Clinical trial NCT03472287
Conditions: Epidermolysis Bullosa (EB) Epidermolysis Bullosa Simplex Dystrophic Epidermolysis Bullosa Junctional Epidermolysis Bullosa
Keywords: EB EBS DEB JEB
Sponsor: Castle Creek Pharmaceuticals, LLC
Start date: 2018-05-18; Completion date: 2019-02-14
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A pharmacokinetic (PK) study in 16-20 EB subjects to be allocated to two cohorts. Cohort 1 to include 8-10 subjects (ages 12 yrs and older); Cohort 2 to include 8-10 subjects (ages 6 months-11 yrs, inclusive). Cohort 2 only included subjects 4 yrs and older. Serial PK blood sampling collected on Days 1 and 10. Analyses were performed to determine the concentrations of diacerein and rhein.

Detailed description:
This was an open-label, single-period study that intended to include subjects with EB consisting of infants/ children (ages 6 months to 11 years, inclusive) and adolescents/ adults (ages 12 years and older). The study included 2 cohorts.

Cohort 1 was to include adolescent/adult subjects with EB (ages 12 years and older);

Cohort 2 was to include infants/children with EB (ages 4 to 11 years, inclusive).

For both cohorts, the study intended to enroll subjects with epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), and junctional epidermolysis bullosa (JEB) with lesions encompassing \>/=2% BSA. The diacerein application area was \>/=5% BSA and included lesioned and non-lesioned skin (if lesions accounted for \<5% BSA); however, topical administration was \</=30% BSA. On Days 1 and 10, the topical dose of study drug was applied by study staff, and blood was sampled for PK analyses of diacerein and rhein pre-dose and through 8 hours post-application. On Days 2 to 9, study drug was applied to the application area(s) at home. For Cohort 1, trough PK samples were collected on any 2 available days from Days 3 through 9, and study drug was applied after blood draw, while for Cohort 2 trough PK analyses were not performed.

Arms: arm 1: Adolescent and adult subjects with EB (aged 12 years and older) received diacerein 1% ointment daily for 10 days. arm 2: Children with EB (aged 4 to 11 years, inclusive) received diacerein 1% ointment daily for 10 days.
Interventions: intervention 1: Diacerein 1% Ointment
Intervention descriptions: intervention 1: Diacerein 1% Ointment administered topically

Protocol documents:
Prot_001.pdf: 
Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 1 of 56 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
CCP-020 (DIACEREIN 1% STERILE OINTMENT) 
CCP-020-101 
A Multi-center Study to Evaluate the Pharmacokinetics of 
Diacerein and Rhein and the Safety of Diacerein after Maximum 
Use, Topical Administration of CCP-020 (Diacerein 1% 
ointment) to Patients with Epidermolysis Bullosa (EB) 
 
 
Confidentiality Statement 
This document is confidential and is a privileged correspondence of Castle Creek Pharmaceuticals, LLC. Accepting this 
document constitutes an agreement by the recipient that no unpublished information herein contained will be used, disclosed or 
published without Castle Creek Pharmaceuticals’ prior written approval. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 2 of 56 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for Diacerein 1% Ointment. I have read the 
CCP-020-101 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 3 of 56 
 
 
STUDY CONTACT INFORMATION 
 
Table 1: 
Emergency Contact Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 4 of 56 
 
 
Table 1: 
Emergency Contact Information (Continued) 
 
Name 
Affiliation / Address 
Responsibility 
 
 
 
 
 
 
 
 
 
 
 
 
 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 5 of 56 
 
 
2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Castle Creek Pharmaceuticals, LLC 
Name of Investigational Product: 
CCP-020 (diacerein 1% ointment) 
Name of Active Ingredient: 
Diacerein 
Title of Study: 
A Multi-center Study to Evaluate the Pharmacokinetics of Diacerein and Rhein and the Safety of 
Diacerein after Maximum Use, Topical Administration of CCP-020 (Diacerein 1% ointment) to 
Patients with Epidermolysis Bullosa (EB) 
Studied period (years): 
Estimated date first patient enrolled: March 2018 
Estimated date last patient completed: November 2018 
Phase of development: I 
Objectives: 
Primary: 
• 
The primary objective of the study is to descriptively characterize the single-dose and steady- 
state pharmacokinetics (PK) of diacerein (if quantifiable) and its active metabolite, rhein, 
after topical application of CCP-020 (diacerein 1% ointment) under maximum use conditions 
in adolescent and adult patients with EB, and in infants/children with EB. 
Secondary: 
• 
The secondary objective of the study is to assess the safety and tolerability of single-dose and 
steady-state topical application of CCP-020 (diacerein 1% ointment) in patients with EB. 
Methodology: 
The study is designed as an open label, single period study in approximately 16-20 patients with EB 
ranging in age from infants/children (ages 6 months – 11 years, inclusive) and adolescents/adults 
(ages 12 and up) with at least 8-10 subjects between the aged 6 months to 11 years, inclusive 
(infants/children). The study will be conducted in two cohorts as follows: 
1. 8-10 adolescent and adult patients with EB (aged 12 and older) 
a. EBS subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be 
≤30% BSA. 
b. DEB/JEB subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be 
≤30% BSA. 
2. 8-10 infants/children with EB (aged 6 months to 11 years, inclusive) 
a. EBS subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 6 of 56 
 
 
 
lesions account for less than 5% BSA); however, topical administration must be 
≤30% BSA. 
b. DEB/JEB subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be 
≤30% BSA. 
NOTE: 1% BSA is defined as the area of the subject’s hand held flat, including the thumb and 
fingers held together 
NOTE: No more than 4-5 DEB/JEB patients (50% of the cohort) may be enrolled into the 
cohort. DEB/JEB patients will not be eligible for the open-label extension study. 
For adolescent/adult patients with EB (Cohort 1): 
Eligible, consented (assented and/or consent via guardian) adolescent and adult patients aged 12 and 
up with EB lesions encompassing ≥ 2% BSA will be enrolled in the study.  On Day 1, the total 
surface area of all available areas for application will be quantified and recorded. The area(s) 
surrounding the lesion/lesions, will be marked (with a marker) encompassing no less than a total of 
5% BSA (across all lesions, total) and separate paper body charts will be completed documenting the 
application area. The area(s) encompassing no less than 5% BSA will be defined as the application 
area(s) and will remain fixed over the course of the 10 Day treatment period. On Day 1, the topical 
dose of CCP-020 will be applied by study staff followed by blood sampling for plasma analysis of 
diacerein and rhein through 8 hours post-application.  PK samples will be collected at pre-dose, 0.5, 
1, 2, 3, 4, 6, and 8 hours post-dose on Days 1 and 10. Trough PK samples will be collected on any 
two available days from Day 3 through Day 9. Patients will be discharged from the study site on Day 
1 and will continue applications to the entire application area for 9 days at home at the same time 
each day.  For the trough sample visits between Days 3 and 9, CCP-020 will be applied after the 
blood draw. The application area should be left uncovered for at least one-hour post-application, after 
which it is acceptable to apply non-absorbent bandages consistent with standard of care. On Day 10, 
patients will return to the study site for a pre-dose blood sample and application of CCP-020 to the 
application area followed by blood sampling for plasma analysis of diacerein and rhein. 
For infant/child patients with EB (Cohort 2): 
Eligible, assented (consented via guardian) infant/child patients aged 6 months to 11 years, inclusive 
with EB lesions encompassing ≥ 2% BSA will be enrolled in the study. On Day 1, the total surface 
area of all available areas for application will be quantified and recorded. The area(s) surrounding the 
lesion/lesions, will be marked (with a marker) encompassing no less than a total of 5% BSA (across 
all lesions, total) and separate paper body charts will be completed documenting the application area. 
The area(s) encompassing no less than 5% BSA will be defined as the application area(s) and will 
remain fixed over the course of the 10 Day treatment period. On Day 1, the topical dose of CCP-020 
will be applied by study staff followed by blood sampling for plasma analysis of diacerein and rhein 
through 8 hours post-application. PK samples will be collected at pre-dose, 1, 2, 4, 6, and 8 hours 
post-dose on Days 1 and 10. Trough samples for Days 3-9 will not be required for this cohort. 
Patients will be discharged from the study site on Day 1 and will continue applications to the entire 
application area for 9 days at home at the same time each day. The application area should be left 
uncovered for at least one-hour post-application, after which it is acceptable to apply non-absorbent 
bandages consistent with standard of care. On Day 10, patients will return to the study site for a pre- 
dose blood sample and application of CCP-020 to the application area followed by blood sampling for 
plasma analysis of diacerein and rhein. For sites participating in the United States (US), children 
under the age of 4 are prohibited from participating due to regulatory restrictions. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 7 of 56 
 
 
 
For both cohorts, on Days 1 and 10, void-volume catheters will be placed to obviate multiple needle 
sticks in blood sampling. 
Safety will be monitored throughout the study by repeated clinical and laboratory evaluations. 
The clinic/study site will attempt to contact subjects using their standard procedures approximately 14 
days after the last study drug application to determine if any adverse events (AEs) have occurred 
since the last dose of study drug. Subjects who terminate the study early will be contacted if the 
Principal Investigator (PI) deems necessary. 
EB (excluding DEB/JEB) patients that complete this study or receive at least one dose of study drug 
will be eligible for consideration to enroll an open-label extension study conducted under a separate 
protocol. 
Number of patients (planned): 
• 
8-10 adolescent/adult patients with EB 
• 
8-10 infant/child patients with EB 
Diagnosis and main criteria for inclusion: 
Inclusion criteria: 
1. Subject/caregiver is able to comprehend and willing to sign an Informed Consent and/or 
Assent Form. 
2. Subject is male or female, at least 12 years of age (Cohort 1) or at least 6 months of age to 11 
years, inclusive (Cohort 2) at screening. US only: subjects must be at least 4 years of age to 
11 years, inclusive (Cohort 2) 
3. The subject must weigh at least 9 kg (19.8 lbs) at Screening. 
4. Subject has a documented genetic mutation consistent with EB. A blood or saliva sample 
will be collected for genetic confirmation if no documented gene mutation data is available. 
diagnosis of EB (EBS, DEB, JEB). 
5. Subject has EB lesions on ≥ 2% body surface area (BSA) and the EB lesions are in the 
following body areas: 
a. Localized: plantar and/or palmar areas 
b. Generalized: arms, legs, torso, hands and feet. 
6. Subject/caregiver agrees to not apply any other topical products to the application area during 
the treatment period 
7. If the subject is a woman of childbearing potential, she has a negative urine pregnancy test 
and agrees to use an approved effective method of birth control, as defined by this protocol, 
for the duration of the study. 
8. Subject is non-pregnant, non-lactating and is not planning for pregnancy during the study 
period 
9. Subject is in good general health and free of any known disease state or physical condition 
which, in the investigator’s opinion, which exposes the subject to an unacceptable risk by 
study participation. 
10. Subject is willing and able to follow all study instructions and to attend all study visits. 
Exclusion criteria: 
1. Subject has EB lesions where drug will be applied that are infected (i.e., EB lesions that 
require anti-microbial therapy to treat an infection) 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 8 of 56 
 
 
 
2. Subject has used any diacerein containing product within 1 month prior to Visit 1 
3. Subject has used systemic immunotherapy or cytotoxic chemotherapy within 60 days prior to 
dosing. 
4. Subject has used systemic steroidal therapy or has used topical steroidal therapy on the EB 
lesions in the application area within 14 days prior to dosing (Note: inhaled, nasal sprays, and 
ophthalmic products containing steroids are allowed) 
5. Subject has evidence of a systemic infection or has used systemic antibiotics within 7 days 
prior to dosing 
6. Subject has used any systemic diuretics or cardiac glycosides or any systemic product that, in 
the opinion of the investigator, might put the subject at undue risk by study participation or 
interferes with the study medication application or the study assessments within 30 days prior 
to dosing 
7. Subject has a current malignancy, or a history of treatment for a malignancy within 2 years 
prior to dosing (Note: does not include non-melanoma skin cancer) 
8. Subject currently has diabetes mellitus (HbA1c ≥6.5%) Note: controlled diabetes (HbA1c < 
6.5%) is also considered exclusionary 
9. Subject has a history of cardiac, hepatic (ALT and or AST >2x ULN, Total bilirubin >1.5x 
ULN at Visit 1), or renal disease (eGFR<30 ml/min/1.73 m2 [MDRD-adults ≥18, Bedside 
Schwartz – children <18]) that, in the opinion of the investigator, might put the subject at 
undue risk by study participation or interferes with the study medication application of the 
study assessments 
10. Subject has an active non-EB skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun 
damage, etc.), or condition (e.g., sunburn) that, in the opinion of the investigator, would put 
the subject at undue risk by study participation or would interfere with the study medication 
application or the study assessments 
11. Subject has a history of sensitivity to any of the ingredients in the study medication 
12. Subject has participated in an investigational drug trial in which administration of an 
investigational study medication occurred within 30 days prior to dosing 
Investigational product, dosage and mode of administration: 
Diacerein 1% Ointment administered topically 
Duration of treatment: 
10 Days; EB (excluding DEB/JEB) patients that complete this study or receive at least one dose of 
study drug will be eligible for an open-label extension study conducted under a separate protocol. 
Reference therapy, dosage and mode of administration: 
None 
Criteria for evaluation: 
Pharmacokinetics: 
Concentrations of diacerein (if measurable) and rhein in plasma will be determined after each 
treatment using validated bioanalytical methods. Relevant plasma PK parameters for diacerein (if 
possible) and rhein will be calculated using standard non-compartmental methodology. All non- 
compartmental analyses will be performed based on actual sample collection times using Phoenix 
WinNonlin (version 6.3 or later). Pharmacokinetic parameters (Cmax, tmax and AUC), if available, 
will be summarized using descriptive statistics. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 9 of 56 
 
