Conditions: Epidermolysis Bullosa Simplex
Keywords: Epidermolysis bullosa simplex EBS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
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. The purpose of this study is to compare the efficacy of diacerein 1% ointment to vehicle ointment when applied once-daily for 8 weeks in subjects with EBS.

Detailed description:
The study is an international, multicenter, randomized, double-blind, vehicle-controlled, parallel group study to evaluate the safety and efficacy of diacerein 1% ointment for the treatment of subjects with EBS. Participants were assigned to study groups receiving either diacerein 1% ointment or vehicle ointment for 8 weeks, followed by an 8 week follow-up period. Approximately 80 subjects were to be randomized to one of the 2 treatment groups.

The primary objective of this study is to compare the efficacy of diacerein 1% ointment to vehicle ointment based on reduction in body surface area (BSA) of EBS lesions being treated when applied once-daily for 8 weeks in subjects with EBS. The secondary objectives are to compare the effects of diacerein 1% ointment to vehicle ointment in subjects with EBS in changes in Investigator Global Assessment (IGA) scores, pain, pruritus, mobility, and safety and tolerability.

Arms:
arm 1: diacerein 1% ointment will be used for 8 weeks arm 2: vehicle ointment will be used for 8 weeks

Interventions: intervention 1: diacerein 1% ointment intervention 2: A placebo ointment
Intervention descriptions: intervention 1: diacerein 1% ointment administered topically intervention 2: vehicle ointment administered topically

Protocol document:
Prot_001.pdf: 
Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 1 of 75 
CLINICAL STUDY PROTOCOL 
 
 
Diacerein 1% Ointment 
 
Protocol Number: CCP-020-301 
Protocol Amendment 3a 
 
Version of Protocol 
Applicable Countries 
Original Protocol 
All 
 Global Protocol Amendment 1 
All 
Local UK Protocol Amendment 1.1 
United Kingdom 
Local Protocol Amendment 1.2 
Austria, France, Germany 
 Global Protocol Amendment 2 
Australia, Israel, USA 
 Global Protocol Amendment 3a 
All 
 
Protocol Title: 
An International, Multicenter, Randomized, Double-Blind, Parallel-Group Phase 2 Study 
Evaluating the Safety and Efficacy of Diacerein 1% Ointment Topical Formulation in 
Subjects with Epidermolysis Bullosa Simplex (EBS) [DELIVERS Study]  
 
IND Number: 
131,384 
 
EudraCT Number: 
2016-004427-24 
 
Indication Studied: 
Epidermolysis Bullosa Simplex 
 
Protocol Date: 
02-JAN-2018 
 
Sponsor Address: 
Castle Creek Pharmaceuticals, LLC 
6 Century Drive 
Parsippany, NJ 07054 
United States of America 
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 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 2 of 75 
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. 
 
SIGNATURES: 
 
 
 
Gregory P. Licholai, MD  
President and Chief Medical Officer 
Castle Creek Pharmaceuticals, LLC 
 
Date 
 
 
 
 
Amir Tavakkol, Ph.D., Dip. Bact. 
Executive VP & Chief Development Officer 
Castle Creek Pharmaceuticals, LLC 
 
 
Date 
 
      
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 3 of 75 
INVESTIGATOR/SPONSOR AGREEMENT 
I have received and read the Investigator’s Brochure for topical Diacerein 1% Ointment 
(CCP-020). I have read CCP-020-301 global protocol amendment 3 and agree to conduct the 
study as outlined in this protocol and relevant revisions. 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 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 4 of 75 
Table of Contents 
INVESTIGATOR/SPONSOR AGREEMENT ...................................................................................... 3 
1. 
SYNOPSIS ........................................................................................................................................ 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................... 15 
2. 
SUMMARY OF CHANGES ........................................................................................................ 17 
3. 
INTRODUCTION ........................................................................................................................... 18 
3.1. 
Dose and Treatment Duration Rationale ............................................................................... 20 
3.2. 
Risks and/or Benefits to Subjects ............................................................................................ 21 
4. 
TRIAL OBJECTIVES .................................................................................................................... 22 
5. 
STUDY ENDPOINTS ................................................................................................................... 22 
5.1. 
Primary Endpoint ....................................................................................................................... 22 
5.2. 
Key Secondary Endpoints ......................................................................................................... 22 
5.3. 
Exploratory End Points .............................................................................................................. 23 
5.4. 
Pharmacokinetic Endpoint .......................................................................................................... 23 
6. 
INVESTIGATIONAL PLAN ...................................................................................................... 24 
6.1. 
Overall Study Design ................................................................................................................ 24 
7. 
SELECTION DISPOSITION OF STUDY POPULATION .................................................... 25 
7.1. 
Number of Subjects .................................................................................................................... 25 
7.2. 
Study Population Characteristics ............................................................................................ 25 
7.3. 
Inclusion Criteria ........................................................................................................................ 25 
7.4. 
Exclusion Criteria ....................................................................................................................... 26 
7.5. 
Previous and Concomitant Therapies ..................................................................................... 28 
7.5.1. 
Previous therapies .................................................................................................................... 28 
7.5.2. 
Concomitant therapies ............................................................................................................ 28 
7.5.3. 
Permitted & Prohibited therapies ......................................................................................... 28 
7.5.4. 
EBS lesions treatment instructions: ...................................................................................... 29 
7.6. 
Infected Lesions .......................................................................................................................... 30 
7.7. 
Subject Discontinuation from the Study ............................................................................... 30 
7.8. 
Subject Identifier (SI) ................................................................................................................ 31 
7.9. 
Replacement Subjects ................................................................................................................ 31 
8. 
INVESTIGATIONAL PLAN ...................................................................................................... 32 
8.1. 
Study Flow Chart ........................................................................................................................ 32 
8.2. 
Study Visits Description and Procedures .............................................................................. 33 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 5 of 75 
8.2.1. 
Visit 1 (Day -42 to 0) ................................................................................................................. 33 
8.2.2. 
Visit 2 (Week 0/Day 1) ............................................................................................................. 34 
8.2.3. 
Visit 3 (Week 1/Day 8) ............................................................................................................. 35 
8.2.4. 
Visit 4 (Week 4/Day 29) ........................................................................................................... 35 
8.2.5. 
Visit 5 (Week 6/Days 43) ......................................................................................................... 36 
8.2.6. 
Visit 6 (Week 8/Day 57); end of the treatment period ....................................................... 37 
8.2.7. 
Visit 7 (Week 12/Day 85) ......................................................................................................... 37 
8.2.8. 
Visit 8 (Week 16/Day 113); end of the study ....................................................................... 38 
8.3. 
EBS Lesion Identification ......................................................................................................... 39 
8.3.1. 
Occluded Lesions ..................................................................................................................... 40 
8.4. 
Subject Instructions ................................................................................................................... 40 
8.5. 
EBS Lesion Care .......................................................................................................................... 41 
8.5.1. 
Blister lancing kit ..................................................................................................................... 41 
8.5.2. 
Bandaging/Dressing Use ........................................................................................................ 41 
8.6. 
Subject Diary ............................................................................................................................... 42 
8.7. 
STUDY DURATION .................................................................................................................. 43 
8.8. 
STUDY MEDICATIONS .......................................................................................................... 43 
8.8.1. 
Study medication identity ...................................................................................................... 43 
8.8.2. 
Study medication formulation .............................................................................................. 44 
8.8.3. 
Study medication packaging and labeling .......................................................................... 44 
8.8.4. 
Method of treatment assignment .......................................................................................... 45 
8.8.5. 
Dispensing study medication ................................................................................................ 45 
8.8.6. 
Study medication application ................................................................................................ 46 
8.8.7. 
Dose compliance record .......................................................................................................... 47 
8.8.8. 
Dose modification .................................................................................................................... 47 
8.9. 
Study medication Management ............................................................................................... 47 
8.9.1. 
Accountability .......................................................................................................................... 47 
8.9.2. 
Return and disposition of study supplies ........................................................................... 48 
8.10. 
Other Study Supplies ................................................................................................................ 48 
8.11. 
Blinding ........................................................................................................................................ 48 
8.11.1. 
Verification of blinding .......................................................................................................... 48 
8.11.2. 
Un-blinding the study medication ....................................................................................... 48 
9. 
STUDY ASSESSMENTS ............................................................................................................. 50 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 6 of 75 
9.1. 
Effectiveness Evaluations ......................................................................................................... 50 
9.1.1. 
Investigator’s Global Assessment (IGA) ............................................................................. 50 
9.1.2. 
Assessment Area ......................................................................................................................... 51 
9.1.3. 
Treatment Area .......................................................................................................................... 52 
9.1.4. 
Reference Lesion Surface Area (LSA) .................................................................................. 52 
9.1.5. 
Body surface area (BSA) of the Assessment Area/Treatment Area/All EBS 
Lesions........................................................................................................................................ 53 
9.1.6. 
Pruritus Intensity (for Subjects aged 8 years and older) .................................................. 53 
9.1.7. 
Pain Intensity (for Subjects aged 8 years and older) ......................................................... 54 
9.1.8. 
Mobility Assessment ............................................................................................................... 54 
9.2. 
Safety Evaluations ...................................................................................................................... 55 
9.2.1. 
Demographics/Medical History ............................................................................................ 55 
9.2.2. 
Vital Signs ................................................................................................................................. 55 
9.2.3. 
Physical Examination .............................................................................................................. 56 
9.2.4. 
Clinical laboratory sampling ................................................................................................. 56 
9.2.5. 
PK Sample Collection ............................................................................................................. 57 
9.2.6. 
Genetic Confirmation of EBS ................................................................................................ 57 
9.2.7. 
Pregnancy tests ......................................................................................................................... 58 
9.3. 
Other Evaluations ....................................................................................................................... 58 
9.3.1. 
Standardized photography ..................................................................................................... 58 
9.3.2. 
Electrocardiogram (ECG) Monitoring .................................................................................. 58 
9.4. 
Total Volume of Blood Collected ............................................................................................ 59 
10. 
ADVERSE EVENTS ...................................................................................................................... 60 
10.1. 
Adverse events(s) ........................................................................................................................ 60 
10.2. 
Adverse (Drug) Reaction ........................................................................................................... 61 
10.3. 
Unexpected Adverse Drug Reaction ....................................................................................... 61 
10.4. 
Assessments of Adverse Events by the Investigator ............................................................ 61 
10.4.1. 
Assessment of Severity: .......................................................................................................... 61 
10.4.2. 
Causality Assessment: ............................................................................................................. 61 
10.4.3. 
Adverse Events of Special Interest ....................................................................................... 63 
10.5. 
Serious Adverse events (SAE) .................................................................................................. 63 
10.5.1. 
Serious Adverse Event Reporting/Adverse Events of Special Interest – 
Procedures for Investigators .................................................................................................. 64 
10.5.1.1 
Initial Reports .......................................................................................................................... 64 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 7 of 75 
10.5.1.2 
Follow-up Reports .................................................................................................................. 65 
10.5.1.3 
Expedited Reports .................................................................................................................. 65 
10.6. 
Pregnancy Reporting .................................................................................................................. 65 
11. 
STATISTICAL ANALYSES ........................................................................................................ 67 
11.1. 
Analysis Populations ................................................................................................................. 67 
11.2. 
Data Analysis............................................................................................................................... 67 
11.2.1. 
Missing Data Handling Methods ......................................................................................... 67 
11.2.2. 
Subject Information ................................................................................................................. 68 
11.2.3. 
Analysis of Efficacy ................................................................................................................. 68 
11.2.4. 
Analysis of Safety .................................................................................................................... 69 
11.3. 
Interim Analysis ......................................................................................................................... 69 
11.4. 
Sample Size Calculation ............................................................................................................ 69 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................................... 70 
12.1. 
Study Monitoring ....................................................................................................................... 70 
12.2. 
Audits and Inspections .............................................................................................................. 71 
12.3. 
Institutional Review Board (IRB) and Ethic Committee (EC) ............................................ 71 
12.4. 
Data Monitoring Committee ........................................................................................................ 71 
13. 
ETHICS ............................................................................................................................................ 72 
13.1. 
Ethics Review .............................................................................................................................. 72 
13.2. 
Ethical Conduct of the Study .................................................................................................... 72 
13.3. 
Written Informed Consent/Assent .......................................................................................... 72 
14. 
DATA HANDLING AND RECORD KEEPING ..................................................................... 73 
14.1. 
Electronic Case Report Forms .................................................................................................... 73 
14.2. 
Inspection of Records ................................................................................................................... 73 
14.3. 
Retention of Records .................................................................................................................... 73 
15. 
PUBLICATION POLICY .............................................................................................................. 74 
16. 
LIST OF REFERENCES ............................................................................................................... 75 
 
 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 8 of 75 
1. 
SYNOPSIS 
Name of Sponsor/Company: 
Castle Creek Pharmaceuticals, LLC 
Name of Investigational Product: 
Diacerein 1% Ointment 
Name of Active Ingredient: 
Diacerein 
Title of Study:  
An International, Multicenter, Randomized, Double-Blind, Parallel-Group Phase 2 
Study Evaluating the Safety and Efficacy of Diacerein 1% Ointment Topical 
Formulation in Subjects with Epidermolysis Bullosa Simplex (EBS) DELIVERS Study  
Study center(s): Approximately 20 
Studied period (years):  
Estimated date first subject enrolled:  
01-JUN-2017  
Estimated date last subject completed: 
31-DEC-2018 
Phase of development:  
Phase 2 
Objectives:  
Primary Objective:  
• To compare the efficacy of Diacerein 1% Ointment to Control Ointment 
based on reduction in body surface area (BSA) of EBS lesions being treated 
when applied once-daily for 8 weeks in subjects with EBS. 
 
