Clinical trial NCT02090283
Conditions: Epidermolysis Bullosa
Keywords: Amicus Therapeutics Scioderm, Inc. Recessive Dystrophic Junctional non-Herlitz Epidermolysis Bullosa Simplex SD-101 6% SD-101-6.0 Allantoin 6% Zorblisa
Sponsor: Scioderm, Inc.
Start date: 2014-03-26; Completion date: 2018-09-14
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the continued safety of topical use of SD-101 cream (6%) in participants with Epidermolysis Bullosa (EB).

Funding Source: FDA Office of Orphan Products Development

Detailed description:
This was an open-label extension study to assess the continued safety of topically applied SD-101 dermal cream (6%) in participants with Simplex, Recessive Dystrophic, and Junctional non-Herlitz EB.

SD-101 dermal cream (6%) was applied topically, once a day to the entire body for the duration of the study. Participants who successfully completed the entire SD-003 study (NCT02014376) had the option to roll over into the SD-004 study (NCT02090283). The baseline visit occurred at the final visit date for the SD-003 study. The body surface area (BSA) coverage of blisters and lesions assessment made at the final SD-003 study visit were used as the baseline information at the baseline visit for the SD-004 study. Participants returned to the study site for the following 13 visits (36 months) to have BSA assessed. BSA was assessed at all subsequent scheduled study center visits. Scheduled study center visits occurred every 6 months after Month 36 (Month 42, 48, and so on). After completion of Month 36, the next participant visit (Month 39) was a phone call from the site to the participant. Telephone visits occurred every 6 months thereafter (Month 45, 51, and so on) and included assessment of adverse events and concomitant medications only. For female participants of childbearing potential, a urine pregnancy test was performed at Month 6 and every 6 months up to and including the final study visit.

Arms: arm 1: All participants applied SD-101 dermal cream topically, once a day, to the entire body for the duration of the study.
Interventions: intervention 1: SD-101 dermal cream (6%)
Intervention descriptions: intervention 1: SD-101 is a white, crystalline powder that is formulated within an odorless, soft, white cream base. SD-101-6.0 cream contains allantoin, a diureide glyoxylic acid, at a concentration of 6% and other excipients.

Protocol documents:
Prot_000.pdf: 
Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 1 of 29 
An Open Label Extension, Multi-Center, Study to Evaluate the Safety of SD-101 Cream 
in Subjects with Epidermolysis Bullosa 
IND No: 107480 
Protocol No: SD-004 
Version No: 4 
Date of Protocol: 17 January, 2014 
Amendment 1 Date: 27 February, 2015 
Amendment 2 Date: 2 December 2015 
Amendment 3 Date: 25 January 2017 
Sponsor: Scioderm, INC. 
An Amicus Therapeutics Company 
4601 Creekstone Drive 
Suite 160 
Durham, NC  27703 
Author(s): 
Confidentiality Statement:   
This protocol contains information which is the property of Scioderm, INC. and therefore is 
provided to you in confidence for review by you, your staff, an applicable ethics committee / 
institutional review board and regulatory authorities. It is understood that this information will not 
be disclosed to others without written approval from Scioderm, INC. 
This study will be conducted in compliance with Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), in accordance with local legal and regulatory 
requirements and in compliance with the applicable parts of the United States Code of 
Federal Regulations. 
Amicus


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 2 of 29 
1.
PROTOCOL SYNOPSIS
PROTOCOL TITLE 
An Open Label Extension, Multi-Center, Study to 
Evaluate the Safety of SD-101 Cream in Subjects 
with Epidermolysis Bullosa 
PROTOCOL No. 
SD-004 
VERSION No. 
4 
SPONSOR 
Scioderm, INC 
An Amicus Therapeutics Company 
4601 Creekstone Drive 
Suite 160 
Durham, NC  27703 
INVESTIGATIONAL PRODUCT 
SD-101 cream administration containing 6% 
allantoin 
PHASE OF DEVELOPMENT 
Open Label Extension 
INDICATION AND RATIONALE 
The aim is to assess the continued safety of 
topical use of SD-101 cream containing 6% 
allantoin in subjects with Epidermolysis Bullosa. 
STUDY DESIGN 
This is an open label extension, multi-center, 
study to assess the continued safety of topically 
applied SD-101 cream containing 6% allantoin in 
subjects with Simplex, Recessive Dystrophic, and 
Junctional non-Herlitz Epidermolysis Bullosa. 
SD-101 cream containing 6% allantoin will be 
applied topically, once a day to the entire body for 
the duration of the study. Subjects who 
successfully complete the entire SD-003 study 
will have the option to roll over into the SD-004 
study. The baseline visit 1 will occur at the final 
visit date for SD-003. The Body Surface Area 
(BSA) coverage of blisters and lesions assessment 
made at the final SD-003 study visit will be used 
as the baseline information at visit 1 for the 
SD-004 study. The subject will return to the study 
site once every 3 months for visit 2 (14 days 
±7 days from baseline) through visit 14 
(1080 days ±7 days from baseline) to have Body 
Surface Area (BSA) assessed. Body Surface Area 
will be assessed at all subsequent scheduled study 
center visits. Scheduled study center visits occur 
every 6 months after visit 14 (visits 16, 18, 20, 
etc.). After completion of visit 14, the next subject 
visit (visit 15) will be a phone call from the site to 
the patient. Telephone visits will occur every 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 3 of 29 
6 months thereafter (visits 17, 19, 21, etc.) and 
include assessment of adverse events and 
concomitant medications only. At the 
Investigator’s discretion, the subject may be asked 
to complete a study center visit in place of a 
phone call visit. If a study center visit is 
requested, no additional assessments for that visit 
(other than collection of information on adverse 
events and concomitant medications) will be 
required. Urine pregnancy tests will be performed 
at visit 4 and every 6 months up to and including 
the final study visit. 
STUDY OBJECTIVES 
Primary Objective 
The primary objective is to demonstrate in 
subjects with Simplex, Recessive Dystrophic, and 
Junctional non-Herlitz Epidermolysis Bullosa, the 
continued safety of SD-101 cream containing 6% 
allantoin.   
Secondary Objective 
The secondary objective is to continue to assess 
the change in Body Surface Area (BSA) of 
blisters or lesions. 
PLANNED SAMPLE SIZE 
Approximately 48 subjects are expected to roll 
over from Study SD-003 into this open-label 
extension. 
PATIENT POPULATION 
Inclusion Criteria 
1.
Informed Consent form signed by the subject
or subject's legal representative; if the subject
is under the age of 18 but capable of providing
assent, signed assent from the subject.
2.
Subject (or caretaker) must be willing to
comply with all protocol requirements.
3.
Subjects must successfully complete the
SD-003 study.
PATIENT POPULATION 
Exclusion Criteria 
1.
Subjects who do not meet the entry criteria
outlined above.
2.
Pregnancy or breastfeeding during the study.
(A urine pregnancy test will be performed at
the final visit for SD-003 for female subjects
of childbearing potential).
3.
Females of childbearing potential who are not
abstinent and not practicing a medically
acceptable method of contraception.


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 4 of 29 
FORMULATION/DOSE 
SD-101 cream will be applied topically, once a 
day to the entire body for the duration of the 
study. Application will consist of SD-101 
containing 6% allantoin. 
ROUTE OF ADMINISTRATION 
Topical administration of SD-101 dermal cream 
containing 6% allantoin 
DURATION/FREQUENCY OF 
TREATMENT 
Topical application of SD-101 containing 6% 
allantoin once daily for the duration of the study. 
The planned duration of the treatment will 
vary among subjects and will continue until 
commercialization or availability of an 
alternate access approach or study termination 
by the Sponsor (see Section 8.4 and 
Section 13 for details). 
SAFETY ASSESSMENTS 
The safety of SD-101 containing 6% allantoin will 
be assessed by monitoring tolerability at the 
application sites, adverse events, and periodic 
physical examinations. 
STATISTICAL CONSIDERATIONS 
This study is an open label extension of SD-003 
and will include those patients completing that 
study and wishing to receive SD-101 (allantoin 
6%). In general, results will be summarized using 
descriptive statistics. 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 5 of 29 
2.
TABLE OF CONTENTS
PAGE 
1.
PROTOCOL SYNOPSIS ......................................................................................................... 2
2.
TABLE OF CONTENTS ......................................................................................................... 5
3.
LIST OF ABBREVIATIONS .................................................................................................. 7
4.
ADMINISTRATIVE STRUCTURE ........................................................................................ 8
5.
BACKGROUND INFORMATION ......................................................................................... 9
5.1. 
Overview of Drug Product .......................................................................................... 9 
5.2. 
Summary of Animal and Human Studies with Allantoin ............................................ 9 
6.
RATIONALE FOR STUDY .................................................................................................. 10
7.
STUDY OBJECTIVES AND PURPOSE .............................................................................. 10
7.1. 
Primary Objective ...................................................................................................... 10 
7.2. 
Secondary Objective .................................................................................................. 10 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS .......................................................... 11
8.1. 
Subject Numbers ....................................................................................................... 11 
8.2. 
Inclusion Criteria ....................................................................................................... 11 
8.3. 
Exclusion Criteria ...................................................................................................... 11 
8.4. 
Withdrawal Criteria/Study Discontinuation .............................................................. 11 
8.5. 
Handling of Withdrawals........................................................................................... 12 
9.
STUDY DESIGN ................................................................................................................... 13
9.1. 
Primary Objective ...................................................................................................... 13 
9.2. 
Secondary Objective .................................................................................................. 13 
9.3. 
Study Design ............................................................................................................. 14 
10. STUDY MEDICATION AND ADMINISTRATION ........................................................... 15
10.1. 
Study Medication and Administration ....................................................................... 15 
10.2. 
Selection of Doses in the Study ................................................................................. 15 
10.3. 
Allocation to Treatment ............................................................................................. 15 
10.4. 
Duration of Patient Participation ............................................................................... 15 
10.5. 
Treatment Accountability and Compliance Checks .................................................. 15 
10.6. 
Concurrent Therapy ................................................................................................... 16 
11. STUDY SCHEDULE ............................................................................................................. 17
11.1. 
Efficacy Assessments ................................................................................................ 19 
11.2. 
Safety Assessments ................................................................................................... 19 
11.3. 
Adverse Events .......................................................................................................... 19 
11.4. 
Definitions ................................................................................................................. 19 
11.4.1. 
Assessment of Causality ........................................................................... 21 
11.4.2. 
Adverse Event Reporting .......................................................................... 21 
11.5. 
Concomitant Medications .......................................................................................... 22 
12. STATISTICAL CONSIDERATIONS ................................................................................... 22
12.1. 
Sample Size ............................................................................................................... 22 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 6 of 29 
12.2. 
Study Populations ...................................................................................................... 22 
12.3. 
Analysis Considerations ............................................................................................ 22 
13. END OF THE STUDY ........................................................................................................... 22 
14. ETHICAL CONDUCT OF THE STUDY .............................................................................. 23 
14.1. 
Independent Ethics Committee (IEC) and Relevant Authorities ............................... 23 
14.2. 
Informed Consent ...................................................................................................... 23 
15. STUDY AND DATA MANAGEMENT ............................................................................... 24 
15.1. 
Protocol Amendments ............................................................................................... 24 
15.2. 
Monitoring ................................................................................................................. 24 
15.3. 
Quality Assurance ..................................................................................................... 24 
15.4. 
Data Recording .......................................................................................................... 24 
15.5. 
Data to be Considered as Source Data ....................................................................... 24 
15.6. 
Confidentiality ........................................................................................................... 25 
15.7. 
Retention of Study Data ............................................................................................ 25 
15.8. 
Communication and Publication of Results .............................................................. 25 
16. SIGNATURES AND AGREEMENT WITH THE PROTOCOL .......................................... 26 
17. APPENDICES ........................................................................................................................ 28
17.1. 
Appendix 1 EB Subtypes ........................................................................................... 28 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 7 of 29 
3.
LIST OF ABBREVIATIONS
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BSA 
Body Surface Area 
BSAI 
Body Surface Area Index 
CRF 
Case Report Form 
EB 
Epidermolysis Bullosa 
EBS 
Epidermolysis Bullosa Simplex 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
JEB-nH 
Junctional non-Herlitz EB 
MOA 
Mechanism of Action 
mITT 
Modified-intent-to-treat 
PP 
Per Protocol 
RDEB 
Recessive Dystrophic Epidermolysis Bullosa 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WMA 
World Medical Association 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
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4.
ADMINISTRATIVE STRUCTURE
Medical Expert (Sponsor) 
1 Cedar Brook Drive 
Cranbury, NJ  08512 
1 Cedar Brook Drive 
Cranbury, NJ  08512 
Contract Research Organization 
Monitors 
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC USA 27560 
Amicus
Amicus