 
 
Safety: 
Adverse events will be collected and evaluated as they occur throughout the study. Safety 
assessments, including physical examinations, application site assessment, vital signs assessments, 
and clinical laboratory tests, will be performed at select time points. 
Statistical methods: 
Analysis Populations: 
Pharmacokinetic Evaluable Population: The PK Evaluable Population will comprise all subjects 
receiving at least one dose of CCP-020 who have sufficient (> 4 quantifiable concentrations) plasma 
concentration data to calculate PK parameters for rhein and if possible, diacerein. 
Pharmacokinetic Concentration Population: The PK Concentration Population will comprise all 
subjects receiving at least one dose of CCP-020 who have at least one quantifiable plasma 
concentration for rhein and if possible, diacerein. Safety Population: The safety population will 
consist of all subjects who receive any amount of study drug. 
Pharmacokinetic Analysis: 
Summaries of plasma concentration will be based on PK Concentration Population. Individual and 
mean graphs of plasma diacerein (if measurable) and rhein concentrations versus time after single 
dose and multiple dose of CCP-020 will be constructed and displayed for relevant treatment 
comparisons, as data permit. 
Plasma concentrations of diacerein and rhein will be summarized by Cohort and EB type using 
descriptive statistics (sample size, mean, median, coefficient of variation [CV%], standard deviation 
[SD], minimum, and maximum). Corresponding by-subject data listings will be tabulated. The 
summary statistics for each scheduled time will only be reported when at least 50% of subjects have 
quantifiable concentrations. 
Summaries of plasmas PK parameters will be based on PK Evaluable Population. Derived plasma PK 
parameters (Cmax, tmax and AUC), if available, for diacerein and rhein will be summarized by 
Cohort and EB type using descriptive statistics (sample size, arithmetic mean, CV%, SD of the 
arithmetic mean, median, minimum, and maximum). Geometric mean and geometric CV will also be 
provided for Cmax and AUC. Corresponding by-subject data listings will be tabulated. 
Safety Analysis: 
The number and percentage of subjects reporting any treatment-emergent AE will be tabulated by 
system organ class and preferred term for each Cohort and EB type (coded using Medical Dictionary 
for Regulatory Activities). Treatment-emergent AEs will be further classified by maximum severity 
and relationship to treatment. 
Physical examinations, vital signs, application site assessment, and clinical laboratory test data 
(observed and change from baseline) will be summarized using appropriate descriptive statistics. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 10 of 56 
 
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ............................................................................................................... 1 
INVESTIGATOR’S AGREEMENT .............................................................................................. 2 
STUDY CONTACT INFORMATION .......................................................................................... 3 
2. 
SYNOPSIS .................................................................................................................. 5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .............. 10 
REPRESENTATIVES FROM CASTLE CREEK PHARMACEUTICALS ............................... 14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 15 
5. 
INTRODUCTION ..................................................................................................... 17 
5.1. 
Rationale For Use of Patients With All Forms of EB in Maximal Use PK 
Study .......................................................................................................................... 19 
5.2. 
Risks and/or Benefits to Subjects .............................................................................. 20 
6. 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 21 
6.1. 
Primary Objective ...................................................................................................... 21 
6.2. 
Secondary Objectives ................................................................................................ 21 
7. 
INVESTIGATIONAL PLAN .................................................................................... 22 
7.1. 
Overall Study Design ................................................................................................. 22 
7.2. 
Number of Subjects ................................................................................................... 23 
7.3. 
Treatment Assignment ............................................................................................... 23 
7.4. 
Dose Adjustment Criteria .......................................................................................... 23 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses .................................................... 24 
7.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses.................................... 24 
7.5. 
Criteria for Study Termination .................................................................................. 24 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 27 
8.1. 
Subject Inclusion Criteria .......................................................................................... 27 
8.2. 
Subject Exclusion Criteria ......................................................................................... 27 
8.3. 
Subject Withdrawal Criteria ...................................................................................... 28 
9. 
TREATMENT OF SUBJECTS ................................................................................. 30 
9.1. 
Description of Study Drug ......................................................................................... 30 
9.2. 
Concomitant Medications .......................................................................................... 30 
9.2.1. 
Permitted & Prohibited therapies ............................................................................... 31 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 11 of 56 
 
 
9.2.2. 
Bandaging/Dressing Use ............................................................................................ 31 
9.3. 
Treatment Compliance ............................................................................................... 32 
9.4. 
Randomization and Blinding ..................................................................................... 32 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT .......................................... 33 
10.1. 
Study Drug ................................................................................................................. 33 
10.2. 
Study Drug Packaging and Labeling ......................................................................... 33 
10.3. 
Study Drug Storage .................................................................................................... 34 
10.4. 
Study Drug Formulation ............................................................................................ 34 
10.5. 
Study Drug Dispensation ........................................................................................... 34 
10.6. 
Study Drug Administration ........................................................................................ 35 
10.6.1. 
Application Area ........................................................................................................ 36 
10.7. 
Study Drug Accountability ........................................................................................ 36 
10.8. 
Study Drug Handling and Disposal ........................................................................... 36 
11. 
PHARMACOKINETIC ASSESSMENTS ................................................................ 37 
11.1. 
PK Blood Sample Collection ..................................................................................... 37 
11.2. 
Total Volume of Blood Collected .............................................................................. 37 
11.3. 
Sample Analysis ........................................................................................................ 38 
12. 
ASSESSMENT OF SAFETY .................................................................................... 39 
12.1. 
Safety Parameters ...................................................................................................... 39 
12.1.1. 
Demographic/Medical History .................................................................................. 39 
12.1.2. 
Vital Signs ................................................................................................................. 39 
12.1.3. 
Weight ........................................................................................................................ 39 
12.1.4. 
Physical Examination ................................................................................................ 39 
12.1.5. 
Laboratory Assessments ............................................................................................ 40 
12.1.5.1. 
Hematology ................................................................................................................ 40 
12.1.5.2. 
Blood Chemistry ........................................................................................................ 40 
12.1.5.3. 
Urinalysis ................................................................................................................... 40 
12.1.5.4. 
Pregnancy Screen ....................................................................................................... 40 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS .................................................. 42 
13.1. 
Adverse events(s) ....................................................................................................... 42 
13.2. 
Adverse (Drug) Reaction ........................................................................................... 43 
13.3. 
Unexpected Adverse Drug Reaction .......................................................................... 43 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 12 of 56 
 
 
13.4. 
Assessments of Adverse Events by the Investigator ................................................. 43 
13.4.1. 
Assessment of Severity .............................................................................................. 43 
13.4.2. 
Causality Assessment ................................................................................................ 43 
13.5. 
Adverse Events of Special Interest ............................................................................ 44 
13.6. 
Serious Adverse events (SAE) ................................................................................... 45 
13.6.1. 
Serious Adverse Event Reporting/Adverse Events of Special Interest – 
Procedures for Investigators ...................................................................................... 45 
13.6.1.1. 
Initial Reports ............................................................................................................ 45 
13.6.1.2. 
Follow-up Reports ..................................................................................................... 46 
13.6.1.3. 
Expedited Reports ...................................................................................................... 46 
13.6.1.4. 
Pregnancy Reporting .................................................................................................. 46 
14. 
STATISTICS ............................................................................................................. 49 
14.1. 
Analysis Populations ................................................................................................. 49 
14.2. 
Pharmacokinetic Analysis.......................................................................................... 49 
14.3. 
Safety Analysis .......................................................................................................... 49 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................ 50 
15.1. 
Study Monitoring ....................................................................................................... 50 
15.2. 
Audits and Inspections ............................................................................................... 50 
15.3. 
Institutional Review Board (IRB) .............................................................................. 51 
16. 
ETHICS ..................................................................................................................... 52 
16.1. 
Ethics Review ............................................................................................................ 52 
16.2. 
Ethical Conduct of the Study ..................................................................................... 52 
16.3. 
Written Informed Consent ......................................................................................... 52 
17. 
DATA HANDLING AND RECORDKEEPING ...................................................... 54 
17.1. 
Electronic Case Report Forms ................................................................................... 54 
17.2. 
Inspection of Records ................................................................................................ 54 
17.3. 
Retention of Records ................................................................................................. 54 
18. 
PUBLICATION POLICY ......................................................................................... 55 
REFERENCES ............................................................................................................................. 56 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 13 of 56 
 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 3: 
Schedule of Assessments ............................................................................................26 
Table 4: 
CCP-020 (Diacerein 1% Ointment) ............................................................................30 
Table 5: 
Study Medication Formulation ...................................................................................34 
Table 6: 
Number of Tubes of Study Drug (by %BSA) .............................................................34 
Table 7: 
PK Blood Sample Collection Times ...........................................................................37 
Table 8: 
Blood Volume Collection ...........................................................................................37 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................25 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 14of57 
 
 
REPRESENTATIVES FROM CASTLE CREEK PHARMACEUTICALS 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and in accordance with the 
principles that have their origin in the Declaration of Helsinki. 
 
 
 
  
 
 
 
 
 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 15 of 56 
 
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
°C 
Degrees Celsius 
CBD 
Cannabidiol 
CMH 
Cochran-Mantel-Haenszel 
CR 
Clinically Relevant 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
EB 
Epidermolysis Bullosa 
EBS 
Epidermolysis Bullosa Simplex 
e.g. 
For Example, (Latin; exempla gratia) 
EC 
Ethics Committee 
CRF 
Case Report Form 
EDC 
Electronic Data Capture 
DEB 
Dystrophic Epidermolysis Bullosa 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotrophin 
HIPAA 
Health Insurance Portability and Accountability Act of 
1996 
Hg 
Mercury 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 16 of 56 
 
 
Table 2: 
Abbreviations and Specialist Terms  (Continued) 
 
Abbreviation or Specialist Term 
Explanation 
ICH 
International Conference on Harmonization 
i.e. 
That Is (Latin; id est) 
IGA 
Investigator’s Global Assessment 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
JEB 
Junctional Epidermolysis Bullosa 
LOCF 
Last Observation Carried Forward 
LSA 
Lesion Surface Area 
MedDRA 
Medical Dictionary for Regulatory Activities 
Ml 
Milliliter 
Mm 
Millimeter 
µMol 
Micro-molar 
NCR 
Not Clinically Relevant 
OTC 
Over-The-Counter 
PK 
Pharmacokinetic 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SI 
Subject Identifier 
SOP 
Standard Operation Procedure 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 
WOCBP 
Women of childbearing potential 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 17 of 56 
 