Secondary Objectives: 
To compare the effects of Diacerein 1% Ointment to Control Ointment in subjects with 
EBS in: 
• Changes in Investigator Global Assessment (IGA) scores  
• Pain 
• Pruritus  
• Mobility 
• Safety and tolerability 
  
 
 
 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 9 of 75 
 
Methodology: 
This is an international, multicenter, randomized, double-blind, vehicle-controlled, 
parallel group study to evaluate the safety and efficacy of topical Diacerein 1% 
Ointment for the treatment of subjects with EBS. Subject randomization will be 
stratified by genotype (KRT5 and/or KRT14 versus other genotypes) and age group 
(<8 and ≥8 years old).  
 
Subjects will be screened for inclusion and exclusion criteria at Visit 1 (Week -6).  
Subjects must have a genotypic confirmation of EBS (based on either existing 
documentation or results from a sample collected as part of the study) to be 
randomized to study medication.  
 
At Visit 2 (Week 0) eligible subjects will be randomized in a 1:1 ratio to either receive 
8 weeks of once-daily application of Diacerein 1% Ointment or Control Ointment to 
all EBS lesions in the Assessment Area except plantar areas where >25% of the area 
has hyperkeratosis that has been present for greater than 12 weeks and the scalp, groin 
and areas where, in the investigator’s opinion, the study medication might become 
occluded are excluded. At Visit 2 (Week 0) all subjects or their caregivers 
(subjects/caregivers) will be instructed on the daily study medication application 
technique. For each application, a thin layer of the assigned study medication, 
sufficient to cover the lesions and approximately ¾ inch (2 cm) of surrounding 
uninvolved skin, will be applied and gently rubbed in. Subjects/caregivers will apply 
the assigned study medication to all EBS lesions, including any new EBS lesions that 
develop, once daily, every evening during the 8-week treatment period. The subject’s 
first study medication application will be observed by a member of the study staff for 
approximately 20 minutes. Subsequent study medication applications will be 
performed by the subject/caregiver. The application technique will be reviewed with 
subjects/caregivers at all treatment period visits. No study medication applications 
will be made to any lesion that becomes infected until the infection resolves with 
appropriate investigational center specific medical care.  
 
Also at Visit 2 (Week 0) subjects/caregivers will be instructed on the use of the 
electronic diary (eDiary) to record patient reported outcomes of pruritus, pain and 
mobility and to document bandage use, blister lancing compliance, new lesions that 
develop in between study visits, routine cleanser use and study medication 
applications. Proper use of the eDiary will be reinforced at every study visit.  
 
Adverse events, clinical laboratory data, PK sampling, efficacy evaluations and 
determination of study medication use will be routinely collected. Subjects/caregivers 
will be instructed on how and when to lance blisters throughout the duration of the 
study.  
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 10 of 75 
The duration of study participation is anticipated to be a maximum of 158 days per 
subject (~22 weeks). The final study visit (Visit 8/Week 16) has a maximum allowable 
visit window of 4 days.  
Study visits are: 
• Visit 1 (Week -6/Day -42 to 0) enrollment, start randomization eligibility 
assessment period 
• Visit 2 (Week 0/Day 1) randomization; first study medication application 
• Visit 3 (Week 1/Day 8) treatment period follow-up 
• Visit 4 (Week 4/Day 29) treatment period follow-up 
• Visit 5 (Week 6/Day 43) treatment period follow-up 
• Visit 6 (Week 8/Day 57) end of the treatment period 
• Visit 7 (Week 12/Day 85) no treatment follow-up 
• Visit 8 (Week 16/Day 113) no treatment follow-up, end of study 
 
An interim analysis will be conducted by an independent data monitoring 
committee (DMC) once a prespecified number of subjects have completed the study.  
A formal unblinded analysis will be planned.  Details regarding the conduct of the 
interim analyses will be specified outside of this protocol (e.g. DMC charter).  The 
DMC will advise whether any changes to the sample size or conduct of the study are 
necessary based on review of safety and efficacy data.   
Number of subjects (planned):  
Approximately 80 subjects are planned to be randomized in this study at 
approximately 20 international investigational centers. A planned interim analysis 
will be performed when approximately 40 subjects have been randomized, and may 
result in an adjustment of the number of randomized subjects.  This will be a formal 
unblinded analysis that will be detailed in the DMC Charter.   
Diagnosis and main criteria for inclusion/exclusion:  
Inclusion criteria:  
1. Subject is male or female at least 4 years of age at Visit 1 
2. Subject has a documented genetic mutation consistent with EBS.  A blood or 
saliva sample will be collected for genetic confirmation if no documented 
gene mutation data is available.  Gene mutations acceptable for inclusion are 
as follows: KRT5, KRT14, PLEC1, TGM5, PKP1, DSP, FERMT1, EXPH5, DST, 
KLHL24. 
3. Subject has an Assessment Area (see Section 9.1.2) of EBS lesions to be 
treated, that is ≥2% body surface area (BSA) and the EBS lesions are in one or 
both of the following body areas: 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 11 of 75 
- 
Localized: plantar and/or palmar areas (plantar areas where >25% of 
the area has hyperkeratosis that has been present for greater than 12 
weeks cannot be included as part of the Assessment Area) 
- 
Generalized: arms, legs, torso, hands and feet (scalp, groin and areas 
where, in the investigator’s opinion, the study medication might 
become occluded cannot be included as part of the Assessment Area 
4. Subject’s EBS lesions in the Assessment Area have an Investigator’s Global 
Assessment (IGA) score of ≥3 
5. Subject/caregiver agrees to not use any topical therapies other than the study 
medication that, might influence the status of the EBS lesions during the 
duration of the study (e.g., medicated cleansers, CBD oil, MediHoney, 
Silvadine cream 1%, [see Section 7.5.3]); the Investigator should consult the 
Medical Monitor regarding therapies not specified in the protocol  
6. Subject/caregiver agrees to follow topical product application instructions 
(see Section 7.5.4) 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 (see Section 10.6), 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, might impair 
evaluation of the EBS lesions or 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  
11. Subject/caregiver is able to comprehend and willing to sign an Informed 
Consent and/or Assent Form. 
Exclusion criteria:  
1. Subject has EBS lesions to be treated that are infected (i.e., EBS lesions that 
require therapy to treat an infection) 
2. Subject has used any diacerein containing product within 6 months prior to 
Visit 1 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 12 of 75 
3. Subject has used systemic immunotherapy or cytotoxic chemotherapy within 
60 days prior to Visit 1 
4. Subject has used systemic steroidal therapy or has used topical steroidal 
therapy on the EBS lesions to be treated within 30 days prior to Visit 2 (Note: 
inhaled 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 Visit 1 
6. Subject is currently using systemic analgesics and/or anti-histamine therapy 
for treatment of EBS lesions, unless on a stable regimen (i.e., the same dosing 
regimen) for at least 4 weeks prior to Visit 1.  Note: As needed (PRN) use of 
acetaminophen/paracetamol or NSAIDs within the 4 weeks prior to Visit 1 
are permitted provided the treatment was unrelated to EBS symptom relief.  
7. 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 Visit 1 
8. Subject has used any topical product containing allantoin on the EBS lesions 
to be treated within 30 days prior to Visit 1 
9. Subject has a current malignancy, or a history of treatment for a malignancy 
within 2 years prior to Visit 1 (Note: does not include non-melanoma skin 
cancer) 
10. Subject currently has diabetes mellitus (HbA1c ≥6.5%).  Note: controlled 
diabetes (HbA1c < 6.5%) is also considered exclusionary 
11. 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) 
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 
12. Subject has a non-EBS skin disease (e.g., psoriasis, atopic dermatitis, eczema, 
sun damage, etc.), or condition (e.g., sunburn) 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  
13. Subject has a history of sensitivity to any of the ingredients in the study 
medications.  See section 8.8.2 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 13 of 75 
14. Subject has participated in any investigational drug/device trial in which 
administration of an investigational study medication occurred within 
30 days prior to Visit 1. 
Investigational product, dosage and mode of administration:  
Diacerein 1% Ointment administered topically 
Duration of study and treatment:  
Twenty-two weeks including an up to 6-week screening period, eight weeks of 
treatment and eight weeks of no-treatment follow up. 
Reference therapy, dosage and mode of administration:  
Control ointment lacking active ingredient but containing a colorizing agent to 
maintain blinding. 
Criteria for evaluation: 
• To evaluate the efficacy of Diacerein 1% Ointment compared to Control 
Ointment on the key efficacy measure of success defined as ≥40% 
reduction in body surface area (BSA) of EBS lesions.  
• To evaluate the safety and tolerability of Diacerein 1% Ointment in 
subjects with EBS.    
All efficacy endpoints will be based on the Assessment Area, defined in the protocol 
Section 9.1.2 
 
The primary efficacy endpoint:  
The primary efficacy endpoint is based on the ITT population, and is the proportion 
of subjects who achieve ≥40% reduction in BSA of EBS lesions from Visit 2 (Week 0) 
to Visit 8 (Week 16). 
 
The key secondary endpoints:  
The secondary endpoints are as follows:  
• The proportion of subjects achieving success on the IGA, where success is 
defined as at least a 2-point reduction, from Visit 2 (Week 0) to Visit 8 (Week 
16).  
• The proportion of subjects who achieve ≥ 40% reduction in BSA of EBS 
lesions from Visit 2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects achieving success on the IGA, where success is 
defined as at least a 2-point reduction, from Visit 2 (Week 0) to Visit 6 (Week 
8). 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 14 of 75 
• The proportion of subjects with a reduction in overall pain intensity from 
Visit 2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects with a reduction in overall pruritus intensity 
from Visit 2 (Week 0) to Visit 6 (Week 8). 
 
If the comparison for the primary endpoint is significant (two-sided p-value < 0.05), 
then testing will continue for the key secondary endpoints. The key secondary 
endpoints will be analyzed in a similar manner as the primary endpoint. To control 
the type I error rate for testing multiple key secondary endpoints, a fixed-sequence 
approach for the key secondary endpoints will be used.   
 
Exploratory end points 
The exploratory endpoints are as follows: 
• The proportion of subjects with a reduction in overall pain intensity from 
Visit 2 (Week 0) to Visit 8 (Week 16).  
• The proportion of subjects with a reduction in overall pruritus intensity 
from Visit 2 (Week 0) to Visit 8 (Week 16). 
• The proportion of subjects with an increase in mobility assessment from 
Visit 2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects with an increase in mobility assessment from 
Visit 2 (Week 0) to Visit 8 (Week 16). 
• The percent change in BSA of EBS lesions from Visit 2 (Week 0) to Visit 6 
(Week 8).  
• The percent change in BSA of EBS lesions from Visit 2 (Week 0) to Visit 8 
(Week 16).  
• The percent change in Reference Lesion Surface Area from Visit 2 (Week 0) 
to Visit 6 (Week 8).  
• The percent change in Reference Lesion Surface Area from Visit 2 (Week 0) 
to Visit 8 (Week 16).  
 
 
Population PK endpoint: 
 
Blood draws for population PK analysis will be drawn at protocol specified 
timepoints. 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
Page 15 of 75 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE  
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
°C 
Degrees Centigrade 
CBD 
Cannabidiol 
CMH 
Cochran-Mantel-Haenszel 
CR 
 
Clinically Relevant 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
EBS 
Epidermolysis Bullosa Simplex 
e.g.  
For Example, (Latin; exempla gratia) 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
EP 
EU 
Electronic Data Capture 
European Pharmacopoeia  
European Union 
DEB 
Dystrophic Epidermolysis Bullosa 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
G 
Gram 
GCP 
Good Clinical Practice 
eGFR 
Estimated Glomerular Filtration Rate 
HCG 
Human Chorionic Gonadotrophin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
Hg 
Mercury 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


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Protocol No. CCP-020-301 
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Abbreviation 
Term 
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 
LOCF 
Last Observation Carried Forward 
LSA 
Lesion Surface Area 
MedDRA 
Medical Dictionary for Regulatory Activities 
Ml 
Milliliter 
Mm 
Millimeter 
µMol 
Micro-molar 
NCR 
NF 
Not Clinically Relevant 
National Formulary 
NRS 
Numeric Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OTC 
PD 
Over-The-Counter 
Pharmacodynamic 
PK 
Pharmacokinetic 
PRN 
As needed 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
SAE 
Serious Adverse Event 
SI 
Subject Identifier 
SOP 
Standard Operation Procedure 
US 
USP 
United States 
United States Pharmacopoeia 
WOCBP 
Women of childbearing potential 


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2. 
SUMMARY OF CHANGES 
This section describes the changes made in Global Amendment #3a.  Added text is 
indicated in bold, deleted text is indicated by strikethrough.  Minor changes to 
punctuation, administrative changes (i.e. changes in numbering, word order, location, 
etc.), changes to the table of contents, additions/subtractions from list of abbreviations, 
changes in the study synopsis, study flow chart, and protocol signatories will not be listed 
in the summary of changes.  Changes repeated throughout the protocol are noted as 
global changes. 
 
For Austria, France, Germany: Refer to Austria_France_Germany_Summary of Changes 
Document Protocol Amendment 3.0a 
 
For Netherlands: Refer to Netherlands_Summary of Changes Document Protocol 
Amendment 3.0a 
 
For United Kingdom: Refer to United Kingdom_Summary of Changes Document 
Protocol Amendment 3.0a 
 
For Australia, Israel, United States: Refer to Australia_Israel_United States_Summary of 
Changes Document Protocol Amendment 3.0a 
 
 
 
 


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3. 
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 mortality.1,2 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 epidermis.3 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 EBS.4  
 
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 IL-6, and the expression of inducible nitric oxide 
synthase (iNOS) and tumor necrosis factor-α (TNF-α). 


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Investigational Product: Diacerein 1% Ointment 
 
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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 EBS.5 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 as part of long-term follow-up 
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 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 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 2013.5 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 multiple European countries 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 EBS.6 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.  


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Investigational Product: Diacerein 1% Ointment 
 
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The results of these studies suggest topical diacerein has potential to down-regulate the 
activity of IL-1β and reduce the auto-inflammatory effects in the skin of patients with 
EBS. The favorable product profile of diacerein, an anti-IL-1β small molecule therapeutic, 
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% Topical Ointment Investigator’s Brochure. 
 