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
 Page 9 of 29 
5. 
       BACKGROUND INFORMATION 
There is a dearth of effective agents for skin disorders involving blistering and lesion formation. 
Current approved therapies are minimally effective and have safety issues. Yet an active 
ingredient currently approved for use in topical OTC products, allantoin, is considered safe and 
effective at low concentrations of 0.5% to 2.0% but only as a “skin protectant”. The OTC 
monograph only allows claims that relate to minor cuts, scrapes, burns or chapped skin. Because 
historical data suggest that allantoin may have significant lesion healing properties, we believe 
there may be an unrealized medical opportunity for allantoin at higher concentrations beyond the 
traditional uses as a cosmetic moisturizer or an OTC skin protectant. Allantoin has been cited in 
the literature as being effective in the treatment of various types of ulcers and lesions. However, 
there is a near absence of well-designed clinical studies to investigate the efficacy of allantoin as 
a single active ingredient in humans. One reason that few studies exist exploring the effectiveness 
of allantoin is that it is very insoluble in any aqueous media above a concentration of 0.5%, and 
degrades quickly in ointments or creams. Higher solubility of allantoin in aqueous solutions is pH 
dependent (at pH levels above 12), but at higher pH levels allantoin is unstable and readily 
degrades. Hence, formulation development has been problematic. Scioderm has patented 
technology that overcomes the chemical stability and solubility challenges present when 
formulating allantoin at higher concentrations. 
5.1. 
Overview of Drug Product 
Pharmacology of Allantoin 
Allantoin is the active ingredient contained within SD-101 skin cream, which is a commercially 
viable formulation with demonstrated stability of allantoin for several years at concentrations up 
to 9%. The capacity to deliver the active moiety to the target in skin is key in topical products, 
since the skin is an effective barrier to penetration. Some skin products contain ingredients 
thought to be active but do not provide the desired effect because of failure to cross the skin 
barrier, e.g., topical application of Cyclosporine A for psoriasis. 
Allantoin is a well characterized substance, which is known to be the active component in the 
Comfrey plant, and the active ingredient in the secretions of maggots used for tissue debridement 
and repair. Comfrey and maggots can produce high amounts of allantoin, as high as 10%, 
depending on the portion of plant and time of harvesting. The mechanism of action (MOA) of 
allantoin is complex, including demonstrated healing properties, antibacterial effects, keratolytic 
activity in humans, in addition to anti-inflammatory / soothing properties. 
Pharmacokinetics of Allantoin 
Allantoin is a compound that is found endogenously in rats, rabbits, pigs, dogs, monkeys, in 
addition to a lesser extent in humans. Allantoin is the main end product of purine metabolism in 
most mammals, and is produced from metabolism of uric acid via the enzyme, uricase. In rats and 
other mammals, uricase is present within peroxisomes of liver parenchymal cells. In man and 
great apes, uricase is not present, so that the primary end product of purine metabolism is uric 
acid. However, small amounts of allantoin have been shown to be produced in great apes and 
humans via non-enzymatic conversion of uric acid. 
5.2. 
Summary of Animal and Human Studies with Allantoin 
Toxicology studies assessing topical administration of SD-101 (containing concentrations of 
allantoin up to 9%) in multiple species demonstrated the lack of local or systemic effects with this 
active in the current formulation. The lack of systemic effects with allantoin in animals 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
 Page 10 of 29  
 
administered SD-101 topically was further supported by additional safety information obtained 
with intravenous administration of allantoin in the monkey. Peak intravenous blood levels in the 
monkeys were achieved that were approximately 700 times higher than endogenous levels 
measured in published healthy human subject pharmacokinetic studies, without any demonstrated 
clinical chemistry abnormalities or organ toxicity at either the macroscopic or microscopic level. 
Additional toxicology studies with SD-101 containing 9% allantoin demonstrated that this 
product was non-sensitizing in the guinea pig and did not produce ocular irritation in the rabbit. 
Lastly, from examination of the excipients and the active ingredient, allantoin, for the ability to 
absorb light in the UV-A and / or UV-B ranges, there were no demonstrated concerns of potential 
phototoxicity with use of this product. 
Studies in normal volunteers with topical use of SD-101 (containing 3, 6, or 9% allantoin), and in 
EB patients with topical usage of SD-101 (containing 1.5% or 3% allantoin) demonstrate to date 
that allantoin at these concentrations (in this formulation) has not produced any local or systemic 
adverse effects of concern. In addition, topical administration of SD-101 (containing 1.5% 
allantoin) was found to be non-sensitizing in healthy subjects. Studies in human subjects or EB 
patients (including children) with SD-101 containing allantoin concentrations above 3% have not 
been conducted to date. However, the lack of local or systemic safety effects demonstrated in 
animals to date with topical SD-101 administration (containing up to 9% allantoin) or systemic 
administration of allantoin (achieving high systemic exposure), suggest that topical 
administration of SD-101 in healthy subjects (containing allantoin at concentrations greater than 
3%) should be well tolerated. 
An open-label study using SD-101 (containing a 3.0% concentration of allantoin) was previously 
conducted. Eight EB subjects with a diagnosis of EB (Simplex, Recessive Dystrophic, or 
Junctional) based on diagnostic immunomapping or electron microscopy, were treated with 3% 
SD-101 cream applied once daily to their entire skin surface, for a period up to 3 months. 
Application of the cream was non-irritating and did not produce any discomfort when applied to 
either unblistered areas or open lesions. The patients treated with 3% SD-101 for three months 
showed significant improvements in the complete healing of lesions (typified by the results with 
the target lesions), statistically significant and clinically meaningful reductions in the extent of 
total skin surface involvement with active disease (BSA), and reduced pain and itching. Daily use 
of 3% SD-101 cream in treatment up to 3 months was well tolerated by all patients in the study, 
with no related adverse events noted. There were no serious adverse events that occurred in any 
patient during the 3 month treatment period. 
6. 
RATIONALE FOR STUDY 
The aim is to assess the continued safety of SD-101 cream (6% allantoin) in the treatment of 
subjects with Epidermolysis Bullosa. 
7. 
STUDY OBJECTIVES AND PURPOSE 
7.1. 
Primary Objective 
The primary objective is to demonstrate in subjects with Simplex, Recessive Dystrophic, and 
Junctional non-Herlitz Epidermolysis Bullosa, the continued safety of SD-101 cream containing 
6% allantoin. 
7.2. 
Secondary Objective 
The secondary objective is to continue to assess the change in Body Surface Area (BSA) of 
blisters or lesions. 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
 Page 11 of 29  
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Numbers 
Up to forty-eight EB patients are expected to be enrolled at seven study centers, following 
completion of their participation in Study SD-003. 
8.2. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study. 
1. Informed Consent form signed by the subject or subject's legal representative; if 
the subject is under the age of 18 but capable of providing assent, signed assent 
from the subject. 
2. Subject (or caretaker) must be willing to comply with all protocol requirements. 
3. Subjects must successfully complete the entire SD-003 study. 
8.3. 
Exclusion Criteria 
Subjects with any of the following exclusion criteria will not be eligible for enrollment into the 
study. 
1. Subjects who do not meet the entry criteria outlined above. 
2. Pregnancy or breastfeeding during the study. (A urine pregnancy test will be performed 
at the final visit for SD-003 for female subjects of childbearing potential). 
3. Females of childbearing potential who are not abstinent and not practicing a medically 
acceptable method of contraception.  
8.4. 
Withdrawal Criteria/Study Discontinuation 
Subjects may withdraw from the study at any time without stating a reason and without prejudice 
to further treatment. The Investigator may withdraw a subject from the study and discontinue 
study treatment and assessments at any time due to safety concerns. Full skin examination will be 
performed at each scheduled study center visit. If SD-101 causes any significant rash that has not 
occurred previously in the subject, the Investigator should consider discontinuing the subject. In 
addition, if lesions appear to significantly worsen above the normal cycle seen in the patient, with 
use of SD-101, the Investigator should consider discontinuing the subject.    
Early discontinuation of any subject who has given informed consent / assent to participate will 
be recorded including the reason for discontinuation. The primary reason for a subject 
withdrawing prematurely will be selected from the following standard categories of early 
discontinuations. 
1. Adverse Event (Adverse Reaction): Clinical events occurred that are reported that in the 
medical judgment of the Investigator are grounds for discontinuation in the best interests of 
the subject. 
2. Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study. The subject is not obligated to provide any reason for withdrawal of consent, but 
where a reason is given this will be recorded on the eCRF. 
3. Protocol Violation: The subject failed to adhere to the protocol requirements, at the 
Investigator’s discretion. 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
 Page 12 of 29  
 
4. Lost to Follow-Up: The subject stopped coming for visits and study personnel were 
unable to contact the subject. 
5. Other: The subject was terminated for a reason other than those listed above, such as, 
termination of study by Sponsor. 
8.5. 
Handling of Withdrawals 
Although a subject is not obligated to give his/her reason for withdrawing prematurely, the 
Investigator will make a reasonable effort to obtain the reason while fully respecting the subject’s 
rights. If there is a medical reason for withdrawal, the subject will remain under the supervision 
of the study physician until in satisfactory health. In the case of withdrawal due to an adverse 
event, the subject will be followed per Section 11.3. Reasonable efforts will be made to contact a 
subject who fails to attend any follow-up appointments, in order to ensure that he/she is in 
satisfactory health.   