 
5. 
INTRODUCTION 
Epidermolysis bullosa simplex (EBS) is a rare, genetic skin disease characterized by fragility of 
the skin and mucous membranes resulting in painful blisters and erosions after minor trauma, 
and is associated with significant morbidity and mortality1,2. EBS is both a pediatric and an adult 
disease that tends to affect younger patients most severely. Most patients with EBS have 10% to 
30% of body surface area (BSA) affected by blisters, although there can be wide variations. EBS 
frequently has palmar and plantar involvement, which can significantly affect patients’ mobility 
and quality of life. In addition to blistering and skin infections, patients suffer from pain and 
severe, continuous itching. There are currently no approved treatments for EBS. 
The simplex form is 1 of 3 major types of EB and is classified by skin blister development in the 
basal epidermis3. Those born with EB are often called “Butterfly Children” because, as the 
analogy goes, their skin is as fragile as the wings of a butterfly. The prevalence of inherited EB 
in the US is estimated to be approximately 11 per million live births according to the National 
Epidermolysis Bullosa Registry in the US; there are around 20 new EB cases per 1 million live 
births, of which approximately 92% are EBS4. 
Diacerein 1% Ointment is a topical ointment containing diacerein (4,5-bis[acetyloxy]-9,10- 
dihydro-9,10-dioxo-2-anthracene carboxylic acid, also known as diacetyl-rhein), a highly 
purified anthraquinone derivative, and is being developed for the treatment of EBS. The capsule 
formulation of diacerein, intended for oral use and systemic absorption, was initially approved 
for use in osteoarthritis (OA) in France in 1992 (as Artodar®, ART50®, or Zondar®). Since 
then, it has received marketing authorization in over 30 countries in Europe, South America, and 
Asia. It is classified as a Symptomatic Slow-Acting Drug in OA. Following oral administration 
of the capsule formulation, diacerein is rapidly metabolized to the deacetylated active metabolite, 
rhein. Similarly, diacerein in the topical formulation is hydrolyzed to rhein in the epidermis and 
dermis following administration. Diacerein and rhein have been shown to inhibit the in vitro and 
in vivo production and activity of interleukin-1β (IL-1β) and other pro-inflammatory cytokines. 
It has a novel mode of action that differentiates it from non-steroidal anti-inflammatory drugs 
(NSAIDs) and other conventional forms of drug therapy. 
IL-1β is a pro-inflammatory cytokine that has been linked to a number of inflammatory and 
autoimmune diseases, including rheumatoid arthritis (RA), OA, hemophilic arthropathy, gouty 
arthritis, type 2 diabetes mellitus (T2DM), diabetic nephropathy (DN), and EBS. In vitro and in 
vivo animal studies have shown that both diacerein and its active metabolite rhein inhibit the 
production and activity of pro-inflammatory and pro-catabolic cytokines such as IL-1 and IL6, 
and the expression of inducible nitric oxide synthase (iNOS ) and tumor necrosis factor-α (TNF- 
α). 
Prior to the first application of diacerein in a phase 1 EBS treatment study, a single topical 
application of 50 mg Diacerein 1% Cream was applied to the skin of a patient with EBS5. The 
amount of rhein detected in the patient’s urine was 2.4% of the amount detected in the urine after 
oral administration of the same dose. Pharmacokinetic (PK) analysis of rhein was performed in 2 
patients with EBS from the phase 2 trial described below. Serum and urine samples were 
collected immediately following 4 weeks of administration of Diacerein 1% Cream to 3% of 
these patients BSA. The highest level of rhein in urine was 39.9 ng/ml and the highest level of 
rhein in serum was 20.1 ng/ml. This serum level represents less than 1% of the serum level 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 18 of 56 
 
 
detectable after oral administration of a single dose of 50 mg diacerein.6 These data suggest that 
upon topical administration, diacerein reaches circulation in the form of rhein and is excreted as 
rhein. Additionally, the most commonly reported adverse effects after oral administration, such 
as diarrhea, nausea, and vomiting, occur at only higher systemic concentrations, which should 
not be achieved following topical administration. 
Phase 1 and phase 2 studies of Diacerein 1% Cream for treatment of EBS have been successfully 
completed. Both studies were conducted in Europe under Dr. Johann Bauer as principal 
investigator. 
A phase 1 clinical pilot study of topical Diacerein 1% Cream to reduce blistering in patients with 
EBS-DM (generalized severe type) was completed in 2012 and its results were published in 
2013. Five patients with EBS-DM initially applied Diacerein 1% Cream underneath both armpits 
in the first 6-week open-label phase. Then, each participant received Diacerein 1% Cream for 
one armpit and placebo for the other in a second, randomized, placebo-controlled 6-week phase 
2. Time to loss of efficacy (defined as halving of the effect observed in phase 1) was chosen as 
the primary endpoint. Results showed a statistically significant reduction of blisters within the 
first 2 weeks of the open-label phase 1. In phase 2, there was no loss of efficacy in both the 
treated and placebo groups. 
A phase 2 clinical study was completed in 2015. This was a placebo-controlled, randomized, and 
double-blinded crossover study of 17 randomized and treated patients, ages 4 to 19, diagnosed 
with generalized severe EBS6. A 4-week treatment period and a three month follow-up period 
was performed in both Year 1 and Year 2 of the study, with a cross over of groups (placebo and 
diacerein) between years. During the 4 week treatment period, patients or their caregivers 
applied 3 finger-tip units of Diacerein 1% Cream or placebo onto a pre defined skin area. Three 
percent of the total BSA was chosen, together with the patients, with the pre-requisite that 
significant numbers of blisters were present at Time 0. 
The results of these studies suggest that topical diacerein has the potential to down-regulate the 
activity of IL-1β and reduce the inflammatory effects in the skin of patients with EBS. The 
favorable product profile of diacerein, an anti-IL-1β small molecule, provides a rationale for 
investigating the clinical utility in reducing the frequency or preventing of blister formation in 
patients with EBS. 
Detailed information about the phase 1 and phase 2 study designs and results are presented in the 
Diacerein 1% Ointment Investigator’s Brochure. 
A global randomized, double-blind, phase 2 study comparing the efficacy of diacerein 1% 
ointment to placebo in treating patients with EBS is ongoing. A phase 2, open-label extension 
study evaluating the long term safety of diacerein 1% ointment in treating patients with EBS is 
ongoing. 
This study is an open-label, phase 1 study evaluating the pharmacokinetics of Diacerein 1% 
Ointment in patients with EB. EB (excluding DEB/JEB) patients that complete this study or 
receive at least one dose of study drug will be eligible for an open-label extension study 
conducted under a separate protocol. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 19 of 56 
 
 
5.1. 
Rationale For Use of Patients With All Forms of EB in Maximal Use 
PK Study 
Epidermolysis bullosa (EB) is cluster of inherited disorders defined by skin blistering, structural 
defects and abnormal disruption of the epidermis or epidermal–dermal junction in response to 
minor mechanical trauma. The primary pathophysiologic factor in all types of EB is skin blisters 
and disruption of normal function as a permeability barrier. The outermost part of the skin, 
epidermis, is composed of stratified layers of flattened cells that overlies a basal layer composed 
of columnar cells arranged perpendicularly. This epidermal layer provides a barrier to 
environmental pathogens and insults and regulates the amount of water and electrolytes released 
from the body into the atmosphere through transepidermal water loss (TEWL), and is perturbed 
due to the presence of blistering. The normal permeability barrier resides in the stratum corneum, 
a resilient layer composed of corneocytes and stratum corneum intercellular lipids, and this layer 
is physically separated from underlying structural skin elements when blistering occurs. The 
main EB types can be classified according to extent of body surface area involvement, as well as 
related histopathophysiology. EB simplex (EBS) is characterized by fragility and blistering 
caused by mutations in keratin intermediate filaments of basal keratinocytes. Such mutations 
lead to a conformational change and an increased self-aggregation of the protein. The presence 
of aggregates in the cytoplasm as a result of stress may subsequently lead to the disintegration 
and collapse of the IF network. EBS can affect the majority of the skin in early years or may be 
as little as 5% of body surface area (BSA) in adulthood. Dystrophic EB (DEB) is defined is due 
to defects in type VII collagen. Clinically, patients suffer from blistering of the skin and mucous 
membranes upon minor trauma, resulting in an impaired life quality due to pain and pruritus. 
Patients with DEB may have 80% or more of their BSA affected by disease. 
Based on mechanistic studies and clinical observation, it is likely that inflammatory cytokines 
including IL-1β are also involved in the pathogenesis of various types of EB. There is evidence 
that both EB simplex as well as dystrophic EB pathology is the result of elevated levels of 
cytokines. 
Therefore, a clinical strategy that seeks to reduce the levels of inflammatory molecules is 
justified in both EBS as well as DEB. To this end, inclusion of patients with DEB in a PK study 
that allows follow up may provide some clues as to diacerein autoinflammatory priorities in 
these patients while at the same time allowing for enrollment of patients with more extensive 
skin involvement to help with requirement for maximal skin involvement. 
In order to assess the possibility of diacerein and rhein to be absorbed through skin under 
maximum use conditions, the sponsor proposes applying diacerein ointment to all types of EB 
skin. While, the target indication is EBS, the blistering symptoms are similar across all major 
types of EB, with the major differences being that patients with dystrophic EB typically have 
greater body surface area involvement than those with the simplex form. The epidermal 
permeability barrier is disrupted in all forms of EB, and to help measure extent of topical drug 
absorption under maximum use conditions it is recommended that patients with all forms of EB 
be evaluated. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 20 of 56 
 
 
5.2. 
Risks and/or Benefits to Subjects 
The application of study drug administered in this study is not anticipated to induce therapeutic 
benefit due to the short treatment duration. However, it is anticipated that continued use of the 
study medication (8 weeks on, 8 weeks off) will reduce the blister severity of the affected area. 
EB-Simplex patients who complete this study or receive at least one dose of study drug will be 
eligible for a long-term open label extension study (DEB/JEB patients are not be eligible for the 
extension due to the lack of efficacy data to support any benefit for patients in these subtypes). 
In addition, subjects will receive study drug at no cost during this open label PK study. 
The safety monitoring practices employed by this protocol (i.e. vital signs, clinical and 
laboratory evaluations, and AE questioning) are adequate to protect the subjects’ safety and are 
expected to be sufficient to detect all treatment emergent adverse events (TEAEs). 
The approximate volume of blood planned for collection from each subject over the course of the 
study is not considered to present undue risk to the subjects. No further risk is present if 
additional blood is required for recheck of safety laboratory tests, as deemed necessary by the PI. 
An indirect health benefit to the EB subjects enrolled in this trial is the medical testing received 
at screening and during the study as outlined in this protocol, will be provided at no cost to the 
subject. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of the study is to descriptively characterize the single-dose and steady- 
state pharmacokinetics (PK) of diacerein (if quantifiable) and its active metabolite, rhein, after 
topical application of CCP-020 (diacerein 1% ointment) under maximum use conditions in 
adolescent and adult patients with EB, and in infants/children with EB. 
 
6.2. 
Secondary Objectives 
The secondary objective of the study is to assess the safety and tolerability of single-dose and 
steady-state topical application of CCP-020 (diacerein 1% ointment) in patients with EB. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 22 of 56 
 
 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open label, single period study in 16 to 20 patients with EB consisting of 
infants/children (ages 6 months – 11 years, inclusive) and adolescents/adults (ages 12 and up) 
with at least 6 subjects between the aged 6 months to 11 years, inclusive (infants/children). The 
study will consist of two cohorts as follows: 
1. 8-10 adolescent and adult patients with EB (aged 12 and older) 
a. Lesions encompassing ≥ 2% BSA for study entry. Diacerein application area to 
be ≥ 5% BSA and include lesioned and non-lesioned skin (if lesions account for 
less than 5% BSA); however, topical administration must be ≤30% BSA. 
2. 8-10 infants/children with EB (aged 6 months to 11 years, inclusive) 
a. Lesions encompassing ≥ 2% BSA for study entry. Diacerein application area to 
be ≥ 5% BSA and include lesioned and non-lesioned skin (if lesions account for 
less than 5% BSA); however, topical administration must be ≤30% BSA. 
For adolescent/adult patients with EB (Cohort 1): 
Eligible, consented (assented and/or consent via guardian) adolescent and adult patients aged 12 
and up with EB lesions encompassing ≥ 2% BSA will be enrolled in the study. On Day 1, the 
total surface area of all available areas for application will be quantified and recorded. The 
area(s) surrounding the lesion/lesions, will be marked (with a marker) encompassing no less than 
a total of 5% BSA (across all lesions, total) and separate paper body charts will be completed 
documenting the application area. The area(s) encompassing no less than 5% BSA will be 
defined as the application area(s) and will remain fixed over the course of the 10 Day treatment 
period. On Day 1, the topical dose of CCP-020 will be applied by study staff followed by blood 
sampling for plasma analysis of diacerein and rhein through 8 hours post-application. PK 
samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Days 1 and 10. 
Trough PK samples will be collected on any two available days from Day 3 through Day 9. 
Patients will be discharged from the study site on Day 1 and will continue applications to the 
entire application area for 9 days at home at the same time each day.  For the trough sample 
visits between Days 3 and 9, CCP-020 will be applied after the blood draw. The application area 
should be left uncovered for at least one-hour post-application, after which it is acceptable to 
apply non-absorbent bandages consistent with standard of care. On Day 10, patients will return 
to the study site for a pre-dose blood sample and application of CCP-020 to the application area 
followed by blood sampling for plasma analysis of diacerein and rhein. 
For infant/child patients with EB (Cohort 2): 
Eligible, assented (consented via guardian) infant/child patients aged 6 months to 11 years, 
inclusive with EB lesions encompassing ≥ 2% BSA will be enrolled in the study. On Day 1, the 
total surface area of all available areas for application will be quantified and recorded. The 
area(s) surrounding the lesion/lesions, will be marked (with a marker) encompassing no less than 
a total of 5% BSA (across all lesions, total) and separate paper body charts will be completed 
documenting the application area. The area(s) encompassing no less than 5% BSA will be 
defined as the application area(s) and will remain fixed over the course of the 10 Day treatment 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 23 of 56 
 
 
period. On Day 1, the topical dose of CCP-020 will be applied by study staff followed by blood 
sampling for plasma analysis of diacerein and rhein through 8 hours post-application. PK 
samples will be collected at pre-dose, 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 10. Trough 
samples for Days 3-9 will not be required for this cohort. Patients will be discharged from the 
study site on Day 1 and will continue applications to the entire application area for 9 days at 
home at the same time each day. The application area should be left uncovered for at least one- 
hour post-application, after which it is acceptable to apply non-absorbent bandages consistent 
with standard of care. On Day 10, patients will return to the study site for a pre-dose blood 
sample and application of CCP-020 to the application area followed by blood sampling for 
plasma analysis of diacerein and rhein. For sites participating in the United States (US), children 
under the age of 4 are prohibited from participating due to regulatory restrictions. 
Safety will be monitored throughout the study by repeated clinical, and laboratory evaluations. 
The clinic/study site will attempt to contact subjects using their standard procedures 
approximately 14 days after the last study drug application to determine if any adverse events 
(AEs) have occurred since the last dose of study drug. Subjects who terminate the study early 
will be contacted if the Principal Investigator (PI) deems necessary. 
Subjects (excluding DEB/JEB) that complete this study or receive at least one application of 
study medication will be eligible for an open-label extension study with CCP-020 treatment 
conducted under a separate protocol. 
 