As part of the clinical development program for Diacerein 1% Ointment there will be an 
administratively separate, 12-month open-label study subsequent to CCP-020-301 in 
subjects with EBS. One inclusion criterion for this subsequent study is that the subject 
has completed study CCP-020-301. 
 
3.1. 
Dose and Treatment Duration Rationale 
In addition to the long history of clinical experience with diacerein after oral 
administration, recent studies with topical diacerein have been conducted.  Results from 
a 12-week, phase 1 pilot study in 5 EBS-DM patients demonstrated a substantial reduction 
in blisters after 2 weeks of daily application of 1% diacerein cream.  In this study, 
treatment continued open-label for an additional 4 weeks.  In period 2 of the study, the 
effects lasted an additional 6 weeks in patients administered diacerein or placebo 
indicating a durable response from the initial open-label 6-week treatment period.  There 
were no adverse events reported during the study.  
 
A recent, multi-center, European, phase 2 placebo-controlled, randomized, double-blind 
crossover study of 17 EBS patients (aged 4 to 19) was completed.  The study was run over 
2 years with a 4-week treatment period and 3-month follow-up period in each year of the 
study (1% diacerein cream or placebo).  In this study, the dose (1%), dose duration (4 
weeks), and application area (3% BSA) established a highly significant reduction in blister 
counts in both years of treatment at the end of the 4-week treatment period as well as 
continued response at 3 months post-treatment compared to placebo.  60% of patients 
applying Diacerein cream for 4 weeks and followed-up to 3 months achieved a clinically 
meaningful reduction of at least 40% in blister numbers as compared to 15% in the  
placebo group, as determined by the investigator.  Secondary endpoints also 
demonstrated an effect of the treatment arm compared to placebo as measured by time 
to reach initial blister counts and patient reported outcomes of improvements in pain and 
itching.  There were no drug-related AEs in the study and no discontinuations related to 
treatment. 
 


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Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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These preliminary clinical studies demonstrated proof-of-concept efficacy of a 1% 
diacerein cream in EBS-DM patients.  This current trial will seek to establish efficacy and 
safety of a 1% diacerein ointment compared to its placebo in patients with EBS after 8 
weeks treatment and 8 weeks off-treatment using reduction in body surface area (BSA) 
of EBS lesions (assessment area being treated when applied once-daily for 8 weeks). In 
addition, an Investigator Global Assessment (IGA) scale will be used to determine the 
proportion of subjects achieving success on the IGA from Visit 2 (Week 0) to Visit 8 (Week 
16).  
 
3.2. 
Risks and/or Benefits to Subjects 
The dose of study medication administered in this study is anticipated to induce 
therapeutic benefit with prolonged treatment. 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. Additionally, subjects will receive study medication at no cost for the duration of 
the study. 
 
The safety monitoring practices employed by this protocol (i.e. vital signs, clinical and 
laboratory evaluations, ECGs, 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 EBS 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. 
 
 
 
 
 
 
 
 
 
 


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Investigational Product: Diacerein 1% Ointment 
 
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4. 
TRIAL OBJECTIVES 
Primary Objective:  
• To compare the efficacy of Diacerein 1% Ointment to Control Ointment based 
on reduction in body surface area (BSA) of EBS lesions being treated when 
applied once-daily for 8 weeks in subjects with EBS. 
 
Secondary Objectives: 
To compare the effects of Diacerein 1% Ointment to Control Ointment in subjects with 
EBS in: 
• Changes in Investigator Global Assessment (IGA) scores  
• Pain 
• Pruritus  
• Mobility 
• Safety and tolerability 
 
5. 
STUDY ENDPOINTS 
5.1. 
Primary Endpoint 
The primary endpoint is the proportion of subjects who achieve ≥ 40% reduction in BSA 
of EBS lesions from Visit 2 (Week 0) to Visit 8 (Week 16). 
 
5.2. 
Key Secondary Endpoints 
• The proportion of subjects achieving success on the IGA, where success is 
defined as at least a 2-point reduction, from Visit 2 (Week 0) to Visit 8 (Week 
16).  
• The proportion of subjects who achieve ≥ 40% reduction in BSA of EBS lesions 
from Visit 2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects achieving success on the IGA, where success is 
defined as at least a 2-point reduction, from Visit 2 (Week 0) to Visit 6 (Week 
8). 
• The proportion of subjects with a reduction in overall pain intensity from Visit 
2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects with a reduction in overall pruritus intensity from 
Visit 2 (Week 0) to Visit 6 (Week 8).  
 


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Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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If the comparison for the primary endpoint is significant (two-sided p-value < 0.05), then 
testing will continue for the key secondary endpoints. The key secondary endpoints will 
be analyzed in a similar manner as the primary endpoint. To control the type I error rate 
for testing multiple key secondary endpoints, a fixed-sequence approach for the key 
secondary endpoints will be used.   
 
5.3. 
Exploratory End Points 
The exploratory endpoints are as follows: 
• The proportion of subjects with a reduction in overall pain intensity from Visit 
2 (Week 0) to Visit 8 (Week 16).  
• The proportion of subjects with a reduction in overall pruritus intensity from 
Visit 2 (Week 0) to Visit 8 (Week 16). 
• The proportion of subjects with an increase in mobility assessment from Visit 
2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects with an increase in mobility assessment from Visit 
2 (Week 0) to Visit 8 (Week 16). 
• The percent change in BSA of EBS lesions from Visit 2 (Week 0) to Visit 6 (Week 
8).  
• The percent change in BSA of EBS lesions from Visit 2 (Week 0) to Visit 8 (Week 
16).  
• The percent change in Reference Lesion Surface Area from Visit 2 (Week 0) to 
Visit 6 (Week 8).  
• The percent change in Reference Lesion Surface Area from Visit 2 (Week 0) to 
Visit 8 (Week 16).  
 
5.4. 
Pharmacokinetic Endpoint 
Blood draws for PK sampling and modeling will be obtained at the timepoints listed in 
the Study Flow Chart (see Section 8.1). Quantification of diacerein and its active 
metabolite, rhein in patient plasma will be performed using a validated bioanalytical 
assay.  Data permitting, population PK and PK/PD analyses will be performed. 
 
 
 
 


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Investigational Product: Diacerein 1% Ointment 
 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is an international, multi-center, randomized, double-blind, parallel group study to 
evaluate the safety and efficacy of topical Diacerein 1% Ointment for the treatment of 
subjects with EBS. Subject randomization will be stratified by genotype (KRT5 and/or 
KRT14 versus other genotype) and age group (<8 and ≥8 years old). Subjects will be 
screened for inclusion and exclusion criteria at Visit 1 (Week -6).  Subjects must have a 
genotypic confirmation of EBS (or have a blood or saliva sample collected for genetic 
confirmation). At Visit 2 (Week 0) eligible subjects will be randomized in a 1:1 ratio to 
either receive 8 weeks of once-daily application of Diacerein 1% Ointment or Control 
Ointment to all EBS lesions in the Assessment Area except plantar areas where >25% of 
the area has hyperkeratosis that has been present for greater than 12 weeks and the scalp, 
groin and areas where, in the investigator’s opinion, the study medication might become 
occluded are excluded. At Visit 2 (Week 0) all subjects or their caregivers 
(subjects/caregivers) will be instructed on the daily study medication application 
technique. For each application, a thin layer of the assigned study medication, sufficient 
to cover the lesion and approximately ¾ inch (2 cm) of surrounding uninvolved skin, will 
be applied and gently rubbed in. Subjects/caregivers will apply the assigned study 
medication to all EBS lesions, including any new lesions that develop, provided that the 
area being treated does not exceed 30% BSA during the 8-week treatment period. At Visit 
2 (Week 0, baseline) the subject’s first study medication application will be observed by 
a member of the study staff.  Subsequent study medication applications will be 
performed by the subject/caregiver. The application technique will be reviewed with 
subjects/caregivers at all treatment period visits. No study medication applications will 
be made to any lesion that becomes infected until the infection resolves with appropriate 
investigational center specific medical care.  
 
At Visit 2 (Week 0), subjects/caregivers will be instructed on the use of the electronic 
diary (eDiary) to record patient reported outcomes of pruritus, pain and mobility and to 
document bandage use, blister lancing compliance, new lesions that develop in between 
study visits, routine cleanser use and study medication applications. Application 
instructions and proper use of the eDiary will be reinforced at every study visit.  
 
Adverse events, clinical laboratory data, efficacy evaluations and determination of study 
medication use will be routinely collected. Subjects/caregivers will be instructed on how 
and when to lance blisters, including blisters outside the treatment area, throughout the 
duration of the study.  Blood draws for pharmacokinetic modeling will also be obtained 
according to the Study Flow Chart. 
 
The duration of study participation is anticipated to be a maximum of 158 days per 
subject (~22 weeks). The final study visit (Visit 8/Week 16) has a maximum allowable 
visit window of 4 days.  


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Study visits are: 
• Visit 1 (Week -6/Day -42 to 0) enrollment, start randomization eligibility 
assessment period 
• Visit 2 (Week 0/Day 1) randomization; first study medication application 
• Visit 3 (Week 1/Day 8) treatment period follow-up 
• Visit 4 (Week 4/Day 29) treatment period follow-up 
• Visit 5 (Week 6/Day 43) treatment period follow-up 
• Visit 6 (Week 8/Day 57) end of the treatment period 
• Visit 7 (Week 12/Day 85) no treatment follow-up 
• Visit 8 (Week 16/Day 113) no treatment follow-up, end of study. 
 
7. 
SELECTION DISPOSITION OF STUDY POPULATION 
7.1. 
Number of Subjects 
Approximately 80 subjects are planned to be randomized to one of the 2 treatment 
groups in this study at approximately 20 international investigational centers. A 
planned interim analysis will be performed and may result in an adjustment of the total 
number of randomized subjects. 
 
7.2. 
Study Population Characteristics 
Male or female subjects at least 4 years of age with a genetic confirmation of EBS who 
meet all the inclusion criteria and none of the exclusion criteria at Visit 1 will be eligible 
for enrollment in the study. 
 
7.3. 
Inclusion Criteria 
In order to be eligible for the study, subjects must fulfill all of the following criteria:  
1. Subject is male or female at least 4 years of age at Visit 1 
2. Subject has a documented genetic mutation consistent with EBS.  A blood or 
saliva sample will be collected for genetic confirmation if no documented gene 
mutation data is available.  Gene mutations acceptable for inclusion are as 
follows: KRT5, KRT14, PLEC1, TGM5, PKP1, DSP, FERMT1, EXPH5, DST, 
KLHL24. 
3. Subject has an Assessment Area (see Section 9.1.2) of EBS lesions to be treated, 
that is ≥2% body surface area (BSA) and the EBS lesions are in one or both of the 
following body areas: 


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- 
Localized: plantar and/or palmar areas (plantar areas where >25% of the 
area has hyperkeratosis that has been present for greater than 12 weeks 
cannot be included as part of the Assessment Area 
- 
Generalized: arms, legs, torso, hands and feet (scalp, groin and areas 
where, in the investigator’s opinion, the study medication might become 
occluded cannot be included as part of the Assessment Area)  
4. Subject’s EBS lesions in the Assessment Area have an Investigator’s Global 
Assessment (IGA) score of ≥3 
5. Subject/caregiver agrees to not use any topical therapies other than the study 
medication that might influence the status of the EBS lesions during the duration 
of the study (e.g., medicated cleansers, CBD oil, MediHoney, Silvadine cream 1%, 
[see Section 7.5.3]; the Investigator should consult the Medical Monitor regarding 
therapies not specified in the protocol 
6. Subject/caregiver agrees to follow topical product application instructions (see 
Section 7.5.4) 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 (see Section 10.6), 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, might impair evaluation of the 
EBS lesions or 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  
11. Subject/caregiver is able to comprehend and willing to sign an Informed 
Consent and/or Assent Form. 
 
7.4. 
Exclusion Criteria 
Any subject who meets one or more of the following criteria will not be included in this 
study:  
1. Subject has EBS lesions to be treated that are infected (i.e., EBS lesions that 
require therapy to treat an infection) 
2. Subject has used any diacerein containing product within 6 months prior to Visit 
1 


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Investigational Product: Diacerein 1% Ointment 
 
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3. Subject has used systemic immunotherapy or cytotoxic chemotherapy within 60 
days prior to Visit 1 
4. Subject has used systemic steroidal therapy or has used topical steroidal therapy 
on the EBS lesions to be treated within 30 days prior to Visit 2 (Note: inhaled 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 Visit 1 
6. Subject is currently using systemic analgesics and/or anti-histamine therapy, for 
treatment of EBS lesions unless on a stable regimen (i.e., the same dosing 
regimen) for at least 4 weeks prior to Visit 1.  Note: As needed (PRN) use of 
acetaminophen/paracetamol or NSAIDs within the 4 weeks prior to Visit 1 are 
permitted provided the treatment was unrelated to EBS symptom relief. 
7. 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 Visit 1 
8. Subject has used any topical product containing allantoin on the EBS lesions to 
be treated within 30 days prior to Visit 1 
9. Subject has a current malignancy, or a history of treatment for a malignancy 
within 2 years prior to Visit 1 (Note: does not include non-melanoma skin cancer) 
10. Subject currently has diabetes mellitus (HbA1c ≥6.5%); Note: controlled diabetes 
(HbA1c < 6.5%) is also considered exclusionary 
11. 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) 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  
12. Subject has a non-EBS skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun 
damage, etc.), or condition (e.g., sunburn) 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   
13. Subject has a history of sensitivity to any of the ingredients in the study 
medications (See section 8.8.2) 
14. Subject has participated in an investigational drug trial/device in which 
administration of an investigational study medication occurred within 30 days 
prior to Visit 1. 


