 
Healed on Week 22 and Week 24, or 
• 
Healed on Week 24 and Week 26.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as 
positive responses. 
Analysis of Key Secondary Efficacy Endpoint: 
The key secondary endpoint of the proportion of primary wound sites with 
complete wound healing of the exact wound surface area selected at baseline, will 
be analyzed using the McNemar Test.  
The primary endpoint is defined as wounds that meet any of the following 
conditions: 
• 
Healed on Week 8 and Week 10, or 
• 
Healed on Week 10 and Week 12.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as 
positive responses. 
Analysis of Secondary Efficacy Endpoint: 
The following secondary endpoint will be analyzed using the Analysis of Covariance 
(ANCOVA) with treatment as the fixed effect and the baseline value as the covariate 
by the time points. 
1. The mean change from baseline in pain severity VAS score per wound site 
associated with wound dressing changes at Weeks 22, 24 and 26 for each 
treated versus placebo for ages 6 and above on the primary wound pair. For 
ages below 6 years, the FLACC-R scale scores will be used instead VAS 
scores. 
Safety Analyses: 
Safety measures include adverse events, physical examinations, vital signs, and 
clinical laboratory tests. All safety analyses results will be performed using the safety 
population. A summary of safety results will be presented for each treatment group. 
Long-term 
follow-up 
Subjects will be asked to transfer to a long-term follow-up study, which will include up 
to 5 years of annual phone check-ins. Subjects may roll into the Long-Term Follow-Up 
Protocol at the Safety Follow-up Visit (30 days following the last dose of B-VEC). 
DSMB Reviews 
A data monitoring board (DSMB) will conduct regular planned safety reviews of study 
data as outlined in the DSMB charter. 

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Schedule of Events  
Table 1. Visit Assessments and Procedures  
 
Randomized-Double Blinded Placebo-Controlled Treatment Period 
Safety Follow-up/ET 
Study Day 
Screen-
ing1 
Week 1 
Week 2 -21 
Week 22 
Week 23 
Week 24 
Week 25 
Week 26 
30 days after last 
dose 
Daily Visit Window  
-60 to 0 
na  
± 3 days 
± 4 days 
Visit  
Screening 
1  
2-21 
22 
23 
24 
25 
26 
SFU 
Obtain Consent / Assent 
X 
X2 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
X2 
 
 
 
 
 
 
 
Medical History 
X 
X2 
 
 
 
 
 
 
 
Genetic Testing 
X1 
 
 
 
 
 
 
 
 
Wound Selection 
 
X 
 
 
 
 
 
 
 
Wound randomization3 
 
X 
 
 
 
 
 
 
 
Pain Assessment- Wound Pair4 
 
X 
 
X 
 
X 
 
X 
 
Quality of Life Questionnaire (EQ-5D)5 
 
X 
 
 
 
 
 
X 
 
Skindex Questionnaire5 
 
X 
 
 
 
 
 
X 
 
 Imaging6 
 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Wound Closure7 
 
X 
X 
X 
X 
X 
X 
X 
 
Swabs for Viral Shedding/Infectivity8 
 
X 
X 
X 
X 
X 
X 
X 
 
Swabs for Viral Shedding on Dressing 
Returned9  
 
 
X 
 
 
 
 
 
 
1 If genetic testing is required, this test may occur up to 60 days prior to the other screening procedures, following subject consent/assent. Genetic testing may take 6-8 weeks to obtain results. 
2 Informed consent/assent, demographics, medical/ procedural history, urine (if male) and blood specimens will not be re-collected, if collected at a Screening visit. 
3 The matched primary wound pair will be randomized. 
4 Pain questionnaires are to be completed during the dressing change of the individual matched wounds. If subject is 6 years of age or older, they will be asked to complete the VAS questionnaire 
for matched wounds during the dressing change. If younger than 6 years of age, their parent/caregiver will be administered the FLACC-R questionnaire for the matched wounds during the 
dressing change (Refer to section 6.2.2). 
5 Both the Quality of Life (EQ-5D) and Skindex Questionnaires will be administered to subjects 12 years of age and older at the time of consent. Questionnaires may be administered for the 
subject to complete after the visit and bring back at the next scheduled visit.  
6 Images will be collected on both closed and open wounds. Image in the same order and orientation at each visit prior to IP application. 
7 Primary wound closure assessments will be evaluated by the Investigator only at Weeks 8, 10 12, 22 24 and 26. Secondary wound closure is assessed weekly, to determine if a new wound may 
be selected to receive treatment, if the originally selected area and its neighboring wound/s has closed, as applicable.  
8 Viral shedding and infectivity swabs will be collected from the primary matched wounds only and will be collected whether or not the wound is open or closed. 
9 Subjects are required to bring the study visit wound dressing back to the site. Primary wounds will be separately bagged. Secondary wound dressing may be bagged together. Once returned to 
the site, viral shedding swabs will be collected for all Primary Wounds dressings that came into contact with the subject’s skin. Attempt collection of (4) four consecutive VS dressing returns, if 
unable, collect at least (4) four dressing VS per subject. Once four (4) VS samples have been collected from the Primary Wound Pair, all dressing may be bagged together and returned to the site 
for disposal and specimen collection will be discontinued. 

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Table 2. Visit Assessments and Procedures (continued)  
 
Randomized-Double Blinded Placebo-Controlled Treatment Period 
Safety Follow-up/ET 
Study Day 
Screen-
ing1 
Week 1 
Week 2 -21 
Week 22 
Week 23 
Week 24 
Week 25 
Week 26 
30 days after last 
dose 
Daily Visit Window  
-60 to 0 
na 
± 3 days 
± 4 days 
Visit  
Screening 
1 
2-21 
22 
23 
24 
25 
26 
SFU 
Physical Exam10 
 
complete 
 
 
 
 
 
Abbrev.  
Abbrev 
Treatment and Procedure Review11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Review11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE and SAE Review  
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs12 
 
X 
X 
 
 
 
X 
 
X 
Urine Pregnancy Test13,14 
 
X 
 
 
 
 
 
X 
 
Urine for Viral Shedding15 
X 
X2 
 
 
 
 
 
X 
 
CMP w/Direct Bilirubin15 
X 
X2 
 
 
 
 
 
X 
 
CBC/Diff15 
X 
X2 
 
 
 
 
 
X 
 
COL7 & HSV Serum ADA15 
X 
X2 
 
 
 
 
 
X 
 
Whole Blood Viral Shedding15 
X 
X2 
 
 
 
 
 
X 
 
Investigational Product (IP) 
Administration16 
 
X 
X 
X 
X 
X 
X 
X 
 
Roll-over to LTFU or OLE Protocol17 
 
 
 
 
 
 
 
 
X 
10 The Physical examination is described in section 0 
11 All medication taken 3 months prior to Screening/Visit 1 through the end of the study will be recorded as well as all applicable procedures and treatments within the last 3 months to 
Screening/Visit 1. 
12 On days in which both vitals and blood draw occur, attempt vitals prior to the blood draw. Vitals are collected every 5 visits (i.e. Visit 1; 5; 9; 13; 17; 21; 25; SFU/ET). Vitals may be obtained 
more frequently as determined by the Investigator.  
13 A urine pregnancy test will be completed on all women of childbearing potential prior to blood collection and drug administration, as determined by the Investigator. 
14 For Subjects with history of genitourinary involvement, including painful urination due to the underlying disease and or Subjects who are 4 years of age and younger, are not required to provide 
a urine sample, as determined by the Investigator. Documentation must be recorded on the CRF and listed in Medical History.  
15 Labs will be attempted, unless per the discretion of the Investigator, it is not in the best interest of the subject. If labs are attempted and not obtained, documentation will be noted in the study 
visit. Furthermore, if labs are not attempted, justification must be recorded in the study visit. The Investigator must determine clinical significance for out-of-range values.  
16 Conduct all other study visit procedures prior to B-VEC and placebo administration. Matched Wounds: IP will be applied to wounds that are open. If a matched wound and neighboring wound is 
closed, no IP will be applied and application will be reinitiated once the wound reopens at a scheduled visit, as determined by the Investigator. Secondary Wounds: IP will only be applied to open 
wounds as determined by the Investigator, not to exceed the Remaining Weekly Dose. IP may be applied to immediate neighboring wounds. Up to four (4) unmatched Secondary Wounds may be 
selected to receive open-label B-VEC during the study treatment. Trace the area that is receiving treatment (including the neighboring wounds). Neighboring wounds are defined as wounds 
approximately 2-3cm away from the original matched and unmatched (Primary and Secondary) wound. 
17 At the Safety Follow-up (30 days ± 4 days) following the last dose of B-VEC, subjects may roll over into an OLE protocol or will be asked to roll over into a LTFU protocol 
 
 

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Table of Contents 
1 
Introduction .......................................................................................................................................... 22 
1.1 
Disease Background ................................................................................................................... 22 
1.2 
Phase I/II Results Summary ........................................................................................................ 22 
1.2.1 
Efficacy Results ................................................................................................................... 22 
1.2.2 
Safety Results ..................................................................................................................... 23 
2 
Study Objectives and Endpoints ......................................................................................................... 23 
2.1 
Study Objective ........................................................................................................................... 23 
2.2 
Study Endpoints .......................................................................................................................... 24 
2.2.1 
Overview ............................................................................................................................. 24 
2.2.2 
Primary Endpoint ................................................................................................................. 25 
2.2.3 
Key Secondary Endpoint ..................................................................................................... 26 
2.2.4 
Secondary Endpoint ............................................................................................................ 27 
2.2.5 
Safety Endpoints ................................................................................................................. 27 
3 
Selection of Subjects ........................................................................................................................... 27 
3.1 
Inclusion Criteria ......................................................................................................................... 27 
3.2 
Exclusion Criteria ........................................................................................................................ 28 
4 
Study Implementation ......................................................................................................................... 28 
4.1 
Study Design ............................................................................................................................... 28 
4.1.1 
Study Design Rationale ....................................................................................................... 29 
4.1.2 
Treatment Period................................................................................................................. 29 
4.2 
Study Visits .................................................................................................................................. 30 
4.2.1 
Sequence of Study Procedures .......................................................................................... 30 
4.2.2 
Protocol Deviations ............................................................................................................. 30 
4.2.3 
Screening ............................................................................................................................ 30 
4.2.4 
Week 1/Visit 1 (First Day of Treatment Cycle) .................................................................... 31 
4.2.5 
Week 2 through 21 .............................................................................................................. 32 
4.2.6 
Week 22 .............................................................................................................................. 32 
4.2.7 
Week 23 .............................................................................................................................. 32 
4.2.8 
Week 24 .............................................................................................................................. 33 
4.2.9 
Week 25 .............................................................................................................................. 33 
4.2.10 
Week 26 .............................................................................................................................. 33 

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4.2.11 
Safety Follow-up/ Early Termination ................................................................................... 34 
4.2.12 
Safety Follow-Up ................................................................................................................. 34 
4.2.13 
Early Termination Scheduling ............................................................................................. 35 
4.3 
Sites and Trial Duration ............................................................................................................... 35 
4.4 
Study Restrictions ....................................................................................................................... 35 
4.5 
Concomitant Medications and Topical Treatments ..................................................................... 35 
4.5.1 
Contraception ...................................................................................................................... 35 
4.6 
Subject Enrollment ...................................................................................................................... 35 
4.6.1 
Subject Identification and Number Assignment .................................................................. 36 
5 
B-VEC and Placebo Administration and Wound Selection ................................................................. 36 
5.1 
Dosing Regimen .......................................................................................................................... 36 
5.1.1 
Dosing Regimen Rationale ................................................................................................. 37 
5.2 
Preparation and Dispensing ........................................................................................................ 37 
5.3 
Packaging and Labeling .............................................................................................................. 37 
5.4 
Storage and Handling ................................................................................................................. 38 
5.5 
Drug Accountability ..................................................................................................................... 38 
5.6 
Drug Disposal, Returns, or Retaining Used Drug ....................................................................... 38 
5.7 
Blinding and Unblinding .............................................................................................................. 38 
5.8 
Wound Selection ......................................................................................................................... 38 
5.9 
Wound Randomization ................................................................................................................ 39 
5.10 
Post-Administration Procedures.................................................................................................. 39 
6 
Assessments ....................................................................................................................................... 40 
6.1 
Timing of Assessments ............................................................................................................... 40 
6.2 
Efficacy Assessments ................................................................................................................. 40 
6.2.1 
Wound Assessments .......................................................................................................... 40 
6.2.2 
Pain Reported Outcome ...................................................................................................... 40 
6.3 
Safety Assessments .................................................................................................................... 41 
6.3.1 
Medical and Medication History .......................................................................................... 41 
6.3.2 
Physical/Skin Examination .................................................................................................. 41 
6.3.3 
Vital Signs ........................................................................................................................... 42 
6.3.4 
Laboratory Evaluations ....................................................................................................... 42 
6.4 
Principal Investigator ................................................................................................................... 43 
6.4.1 
Protocol Adherence ............................................................................................................. 43 

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6.4.2 
Treatments .......................................................................................................................... 43 
6.4.3 
Safety Assessments ............................................................................................................ 43 
6.4.4 
Adverse Events ................................................................................................................... 43 
6.5 
Definitions .................................................................................................................................... 44 
6.5.1 
Adverse Events ................................................................................................................... 44 
6.5.2 
Immune Response Adverse Events .................................................................................... 45 
6.5.3 
Serious Adverse Event ........................................................................................................ 45 
6.6 
Severity ....................................................................................................................................... 45 
6.7 
Relationship................................................................................................................................. 45 
6.8 
Study IP Action Taken ................................................................................................................. 46 
6.9 
Outcome ...................................................................................................................................... 46 
6.10 
Reporting Procedures ................................................................................................................. 46 
6.10.1 
SAE Reporting Procedures ................................................................................................. 47 
6.10.2 
Pregnancy ........................................................................................................................... 47 
6.11 
Data Monitoring Board Review and Regulatory Reporting ......................................................... 47 
6.12 
Expedited Reporting and Safety Letters ..................................................................................... 48 
6.13 
Safety Monitoring ........................................................................................................................ 48 
7 
Study Completion ................................................................................................................................ 48 
7.1 
Long Term Follow-Up Protocol ................................................................................................... 48 
7.2 
Discontinuation, Withdrawal, Lost to Follow-Up, or Early Termination ....................................... 49 
8 
Statistical Considerations .................................................................................................................... 49 
8.1 
Primary Efficacy Endpoint ........................................................................................................... 49 
8.2 
Key Secondary Efficacy Endpoint ............................................................................................... 50 
8.3 
Number of Subjects ..................................................................................................................... 50 
8.4 
Data Management ....................................................................................................................... 50 
8.5 
Analysis Populations ................................................................................................................... 51 
8.6 
Demographic and Baseline Characteristics ................................................................................ 51 
8.7 
Efficacy Analyses ........................................................................................................................ 51 
8.7.1 
General Approach ............................................................................................................... 51 
8.7.2 
Analysis of Primary Efficacy Endpoint................................................................................. 52 
8.7.3 
Analysis of Key Secondary Efficacy Endpoint .................................................................... 52 
8.7.4 
Analysis of Secondary Efficacy Endpoint ............................................................................ 53 
8.8 
Safety Analyses .......................................................................................................................... 53 