7.2. 
Number of Subjects 
The study will enroll 8-10 adolescent/adult patients with EB and 8-10 infant/child patients with 
EB. The intention is to obtain a full complement of PK samples (on Day 1 and Day 10) on at 
least 8 patients with no patients replaced. However, additional patients may be enrolled to 
achieve this; up to 10 patients per cohort, if is deemed necessary as determined by the Sponsor. 
Only 50% of each cohort (e.g. 4-5 patients) may contain the EB subtypes of DEB and JEB. For 
sites participating in the United States (US), children under the age of 4 are prohibited from 
participating due to regulatory restrictions. 
7.3. 
Treatment Assignment 
All subjects will be dosed open label with CCP-020 (Diacerein 1% ointment). 
 
7.4. 
Dose Adjustment Criteria 
Subjects/caregivers should not modify the study drug application procedure or frequency. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 24 of 56 
 
 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
If any significant study drug intolerance or safety issue occurs the investigator or designee may 
direct the subject/caregiver to discontinue use of the product and withdraw from the study. 
Moderate-to-severe diarrhea has been observed in some patients administered oral diacerein for 
the treatment of osteoarthritis: 
• 
Moderate diarrhea: 5-10 watery stools per day 
• 
Severe diarrhea: >10 watery stools per day 
Study medication applications should be discontinued if the subject experiences moderate or 
severe diarrhea. 
Study medication should also be discontinued if the subject experiences any instance of diarrhea 
with bleeding and there is no clear medical rationale for the occurrence. 
The diarrhea must be reported as an adverse event in the CRF. These subjects should be 
withdrawn from the study. 
Subjects/caregivers should not make study medication applications to infected EBS lesions. 
Infected EBS lesions should be managed following the investigator’s routine practice. The 
infection must be reported as an adverse event in the CRF. 
 
7.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
There are no PK criteria for adjusting the dose in this study. If the site staff is unable to place the 
collection catheter or cannot obtain the samples required for the study, the subject will be 
terminated from the study. 
 
7.5. 
Criteria for Study Termination 
The study may be discontinued at the discretion of Castle Creek Pharmaceuticals, LLC. Some 
examples of reasons for discontinuation are the occurrence of the following: 
• Increased frequency, severity or duration of known AEs 
• Medical, regulatory or ethical reasons affecting the continued performance of the 
study 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 25 of 56 
 
 
Figure 1: 
Study Design 
 
Cohort 1 (adolescents and adults) 
 
CCP-020 (Diacerein 1% Ointment) Application 
 
Screening 
Day 1 
Day 3 - Day 9 
Day 10 
PK Blood Sampling Times 
Pre-dose, 0.5, 1, 
2, 3, 4, 6, and 8 
hours post-dose 
Pre – Dose 
(Samples to be collected on any two 
days prior to CCP-020 application) 
Pre-dose, 0.5, 1, 
2, 3, 4, 6, and 8 
hours post-dose 
 
 
Cohort 2 (infants and children*) 
 
CCP-020 (Diacerein 1% Ointment) Application 
 
Screening 
Day 1 
Day 3 - Day 9 
Day 10 
PK Blood Sampling Times 
Pre-dose, 1, 2, 4, 
6, and 8 hours 
post-dose 
None 
Pre-dose, 1, 2, 4, 
6, and 8 hours 
post-dose 
*Children in the US under the age of 4 are prohibited from participating in this study 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 26 of 56 
 
 
Table 3: 
Schedule of Assessments 
 
Assessment 
Screening 
Application 
Follow 
Up 
Study Day 
-42 
1 
3-91 
3-91 
10 
24 
Informed Consent/Assent 
X 
Inclusion/ Exclusion 
X 
X 
Genotyping Sample 
X2 
Medical History 
X 
Identify Application Area 
X 
X 
Vital Signs 
X 
X 
X 
Physical Exam 
X 
CCP-020 Application 
X 
X 
X 
X 
CCP-020 Application Diary 
X 
X 
X 
X 
Pharmacokinetics 
Full Sampling 
X3 
X3 
Trough Samples 
X4 
X4 
Safety 
Adverse Events5 
X 
X 
X 
X 
X6 
Urine Pregnancy Test7 
X 
X 
X 
Urinalysis 
X 
X 
Lab Tests 
X 
X8 
X 
Body Weight 
X 
X 
1 Visit is eligible to be performed at the subject’s home (Cohort 1) 
2 Only if the subject does not have documented genotype confirming EB 
3 Samples drawn at pre-dose and 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose for Cohort 1; pre-dose, 1, 2, 4, 6, and 8 for 
Cohort 2. 
4 Trough PK samples will be collected on any two available days from Day 3 through Day 9 for Cohort 1 only 
5 At each visit the Investigator should examine the lesions being treated for any adverse events specific to treatment 
6 Phone call only 
7 For WOCBP only 
8 If Day 1 is within 7 days of Screening, labs do not need to be repeated 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 27 of 56 
 
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. Subject/caregiver is able to comprehend and willing to sign an Informed Consent and/or 
Assent Form. 
2. Subject is male or female at least 12 years of age (Cohort 1) or at least 6 months of age to 
11 years, inclusive (Cohort 2) at screening. US only: subjects must be at least 4 years of 
age to 11 years, inclusive (Cohort 2) at time of consent. 
3. The subject must weigh at least 9 kg (19.8 lbs) at Screening. 
4. Subject has a documented genetic mutation consistent with EB. A blood or saliva sample 
will be collected for genetic confirmation if no documented gene mutation data is 
available. 
5. Subject has EB lesions on ≥ 2% body surface area (BSA) and the EB lesions are in the 
following body areas: 
a. Localized: plantar and/or palmar areas 
b. Generalized: arms, legs, torso, hands and feet. 
6. Subject/caregiver agrees to not apply any other topical products to the application area 
during the treatment period 
7. If the subject is a woman of childbearing potential, she has a negative urine pregnancy 
test and agrees to use an approved effective method of birth control, as defined by this 
protocol, for the duration of the study. 
8. Subject is non-pregnant, non-lactating and is not planning for pregnancy during the study 
period 
9. Subject is in good general health and free of any known disease state or physical 
condition which, in the investigator’s opinion, which exposes the subject to an 
unacceptable risk by study participation. 
10. Subject is willing and able to follow all study instructions and to attend all study visits. 
 
8.2. 
Subject Exclusion Criteria 
1. Subject has EB lesions where drug will be applied that are infected (i.e., EB lesions that 
require anti-microbial therapy to treat an infection) 
2. Subject has used any diacerein containing product within 1 month prior to Visit 1 
3. Subject has used systemic immunotherapy or cytotoxic chemotherapy within 60 days 
prior to dosing. 
4. Subject has used systemic steroidal therapy or has used topical steroidal therapy on the 
EB lesions in the application area within 14 days prior to dosing (Note: inhaled, nasal 
sprays, and ophthalmic products containing steroids are allowed) 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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5. Subject has evidence of a systemic infection or has used systemic antibiotics within 7 
days prior to dosing 
6. Subject has used any systemic diuretics or cardiac glycosides or any systemic product 
that, in the opinion of the investigator, might put the subject at undue risk by study 
participation or interferes with the study medication application or the study assessments 
within 30 days prior to dosing 
7. Subject has a current malignancy, or a history of treatment for a malignancy within 2 
years prior to dosing (Note: does not include non-melanoma skin cancer) 
8. Subject currently has diabetes mellitus (HbA1c ≥6.5%) Note: controlled diabetes (HbA1c 
< 6.5%) is also considered exclusionary 
9. Subject has a history of cardiac, hepatic (ALT and or AST >2x ULN, Total bilirubin 
>1.5x ULN at Visit 1), or renal disease (eGFR<30 ml/min/1.73 m2 [MDRD-adults ≥18, 
Bedside Schwartz – children <18]) that, in the opinion of the investigator, might put the 
subject at undue risk by study participation or interferes with the study medication 
application of the study assessments 
10. Subject has an active non-EB skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun 
damage, etc.), or condition (e.g., sunburn) that, in the opinion of the investigator, would 
put the subject at undue risk by study participation or would interfere with the study 
medication application or the study assessments 
11. Subject has a history of sensitivity to any of the ingredients in the study medication 
12. Subject has participated in an investigational drug trial in which administration of an 
investigational study medication occurred within 30 days prior to dosing 
 
8.3. 
Subject Withdrawal Criteria 
Subjects/caregiver will be informed that the subjects are free to withdraw from the study at any 
time and for any reason. 
The investigator may remove a subject from the study if, in the investigator's opinion, it is not in 
the best interest of the subject to continue the study. 
Examples of other reasons subjects may be discontinued from the study are: 
• A change in compliance with an inclusion or exclusion criterion 
• Occurrence of AEs 
• Occurrence of pregnancy 
• Use of a prohibited therapy 
• Failure to maintain the required application frequency 
• The study is discontinued by the sponsor 
In case of premature discontinuation of study participation, efforts will be made to perform all 
final study day assessments. The date the subject is withdrawn from the study and the reason for 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 29 of 56 
 
 
discontinuation will be recorded on the subject’s CRFs. All withdrawn subjects with ongoing 
AEs will be followed as appropriate. 
The investigator must immediately (within 24 hours) notify the Castle Creek Pharmaceuticals, 
LLC assigned study monitor of a subject discontinuation. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 30 of 56 
 
 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
The study medication must be stored in a secure area with limited access under appropriately 
controlled and monitored storage conditions. 
Table 4: 
CCP-020 (Diacerein 1% Ointment) 
 
Investigational Product 
Product Name: 
Diacerein (CCP-020) 1% Ointment 
Dosage Form: 
Ointment 
Unit Dose 
Once-daily application to all EB lesions identified in the 
application area 
Route of Administration 
Topical 
Physical Description 
The study medication is a yellow ointment. 
Manufacturer 
 
 
 
9.2. 
Concomitant Medications 
Concomitant therapies are any new or existing/ongoing therapy received from Visit 1 until 
discharge from the study, including therapies modified for non-medical reasons and therapies 
used for prophylaxis. 
Concomitant therapies include drug (e.g., prescription, over-the-counter [OTC]) and non-drug 
(e.g., chiropractic, physical therapy, energy-based treatments [e.g. lasers, light-based therapy]) 
therapies. Subjects will refrain from receipt of any therapy in compliance with the 
inclusion/exclusion criteria. Subjects should refrain, if possible, from changing the use of any 
concomitant therapies during the study. 
All new or modified concomitant therapies used during the study must be recorded. 
Any new or modified concomitant therapy must be considered to determine if it is related to an 
adverse event (AE). An AE must be reported unless the therapy is modified for non-medical 
reasons (e.g., health insurance purposes) or it is for prophylaxis (e.g., vaccinations, topical 
anesthetics used during blood sampling). 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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9.2.1. 
Permitted & Prohibited therapies 
A non-exhaustive list of products permitted for use are bland, non-medicated 
emollient/moisturizers such as: 
• Emu oil 
• Restore® Dimethicreme 
• A&D® 
• Aquaphor® 
• White petroleum 
• Coconut Oil 
The use of bland, non-medicated emollients/moisturizers must be restricted so as not to interfere 
with the study medication. Therefore, emollients moisturizers may not be used in the application 
area 1 hour prior to the application of study medication and at any time within 6 hours after the 
study medication application. On Days 1 and 10, emollients/moisturizers should not be used 
until after the final PK draw (8 hr). 
The investigator should consult with the Medical Monitor for discussion on any moisturizers or 
therapies in question that are not directly specified in the protocol. 
Routine cleansers and cleaning products, bleach baths, and essential topical antiseptics are 
permitted at least 2 hours before and 6 hours after the study medication application. 
A non-exhaustive list of therapies prohibited during the study are: 
• CBD oil 
• MediHoney 
• Silvadine cream 1% 
• Restore Silver contact layer and 
foam 
• Mepilex® AG 
• Acticoat 
• Aquacel® AG 
• SilvaSorb 
• Silverlon 
• Contreet 
• Sunscreens 
The investigator should notify the Medical Monitor immediately if any prohibited therapies are 
required to ensure subject safety. 
 
9.2.2. 
Bandaging/Dressing Use 
Bandaging is not prohibited provided the subject maintains their current bandaging routine and 
remains consistent throughout their participation in the study. However, subjects should be 
restricted from using dressings to cover the application area for the first hour after study 
medication application. 
In general, the types of dressings to be used for the study should be minimally absorptive, non- 
adhesive (to the skin), not-intended to treat the wounds (i.e. antimicrobial, honey, keratin, 
collagen and/or impregnated dressings) and used in a manner that, based on the subject’s 
experience, do not promote new lesion emergence. 