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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9. 
STUDY DESIGN 
9.1. 
Primary Objective 
The primary objective is to demonstrate in subjects, with Simplex, Recessive Dystrophic, and 
Junctional non-Herlitz Epidermolysis Bullosa, the continued safety of SD-101 cream containing 
6% allantoin. 
9.2. 
Secondary Objective 
• 
Body coverage in blisters or lesions based on body surface area (BSA) measurements at 
Baseline (end of Study visit measurement from Study SD-003) week 2, month 3, 
month 6, month 9, month 12, month 15, month 18, month 21, month 24, month 27, 
month 30, month 33, and month 36, and each subsequent scheduled study center visit will 
be measured using the following: 
Body Surface Area Index (BSAI) is a global measure of disease “spread” with weighting 
factors. The BSA affected with lesional skin will be calculated at Baseline and at each 
scheduled study center visit to assess the total affected area before and after using the 
product.    
BSAI of Lesional Skin Calculation Charts 
(check only one box and complete the appropriate sections for each region) 
1  Ages 0 to 7 years                                                                                               
  Column 1         Column 2 
      Column 3       Column 4                 Column 5 
    
Region 
Number 
Region 
Description 
Regional BSA 
% that is 
affected* 
Weighting 
Factor 
Total BSA % that is 
affected ** 
1 
Head / Neck 
 
x .2 
 
2 
Upper Limbs 
 
x .2 
 
3 
Trunk (includes 
groin) 
 
x .3  
 
4 
Lower Limbs 
 
x .3  
 
 
 
 
TOTAL 
 
 
 
 
 


Investigational product: 
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Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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2  Age 8 years or greater 
  Column 1         Column 2 
      Column 3       Column 4                 Column 5 
    
Region 
Number 
Region 
Description 
Regional BSA 
% that is 
affected* 
Weighting 
Factor 
Total BSA % that is 
affected ** 
1 
Head / Neck 
 
x .1 
 
2 
Upper Limbs 
 
x .2 
 
3 
Trunk (includes 
groin) 
 
x .3 
 
4 
Lower Limbs 
 
x .4 
 
 
 
 
TOTAL 
 
 
*For each region, enter the % of BSA that is affected with blisters and/or lesions. Score 
each region separately from 0% - 100%. 
**Multiply the value in column 3 by the factor in column 4. The Total value at the 
bottom of the table is the sum of Column 5 values for each region. 
 
9.3. 
Study Design 
This is an open label extension, multi-center study to assess the continued safety of SD-101 
cream (containing 6% allantoin) in treating subjects with Simplex, Recessive Dystrophic, and 
Junctional non-Herlitz Epidermolysis Bullosa. 
 
SD-101 cream (containing 6% allantoin) will be applied topically, once a day to the entire body 
for the duration of the study. Subjects who successfully complete the SD-003 study will be 
eligible to roll over into the SD-004 study. The baseline visit 1 will occur at the final visit date 
for SD-003. The BSA assessment from the final SD-003 study will be used as the baseline 
information at visit 1 for the SD-004 study. The subject will return to the study site once every 
3 months for visit 2 (14 days ±7 days from baseline) through visit 14 (1080 days ±7 days from 
baseline) to have BSA assessed. Body Surface Area will be assessed at all subsequent scheduled 
study center visits. Scheduled study center visits occur every 6 months after visit 14 (visits 16, 
18, 20, etc.). After completion of visit 14, the next subject visit (visit 15) will be a phone call 
from the site to the patient. Telephone visits will occur every 6 months thereafter (visits 17, 19, 
21, etc.) and include assessment of adverse events and concomitant medications only. At the 
Investigator's discretion, the subject may be asked to complete a study center visit in place of a 
phone call visit. If a study center visit is requested, no additional assessments (other than 
collection of information on adverse events and concomitant medications) will be required (see 
Section 11 – Study Schedule for details). 
All females of childbearing potential must have a negative urine pregnancy test prior to enrolling 
in the study and must agree to use some form of birth control or agree to remain abstinent until 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
 Page 15 of 29  
 
the study is completed. Since a pregnancy test will be performed at the final visit for SD-003, the 
results from that test can be utilized for entry into the SD-004 study. In addition, a urine 
pregnancy test will be performed every 6 months and at the final visit. 
Safety assessments will include monitoring of tolerability, adverse events, and physical 
examinations.   
10. 
STUDY MEDICATION AND ADMINISTRATION 
10.1. 
Study Medication and Administration 
The SD-101 cream (containing 6% allantoin) concentrations will be supplied in 8 ounce tubes, to 
be reclosed after use and stored at room temperature. 
SD-101 dermal cream (containing 6% allantoin) will be applied once a day to the entire body for 
the duration of the study.  
The study cream will be returned during each study center visit to evaluate compliance. Any 
unused study medication will be re-dispensed to the patient at each visit. 
Additional information on the composition of the SD-101 dermal cream is contained in the 
SD-101 Investigator’s Brochure. 
10.2. 
Selection of Doses in the Study 
SD-101 dermal cream (containing 6% allantoin) will be applied topically once a day to the entire 
body.  
10.3. 
Allocation to Treatment 
Up to forty-eight subjects may be eligible to roll over to this study and receive SD-101 
(containing 6% allantoin). 
10.4. 
Duration of Patient Participation 
The planned duration of the treatment will vary among subjects and will continue until 
commercialization or availability of an alternate access approach or study termination by the 
Sponsor (see Section 8.4 and Section 13 for additional details). 
10.5. 
Treatment Accountability and Compliance Checks 
The Sponsor or Designee will be responsible for performing drug accountability for the dermal 
cream. The medication provided for this study is for use only as directed in the protocol. It is the 
Investigator / Institution’s responsibility to establish a system for handling study treatments, 
including investigational medicinal products, so as to ensure that: 
• 
Deliveries of such products are correctly received by a responsible person 
• 
Such deliveries are recorded 
• 
Study treatments are handled and stored safely and properly as stated on the label 
• 
Study treatments are only dispensed to study patients in accordance with the protocol 
• 
Any unused products will be destroyed in accordance with CRO processes 


Investigational product: 
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Protocol No.: SD-004 
SD-101 Dermal Cream  
Scioderm, INC. 
25 January 2017 (Version 4) 
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At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed stock. Records of usage should include the identification of the person to whom the 
study treatment was dispensed, the quantity of the study cream and date of dispensing and 
re-dispensing. This record is in addition to any drug accountability information recorded on the 
eCRF. Any discrepancies must be accounted for on the appropriate forms. Certificates of initial 
and any subsequent deliveries and destruction must be signed, preferably by the Investigator or a 
pharmacist, and copies retained in the Investigator Site File. 
10.6. 
Concurrent Therapy 
Medications considered necessary for the subject’s welfare (intercurrent illness or AEs) may be 
given at the discretion of the Investigator. The Investigator should consider the necessity of any 
therapy before prescribing it to the patient. Subjects must be instructed not to take any 
medications without prior consultation with the Investigator, as feasible. The administration of 
all such medication / therapy must be recorded in the appropriate section of the eCRF and will be 
assessed at each visit. 


Investigational product: 
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Protocol No.: SD-004 
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11. 
STUDY SCHEDULE 
Procedure 
Visit 
 
1 
Screening/ 
Baseline 
 
2 
Week 2 
 
3 
Month 
3 
 
4 
Month 
6 
 
5 
Month 
9 
 
6 
Month 
12 
 
7, 9, 11, 
and 13 
Months 
15, 21, 27, 
and 33 
 
8, 10, 12, 
and 14 
Months 
18, 24, 30,  
and 36 
 
15 
(odd 
visits) 
Month 
39 
 
Phone 
Call 
 
16 
(even 
visits) 
Month 
42 
 
Site 
Visit 
 
Alternate  
Phone Call and 
Site Visit until 
Final Study 
Visit/Early 
Terminationa 
 
Final Study 
Visit/Early 
Termination 
Study Day  
(± 7 Days)  
0 
14 
90 
180 
270 
 
360 
450, 630, 
810, and 
990 
540, 720, 
900, and 
1080 
1170 
1260 
- 
- 
Informed consent / 
assent signed 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
assessment  
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic, medical 
and medication history 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Physical examinationb 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height, weight, and 
temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 
Assess BSAc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urine pregnancy test 
(females only)d 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense/re-dispense  
SD-101 creame 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Collect SD-101 cream 
for the purpose of drug 
accountability 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Collect all SD-101 
cream 
 
 
 
 
 
 
 
 
 
 
 
X 


Investigational product: 
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Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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Procedure 
Visit 
 
1 
Screening/ 
Baseline 
 
2 
Week 2 
 
3 
Month 
3 
 
4 
Month 
6 
 
5 
Month 
9 
 
6 
Month 
12 
 
7, 9, 11, 
and 13 
Months 
15, 21, 27, 
and 33 
 
8, 10, 12, 
and 14 
Months 
18, 24, 30,  
and 36 
 
15 
(odd 
visits) 
Month 
39 
 
Phone 
Call 
 
16 
(even 
visits) 
Month 
42 
 
Site 
Visit 
 
Alternate  
Phone Call and 
Site Visit until 
Final Study 
Visit/Early 
Terminationa 
 
Final Study 
Visit/Early 
Termination 
Monitor adverse 
events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Monitor use of 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
a. 
After completion of visit 14, the subject will return to the site once every 6 months (visits 16, 18, 20, etc.), with the intermittent 3 month visits conducted via telephone (visits 15, 
17, 19, etc.). Telephone visits will include assessment of adverse events and concomitant medications only. At the Investigator’s discretion, the subject may be asked to complete a 
study center visit in place of a phone call visit. If a study center visit is requested, no additional assessments (other than collection of information on adverse events and 
concomitant medications) will be required. 
b. 
A complete physical examination will be performed at the final visit. The physical examination performed at the final visit for SD-003 will be utilized as the baseline assessment 
for SD-004. 
c. 
The BSA assessment will be performed at visits 2 through 14 and at all subsequent scheduled study center visits. The BSA assessment performed at the final visit for SD-003 will 
be utilized as the baseline assessment for SD-004. 
d. 
Urine pregnancy test will be performed at visits 4, 6, 8, 10, 12, 14, and at all subsequent scheduled study center visits. The urine pregnancy test performed at the final visit for 
SD-003 will be utilized for entry into SD-004. 
e. 
Re-dispense any unused SD-101 cream. Ensure the subject is dispensed sufficient SD-101 cream until the next study visit. 
 