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8.9 
Missing Values and Imputations ................................................................................................. 54 
8.10 
Interim Safety Analyses .............................................................................................................. 54 
9 
Regulatory Obligations ........................................................................................................................ 54 
9.1 
Informed Consent ........................................................................................................................ 54 
9.2 
Institutional Review Board ........................................................................................................... 54 
9.3 
Pre-Study Documentation Requirements ................................................................................... 55 
9.4 
Subject Confidentiality ................................................................................................................. 55 
10 
Administrative and Legal Obligations .............................................................................................. 55 
10.1 
Protocol Amendments and Study Terminations .......................................................................... 55 
10.2 
Study Documentation and Storage ............................................................................................. 56 
10.2.1 
Delegation Log .................................................................................................................... 56 
10.2.2 
Source Documents .............................................................................................................. 56 
10.2.3 
Study File ............................................................................................................................ 56 
10.3 
Study Monitoring and Data Collection ......................................................................................... 56 
10.3.1 
Data Quality Control and Reporting .................................................................................... 57 
10.3.2 
Retention of Records .......................................................................................................... 57 
10.4 
Publication Policy ........................................................................................................................ 58 
11 
References ...................................................................................................................................... 59 

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Figures 
Figure 1. Change in Wound Area from Baseline in B-VEC vs. Placebo Treated in Phase I/II Study ......... 26 
Figure 2. B-VEC-03 Study Design .............................................................................................................. 29 
Figure 3. Wound Pairing, Labeling, and Selection Example ....................................................................... 39 
 
Tables 
Table 1. Visit Assessments and Procedures .............................................................................................. 13 
Table 2. Maximum Weekly dose based on age at the visit ......................................................................... 36 
Table 3. Unit dose based on wound area ................................................................................................... 36 
 

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Abbreviations 
AEs ............................ adverse events  
AF ............................... anchoring fibrils 
ALT (SGPT) ............... alanine aminotransferase, included in metabolic panel 
AST (SGOT) .............. aspartate aminotransferase, included in metabolic panel 
BMZ............................ basement membrane zone 
B-VEC ........................ Beremagene Geperpavec 
CBC............................ complete blood count 
CBL ............................ Change from baseline 
CFR ............................ Code of Federal Regulations 
CLIA ........................... Clinical Laboratory Improvement Amendments 
CM.............................. centimetre 
COL7 .......................... collagen VII 
COL7A1 ..................... collagen 7 gene 
CRF ............................ case report form 
DEB ............................ dystrophic epidermolysis bullosa 
DNA............................ deoxyribonucleic acid 
DSMB ......................... data safety monitoring board  
EB .............................. epidermolysis bullosa 
eGFP .......................... enhanced green fluorescent protein 
ELISA ......................... enzyme-linked immunosorbent assay 
EM .............................. electron microscopy 
ET ............................... early termination 
FDA ............................ Food and Drug Administration 
GCP ........................... Good Clinical Practice 
GFP ............................ green fluorescent protein 
GMP ........................... Good Manufacturing Practice 
HEENT ....................... head, ears, eyes, nose, throat 
Hep............................. hepatitis 
HIPAA ........................ Health Insurance Portability and Accountability Act 
HIV ............................. human immunodeficiency virus 
HSV ............................ herpes simplex virus 
ICF ............................. informed consent form 
IEM ............................. immunoelectron microscopy 
IF ................................ immunofluorescence 
Ig ................................ immunoglobulin 
IND ............................. Investigational New Drug application 
IP ................................ Investigational Product 
IRB ............................. Institutional Review Board 
ITT .............................. Intent-to-treat 

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LTFU .......................... long-term follow-up 
MCH ........................... mean corpuscular hemoglobin 
MCHC ........................ mean corpuscular hemoglobin concentration 
MCV ........................... mean cell volume 
mRNA......................... messenger ribonucleic acid 
NC1 ............................ noncollagenous 1 domain 
NC2 ............................ noncollagenous 2 domain 
NCI  ............................ National Cancer Institute 
OLE……………………Open Label Extension 
PCR............................ polymerase chain reaction 
PFU ............................ plaque-forming units 
PHI ............................. protected health information 
PP .............................. per protocol 
RBC............................ red blood cell count 
RDEB ......................... recessive dystrophic epidermolysis bullosa 
RDW........................... red blood cell distribution width 
SAE ............................ serious adverse event 
SD .............................. standard deviation 
SOPs .......................... standard operating procedures 
WBC ........................... white blood cell 
 

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Protocol 
1 Introduction 
1.1 
Disease Background 
Dystrophic epidermolysis bullosa (DEB) is a group of heritable skin diseases characterized by skin fragility, 
blister formation, milia, and scarring (Intong, 2012). Dystrophic epidermolysis bullosa (DEB) is one of the 
major forms of EB and is the result of mutations to the COL7A1 gene encoding collagen VII (Varki, et al., 
2007), (Uitto & Christiano, 1994). Severe generalized recessive dystrophic epidermolysis bullosa, formerly 
termed Hallipeau-Siemens, is characterized by extensive blistering and scarring of the skin and mucosal 
membranes. Blisters and erosions affect skin as well as certain mucosa exposed to disruptive external 
environment, including oropharynx, esophagus, rectum, genitourinary system and eyes. Healing of 
erosions results in debilitating scarring. Damage to the mouth and esophagus can make it difficult to chew 
and swallow food, leading to chronic malnutrition and slow growth. Complications from extensive scarring 
can include fusion of the fingers and toes, joint deformities, and vision impairment. Given the severity of 
this disorder and the lack of effective treatment options, there exists a clear need for alternative treatment 
options that focus on the root cause of the debilitating symptoms and can be administered in a minimally 
invasive way. 
1.2 
Phase I/II Results Summary 
Krystal conducted a Phase I/II clinical trial entitled: “A Phase I/II Study of B-VEC, a Non-Integrating, 
Replication-Incompetent HSV Vector Expressing the Human Collagen VII Protein, for the Treatment of 
Dystrophic Epidermolysis Bullosa (DEB).” The purpose of the study was to evaluate the safety and efficacy 
of B-VEC. 
This trial was an intra-subject comparison of wounds administered topical B-VEC against wounds that were 
administered placebo. Wounds were randomized to be administered either topical B-VEC or topical placebo 
prior to administration. The first-in-human Phase I protocol enrolled 2 adult subjects, and the Phase II 
portion of the protocol enrolled 10 subjects: 5 adults and 5 pediatric subjects.  
1.2.1 
Efficacy Results 
Efficacy was analyzed by looking at both mechanistic endpoints and clinical endpoints. Mechanistic 
endpoints include evidence of COL7 using IF and anchoring fibrils using IEM. Clinical endpoints focus on 
wound healing and measured parameters such as percent (%) by area of wound closure, duration of wound 
closure, and time to wound closure. 
The IF analyses conducted post B-VEC administration revealed clearly detectable and correctly localized 
(at the Basement Membrane Zone, BMZ) COL7 expression by immunofluorescence in the biopsy samples 
from both the intradermal injection sites and topically applied wounds. Expression was observed as early 
as 48 hours post-administration and was continually observed at each monthly timepoint out to Day 90. 
The presence of the NC2 domain in conjunction with NC1 and linear deposition at the BMZ demonstrates 
production of functional COL7. 
The IEM analyses conducted post B-VEC administration revealed clearly detectable and correctly localized 
anchoring fibrils at the BMZ in biopsy samples from both the intradermal injection sites and topically applied 
wounds. Anchoring fibrils were observed as early as Day 8 and as late as Day 97. Importantly, in the later 
timepoints (samples from Days 84 and 97), mature NC2-positive fibrils were observed which strongly 
demonstrates the presence of functional full-length COL7. 

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The IF and IEM results were supported by clinical wound closure data. Subject-specific wound images and 
wound closure data showing percent change from baseline of B-VEC- and placebo-administered wounds 
were used to evaluate wound area reduction, duration of closure, and time to closure.  
Findings from our previous GEM Phase I/II study in which each subject served as their own control 
disclosed an effect size of at least 0.8 for the average percent change in wound area from baseline over 12 
weeks, comparing B-VEC treatment to placebo control. The observed proportion of complete wound healing 
for Week 8, 10 and 12 ranged from 67% to 85% for B-VEC treatment and from 0% to 33% for placebo 
control and showed a statistically significant difference (p-value <.00001, based on the Cochran-Mantel-
Haenszel test stratified by the timepoints of weeks) difference. At Week 12, B-VEC-treated wounds showed 
a median reduction of 94%, compared to a median increase of 27% for the placebo-treated wounds 
resulting in a statistically significant (p-value = 0.02, based on Wilcoxon rank-sum test) difference. 
Complementary analysis was performed to show that the 87% of subjects had at least a 75% reduction in 
average wound size for the B-VEC-treated wounds at week 12, compared with 14% of subjects for the 
placebo-treated wounds. 
1.2.2 
Safety Results 
In every phase of the study, the safety of B-VEC was assessed through analysis of AEs, including clinically 
significant changes in laboratory results, vitals, and physical exam findings. In addition, viral shedding was 
analyzed through the collection of serum, urine, and skin swabs, and antibodies to HSV and COL7 were 
analyzed through collection of blood. 
There were no deaths, serious adverse events or significant adverse events reported. Thirty (30) AEs were 
reported; twenty-nine (29) were mild in severity and one (1) was moderate in severity. The moderate AE 
was facial itching and redness and unrelated to the Investigational Product. All of the AEs resolved during 
the study and of the thirty (30), fifteen (15) were unlikely or unrelated, and fifteen (15) were possibly or 
probably related. Of the fifteen (15) possibly or probably related, four (4) were associated with topical B-
VEC administration including rash, fever, itching and peculiar taste. 
There were no clinically meaningful changes in laboratory parameters, including liver enzymes. Changes 
from baseline were small (usually less than 10%) and showed no distinct shifts over time. 
Sera samples, collected pre-dose and during specific visits per the Schedule of Events, were evaluated for 
Anti-Drug Antibodies against HSV and COL7 using a qualified Plaque Reduction Neutralization Test 
(PRNT). Existing antibodies, as well as any changes in antibodies detected after B-VEC treatment, did not 
have any apparent impact on subject safety as any possibly related AEs were mild in severity and transient. 
Efficacy was also not impacted, as evidenced by the robust efficacy of the vector (e.g., indicated by 
improved wound healing, as compared to intra-subject placebo controls; the observed molecular correction 
of the collagen VII defect, demonstrated by linear collagen VII deposition and formation of anchoring fibrils 
along the Basement Membrane Zone (BMZ) by Immunofluorescence (IF) and Immunoelectron Microscopy 
(IEM). 
2 Study Objectives and Endpoints 
2.1 
Study Objective 
The primary objective is to determine whether administration of B-VEC in addition to standard of care 
improves wound healing as compared to placebo in children, adolescents, and adults with Dystrophic 
Epidermolysis Bullosa (DEB). 

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2.2 
Study Endpoints 
2.2.1 
Overview 
GEM-3 is a multi-center, intra-patient randomized, placebo-controlled, double-blinded, Phase III study of 
B-VEC for the topical treatment of DEB wounds. Each site will have a designated Principal Investigator. 
Weekly Treatment: 1 unit-dose of B-VEC or placebo 
Treatment Cycle: Weekly Treatment until complete wound closure 
Maximum Weekly Dose per subject:  
Age  
Maximum Weekly Dose 
≥ 6 months to < 3 years  1.6×109 PFU/week 
≥ 3 years to < 6 years 
2.4×109 PFU/week 
≥ 6 years 
3.2×109 PFU/week 
Two (2) matched wounds (“Primary Wounds”), in a 1:1 ratio per subject will be selected to evaluate the 
primary and secondary end points. The matched wound pair will be randomized, such that one wound will 
receive Weekly Treatment of B-VEC and the other will receive placebo. 
Remaining Weekly Dose: The difference between Maximum Weekly Dose per subject per week 
and the sum total of the B-VEC Dose(s) applied to the Primary Wound Pair per subject per week. 
Re-dosing regimen: During the study, if one wound in the matched Primary Wound Pair and its 
neighboring wounds close completely, as determined by the Investigator during a weekly visit, that 
particular wound and its neighboring wound/s will stop receiving Weekly Treatment. Treatment of 
the Primary Wound and its neighboring wound/s will resume Weekly Treatment when that particular 
wound or neighboring wound/s is determined to be open by the Investigator during a weekly visit. 
During the treatment of a Primary Wound, it the originally selected wound closes, its neighboring 
wound (approximately 2-3cm away from the originally selected wound) wound may continue to 
receive treatment, at the discretion of the Investigator. If treating a neighboring wound, avoid 
treating if it is in close proximity to the other matched wound or a Secondary Wound. The re-dosing 
regimen will be followed throughout the study.  
For example, if a subject age 4, presents with a primary wound pair <20 cm2, then the Remaining 
Weekly Dose during a weekly visit = Difference of (2.4×109 PFU– (4×108 PFU)) = 2.0×109 
PFU/subject/week. The Remaining Weekly Dose will be applied to Secondary Wounds for 
monitoring safety and efficacy. 
The Remaining Weekly Dose calculated during a weekly visit will be applied to additional unmatched 
wounds (“Secondary Wounds”). A maximum of four (4) Secondary Wounds will receive a Weekly Treatment 
of B-VEC for the Treatment Cycle. The number of Secondary Wounds treated will depend on wound area 
of the Secondary Wound(s), and the total dose applied to Secondary Wounds is not to exceed the 
Remaining Weekly Dose. During the treatment of the Secondary Wounds, if a neighboring wound 
(approximately 2-3cm from the originally selected wound) opens, then that wound may receive treatment, 
at the discretion of the Investigator. 
If a Secondary Wound is closed completely, as well as the neighboring wounds, as determined by an 
Investigator during a weekly visit, no treatment will occur. Treatment to neighboring wound/s may continue 
even though the originally selected Secondary Wound is closed. Avoid application to neighboring wounds 
in close proximity to a Primary Wound. The total dose applied to Secondary Wounds is not to exceed the 
Remaining Weekly Dose.  