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CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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9.3. 
Treatment Compliance 
Each subject/caregiver will record the subject’s compliance with the study medication 
application frequency (including time dosed) on a daily basis using a paper diary. 
9.4. 
Randomization and Blinding 
This is an open label study; no randomization or blinding is employed. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The study medication is a yellow colored ointment and will be packaged in aluminum tubes that 
each contain 25 grams of sterile study medication. 
A bulk supply of Diacerein 1% Ointment study medication, with one tube in each carton, will be 
provided to each investigational center. A sufficient supply of study medication will be provided 
to each site prior to the initiation of subject enrollment and replenished as needed. 
 
10.2. 
Study Drug Packaging and Labeling 
A bulk supply of Diacerein 1% Ointment study medication, with one tube in each carton, will be 
provided to each investigational center. A sufficient supply of study medication will be provided 
to each site prior to the initiation of subject enrollment and replenished as needed. 
Each study medication carton will be labeled with a one-part label that is completed when the 
tube is dispensed, remains attached to the carton. 
The carton label shows at least the following: 
• Protocol number 
• Tube number 
• Study medication identity 
• Investigational drug warning 
• Space to enter the SI 
Each study medication tube will be labeled with a two-part label. Both parts of the label are 
completed when the tube is dispensed, one part of the completed label remains attached to the 
tube, the other part (tear-off) is separated and attached to the subject’s drug accountability log. 
Both parts of the carton label show at least the following: 
• Protocol number 
• Tube number 
• Study medication identity 
• Storage conditions 
• Instructions for use 
• Sponsor information 
• Investigational drug warning 
• Space to enter the SI 
• Space to enter the date dispensed 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 34 of 56 
 
 
10.3. 
Study Drug Storage 
Study drug must be stored between 59°F to 86°F (15°C to 30°C) 
 
10.4. 
Study Drug Formulation 
Table 5: 
Study Medication Formulation 
10.5. 
Study Drug Dispensation 
The amount of study drug dispensed to each subject on Day 1 will depend on the subject’s 
% BSA of lesions identified in the application area. 
Table 6: 
Number of Tubes of Study Drug (by %BSA) 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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Table 6: 
Number of Tubes of Study Drug (by %BSA) (Continued) 
 
1 Assumptions based on 23g of product will be used per tube 
 
10.6. 
Study Drug Administration 
The study medication is for external, topical use on the subject’s EB lesions and assigned, un- 
involved skin only as defined by the application area. 
At Study Day 1, an investigational center staff member will review the appropriate application 
technique with the subject/caregiver. 
To perform a study medication application, the subject/caregiver should: 
• Wash her/his hands before starting the application 
• Apply sufficient quantity of the assigned study medication to cover all EB lesions and 
to uninvolved skin within the application area with a thin layer and gently rub it in 
• For at least 6 hours after a study medication application, DO NOT: 
− Wash/submerge the treated EB lesions 
− Participate in any activity that might result in profuse perspiration (e.g., vigorous 
exercise, saunas, steam rooms, etc.). 
• Follow the instructions for blister lancing management and care 


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CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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• Not cover the treated area with any type of bandage or dressing for 1 hour after the 
application per clinical discretion of the PI 
• Wash her/his hands after completing the application. 
10.6.1. 
Application Area 
EB patients that have ≥2% BSA of lesions will be instructed to apply the ointment to all 
designated lesions identified by the investigator. In addition, subjects that do not have at least 
5% BSA will be instructed to apply the ointment to lesions as well as surrounding, uninvolved 
skin so that the total application is at minimum, 5% BSA not to exceed 30% BSA. This will be 
the “application area”. The application area will be defined at Day 1 and will not change 
throughout the 10 day application period. The application area will be outlined using an 
appropriate marking tool in order to ensure the subject consistently applies the ointment to the 
same area each day as directed by the site staff. In addition, body charts will be kept with the site 
and a copy given to the patients that clearly outline the application area. 
An investigational center staff member will dispense a blister lancing kit and instructions to 
every subject/caregiver as appropriate. The subject will be instructed to lance all EB blisters in 
the application area within 24 hours. Blister lancing kits and written instructions for use of the 
kits will be provided to each investigational center prior to the initiation of subject enrollment; 
however, if the subject prefers to use alternative lancing kits, this is acceptable. 
EB lesions that are excluded from applications with the study medication (e.g. those exceeding 
30% BSA) may be treated following the typical standard of care regimen used by the subject as 
long as the standard of care regimen is permitted by protocol and does not include prohibited 
medications. 
No study drug applications should be made to infected lesions. If study medication is not applied 
to any EB lesions because they are infected this situation must be noted as an adverse event. 
10.7. 
Study Drug Accountability 
The investigator or designee will maintain an accurate record of the receipt of the study 
medications as shipped by Castle Creek Pharmaceuticals, LLC (or designee), including the date 
received and the condition of the study medications. One copy of this receipt will be returned to 
Castle Creek Pharmaceuticals, LLC when the contents of the study medication shipment have 
been verified and one copy maintained in the study file. In addition, an accurate study 
medication disposition record will be kept, specifying the amount dispensed to each 
subject/caregiver and the date of dispensing. This inventory record will be available for 
inspection at any time. At the completion of the study, the original inventory record will be 
available for review by Castle Creek Pharmaceuticals, LLC upon request. 
 
 
10.8. 
Study Drug Handling and Disposal 
At the completion of the study, all unused study medication will be returned to Castle Creek 
Pharmaceuticals, LLC (or designee) for disposal per Castle Creek Pharmaceuticals, LLC’s (or 
designee’s) written instructions. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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11. 
PHARMACOKINETIC ASSESSMENTS 
11.1. 
PK Blood Sample Collection 
Sites will receive a laboratory manual with detailed instructions for collecting, handling, and 
processing PK samples. Sites will receive PK sample kits from the central laboratory. 
On Day 1, the topical dose of CCP-020 will be applied by study staff followed by blood 
sampling for plasma analysis of diacerein and rhein through 8 hours post-application. PK 
samples for Cohort 1 will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on 
Days 1 and 10 and PK samples for Cohort 2 will be collected at pre-dose, 1, 2, 4, 6, and 8 hours 
post-dose on Days 1 and 10. Trough PK samples will be collected on any two available days 
from Day 3 through Day 9 for Cohort 1 only. For the trough sample visits between Days 3 and 9 
(Cohort 1), CCP-020 will be applied at the site after the blood draw. The dosing area should be 
left uncovered for at least one-hour post-application and then it is acceptable to apply non- 
absorbent bandages consistent with standard of care. On Day 10, patients will return to the study 
site for a pre-dose blood sample and application of CCP-020 to the application area followed by 
blood sampling for plasma analysis of diacerein and rhein through 8 hours post-application. 
For both cohorts on Days 1 and 10, void-volume catheters will be placed to obviate multiple 
needle sticks in blood sampling. 
Table 7: 
PK Blood Sample Collection Times 
 
Cohort 
Day 1 
Day 3-9 
Day 10 
Hour1 
Pre 
0.5 
1 
2 
3 
4 
6 
8 
Pre 
Pre 
Pre 
.5 
1 
2 
3 
4 
6 
8 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Collection time window allowances will be included in a document separate from this protocol 
 
11.2. 
Total Volume of Blood Collected 
The total blood volume collected for each subject for the entire study will be compliant with 
WHO guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 on whether blood sample for genotyping is necessary. 4 mL is required for genotyping 


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CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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11.3. 
Sample Analysis 
Individual and mean graphs of plasma diacerein (if measurable) and rhein concentrations versus 
time after administration of CCP-020 will be constructed and displayed for relevant treatment 
comparisons, as data permit. 
Plasma concentrations of diacerein and rhein will be summarized by treatment using descriptive 
statistics (sample size, mean, median, coefficient of variation [CV%], standard deviation [SD], 
minimum, and maximum). Corresponding by-subject data listings will be tabulated. The 
summary statistics for each scheduled time will only be reported when at least 50% of subjects 
have quantifiable concentrations. 
Derived plasma PK parameters (Cmax, Tmax and AUC), if available, for diacerein and rhein 
will be summarized by treatment using descriptive statistics (sample size, arithmetic and 
geometric mean, CV%, SD of the arithmetic mean, median, minimum, and maximum). 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 39 of 56 
 
 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Demographic/Medical History 
At the timepoints specified in the Study Flow Chart, the investigator or designee will interview 
each subject/caregiver to obtain demographic information including date of birth, sex at birth, 
race and ethnicity. 
Medical history information will be recorded including all medical conditions and disease states 
that, at Day 1: 
• Are ongoing 
• Require concomitant therapy 
• Are, in the opinion of the investigator, relevant to the subject’s study participation. 
12.1.2. 
Vital Signs 
At the timepoints specified in the Study Flow Chart, a qualified staff member will measure each 
subject’s vital signs. The following items will be measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 
• Blood pressure (systolic and diastolic) after the subject remains at rest for at least 5 
minutes (to the extent that this is possible with infants/children) 
 
12.1.3. 
Weight 
At the timepoints specified in the study flow chart, the subject’s weight will be collected. 
 
12.1.4. 
Physical Examination 
At the timepoints specified in the Study Flow Chart, the investigator or designee will perform a 
complete physical examination that will include, at a minimum, evaluation of the following body 
systems and organs: 
• Skin 
• Cardiovascular system 
• Respiratory system 
• Head, eyes, ears, nose and throat 
• Lymph nodes 
• Abdominal Exam 


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CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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12.1.5. 
Laboratory Assessments 
Sites will receive a laboratory manual with detailed instructions for collecting, handling, and 
processing samples. Sites will receive clinical laboratory kits from the central laboratory. 
Subjects will not be required to fast prior to laboratory sample collection. 
 
12.1.5.1. 
Hematology 
At the timepoints specified in the Study Flow Chart, the following hematology labs will be 
drawn: 
 
Hematocrit 
% and absolute: 
Hemoglobin 
Basophils 
Platelet count 
Eosinophils 
Red blood cell morphology 
Lymphocytes 
Red blood cell count 
Monocytes 
White blood cell count 
Neutrophils 
White blood cell differential 
The results of the clinical laboratory tests will be reported on the central laboratory’s standard 
reports. 
12.1.5.2. 
Blood Chemistry 
At the timepoints specified in the Study Flow Chart, the following clinical chemistry labs will be 
drawn: 
 
Albumin 
Glucose 
Alkaline phosphatase (ALP) 
HbA1c 
Alanine aminotransferase (ALT) 
Lactate dehydrogenase (LDH) 
Amylase 
Lipase 
Aspartate aminotransferase (AST) 
Potassium 
Blood urea nitrogen (BUN) 
Sodium 
Bicarbonate 
Total bilirubin 
Chloride 
Total protein 
Creatinine 
Uric acid 
Gamma-glutamyl transferase (GGT) 
The results of the clinical laboratory tests will be reported on the central laboratory’s standard 
reports. 
 
12.1.5.3. 
Urinalysis 
A complete urinalysis will be performed at the timepoints listed in the schedule of assessments. 
 
12.1.5.4. 
Pregnancy Screen 
At the timepoints specified in the Study Flow Chart, a qualified staff member will perform a 
urine pregnancy test for subjects who are WOCBP. Sites will receive urine pregnancy test kits 
from the central laboratory. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 41 of 56 
 
 
Subjects who are WOCBP must have a negative pregnancy test result at Day 1 to be enrolled in 
the study. 
If the result of any post-study medication application urine pregnancy test is positive, the subject 
will be withdrawn from the study and the subject’s pregnancy will be documented and followed 
until completion and for at least 6 weeks after birth. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 42 of 56 
 
 
13. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
Adverse events will be monitored throughout the study and immediately reported on the 
appropriate AE eCRF. 
13.1. 
Adverse events(s) 
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. All adverse events, including observed or volunteered 
problems, complaints, or symptoms, are to be recorded on the appropriate eCRF. 
At each visit the Investigator should examine the lesions being treated for any adverse events 
specific to treatment. Events should be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of the first study medication application until 30 days after the 
subject’s last study medication application. 
Subject/caregivers should be instructed to report any adverse event that they experience to the 
Investigator. Beginning with the start of the first study medication application, investigators 
should make an assessment for adverse events at each visit and record the event on the 
appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure. 
Any medical condition already present at screening should not be reported as an adverse event 
unless the medical condition or signs or symptoms present at screening worsens in severity or 
seriousness at any time during the study. In this case, it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (e.g., physical examination) 
findings that are detected during the study or are present at screening and worsen during the 
study to the point where the investigator defines it as clinically significant should be reported as 
adverse events. The Investigator will exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. Clinically significant abnormal laboratory values occurring during the clinical study 
will be followed until repeat tests return to normal, stabilize, or are no longer clinically 
significant. Any abnormal test that is determined to be an error does not require reporting as an 
adverse event. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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13.2. 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “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). 
 