 
 


Investigational product: 
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Protocol No.: SD-004 
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25 January 2017 (Version 4) 
 
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11.1. 
Efficacy Assessments 
The body surface coverage (BSA) of lesional skin will be measured during the study to monitor 
the extent of coverage with extended use of SD-101 (containing 6% allantoin). 
11.2. 
Safety Assessments 
The safety of SD-101 dermal cream (containing 6% allantoin) applied to the skin, will be 
assessed by monitoring tolerability at the application sites, adverse events, and physical 
examinations. 
For timing of individual measurements, refer to Section 11 - Study Schedule. 
Physical Examination including height, weight, and temperature 
Physical examinations will be done by a physician at the final study visit. The physical 
examination performed at the final visit for SD-003 will be utilized as the baseline assessment for 
SD-004. The following sites will be examined: head, eyes, ears, nose, throat, neck, chest, lungs, 
heart, abdomen, skin, and lymph nodes; and the following systems will be assessed: 
musculoskeletal and neurological. Weight, height, and temperature will be recorded. 
Urinalysis 
Urine pregnancy test for female subjects of child bearing potential (sensitivity at least 
25 mIU/mL) will be performed at visits 4, 6, 8, 10, 12, 14, and at all subsequent study center 
visits. The urine pregnancy test performed at the final visit for SD-003 will be utilized for entry 
into SD-004. 
11.3. 
Adverse Events 
Adverse events may be volunteered spontaneously by the patient or discovered as a result of 
general, non-leading questioning. All adverse events should be recorded in the Case Report Form. 
Adverse events will be collected after signing the informed consent / assent at all visits through 
the final study visit. Information on AEs will be followed to 30 days after the last dose of study 
drug has been administered. 
In the case of withdrawal due to an AE/SAE, the patient will be followed until resolution of the 
AE, or until in the opinion of the Investigator the event has stabilized, or the Investigator does not 
expect any further improvement or worsening of the subject’s condition, and the patient is 
referred to their primary physician for appropriate management of the ongoing event. Reasonable 
efforts will be made to contact a patient who fails to attend any follow-up appointments, in order 
to ensure that he/she is in satisfactory health. 
11.4. 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a patient, administered a medicinal product and which does 
not necessarily have to have a causal relationship with this treatment. An adverse event (AE) can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
 Page 20 of 29  
 
whether or not considered related to the medicinal product. AEs may include the onset of new 
illness and the exacerbation of pre-existing conditions. 
The routine evolution of the disease condition under treatment according to the protocol will be 
evaluated as part of the disease symptoms assessments. Changes in the disease condition may not 
qualify as AEs. However, if there is a clinically relevant worsening of a sign or symptom of the 
condition under treatment and the outcome fulfills the definition of an AE, it must be reported as 
directed in the protocol. 
Adverse Drug Reaction (ADR) 
All events considered to be noxious and unintended responses to a medicinal product related to 
any dose should be considered adverse drug reactions, with the exception of skin site changes 
determined by the Investigator to be related to SD-101 dermal cream. These changes will be 
captured during the skin site evaluations (refer to Section 9.3). The phrase “responses to a 
medicinal product” means that a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
Serious Adverse Event (SAE) 
An adverse event that at any dose: 
• 
Results in death 
• 
Is life-threatening (i.e. the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
• 
Results in hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly / birth defect 
• 
Is considered to be an important medical event 
Based upon medical and scientific judgment, important medical events that may not be 
immediately life-threatening, or result in death or hospitalization, but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above 
may be considered a serious adverse event. 
Hospitalizations are defined as initial or prolonged admissions that include an overnight stay. 
Hospitalization or prolonged hospitalization for technical, practical or social reasons, in the 
absence of an adverse event is not an SAE. 
Pregnancy 
Pregnancy itself is not considered an AE. Pregnancies will be reported and documented on a 
separate pregnancy report form provided to the sites. However, any pregnancy complication, 
spontaneous or elective abortion, still birth, neonatal death, or congenital anomaly will be 
recorded as an AE or SAE. 
Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational medicinal product). 


Investigational product: 
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Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse event that is suspected to be related to the administered medicinal 
product and the nature or severity of which is not consistent with applicable product information. 
11.4.1. 
Assessment of Causality 
Severity 
The severity (intensity) of each adverse event will be classified by the Investigator as: 
• 
Mild 
Awareness of sign of symptom, but easily tolerated 
• 
Moderate 
Sign or symptom causes discomfort, but does not interfere 
with normal activities 
• 
Severe 
Sign or symptom of sufficient intensity to interfere with 
normal activities 
Causality 
 
The likely relationship of each adverse event to the medicinal product will be assessed by the 
Investigator and reported according to the definitions below: 
 
• 
Unrelated  
- Event occurred before dosing or  
- Event or intercurrent illness due wholly to factors other than 
drug treatment. 
• 
Possibly 
- Reasonable temporal relationship with drug treatment.  
- Event could be explained by patient’s clinical state or other 
factors. 
• 
Probably 
- Reasonable temporal relationship with drug treatment.  
- Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology.  
- Event cannot easily be explained by patient’s clinical state or 
other factors. 
• 
Definitely 
- Distinct temporal relationship with drug treatment.  
- Known reaction to agent or chemical group, or predicted by 
known pharmacology.  
- Event cannot be explained by patient’s clinical state or other 
factors. 
11.4.2. 
Adverse Event Reporting 
The Investigator shall immediately report any serious adverse event that occurs to the Sponsor. 
Immediate reporting allows the Sponsor to take the appropriate measures to address potential new 
risks in a clinical trial. Therefore, the immediate report should be made by the Investigator within 
a very short period of time and under no circumstances should this exceed 24 hours following 
knowledge of the serious adverse event. 
The Sponsor is required to expedite the reporting to all concerned Investigators / Institutions, to 
the IRBs, where required, and to the regulatory authorities of all adverse drug reactions (ADRs) 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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that are serious, unexpected and reasonably associated with the investigational product as 
assessed by the Sponsor. Such expedited reports should comply with the applicable regulatory 
requirements and with the ICH Guideline for Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting (E2A).  
The Sponsor will submit to the regulatory authorities all safety updates and periodic reports, as 
required by applicable regulatory requirements. 
11.5. 
Concomitant Medications 
All concomitant medications and non-drug therapies will be recorded. In addition, concomitant 
medications and non-drug therapies will be coded for those subjects that experience adverse 
events. 
12. 
STATISTICAL CONSIDERATIONS 
12.1. 
Sample Size 
All patients who complete the basic protocol SD-003 and who wish to receive SD-101 
(containing 6% allantoin) will be eligible to enter this open label extension. 
12.2. 
Study Populations 
Study populations are the same as defined for SD-003. 
12.3. 
Analysis Considerations 
This study is an open label extension of SD-003 and will include those patients completing that 
protocol and wishing to receive SD-101 (containing 6% allantoin). In general, results will be 
summarized using descriptive statistics. Additional evaluations may be made to compare 
responses of patients in this extension study with their responses in SD-003. 
13. 
END OF THE STUDY 
The end of the study will be defined as the last patient’s last visit. 
The study will be terminated early if, in the opinion of the Sponsor, Investigators, or IRBs/ECs, 
an unacceptable risk to the safety and welfare of subjects is posed by the continuation of the study 
in light of review of the key unexpected adverse events occurring during the trial. 
Within the provisions of informed consent / assent and good clinical judgment with respect to 
safety, every attempt will be made to have subjects complete the study. 
The following reasons are grounds to terminate a subject’s participation in the study: 
1. Subject develops intolerable adverse effects, including but not limited to: 
• 
Severe and widespread dermatological reactions beyond the area of application. 
• 
Severe local reactions requiring systemic steroid therapy. 
2. Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment when 
the circumstances increase risk to the subject or substantially compromise the 
interpretation of study results. 
3. The subject’s health would be jeopardized by continued participation. 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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4. Investigator judgment deems it appropriate. 
5. The subject wishes to withdraw for any reason. 
6. The Sponsor elects to end the study, or any portion thereof, for any reason. 
7. If SD-101 becomes commercially available, the Sponsor may transition subjects to 
commercial drug supply. 
14. 
ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki and in compliance with the protocol, International Conference on Harmonisation [ICH] 
GCP, and applicable local legal and regulatory requirements (including ICH guidelines, the 
European Union Clinical Trials Directive 2001/20/EC, the GCP Directive 2005/28/EC, the 
requirements of local IEC/IRB, and the US Code of Federal Regulations, Title 21 CFR Part 50, 
54, 56 and 312). 
14.1. 
Independent Ethics Committee (IEC) and Relevant Authorities 
This protocol and the subject informed consent form (ICF) must be reviewed and approved by an 
institutional review board (IRB)/independent ethics committee (IEC) complying with the 
requirements of 21 CFR Part 56 and local regulatory requirements before subject enrollment at 
each site. The letter (or certificate of approval) from the IRB/IEC must be received by the 
Sponsor or its designee prior to delivery of clinical supplies. The IRB/IEC will be notified of any 
SAE or suspected unexpected serious adverse reaction in accordance with local regulatory 
requirements. 
Any changes to the study design will be formally documented in protocol amendments and 
approved by the IRB prior to implementation, except in the case of changes made to protect 
patient safety, which will be implemented immediately. 
Clinical Trial Authorization will be obtained prior to initiation of the study from the U.S. Food 
and Drug Administration. 
14.2. 
Informed Consent  
The principles of informed consent in the Declaration of Helsinki, in ICH Good Clinical Practice 
and in US 21 CFR Part 50 (Protection of Human Subjects) will be implemented before any 
protocol-specified procedures or interventions are carried out. 
A signed informed consent / assent form (ICF) shall be obtained from each patient and/or legal 
guardian if under 18 years of age prior to entering the study. The Investigator is responsible for 
obtaining written informed consent / assent from the patient and or legal guardian after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study and 
before any protocol specific screening procedures or any study medications are administered. 
Information should be given in both oral and written form whenever possible and deemed 
appropriate by the IRB. Patients will also be asked to consent to allow the Sponsor, Sponsor 
representative or external regulatory auditor to review their medical records to confirm 
compliance with GCP. 
The acquisition of informed consent / assent should be documented in the patient’s medical 
record and the ICF should be signed and personally dated by the patient and or legal guardian and 
by the person who conducted the informed consent / assent discussion (not necessarily by the 
Investigator). The original signed ICF should be retained in the Investigator Site File and a copy 
of the signed consent should be provided to the patient prior to participation in the trial. 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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The patient will be informed that they may withdraw from the study at any time without prejudice 
to further treatment. They will receive all information that is required by local regulations and 
ICH guidelines. 
15. 
STUDY AND DATA MANAGEMENT 
15.1. 
Protocol Amendments 
No amendments to the protocol will be implemented prior to agreement from the Sponsor, and 
prior to approval from appropriate authorities. 
15.2. 
Monitoring 
The study monitor will review the progress of the study on a regular basis to ensure adequate and 
accurate data collections. Monitoring site visits to review eCRFs, patient case notes, and 
administrative documentation including the Investigator Site File and frequent telephone 
communications with site will be performed throughout the study. 
At each study monitoring visit the Investigator will make available all records pertaining to the 
study. To allow sufficient time to assemble documentation for the study monitor, monitoring 
visits will be confirmed in advance of planned visits. 
All communications, between the Sponsor, designated study representative, and Investigator 
should be documented for the study file. 
15.3. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the 
investigator[s]/institution[s] will permit study-related audits, IRB/IEC review, and regulatory 
inspection[s], providing direct access to source data/documents. 
The Sponsor or Sponsor representative or external regulatory agency may at any time during or 
after completion of the study conduct a Good Clinical Practice (GCP) audit. 
Prior notice will be given to each site selected for audit in advance of a planned GCP audit. 
15.4. 
Data Recording 
The Investigator has the responsibility for ensuring that all source documents (i.e., study and/or 
medical records) are completed and maintained according to the study protocol, and are available 
at the site. 
15.5. 
Data to be Considered as Source Data 
The following are considered source data: Informed consents, laboratory reports, patient files, and 
IMP accountability list. 
The following information must be entered in the patient’s file: 
- 
Patient’s name, address and date of birth 
- 
Subject’s weight, height, and temperature 
- 
Medical history 
- 
Concomitant medication 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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- 
Unambiguous reference to the clinical study (clinical study number, screening number 
and patient number) 
- 
Information on main selection criteria (diagnosis) 
- 
Dates of study drug administration, and tube count of study drug obtained at each visit 
indicated  
- 
Date of informed consent / assent 
- 
Physical examinations and results done at the appropriate visits  
- 
Dates and time of urine pregnancy test 
- 
Did AE(s) occur, improve or worsen? 
- 
Date of discontinuation / completion of the clinical study   
- 
For subjects that are lost to follow-up, the site is to document attempts made to contact 
the subject i.e., telephone, email, certified letter 
All other data recorded directly in the eCRF [i.e., no prior written or electronic record of data] 
will be considered as source data. 
15.6. 
Confidentiality 
The Investigator must assure that the patients’ anonymity will be maintained. On all study 
documentation, with the exception of the consent form and patient ID logs, patients will only be 
identified by their unique identification code and initials and will not be referred to by name. 
15.7. 
Retention of Study Data 
The Investigator is required to maintain all study documentation, including regulatory documents, 
copies of eCRFs, signed informed consent forms, and records for the receipt and disposition of 
study medications, for a period of two years following approval date of a New Drug Application 
for the drug, or until 15 years after completion of the study, whichever is later. 
During the study, the Investigator must make study data accessible to the Sponsor, IRB and the 
Food and Drug Administration. A file for each patient must be maintained that includes the 
signed informed consent / assent form and copies of all source documentation related to that 
patient. The Investigator must ensure the availability of source documents from which the 
information on the eCRF was derived. 
15.8. 
Communication and Publication of Results 
The results of the study will be presented in an integrated Clinical Study Report according to 
GCP. 
The results from the study will be presented to the principal investigators when the statistical 
analyses have been completed. On the basis of these data, the CRO in cooperation with the 
sponsor, will write and report on the trial. 
A summary of the Clinical Study Report will be sent to the regulatory authorities and to the IRB 
after termination of the study. 
The Clinical Study Report shall form the basis for a manuscript intended for publication in an 
international, scientific journal at a suitable time agreed to by the Sponsor. 
No data from the study will be published, presented, or communicated without the mutual 
agreement of the Sponsor. 