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2.2.2 
Primary Endpoint 
The primary endpoint is the proportion of DEB primary wound sites with complete wound healing from 
baseline in B-VEC versus placebo treated intra-subject wound sites at Weeks 22 and 24 or 24 and 26, as 
determined by the Investigator, to evaluate durability and repeat dosing. The complete wound healing is 
defined as 100% wound closure from the exact wound area selected at baseline, specified as skin re-
epithelialization without drainage. If new neighboring wounds forms, around the original traced baseline 
wound, during the primary and secondary evaluation time points, these wounds will not be included in the 
evaluation. 
 The primary endpoint is defined as wounds that meet any of the following conditions: 
• 
Healed on Week 22 and Week 24, or 
• 
Healed on Week 24 and Week 26.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as positive 
responses. 
2.2.2.1 
Primary Endpoint Rationale 
The GEM-3 pivotal study has been designed as an adequate well-controlled clinical study per Agency 
guidance (21 CFR 314.126) to provide substantial evidence of product effectiveness. The double-blinded, 
placebo-controlled study design will minimize bias on the part of subjects, and Investigators. The FDA’s 
guidance Gene Therapy for Rare Diseases (July 2018) suggests that an intra-subject control approach, for 
such rare skin diseases, may be a useful design. The wounds will be matched in respect to size and 
anatomical location. 
Complete wound healing will be defined as complete closure of the initial wound surface selected at 
baseline, specified as skin re-epithelialization without drainage for two (2) consecutive weeks, as evaluated 
by the Investigator at Weeks 22 and 24 or 24 and 26. If new neighboring wounds form around the original 
traced baseline wound during the primary evaluation time points, these areas will not be included in the 
evaluation.   
B-VEC is a transient non-integrating episomal vector that can be detected up to five days in B-VEC in vivo 
studies. The Phase I/II B-VEC completed study, that has evaluated different dosing regimens shows that 
continuous expression of COL7 during the wound healing process allows for durability of the healed wound 
with no safety outcomes. Therefore, a weekly dosing regimen has been proposed based on life span of 
B-VEC and results from the Phase I/II clinical study that would allow for functional restoration of COL7 at 
basement membrane zone. It has been shown that the half-life of human COL7 is approximately 30 days. 
Based on a half-life assumption of about one month for COL7, a residual protein amount of 25% should be 
present after two months (Kuhl, et al., 2016). It is known that about 30-40% of COL7 levels are needed to 
protect the skin from frictional damage (Kern, et al., 2009) (Kuhl, et al., 2016) and even lower levels of 
COL7 may improve the phenotype of full COL7 deficiency remarkably (Fritsch, et al., 2008) (Alexeev, et al., 
2011) (Schweiger-Briel, et al., 2015). The basement membrane and its constitutive components undergo 
constant remodeling (Kivirikko, et al., 1996) which has implications for anchoring fibril turnover 
approximately every 60 days to 90 days (8 weeks to 12 weeks). Therefore, the proposed evaluation of the 
primary endpoint at Weeks 22 and 24 or 24 and 26, for two (2) consecutive weeks, is justified.   
In addition, in the previously conducted Phase 1/2 B-VEC clinical study, the placebo response (change in 
wound area from baseline) mimicked the frequent opening and closing of untreated DEB wounds as shown 
below: 

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Figure 1. Change in Wound Area from Baseline in B-VEC vs. Placebo Treated in Phase I/II Study 
 
The usual pattern in a placebo response is often similar to active treatment with or without significant 
separation. Due to the nature of the DEB wounds, frequent closing and opening cycle is observed, therefore 
a fixed assessment may lead to a biased conclusion in comparing a normal treatment profile to an abnormal 
profile of a placebo response. To accommodate this variability of the placebo response, an assessment of 
two (2) consecutive weeks, at Weeks 22 and 24 or 24 and 26, are considered to evaluate durability of 
wound healing and frequency of repeat administration.  
2.2.3 
Key Secondary Endpoint 
The key secondary endpoint is defined as the proportion of primary wound sites with complete wound 
healing from baseline (as defined in the primary endpoint) in B-VEC-treated versus placebo at Weeks 8 
and 10 or 10 and 12 (as determined by the Investigator) to evaluate durability. The complete wound healing 
is defined as 100% wound closure of the originally selected wound area at baseline, specified as skin re-
epithelialization without drainage. If new neighboring wounds form around the original traced baseline 
wound during the key secondary evaluation time points, these areas will not be included in the evaluation.   
 The key secondary endpoint is defined as wounds that meet any of the following conditions: 
• 
Healed on Week 8 and Week 10, or 
• 
Healed on Week 10 and Week 12.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as positive 
responses. 
 

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2.2.3.1 
Key Secondary Endpoint Rationale 
As mentioned above, B-VEC is a transient non-integrating episomal vector that can be detected up to five 
days after administration in patients. Also as referenced above, it has been shown that the basement 
membrane and its constitutive components undergo constant remodeling (Kivirikko, et al., 1996) which has 
implications for anchoring fibril turnover approximately every 60 days to 90 days (8 weeks to 12 weeks). 
Therefore, the proposed evaluation of key secondary endpoint at Weeks 8 and 10 or 10 and 12 will help 
evaluate durability of the initial treatment.  
2.2.4 
Secondary Endpoint 
The secondary endpoint is the mean change in pain severity using a VAS score per primary wound site 
associated with wound dressing changes at Weeks 22, 24, and 26 for ages 6 and above on the primary 
wound pair. For ages below 6 years, the Face Legs Activity Cry and Consolability-Revised (FLACC-R) 
scale will be used. 
2.2.4.1 
Secondary Endpoint Rationale 
The secondary endpoint was obtained based on input from patients with DEB, and their caregivers to 
provide a complete understanding of the disease or condition.  
2.2.5 
Safety Endpoints 
The safety and tolerability of B-VEC based on the assessment of adverse events, physical examinations, 
vital signs, and clinical laboratory test results.   
2.2.5.1 
Safety Endpoint Rationale  
Safety endpoints were chosen to obtain a comprehensive picture of overall safety and tolerability of B-VEC 
across the study period. 
3 Selection of Subjects 
This study is planned to enroll approximately 24 participants with DEB, aged 6 months or older at the time 
of Informed Consent. 
The study team cooperates with national and international networks of families, researchers, and physicians 
who care for children and adults with EB, and it is planned to use these groups to recruit participants for this 
study. In addition, an email and clinical study information may be posted to national communities 
(EB foundations, e.g., Dystrophic Epidermolysis Bullosa Research Association of America, site-specific EB 
websites) regarding recruiting for this study. 
3.1 
Inclusion Criteria 
To be eligible for inclusion, each subject must fulfill each of the following criteria: 
1. The subject or legally appointed and authorized representative must have read, understood 
and signed an Institutional Review Board/Ethics Committee (IRB/EC) approved Informed 
Consent or Assent Form and must be able to and willing to follow study procedures and 
instructions. 
2. Age ≥ 6 months and older at the time of Informed Consent. 
3. Clinical diagnosis of the Dystrophic Epidermolysis Bullosa. 

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4. Confirmation of DEB diagnosis (either DDEB or RDEB) by genetic testing including 
COL7A1.  
5. Two (2) cutaneous wounds meeting the following criteria: 
a. Location: similar in size, located in similar anatomical regions, and have similar 
appearance (Refer to section 5.8 for more details). 
b. Appearance: clean with adequate granulation tissue, excellent vascularization, 
and do not appear infected. 
6. Subjects and caregivers who, in the opinion of the Investigator, are able to understand the 
study, co-operate with the study procedures and are willing to return to the clinic for all the 
required follow-up visits. 
7. Male or Female of childbearing potential must use a reliable birth control method 
throughout the duration of the study and for three (3) months post last dose of B-VEC. 
Refer to Section 4.5.1 for more details. 
8. Negative pregnancy test at Visit 1 (Week 1), if applicable. 
3.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria are met: 
1. Medical instability limiting ability to travel to the Investigative Center. 
2. Diseases or conditions that could interfere with the assessment of safety and efficacy of the 
study treatment and compliance of the subject with study visits/procedures, as determined by 
the Investigator. 
3. Current evidence or a history of squamous cell carcinoma in the area that will undergo 
treatment. 
4. Subject’s actively receiving chemotherapy or immunotherapy at Visit 1 (Week 1). 
5. Active drug or alcohol addiction as determined by the Investigator. 
6. Hypersensitivity to local anesthesia (lidocaine/prilocaine cream). 
7. Participation in an interventional clinical trial within the past three (3) months (not including B-
VEC administration).  
8. Receipt of a skin graft in the past three (3) months. 
9. Pregnant or nursing women. 
4 Study Implementation 
Blood tests, or medical interventions may occur at the discretion of the Principal Investigator due to clinical 
changes that require evaluation or therapy. Detailed information for the study visits is provided in the 
sections below and in the Schedule of Events (Table 1). 
4.1 
Study Design 
GEM-3 is a multi-center, intra-subject randomized, placebo-controlled, double-blind, Phase III study of 
B-VEC for the topical treatment of DEB wounds. A schematic of the study design is shown in Figure 2 
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Figure 2. B-VEC-03 Study Design 
 
  
B-VEC: Beremagene Geperpavec, single dose/wound administered 4 ×108 PFU B-VEC/wound (<20 cm2), 8 × 108 PFU B-VEC/wound 
(20 to 40 cm2) or 1.2 ×109 PFU B-VEC/wound (40 to 60 cm2) , once a week for up to 26 weeks, Placebo, single matching dose/ wound 
adminstered once a week for up to 26 weeks.  
4.1.1 
Study Design Rationale 
The primary objective is to determine whether administration of B-VEC in addition to standard of care 
improves wound healing as compared to placebo in children, adolescents, and adults with Dystrophic 
Epidermolysis Bullosa (DEB). 
The FDA’s guidance Gene Therapy for Rare Diseases (July 2018) suggests that an intra-subject control 
approach, for such rare skin diseases, may be a useful design. Based on our previous experience 
(completed B-VEC Phase I/II study) and suggestions from the guidance we will continue to use the 
intra-subject design in the Phase III study. Each subject will serve as their own control; subjects will have 
two matched wounds (primary wounds). The primary wounds will be randomized such that one wound will 
receive B-VEC (active treatment) and the other will receive placebo (inactive treatment). The secondary 
wounds will receive B-VEC (active treatment), not to exceed the Remaining Weekly Dose. Subjects who 
enrolled under previous protocol versions, where more than one wound pair was selected, the Investigator’s 
determined a single pair, most closely matched in size, followed by location, to be used for efficacy analysis, 
following the Agency’s guidance.  
This Phase III protocol is designed to minimize subject burden by limiting blood draws and removing the 
collection of biopsies. Experience from the phase I/II portion of the B-VEC trial combined with the advice 
provided in the FDA’s guidance Epidermolysis Bullosa: Developing Drugs for Treatment of Cutaneous 
Manifestations (June 2019) justifies the proposed design. Molecular correction evaluation from all of the 
subjects from the Phase I/II study have shown full length COL7 expression by Immuno-fluorescence (IF) 
(staining for both NC1 and NC2 antibodies) and/or anchoring fibrils by Immuno-electron microscopy (IEM). 
We believe that robust molecular correction has been demonstrated with wound healing hence the 
proposed Phase III will mainly focus on evaluation of wound healing as the efficacy endpoint. 
4.1.2 
Treatment Period 
Each subject visits the Investigative site at the beginning of the study for Visit 1 (Week 1) and the matched 
wounds are randomized (if entry criteria are met) and the assessment/treatment period begins and will 
continue for 25 weeks. Additionally, the subject will return to the Investigative site for a single day Safety 
Follow-up Visit 30 days (±4 days) from the last dose of B-VEC. 

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4.1.2.1 
Guidance for Subjects Enrolled under Previous Protocol Versions 
Subjects enrolled under previous protocol versions, in which more than one (1) Primary Wound Pair was 
selected, will continue to receive their randomized treatment for the duration of the study. However, the 
Investigator will select a single matched pair, which most closely match in both size and anatomical location. 
This single Primary Wound Pair will be used for evaluation and will be included in the outcome 
measurements.  
For subjects who had more than four (4) Secondary Wounds, no new Secondary Wounds will be selected, 
and treatment will continue on the previously selected Secondary Wounds for the study duration. If subjects 
had less than four (4) Secondary Wounds selected, the Investigator may select additional Secondary 
Wounds, until four (4) have been selected, not exceeding the Weekly Maximum Dose.  
4.2 
Study Visits 
Study visit procedures are performed only after a signed informed consent / assent (as applicable) is 
obtained. During the study, every effort should be made to adhere to the visit schedule provided in the 
Schedule of Events (Table 1).  
4.2.1 
Sequence of Study Procedures 
The following must be taken into account regarding the sequence of study procedures: 
- 
Questionnaires should be completed with wound dressing removal during the visit. The EQ-5D and 
Skindex-29 may be administered at the end of the study visit, for the subject to complete, and return 
at their next scheduled visit.  
- 
At scheduled visits (refer to Table 1) in which a urine pregnancy test must be completed, the test 
must result negative, prior to applying B-VEC or placebo, for women of childbearing potential, as 
determined by the Investigator. 
- 
At visits in which blood is drawn, attempt collection of vital signs prior to the blood draw. 
- 
On days in which B-VEC and placebo administration(s) occur, all study procedures and 
assessments must occur pre-dose. 
4.2.2 
Protocol Deviations 
Any deviations from the protocol are discouraged. A protocol deviation will be defined as any excursion 
from the protocol, or any instance of protocol noncompliance. If deviations do occur, the Principal 
Investigator must inform the monitor/Sponsor, and the implications of the deviation must be reviewed and 
discussed. Any paper documentation must be kept in the Investigator’s File or Subject Binder and the 
Sponsor will file in the TMF. If the Investigator determines a deviation is necessary, they are to contact the 
Sponsor prior to the occurrence for approval, if time permits.   
4.2.3 
Screening 
If a subject has not undergone genetic testing, which is needed for inclusion criteria, they may visit the site 
up to 60 days prior to Visit 1 (Week 1). The genetic test may take 6 to 8 weeks to obtain results.  
- 
Review and signature of informed consent form/assent 
- 
Collection of demographic data (e.g. sex, age, race, and ethnicity) 
- 
Obtain Medical History 
- 
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- 
Obtain Medication History 
- 
Obtain Genetic testing specimens 
- 
Collection of urine for viral shedding 
- 
Collection of blood for clinical laboratory tests: 
o 
Complete Metabolic Panel with Direct Bilirubin  
o 
Complete Blood Count with Differential and Platelets 
o 
HSV and COL7 Serum ADA 
o 
Whole blood for viral shedding 
4.2.4 
Week 1/Visit 1 (First Day of Treatment Cycle) 
- 
Review and signature of informed consent form/assent, if not previously obtained at Screening. 
- 
Collection of demographic data (e.g. sex, age, race, and ethnicity), if not previously obtained at 
Screening 
- 
Obtain Medical History, if not previously obtained at Screening 
- 
Treatment/Procedural review 
- 
Medication review 
- 
Inclusion/Exclusion  
- 
Selection of two (2) matched wounds to be assessed as Primary Wounds and selection of up to 
four (4) Secondary Wounds (not to exceed the Remaining Weekly Dose) 
- 
Primary Wound Pain Questionnaire  
• 
FLACC-R (Subjects less than 6 years of age) 
• 
VAS (Subjects 6 years of age and older) 
- 
Quality of Life Questionnaire (Subjects 12 years of age and older) 
- 
Skindex Questionnaire (Subjects 12 years of age and older) 
- 
Selection of Secondary Wounds depending on the Remaining Weekly Dose 
- 
Wound imaging of all selected wounds 
- 
Assess selected wounds  
- 
Physical exam 
- 
Vital signs 
- 
Collection of skin swabs for viral shedding and infectivity from all the selected primary wounds 
- 
Collection of urine for a pregnancy test, if applicable as determined by the Investigator 
- 
Collection of urine for viral shedding, if not collected at Screening 
- 
Collection of blood for clinical laboratory tests, if not collected at Screening: 
• 
Complete Metabolic Panel with Direct Bilirubin  