13.3. 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information. 
13.4. 
Assessments of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes or no. 
13.4.1. 
Assessment of Severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
13.4.2. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
 
Association 
Definition 
Not related 
(1) the existence of a clear alternative explanation (e.g., mechanical bleeding at 
surgical site) or (2) non-plausibility, e.g., the subject is struck by an automobile 
or cancer developing a few days after drug administration. 
Unlikely 
There is no medical evidence to suggest that the AE may be related to study drug 
usage, or there is another more probable medical explanation. 
Possible 
There is medical evidence to suggest that there is a reasonable possibility that the 
AE may be related to study drug usage. However, other medical explanations 
cannot be excluded as a possible cause. 
Probable 
There is strong medical evidence to suggest that the AE is related to study drug 
usage. 
Definite 
A clinical event, including laboratory test abnormality (if applicable), in which 
there is no uncertainty in its relationship to test drug (e.g., positive re-challenge). 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 44 of 56 
 
 
The following factors should also be considered: 
• The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
• Concomitant drug- 
o The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
• Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
• The pharmacology and pharmacokinetics of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
 
13.5. 
Adverse Events of Special Interest 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor may be appropriate. Suspicion of such an event might warrant further 
investigation in order to characterize and understand it. The following AEs will be categorized 
as AEs of special interest (AESIs) in this study: 
• Moderate to severe diarrhea 
• Hepatic injury 
• Pancreatitis 
• Urticaria/angioedema 
• Epidermal necrolysis 
• Drug reaction with eosinophilia and systemic symptoms (DRESS) 
• Purpura/cutaneous vasculitis 
• Jaundice 
All AESIs will be summarized as narratives in the Clinical Study Report. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 45 of 56 
 
 
13.6. 
Serious Adverse events (SAE) 
An adverse event or adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death, 
• A life-threatening adverse event, 
− NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in 
view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death. It does not include an event that, had it occurred in a 
more severe form, might have caused death. 
• Requires hospitalization or prolongation of existing hospitalizations, 
− NOTE: Any hospital admission with at least one overnight stay will be considered 
an inpatient hospitalization. An emergency room visit without hospital admission 
will not be recorded as a SAE under this criterion, nor will hospitalization for a 
procedure scheduled or planned before signing of informed consent. However, 
unexpected complications and/or prolongation of hospitalization that occur during 
elective surgery should be recorded as adverse events and assessed for 
seriousness. Admission to the hospital for social or situational reasons (i.e., no 
place to stay, live too far away to come for hospital visits) will not be considered 
inpatient hospitalizations. 
• A persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions, 
• A congenital anomaly/birth defect, or 
• An important medical event. 
− NOTE: Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalizations, or the development of 
drug dependency. 
 
13.6.1. 
Serious Adverse Event Reporting/Adverse Events of Special Interest – 
Procedures for Investigators 
 
13.6.1.1. Initial Reports 
All SAEs/AESI, regardless of causality, occurring from the time of informed consent until 30 
days after the subject’s last application of study medication, must be reported to Medpace 
Clinical Safety within 24 hours of the knowledge of the occurrence (this refers to any adverse 
event that meets any of the aforementioned serious criteria). SAEs/AESI occurring after the 30- 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 46 of 56 
 
 
day follow-up period AND considered related to study drug must also be reported to the 
Sponsor. 
To report an SAE/AESI, complete the SAE/AESI form electronically in the electronic data 
capture (EDC) system for the study. When the form is completed, Medpace Safety personnel will 
be notified electronically. If the event meets serious criteria and it is not possible to access the 
EDC system, send an email to Medpace Safety at medpace-safetynotification@medpace.com or 
call the Medpace SAE/AESI hotline (phone number listed below), and fax the completed paper 
SAE form to Medpace (fax number listed below) within 24 hours of awareness. When the EDC 
system becomes available, the SAE/AESI information must be entered within 24 hours of the 
system becoming available. 
 
 
 
 
 
 
 
13.6.1.2. Follow-up Reports 
The Investigator must continue to follow the subject until the SAE/AESI has subsided or until 
the condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE/AESI 
form electronically in the EDC system for the study and submit any supporting documentation 
(e.g., subject discharge summary, autopsy reports, etc.) to Medpace Clinical Safety via fax or e- 
mail. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs/AESI. 
13.6.1.3. Expedited Reports 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the FDA, applicable competent 
authorities in all the Member States concerned, and to the Central Ethics Committee, and in any 
case, no later than 7 days after knowledge by the Sponsor of such a case, and that relevant 
follow-up information will subsequently be communicated within an additional 8 days. 
All other suspected unexpected serious adverse reactions/AESI will be reported to the FDA, 
applicable competent authorities concerned and to the Central Ethics Committee concerned as 
soon as possible but within a maximum of 15 days of first knowledge by the Sponsor. 
The Sponsor will also inform all investigators as required. 
 
13.6.1.4. Pregnancy Reporting 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (e.g., hysterectomy, bilateral tubal ligation, bilateral 
oophorectomy) or is not postmenopausal. Postmenopausal is defined as ≥12 months with no 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 47 of 56 
 
 
menses without an alternative medical cause. Women who are WOCBP and are using an active 
method of birth control, are practicing abstinence or where the partner is sterile (e.g., 
vasectomy), should be considered to be WOCBP. 
Sexually active WOCBP must use an effective method of birth control for the duration of study 
participation in a manner such that risk of failure is minimized. Periodic and/or temporary 
abstinence such as declaration of abstinence during study participation or fertility awareness- 
based methods to prevent pregnancy (including but not limited to symptothermal and ovulation 
estimation by either calendar day or salivary/cervical secretions) are not considered effective 
methods of birth control; however, true [absolute] sexual abstinence (i.e., in line with the 
preferred and usual lifestyle of the patient) may be permitted. Effective methods of birth control 
approved for use in this study are: 
• Implants (e.g., Norplant ® system) 
• Injectable (e.g., Depo-Provera®) 
• Transdermal patch 
• Combined oral contraceptives 
• Barrier methods (condoms and diaphragm with spermicide) – note: double barrier 
method is required if no other methods of birth control are in use 
• Intrauterine devices (e.g. ParaGard® and Mirena®) 
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for a pregnancy. The subject/caregiver 
must sign an informed consent/assent form documenting this discussion. During the trial, all 
WOCBP will be instructed to contact the investigator immediately if they suspect they might be 
pregnant (e.g., missed or late menstrual period). 
If a subject becomes pregnant during the study, or within 30 days of discontinuing study 
medication, the Investigator should report the pregnancy to Medpace Clinical Safety within 24 
hours of being notified. Medpace Clinical Safety will then forward the Exposure in utero form to 
the Investigator for completion. 
If a subject/caregiver or investigator suspects that the subject may be pregnant prior to study 
medication administration, the study medication must be withheld until the results of a 
pregnancy test are available. If pregnancy is confirmed, the subject must not receive study 
medication and must be discharged from the study. 
If, following study medication administration, it is determined that the subject may have been or 
was pregnant at the time of study medication exposure (including at least 2 days after study 
medication administration), the subject will immediately be withdrawn from the study. The 
investigator must immediately (within 24 hours) notify the Castle Creek Pharmaceuticals, LLC 
Medical Monitor. 
Protocol-required procedures for trial discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy. Other appropriate pregnancy follow-up procedures 
should be considered if indicated. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 48 of 56 
 
 
The subject’s pregnancy should be followed by the Investigator until completion and for at least 
6 weeks after birth. If the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify Medpace Clinical Safety. At the completion of the pregnancy, the 
Investigator will document the outcome of the pregnancy. If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the 
procedures for reporting an SAE. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 49 of 56 
 
 
14. 
STATISTICS 
14.1. 
Analysis Populations 
Pharmacokinetic Evaluable Population: The PK Evaluable Population will comprise all subjects 
receiving at least one dose of CCP-020 who have sufficient (> 4 quantifiable concentrations) 
plasma concentration data to calculate PK parameters for rhein and if possible, diacerein. 
Pharmacokinetic Concentration Population: The PK Concentration Population will comprise all 
subjects receiving at least one dose of CCP-020 who have at least one quantifiable plasma 
concentration for rhein and if possible, diacerein. 
Safety Population: The safety population will consist of all subjects who receive any amount of 
study drug. 
 
14.2. 
Pharmacokinetic Analysis 
Summaries of plasma concentration will be based on PK Concentration Population. 
Individual and mean graphs of plasma diacerein (if measurable) and rhein concentrations versus 
time after single dose and multiple dose of CCP-020 will be constructed and displayed for 
relevant comparisons, as data permit. 
Plasma concentrations of diacerein and rhein will be summarized by Cohort and EB type using 
descriptive statistics (sample size, mean, median, coefficient of variation [CV%], standard 
deviation [SD], minimum, and maximum). Corresponding by-subject data listings will be 
tabulated. The summary statistics for each scheduled time will only be reported when at least 
50% of subjects have quantifiable concentrations. 
Summaries of plasmas PK parameters will be based on PK Evaluable Population. 
Derived plasma PK parameters (Cmax, tmax and AUC), if available, for diacerein and rhein will 
be summarized by Cohort and EB type using descriptive statistics (sample size, arithmetic mean, 
CV%, SD of the arithmetic mean, median, minimum, and maximum). Geometric mean and 
geometric CV will also be provided for Cmax and AUC. Corresponding by-subject data listings 
will be tabulated. 
14.3. 
Safety Analysis 
The number and percentage of subjects reporting any treatment-emergent AE will be tabulated 
by system organ class and preferred term for each Cohort and EB type (coded using Medical 
Dictionary for Regulatory Activities). Treatment-emergent AEs will be further classified by 
maximum severity and relationship to treatment. 
Physical examinations, electrocardiogram, vital signs, application site assessment, and clinical 
laboratory test data (observed and change from baseline) will be summarized using appropriate 
descriptive statistics. 


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CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of Castle Creek 
Pharmaceuticals, LLC will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Castle Creek Pharmaceuticals, LLC or its 
representatives. This will be documented in a Clinical Study Agreement between Castle 
Creek Pharmaceuticals, LLC and the investigator. 
During the study, a monitor from Castle Creek Pharmaceuticals, LLC or representative will have 
regular contacts with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data is being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study. This will require access to all records for each patient (e.g., 
clinic charts). 
• Record and report any protocol deviations not previously sent to Castle Creek 
Pharmaceuticals, LLC. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Castle Creek Pharmaceuticals, LLC, and their 
representatives and confirm those SAEs that met criteria for reporting have been 
forwarded to the IRB/EC, as applicable. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
 
15.2. 
Audits and Inspections 
Authorized representatives of Castle Creek Pharmaceuticals, LLC, a regulatory authority, an 
Independent Ethics Committee or an Institutional Review Board may visit the site to perform 
audits or inspections, including source data verification. The purpose of a Castle Creek 
Pharmaceuticals, LLC audit or inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice guidelines of the International Conference on Harmonization, and any applicable 
regulatory requirements. The investigator should contact Castle Creek Pharmaceuticals 
immediately if contacted by a regulatory agency about an inspection. 


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Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


Castle Creek Pharmaceuticals LLC 
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Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 52 of 56 
 
 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
investigator must submit written approval to Castle Creek Pharmaceuticals, LLC before he or she 
can enroll any patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Castle Creek Pharmaceuticals, LLC will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements. 
 
16.3. 
Written Informed Consent 
The investigator at each investigational center will ensure that written informed consent forms 
that provide information about the study will be given to adult subjects. For child/adolescent 
subjects, written informed consent and assent forms will be given to the caregiver and to the 
applicable subject, respectively. Informed consent forms will contain all the elements required by 
the ICH E6 Guideline for GCP and any additional elements required by local regulations. The 
information provided in the informed consent will be in a language understandable to the adult 
subjects or caregiver of child/adolescent subjects. 
The investigator will provide the subject and/or caregiver sufficient time to consider whether to 
participate in the trial. The investigator will explain to the subject/caregiver that trial 
participation is voluntary and withdrawal from the study is allowed at any time and withdrawal 
will not adversely affect the subject’s medical care. 
At the first study visit, prior to the initiation of any study related procedures, subjects/caregivers 
will be asked to give written informed consent, and child/adolescent subjects will be asked to 
give assent, after having been informed of the nature of the study, study procedures and 
restrictions and risks and benefits. The informed consent and assent documents, as applicable, 
must be signed and dated by the subject/caregiver prior to study participation. Copies of the 
signed informed consent and assent documents must be given to the subject/caregiver. 


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CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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The US FDA does not define the required elements of an assent; however, they must be accurate, 
not be coercive and must incorporate age appropriate wording. The assent must have a date and 
signature line for the child. Use of an assent is not a substitute for parental permission. 
Parents/guardians (caregivers) must be given an IRB/EC approved ICF to review, sign and date. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 54 of 56 
 
 
17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Electronic Case Report Forms 
Adequate and accurate case records will be maintained, and all relevant observations and data 
related to the study will be recorded. This will include at minimum, medical history/physical 
examination, hematology, clinical chemistry, inclusion and exclusion criteria, drug 
administration, and a record of sample collection, clinical assessments, AEs, and final 
evaluation, as appropriate. 
Electronic eCRFs will be used in this study. The eCRF will be electronically signed and dated by 
the Principal Investigator or his designee after his/her review. After the completion of the study, 
completed eCRFs will be retained in the archives. 
Completed eCRFs will be reviewed by the study monitor in the electronic data capture system 
against the source documentation for accuracy and completeness. 
 