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7.5. 
Previous and Concomitant Therapies 
7.5.1. 
Previous therapies 
During Visit 1 (Week -6), the investigator or designee will question the subject/caregiver 
to ensure they have not used any therapies noted in the Exclusion Criteria. 
 
7.5.2. 
Concomitant therapies 
Concomitant therapies are any new or existing/ongoing therapy received from Visit 1 
(Week -6) 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). 
 
The use of an investigator approved bland, non-medicated emollient/moisturizer must 
be reported as a concomitant therapy in the electronic case report forms (eCRFs). 
 
7.5.3. 
Permitted & Prohibited therapies 
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.  
 
A non-exhaustive list of permitted bland, non-medicated emollient/moisturizers are: 
• Emu oil 
• Restore Dimethicreme 
• A&D 
• Aquaphor 
• White petroleum 
• Coconut Oil 
 


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Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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In addition, routine cleansers and cleaning products, bleach baths, topical antiseptics, 
and sunscreens are permitted. 
 
A non-exhaustive list of prohibited therapies are: 
• CBD oil 
• MediHoney 
• Silvadine cream 1% 
• Restore Silver contact layer and foam 
• Mepilex AG 
• Acticoat 
• Aquacel AG 
• SilvaSorb 
• Silverlon 
• Contreet 
 
The investigator should notify the Medical Monitor immediately if any prohibited 
therapies are required to ensure subject safety. 
 
7.5.4. 
EBS lesions treatment instructions: 
EBS lesions may be treated as follows during the study: 
 
 
Time Period 
Screening 
Period  
(Visit 1 until up 
to 6 hours prior 
to Visit 2) 
Randomization 
Day 
(Visit 2) 
Treatment 
Period 
(Day after Visit 
2 until up to 6 
hours prior to 
Visits 3, 4, 5 & 
6) 
No Treatment 
Follow-up 
Period  
(Day after Visit 
6 until up to 6 
hours prior to 
Visits 7 & 8) 
Lesion 
Assessment 
Area 
Bland, 
non-
medicated 
emollient/ 
moisturizer 
Study 
medication at the 
study 
site 
for 
observation 
Study 
medication 
daily, 
in 
the 
evening, 
regardless 
of 
lesion 
resolution 
Bland, 
non-
medicated 
emollient/ 
moisturizer 
Treatment Area 
(new lesions) 
NA (treatment 
area exists after 
Visit 2) 
NA 
(treatment 
area exists after 
Visit 2) 
Study 
medication 
daily, 
in 
the 
evening, until 
lesion 
resolution 
Bland, 
non-
medicated 
emollient/ 
moisturizer 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 30 of 75 
All other EBS 
lesions (lesions 
>30% 
BSA, 
lesions that are 
occluded 
(e.g. 
scalp)) 
Bland, 
non-
medicated 
emollient/ 
moisturizer 
Bland, 
non-
medicated 
emollient/ 
moisturizer 
Bland, 
non-
medicated 
emollient/ 
moisturizer 
Bland, 
non-
medicated 
emollient/ 
moisturizer 
 
7.6. 
Infected Lesions 
EBS lesions that become infected (i.e., EBS lesions that require therapy to treat an 
infection) during the course of the study should be managed following the investigator’s 
routine practice and all concomitant therapies reported in the eCRFs. 
 
No study medication applications should be made to infected lesions. If any EBS lesions 
are not treated with study medication because they are infected, this situation must be 
noted as an adverse event. If the subject does not apply the study medication once daily 
to all EBS lesions for more than seven consecutive days, the subject must be withdrawn 
from treatment.  
 
7.7. 
Subject Discontinuation from the Study 
Subjects/caregiver will be informed that the subjects are free to withdraw from the study 
at any time and for any reason.  Subjects also have the option to withdraw from treatment 
at any time.  Subjects that withdraw from treatment will continue to follow their visit 
schedule but will no longer apply the study medication. 
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. If the subject does not 
apply the study medication once daily to all EBS lesions for more than seven 
consecutive days, the subject must be withdrawn from treatment.  
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.  
 
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 discontinuation will be recorded on the subject’s eCRFs. 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 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 31 of 75 
 
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 
• 
Difficulties in the recruitment of subjects. 
 
7.8. 
Subject Identifier (SI) 
The investigator or designee will register each subject in the Medpace, Inc. Interactive 
Response Technology (IRT) system at Visit 1 (Week -6) to obtain a SI.  
 
The SI format will be NN-NNN where the first 2 digits are the investigational center site 
number (using leading zeroes as appropriate). The final 3 digits are the subject number  
 
The subject will be identified using the SI in all study documentation for the duration of 
the study. 
 
Instructions for use of the IRT system will be provided to each investigator prior to the 
initiation of subject enrollment at her/his center. 
 
7.9. 
Replacement Subjects 
Subject enrollment will continue until approximately 80 subjects have been randomized.  
Subjects who are randomized and do not complete the study will not be replaced. 
 
 
 
 
 
 
 
 
 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 32 of 75 
8. 
INVESTIGATIONAL PLAN 
8.1. 
Study Flow Chart 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Enrollment 
Randomization 
Treatment period e 
No treatment 
follow-up e 
Study Day 
-42 to 0 
1 
8 
29 
43 
57 
85 
113 
Study Week 
-6 
0 
1 
4 
6 
8 
12 
16 
Informed Consent 
X 
 
 
 
 
 
 
 
Register subject 
X 
 
 
 
 
 
 
 
Inclusion & exclusion 
X 
X 
 
 
 
 
 
 
Demographics & medical hx 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
X 
X 
 
X 
 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory samples 
X 
Xb 
 
X 
 
X 
 
X 
ECG 
 
X 
 
 
 
X 
 
X 
Sample for PK analysis 
 
 
 
X 
 
X 
 
X 
EBS genotyping blood or saliva 
sample (if required)  
X 
 
 
 
 
 
 
 
Dispense blister lancing kitc 
X 
X 
X 
X 
X 
X 
X 
 
IGA of Assessment Area 
X 
X 
X 
X 
X 
X 
X 
X 
BSA of Assessment Area 
X 
X 
X 
X 
X 
X 
X 
X 
BSA of Treatment Aread 
 
 
X 
X 
X 
X 
 
 
Reference Lesion LSA 
 
X 
 
 
 
X 
 
X 
Total BSA of all EBS Lesions 
 
X 
 
 
 
X 
X 
X 
Photography 
 
X 
 
 
 
X 
 
X 
Pruritus severity 
 
 
Pain severity 
 
 
Mobility Assessment 
 
 
Identify emollient/moisturizer 
X 
 
 
 
 
 
 
 
Dispense/collect/weigh study 
medication 
 
X 
X 
X 
X 
X 
 
 
Apply study medication 
 
 
 
 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsf 
 
X 
X 
X 
X 
X 
X 
X 
a)  For WOCBP only 
b)  V2 clinical labs need not be drawn if within 7 days of the V1 lab draw 
c)  Subject is not required to use the study issued lancing kits; however, all blisters must be lanced within 24 hours 
d)  Treatment Area is defined as any NEW lesions that appear after Visit 2. Treatment Area may not exceed 30% BSA.   
e)  All visit windows during the Treatment and No Treatment Periods are +/- 4 days 
f) At each visit the Investigator should examine the lesions being treated for any adverse events specific to treatment 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 33 of 75 
8.2. 
Study Visits Description and Procedures 
A written, signed informed consent form (ICF) and assent form as appropriate must be 
obtained from each subject/caregiver prior to performing any study related procedure. 
 
8.2.1. 
Visit 1 (Day -42 to 0)  
At this visit, the investigator or designee will: 
1. Review and explain the nature of the study to the subject/caregiver, obtain the 
subject’s/caregiver’s signature on the appropriate approved ICF, assent form as 
appropriate and Health Insurance Portability and Accountability Act (HIPAA) 
authorization and provide a signed and dated copy to the subject/caregiver 
2. Register subject in the IRT system to obtain a Subject Identifier 
3. Confirm the subject meets all inclusion criteria and no exclusion criterion 
4. Collect demographic and medical history information 
5. Conduct a physical examination 
6. Measure vital signs 
7. Collect blood and urine samples for clinical laboratory tests 
8. Collect a blood or saliva sample for EBS genotyping if documented EBS 
genotyping is not already available 
9. Perform a urine pregnancy test for women of childbearing potential (WOCBP); 
results must be negative for the subject to continue in the study 
10. Collect concomitant therapies information 
11. Define the Assessment Area 
12. Perform BSA of the Assessment Area using the palmar method 
13. Perform the IGA evaluation, IGA grade must be ≥3 in the Assessment Area 
14. Identify an investigator approved bland, non-medicated emollient/moisturizer  
15. Dispense a blister lancing kit and instructions to the subject/caregiver 
16. Dispense a Subject Instruction Sheet 
17. Review the study instructions, including approved emollient/moisturizer use, 
with the subject/caregiver 
18. Schedule Visit 2 to occur within 6 weeks/42 days. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
 
 


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8.2.2. 
Visit 2 (Week 0/Day 1)  
This visit must occur within 42 days after Visit 1.  
 
Subsequent study visit dates must be scheduled based on the date of Visit 2. 
 
This visit may not occur until the investigator confirms all items necessary to determine 
a subject’s eligibility for randomization are available. 
 
At this visit, the investigator or designee will perform the following procedures PRIOR 
TO RANDOMIZATION: 
1. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 
2. Confirm the subject/caregiver continues to comply with all study restrictions and 
that the subject is eligible to continue in the study  
3. Perform a urine pregnancy test for WOCBP; results must be negative for the 
subject to be randomized 
4. Measure vital signs 
5. Perform the IGA evaluation, IGA grade must be ≥3 in the Assessment Area 
6. Confirm subject is eligible for randomization 
7. Screen fail the study subjects who are not eligible for randomization. Note: subjects 
may be re-screened if, at a later date, the subject meets eligibility requirements. All 
protocol required procedures must be repeated (with the exception of genetic 
testing) 
8. Perform Baseline ECG 
 
For subjects who are eligible for randomization the investigator or designee will 
perform the following procedures:  
1. Take standardized color photographs prior to the first study medication 
application 
2. Determine Total BSA of the Assessment Area and of all EBS lesions using the 
palmar method  
3. Identify the Reference Lesion and measure the Lesions Surface Area (LSA) 
4. Collect blood & urine samples for clinical laboratory tests prior to the first study 
medication application 
5. Register eligible subjects in the eDiary system in the IRT 
6. Randomize eligible subjects 
7. Weigh the study medication tube and dispense the tube to the subject 
8. Instruct the subject/caregiver on the study medication application technique 
9. Observe the first study medication application 
10. Weigh the study medication tube after the first study medication application and 
then return the tube to the subject 
11. Monitor the subject for at least 20 minutes after the application to detect any 
adverse events 


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Protocol No. CCP-020-301 
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12. Dispense a blister lancing kit and instructions to the subject/caregiver if needed 
13. Review the study instructions, including eDiary, use of body charts and approved 
bland, non-medicated, emollient/moisturizer use, with the subject/caregiver 
14. Schedule Visit 3 for Week 1/Day 8. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
 
8.2.3. 
Visit 3 (Week 1/Day 8)  
This visit must occur 1 week/7 days (±4 days) after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject/caregiver in a non-directive manner about any changes in the 
subject’s health since the previous visit and report all AEs on the appropriate form 
2. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions, is eligible to 
continue in the study and has followed all study instructions 
4. Measure vital signs 
5. Identify any new lesions that require treatment (Treatment Area) 
6. Determine BSA of EBS lesions in the Assessment Area and in the Treatment Area 
(if new lesions exist) using the palmar method; Note: the area being treated may 
not exceed 30% BSA 
7. Perform the IGA evaluation on the Assessment Area 
8. Dispense, collect and weigh study medication as appropriate 
9. Dispense a blister lancing kit and instructions to the subject/caregiver if needed 
10. Review the study instructions, including eDiary, use of body charts and approved 
bland, non-medicated, emollient/moisturizer use, with the subject/caregiver 
11. Schedule Visit 4 for Week 4/Day 29. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
 
8.2.4. 
Visit 4 (Week 4/Day 29)  
This visit must occur 4 weeks/28 days (±4 days) after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject/caregiver in a non-directive manner about any changes in the 
subject’s health since the previous visit and report all AEs on the appropriate form 
2. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 36 of 75 
3. Confirm the subject continues to comply with all study restrictions, is eligible to 
continue in the study and has followed all study instructions 
4. Measure vital signs 
5. Perform a urine pregnancy test for WOCBP 
6. Identify any new lesions that require treatment (Treatment Area) 
7. Determine BSA of EBS lesions in the Assessment Area and in the Treatment Area 
(if new lesions exist) using the palmar method; Note:  the area being treated may 
not exceed 30% BSA 
8. Perform the IGA evaluation on the Assessment Area 
9. Collect blood & urine samples for clinical laboratory tests 
10. Dispense, collect and weigh study medication as appropriate 
11. Dispense a blister lancing kit and instructions to the subject/caregiver if needed 
12. Review the study instructions, including eDiary, use of body charts and approved 
bland, non-medicated, emollient/moisturizer use, with the subject/caregiver 
13. Schedule Visit 5 for Week 6/Day 43. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
 