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• 
Complete Blood Count with Differential and Platelets 
• 
HSV and COL7 Serum ADA 
• 
Whole blood for viral shedding 
- 
Randomization of wound pair 
- 
IP administration 
- 
AE/SAE review 
4.2.5 
Week 2 through 21   
- 
Medication review 
- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Wound imaging of all selected wounds 
- 
Assess Primary Wound Closure at Visit 8, 10, and 12 only 
- 
Assess Secondary Wound/s  
- 
Vital signs will be collected at Visit 5, 9, 13, 17, 21, and 25 only 
- 
Collection of skin swabs for viral shedding and infectivity from all the selected Primary Wounds 
- 
Collection of bandage swabs for viral shedding from all the Primary Wounds, if applicable 
- 
IP administration  
4.2.6 
Week 22 
- 
Medication review 
- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Primary Wound Pain Questionnaire  
• 
FLACC-R (Subjects less than 6 years of age) 
• 
VAS (Subjects 6 years of age and older) 
- 
Wound imaging of all selected wounds 
- 
Assess Primary Wound Closure  
- 
Assess Secondary Wound/s 
- 
Collection of skin swabs for viral shedding and infectivity from all the selected Primary Wounds 
- 
Collection of bandage swabs for viral shedding from all the Primary Wounds, if applicable 
- 
IP administration  
4.2.7 
Week 23 
- 
Medication review 

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- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Wound imaging of all selected wounds 
- 
Assess Secondary Wound/s 
- 
Collection of skin swabs for viral shedding and infectivity from all the selected Primary Wounds 
- 
Collection of bandage swabs for viral shedding from all the Primary Wounds, if applicable 
- 
IP administration  
4.2.8 
Week 24 
- 
Medication review 
- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Primary Wound Pain Questionnaire  
• 
FLACC-R (Subjects less than 6 years of age) 
• 
VAS (Subjects 6 years of age and older) 
- 
Wound imaging of all selected wounds 
- 
Assess Primary Wound Closure  
- 
Assess Secondary Wound/s 
- 
Collection of skin swabs for viral shedding and infectivity from all the selected Primary Wounds 
- 
Collection of bandage swabs for viral shedding from all the Primary Wounds, if applicable 
- 
IP administration  
4.2.9 
Week 25 
- 
Medication review 
- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Wound imaging of all selected wounds 
- 
Assess Secondary Wound/s 
- 
Vital signs will be collected  
- 
Collection of skin swabs for viral shedding and infectivity from all the selected Primary Wounds 
- 
Collection of bandage swabs for viral shedding from all the Primary Wounds, if applicable 
- 
IP administration  
4.2.10 Week 26 
- 
Medication review 

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- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Primary Wound Pain Questionnaire  
• 
FLACC-R (Subjects less than 6 years of age) 
• 
VAS (Subjects 6 years of age and older) 
- 
Quality of Life Questionnaire (Subjects 12 years of age and older) 
- 
Skindex Questionnaire (Subjects 12 years of age and older) 
- 
Wound imaging of all selected wounds 
- 
Assess Primary Wound Closure  
- 
Assess Secondary Wound/s 
- 
Abbreviated Physical Exam 
- 
Collection of skin swabs for viral shedding and infectivity from all the selected Primary Wounds 
- 
Collection of bandage swabs for viral shedding from all the Primary Wounds, if applicable 
- 
Collection of urine for a pregnancy test, if applicable as determined by the Investigator 
- 
Collection of urine for viral shedding 
- 
Collection of blood for clinical laboratory tests: 
• 
Complete Metabolic Panel with Direct Bilirubin  
• 
Complete Blood Count with Differential and Platelets 
• 
HSV and COL7 Serum ADA 
• 
Whole blood for viral shedding 
- 
IP administration  
4.2.11 Safety Follow-up/ Early Termination 
- 
Roll-Over into OLE or LTFU Protocol 
- 
Medication review 
- 
AE/SAE review 
- 
Treatment/Procedural review 
- 
Wound imaging of all selected wounds 
- 
Abbreviated Physical Exam 
- 
Vital Signs 
4.2.12 Safety Follow-Up  
The Safety Follow-up will occur 30 days (±4 days) following the last dose of B-VEC. At the Safety Follow-up 
Visit, subjects may be asked to enroll into an OLE protocol to continue to receive treatment or a LTFU 
protocol where they will be monitored for an additional 5 years following the SFU visit. 

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4.2.13 Early Termination Scheduling 
An early termination (ET) visit should be scheduled as soon as possible after the subject, Investigator or 
Sponsor decides to terminate study treatment. Subjects who prematurely discontinue treatment will be 
required to complete the Safety Follow-up Visit (ET) visit approximately 30 days (±4) after their last dose of 
Investigational Product. 
4.3 
Sites and Trial Duration 
Approximately three (3) sites are planned for this study in the US.  
The trial duration for each subject is about 6 months. A Safety Follow-up Visit occurring 30 days from the 
date of final treatment with the Investigational Product, B-VEC, will also occur. 
4.4 
Study Restrictions 
Throughout the study assessments period, up to Week 26, topical administration of any medication (other 
than B-VEC and placebo) to a study target wound is prohibited, unless approved in advance by the Medical 
Monitor/Sponsor. Secondary wounds that are not naturally occurring, such as wounds that manifest after a 
surgical procedure are excluded from receiving the Investigational Product.  
4.5 
Concomitant Medications and Topical Treatments 
Medications including prescriptions, herbal and dietary supplements, over the counter medications, 
injections, and topical treatments the subject has taken within three (3) months prior to the Visit 1 (Week 1) 
or Screening visit will be obtained and documented. At subsequent visits, medication reviews will occur, 
noting if the medication is continuing or if the subject has begun any new medication.  
Topical concomitant medications or treatments deemed necessary to provide adequate supportive care to 
non-target wounds may be prescribed and will be documented on the concomitant medication log. 
Additionally, the Investigator may prescribe Tacrolimus, Clobetasol or Regranex, to be topically applied to 
all study target wounds, during the study.  
4.5.1 
Contraception 
Women of childbearing potential must have a negative urine pregnancy test at the Visit 1 (Week 1) visit and 
must commit to using an acceptable form of contraception during the entire study period, up to three (3) 
months following the last dose of B-VEC. Acceptable forms of contraception include abstinence, intrauterine 
device, oral, implantable, or injectable contraception, or a combination barrier method, such as female or 
male condom, a diaphragm or cervical cap and a spermicide. Women using oral contraception must have 
consistently been taking their birth control for three (3) months prior to Visit 1 (Week 1) or utilize a 
combination barrier method, as stated above.  
Male subjects must be surgically sterile, prepubescent or agree to use (you or your childbearing partner) 
an effective form on contraception from Visit 1 (Week 1) to three (3) months following study completion (last 
dose of B-VEC), such as abstinence, intrauterine device, oral, implantable or injectable contraception, or a 
combination barrier method, such as female or male condom, a diaphragm or cervical cap and a 
spermicide. 
4.6 
Subject Enrollment 
Written protocol and informed consent approval are required from the IRB prior to enrollment. Assent form 
approval is required from the IRB prior to enrolling subjects below the age of consent. All subjects or their 
respective legal guardians must personally sign and date the relevant consent and/or assent form before 

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enrollment. Subjects who withdraw prior to the first B-VEC administration are considered a screen failure 
and are not considered a participant and can be re-screened. 
4.6.1 
Subject Identification and Number Assignment 
Subjects who sign the informed consent form are assigned a 2-digit subject identification number within 
each study site. Subject identification numbers at each site begin with the specific 2-digit study site number 
(assigned by the Sponsor) followed by the subject’s specific 2-digit subject number (XX-XX). This number 
identifies the subject throughout the study and must be used on all study documentation related to that 
subject. 
5 B-VEC and Placebo Administration and Wound Selection 
5.1 
Dosing Regimen 
Table 3. Maximum Weekly dose based on age at the visit 
Age  
Maximum Weekly Dose 
≥ 6 months to < 3 years  1.6×109 PFU/week 
≥ 3 years to < 6 years 
2.4×109 PFU/week 
≥ 6 years 
3.2×109 PFU/week 
Table 4. Unit dose based on wound area 
Wound Area 
Unit Dose 
<20 cm2 
4×108 PFU/wound 
20 to 40 cm2 
8×108 PFU/wound 
40 to 60 cm2 
1.2×109 PFU/wound 
At Visit 1 (Week 1) the wounds will be measured by an Investigator using a validated Canfield photography 
quantitation system. The unit dose will be determined based on this initial measurement, which is recorded 
in the CRF, for the Treatment Cycle and will not exceed the Maximum Weekly Dose based on the Subject’s 
age at the time of the visit. Subsequent Secondary Wounds, not selected at Week 1, will have the wound 
area determined during their initial selection. If a Secondary wound selected, exceeds 60cm2, split the 
wound, to allow it to meet the unit dose criteria above, and treat accordingly.  
Two matched wounds (Primary Wound Pair) will be selected to evaluate the primary and key secondary 
end points. The Primary Wound Pair will be randomized, such that one wound in the pair will receive one-
unit dose of B-VEC and the other will receive placebo for a Treatment Cycle. One unit of B-VEC or placebo 
weekly for 26 weeks, to evaluate durability and repeat dosing. During the study, the originally selected 
wound, as well as neighboring wounds in proximity (approximately 2-3cm) to the originally selected wound, 
may receive treatment and will receive treatment until both the originally selected wound and its neighboring 
wounds have closed. Avoid application if a neighboring secondary wound is near a primary wound or 
another primary wound. Weekly treatment on the wound will resume when that original wound or 

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neighboring wounds to the originally selected wound re-opens, as determined by the Investigator at a 
weekly visit.  
Unmatched Secondary open wounds (up to four (4) maximum) may be treated if there is remaining Weekly 
Dose available. For example: if a 12 month old subject, presents with a primary wound pair of 24 cm2 then 
the remaining weekly dose during a weekly visit = (1.6×109 PFU –8×108 PFU)= 8×108 PFU (i.e. there would 
be enough remaining weekly dose to treat one (1) 20cm2 to 40cm2 secondary wound). A neighboring wound 
in close proximately (approximately 2-3cm) to the originally selected wound may receive treatment. 
Treatment to the area will resume until the area is closed. However, avoid application to neighboring 
wounds in close proximity to the matched wounds.  
5.1.1 
Dosing Regimen Rationale 
The proposed Maximum Weekly Dose of 3.2×109 PFU /subject (6 years of age and older) and the Unit 
Dose by Wound Area of 4.0×108 PFU/20 cm2, are based on efficacy and safety data obtained from similar 
dosing regimens in the Phase II study. Out of the 9 subjects enrolled in the Phase II study, the maximum 
weekly dose per subject ranged from 1.2×109 PFU/week to 6.0×109 PFU/week (median 4.2×109 PFU/week, 
average 2.6×109 PFU/week) with no B-VEC related adverse events.  
The proposed weekly dose of 3.2×109 PFU falls within the doses administered to patients in Phase II. 
Furthermore, robust efficacy as evident by wound healing supported by molecular correction was observed 
(“surrogate measurement”) with no drug related safety events. 
The dose and the weekly dosing regimen proposed is to demonstrate the safety and efficacy of B-VEC in 
subjects chronically open wounds. The unit dose is based on a wound area of ≤20 cm2 because 80% of 
RDEB wounds are in the ≤20 cm2 range and occasionally span 40 to 60 cm2 or larger (Eng, et al. 2020).  
In the Phase II study, 18 wounds ≤20 cm2 were given a unit dose between (2.0 ×108 to 6.0 ×108) PFU for 
5 consecutive treatments, daily or every other day. Therefore, a unit dose of 4.0 ×108 PFU to treat wounds 
≤20 cm2 is well within the unit dose range seen in the Phase II study. 
Furthermore, the following Maximum Weekly dose is based off the average body surface area for pediatric 
subjects below the age of 6 (Center for Disease Control 2002) (Nelson, et al. 2006). A proposed fixed dose 
based on age group was determined to mitigate dosing error and allows for better compliance from the 
Investigator (Shi and Derendorf 2010).  
The proposed unit dose by wound area and maximum weekly dose were both safe and efficacious based 
on the results of the Phase II trial. 
5.2 
Preparation and Dispensing 
Investigational Product may be dispensed under the supervision of the Investigator or an authorized 
designee and only for the application/administration of study subjects. Further details on preparation and 
application can be found in the Pharmacy Manual. 
5.3 
Packaging and Labeling 
Both the Methocel™ and the B-VEC will be packaged in vials. The labeling will be in compliance with 
applicable local and national regulations. Further details on packaging, dispensing, and labeling can be 
found in the Pharmacy Manual.  