17.2. 
Inspection of Records 
Castle Creek Pharmaceuticals, LLC will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and study source documents, and other records relative to study conduct. 
 
17.3. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for Castle Creek 
Pharmaceuticals, LLC or the Regulatory Authority to review any documentation relating to the 
study, the Investigator must permit access to such records. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
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18. 
PUBLICATION POLICY 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
If the study is being conducted as part of a multicenter clinical study, data from all sites 
participating in the study will be pooled and analyzed by the Sponsor or the Sponsor’s designee. 
The first publication of the study results shall be made in conjunction with the results from other 
study sites as a multicenter publication. If a multicenter publication is not forthcoming within 24 
months of completion of the study at all sites, the investigator may publish or present the results 
generated at his or her site. 
The investigator will provide the Sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication. The Sponsor shall inform the investigator in writing of any changes or deletions 
in such presentation or publication required to protect the Sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results. At the expiration of such 60-day period, the 
investigator may proceed with the presentation or submission for publication unless the Sponsor 
has notified the institution or the investigator in writing that such proposed publication or 
presentation discloses the Sponsor’s confidential and proprietary technical information. Further, 
upon the request of the Sponsor, the investigator will delay the publication or presentation for an 
additional 90 days to permit the Sponsor to take necessary actions to protect its intellectual 
property interests. 


Castle Creek Pharmaceuticals LLC 
CCP-020 (Diacerein 1% Ointment) 
Protocol No: CCP-020-101 
Original Protocol: 07 February 2018 
Page 56 of 56 
 
 
REFERENCES 
1. Salavastru, C.M. et al, Recommended strategies for epidermolysis bullosa management in 
Romania. Maedica (Buchar), 2013. 8(2): p.200-5 
2. Hon, K.L., et al., Age and etiology of childhood epidermolysis bullosa mortality. J 
Dermatolog Treat, 2015. 26(2): p. 178-82. 
3. Fine, J.D., et al., Inherited epidermolysis bullosa: updated recommendations on diagnosis 
and classification. J Am Acad Dermatol, 2014. 70(6): p. 1103-26. 
4. Fine, J., Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and 
Prevalence Estimates From the National Epidermolysis Bullosa Registry. JAMA 
Dermatology, 2016: p. 2473. 
5. Nicolas, P., Clinical Pharmacokinetics of Diacerein, Clin Pharmacokinet, 1998 Nov; 35 
(5), p. 347-59. 
6. Wally, V., et. al., Diacerein for the treatment of epidermolysis bullosa – a phase II 
randomized, placebo controlled, double-blind multi-center clinical trial. Presented at the 
25th European Academy of Dermatology and Venerology Congress, 2016 October 2, 
Vienna, Austria. 

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN 
 
A MULTI-CENTER STUDY TO EVALUATE THE 
PHARMACOKINETICS OF DIACEREIN AND RHEIN AND THE 
SAFETY OF DIACEREIN AFTER MAXIMUM USE, TOPICAL 
ADMINISTRATION OF CCP-020 (DIACEREIN 1% OINTMENT) TO 
PATIENTS WITH EPIDERMOLYSIS BULLOSA (EB) 
 
 
Protocol Number: 
CCP-020-101 
EudraCT No: 
2018-000439-29 
IND Number: 
131,384 
Study Medication: 
CCP-020 (Diacerein 1% Ointment) 
Sponsor: 
Castle Creek Pharmaceuticals, LLC 
6 Century Drive, 2nd Floor 
Parsippany, NJ 07054 
Current Protocol: 
V1.0 / February 07, 2018 
 
 
SAP: 
V1.0 / January 7, 2019 


DocuSign Envelope ID: 27C69524-87C1-4B4E-97E2-7FC6388D7002 
 
Castle Creek Pharmaceuticals, LLC 
CCP-020-101 Statistical Analysis Plan 
Page 2 of20 
 
Protocol: A Multi-center Study to Evaluate the Pharmacokinetics of Diacerein and 
Rhein and the Safety of Diacerein after Maximum Use, Topical Administration of CCP- 
020 (Diacerein 1% ointment) to Patients with Epidermolysis Bullosa (EB) 
Protocol Number: 
CCP-020-101 
Current Protocol: 
SAP: 
Vl.0 / February 07, 2018 
Vl.0 / January 7, 2019 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
f. 


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CCP-020-101 Statistical Analysis Plan 
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TABLE OF CONTENTS 
1 
SUMMARY OF CHANGES ........................................................................................................... 5 
2 
INTRODUCTION ........................................................................................................................... 6 
3 
STUDY OBJECTIVES .................................................................................................................... 6 
3.1 
Primary Objective .................................................................................................................. 6 
3.2 
Secondary Objectives ............................................................................................................. 6 
4 
STUDY OVERVIEW ...................................................................................................................... 6 
4.1 
Study Design .......................................................................................................................... 6 
4.2 
Randomization and Blinding .................................................................................................. 9 
4.3 
Investigational Medicinal Products ...................................................................................... 10 
4.4 
Duration of Treatment .......................................................................................................... 10 
5 
CRITERIA FOR EVALUATION ................................................................................................. 10 
5.1 
Pharmacokinetics ................................................................................................................. 10 
5.2 
Safety ................................................................................................................................... 10 
6 
STATISTICAL METHODOLOGY .............................................................................................. 11 
6.1 
General Statistical Considerations ....................................................................................... 11 
6.2 
Analysis Populations ............................................................................................................ 11 
6.2.1 
Safety Population .................................................................................................... 11 
6.2.2 
Pharmacokinetic Concentration Analysis Set ......................................................... 11 
6.2.3 
Pharmacokinetic Evaluable Population ................................................................... 11 
6.3 
Subject Disposition .............................................................................................................. 11 
6.4 
Eligibility Criteria ................................................................................................................ 11 
6.5 
Protocol Deviation ............................................................................................................... 12 
6.6 
Demographic and Baseline Characteristics .......................................................................... 12 
6.7 
Medical History and Genotyping Sample ............................................................................ 12 
6.8 
Concomitant Medications/Procedures .................................................................................. 12 
6.9 
Treatment Compliance/Drug Accountability ....................................................................... 13 
6.10 Diary..................................................................................................................................... 13 
6.11 Safety Analyses .................................................................................................................... 13 
6.11.1 Adverse Events ........................................................................................................ 13 
6.11.2 Serious Events ......................................................................................................... 14 
6.11.3 Adverse Events of Special Interest .......................................................................... 14 
6.11.4 Treatment-Emergent Adverse Events ..................................................................... 15 
6.11.5 Vital Signs and Weight ........................................................................................... 16 
6.11.6 Laboratory Assessments .......................................................................................... 16 
6.11.6.1 
Hematology ........................................................................................................ 16 
6.11.6.2 
Blood Chemistry ................................................................................................. 17 
6.11.6.3 
Urinalysis ........................................................................................................... 17 
6.11.6.4 
Pregnancy Screen ............................................................................................... 18 
6.11.7 Physical Examination .............................................................................................. 18 


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6.11.8 Follow-Up Phone contact ........................................................................................ 18 
7 
GENERAL INFORMATION ........................................................................................................ 18 
7.1 
Statistical Software ............................................................................................................... 18 
7.2 
Format .................................................................................................................................. 19 
8 
APPENDIX .................................................................................................................................... 20 
8.1 
Study Flow Chart ................................................................................................................. 20 


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CCP-020-101 Statistical Analysis Plan 
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1 
SUMMARY OF CHANGES 
 
SAP Version History 
Version Date 
Description of Changes 
0.1 
March 21, 2018 
Original Document 
0.2 
October 26, 2018 
Update Section 5.1 by adding Nuventra which was 
contracted to perform the statistical analysis of PK data 
0.3 
December 28, 2018 
Accepted revision 
1.0 
January 7, 2019 
Deleted language about PK analysis in Section 5.1 


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CCP-020-101 Statistical Analysis Plan 
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2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a description of the statistical methods and 
procedures to be implemented for the analyses of data from Castle Creek Pharmaceuticals, 
LLC Protocol CCP-020-101. Any deviations from this analysis plan will be substantiated by 
sound statistical rationale and will be documented in the final clinical study report. 
 
3 
STUDY OBJECTIVES 
 
3.1 
Primary Objective 
The primary objective of the study is to descriptively characterize the single-dose and steady 
state pharmacokinetics (PK) of diacerein (if quantifiable) and its active metabolite, rhein, after 
topical application of CCP-020 (diacerein 1% ointment) under maximum use conditions in 
adolescent and adult patients with EB, and in infants/children with EB. 
 
3.2 
Secondary Objectives 
The secondary objective of the study is to assess the safety and tolerability of single-dose and 
steady-state topical application of CCP-020 (diacerein 1% ointment) in patients with EB. 
 
4 
STUDY OVERVIEW 
 
4.1 
Study Design 
The study is designed as an open label, single period study in approximately 16-20 patients 
with EB ranging in age from infants/children (ages 6 months – 11 years, inclusive) and 
adolescents/adults (ages 12 and up) with at least 8-10 subjects between the aged 6 months to 
11 years, inclusive (infants/children). The study will be conducted in two cohorts as follows: 
1. 8-10 adolescent and adult patients with EB (aged 12 and older) 
a. EBS subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be ≤ 
30% BSA. 
b. DEB/JEB subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be ≤ 
30% BSA. 


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CCP-020-101 Statistical Analysis Plan 
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2. 8-10 infants/children with EB (aged 6 months to 11 years, inclusive) 
a. EBS subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be ≤ 
30% BSA. 
b. DEB/JEB subjects: lesions encompassing ≥ 2% BSA for study entry. Diacerein 
application area to be ≥ 5% BSA and include lesioned and non-lesioned skin (if 
lesions account for less than 5% BSA); however, topical administration must be ≤ 
30% BSA. 
NOTE: 1% BSA is defined as the area of the subject’s hand held flat, including the thumb 
and fingers held together. 
NOTE: No more than 4-5 DEB/JEB patients (50% of the cohort) may be enrolled into the 
cohort. DEB/JEB patients will not be eligible for the open-label extension study. 
For adolescent/adult patients with EB (Cohort 1): 
Eligible, consented (assented and/or consent via guardian) adolescent and adult patients aged 
12 and up with EB lesions encompassing ≥ 2% BSA will be enrolled in the study. On Day 1, 
the total surface area of all available areas for application will be quantified and recorded.  The 
area(s) surrounding the lesion/lesions, will be marked (with a marker) encompassing no less 
than a total of 5% BSA (across all lesions, total) and separate paper body charts will be 
completed documenting the application area. The area(s) encompassing no less than 5% BSA 
will be defined as the application area(s) and will remain fixed over the course of the 10 Day C 
period. On Day 1, the topical dose of CCP-020 will be applied by study staff followed by blood 
sampling for plasma analysis of diacerein and rhein through 8 hours post-application. PK 
samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, and 8 hours post-dose on Days 1 and 10. 
Trough PK samples will be collected on any two available days from Day 3 through Day 9. 
Patients will be discharged from the study site on Day 1 and will continue  applications to the 
entire application area for 9 days at home at the same time each day. For the trough sample 
visits between Days 3 and 9, CCP-020 will be applied after the blood draw. The application 
area should be left uncovered for at least one-hour post-application, after which it is acceptable 
to apply non-absorbent bandages consistent with standard of care. On Day 10, patients will 
return to the study site for a pre-dose blood sample and application of CCP-020 to the 
application area followed by blood sampling for plasma analysis of diacerein and rhein. 
For infant/child patients with EB (Cohort 2): 
Eligible, assented (consented via guardian) infant/child patients aged 6 months to 11 years, 
inclusive with EB lesions encompassing ≥ 2% BSA will be enrolled in the study. On Day 1, 


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CCP-020-101 Statistical Analysis Plan 
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the total surface area of all available areas for application will be quantified and recorded. The 
area(s) surrounding the lesion/lesions, will be marked (with a marker) encompassing no less 
than a total of 5% BSA (across all lesions, total) and separate paper body charts will be 
completed documenting the application area. The area(s) encompassing no less than 5% BSA 
will be defined as the application area(s) and will remain fixed over the course of the 10 Day 
treatment period. On Day 1, the topical dose of CCP-020 will be applied by study staff followed 
by blood sampling for plasma analysis of diacerein and rhein through 8 hours post- application. 
PK samples will be collected at pre-dose, 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 10. 
Trough samples for Days 3-9 will not be required for this cohort. Patients will be discharged 
from the study site on Day 1 and will continue applications to the entire application area for 9 
days at home at the same time each day. The application area should be left uncovered for at 
least one-hour post-application, after which it is acceptable to apply non-absorbent bandages 
consistent with standard of care. On Day 10, patients will return to the study site for a predose 
blood sample and application of CCP-020 to the application area followed by blood sampling 
for plasma analysis of diacerein and rhein. For sites participating in the United States (US), 
children under the age of 4 are prohibited from participating due to regulatory restrictions. 
For both cohorts, on Days 1 and 10, void-volume catheters will be placed to obviate multiple 
needle sticks in blood sampling. 
Safety will be monitored throughout the study by repeated clinical and laboratory evaluations. 
The clinic/study site will attempt to contact subjects using their standard procedures 
approximately 14 days after the last study drug application to determine if any adverse events 
(AEs) have occurred since the last dose of study drug. Subjects who terminate the study early 
will be contacted if the Principal Investigator (PI) deems necessary. 
EB (excluding DEB/JEB) patients that complete this study or receive at least one dose of study 
drug will be eligible for consideration to enroll an open-label extension study conducted under 
a separate protocol. 