Amicus
Amicus
Amicus


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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Principal Investigator Approval 
I agree to conduct the study according to the terms and conditions of this protocol, current Good 
Clinical Practice and with applicable regulatory requirements. All information pertaining to the 
study shall be treated in a confidential manner. 
 
 
 
 
Signature: 
________________________ 
 
Date: 
                                         
 
 
Name of Principal Investigator 
 
 
Title 
 
 
 
Printed:  
________________________ 
 
Name of Principal Investigator 


Investigational product: 
CONFIDENTIAL 
Protocol No.: SD-004 
SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
 Page 28 of 29  
 
17. 
APPENDICES 
17.1. 
Appendix 1 
EB Subtypes 
Clinical Features of EB 
Epidermolysis Bullosa Simplex (EBS) 
EBS Subtypes  
Features  
Weber-Cockayne  
• 
Most common and localized form of EBS.  
• 
Blisters develop on hands and feet in response to friction.  
• 
Usually presents in infancy as child is starting to crawl and walk.  
• 
Lesions heal without scarring but there may be thickening of the 
skin on soles and palms.  
Koebner  
• 
Generalized EBS where blisters develop all over the body but 
commonly on hands, feet and extremities.  
• 
Presents at birth or early in infancy.  
• 
May be mild involvement of mucous membranes and nails.  
• 
Thickening of skin and plaques develop on palms and soles.  
Dowling-Meara  
• 
Generalized and severe form of EBS.  
• 
Presents at birth with blistering on the face, trunk and limbs.  
• 
Thickened skin may cause calluses that limit or interfere with joint 
movement.  
• 
Nails often affected.  
• 
May involve other organs including inside the mouth, 
gastrointestinal and respiratory tract.  
• 
Widespread involvement may cause death in infancy but usually 
there is significant improvement with age.  
EB with muscular 
dystrophy  
• 
Due to plectin mutation.  
• 
Variable degree of blistering followed later in life by muscular 
dystrophy.  
• 
Muscular dystrophy does not arise in all cases with plectin 
mutation.  
 
 
 


Investigational product: 
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SD-101 Dermal Cream  
 
Scioderm, INC. 
 
 
25 January 2017 (Version 4) 
 
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Recessive Dystrophic Epidermolysis Bullosa (RDEB) 
DEB Subtypes  
Features  
Recessive DEB  
• 
May present with severe blistering (Hallopeau-Siemens) or mild 
disease (non-Hallopeau-Siemens).  
• 
Generalized severe blistering is more common and involves large 
areas of skin and mucous membranes.  
• 
Blisters heal but with scarring and deformity causing limited 
movement as fingers and toes may be fused together (mitten 
hands).  
• 
Complications such as infection, malnutrition and dehydration may 
cause death in infancy and those that survive are at great risk of 
developing squamous cell carcinoma.  
• 
Milia (small white cysts) are often present at healed but scarred 
sites. 
 
Junctional Epidermolysis Bullosa (JEB) 
JEB Subtypes  
Features  
Non-Herlitz JEB  
• 
Generalized blistering and mucosal involvement present at birth or 
soon after.  
• 
Scalp, nails and teeth involved.   
• 
Often sparse hair. 
• 
Complications such as infection, malnutrition and dehydration may 
cause death in infancy but many survive.  
 

SAP_001.pdf: 
Protocol SD-004 
 
An Open Label Extension, Multi-Center, Study to Evaluate the Safety of 
SD-101 Cream in Subjects with Epidermolysis Bullosa 
 
Statistical Analysis Plan 
 
 
Final Version 2.0 
Date 20Dec2018 
 
 
Confidential 
 
 
 
Sponsor: 
Scioderm, Inc. 
An Amicus Therapeutics Company 
4601 Creekstone Drive 
Suite 160 
Durham, NC 27703 
 
 
The information in this document is the property of Amicus Therapeutics, Inc. and is 
strictly confidential. Neither the document nor the information contained herein may be 
reproduced or disclosed outside of Amicus Therapeutics, Inc. without the prior consent of 
the company. 


Statistical Analysis Plan 
Scioderm, INC. 
Protocol: SD-004 
Final 2.0 
PCN: VPF0001 
20December2018 
Page 2 of 25 
REVISION HISTORY 
Version 
Date 
Revision Author 
Comments 
Draft 0.2 
30June2016 
Initial release 
Final 1.0 
26July2017 
Updates based on protocol 
amendment 3 and standard safety 
text. Updates of safety section for 
consistency with pivotal study 
SD-005. 
Final 2.0 
20December2018 
Updates based on Dear Doctor 
Letter of June 4, 2018. Deletion 
of analysis of skin reactions and 
concomitant medication of 
interest. 
Amicus


Amicus
Amicus
Amicus


 
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TABLE OF CONTENTS 
REVISION HISTORY.....................................................................................................................2 
SIGNATURE PAGE .......................................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...............................7 
2. 
INTRODUCTION ........................................................................................................8 
3. 
STUDY OBJECTIVE ...................................................................................................8 
4. 
STUDY DESIGN .........................................................................................................8 
4.1. 
General Design .............................................................................................................8 
4.2. 
Method of Assignment of Subjects to Treatment Groups ............................................8 
4.3. 
Blinding ........................................................................................................................9 
4.4. 
Determination of Sample Size ......................................................................................9 
5. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS ...................................................................................................................9 
5.1. 
Changes in the Conduct of the Study ...........................................................................9 
5.2. 
Changes from the Analyses Planned in the Protocol/CIP ............................................9 
6. 
BASELINE, EFFICACY, AND SAFETY EVALUATIONS ......................................9 
6.1. 
Schedule of Evaluations ...............................................................................................9 
6.2. 
Time Point Algorithms ...............................................................................................13 
6.2.1. 
Study Day ...................................................................................................................13 
6.2.2. 
Windows .....................................................................................................................13 
6.3. 
Baseline Definition and Assessments .........................................................................14 
6.3.1. 
Baseline Definition .....................................................................................................14 
6.3.2. 
Baseline Assessments .................................................................................................14 
6.4. 
Efficacy Assessments .................................................................................................15 
6.4.1. 
Change in Body Surface Area Index (BSAI) .............................................................15 
6.5. 
Safety Assessments .....................................................................................................15 
6.5.1. 
Extent of Exposure and Compliance to Study Treatment ..........................................15 
6.5.2. 
Adverse Events ...........................................................................................................15 
6.5.3. 
Clinical Laboratory Evaluations .................................................................................16 
6.5.4. 
Physical Examination Including Height/Length, Weight, and Temperature ..............16 