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5.4 
Storage and Handling 
While at the clinical site, the Investigator, or an authorized designee, will ensure that all study products are 
stored in a secure location, under recommended storage conditions and in accordance with applicable 
regulatory requirements. For further instructions refer to the Pharmacy Manual.  
5.5 
Drug Accountability 
The pharmacist or authorized unblinded designee will maintain information regarding the dates and 
amounts of study products received, Investigational Product dispensed to the individual subjects, and study 
products that may have been damaged in a shipment. These materials are retained by the site according 
to the Sponsor representative. The study products and Investigational Product will be monitored throughout 
the study by a designated monitor, who will review all records and inventory.  
5.6 
Drug Disposal, Returns, or Retaining Used Drug 
The pharmacist and or unblinded authorized designee will retain all vials used to mix the Investigational 
Product as well as empty syringes, as applicable, for subject administration until the study monitor has 
performed accountability. The monitor will provide confirmation that the vials/syringes may be disposed of 
(both used and unused drug inventory). If authorization for onsite destruction is granted, the Investigator 
will ensure that the materials are destroyed in compliance with applicable policies and guidelines. 
Destruction will be documented. 
5.7 
Blinding and Unblinding 
The subjects (including their caregivers) and Investigator as well as Sub-Investigator (conducting outcome 
related assessments and procedures) will be blinded to the identity of treatment for the Primary Wounds. 
The un-blinded staff, including the pharmacist or authorized designee, and the monitor will remain separate 
from the primary study team and will not be involved in any study conduct outside their functions of 
managing the receipt, storage, preparation, dispensing and reconciliation of all study products. All un-
blinded material will be secured in a secondary locked location, that is not accessible to the primary study 
team. 
The following precautions will be taken to ensure the integrity of the study blind to minimize potential impact 
on interpretation and of other efficacy and safety measurements: 
- 
In order to maintain the blind, if a matched wound is determined to be closed at a weekly visit, the 
Remaining Dose will not be used to treat Secondary Wounds and Secondary Wounds will be 
capped at four (4).  
- 
In addition, treatment may be unblinded in a medical emergency. Materials will be provided to the 
site for emergency unblinding and will be maintained in a secure location where study personnel 
access is limited.  
In the case of a medical emergency necessitating unblinding, the Investigator or designee should, whenever 
possible, contact the Medical Monitor/Sponsor directly, prior to breaking the blind to discuss if unblinding 
needs to occur. If unblinding must occur, the designated unblinded staff may provide the information to the 
Investigator and this must be captured on the CRF. If unblinded for any reason this must be reported to the 
Sponsor.  
5.8 
Wound Selection 
One (1) matched wound pair will be selected to be part of the study, that meet the inclusion criteria (Figure 
3).  

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Prior to randomization, wounds will be selected and labeled. The Primary Wound Pair will be labeled P1 & 
P2. For the Primary Wound Pair, one is randomized to B-VEC and one to Placebo.  
Up to four (4) Secondary unmatched wounds may be chosen to receive the Remaining Weekly Dose of B-
VEC. Secondary wounds will be labeled as they are selected starting with S1, S2, S3 and S4.  
Figure 3. Wound Pairing, Labeling, and Selection Example 
 
5.9 
Wound Randomization 
Using a pre-generated randomization schedule, the matched wounds are randomized to receive either B-
VEC or Placebo gel.  
5.10 Post-Administration Procedures 
Following Investigational Product application, the subject will keep the treated wounds covered for roughly 
24 hours.  
 
 

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6 Assessments 
6.1 
Timing of Assessments 
Timing of assessments must be performed per the Schedule of Events (Table 1). 
6.2 
Efficacy Assessments 
6.2.1 
Wound Assessments 
6.2.1.1 
Wound Measurement and Imaging 
Target wounds are imaged and measured on the study days outlined in the Schedule of Events (Table 1). 
Wound assessments should be performed by the PI. A trained, qualified Sub-I should only perform the 
wound assessments if the PI is unavailable. A validated Canfield tracing and imaging system will be used 
for the study. Trace where IP will be applied at each weekly visit, including the neighboring wounds and the 
originally selected wound, as applicable. Additional information about the Canfield system can be found in 
Appendix 1. Image the wounds in the same order and orientation at each visit.  
6.2.1.2 
Investigator Assessment of Complete Wound Closure 
Investigator Assessment of Complete Wound Closure will be performed at the time points indicated in the 
Schedule of Events (Table 1) after removal of subject’s dressings from target wounds prior to any potential 
disruption of the target wounds (i.e., markings, bacterial culture of wounds for clinical purposes, or B-VEC 
administration). 
The Investigator Assessment of Complete Wound Closure of Primary and Secondary wounds should be 
performed by the PI. A trained, medically qualified Sub-I should only perform if the PI is unavailable. 
Evaluator information will be recorded on the applicable assessments.  
In order to reduce inter-evaluator variability, it is important that the same evaluator assess complete wound 
closure for the same subject at all study visits, whenever feasible. If it is not possible for the same evaluator 
to continue performing the assessment, it is recommended that the primary and subsequent evaluator both 
examine and discuss their respective scoring during at least one visit. 
Wound healing will be defined as complete closure of the originally selected wound surface identified at 
baseline, specified as skin re-epithelialization without drainage, as evaluated by the Investigator.  If new 
neighboring wounds form during the key evaluation time periods at Weeks 8, 10 12, 22, 24 and 26 those 
wounds will not be included in the wound closure evaluation. Primary efficacy wound assessment occurring 
at two (2) consecutive weeks at Week 22 and 24 or 24 and 26 will be assessed live, followed by a review 
against the 2D and 3D images.  
6.2.2 
Pain Reported Outcome 
6.2.2.1 
Faces Legs Activity Cry Consolability Revised Scale (FLACC-R) 
The Faces, Legs, Activity, Cry, Consolability- Revised Scale (FLACC-R) will be completed at the time points 
indicated in the Schedule of Events (Table 1) following the removal of the dressings on the matched wounds 
(Primary Wound Pair).  
The FLACC-R Scale is used for children, under 6 years of age, who cannot accurately report their pain, 
due to being too young or not being able to understand what is being asked of them. A child is evaluated 
for each Primary Wound dressing change and will receive either a 0, 1 or 2 in each category based off of 
their behavior during the dressing removal. A total score is then calculated by study personnel, to determine 

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the overall pain and discomfort a subject is experiencing. The subject’s caregiver will complete the scale at 
scheduled visits.  
It is important that the same caregiver completes the assessment at all subject visits, whenever feasible, 
to reduce inter-evaluator variability. Additionally, this scale should continue to be used throughout the study 
even if the age of the subject changes during the study. 
The FLACC-R is provided in Appendix 2. 
6.2.2.2 
Visual Analog Scale (VAS) 
The Visual Analog Scale (VAS) will be completed at the time points indicated in the Schedule of Events 
(Table 1) following the removal of the dressings on the matched wounds. VAS uses a 10cm line with 1cm 
tick marks, where subjects indicate their level of pain by marking the appropriate tick mark on the scale 
from 0 cm (no pain) to 10 cm (the worst possible pain). VAS is used to provide indices of overall pain 
intensity during the dressing change.  
VAS will be administered to subjects 6 years of age and older, who will complete assessment themselves 
(Appendix 3).  
6.3 
Safety Assessments 
6.3.1 
Medical and Medication History 
The Investigator or delegated staff performs a complete medical history (from the time of birth), including a 
medication history and procedure and treatment history within the past (3) months. The Investigator or 
delegated staff must record all clinically or medically relevant information. Medical, procedure/treatment 
and medication history are reviewed and updated during the study. All medication taken within the past (3) 
three months from Screening or Visit 1 (Week 1) (including prescriptions, herbal and dietary supplements, 
over the counter medications, injections, and topical treatments) will be recorded on the CRF. The medical 
history includes respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, hematological, 
neurological, psychiatric, and other diseases.  
6.3.2 
Physical/Skin Examination 
A qualified individual performs a complete physical examination. Body systems evaluated include: 
General appearance 
Skin 
HEENT (Head, Ears, Eyes, Nose, Throat) 
Spine/Neck/Thyroid 
Respiratory 
Cardiovascular 
Abdomen 
Nervous System 
Musculoskeletal 
 
Abnormalities or changes in severity noted during the exam should be reported in the source document 
and on the appropriate CRF page and recorded as an AE, if noted after the initial exam.  
Abbreviated exams include evaluations of the general appearance; HEENT; abdomen; and skin will be 
compared against the original exam (i.e., if noted to be “abnormal skin” with erosions at the baseline, a 
subsequent visit exam would be considered “normal,” if the findings are consistent to the baseline exam). 
At other visits, symptom-directed PEs can be performed at the discretion of the Investigator.  
If at any point in the study a skin cancer occurs in the region of the B-VEC administration, attempts are 
made to collect samples of the skin cancer to evaluate cells for the presence of viral vector. 

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6.3.3 
Vital Signs 
Vital sign measurements include pulse, respiratory rate as well as temperature. Pulse and respiratory rate 
are taken after subjects are in a rested state. The method used for temperature measurement is at the 
discretion of the Investigator; however, the same method should be used throughout the study. Changes 
in vital signs that are reviewed and determined to be not clinically significant by the Investigator are not 
considered AEs. 
On visits in which a blood draw occurs, vitals should be collected prior to the blood draw. 
Vital signs are assessed monthly during the 26 weeks (i.e. Week 1; 5; 9; 13; 17; 21; 25; and SFU/ET). 
Symptom-directed vital sign assessments can be performed at the discretion of the Investigator.  
6.3.4 
Laboratory Evaluations 
6.3.4.1 
Complete Metabolic Panel with Direct Bilirubin & Compete Blood Count with Differential 
and Platelets 
The amount of blood collected should be minimized. Reference ranges are used to assess the laboratory 
data for clinical significance. Abnormal laboratory values which are unexpected or not explained by the 
subject’s clinical condition should be repeated as feasible until confirmed, explained, or resolved. Changes 
from baseline (Screening or Visit 1) are recorded as an AE if deemed clinically significant by the Investigator 
or qualified designee.  
The following evaluations are conducted: 
CMP14+ DBili 
CBC With Differential/ Platelet 
Glucose 
Blood Urea Nitrogen (BUN) 
Creatinine 
Sodium 
Potassium 
Chloride 
Carbon Dioxide 
Calcium 
Protein, Total 
Albumin 
Bilirubin, Total 
Bilirubin, Direct 
Bilirubin, Indirect 
Alkaline Phosphatase 
Aspartate Aminotransferase (AST) 
Alanine Aminotransferase (ALT) 
White blood cells (WBC) 
Red blood cells (RBC) 
Hemoglobin 
Hematocrit 
Mean Corpuscular Volume (MCV) 
Mean Corpuscular Hemoglobin (MCH) 
Mean Corpuscular Hemoglobin Concentration 
(MCHC) 
Red Cell Distribution Width (RDW) 
Platelets 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
6.3.4.2 
Urine and Pregnancy Test 
A urine pregnancy test is performed for women of childbearing potential and must be negative prior to any 
invasive study related procedure and Investigational Product application, at the specified study visits, as 
determined by the Investigator. 

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6.3.4.3 
HSV Antibody Assay 
Serum is collected per the Schedule of Events (Table 1) for the purpose of screening for antibodies against 
HSV using a qualified Plaque Reduction Neutralization Test (PRNT). 
6.3.4.4 
Collagen VII Antibody Assay 
Serum is collected per the Schedule of Events (Table 1) for the purpose of screening for antibodies against 
collagen VII using a commercially available CE IVD ELISA. 
6.3.4.5 
Viral Shedding 
Whole blood, skin and bandage swabs and urine are collected per the Schedule of Events (Table 1) for 
evaluation of viral shedding by real time quantitative PCR. 
6.3.4.6 
Infectivity 
Skin swabs are collected per the Schedule of Events (Table 1) for evaluation of viral infectivity by plaque 
titer analysis.  
6.4 
Principal Investigator 
At each study site, a physician with expertise caring for patients with DEB will be designated as the Principal 
Investigator (PI). In close communication and coordination with the study monitor and Sponsor, the PI will 
have the following responsibilities in addition to overseeing all other study processes at their site. 
6.4.1 
Protocol Adherence 
The Investigator will review deviations from the clinical protocol (e.g., lab results not within stated limits, 
additional clinical abnormalities not specified in protocol, exceptions to target wound criteria.) The PI or 
designee will consult with the study monitor and Sponsor as required. All deviations from the protocol must 
be documented and handled per institutional/Sponsor policies. 
6.4.2 
Treatments 
The Investigator will determine treatments needed from complications that may arise, either due to the 
underlying disease (e.g., low hemoglobin or hematocrit, wound infection, other medical conditions) or B-
VEC application (adverse events, wound infection, post-release criteria out of specification); Determine if 
the subject needs additional wound or systemic treatments; Determine which procedures will occur at 
unscheduled visits; Determine corrective actions for adverse events; and Determine whether to re-treat or 
perform additional treatment sessions post-adverse event. 
6.4.3 
Safety Assessments 
The Investigator will review and assess all adverse events (e.g., severity, causality); Assess laboratory 
results for clinically significant abnormalities; and assess vital signs including blood pressure, temperature, 
and heart rate at every visit per the schedule of events (Table 1) and perform abbreviated physical 
examination for clinically significant abnormalities.  
6.4.4 
Adverse Events 
Throughout the course of the study (following the initial IP application), all adverse events (AEs) will be 
monitored and reported on the AE Log. If an adverse event occurs, the first concern will be the safety of 
the study participants. All AEs occurring after administration will be followed throughout the study. All AEs 
related to study treatments or procedures will be followed until resolved or stabilized or until follow-up is no 
longer possible. 