8.2.5. 
Visit 5 (Week 6/Days 43) 
This visit must occur 6 weeks/42 days (±4 days) after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject/caregiver in a non-directive manner about any changes in the 
subject’s health since the previous visit and report all AEs on the appropriate form 
2. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions, is eligible to 
continue in the study and has followed all study instructions 
4. Measure vital signs 
5. Identify any new lesions that require treatment (Treatment Area) 
6. Determine BSA of EBS lesions in the Assessment Area and in the Treatment Area 
(if new lesions exist) using the palmar method; Note:  the area being treated may 
not exceed 30% BSA 
7. Perform the IGA evaluation on the Assessment Area 
8. Dispense, collect and weigh study medication as appropriate 
9. Dispense a blister lancing kit and instructions to the subject/caregiver if needed 
10. Review the study instructions, including eDiary, use of body charts and approved 
bland, non-medicated, emollient/moisturizer use, with the subject/caregiver 
11. Schedule Visit 6 for Week 8/Day 57. 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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8.2.6. 
Visit 6 (Week 8/Day 57); end of the treatment period 
This visit must occur 8 weeks/56 days (±4 days) after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject/caregiver in a non-directive manner about any changes in the 
subject’s health since the previous visit and report all AEs on the appropriate form 
2. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions, is eligible to 
continue in the study and has followed all study instructions 
4. Conduct a physical examination 
5. Measure vital signs 
6. Perform a urine pregnancy test for WOCBP  
7. Identify any new lesions that appeared since the last visit 
8. Determine BSA of EBS lesions in the Assessment Area and new lesions (if new 
lesions exist), as well as EBS lesions that are not being treated (e.g. >30% BSA or 
lesions that are occluded) using the palmar method 
9. Measure the LSA of the Reference Lesion  
10. Perform the IGA evaluation on the Assessment Area 
11. Collect blood & urine samples for clinical laboratory tests 
12. Take standardized color photographs 
13. Collect and weigh all study medication as appropriate 
14. Dispense a blister lancing kit and instructions to the subject/caregiver if needed 
15. Review the study instructions, including eDiary, use of body charts and approved 
bland, non-medicated, emollient/moisturizer use, with the subject/caregiver 
16. Perform ECG 
17. Schedule Visit 7 for Week 12/Day 84. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
 
8.2.7. 
Visit 7 (Week 12/Day 85) 
This visit must occur 12 weeks/84 days (±4 days) after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject/caregiver in a non-directive manner about any changes in the 
subject’s health since the previous visit and report all AEs on the appropriate form 
2. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 38 of 75 
3. Confirm the subject continues to comply with all study restrictions, is eligible to 
continue in the study and has followed all study instructions 
4. Measure vital signs 
5. Perform a urine pregnancy test for WOCBP  
6. Identify any new lesions that appeared since last visit 
7. Determine BSA of EBS lesions in the Assessment Area and new lesions (if new 
lesions exist) using the palmar method 
8. Calculate the total BSA of all EBS lesions 
9. Perform the IGA evaluation on the Assessment Area 
10. Dispense a blister lancing kit and instructions to the subject/caregiver if needed 
11. Review the study instructions, including eDiary, use of body charts and approved 
bland, non-medicated, emollient/moisturizer use, with the subject/caregiver 
12. Schedule Visit 8 for Week 16/Day 113. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
 
8.2.8. 
Visit 8 (Week 16/Day 113); end of the study 
This visit must occur 16 weeks/112 days (±4 days) after Visit 2. 
 
At this visit, the investigator or designee will perform the following procedures: 
1. Query the subject/caregiver in a non-directive manner about any changes in the 
subject’s health since the previous visit and report all AEs on the appropriate form 
2. Query the subject/caregiver about any changes in the subject’s concomitant 
therapies since the previous visit and report changes on the appropriate form 
3. Confirm the subject continues to comply with all study restrictions, is eligible to 
continue in the study and has followed all study instructions 
4. Measure vital signs 
5. Identify any new lesions that appeared since last visit 
6. Determine BSA of EBS lesions in the Assessment Area new lesions (if new lesions 
exist) using the palmar method 
7. Calculate the total BSA of all EBS lesions 
8. Measure the LSA of the Reference Lesion 
9. Perform the IGA evaluation on the Assessment Area 
10. Collect blood & urine samples for clinical laboratory tests 
11. Perform a urine pregnancy test for WOCBP  
12. Take standardized color photographs 
13. Perform ECG 
14. Discharge the subject from the study. 
 
The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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8.3. 
EBS Lesion Identification 
For this study, an EBS lesion is defined as a blister (i.e., a fluid filled thin-walled structure), 
or the crust and/or erosion arising from a previous blister, and the immediately 
surrounding intense erythema. At Visit 1 (Week -6), for each subject the investigator will 
determine if the subject has EBS lesions that fulfill the inclusion criteria. 
 
The EBS lesions must be on one or both of the following body areas: 
• Localized involvement:  
o plantar or palmar areas only 
o plantar areas where >25% of the area has hyperkeratosis that has been 
present for greater than 12 weeks are excluded. 
• Generalized involvement: 
o Arms from the shoulder to the tips of the fingers 
o Legs from the hip to the tips of the toes 
o Front and back of the torso, including the neck from the mandibular line in 
the front and the hairline in the back, to the beltline 
 
The Assessment Area of EBS lesions to be treated must be ≥2% and ≤30% BSA at Visit 1 
(Week -6) for the subject to be enrolled and at Visit 2 (Week 0) for the subject to be eligible 
for randomization.  The area being treated must not exceed 30% BSA at any time.  
 
Between Visit 1 (Week -6) and Visit 2 (Week 0) the status of EBS lesions may change, 
therefore, at Visit 2 (Week 0), the investigator will evaluate each subject to determine 
which of the following categories describe the subject’s EBS lesions identified at Visit 1 
(Week -6): 
1. The V1 Assessment Area lesions do not meet the protocol requirements for the 
subject to be eligible for randomization, and the subject does not have EBS lesions 
that meet the requirements  
2. The V1 Assessment Area lesions meet the protocol requirements for the subject to 
be eligible for randomization 
3. The V1 Assessment Area lesions do not meet the protocol requirements for the 
subject to be eligible for randomization, but the subject has additional/other EBS 
lesions that meet the requirements.  The Assessment Area is re-defined. 
 
At Visit 2 (Week 0), the investigator will discharge subjects from the study who are in 
category 1. 
 
At Visit 2 (Week 0), for subjects who are in category 2 or 3 the investigator will follow the 
procedures below to identify EBS lesions to be treated. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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The investigator will mark the general location of all the EBS lesions on the appropriate 
body chart(s) at each study visit.  
8.3.1. 
Occluded Lesions 
The scalp, groin and areas where, in the investigator’s opinion, the study medication 
might become occluded are excluded from treatment with study medication.  
 
8.4. 
Subject Instructions 
An investigational center staff member will dispense the following items to each 
subject/caregiver to help with compliance to the study requirements as needed at a 
specified visit schedules  
• Subject Instruction Sheet, and blister lancing instructions 
• eDiary instructions and body charts. 
 
Updated information and instruction for subjects will be provided as necessary. 
 
Throughout the study, the subjects should: 
• Continue their routine cleansing regimen; however, products that, might affect the 
signs or symptoms of EBS being evaluated (e.g., medicated cleansers, MediHoney, 
Silvadine cream 1%, CBD oil, etc.) are prohibited. 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.  
o Subjects with evening bathing habits (e.g. pediatric patients), should bathe 
prior to study medication application and modify evening habits such that 
sufficient time is left to allow for at least 1 hour before dressing the lesions 
(if applicable), wearing clothing or retiring to bed to allow for absorption of 
medication.  Loose fitting garments (e.g. robes) that do not rub against the 
treated areas are acceptable within the hour. 
• Continue their routine cosmetics and skin care products 
• Avoid exposing the treated EBS lesions to excessive natural or artificial ultraviolet 
radiation (e.g., sunlight, tanning beds) and use sunscreen on the lesions, if 
excessive exposure cannot be avoided 
• Apply study medications to lesions identified by the Investigator that require 
treatment as described in section 7.5.4: 
o If the lesion is identified as part of the Assessment area, apply study 
medication to the lesions daily, in the evening, regardless of lesion 
resolution 
o If the lesion is NEW (appears after Visit 2), apply study medication to the 
lesion until lesion resolution 
 Make note using subject body charts any NEW lesions requiring 
treatment that appear in between study visits (not to exceed 30% 
BSA) 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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• Not wear tight clothing or retire to bed for at least 1 hour post application to allow 
for absorption of medication.   
• Use only a bland, non-medicated emollient/moisturizer or routine cleansing 
products (e.g. Emu oil, Aquaphor, bleach baths, topical antiseptics) to treat EBS 
lesions as described in sections 7.5.3 & 7.5.4 
• For at least 6 hours after a study medication application, DO NOT: 
o Wash/submerge the treated EBS lesions 
o Apply any topical products to the treated EBS lesions 
o 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  
• Bring the subject instruction sheet and all study medication tubes with them to 
each visit. 
 
On study visit days, the subjects should: 
• Wear appropriate clothing to ease the photography procedures 
• Starting with Visit 3 (Week 1), not apply the study medication or any topical 
products to the treated EBS lesions within 6 hours prior to a study visit. 
 
8.5. 
EBS Lesion Care 
8.5.1. 
Blister lancing kit 
At Visits 1-7, an investigational center staff member will dispense a blister lancing kit(s) 
and instructions to every subject/caregiver as appropriate. The subject will be instructed 
to lance all EBS lesions, including study medication treated lesions and those not treated 
with study medication (e.g., lesions on the face), within 24 hours of appearance.    
 
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. 
8.5.2. 
Bandaging/Dressing Use 
The following section applies to all EBS lesions. Bandaging may be a part of a subject’s 
routine lesion care.  Because EB skin may be more fragile in the heat and humidity and 
due to the fact that there is considerable variation in how and when lesions are dressed 
and the types of dressings used, subjects should generally be discouraged from 
bandaging their lesions during their participation in the study.  However, bandaging is 
not prohibited provided the subject maintains their current bandaging routine and 
remains consistent throughout their participation in the study. Subjects should indicate 
their bandaging routine which will be recorded in the eCRF as follows: 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 42 of 75 
1) The subject never bandages their EBS lesions 
2) The subject occasionally bandages their EBS lesions when: 
a. The lesion requires protection from further trauma or contact and friction 
from clothes. 
b. The lesion is draining or bleeding. 
c. The lesion is painful, and a dressing may improve comfort. 
3) The subjects always bandages their EBS lesions 
 
Note: All bandaging is prohibited 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. 
 
8.6. 
Subject Diary 
At Visit 2 (Week 0), an investigational center staff member will explain the use of the 
electronic diary (eDiary) to each subject/caregiver. The eDiary will be used to collect 
daily information regarding: 
• Study medication application frequency compliance 
• Blister lancing compliance 
• New lesions that develop in between study visits 
• Bandage use  
• Use of routine cleansers 
• Pruritus Severity 
• Pain Severity 
• Mobility 
 
At Visit 2 an investigational center staff member will register each subject who is 
randomized into the eDiary in the IRT system.  
 
At Visits 3-7 an investigational staff member will reinforce the instructions for proper use 
of the eDiary with each subject/caregiver. Specifically, staff will ensure each 
subject/caregiver understands the palmar method for BSA% measurement to estimate 
new lesions that develop in between study visits and record the information in the 
eDiary.  Staff will also emphasize the importance of not exceeding 30% BSA being treated 
at any time throughout the treatment period of the study. 
 
Instructions for use of the IRT system will be provided to each investigator prior to the 
initiation of subject enrollment at her/his center. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 43 of 75 
8.7. 
STUDY DURATION 
The duration of study participation for a subject is anticipated to be a maximum of 158 
days. This includes the up to 6-week screening period, an 8-week treatment period and 
an 8-week no-treatment follow-up period. The final study visit (Visit 8/Week 16) has a 
maximum allowable visit window of 4 days.   
 
The study end date is the date of the last subject’s last visit.  
 
8.8. 
STUDY MEDICATIONS 
8.8.1. 
Study medication identity 
The study medications are yellow ointments that are indistinguishable in physical 
appearance. The study medications must be stored in a secure area with limited access 
under appropriately controlled and monitored storage conditions. 
 
Study Medication Information 
Study medication name 
Diacerein (CCP-020) 1% 
Ointment 
Control Ointment 
Manufacturer 
TWi Pharmaceuticals, Inc., Taoyuan City, Taiwan 
Diacerein concentration (%) 
1 
0 
Pharmaceutical Form 
Ointment 
Storage Conditions 
59°F to 86°F (15°C to 30°C) 
Dose regimen 
 
Route 
Topical 
Frequency 
Once-daily application to all EBS lesions 
Duration of administration 
Once-daily applications for 8 weeks 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 44 of 75 
8.8.2. 
Study medication formulation  
 
Ingredients 
Function 
Specification 
Proposed 
Clinical 
Trial Formulation  
(% w/w) 
Diacerein  
(CCP-020)  
1% Ointment 
Diacerein 
Active 
EP monograph 2409 
1.0 
Mineral oil, light, 
NF 
Ointment base 
NF 
12.0 
Petrolatum, 
white, 
USP 
Ointment base 
USP 
84.5 
Cetyl alcohol, NF 
Thickener 
NF 
2.0 
Ethylparaben, NF 
Preservative 
NF 
0.5 
Control Ointment 
FD&C Yellow #5, 
AL 15% - 17%, 
Aluminum 
Lake 
(5175) 
Colorant 
EU 231/2012 
0.025 
Mineral oil, light 
Ointment base/ skin 
protectant 
NF 
12.0 
Petrolatum white 
Ointment base/ skin 
protectant 
USP 
85.475 
Cetyl alcohol 
Thickener 
NF 
2.0 
Ethylparaben 
Preservative 
NF 
0.5 
 
8.8.3. 
Study medication packaging and labeling 
The study medications are yellow colored ointments and will be packaged in identical 
appearing, aluminum tubes that each contain 30 grams of study medication. 
 
A bulk supply of each 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 carton will be labeled with a two-part label. One part of the label remains attached 
to the carton, the other part (tear-off) is separated and attached to the subject’s drug 
accountability log when the tube is dispensed. 
 
Both parts of the carton label show at least the following: 
• Tube number 
• Protocol number 
• Storage conditions 
• Instructions for use 
• Sponsor information 
• Investigational drug warning 
• Space to enter site number 
• Space to enter subject number. 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 45 of 75 
 
Each study medication tube will be labeled with a one-part label that remains attached to 
the tube and shows at least the following: 
• Tube number 
• Protocol number 
• Investigational drug warning 
• Space to enter site number 
• Space to enter the subject number. 
 