 
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7. 
STATISTICAL METHODS .......................................................................................17 
7.1. 
General Methodology .................................................................................................17 
7.2. 
Adjustments for Covariates ........................................................................................17 
7.3. 
Handling of Dropouts or Missing Data ......................................................................17 
7.4. 
Multi-center Studies and Pooling of Centers ..............................................................17 
7.5. 
Multiple Comparisons/Multiplicity ............................................................................17 
7.6. 
Examination of Subgroups .........................................................................................18 
8. 
STATISTICAL ANALYSIS ......................................................................................18 
8.1. 
Disposition of Subjects ...............................................................................................18 
8.2. 
Protocol Deviations ....................................................................................................18 
8.3. 
Analysis Populations ..................................................................................................18 
8.3.1. 
Intent-to-Treat (ITT) Population .................................................................................18 
8.3.2. 
Safety Population ........................................................................................................18 
8.4. 
Demographic and Other Baseline Characteristics ......................................................18 
8.5. 
Prior and Concomitant Therapy ..................................................................................19 
8.6. 
Analysis of Efficacy Parameters .................................................................................19 
8.6.1. 
Analysis of Body Surface Area Index (BSAI) ...........................................................19 
8.7. 
Analysis of Safety .......................................................................................................20 
8.7.1. 
Extent of Exposure .....................................................................................................20 
8.7.2. 
Adverse Events by Preferred Term and System Organ Class ....................................20 
8.7.3. 
Summaries of Adverse Event Incidence Rates for All Subjects .................................20 
8.7.4. 
Missing Adverse Event Onset, Severity, and Relationship ........................................21 
8.7.4.1. 
Missing or Partial Adverse Event Dates .....................................................................21 
8.7.4.2. 
Missing Severity .........................................................................................................22 
8.7.4.3. 
Missing Relationship ..................................................................................................22 
8.7.5. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death ..........................................................................22 
8.7.6. 
Discontinuation from the Study ..................................................................................22 
8.7.7. 
Clinical Laboratory Evaluations .................................................................................22 
8.7.8. 
Other Observations Related to Safety .........................................................................22 
8.7.8.1. 
Weight, Height/length, and Temperature ...................................................................22 


 
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8.7.8.2. 
Physical Findings ........................................................................................................23 
9. 
COMPUTER SOFTWARE ........................................................................................23 
10. 
REFERENCES ...........................................................................................................24 
11. 
APPENDIX .................................................................................................................25 
11.1. 
Body Surface Area Index (BSAI) of Lesional Skin ...................................................25 
 
LIST OF TABLES 
Table 1: 
Assessments Conducted at Each Scheduled Visit ......................................................10 
Table 2: 
Analysis Windows ......................................................................................................13 
 


 
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Protocol: SD-004 
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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
BSA 
Body surface area 
BSAI  
Body surface area index 
EB 
Epidermolysis bullosa 
ITT  
Intent-to-treat 
Placebo 
Contains 0% allantoin 
PT 
Preferred term 
SAE  
Serious adverse event  
SD-101  
Drug Product formulation  
SD-101-3.0 
Contains 3% allantoin  
SD-101-6.0  
Contains 6% allantoin 
Placebo –> SD-101-6.0  
Rolled over from 003 study placebo group (referred to as SD-101-0.0) 
in the protocol) 
SD-101-3.0 –> SD-101-6.0 
Rolled over from 003 study SD-101-3.0 group 
SD-101-6.0 –> SD-101-6.0 
Rolled over from 003 study SD-101-6.0 group 
SOC 
System organ class 
TEAE  
Treatment-emergent adverse event 


 
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Protocol: SD-004 
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2. 
INTRODUCTION 
This statistical analysis plan (SAP) defines the methodology and strategy for performing safety 
and efficacy analysis for subjects with epidermolysis bullosa (EB) in the study SD-004. This 
SAP is based on the protocol amendment 3, version 4 dated 25 January 2017. 
3. 
STUDY OBJECTIVE 
The primary objective is to demonstrate the long-term safety of SD-101-6.0 in subjects with 
Simplex, Recessive Dystrophic, and Junctional non-Herlitz epidermolysis bullosa. 
The secondary objectives are to assess the efficacy of SD-101-6.0 in terms of the change in body 
surface area index (BSAI) of lesional skin in subjects rolling over from the SD-003 study. 
4. 
STUDY DESIGN 
4.1. 
General Design 
This is an open label extension, multi-center study to assess the continued safety of SD-101-6.0 
cream (containing 6% allantoin) in treating subjects with epidermolysis bullosa simplex (EBS), 
recessive dystrophic epidermolysis bullosa (RDEB), and junctional non-Herlitz epidermolysis 
bullosa (JEB).  
SD-101-6.0 cream has been applied topically, once a day to the entire body for the duration of 
the study. Subjects who successfully completed the SD-003 study have been eligible to roll over 
into the SD-004 study. The Baseline Visit 1 occurred at the final visit date for SD-003. The body 
surface area (BSA) assessment from the final SD-003 study was used as the baseline information 
at Visit 1 for the SD-004 study. The subject has returned to the study site once every 3 months 
for Visit 2 (14 days ± 7 days from baseline) through Visit 14 (1080 days ± 7 days from baseline) 
to have BSA assessed. Body surface area has been assessed at all subsequent scheduled study 
center visits. Scheduled study center visits has occurred every 6 months after Visit 14 (Visits 16, 
18, 20, etc.). After completion of Visit 14, the next subject visit (Visit 15) is to be a phone call 
from the site to the subject. Telephone visits are to occur every 6 months thereafter (Visits 17, 
19, 21, etc.) and include assessment of adverse events (AEs) and concomitant medications only. 
At the Investigator's discretion, the subject may be asked to complete a study center visit in place 
of a phone call visit. If a study center visit is requested, no additional assessments (other than 
collection of information on AEs and concomitant medications) will be required (see 
Section 6.1 – Schedule of Evaluations for details).  
4.2. 
Method of Assignment of Subjects to Treatment Groups 
There will only be one treatment group so subjects will not be randomized to treatment. All 
subjects will receive SD-101-6.0. 


 
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4.3. 
Blinding 
This was an open label trial; therefore, blinding was not performed. 
4.4. 
Determination of Sample Size 
All subjects who complete the protocol SD-003 (on study drug at Visit 5) and who meet all 
eligibility criteria, may be eligible to enter this open label extension. Up to approximately 
48 subjects are expected to roll over from Study SD-003 into this open label extension. 
5. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS  
5.1. 
Changes in the Conduct of the Study 
There were three amendments to the SD-004 protocol. The first amendment was finalized on 
27 February 2015, the second amendment was finalized on 2 December 2015, and the third 
amendment was finalized on 25 January 2017. The latest amendment extended the study duration 
and introduced intermittent 3 month phone call visits every 6 months starting at Month 36. On 
June 4, 2018, a Dear Doctor Letter was sent instructing all sites to discontinue the applications of 
SD-101 cream immediately, bring the subjects back to the sites for the end of study visit, and 
collect all the remaining tubes of SD-101. This was because the manufacturer of SD-101 had 
received a warning letter from the FDA for several violations of GMP regulations that, although 
not mentioning SD-101, may have resulted in the adulteration of SD-101.  
5.2. 
Changes from the Analyses Planned in the Protocol/CIP 
There were no changes in the analysis planned in the protocol of the study at the time of 
preparing this SAP. 
6. 
BASELINE, EFFICACY, AND SAFETY EVALUATIONS 
6.1. 
Schedule of Evaluations 


 
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Table 1: 
Assessments Conducted at Each Scheduled Visit 
 
Procedure 
Visit 
 
1 
Screening/ 
Baseline 
 
2 
Week 2 
 
3 
Month 
3 
 
4 
Month 
6 
 
5 
Month 
9 
 
6 
Month 
12 
7, 9, 11, 
and 13  
Months 
15, 21, 
27, and 
33 
8, 10, 12, 
and 14  
Months 
18, 24, 
30, and 
36  
15  
(odd 
visits)  
Month 
39  
Phone 
Call 
16  
(even 
visits)  
Month 
42  
Site 
Visit  
Alternate 
Phone Call 
and Site Visit 
until Final 
Study 
Visit/Early 
Terminationa 
Final Study 
Visit/Early 
Termination  
 
Study Day  
(± 7 Days)  
0 
14 
90 
180 
270 
360 
450, 630, 
810, and 
990 
540, 720, 
900, and 
1080 
1170 
1260 
 
- 
- 
Informed 
consent/ 
assent signed 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic, 
medical, and 
medication 
history  
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Physical 
examinationb  
X 
 
 
 
 
 
 
 
 
 
 
X 
Height, 
weight, and 
temperature 
X 
 
 
 
 
 
 
 
 
 
 
X 


 
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Table 1: 
Assessments Conducted at Each Scheduled Visit (Continued) 
 
Procedure 
Visit 
 
1 
Screening/ 
Baseline 
 
2 
Week 2 
 
3 
Month 
3 
 
4 
Month 
6 
 
5 
Month 
9 
 
6 
Month 
12 
7, 9, 11, 
and 13  
Months 
15, 21, 
27, and 
33 
8, 10, 12, 
and 14  
Months 
18, 24, 
30, and 
36  
15  
(odd 
visits)  
Month 
39  
Phone 
Call 
16  
(even 
visits)  
Month 
42  
Site 
Visit  
Alternate 
Phone Call 
and Site Visit 
until Final 
Study 
Visit/Early 
Terminationa 
Final Study 
Visit/Early 
Termination  
 
Assess BSAI 
of lesional 
skinc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urine 
pregnancy 
test (females 
of 
child-bearing 
potential 
only)d 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense 
SD-101-6.0e 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Collect 
SD-101-6.0 
for the 
purpose of 
drug 
accountability 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Collect all 
SD-101-6.0 
 
 
 
 
 
 
 
 
 
 
 
X 
Monitor 
adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


 
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Table 1: 
Assessments Conducted at Each Scheduled Visit (Continued) 
 
Procedure 
Visit 
 
1 
Screening/ 
Baseline 
 
2 
Week 2 
 
3 
Month 
3 
 
4 
Month 
6 
 
5 
Month 
9 
 
6 
Month 
12 
7, 9, 11, 
and 13  
Months 
15, 21, 
27, and 
33 
8, 10, 12, 
and 14  
Months 
18, 24, 
30, and 
36  
15  
(odd 
visits)  
Month 
39  
Phone 
Call 
16  
(even 
visits)  
Month 
42  
Site 
Visit  
Alternate 
Phone Call 
and Site Visit 
until Final 
Study 
Visit/Early 
Terminationa 
Final Study 
Visit/Early 
Termination  
 
Monitor use 
of 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Abbreviations: BSA = Body surface area; BSAI = Body surface area index 
a. After completion of Visit 14, the subject will return to the site once every 6 months (Visits 16, 18, 20, etc.), with the intermittent 3 month visits conducted via 
telephone (Visits 15, 17, 19, etc.). Telephone visits will include assessment of adverse events and concomitant medications only. At the Investigator’s 
discretion, the subject may be asked to complete a study center visit in place of a phone call visit. If a study center visit is requested, no additional assessments 
(other than collection of information on adverse events and concomitant medications) will be required.  
b. A complete physical examination will be performed at the final visit. The physical examination performed at the final visit for SD-003 will be utilized as the 
baseline assessment for SD-004.  
c. The BSA assessment will be performed at Visits 2 through 14 and at all subsequent scheduled study center visits. The BSA assessment performed at the final 
visit for SD-003 will be utilized as the baseline assessment for SD-004.  
d. Urine pregnancy test will be performed at Visits 4, 6, 8, 10, 12, 14, and at all subsequent scheduled study center visits. The urine pregnancy test performed at 
the final visit for SD-003 will be utilized for entry into SD-004.  
e. Re-dispense any unused SD-101 cream. Ensure the subject is dispensed sufficient SD-101 cream until the next study visit. 
 