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In general, even when not participating in a clinical trial, the study subjects and their caretakers 
communicate with their EB doctor on a regular basis via phone. Study subjects and their caretakers will be 
instructed to report via phone any adverse events that occur during the study while off-site. The events will 
then be transcribed to the AE Log. The Investigator is responsible for verifying that all serious and non-
serious adverse event are reported to the appropriate regulatory bodies. 
6.5 
Definitions 
6.5.1 
Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject administered 
an investigational product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, disease or exacerbation of a pre-existing condition temporally associated with the use of a 
medicinal (investigational) product.  
Subjects are asked a non-leading question in order to avoid bias in eliciting AEs. The question is asked in 
an open manner using language such as: “Have you experienced any change in your health or in your 
general condition since your last visit?” 
It is important to question the subject in a non-leading way about changes in their health or concomitant 
medication usage since their last visit. Where possible, a diagnosis rather than a list of symptoms should 
be recorded. If a diagnosis has not been made, then each symptom should be listed individually. 
Each AE requires a complete description including date of onset and corrective actions taken. The intensity 
of the AE, its relationship to the Investigational Product, as well as its outcome, must be recorded in the 
eCRF.  
Symptoms of the disease under study/lack of efficacy should not be considered as AEs, as long as they 
are within the normal day-to-day fluctuation or expected progression of the disease. However, significant 
worsening of the symptoms should be recorded as an AE. 
A change in the value of a safety laboratory evaluation can represent an AE if the change is clinically 
relevant (as determined by the Investigator) or if, during treatment with B-VEC, a shift of a parameter is 
observed from a normal value to a pathological value, or a further worsening of an already pathological 
value. When evaluating such changes, the extent of deviation from the reference range, the duration until 
return to the reference range, either while continuing treatment or after the end of treatment with B-VEC, 
and the range of variation of the respective parameter within its reference range, should be taken into 
consideration. The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter represents an AE. For pathological laboratory values 
that were not present at baseline, follow-up laboratory evaluations should be performed until the values 
return to within reference range or until a plausible explanation is found. 
AEs should be recorded after the initial IP application through SFU/ET. AEs are to be recorded on the 
appropriate AE pages in the CRF and in source documents. Where possible, all AEs should be followed to 
resolution, or an outcome is reached.  
Medical tests and examinations are performed, as appropriate, to document resolution of event(s). Where 
applicable and/or possible, AEs should be recorded as target wound specific. 
Adverse events will be graded according to the National Cancer Institute’s (NCI’s) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 as applicable. 

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6.5.2 
Immune Response Adverse Events 
Observation of a severe immune response determined by the Investigator to be possibly, probably, or 
definitely related to B-VEC should be relayed to the Medical Monitor/Sponsor.  
6.5.3 
Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be related to 
B-VEC or not) that at any dose: 
- 
Is fatal 
- 
Is life-threatening (places the subject at immediate risk of death) 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Is a persistent or significant disability/incapacity, or 
- 
Is a congenital abnormality/birth defect 
A hospitalization meeting the regulatory requirement for the “serious” criteria is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility, that was not planned.  
Any event that does not exactly meet this definition, yet in the investigator’s opinion represents a significant 
hazard can be assigned the “other significant hazard” regulatory reporting serious criteria.  
Additionally, important medical events that may not be immediately life threatening or result in death or 
hospitalization but that may jeopardize the subject or require intervention to prevent one of the outcomes 
listed above, or result in urgent investigation, may be considered serious. Examples include allergic 
bronchospasm, convulsions, and blood dyscrasias.  
SAEs are collected and reported after the initial IP application through SFU/ET. If early termination of study 
treatment occurs, SAEs continue to be collected until the event resolves. 
6.6 
Severity 
Definitions for classification of severity appear below. The Investigator will review these definitions with the 
subject. The Investigator will determine the severity classification based on these definitions, their clinical 
experience with DEB subjects, and/or the subject’s description of the event.  
[Note: A “severe” AE is not the same as an “SAE” (serious adverse event), which is defined above.] 
Mild (Grade 1): Symptoms are barely noticeable or do not make the subject uncomfortable. The 
AE does not influence performance or functioning. Prescription drugs are not ordinarily needed for 
relief of symptom(s). 
Moderate (Grade 2): Symptoms are of sufficient severity to make the subject uncomfortable. 
Performance of daily activities is influenced. Treatment of symptom(s) with prescription drugs or 
therapies may be needed. 
Severe (Grade 3): Symptoms are of sufficient severity to cause the subject severe discomfort. 
Performance of daily activities is compromised. Treatment for symptom(s) with prescription drugs 
or therapies may be needed. 
Life-threatening (Grade 4): Any adverse drug event that places the subject, in the view of the 
Investigator, at immediate risk of death 
6.7 
Relationship 
The Investigator will categorize the subject’s adverse event as one of the following: 

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Not Related: No evidence of any causal relationship with the trial intervention. An alternative 
etiology will be documented in the subject’s medical record. 
Unlikely Related: Little evidence to suggest a causal relationship (e.g. the event did not occur 
within a reasonable time after administration of the Investigational Product) or another reasonable 
explanation for the event (e.g. another clinical condition or other concomitant treatment). 
Possibly Related: Some evidence to suggest a causal relationship (e.g. occurrence within a 
reasonable time after administration of the Investigational Product), but other factors may have 
contributed to the event (e.g. another clinical condition or other concomitant treatment). 
Related: Evidence that there is an association between the event and the administration of the trial 
medication. Causes other than the Investigational Product have been ruled out and/or the event 
re-appeared on re-exposure to the Investigational Product. 
6.8 
Study IP Action Taken 
The Investigator will classify the study IP action taken as a result of the AE. The action taken will be one of 
the following: 
Dose Not Changed: Study IP application was not changed in response to an AE 
Drug Interrupted: Study IP application was interrupted in response to an AE 
Drug Withdrawn: Study IP application was permanently discontinued in response to an AE 
Not Applicable: Action taken regarding study IP application does not apply. Not applicable will be 
used in such circumstances such that the AE began after treatment completed. 
6.9 
Outcome 
The AE will be followed until the Investigator determines and provides a final outcome. Adverse event 
outcomes are classified as one of the following:  
Recovered/resolved: AE resolved with no residual signs or symptoms  
Recovered/resolved with sequelae: AE resolved but symptoms remain, and a new baseline is 
established since full recovery is not expected (if Lyme’s disease is the AE, the sequelae may be 
facial paralysis) 
Not recovered/ resolved (continuing): AE has either no improvement or partial improvement, 
such that the AE remains ongoing 
Fatal: Outcome of AE is death and may possibly be related to study IP as determined by the 
investigator  
Unknown: The outcome of the AE is unknown (example lost to follow-up) 
6.10 Reporting Procedures 
All adverse events occurring after B-VEC administration observed by the Investigator or reported by the 
subject (whether or not attributed to B-VEC), are reported on the case report form.  
Medically significant adverse events considered related to B-VEC by the Investigator or the Sponsor are 
followed until resolved or considered stable. The Investigator must assign the following attributes: 
description; dates of onset and resolution; severity; assessment of relatedness to B-VEC, and action taken. 
The Investigator may be asked to provide follow-up information.  

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All deaths occurring on study must be reported to the Sponsor; available autopsy reports and relevant 
medical reports may be requested.  
The Investigator should notify the IRB/IEC of serious adverse events occurring at the site and other adverse 
event reports received from the Sponsor, in accordance with local procedures.  
It is left to the Investigator’s clinical judgment whether or not an adverse event is of sufficient severity to 
require the subject’s removal from study. A subject may also voluntarily withdraw from study due to what 
he or she perceives as an intolerable adverse event. If either of these occurs, the subject is asked to 
undergo an early termination assessment and be given appropriate care under medical supervision until 
symptoms cease or the condition becomes stable. If the subject was permanently withdrawn from the study 
due to a serious adverse event, this information must be included in either the initial or follow-up Serious 
Adverse Event Report Form, and in the End of Study Case Report Form. 
6.10.1 SAE Reporting Procedures 
All serious adverse events (SAEs) that occur after IP application must be reported to the Sponsor. All 
subjects with an SAE must be followed and the outcomes reported. The Investigator should supply the 
Sponsor and the IRB with any additional requested information (e.g., hospital discharge summary, autopsy 
reports and terminal medical reports). The Sponsor shall evaluate all SAEs and determine if they meet FDA 
reporting requirements. In the event of an SAE, the Investigator must: 
1. Notify the Sponsor within 24 hours of the Investigator’s awareness of the event. 
2. Obtain and maintain all pertinent medical records, information, and medical judgments from 
colleagues who assisted in the treatment and follow-up of the subject. 
3. Provide the Sponsor with a complete, written case history, including copies of supporting reports 
(e.g., progress notes, laboratory reports) and a statement from the Investigator as to whether or 
not the event was related to the use of B-VEC. 
4. Promptly inform the governing IRB/IEC of the event if it is related. For other SAEs, notify the 
governing IRB as required by the IRB, local regulations, and the governing health authorities. 
Immediately report any SAE that meets the following to the Medical Monitor/Sponsor and suspend study 
intervention: 
1. Occurrence of an SAE related or possibly related to the study intervention, 
2. Systemic infection determined to be related to B-VEC, 
3. Outside information is discovered that may affect the study and its participants.  
6.10.2 Pregnancy 
The Investigator must report all pregnancies to the Sponsor within 24 hours of their first knowledge of the 
pregnancy. If a subject become pregnant, they must be terminated from the study immediately. Pregnancies 
occurring up to three (3) months after the last application of B-VEC must be reported to the Investigator. 
The Investigator should counsel the subject on the potential risks of continuing the pregnancy and possible 
effects of the fetus. The female subject or their pregnant partner will be followed until the end of pregnancy. 
The infant will be followed for a year after birth if consent has been obtained to do so. Pregnancy itself is 
not considered an AE; however spontaneous abortion is. 
6.11 Data Monitoring Board Review and Regulatory Reporting 
A Data Safety Monitoring Board (DSMB) will be established for this study. The DSMB will be responsible 
for ensuring the safety of the subjects and to alert the Sponsor of any safety issues related to the conduct 
of the study. Members will be completely independent Investigators who have no financial, scientific, or 

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other conflicts of interest with the study. Details of DSMB membership requirements including potential 
conflicts of interest, as well as DSMB objectives, operational details and meeting scheduling are provided 
in the DSMB Charter. 
The following will require reporting by the Investigator to the Sponsor for DSMB discussion: 
- 
Occurrence of an unexpected SAE related or possibly related to the study intervention 
- 
Systemic infection determined to be related to B-VEC 
- 
Evidence of allergic reaction at B-VEC treatment site 
- 
Evidence of malignancy at B-VEC treatment site 
- 
Death of a study participant 
The DSMB provides recommendations about stopping or continuing the trial and has the authority to 
recommend dose or regimen modifications for safety concerns. The DSMB may also make 
recommendations regarding the selection or retention of participants, their management, improving 
adherence to protocol-specified regimens, and the procedures for data management and quality control. 
The end of the Data Safety Monitoring Board (DSMB) oversight is approximately six (6) months after the 
last subject is enrolled. More information can be found in the Data Safety Monitoring Plan and DSMB 
Charter.  
6.12 Expedited Reporting and Safety Letters  
Krystal Biotech, Inc. is responsible for reporting any suspected, unexpected, serious, adverse reactions 
and unexpected fatal or life-threatening suspected adverse reactions involving the Investigational Product 
to all regulatory authorities, IRB/IECs, and other participating Investigators in accordance with ICH GCP 
and local regulatory authorities as applicable.  
Krystal Biotech, Inc. will be responsible for submitting Safety Letters to central IRB/IEC. It is the 
responsibility of the Investigator or designee to promptly notify local IRB/IEC of any of the events above, 
which involve risk to the human subject. 
6.13 Safety Monitoring 
The Medical Monitor/Sponsor will assess aggregate safety data across study sites on an ongoing basis. 
Routine meetings of the DSMB will be held every six (6) months at minimum or at the DSMB’s request. Safety 
data, primary safety endpoints, all grade 3 and 4 adverse events, and all serious adverse events will be 
reviewed on a regular basis. 
7 Study Completion 
7.1 
Long Term Follow-Up Protocol 
The study will end after the last enrolled subject has completed the SFU/ET visit. 
After the SFU/ET visit subjects will have the option to enroll in a long-term follow-up protocol under this 
IND, in which they will be followed for five (5) additional years after the SFU/ET Visit. 
Any subject who completes the study, discontinues early, or withdraws from the study after receipt of B-VEC 
will be asked to participate in the Long-Term Follow-Ip protocol. The subject will have the option to not 
follow the Investigator’s suggestions, but attempts will still be made to contact the subject. If a subject does 
not follow directions or refuses to return for follow-up, attempts will still be made to evaluate them or to have 
their local physician evaluate them. 

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7.2 
Discontinuation, Withdrawal, Lost to Follow-Up, or Early Termination 
Subjects who discontinue due to adverse events or protocol deviations/violations will be replaced at the 
discretion of the Sponsor. Subjects who withdraw prior to the first B-VEC administration are considered a 
screen failure and are not considered a participant and can be re-screened. 
A subject is free to withdraw from the study at any time for any reason without prejudice to their future 
medical care by the physician or at the institution. The Investigator or Sponsor may also withdraw the 
subject at any time in the interest of subject safety or for other reasons. Criteria for withdrawal include: 
- 
Consent/assent is withdrawn 
- 
The subject refuses treatment and/or procedures/observations 
- 
Occurrence of unmanageable adverse events or pregnancy 
- 
For other reasons (e.g., significant protocol violation, non-compliance) 
The Sponsor may be contacted if clarification is required. The primary reason for withdrawal must be 
recorded on the CRF. Comments or complaints made by the subject must also be recorded on the CRF. 
Withdrawal should be discussed with the medical monitor prior to withdrawal when possible. This 
information will be communicated to the DSMB at each meeting in the enrollment update. 
A subject may withdraw at any time but treated participants will be followed yearly for at least 5 years in a 
Long-Term Follow-up Protocol. The subject will have the option to not follow the Principal Investigator’s 
suggestions, but attempts will still be made to contact the participant.  
If the subject withdraws for other reasons, attempts will be made to contact them at least once per year to 
perform safety monitoring as described above. Subjects may be contacted more frequently if it is deemed 
necessary by the investigator. If a subject is lost to follow up, the attempts to contact the subject will be 
documented in an effort to show due diligence. If a subject is terminated early from the study, the same 
process as for “withdrawal” of a subject will be followed  
The Sponsor reserves the right to terminate the study. 
8 Statistical Considerations 
Continuous variables will be summarized in tables and will include the number of subjects, mean, standard 
deviation (SD), percent of coefficient of variance (CV%), median, minimum, and maximum. Categorical 
variables will be presented in tables as frequencies and percentages. A statistical analysis plan (SAP) will 
provide additional details on the approach to the analysis and data displays. 
8.1 
Primary Efficacy Endpoint  
The following hypothesis for the primary endpoint of the proportion of DEB wounds sites with complete 
wound healing (CWH) from baseline in B-VEC versus placebo treated intra-subject wound sites at Weeks 
22 and 24 or 24 and 26 as determined by the Investigator will be tested: 
Null Hypothesis  
H0:  %CWH in B-VEC = %CWH in Placebo   
Alternate Hypothesis  
H1:  %CWH in B-VEC > %CWH in Placebo   
Where % CWH is the percentage of primary wounds with a complete wound healing from baseline at Week 
22 and 24 or 24 and 26.  A two-sided significance level of 0.05 is considered.  
The complete wound healing is defined as 100% wound closure from the exact wound area selected at 
baseline, specified as skin re-epithelialization without drainage. If new neighboring wounds form around the 