8.8.4. 
Method of treatment assignment 
Prior to the start of the study, Castle Creek Pharmaceuticals, LLC or a designated third 
party will generate a list of randomization numbers that shall be transmitted to the 
assigned clinical packaging organization for study medication labeling. 
 
The randomization list will be stored with access limited to designated personnel for 
study medication labeling. The randomization list will be made available as appropriate 
to un-blind the database. 
 
8.8.5. 
Dispensing study medication 
The study medication must be dispensed only to study subjects, only at investigational 
centers specified on the Form FDA 1572 (or its equivalent) and only by authorized 
personnel as required by applicable regulations and guidelines. 
 
The subject/caregiver must bring dispensed study medication tubes and, if possible, 
cartons with them to all visits. 
 
At Visit 2 (Week 0), after the subject is randomized and the assigned study medication 
tubes have been identified an investigational center staff member will weigh each tube of 
study medication (without the carton and with the cap) to the nearest 0.1 gram then give 
the tube(s) and the carton(s) of study medication to the subject/caregiver.  
 
An investigational staff member will also weigh the study medication tube used for the 
first study medication to the nearest 0.1 gram after the application. 
 
At Visits 3-5, examine the tube(s) of study medication dispensed to the subject/caregiver, 
and weigh each opened tube of study medication (without the carton and with the cap) 
to the nearest 0.1 gram.  
 
Collect tubes and cartons that do not contain a useable amount of study medication. 
Weigh the returned study medication tubes (without the carton and with the cap).  
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 46 of 75 
Dispense an appropriate number of study medication tubes with cartons to the 
subject/caregiver. Weigh each tube of study medication (without the carton and with the 
cap) to the nearest 0.1 gram. 
 
At Visit 6 (Week 8), collect all study medication tubes and, if possible, cartons from the 
subject/caregiver and weigh all the tubes (without the carton and with the cap), whether 
they were opened or not, to the nearest 0.1 gram. 
  
The investigational center staff should make every effort to obtain all dispensed and 
unused study medication. Two documented telephone contacts followed by a registered 
letter to the subject/caregiver are adequate follow-up efforts. If these efforts fail, the 
reason for the failure must be noted in the eCRF. All unused and un-dispensed study 
medication should be held for inspection by the monitor. Upon completion of the study, 
all study medication will be returned to Castle Creek Pharmaceuticals, LLC or a 
designated third party by the monitor using a traceable method. 
 
8.8.6. 
Study medication application 
The study medications are for external, topical use on the subject’s EBS lesions only.  
 
At Visit 2 (Week 0), an investigational center staff member will instruct the 
subject/caregiver on the appropriate application technique. The subject/caregiver will 
perform the first study medication application and a staff member will observe the 
application. The staff member must ensure the study medication tube is weighed before 
AND after the first application. 
  
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 EBS lesions 
and to about ¾ inch (2cm) of uninvolved skin surrounding each lesion with a thin 
layer and gently rub it in 
o A general rule to follow is 1 fingertip unit of study medication is sufficient 
to cover approximately 1 % BSA (palmar method measurement) for that 
particular subject 
• Not cover the treated area with any type of bandage or dressing for 1 hour after 
the application  
• Wash her/his hands after completing the application.  
 
At Visit 2 a staff member should monitor the subject for at least 20 minutes after the first 
application to detect any immediate adverse events. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 47 of 75 
8.8.7. 
Dose compliance record 
Each subject/caregiver will record the subject’s compliance with the study medication 
application frequency on a daily basis in an eDiary. 
 
8.8.8. 
Dose modification 
Subjects/caregivers should not modify the study medication application procedure or 
frequency without approval from the investigator or designee.  
If any significant study medication intolerance or safety issue occurs the investigator or 
designee may direct the subject/caregiver to reduce the study medication application 
frequency as determined by the Investigator. 
If the subject does not apply the study medication once daily to the assessment area for 
more than seven consecutive days, the subject must be removed 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 eCRF. These subjects should 
be withdrawn from the study. 
 
8.9. 
Study medication Management 
8.9.1. 
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. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 48 of 75 
8.9.2. 
Return and disposition of study supplies 
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. 
 
8.10. 
Other Study Supplies 
Castle Creek Pharmaceuticals, LLC (or designee) will provide the following items to each 
investigational center prior to the initiation of subject enrollment: 
 
• Supplies and instructions for collecting, labeling, shipping and result reporting for 
the clinical laboratory tests 
• Urine pregnancy tests 
• Supplies and instructions for blister lancing 
• Equipment, supplies and training for taking standardized photographs 
• Other supplies as identified by the study site. 
 
8.11. 
Blinding 
8.11.1. 
Verification of blinding 
Blinding of the study medications is important for validity of this study. This study 
uses a double-blind design. The study medications are indistinguishable in appearance, 
packaging and labeling. 
 
8.11.2. 
Un-blinding the study medication 
Blinding is important for validity of this clinical study. However, the blind may be broken 
in the event of a medical emergency, in which knowledge of the study medication 
identity is critical to the management of the subject’s course of treatment. Before breaking 
the blind the investigator should determine that the information is necessary (i.e., that it 
will alter the subject’s immediate course of treatment). In many cases, particularly when 
the emergency is clearly not study medication-related, the problem may be effectively 
managed by assuming that the subject is receiving an active study medication without 
the need for un-blinding. If deemed necessary to break the blind for a study subject, the 
investigator has the final decision and unilateral right to break the blind and should 
notify the Castle Creek Pharmaceuticals, LLC Medical Monitor as soon as possible after 
breaking the blind for a subject. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 49 of 75 
To identify a subject’s study medication the investigator or designee must electronically 
contact the Medpace, Inc. IRT system to identify a subject’s study medication assignment. 
Record the date of un-blinding, the reason for un-blinding and the initials of the 
investigational center staff member who performed the un-blinding on the subject’s 
study file.  
 
Any subject whose blind has been broken must be discharged from the study.  
 
Instructions for use of the IRT system will be provided to each investigator prior to the 
initiation of subject enrollment at her/his center. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 50 of 75 
9. 
STUDY ASSESSMENTS 
The investigator, or a designated and appropriately trained staff member, will perform 
the efficacy assessments according to the schedules noted below.  
 
The same individual should perform the assessments for a given subject throughout the 
study. If this becomes impossible, an appropriate designee with overlapping experience 
with the subject and study should perform the assessments.  
 
Similar lighting conditions and subject positioning should be used for all evaluations for 
a given subject. 
 
9.1. 
Effectiveness Evaluations 
For this study an EBS lesion is defined as a blister, or the crust and/or erosion arising 
from a previous blister, and the immediately surrounding intense erythema. 
 
9.1.1. 
Investigator’s Global Assessment (IGA) 
The IGA is the investigator’s (who must be a physician or Physician’s Assistant/nurse 
practitioner in dermatology) clinical assessment of the average overall severity of all the 
EBS lesions, considered together, at a particular time point. The investigator should NOT 
refer to any other assessments, study photographs or notes to assist with these assessments. 
 
At Visits 1-8, the investigator will assess the subject’s EBS lesions using the scale below and 
report the one integer that best describes the average overall severity of all the EBS lesions 
considered together. 
 
Investigator’s Global Assessment 
Score 
Definition 
0 
Clear: No blisters, no erosions, no crusting, no erythema and/or pigmentary 
changes may be present 
1 
Near Clear: Two or few small blisters, faint signs of erosion may be present, 
barely perceptible evidence of crusting, slight erythema  
2 
Mild: Predominantly small and some medium blisters, minimal erosions, clear 
crusting, definite well-defined erythema 
3 
Moderate: Mix of small and medium blisters, definite erosions, limited areas 
of crusting, marked erythema 
4 
Severe: Mix of medium and large blisters, marked erosions, ulceration may be 
present, marked and extensive crusting, intense erythema 
  
For this evaluation, a blister is defined as a fluid filled thin-walled structure.  
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 51 of 75 
Blister size is defined as: 
• Small: visible to ≤1cm2 
• Medium: >1cm2 to ≤2cm2 
• Large: >2cm2. 
 
At Visit 1 (Week -6) for a subject to be enrolled, and at Visit 2 (Week 0) for the subject to be 
randomized, the IGA must be ≥3. 
 
At Visit 2 (Week 0) the investigator must complete the IGA prior to the first study 
medication application. 
 
The IGA must be completed prior to the evaluator reviewing any study photographs. 
 
9.1.2. 
Assessment Area 
At Visit 1, the investigator or designee will identify an “Assessment Area” of EBS 
lesions to be treated.  The Assessment Area is a targeted treatment area from which all 
IGA assessments and the primary endpoint will be made.  The Assessment Area does 
not need to be contiguous.  At Visit 1 (Week -6) for a subject to be enrolled, and at Visit 
2 (Week 0) for the subject to be randomized, the Assessment Area must be ≥2% body 
surface area (BSA), the IGA of the Assessment Area must be ≥3, and the EBS lesions 
must be in one or both of the following body areas:  
 
- 
Localized: plantar and/or palmar areas (plantar areas where >25% of the 
area has hyperkeratosis that has been present for greater than 12 weeks 
cannot be included as part of the Assessment Area) 
- 
Generalized: arms, legs, torso, hands and feet (scalp, groin and areas 
where, in the investigator’s opinion, the study medication might become 
occluded cannot be included as part of the Assessment Area)  
 
In this study, the palmer method will be used to determine BSA of EBS lesion.   1% BSA 
is defined as the area of the subject’s hand held flat, including the thumb and fingers 
held together.   Investigational drug will be applied to the Assessment Area for the 
entire duration of the study 8-week treatment period. 
 
The Assessment Area will remain fixed for the duration of the study with the notable 
exception at Visit 2 (see also Section 8.3).   At Visit 2, the Investigator may re-designate 
the Assessment Area assigned at Visit 1 for purposes of inclusion provided all criteria 
noted above are satisfied.  All IGAs and the primary endpoint will be graded from the 
Assessment Area. 
 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 52 of 75 
9.1.3. 
Treatment Area 
For purposes of this study, the Treatment Area is established after Visit 2 and is defined 
as all BSA where treatment is applied throughout the treatment period of the study.  
The treatment area may increase or decrease subsequent to Visit 2 depending on the 
emergence of blisters and is always inclusive of the Assessment Area.  The Treatment 
Area is NOT the area from which the determination of BSA of EBS lesions or IGA are to 
be assessed; only the Assessment Area will be assigned an IGA grade and will be 
assessed for the BSA of EBS lesions.  Additional areas of EBS lesions may be added to 
the Treatment Area during the Treatment Period but Treatment Area cannot be more 
than 30% BSA at any time. Lesions that are not being treated with study medication (i.e. 
occluded) are not considered as part of the treatment area.  Note: A subject may never 
have a defined Treatment Area if the subject does not develop lesions outside of the 
Assessment Area during the Treatment Period. 
 
9.1.4. 
Reference Lesion Surface Area (LSA) 
At Visit 2 the investigator will identify one of each subject’s EBS lesions, the Reference 
Lesion, for measurement of the LSA. The Reference Lesion should have a severity that is 
approximately equal to the IGA grade, however the investigator is NOT required to 
perform a separate IGA evaluation for the Reference Lesion.   
 
The investigator must clearly mark the location of the Reference Lesion on the subject’s 
body chart (e.g., using landmarks and distance measurements) so the lesion can be 
accurately and consistently identified at subsequent visits.  
 
At Visits 2 (Week 0), 6 (Week 8) and 8 (Week 16) the investigator will measure the length 
and width of the Reference Lesion using the ruler provided (or an equivalent) as follows: 
• Length (i.e., the length of the longest axis) to the nearest millimeter (mm) 
• Width (i.e., the length of the longest axis perpendicular to the length) to the nearest 
mm. 
 
At Visit 2 the Lesion Dimensions must be measured prior to the first study medication 
application.  
 
At Visits 6 and 8 the investigator will measure the Reference Lesion on approximately the 
same axes for length and width. The investigator should report 0mm for the 
measurements if the Reference Lesion is clear at Visits 6 or 8.  
 
The length and width will be used to estimate the surface area of the Reference Lesion. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 53 of 75 
9.1.5. 
Body surface area (BSA) of the Assessment Area/Treatment Area/All 
EBS Lesions  
All BSA measurements collected at the study site will be obtained by the investigator 
(who must be a physician, physician’s assistant or dermatology nurse practitioner). The 
investigator should NOT refer to any other assessments, study photographs or notes to 
assist with these assessments. For this study 1% BSA is defined as the area of the subject’s 
hand held flat, including the thumb and fingers held together. 
 
The BSA of the Assessment Area will be collected for all lesions included within the 
Assessment Area using the palmar method. 
 
The BSA of the Treatment Area will be collected for all NEW lesions that appear after 
Visit 2 (if new lesions exist) using the palmar method. The subject/caregiver will use the 
palmar method for BSA% measurement to estimate new lesions that appear after Visit 2 
in between study visits (if new lesions exist) and record the information in the eDiary.  
 
The total BSA of EBS Lesions will be collected for all lesions that are NOT being treated 
with study medication (e.g. lesions that exceed 30% BSA or lesions that are occluded).  
 
9.1.6. 
Pruritus Intensity (for Subjects aged 8 years and older) 
The Pruritus Intensity Assessment is the subject’s assessment of pruritus at its worst 
experienced over the previous 24 hours on all EBS lesions. The subject should NOT refer to 
any other assessments to assist with these assessments.  
 
Starting at Visit 2 (Week 0) and continuing each day for the duration of the subject’s 
study participation, the subject will report his/her experience of pruritus at its worst in 
an electronic diary.  
 