 
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6.2. 
Time Point Algorithms 
6.2.1. 
Study Day 
The date of informed consent/assent (Visit 1), will be considered Study Day 0. Days prior to 
Study Day 1 will be negative. Study days will be calculated as follows only when the full 
assessment date is known (ie, partial dates will have missing relative days). 
Study day will be calculated as follows: 
Date of Assessment – Date of Informed Consent. 
For relative day on study drug, the date of first study drug administration will be used. The first 
date of drug administration will be either the randomization day or the first day of study drug 
administration recorded on diary, if the study drug was not administered during the 
randomization office visit. 
The relative day on study drug will be calculated as follows: 
Date of Assessment – Date of the First Study Drug Administration + 1. 
6.2.2. 
Windows  
For analysis purposes, the visit numbers will be allotted into windowed visits, as illustrated in the 
following table: 
Table 2: 
Analysis Windows 
Week 
Visit 
Scheduled Study Day 
Visit Window for Analysis (Days) 
Screening/Baseline 
Visit 1 
0 
Day -13 to Day 0 
Week 2 
Visit 2 
14 
Day 1 – Day 60 
Month 3 
Visit 3 
90 
Day 61 – Day 135 
Month 6 
Visit 4 
180 
Day 136 – Day 225 
Month 9 
Visit 5 
270 
Day 226 – Day 315 
Month 12 
Visit 6 
360 
Day 316 – Day 405 
Month 15 
Visit 7 
450 
Day 406 – Day 495 
Month 18 
Visit 8 
540 
Day 496 – Day 585 
Month 21 
Visit 9 
630 
Day 586 – Day 675 
Month 24 
Visit 10 
720 
Day 676 – Day 765 
Month 27 
Visit 11 
810 
Day 766 – Day 855 
Month 30 
Visit 12 
900 
Day 856 – Day 945 


 
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Table 2: 
Analysis Windows (Continued) 
Week 
Visit 
Scheduled Study Day 
Visit Window for Analysis (Days) 
Month 33 
Visit 13 
990 
Day 946 – Day 1035 
Month 36 
Visit 14 
1080 
Day 1036 – Day 1125 
Month 39 
Visit 15 
1170 
Day 1126 – Day 1215 
Month 42  
Visit 16 
1260 
Day 1216 – Day 1405 
….. 
 
 
 
Final Visit 
 
 
Up to Completion 
If two visits fall within the window, then the closest one will be selected. If two visits are equal 
distance from the nominal visit day, then the first one is used. 
6.3. 
Baseline Definition and Assessments 
6.3.1. 
Baseline Definition 
The baseline visit (Visit 1) will occur at Visit 5 for SD-003.  
6.3.2. 
Baseline Assessments 
The following screening and baseline assessments will be conducted prior to initial application 
of study treatment: 
• Informed consent/assent signed and dated 
• Inclusion/exclusion assessment 
• Medical and medication history (including disease subtype) obtained from SD-003. 
Adverse events continuing in Study SD-003 and those originating within the gap 
between Studies SD-003 and SD-004 will be transcribed into Medical History. All 
AEs experienced in SD-003 and medical events occurring between the end of SD-003 
and the enrollment into SD-004 after completion of SD-003 should be noted in the 
medical history for SD-004 at Visit 1 only.  
• Demographics (date of birth, race, gender, ethnicity) obtained from SD-003 
• Height/length, weight, and temperature obtained from final visit of SD-003 
• Physical examination obtained from final visit of SD-003 
• BSAI of lesional skin obtained from final visit of SD-003 
• The urine pregnancy test performed at the final visit for SD-003 will be utilized for 
entry (Visit 1) into SD-004.  
• Dispense sufficient SD-101-6.0 until next study visit 


 
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6.4. 
Efficacy Assessments 
6.4.1. 
Change in Body Surface Area Index (BSAI) 
Change in lesional skin based on BSA estimates at Week 2, and Month 3, 6, 9, 12, 15, 18, 21, 24, 
27, 30, 33, 36, and then every 6 months, as compared to baseline will be measured using the 
BSAI, where change is defined as the corresponding month value minus the baseline value. 
The BSAI is a global measure of disease extent with weighting factors. The BSA affected with 
lesional skin will be calculated at baseline and at each visit to assess the total affected area before 
and after using the product. The BSAI of lesional skin will be assessed as listed in Section 11.1. 
6.5. 
Safety Assessments 
6.5.1. 
Extent of Exposure and Compliance to Study Treatment 
SD-101-6.0 will be applied once a day to the entire body for the study duration. No daily use 
data are collected in this study. 
6.5.2. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are any untoward medical occurrence in a subject, 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. Adverse events may include the onset of new illness and the exacerbation of 
pre-existing conditions. Adverse events will be collected after signing the informed 
consent/assent through the last study visit. If there is a gap between the completion of the 
Study SD-003 and the start of Study SD-004, AEs starting after the last study day or changing in 
severity or relationship to treatment within the gap will be recorded in the medical history for 
study SD-004. Continuing AEs will be also captured in medical history for the extension study 
SD-004. All AEs will be TEAEs unless they started or increased in severity or relationship to 
treatment between signing the informed consent and the first dose of study drug in 
Study SD-004. 
The investigator’s verbatim term of both serious and non-serious AEs will be mapped to system 
organ class (SOC) and preferred terms (PTs) using the 19.1 or later version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Partial dates will be imputed as the following: 
1. If year is not missing and is after the year of first application of study drug: 
a. If Month is missing, then Month will be imputed as January. 
b. If Day is missing, then Day will be imputed as the first of the month. 


 
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2. If year is not missing and is the same as the year of the first application of study drug: 
a. If Month is missing, then impute the Month as the month of the first application of 
study drug. 
b. If Day is missing but Month is on or after the month of first application of study drug, 
then impute Day as the first day of the month. 
c. If the Day and Month are missing then impute Day and Month as the Day and Month 
of the first study drug application. 
3. If year is missing, then impute the year as the year of the first study drug application: 
a. If Month is missing, then impute the Month as the Month of the first study drug 
application. 
b. If Day is missing, then impute the Day as the day of the first study drug application. 
4. If the start date is completely missing, but the AE is either ongoing or the stop date is 
after the first date of drug application, then impute the start date as the first date of study 
drug application. 
5. If using the above rules, the stop date is before the start date, then leave the stop date 
missing and assume that AE is treatment-emergent for the purpose of the analysis. 
Completely missing stop dates will not be imputed. The partial stop dates will be imputed as 
follows: 
1. If the year is missing, the stop date will not be imputed. 
2. If the month is missing, then the month will be imputed as December. 
3. If the day is missing, then the day will be imputed as the last day of the month. 
6.5.3. 
Clinical Laboratory Evaluations 
The urine pregnancy test performed at the final visit for SD-003 will be utilized for entry 
(Visit 1) into SD-004 only if the visits occur on the same day, otherwise, urine pregnancy test 
will be performed at Visit 1. Urine pregnancy tests for female subjects of child bearing potential 
(sensitivity at least 25 mIU/mL) will also be performed every 6 months (Table 1) through final 
office visit.  
6.5.4. 
Physical Examination Including Height/Length, Weight, and Temperature 
The physical examination performed at the final visit for SD-003 will be utilized as the baseline 
assessment for SD-004. An additional physical examination will be done by a physician at the 
final office visit. The following sites will be examined: head, eyes, ears, nose, throat, neck, chest, 
lungs, heart, abdomen, skin, and lymph nodes; and the following systems will be assessed: 
musculoskeletal and neurological. Weight, height/length, and temperature will be recorded. 


 
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7. 
STATISTICAL METHODS 
7.1. 
General Methodology 
The final analysis after the study completion will be preceded by at least one interim analysis.  
Data will be summarized by treatment groups (based on SD-003 study treatment:  
Placebo –> SD-101-6.0, SD-101-3.0 –> SD-101-6.0, and SD-101-6.0 –> SD-101-6.0) and 
overall (where appropriate). Summary and analysis tables will include number of subjects (n), 
mean, standard deviation, median, minimum, and maximum values for all continuous variables. 
When appropriate, two-sided 95% confidence intervals may be used. 
In summary tables of categorical variables, counts and percentages will be presented. The 
denominator for each percentage will be the number of subjects within the population, treatment 
group, or subgroup as specified in table templates. 
All analyses for efficacy will be performed using the intent-to-treat (ITT) population and all 
safety analyses will be performed using the safety population. No comparison between treatment 
groups will be performed. The comparison to baseline will be done by visit in  
Placebo –> SD-101-6.0 group, SD-101-3.0 –> SD-101-6.0, and SD-101-6.0 –> SD-101-6.0 
group. All hypothesis testing will be two-sided. P-values less than 0.001 will be reported as 
< 0.001 in summary tables. 
All statistical analysis will be performed using SAS® v9.2 or higher. 
7.2. 
Adjustments for Covariates 
No covariates are planned to be used in the analyses for this study. 
7.3. 
Handling of Dropouts or Missing Data 
Dropout subjects will not be replaced in this study. Missing data will not be imputed unless 
specified otherwise in the following section. 
7.4. 
Multi-center Studies and Pooling of Centers 
Data will be pooled across all study sites. The justification for pooling is made on the basis of 
three important factors: 1) all study sites use one common protocol, 2) sites are actively and 
adequately monitored to ensure protocol compliance, 3) all sites use a common data reporting 
method and data collection procedures. (1)  
7.5. 
Multiple Comparisons/Multiplicity 
No multiple comparisons and multiplicity adjustment will be used for this study. 