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original traced baseline wound during the primary evaluation time points, these areas will not be included 
in the evaluation.  
 The primary endpoint is defined as wounds that meet any of the following conditions: 
• 
Healed on Week 22 and Week 24, or 
• 
Healed on Week 24 and Week 26.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as positive 
responses. 
8.2 
Key Secondary Efficacy Endpoint 
The following hypothesis for the key secondary endpoint of the proportion of primary wound sites with 
complete wound healing from baseline, in B-VEC-treated versus baseline at Week 8 and 10 or 10 and 12 
(as determined by the Investigator) will be tested: 
Null Hypothesis  
H0:  %CWH in B-VEC = %CWH in Placebo   
Alternate Hypothesis  
H1:  %CWH in B-VEC > %CWH in Placebo   
Where % CWH is the percentage of matched wound sites with a complete wound healing from baseline at 
Week 8 and 10 or 10 and 12. A two-sided significance level of 0.05 is considered.  
The complete wound healing is defined as 100% wound closure from the exact wound area selected at 
baseline, specified as skin re-epithelialization without drainage. If new neighboring wounds form around the 
original traced baseline wound during the secondary evaluation time points these areas will not be included 
in the evaluation.   
 The secondary key endpoint is defined as wounds that meet any of the following conditions: 
• 
Healed on Week 8 and Week 10, or 
• 
Healed on Week 10 and Week 12.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as positive 
responses. 
8.3 
Number of Subjects 
Per Agency’s recommendation, a McNemar Test has been used for sample size calculation. In the Phase 
I/II study, the response rates for Weeks 8 through 12 were from 70-100% for wounds randomized to B-VEC 
and 0-33% for wounds randomized to placebo, respectively. Therefore, assuming a response rate of 75% 
among wounds randomized to B-VEC and a response rate of 25% among wounds randomized to placebo, 
with 90% power and a two-sided Type 1 error rate of 5%, 24 subjects (i.e., 24 wound pairs) are required.  
8.4 
Data Management 
Pre-designed CRFs are used to collect information for safety and proof of mechanism analyses. An 
electronic CRF (eCRF) is managed and maintained by the Sponsor for this study. The eCRF is constructed 
based on the CRF data entry requirements of the protocol.  Data queries are generated and resolved within 
the eCRF. In addition, range checks of the eCRF fields, plausibility and consistency checks across eCRF 
pages will be performed to assess consistency, accuracy and completeness of the data collected and 
entered into the eCRF. Standard SAS datasets are generated and provided for analysis. 

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8.5 
Analysis Populations 
Safety Population 
This population is defined as all subjects who were administered with either B-VEC or placebo. Safety 
population will be used for all the safety analyses. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population includes subjects whose primary wounds were randomized with or 
without either B-VEC or Placebo administration. ITT population will be used for all the primary and 
secondary efficacy sensitivity analyses and baseline summaries. 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population includes subjects whose primary wounds were randomized 
and received B-VEC treatment with at least one post baseline primary endpoint assessment.  The mITT 
population will be used for all the primary and secondary efficacy analyses. 
Per Protocol Population 
The per-protocol (PP) population includes all the safety population subjects who completed the study 
without major protocol deviations. PP population will be used for all the primary and secondary efficacy 
sensitivity analyses. 
8.6 
Demographic and Baseline Characteristics 
The descriptive summaries of subjects’ demographic and baseline characteristics are presented by 
treatment, where applicable, for the safety, ITT, mITT and PP populations. A detailed description of subject 
disposition is provided.   
Subject characteristics include a summary of the following: 
- 
Subject demographics 
- 
Baseline disease characteristics  
- 
Pre-existing medical conditions 
Continuous variables are summarized using number of observations, mean and standard deviation, 
median, and minimum and maximum values. Categorical values are summarized using number of 
observations and percentages. 
Medical History and AEs will be summarized by MedDRA System Organ Class and Preferred Term. 
8.7 
Efficacy Analyses 
8.7.1 
General Approach 
The study has a complete randomized-block design in which each subject serves as a block to receive all 
of the treatment conditions.  In this study, each subject provides at least one pair of target wounds with one 
wound from each pair being treated with B-VEC and the other wound from each pair with placebo in the 
primary target wound pair. Efficacy measurements are taken multiple times (or repeatedly) over the on-
treatment period from each subject. 
All data will be presented using summary statistics or frequency tables, as appropriate, and will be analyzed 
for superiority comparisons between B-VEC and placebo treatments. The description of the sample will be 
done using summary statistics (n, mean, standard deviation, median, and maximum/minimum) for 
continuous data and using frequency statistics (counts and percentages) for categorical data. Hypothesis 

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testing, unless otherwise indicated, will be performed at the 5% significance level (1-sided). All P-values 
will be rounded to four decimal places; P-values less than 0.0001 will be presented as '<0.0001' in all tables. 
Unless specifically stated, all confidence intervals will be two-sided with 95% coverage. 
Efficacy measures collected pre-dosing at Screening or Visit 1 (Week 1) will be considered as the baseline 
measurement in this study. 
The Sponsor, or their designee, will analyze the data using SAS® Statistical Analysis System Version 9.1.3 
or higher. Detailed descriptions of the statistical analysis methods, data conventions, and sensitivity 
analysis, as well as handling of missing data for both efficacy and safety measures will be described in 
detail in the Statistical Analysis Plan (SAP). 
8.7.2 
Analysis of Primary Efficacy Endpoint 
The primary endpoint of the proportion of DEB primary wound sites with complete wound healing from 
baseline will be analyzed using the McNemar Test at Weeks 22 and 24 or 24 and 26.  
The complete wound healing is defined as complete wound closure from the exact wound area selected at 
baseline, specified as skin re-epithelialization without drainage. If new neighboring wounds form around the 
original traced baseline wound during the primary evaluation time points will not be included in the 
evaluation.  
 The primary endpoint is defined as wounds that meet any of the following conditions: 
• 
Healed on Week 22 and Week 24, or 
• 
Healed on Week 24 and Week 26.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as positive 
responses. 
The mITT population will be used for this primary efficacy analysis. The ITT and PP populations may also 
be used as part of the sensitivity analyses. 
The primary endpoint results will be summarized by treatment and timepoints for all the subjects in mITT 
population. A listing of these results will also be presented for all the subjects in the ITT population. 
8.7.3 
Analysis of Key Secondary Efficacy Endpoint 
The key secondary endpoint of the proportion of primary wound sites with complete wound healing from 
baseline, will be analyzed using the McNemar Test at Weeks 8 and 10 or 10 and 12. 
The complete wound healing is defined as complete wound closure from the exact wound area selected at 
baseline, specified as skin re-epithelialization without drainage. If new neighboring wounds form around the 
original traced baseline wound during the secondary evaluation time points these areas will not be included 
in the evaluation.   
 The primary endpoint is defined as wounds that meet any of the following conditions: 
• 
Healed on Week 8 and Week10, or 
• 
Healed on Week 10 and Week 12.  
Only wounds that are healed for at least two (2) consecutive weeks are counted as positive 
responses. 
The ITT population will be used for this primary efficacy analysis. The PP populations may also be used as 
part of the sensitivity analyses. 
The key secondary endpoint results will be summarized by treatment and timepoints for all the subjects in 
ITT population. A listing of these results will also be presented for all the subjects in the ITT population. 

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8.7.4 
Analysis of Secondary Efficacy Endpoint 
The following secondary endpoint will be analyzed using the Analysis of Covariance (ANCOVA) with 
treatment as the fixed effect and the baseline value as the covariate by the time points. 
The mean change from baseline in pain severity VAS score per wound site associated with wound dressing 
changes at Weeks 22, 24 and 26 for each treated versus placebo for ages 6 and above on the primary 
wound pair. For ages below 6 years, the FLACC-R scale scores will be used instead of VAS scores. 
The ITT population will be used for this primary efficacy analysis. The ITT and PP populations may also be 
used as part of the sensitivity analyses. 
The secondary endpoint results will be summarized by treatment and timepoints for all the subjects in the 
ITT population. A listing of these results will also be presented for all the subjects in the ITT population. 
8.8 
Safety Analyses 
The safety and tolerability of B-VEC based on the assessment of adverse events, physical examinations, 
vital signs, and clinical laboratory test results. All safety analysis results will be performed using the safety 
population. 
Adverse events will be coded using the version of MedDRA System Organ Class and Preferred Term 
available at the start of the trial. Adverse events will be grouped into treatment-emergent adverse events 
and post-treatment adverse events and will be tabulated by preferred terminology and by body system. 
Each AE will be counted once for each subject unless it resolves and recurs, in which case it may appear 
as multiple AEs. Severity, frequency, and relationship of AEs to study intervention will be presented by 
System Organ Class (SOC) and preferred term. Incidence of target-wound-related adverse events will be 
summarized by treatment, respectively, for each wound pair.  
Listings will be provided for discontinuations, deviations, compliance, AEs leading to discontinuation, and 
target-wound-related adverse events. AE listings will include severity and relationship to study medication, 
as well as actions taken. 
Tables will be provided summarizing reasons for premature discontinuation, protocol deviations, subject 
compliance, treatment-emergent AEs (TEAEs), TEAEs of target wound, TEAEs by severity, SAEs, and 
TEAEs leading to discontinuation. 
The prior and concomitant medications will be summarized and listed by treatment. Medications will be 
coded with WHO Drug and categorized as either prior medications (any medication that was started before 
the first application of B-VEC) or concomitant medications (medication continued or newly started on or 
after the date of first application of B-VEC). 
Medical/procedural history data collected during Screening or Visit 1 (Week 1), will be summarized by 
MedDRA System Organ Class and Preferred Term.  
Descriptive summary of physical examinations, vital signs, and clinical laboratory tests will be reported 
along with data listings. 
Evaluations of viral shedding, infectivity, COL7 and HSV antibodies will be done descriptively. 
Any abnormal lab tests obtained during the study will be listed for individual subjects. Any positive findings 
of the pregnancy test will be listed. 

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8.9 
Missing Values and Imputations 
Multiple imputation method will be used to handle missing data for primary efficacy analysis. For all the 
exploratory endpoints, the missing values will not be imputed.  
8.10 Interim Safety Analyses 
A Data Safety Monitoring Board (DSMB) as described in Section 6.11, will be instituted for the interim 
analyses use in this study. They will operate under an approved charter describing their roles and 
responsibilities for the interim analysis Their main responsibility will be to review and adjudicate safety 
findings.  
9 Regulatory Obligations 
9.1 
Informed Consent 
Before a subject’s participation in the trial, the Investigator (or designee) is responsible for obtaining written 
informed consent from the subject or legally acceptable representative (see note below) after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific procedures or any investigational products are administered. A legally acceptable 
representative is an individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical trial.  
The acquisition of informed consent should be documented in the subject’s records, and the informed 
consent form should be signed and personally dated by the subject or a legally acceptable representative 
and by the person who conducted the informed consent discussion (not necessarily an Investigator). The 
original signed informed consent form must be retained in accordance with institutional policy, and a copy 
of the signed consent form must be provided to the subject or legally acceptable representative.  
If a potential subject is illiterate or visually impaired and does not have a legally acceptable representative, 
the Investigator must provide an impartial witness to read the informed consent form to the subject and 
must allow for questions. Thereafter, both the subject or legally acceptable representative and the witness 
must sign the informed consent form to attest that informed consent was freely given and understood. 
9.2 
Institutional Review Board 
The protocol proposed informed consent form, other written subject information, and any proposed 
advertising material including the information letters must be submitted to the IRB/IEC for written approval. 
A copy of the written approval of the protocol, informed consent form, and advertising material must be 
received by the sponsor before recruitment of subjects into the study and shipment of investigational 
product.  
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC for all subsequent 
changes to the above-named documents. The Investigator should notify the IRB/IEC of important deviations 
from the protocol or serious adverse events occurring at the site and other adverse event reports received 
from the Sponsor, in accordance with IRB/IEC procedures.  
The Investigator is responsible for obtaining IRB/IEC approval/renewal throughout the duration of the study 
at the frequency specified by the IRB/IEC. Copies of the Investigator’s reports and the IRB/IEC’s written 
continuance of approval must be sent to the Sponsor. 

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9.3 
Pre-Study Documentation Requirements 
The Investigator is responsible for forwarding the following documents to the Sponsor for review before 
study initiation from the Sponsor can occur:  
- 
Signed and dated protocol signature page (Investigator’s Agreement) 
- 
Copy of the IRB/IEC approval of the protocol, information letter, consent form, and assent form 
- 
Up-to-date curricula vitae of Principal Investigator and all Sub-Investigators 
- 
The IRB composition and/or written statement that IRB is in compliance with regulations 
- 
Signed study contract 
- 
Completed FDA form 1572. Laboratories providing primary and secondary endpoint data and any 
central laboratories for the study must be listed on the form 
- 
For studies covered under 21 CFR Part 54.2(e), “Financial Disclosure,” completed Financial 
Disclosure statements for the Principal Investigator, all Sub-Investigators, and their spouses (legal 
partners) and dependent children 
9.4 
Subject Confidentiality 
The Investigator must take all reasonable measures to ensure that the subject’s confidentiality is 
maintained. On the case report forms or other documents submitted to the study Sponsor and those working 
with the study Sponsor, subjects should be identified by their initials and a subject study number. 
Documents that are not for submission to the study Sponsor and those working with the study Sponsor 
should be kept in strict confidence by the Investigator.  
In compliance with Federal regulations/ICH GCP Guidelines, the Investigator and Institution shall permit 
authorized representatives of the Sponsor and companies that work with the Sponsor, of the regulatory 
agency(s), and the IRB direct access to review the subject’s original medical records for verification of 
study-related procedures and data. Direct access includes examining, analyzing, verifying, and reproducing 
any records and reports that are important to the evaluation of the study. The Investigator is obligated to 
inform and obtain the consent of the subject to permit such named representatives to have access to their 
study-related records without violating the confidentiality of the subject. 
10 Administrative and Legal Obligations 
10.1 Protocol Amendments and Study Terminations 
Protocol amendments must be made only with the prior approval of the sponsor. Agreement from the 
sponsor must be obtained for all protocol amendments and amendments to the informed consent 
document. The IRB/IEC must be informed of all amendments and give approval for any amendments likely 
to affect the safety of the subjects or the conduct of the trial. The Investigator must send a copy of the 
approval letter from the IRB/IEC to the Sponsor.  
The Sponsor reserves the right to terminate the study, according to the study contract. The Investigator 
should notify the IRB/IEC in writing of the trial’s completion or early termination and send a copy of the 
notification to the Sponsor. 