This assessment should be completed just prior to the daily study medication application 
using the following scale: 
Pruritus Intensity 
Instructions: The following question is about itch related to your epidermolysis 
bullosa simplex (EBS).  Please select the number that best describes your experience 
with itch at its worst over the past 24 hours.  Please select only one answer.  There is 
no right or wrong answer to this question. 
Rate your itch at its 
worst over the past 
24 hours.  
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No itch at 
all 
 
 
 
 
 
 
 
 
 
Worst 
possible 
itch 
 
 
 
 
 
 
 
 
 
 
 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 54 of 75 
9.1.7. 
Pain Intensity (for Subjects aged 8 years and older) 
The Pain Intensity Assessment is the subject’s assessment of pain at its worst experienced 
over the previous 24 hours on all EBS lesions. The subject should NOT refer to any other 
assessments to assist with these assessments.  
 
Starting at Visit 2 (Week 0) and continuing each day for the duration of the subject’s study 
participation, the subject will report the average overall intensity of pain in an electronic 
diary.  
 
This assessment should be completed just prior to the daily study medication application.  
 
Pain Intensity 
Instructions: The following question is about pain related to your epidermolysis 
bullosa simplex (EBS).  Please select the number that best describes your experience 
with pain at its worst over the past 24 hours.  Please select only one answer for each 
question.  There is no right or wrong answer to this question. 
Rate your pain at its 
worst over the past 
24 hours.  
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
No pain 
at all 
 
 
 
 
 
 
 
 
 
Worst 
possible 
pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.8. 
Mobility Assessment 
The Mobility Assessment is the subject/caregiver’s assessment of the subject’s degree of 
mobility over the previous 24 hours. The subject/caregiver should NOT refer to any other 
assessments to assist with these assessments. The same individual, subject or caregiver, 
should perform all Mobility Assessments for a given subject for the duration of the study. 
Note that the assessment of pain and pruritus must be done by the subject.  
 
Starting at Visit 2 (Week 0) and continuing each day for the duration of the subject’s study 
participation, the subject/caregiver will report the subject’s degree of mobility by 
answering a series of age-appropriate questions in the eDiary. This assessment should be 
completed at approximately the same time each day, just prior to the study medication 
application, using the following scale: 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 55 of 75 
Score Definition 
1 
Uses wheelchair (May stand for transfers, may do some stepping supported 
by another person or using a walker/frame) 
2 
Uses walker or frame: Without help from another person 
3 
Uses crutches: without help from another person 
4 
Uses sticks (e.g., canes) (one or two): Without help from another person 
5 
Independent on level surfaces: Does not use walking aids or need help from 
another person (if uses furniture, walls, fences, shop fronts for support use 4 
description). Requires rails for stairs 
6 
Independent on all surfaces: Does not use any walking aids or need any help 
from another person when walking over all surfaces including uneven 
ground, curbs, etc. and in a crowded environment 
7 
Crawling: Child crawls for mobility at home 
8 
Does not apply: For example, child does not complete the distance 
 
This scale is assessed for 3 distances: 5 meters (yards); 50 meters (yards); 500 meters 
(yards). 
 
9.2. 
Safety Evaluations 
In addition to reporting adverse events throughout the study the investigator, a 
designated and appropriately trained staff member or the subject/caregiver, will perform 
the following safety assessments according to the schedules noted below. 
 
9.2.1. 
Demographics/Medical History 
At Visit 1 (Week -6), 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 Visit 1 (Week -6): 
• Are ongoing 
• Require concomitant therapy 
• Are, in the opinion of the investigator, relevant to the subject’s study participation. 
 
9.2.2. 
Vital Signs 
At Visits 1-8 a qualified staff member will measure each subject’s vital signs. At Visit 1 
(Week -6) these measurements will be part of the physical examination. The following 
items will be measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 56 of 75 
• Blood pressure (systolic and diastolic) after the subject sits quietly for at least 5 
minutes 
• Height (at Visit 1, 6 and 8) 
• Weight (at Visit 1, 6 and 8). 
 
Abnormal vital signs must be defined as clinically relevant (CR) or not clinically relevant 
(NCR) on the eCRFs.  
 
9.2.3. 
Physical Examination 
At Visit 1 (Week -6) and Visit 6 (Week 8) 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 (excluding EBS lesions) 
• Cardiovascular system 
• Respiratory system 
• Head, eyes, ears, nose and throat 
• Lymph nodes 
• Gastrointestinal/Hepatobiliary 
(specifically 
assess 
for 
the 
presence 
of 
hepatomegaly and splenomegaly) 
• Vital signs. 
 
9.2.4. 
Clinical laboratory sampling 
At Visits 1, 2, 4, 6 and 8 a qualified staff member will collect blood and urine samples for 
clinical laboratory analysis. Topical anesthetics may be used during the blood sample 
collection. If used the topical anesthetics should be reported as a concomitant therapy. 
Non-fasting blood samples will be collected at all Visits. At Visit 2 (Week 0) the samples 
must be collected prior to the first study medication application. The following tests will 
be performed: 
 
Chemistry Panel 
Complete Blood Count 
Albumin 
Hematocrit 
Alkaline phosphatase (ALP) 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet count 
Amylase 
Red blood cell morphology 
Aspartate aminotransferase (AST) Red blood cell count 
Blood urea nitrogen (BUN) 
White blood cell count 
Bicarbonate 
White blood cell differential  
Chloride 
% and absolute: 
Creatinine 
    Basophils 
Gamma-GT 
    Eosinophils 
Glucose 
    Lymphocytes 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 57 of 75 
HbA1c 
    Monocytes 
Lactate dehydrogenase (LDH) 
    Neutrophils 
Lipase 
 
Potassium 
 
Sodium 
Complete Urinalysis 
Total bilirubin 
 
Total protein 
 
Uric acid 
 
 
The results of the clinical laboratory tests will be reported on the laboratory’s standard 
reports. The investigator must review all laboratory reports in a timely manner and note 
NCR or CR to define the clinical relevance of any result that is outside the normal range 
for the laboratory. The investigator must date and initial every laboratory report.  
 
The investigator must review the Visit 1 (Week -6) laboratory results for all the measured 
analytes for each subject prior to Visit 2 (Week 0). The subject must not be randomized at 
Visit 2 (Week 0) if any of the Visit 1 (Week -6) results are outside normal range for the 
laboratory AND, in the opinion of the investigator, CR. 
 
The investigator must report all laboratory results that are BOTH outside the normal 
range for the laboratory AND, in the opinion of the investigator, CR as medical history if 
found prior to the first study medication treatment or as an AE if found after the first 
study medication treatment begins.  
 
9.2.5. 
PK Sample Collection 
 
Blood samples for Pharmacokinetic (PK) analyses of diacerein and rhein will be collected 
at the time points listed in the Study Flow Chart.  Population PK modeling and PK/PD 
analyses will be performed according to a PK/PD analysis plan separate from this 
protocol and data permitting. 
 
9.2.6. 
Genetic Confirmation of EBS 
At Visit 1 (Week -6), the investigator or designee will obtain a blood or saliva sample to 
perform EBS genotyping from each subject, unless the subject provides written 
confirmation of a laboratory diagnosis of EBS. 
 
Documentation (i.e., a written laboratory report) of the presence of KRT5 and/or KRT14 
or KRT5, KRT14, PLEC1, TGM5, PKP1, DSP, FERMT1, EXPH5, DST, KLHL24 is 
acceptable. 
 
Genetic confirmation of EBS is required for a subject to be randomized at Visit 2. 


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Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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Supplies and detailed instructions for obtaining these samples will be provided to 
investigational center prior to the initiation of subject enrollment.  
 
9.2.7. 
Pregnancy tests 
The investigator or designee will perform a urine pregnancy test for subjects who are 
WOCBP at Visits 1, 2, 4, 6, 7 and 8. The urine pregnancy test kits used must have a 
minimum sensitivity of 25-mIU ß-HCG/mL of urine.  
 
Subjects who are WOCBP must have a negative pregnancy test result at Visit 1 (Week -6) 
to be enrolled in the study and at Visit 2 (Week 0) to be randomized. 
 
If the result of any post-randomization urine pregnancy test is positive, the subject will 
be withdrawn from the study and the subject’s pregnancy documented and followed 
until completion and for at least 6 weeks after birth. 
 
9.3. 
Other Evaluations 
9.3.1. 
Standardized photography 
At Visits 2, 6 and 8 standardized color photographs will be taken as outlined below. 
These photographs will be used to document the status of the EBS lesions being treated. 
 
Standardized photographs will include: 
• Four ½ body images (i.e., anterior and posterior; right-side lateral and left side 
lateral) 
• Body charts including plantar chart. 
Photography equipment, supplies and training will be provided to each investigator 
prior to the initiation of subject enrollment at her/his center. 
 
9.3.2. 
Electrocardiogram (ECG) Monitoring 
 
Single 12 lead ECGs will be performed as outlined in the Study Flow Chart using 
sensitive electrodes (or other precautionary measure) ensuring the subject’s skin is not 
harmed from the procedure (e.g. SofTouch™ Electrodes).  ECGs will be performed on 
subjects in supine position. All ECG tracings will be reviewed by the Study Physician or 
his/her designee.  A subject will be withdrawn from the study by the Study Physician 
or his/her designee if, in their medical judgment, ECG findings are present which make 
continued study participation not in the subject’s best interest. 
 


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Protocol No. CCP-020-301 
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9.4. 
Total Volume of Blood Collected 
The total number of venipunctures and the total volume of blood collected during the 
study will be limited to that needed for safety monitoring and genotyping 
measurement. The total blood volume collected for each subject for the entire study will 
be compliant with WHO guidelines. Due to WHO compliance, safety laboratory tests 
will be prioritized if not all laboratory samples can be collected due to volume. 
 
 
Screening 
Visit 1 
Visit 2 
Visit 4 
Visit 6 
Visit 8 
Adults 
10 ml 
10 ml 
10 ml 
10 ml 
10 ml 
Children 
(<18 years) 
3.5 ml 
3.5 ml 
3.5 ml 
3.5 ml 
3.5 ml 
 


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Protocol No. CCP-020-301 
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Global Protocol Amendment 3a 
 
Page 60 of 75 
10. 
ADVERSE EVENTS 
Adverse events will be monitored throughout the study and immediately reported on the 
appropriate AE eCRF.   
 
10.1. 
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. 
Worsening of any EBS lesion assessment should be reported as an AE ONLY if the use of 
the study medication is interrupted or discontinued, or if therapy is required to manage 
the event. 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 the subject’s 
study participation is complete (Visit 8/Week 16) OR until 30 days after the subject’s last 
study medication application, whichever is longer.  
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 Visit 1 (Week -6) should not be reported as an 
adverse event unless the medical condition or signs or symptoms present at Visit 1 (Week 
-6) 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., electrocardiogram) 
findings that are detected during the study or are present at Visit 1 (Week -6) and worsen 
during the study to the point where the investigator defines it as clinically significant 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 61 of 75 
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. 
 
10.2. 
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). 
 
10.3. 
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. 
  
10.4. 
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. 
 
10.4.1. 
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. 
 
10.4.2. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be 
assessed according to the following definitions: 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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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 Rechallenge). 
 
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. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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10.4.3. 
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 
• 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. 
 
10.5. 
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, 
o 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, 
o 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, 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 64 of 75 
• A congenital anomaly/birth defect, or 
• An important medical event. 
o 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. 
 
10.5.1. 
Serious Adverse Event Reporting/Adverse Events of Special Interest – 
Procedures for Investigators 
10.5.1.1 
Initial Reports 
All SAEs/AESI, regardless of causality, occurring from the time of informed consent until 
30 days following study completion OR until 30 days after the subject’s last application 
of study medication, whichever is longer, 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-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. 
 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE/AESI hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Fax: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
 


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Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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10.5.1.2 
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. 
 
10.5.1.3 
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. 
  
10.6. 
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 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. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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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, whichever is longer, 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 and early termination study procedures will be performed unless 
contraindicated by pregnancy. The investigator must immediately (within 24 hours) 
notify the Castle Creek Pharmaceuticals, LLC Medical Monitor.  
 


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Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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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. 
 
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. 
 
11. 
STATISTICAL ANALYSES 
11.1. 
Analysis Populations 
The Intent-to-Treat (ITT) Population will consist of all randomized subjects with at least 
one post-baseline BSA of EBS lesion assessment. 
The Per Protocol (PP) Population will consist of all ITT subjects with a BSA of EBS lesions 
at Week 16 and without a major protocol violation that may interfere with the assessment 
of drug efficacy.  Before data are released for statistical analysis, a blinded review of all 
data will be performed by the clinical team to identify protocol deviations that may 
potentially affect the results.  At this time, it will be determined if patients and/or data 
should be excluded from the PP Population.  The list of subjects or observations to be 
excluded from the PP Population, along with the reason for exclusion, will be finalized 
prior to database unblinding. The Safety Population will consist of all subjects who 
receive at least one application of study drug. 
 
11.2. 
Data Analysis 
A statistical analysis plan (SAP) will provide additional details on the approach to the 
analyses and data displays. 
 
11.2.1. 
Missing Data Handling Methods 
 Missing data imputation will only be applied to the primary efficacy endpoint, the 
percentage of subjects with success defined as a ≥40% reduction in BSA of EBS lesions at 
Week 16, for analysis with the ITT Population. If a BSA value at Week 16 is missing, the 
value will be imputed using last observation carried forward (LOCF). Other sensitivity 
imputations will be used to test the robustness of this imputation method corresponding 
to a best-case and worst-case scenario.  The best-case scenario will involve missing values 
at Week 16 being imputed as a success, while the worst-case scenario will involve missing 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 68 of 75 
values at Week 16 being imputed as a failure. No missing data imputation will be applied 
to the secondary efficacy endpoints. 
 
Adverse events with missing start dates will be considered as treatment-emergent unless 
the partial date excludes that possibility, e.g. the adverse event month is prior to the 
treatment infusion month.  Otherwise, the first day of the month will be used to impute 
missing start days and January will be used to impute missing start months. 
11.2.2. 
Subject Information 
A detailed description of subject disposition will be provided. Descriptive summaries of 
demographic and baseline characteristics will be presented by treatment group based on 
the ITT Population. 
 