 
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7.6. 
Examination of Subgroups 
Safety summaries will be presented by subgroups of gender, and age (0 to 27 days, 28 days to 
< 2 years, 2 years to < 12 years, 12 years to ≤ 18 years, > 18 years), , independently. 
8. 
STATISTICAL ANALYSIS 
8.1. 
Disposition of Subjects 
The number and percentage of subjects who were enrolled, treated, and completed the study will 
be summarized. Similar summaries will be provided for those subjects who discontinued from 
the study prematurely. For those subjects who discontinue early, the reasons for discontinuing 
including general discontinuations at sponsor’s request will also be summarized. The disposition 
of all subjects will be listed.  
Data on screening failures (subjects who signed informed consent but were not entered into the 
trial) will be collected with a yes or no on the CRF and will be presented in a listing. 
8.2. 
Protocol Deviations 
Number and percentage of subjects with major protocol deviations will be summarized for each 
treatment group in the ITT population. A listing of subjects with major protocol deviations will 
also be provided.  
8.3. 
Analysis Populations 
8.3.1. 
Intent-to-Treat (ITT) Population 
The ITT population will be defined as all subjects who have rolled over from SD-003. 
8.3.2. 
Safety Population 
The Safety population is defined as all randomized subjects who applied/were administered the 
study medication at least once. 
The ITT population will be used for all efficacy analyses. The Safety population will be used for 
all safety analyses.  
If the Safety population and ITT populations are identical, then the efficacy and safety analyses 
will be performed using the ITT population only. 
8.4. 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented for the ITT 
population.  
Continuous variables such as subject age, weight, height, body mass index (BMI), BSAI for 
lesional skin, and temperature will be summarized as described previously. Categorical variables 


 
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such as subject gender, race, ethnicity, age group (0 to 27 days, 28 days to < 2 years, 2 years to 
< 12 years, 12 years to ≤ 18 years, > 18 years), race, and EB type will be summarized using 
number of observations and percentages for each category. 
Medical history, including disease history will be summarized and listed. 
8.5. 
Prior and Concomitant Therapy 
The World Health Organization (WHO) Drug Dictionary of March 2017 will be used to classify 
medications. The WHO Drug Dictionary version might be updated in the future analyses and if 
so it will be properly footnoted on all tables and listings. Any medication taken before and 
continuing after first application of SD-101-6.0 in the study SD-004 is considered a concomitant 
medication. Any medication given before first application but discontinued prior to first 
application is considered a prior medication. A medication can be considered both prior and 
concomitant. Medications missing both start and stop dates, or having a start date prior to the last 
dose of study drug and missing the stop date, or having a stop date after the start of study drug 
and missing the start date, will be considered concomitant. Medications will also be considered 
concomitant if partial start and stop dates are present but it cannot be determined if the 
medication ended prior to start of study drug. 
A summary table will be provided in the safety population: 
Number and percentage of subjects who had concomitant therapies/medications by ATC text 
and WHO drug name 
Previous medications will be listed. 
8.6. 
Analysis of Efficacy Parameters 
8.6.1. 
Analysis of Body Surface Area Index (BSAI) 
No comparison between treatment groups will be performed. The comparison to baseline will be 
done by visit in Placebo –> SD-101-6.0 group and in SD-101-3.0 –> SD-101-6.0 group using the 
paired t-test.  
• Change in extent of lesional skin based on BSAI at each visit compared to baseline. 
To evaluate post-baseline BSAI of lesional skin, both change from baseline and 
percentage change from baseline will be explored using descriptive statistics. Change 
from baseline will be calculated as the post-baseline measurement minus the baseline 
value. Percentage change from baseline will be calculated as the change from 
baseline divided by the baseline value times 100. 
Graphs of the mean change and mean percentage change from baseline over time will 
also be presented. 


 
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8.7. 
Analysis of Safety 
8.7.1. 
Extent of Exposure  
The number of days on the study will be considered number of days of exposure. It will be 
summarized using descriptive statistics by treatment group and overall. Descriptive statistics will 
also be provided for duration of exposure into categorical summary of < 1 year, 1 to 2 years, and 
> 2 years.  
8.7.2. 
Adverse Events by Preferred Term and System Organ Class  
For the first interim analysis, serious AEs will be mapped to SOC and PTs using the 19.1 version 
of MedDRA. 
If there is a gap between the completion of the study SD-003 and the start of the study SD-004, 
AEs starting after the last study day or changing the severity or relationship to treatment within 
the gap will be counted as medical history for the extension study SD-004. Continuing AEs will 
also be captured in medical history for the extension study SD-004. If the severity or relationship 
to treatment changed on or after the first dose of study medication, then that AE is considered a 
TEAE after that change. 
8.7.3. 
Summaries of Adverse Event Incidence Rates for All Subjects 
The number and percentage of subjects who experienced TEAEs will be presented by PT within 
SOC for each treatment group. Treatment-emergent AEs will be similarly presented by severity 
(mild, moderate, and severe), by relationship to study drug (unrelated, definite, probable, and 
possible) and by outcome of events. Additionally, the number of TEAEs (as opposed to the 
number and percentage of subjects) will be presented by treatment group.  
The proportion of subjects with TEAEs will also be presented by the following subgroups of 
gender, and age (0 to 27 days, 28 days to < 2 years, 2 years to < 12 years, 12 years to ≤ 18 years, 
> 18 years); independently. Subgroups for age are defined based at the subject’s age at Baseline. 
To count the number of subjects who experienced each TEAE, a subject experiencing the same 
TEAE multiple times will only be counted once for the corresponding PT. Similarly, if a subject 
experiences multiple TEAEs within the same SOC, the subject will be counted only once for that 
SOC. If a subject experiencing more than one TEAE within different severity or relationship 
categories within the same SOC/PT, only the worst case (worst severity and related TEAE) will 
be reported. Treatment-emergent AEs will be sorted alphabetically by SOC, and within each 
SOC, the PT will be presented by decreasing order of total frequency.  
For TEAE summary by outcome, if a subject experienced more than one TEAE, the worst 
outcome will be counted under that subject. If a subject experienced more than one outcome 
within a SOC (or PT), the subject is only counted once under worst outcome in that SOC (or PT). 
In addition, all AEs will be provided by study site and by treatment group, in a listing, which will 
include the subject identifier, the PT, the reported term, the severity, the seriousness, the action 
taken, the outcome, the causality, the date onset, date of onset relative to the date of the first 


 
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study drug administration, date of resolution, date of resolution related to the first study drug 
administration, and the TEAE duration (resolution date –onset date + 1).  
Additionally, the incidence and the number of non-serious TEAEs will be presented by treatment 
group.  
Non-treatment-emergent AEs, if any, will be listed. 
8.7.4. 
Missing Adverse Event Onset, Severity, and Relationship 
8.7.4.1. 
Missing or Partial Adverse Event Dates 
The following list describes how partially missing date information will be handled as it relates 
to partial or missing start dates. Partial dates will be imputed as follows: 
1. If year is not missing and is after the year of first application of study drug: 
a. If Month is missing, then Month will be imputed as January. 
b. If Day is missing, then Day will be imputed as the first of the month. 
2. If year is not missing and is the same as the year of the first application of study drug: 
a. If Month is missing, then impute the Month as the month of the first application of 
study drug. 
b. If Day is missing but Month is on or after the month of first application of study drug, 
then impute Day as the first day of the month. 
c. If the Day and Month are missing, then impute Day and Month as the Day and Month 
of the first study drug application. 
3. If year is missing, then impute the year as the year of the first study drug application: 
a. If Month is missing, then impute the Month as the Month of the first study drug 
application. 
b. If Day is missing, then impute the Day as the day of the first study drug application. 
4. If the start date is completely missing, but the AE is either ongoing or the stop date is 
after the first date of drug application, then impute the start date as the first date of study 
drug application. 
5. If using the above rules, the stop date is before the start date, then leave the stop date 
missing and assume that AE is treatment-emergent for the purpose of the analysis. 
Completely missing stop dates will not be imputed. The partial stop dates will be imputed as 
follows: 
1. If the year is missing, the stop date will not be imputed. 
2. If the month is missing, then the month will be imputed as December. 
3. If the day is missing, then the day will be imputed as the last day of the month. 
Imputed dates will be flagged in the individual supportive subject listings. 


 
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8.7.4.2. 
Missing Severity 
If severity is missing for any AE, then its severity will be classified as missing in the summary 
tables. 
8.7.4.3. 
Missing Relationship 
If the assessment of relationship of the AE to study treatment is missing for any AE, then it will 
be presented as missing in the listings and in the summary tables. 
8.7.5. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death 
During the treatment period, the number and percentage of subjects who experienced 
treatment-emergent SAEs (TESAEs) and separately TEAEs leading to withdrawal from the 
study will be presented by PT within each SOC for each treatment. Treatment-emergent SAEs 
and separately TEAEs resulting in withdrawal from the study will be similarly presented by 
severity (mild, moderate, and severe), by relationship to study drug (related would include 
definite, probable, and possible) and by outcome of events. Additionally, the number of TESAEs 
(as opposed to the number and percentage of subjects) will be presented. 
In case that there are non-treatment-emergent AEs observed, the number and percentage of 
subjects with all SAEs will be summarized by SOC and PT within each SOC. Additionally, the 
number of SAEs (as opposed to the number and percentage of subjects) will be presented.  
A listing of all SAEs and discontinuations due to AEs will be included. Subject with deaths, 
SAEs, or subjects who withdraw due to AE will be listed separately and discussed with subject 
narratives.  
8.7.6. 
Discontinuation from the Study 
Number of subjects who discontinued from the study and reasons for discontinuation will be 
summarized. 
8.7.7. 
Clinical Laboratory Evaluations 
Pregnancy test results will be listed for all female subjects of child bearing potential only. 
8.7.8. 
Other Observations Related to Safety 
8.7.8.1. 
Weight, Height/length, and Temperature 
Weight, height/length, and temperature conducted under the physical examination will be 
summarized using descriptive statistics for both actual results and change from baseline for each 
treatment group. Vital signs assessments will also be presented in a listing. All vital signs will be 
presented metric units. 


 
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8.7.8.2. 
Physical Findings 
Physical examination findings will be summarized in shift tables that will be presented to display 
the shift in the normal range categories (normal vs. abnormal) from baseline to the final 
evaluation. Baseline is defined in Section 6.3. 
9. 
COMPUTER SOFTWARE 
All analyses will be performed by FMD K&L Inc. using Version 9.2 or later of SAS software. 
All summary tables, data listings, and figures will be prepared utilizing SAS software. 
The standard operating procedures (SOPs) of FMD K&L Inc. will be followed in the creation 
and quality control of all data displays and analyses. 


 
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10. 
REFERENCES 
1) 
Meinert, C. Clinical Trials: Design, Conduct, and Analysis. New York, NY: Oxford 
University Press; 1986. 


 
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Protocol: SD-004 
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11. 
APPENDIX 
11.1. 
Body Surface Area Index (BSAI) of Lesional Skin 
(Check only one box and complete the appropriate sections for each region) 
 
1  Ages 1 month to 7 years1                                                                                               
Column 1 
Column 2 
Column 3 
Column 4 
Column 5 
Region 
Number 
Region 
Description 
Regional BSA % 
that is affected* 
Weighting 
Factor 
Total BSA %  
that is affected ** 
1 
Head/Neck 
 
x .2 
 
2 
Upper Limbs 
 
x .2 
 
3 
Trunk  
(includes groin) 
 
x .3 
 
4 
Lower Limbs 
 
x .3 
 
 
 
 
TOTAL 
(BSAI) 
 
 
2  Age 8 years or greater 
Column 1 
Column 2 
Column 3 
Column 4 
Column 5 
Region 
Number 
Region 
Description 
Regional BSA % 
that is affected* 
Weighting 
Factor 
Total BSA %  
that is affected ** 
1 
Head/Neck 
 
x .1 
 
2 
Upper Limbs 
 
x .2 
 
3 
Trunk  
(includes groin) 
 
x .3 
 
4 
Lower Limbs 
 
x .4 
 
 
 
 
TOTAL 
(BSAI) 
 
* For each region, enter the % of BSA that is affected with lesional skin. Score each region 
separately from 0% - 100%. 
** Multiply the value in Column 3 by the factor in Column 4. The Total value at the bottom 
of the table is the sum of Column 5 values for each region.