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10.2 Study Documentation and Storage 
10.2.1 Delegation Log 
The Investigator should maintain a list of appropriately qualified persons to whom he/she has delegated 
trial duties. All persons authorized to make entries and/or corrections on case report forms are included on 
the Delegation of Authority Form. The Delegation of Authority Form must be continuously updated as 
needed, and those delegated specified tasks, should have appropriate and up-to-date training.   
10.2.2 Source Documents 
Source documents are original documents, data, and records from which the subject’s case report form 
data are obtained. These include but are not limited to hospital records, clinical and office charts, laboratory 
and pharmacy records, diaries, microfiches, radiographs, and correspondence.  
10.2.3 Study File 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized filing 
system of all study-related (essential) documentation, in a complete, accurate, and legible manner, suitable 
for inspection at any time by representatives from the sponsor, companies that work for and with the 
Sponsor, and/or applicable regulatory authorities. Elements should include but are not limited to the 
following:  
- 
Subject files containing completed case report forms, informed consents, and supporting copies of 
source documentation.  
- 
Study files containing the protocol with all amendments, investigator’s brochure, copies of pre-study 
documentation, training documentation and all correspondence to and from the IRB and the 
sponsor.  
- 
Proof of receipt, Investigational Product Accountability Record, Return of Investigational Product 
for Destruction, Final Investigational Product Reconciliation Statement, and all drug-related 
correspondence.  
In addition, all original source documents supporting entries in the case report forms must be maintained 
and be readily available.  
No study document should be destroyed, moved to another location, or assigned to another party without 
prior written consent of the sponsor. 
10.3 Study Monitoring and Data Collection 
Representatives of the Sponsor, following ICH Guidelines for GCP (E6), will monitor the conduct of this 
study at regular intervals to verify adherence to the protocol; completeness, accuracy, and consistency of 
the data entered into the eCRFs; and adherence to Federal and local regulations on the conduct of clinical 
research. In addition, audits or inspections may be carried out by the Sponsor’s or its designee’s 
independent Quality Assurance Department, the FDA, local regulatory authority or the IRB. In accordance 
with ICH Guidelines for GCP, the Investigator must provide direct access to all study records including 
subject’s source data/documents (e.g., subject’s medical records), eCRFs, and other study related 
documents (e.g., Investigator Study File, investigational product drug accountability records). In addition, 
the Investigator agrees to provide to representatives of the Sponsor, regulatory agency or IRB/IEC access 
to facilities and personnel necessary for the effective conduct of any inspection or audit. 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, authorized 
representatives of the Sponsor may conduct a quality assurance audit. The purpose of a Sponsor audit is 
to systematically and independently examine all study-related activities and documents to determine 

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whether these activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the protocol and any supporting documentation, ICH Guidelines for GCP, and any applicable 
regulatory requirements.  
The Investigator agrees to cooperate with the Sponsor’s representatives to ensure that any problems 
detected in the course of monitoring and/or audit visits, including delays in completing eCRF data entry and 
answering queries, are resolved in a timely manner. 
In addition, authorized representatives of regulatory agencies and/or an IRB may visit the site to perform 
audits or inspections. If the Investigator is notified of an inspection by a regulatory authority the Investigator 
agrees to notify the Sponsor immediately. 
For this study, subject data will be entered into the Sponsor-defined eCRFs and combined with data 
provided from other sources, as applicable, in a validated data system. Data will be appropriately 
documented in the subject’s source documents and entered into the eCRF when the information is 
available. Applicable data from the subject’s source documents should be recorded in the eCRFs 
completely and promptly. Completed eCRFs should be ready for review by the Sponsor or its designee 
within 3 business days of each study visit for any given subject. 
Management of clinical data will be performed in accordance with the Sponsor’s standards and data 
cleaning procedures, and will be used to ensure the integrity of the data, e.g., inconsistencies and errors 
queried in the data per the study specific Data Management Plan (DMP) and the eCRF Completion 
Guidelines (CCGs). 
Adverse events and relevant medical history will be coded using MedDRA System Organ Class and 
Preferred Term. Concomitant medications will be coded using the World Health Organization Drug Global 
Dictionary (WHO Drug Global). 
Corrections of data entered into the eCRF must be made in the eCRF and supported by source documents, 
as appropriate. Corrections to the eCRF through queries and comments will be tracked by the eCRF internal 
audit trail. 
The Investigator is responsible for all information collected on study subjects enrolled in this study. The 
data collected during the course of this study must be reviewed and verified for completeness and accuracy 
by the Investigator. After a full review of the eCRFs by the Sponsor or its designee and resolution of any 
data clarifications, the Investigator will review, sign, and approve the subject’s eCRF. 
Copies of the final completed eCRFs will be provided on a data storage device (e.g., USB flash drive) for 
archiving at the investigative site following database lock at or prior to study closure. 
10.3.1 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation checks will 
be implemented and applied to the database on a regular basis. Queries are entered, tracked, and resolved 
through the electronic data capture (EDC) system directly. Additional manual reviews are done on a regular 
basis to ensure consistency and data quality. The study database will be updated in accordance with the 
resolved queries. All changes to the study database will be documented. 
10.3.2 Retention of Records 
All study documents (e.g., subject files, signed informed consent forms, copies of eCRFs, Investigator Study 
File notebook, etc.) must be kept secure and retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) and until there 
are no pending or contemplated marketing applications in an ICH region; or, if no application is filed or if 

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the application is not approved for such indication, until 2 years after the investigation is discontinued and 
regulatory authorities have been notified. Investigators may be required to retain documents longer if 
required by applicable regulatory requirements, by local regulations, or by an agreement with the Sponsor. 
The Investigator must notify and receive prior written consent of the Sponsor before any study documents 
are destroyed, moved to another location, or assigned to another party. 
10.4 Publication Policy 
The information provided in support of or generated as a result of this study is confidential. Any use or 
reproduction thereof, including but not limited to publications or presentations by the Investigator or his 
associates, must be submitted to the Sponsor for review and approval prior to publication or presentation 
in any form. All publications must acknowledge the sponsorship. 

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11 References 
Alexeev, V., Uitto, J. & Igoucheva, O., 2011. Gene expression signatures of mouse bon marrow-derived 
mesenchymal stem cells in the cutaneous environment and therapeutic implications for blistering skin 
disorder. Cytotherapy, Volume 13, pp. 30-45. 
Center for Disease Control, 2002. 2000 CDC Growth Charts for the United States: Methods and 
Development. [Online] Available at: https://www.cdc.gov/growthcharts/2000growthchart-us.pdf 
[Accessed 13 05 2020]. 
Eng, V. et al., 2020. Patient Reported Outcomes and Quality of Life in Recessive Dystrophic Epidermolysis 
Bullosa: A Global Cross-sectional Survey. Journal of the American Academy of Dermatology. 
Fritsch, A. et al., 2008. A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals 
mechanisms of disease and response to fibroblast therapy. The Journal of Clinical Investigation, pp. 1669-
1679. 
Intong, R., 2012. Inherited epidermolysis bullosa: A new diagnostic criteria and classification. Clinics in 
Dermatology, pp. 70-77. 
Kern, J. et al., 2009. Mechanisms of Fibroblast Cell Therapy for Dystrophic Epidermolysis Bullosa: High 
Stability of Collagen VII Favors Long-term Skin Integrity. Molecular Therapy, 17(9), pp. 1605-1615. 
Kivirikko, S., Li, K., Christiano, A. & Uitto, J., 1996. Cloning of Mouse Type VII Collagen Reveals 
Evolutionary Conservation of Functional Protein Domains and Genomic Organization. Journal of 
Investigative Dermatology, pp. 1300-1307. 
Kuhl, T. et al., 2016. Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for 
Mechanisms and Therapy of Genodermatoses. Journal of Investigative Dermatology, pp. 1116-1123. 
Nelson, A. et al., 2006. How much of a topical agent should be prescribed for children of different sizes?. 
Journal of Dermatological Treatment, pp. 224-228. 
O'Brien, P. & Fleming, T., 1979. A Multiple Testing Procedure for Clinical Trials. Biometrics, 35(3), pp. 549-
556. 
Schweiger-Briel, A. et al., 2015. A COL7A1 variant leading to in-frame skipping of exon 15 attenuates 
disease severity in recessive dystropic epidermolysis bullosa. British Journal of Dermatology, Volume 173, 
pp. 1308-1311. 
Shi, R. & Derendorf, H., 2010. Pediatric Dosing and Body Size in Biotherapeutics. Pharmaceutics, pp. 389-
418. 
Uitto, J. & Christiano, A. M., 1994. Molecular basis for the dystrophic forms of epidermolysis bullosa: 
Mutations in the type VII collagen gene.. Arch. Dermatol. Res., Volume 287, p. 16–22. 
Varki, R., Sadowski, S., Uitto, J. & Pfendner, E., 2007. Epidermolysis bullosa. II. Type VII collagen mutations 
and phenotype-genotype correlations in the dystrophic subtypes.. J. Med. Genet., Volume 44, pp. 181-92. 
 
 

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Appendix 1: Procedure for Digital Photography Using RUBI 3D 
Imaging 
Canfield RUBI 3D Imaging System: 
• 
iPad with Occipital Scanner and Canfield custom external flash 
• 
Canfield Capture Mobile Application (software includes modules for capturing, viewing, measuring, 
and exporting 2D and 3D object data). 
Proper Subject Preparation & Positioning: 
For the duration of the study, the only variable that should change is the area of interest.  Any extraneous 
objects (jewelry, makeup, clothing, etc.) should be eliminated from the field to be photographed.   
For optimal imaging of the skin surface, the subject’s photographic target wound area must be non-shiny/dry 
and clean (free of any extraneous items, e.g. lint).  There must be no hair in the photographic target area 
field of view.  Any hair within the target area field of view must be cut/trimmed (ideally shaved) from the 
region prior to imaging.  
Careful preparation and positioning of the subject are critical to the accuracy of the image capture. Capture 
images in a well-lit room with the same lighting, throughout the study. 
Photographic Procedures: 
1. Prior to capturing the subject images using the camera system, the photographer launches the 
Canfield Capture Mobile Application. 
2. The photographer either creates a New Subject for an initial visit or, for a return subject, highlights 
the appropriate existing Subject ID listed in the Canfield Capture database.  The visit name (as per 
the study schedule) is selected by the photographer and the image date is captured by the software. 
3. Positioning the Subject correctly in relation to the camera system depends on where the target area 
is located on the body.  
4. With the Subject’s target area positioned correctly within the frame of the camera system, the 
Photographer adjusts the camera distance for accurate image capture.  The initial reference image 
is a 2D image capture. 
5. The Photographer then captures the 3D image following the model on the screen.  Once complete, 
the photographer is prompted to review the 3D build of the data model for image acceptability.  The 
Photographer either accepts the image and moves on to the next capture or does not accept and 
recaptures the image.   
6. After the 3D image capture the image is displayed for measurement.  The Investigator or assigned 
Designee, will annotate the involved wound area and the software will report the surface area 
measurement (cm²). If the target area is considered closed, the healed checkbox may be marked. 
7. Following the session, the Photographer submits the images to Canfield. Upon exiting, the software 
automatically reads, checksums, encrypts, packages, and duplicates the data to submit to Canfield 
via internet submission.   
A secure, validated, compliant web server set up at Canfield is used for secure transfer of study images by 
study sites.  Images are to be transferred the day they are recorded.  Only approved individuals by the 
Sponsor have access to the website.  

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The application logs a record of this action to a local database and prompts the Photographer when 
completed.   
8. Trained Canfield staff review the data files for technical quality and acceptability and communicate 
any technical comments to the site. 
9. Data Transfers are provided to sponsor as per the data transfer specifications.  At the end of the 
study, a copy of site-specific subject images will be provided to each site.  This is in addition to the 
Photography Result Reports available for printing from the Clinical Services Website after each 
session.  Remote access to all images by the Sponsor is also provided.   
10. Canfield will provide each study site with the necessary hardware as well as technical support as 
needed.  All supplied photographic equipment remains the property of Canfield.  Any questions 
regarding the photographic portion of this study are to be forwarded to the assigned Project 
Manager at Canfield Scientific. 

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Appendix 2: Face, Legs, Arms, Cry, Consolability Revised (FLACC-R) 
Categories 
0 
1 
2 
Participant’s 
Score 
Face 
No particular 
expression or smile 
Occasional grimace 
or frown, withdrawn, 
disinterested, sad, 
appears worried 
Frequent to constant 
quivering chin, 
clenched jaw, 
distressed looking 
face, expression of 
fright/panic 
 
Legs 
Normal position or 
relaxed, usual tone 
& motion to limbs 
Uneasy, restless, 
tense occasional 
tremors  
Kicking, or legs 
drawn up, marked 
increase in 
spasticity, constant 
tremors, jerking 
 
Activity 
Lying quietly, normal 
position, moves 
easily, regular, 
rhythmic 
respirations 
Squirming, shifting 
back and forth, 
tense, 
tense/guarded 
movements, mildly 
agitated, 
shallow/splinting 
respirations, 
intermittent sighs 
Arched, rigid or 
jerking, severe 
agitation, head 
banging, shivering, 
breath holding, 
gasping, severe 
splinting 
 
Cry 
No cry (awake or 
asleep) 
Moans or 
whimpers, 
occasional 
complaint, 
occasional verbal 
outbursts, grunting 
Crying steadily, 
screams or sobs, 
frequent complaints, 
repeated outburst, 
constant grunting 
 
Consolability 
Content, relaxed 
Reassured by 
occasional touch, 
hugging or being 
talked to, 
distractible 
Difficult to console or 
comfort, pushing 
caregiver away, 
resisting care or 
comfort measures 
 

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Appendix 3: Visual Analog Scale (VAS)