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CCP-020-101 Statistical Analysis Plan 
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4.2 
Randomization and Blinding 
This is an open label study; no randomization or blinding is employed. 


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4.3 
Investigational Medicinal Products 
Diacerein 1% Ointment will be administered topically. The study medication must be stored 
in a secure area with limited access under appropriately controlled and monitored storage 
conditions. 
 
 
4.4 
Duration of Treatment 
The duration of treatment is 10 Days; EB (excluding DEB/JEB) patients that complete this 
study or receive at least one dose of study drug will be eligible for rollover into an open-label 
extension study conducted under a separate protocol (Study CCP-020-301). 
 
5 
CRITERIA FOR EVALUATION 
 
5.1 
Pharmacokinetics 
The PK statistical analysis will be performed by Nuventra using their Bioanalystical methods 
and standards. 
 
5.2 
Safety 
Adverse events will be collected and evaluated as they occur throughout the study. Safety 
assessments, including physical examinations, application site assessment, vital signs 
assessments, and clinical laboratory tests, will be performed at select time points. 


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CCP-020-101 Statistical Analysis Plan 
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6 
STATISTICAL METHODOLOGY 
 
6.1 
General Statistical Considerations 
Descriptive statistics (n, mean, standard deviation [SD], coefficient of variation [CV%], 
minimum, median, and maximum) will be used to summarize the continuous data. 
Individual subject data will be listed by subject identification, cohort and EB type, and, if 
applicable, by assessment time. 
Unless specified otherwise, data will be used as it is reported. 
 
6.2 
Analysis Populations 
 
6.2.1 
Safety Population 
The safety population will consist of all subjects who receive any amount of study drug. 
 
6.2.2 
Pharmacokinetic Concentration Analysis Set 
The PK Concentration Population will comprise all subjects receiving at least one dose of CCP-
020 who have at least one quantifiable plasma concentration for rhein and, if possible, 
diacerein. 
 
6.2.3 
Pharmacokinetic Evaluable Population 
The PK Evaluable Population will comprise all subjects receiving at least one dose of CCP-
020 who have sufficient (> 4 quantifiable concentrations) plasma concentration data to 
calculate PK parameters for rhein and if possible, diacerein. 
 
6.3 
Subject Disposition 
Subject disposition will be presented overall and by cohort and EB type using randomized 
subjects. 
Number and percentage of subjects who received any amount of drug, who are in each analysis 
population, who complete the study, and who withdraw early from the study will be presented. 
The primary reasons for early withdrawals will also be tabulated. The number of randomized 
subjects within each group will be used as the denominator for the percentage calculations. 
 
6.4 
Eligibility Criteria 
Eligibility criteria (inclusion/exclusion) will be listed based on the screened subjects. 


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CCP-020-101 Statistical Analysis Plan 
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6.5 
Protocol Deviation 
Subjects with protocol deviations will be listing for Safety Population. 
 
6.6 
Demographic and Baseline Characteristics 
At the timepoints specified in the Study Flow Chart, the investigator or designee will interview 
each subject/caregiver to obtain demographic information including date of birth, sex at birth, 
race and ethnicity. 
Demographics and baseline characteristics will be summarized descriptively overall and by 
cohort and EB type for Safety Population. 
Demographic and baseline characteristics include, but are not limited to, age at informed 
consent, gender, race, ethnicity, and body weight. The baseline is defined as the values at 
Screening. If the value is missing, the last reading prior to dosing will be used as baseline. 
 
6.7 
Medical History and Genotyping Sample 
Medical history information will be recorded including all medical conditions and disease 
states that, at Day 1: 
• Are ongoing; 
• Require concomitant therapy; and 
• Are, in the opinion of the investigator, relevant to the subject’s study participation. 
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and data will be summarized by cohort and EB type. At each level of 
summation (overall, system organ class, preferred term), subjects reporting more than one 
event are counted only once. A subject may contribute to more than one preferred term. 
All data for medical history and genotyping sample will be listed for Safety Population. 
 
6.8 
Concomitant Medications/Procedures 
Concomitant therapies are any new or existing/ongoing therapy received from Visit 1 until 
discharge from the study, including therapies modified for non-medical reasons and therapies 
used for prophylaxis. 
All concomitant medication verbatim terms will be coded using the World Health Organization 
Drug Dictionary. The numbers and percentages of subjects taking concomitant medications 
will be summarized by anatomic and therapeutic chemical term and preferred term for each 
cohort and EB type and overall using Safety Population. 
All concomitant medications will also be listed. 


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6.9 
Treatment Compliance/Drug Accountability 
Each subject/caregiver will record the subject’s compliance with the study medication 
application frequency (including time dosed) on a daily basis using a paper diary. 
The investigator or designee will maintain an accurate record of the receipt of the study 
medications as shipped by Castle Creek Pharmaceuticals, LLC (or designee), including the 
date received and the condition of the study medications. One copy of this receipt will be 
returned to Castle Creek Pharmaceuticals, LLC when the contents of the study medication 
shipment have been verified and one copy maintained in the study file. In addition, an accurate 
study medication disposition record will be kept, specifying the amount dispensed to each 
subject/caregiver and the date of dispensing. This inventory record will be available for 
inspection at any time. At the completion of the study, the original inventory record will be 
available for review by Castle Creek Pharmaceuticals, LLC upon request. 
Data will be listed for Safety Population. 
 
6.10 
Diary 
Diary data will be listed by subject based on Safety Population. 
 
6.11 
Safety Analyses 
Adverse events will be collected and evaluated as they occur throughout the study. Safety 
assessments, including physical examinations, application site assessment, vital signs 
assessments, and clinical laboratory tests, will be performed at select time points. 
All safety analyses will be conducted on Safety Population. 
 
6.11.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, 
or severe, and will also categorize each adverse event as to its potential relationship to study 
drug using the categories of yes or no. 


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The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
 
 
6.11.2 
Serious Events 
Any untoward medicinal occurrence or effect that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability or incapacity, or 
• Is a congenital anomaly or birth defect. 
 
6.11.3 
Adverse Events of Special Interest 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor may be appropriate. Suspicion of such an event might warrant 
further investigation in order to characterize and understand it. The following AEs will be 
categorized as AEs of special interest (AESIs) in this study: 
• Moderate to severe diarrhea, 
• Hepatic injury, 
• Pancreatitis, 
• Urticaria/angioedema, 


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• Epidermal necrolysis, 
• Drug reaction with eosinophilia and systemic symptoms (DRESS), 
• Purpura/cutaneous vasculitis, and 
• Jaundice. 
All AESIs will be summarized as narratives in the Clinical Study Report. 
 
6.11.4 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as those AEs that start on or after the 
first dose of study medication, or occur prior to the first dose and worsen in severity or 
relationship to study medication after the first dose. 
Adverse events will be coded and classified by system organ class (SOC) and preferred term 
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA). Subjects with more 
than one AE for a given SOC or PT will be counted only once for that term using the most 
severe incident. 
An overview of AEs will be provided by cohort and EB type and overall for the following 
information: 
• All AEs, 
• All TEAEs, 
• Study drug-related TEAEs, 
• Maximum severity of TEAEs, 
• Maximum severity of drug-related TEAEs, 
• All AESI, if applicable, 
• Drug-related AESIs, if applicable, 
• Maximum severity of AESIs, if applicable, 
• All treatment-emergent SAEs, 
• Drug-related treatment-emergent SAEs, 
• Death due to TEAEs, 
• Withdrawals due to TEAEs, and 
• Withdrawals due to study drug-related TEAEs. 
TEAEs, if applicable, and AESI, will be summarized by treatment at onset and EB type and 
overall. The following summaries will be presented: 


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• TEAEs by SOC and PT; 
• TEAEs by SOC, PT, and relationship to the study drug; 
• TEAEs by SOC, PT, and maximum severity; 
• TEAEs by SOC, PT, maximum severity, and the relationship to the study drug. 
All AEs will be listed. If any serious adverse events (SAEs), AEs leading to death, AEs 
leading to the discontinuation of study drug occur, they will be listed in separate data listings. 
 
6.11.5 
Vital Signs and Weight 
At the timepoints specified in the Study Flow Chart, a qualified staff member will measure 
each subject’s vital signs. The following items will be measured: 
• Body temperature, 
• Pulse rate, 
• Respiration rate, and 
• Blood pressure (systolic and diastolic) after the subject remains at rest for at least 5 
minutes (to the extent that this is possible with infants/children). 
At the timepoints specified in the study flow chart, the subject’s weight will be collected. 
The observed values will be summarized by cohort and EB type and scheduled time point. 
Change and percentage change from baseline to each scheduled post-dose time point will also 
be summarized similarly. Baseline is defined as the last measurement prior to the first dosing. 
All data will also be listed for Safety Population. 
 
6.11.6 
Laboratory Assessments 
Subjects will not be required to fast prior to laboratory sample collection. 
 
6.11.6.1 
Hematology 
At the timepoints specified in the Study Flow Chart, the following hematology labs will be 
drawn: 


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The results of the clinical laboratory tests will be reported on the central laboratory’s 
standard reports. 
The observed values will be summarized by cohort and EB type and scheduled time point. 
Change and percentage change from baseline to each scheduled post-dose time point will also 
be summarized similarly. Baseline is defined as the last measurement prior to the first dosing. 
All data will also be listed for Safety Population. 
 
6.11.6.2 
Blood Chemistry 
At the timepoints specified in the Study Flow Chart, the following clinical chemistry labs 
will be drawn: 
 
The results of the clinical laboratory tests will be reported on the central laboratory’s 
standard reports. 
The observed values will be summarized by cohort and EB type and scheduled time point. 
Change and percentage change from baseline to each scheduled post-dose time point will also 
be summarized similarly. Baseline is defined as the last measurement prior to the first dosing. 
All data will also be listed for Safety Population. 
 
6.11.6.3 
Urinalysis 
A complete urinalysis will be performed at the timepoints listed in the Study Flow Chart. 
The observed values will be summarized by cohort and EB type and scheduled time point. 
Change and percentage change from baseline to each scheduled post-dose time point will also 
be summarized similarly. Baseline is defined as the last measurement prior to the first dosing. 
All data will also be listed for Safety Population. 


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6.11.6.4 
Pregnancy Screen 
At the timepoints specified in the Study Flow Chart, a qualified staff member will perform a 
urine pregnancy test for subjects who are women of childbearing potential (WOCBP). Sites will 
receive urine pregnancy test kits from the central laboratory. 
Subjects who are WOCBP must have a negative pregnancy test result at Day 1 to be enrolled 
in the study. 
If the result of any post-study medication application urine pregnancy test is positive, the 
subject will be withdrawn from the study and the subject’s pregnancy will be documented and 
followed until completion and for at least 6 weeks after birth. 
All data will also be listed for Safety Population. 
 
6.11.7 
Physical Examination 
At the timepoints specified in the Study Flow Chart, the investigator or designee will perform 
a complete physical examination that will include, at a minimum, evaluation of the following 
body systems and organs: 
• Skin; 
• Cardiovascular system; 
• Respiratory system; 
• Head, eyes, ears, nose and throat; 
• Lymph nodes; and 
• Abdominal Exam. 
Data will be listed for Safety Population. 
 
6.11.8 
Follow-Up Phone contact 
Data will be listed for Safety Population. 
 
7 
GENERAL INFORMATION 
The mock-ups for SAS-generated tables/figures/listings will be prepared in a separate 
document and finalized before database lock for the study. 
 
7.1 
Statistical Software 
The creation of analysis datasets and all statistical analyses will be done using SAS® version 
9.4 or higher. The Medpace standard operating procedures will be followed for the validation 
of all SAS programs and outputs. 


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7.2 
Format 
The format of tables, listings, and figures will be described in a stand-alone programming 
specifications document 


 
8 
APPENDIX 
 
8.1 
Study Flow Chart 
 
1 Visit is eligible to be performed at the subject’s home (Cohort 1) 
2 Only if the subject does not have documented genotype confirming EB 
3 Samples drawn at pre-dose and 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose for Cohort 1; pre-dose, 1, 2, 4, 6, and 8 
for Cohort 2. 
4 Trough PK samples will be collected on any two available days from Day 3 through Day 9 for Cohort 1 only 
5 At each visit the Investigator should examine the lesions being treated for any adverse events specific to 
treatment 
6 Phone call only 
7 For WOCBP only 
8 If Day 1 is within 7 days of Screening, labs do not need to be repeated.