11.2.3. 
Analysis of Efficacy 
Descriptive summaries of efficacy endpoints will be presented by treatment group. The 
primary efficacy endpoint; the proportion of subjects who achieve success, defined as 
≥40% reduction in body surface area (BSA) of EBS lesions from Visit 2 (Week 0) to Visit 8 
(Week 16) will be analyzed with a CMH test, with treatment (Diacerein 1% Ointment or 
Control Ointment) as a factor, and genotype and age group (<8 and ≥8 years old) as strata. 
Estimated odds ratio and associated 95% confidence interval (CI) and p value will be 
provided.  
 
Key Secondary efficacy endpoints include the following: 
• The proportion of subjects achieving success on the Investigator’s Global 
Assessment (IGA), where success on the IGA is defined as at least a 2-point 
reduction from Visit 2 (Week 0) to Visit 8 (Week 16).  
• The proportion of subjects with ≥ 40% reduction in BSA of EBS lesions from 
Visit 2 (Week 0) to Visit 6 (Week 8). 
• The proportion of subjects achieving success on the IGA, where success on 
the IGA is defined as at least a 2-point reduction from Visit 2 (Week 0) to Visit 
6 (Week 8).  
• The proportion of subjects with a reduction in overall pain intensity from 
Visit 2 (Week 0) to Visit 6 (Week 8).  
• The proportion of subjects with a reduction in overall pruritus intensity from 
Visit 2 (Week 0) to Visit 6 (Week 8). 
 
All key secondary efficacy endpoints will be summarized and listed by treatment group 
and visit. Count and percentage of subjects in each category will be presented. The 
percentage of subjects who achieve success in the IGA from baseline to Visit 6 (Week 16) 
will be analyzed using the same CMH test for primary endpoint. For other endpoints, 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 69 of 75 
Analysis of Covariance (ANCOVA), Chi-square tests or logistic regression will be used 
for secondary efficacy endpoints, if appropriate. Some secondary efficacy endpoints can 
be dichotomized before the analysis. For example, for the endpoint 5-Point IGA, all 
subjects can be dichotomized based on if they have a 2-grade or more improvement in 
IGA at Visit 8 (Week 16) from baseline Visit 2 (Week 0). Details will be provided in the 
SAP. 
Exploratory end points will be analyzed as described in the SAP. 
11.2.4. 
Analysis of Safety 
Safety measures will include the following assessments: 
• Demographics\Medical History 
• Adverse events and SAEs 
• Vital Signs 
• Physical Examination 
• Clinical laboratory 
• ECGs 
• Urine pregnancy tests. 
 
Adverse events and medical histories will be coded using the most current version of 
the Medical Dictionary for Regulatory Activities (MedDRA). New or worsening adverse 
events after dosing of study drug will be summarized by system organ class, preferred 
term, and treatment. Lists of subjects who have an SAE or who discontinue from the 
study due to an adverse event will be provided. 
 
Summary statistics for laboratory values will be provided at baseline, post-baseline 
visits, and for changes from baseline to post-baseline by treatment. Vital signs 
parameters will be summarized similarly. Occurrence of significant laboratory 
abnormalities will be summarized by treatment. Physical examination and urine 
pregnancy tests data will be summarized and listed. 
 
11.3. 
Interim Analysis 
An interim analysis will be conducted by an independent data monitoring committee 
(DMC) after approximately 40 subjects have completed the study.  Details regarding the 
conduct of the interim analyses will be specified in a separate document outside of this 
protocol (e.g. DMC charter).  After each meeting, the DMC will advise whether any 
changes to the sample size or conduct of the study are necessary based on review of 
unblinded safety and efficacy data. 
 
11.4. 
Sample Size Calculation 
Suppose the percentage of subjects with ≥40% reduction in BSA of EBS lesions at Week 16 are 
60% and 30%, in Diacerein 1% Ointment or Control Ointment, respectively.  Based on a two-


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 70 of 75 
sided, two-sample parallel design for large sample test of proportions with a power of 
80% and significance level of 0.057, the sample size needed for a fixed sample size 
design without interim analysis and sample reconsideration is: 
𝑛𝑛1 = 𝑛𝑛2 =
൫𝑧𝑧𝛼𝛼2
⁄ +𝑧𝑧𝛽𝛽൯
2൫𝑝𝑝1(1−𝑝𝑝1)+𝑝𝑝2(1−𝑝𝑝2)൯
(𝑝𝑝2−𝑝𝑝1)2
=
(1.96+0.84)2൫0.6×(1−0.6)+0.3×(1−0.3)൯
(0.6−0.3)2
≈39. 
 
One interim analysis is planned and sample size will be reconsidered then. We employ 
O’Brien and Fleming's method7, and the sample size is inflated to: 
𝑛𝑛1
′ = 𝑛𝑛2
′ = 𝑛𝑛1𝑅𝑅𝐵𝐵(2,0.05,0.2) = 39 × 1.008 ≈40, 
 
in which 𝑅𝑅𝐵𝐵(2,0.05,0.2) = 1.008 is the O'Brien and Fleming's method constant for two-
sided test with 𝛼𝛼= 0.05 and 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝= 1 −0.2 = 0.8. 
 
Thus, at the interim analysis, the sample size per treatment group is 40 2
⁄
= 20. The 
conditional power will be calculated at the interim analysis, based on which the sample 
size will be recalculated. 
 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
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, 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
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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. 
 
12.2. 
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. 
 
12.3. 
Institutional Review Board (IRB) and Ethic Committee (EC) 
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. 
 
12.4. 
Data Monitoring Committee 
An interim analysis will be conducted by an independent data monitoring committee 
(DMC) after approximately 40 subjects have completed the study.  Details regarding the 
conduct of the interim analyses will be specified in a separate document outside of this 
protocol (e.g. DMC charter).  After each meeting, the DMC will advise whether any 
changes to the sample size or conduct of the study are necessary based on review of 
unblinded safety and efficacy data. 
 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 72 of 75 
 
13. 
ETHICS 
13.1. 
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. 
13.2. 
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 and the Castle Creek Pharmaceutical’s policy on 
Bioethics. 
13.3. 
Written Informed Consent/Assent 
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.  


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 73 of 75 
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. 
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. 
 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
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 medical history/ 
physical examination, hematology, clinical chemistry and serology results, inclusion 
and exclusion criteria, drug administration, and a record of sample collection, 
hemodynamic measurements, clinical assessments, AEs, and final evaluation as 
appropriate. 
Electronic eCRFs and subject diaries 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.  
14.2. 
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. 
14.3. 
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 


Castle Creek Pharmaceuticals LLC 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 74 of 75 
any documentation relating to the study, the Investigator must permit access to such 
records. 
15. 
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 
 
Protocol No. CCP-020-301 
Investigational Product: Diacerein 1% Ointment 
 
Global Protocol Amendment 3a 
 
Page 75 of 75 
16. 
LIST OF 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. 
 
7. Chow, SC, Shao, J, and Wang, HS. Sample size calculation in clinical research. 
2011. John Wiley & Sons, Inc. 
 
 
 
 
 
 
 
 
 
 
 
                                                 
 

SAP_000.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
An International, Multicenter, Randomized, Double-Blind, Parallel- 
Group Phase 2 Study Evaluating the Safety and Efficacy of 
Diacerein 1% Ointment Topical Formulation in Subjects with 
Epidermolysis Bullosa Simplex (EBS) [DELIVERS Study] 
 
 
Investigational Product: Diacerein 1% Ointment 
Protocol Number: CCP-020-301 
 
 
Sponsor: 
Castle Creek Pharmaceuticals, LLC 
6 Century Drive 
Parsippany, NJ 07054 
United States of America 
 
Version Number: 2.0 
Date: 31 August 2018 
 
 
CONFIDENTIAL 
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. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
Version Number: 2.0 
Page 2 
Protocol Number: CCP-020-301 
Version Date: 31 August 2018 


Statistical Analysis Plan 
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Protocol Number: CCP-020-301 
Version Date: 31 August 2018 
Page 3 
 
VERSION HISTORY 
 
Version 
Date 
Description 
1.0 
2 January 2018 
Original signed version 
2.0 
31 August 2018 
Revised for primary endpoint and FDA Advice Letter 


Statistical Analysis Plan 
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Protocol Number: CCP-020-301 
Version Date: 31 August 2018 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................7 
2. 
OVERVIEW .................................................................................................................7 
2.1. 
Objectives .....................................................................................................................7 
2.2. 
Trial Design ..................................................................................................................7 
3. 
STUDY ENDPOINTS ................................................................................................10 
3.1. 
Efficacy Variables .......................................................................................................10 
3.1.1. 
Primary Endpoint ........................................................................................................10 
3.1.2. 
Key Secondary Endpoint ............................................................................................10 
3.1.3. 
Other Secondary Endpoints ........................................................................................10 
3.1.4. 
Exploratory Endpoints ................................................................................................10 
3.2. 
Safety Variables ..........................................................................................................10 
3.2.1. 
Adverse Events ...........................................................................................................10 
3.2.2. 
Safety Laboratory Evaluations....................................................................................11 
3.2.3. 
Vital Signs ..................................................................................................................12 
3.2.4. 
Physical Examination .................................................................................................12 
3.2.5. 
Electrocardiogram (ECG) Monitoring ........................................................................12 
3.2.6. 
Pharmacokinetic Variables .........................................................................................12 
4. 
ANALYSIS POPULATIONS ....................................................................................13 
4.1. 
Intent-to-Treat Population ..........................................................................................13 
4.2. 
Safety Population ........................................................................................................13 
4.3. 
Per Protocol Population ..............................................................................................13 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ....................................13 
5.1. 
Evaluation of Center Effect ........................................................................................13 
5.2. 
Assessment Windows .................................................................................................13 
5.3. 
Handling of Dropouts and Missing Data ....................................................................14 
5.4. 
Date Values .................................................................................................................14 
5.5. 
Non-Date Values ........................................................................................................14 
6. 
ANALYSIS OF DISPOSITION AND SUBJECT CHARACTERISTICS ................15 
6.1. 
Disposition and Analysis Populations ........................................................................15 
6.2. 
Protocol Deviations ....................................................................................................15 


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6.3. 
Demographics and Baseline Characteristics ...............................................................15 
6.4. 
Concomitant Medications ...........................................................................................16 
7. 
ANALYSIS OF EFFICACY ......................................................................................16 
7.1. 
Primary Efficacy Analysis ..........................................................................................16 
7.2. 
Key Secondary Efficacy Analysis ..............................................................................16 
7.3. 
Other Secondary Efficacy Analyses ...........................................................................17 
7.3.1. 
Percent Change in Reference Lesion Surface Area (LSA) .........................................17 
7.3.2. 
BSA success at Visit 8 (Week 16) ..............................................................................17 
7.3.3. 
IGA Success at Visit 8 (Week 16) ..............................................................................17 
7.4. 
Exploratory Efficacy Analyses ...................................................................................17 
7.4.1. 
Reduction in Pain Intensity at Visit 6 (Week 8) and Visit 8 (Week 16) .....................17 
7.4.2. 
Reduction in Pruritus Intensity at Visit 6 (Week 8) and Visit 8 (Week 16) ...............17 
8. 
ANALYSIS OF SAFETY ..........................................................................................18 
8.1. 
Extent of Exposure .....................................................................................................18 
8.2. 
Adverse Events ...........................................................................................................18 
8.3. 
Safety Laboratory Parameters .....................................................................................19 
8.4. 
Vital Signs ..................................................................................................................19 
8.5. 
ECG Parameters ..........................................................................................................19 
8.6. 
Physical Examinations ................................................................................................19 
8.7. 
Pharmacokinetic Analysis ..........................................................................................19 
9. 
DATA MONITORING COMMITTEE ......................................................................20 
10. 
INTERIM ANALYSIS ...............................................................................................20 
11. 
SAMPLE SIZE AND POWER CONSIDERATIONS ...............................................21 
12. 
CHANGES FROM THE PROTOCOL ......................................................................21 
13. 
REFERENCES ...........................................................................................................25 
 
LIST OF TABLES 
Table 1: Study Flow Chart ...............................................................................................................9 
Table 2: Summary of Changes and Impact to Protocol (CCP-020-301; 3a) ..................................22 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
BSA 
Body Surface Area 
CMH 
Cochran-Mantel-Haenszel 
CR 
Clinically Relevant 
CSR 
Clinical Study Report 
EBS 
Epidermolysis Bullosa Simplex 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
ICH 
International Conference on Harmonization 
IGA 
Investigator’s Global Assessment 
ITT 
Intent-To-Treat 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAR 
Missing at random 
NCR 
Not Clinically Relevant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operation Procedure 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
The purpose of this document is to provide a description of the statistical methods and 
procedures to be implemented for the analysis of data from protocol number CCP-020-301 
(DELIVERS trial). During the conduct of the DELIVERS trial, the Sponsor, Investigators, and 
all currently blinded teams at Medpace will be remain blinded until completion of the trial. This 
document is based on the Global Protocol Amendment 3a document. If circumstances arise 
during the study such that more appropriate analytic procedures become available, the statistical 
analysis plan (SAP) may be revised. Any revisions to the SAP (both alternative and additional 
methods) will be made prior to database lock. Reasons for such revisions will be described in the 
final Clinical Study Report (CSR). 
 
2. 
OVERVIEW 
2.1. 
Objectives 
The primary objective of the study is to compare the efficacy of Diacerein 1% Ointment to 
Control Ointment when applied once-daily for 8 weeks in subjects with epidermolysis bullosa 
simplex (EBS). 
The secondary objectives are to compare the effects of Diacerein 1% Ointment to Control 
Ointment in subjects with EBS in: 
• Pain 
• Pruritus 
• Safety and tolerability 
2.2. 
Trial Design 
This is an international, multicenter, randomized, double-blind, vehicle-controlled, parallel group 
study to evaluate the safety and efficacy of topical Diacerein 1% Ointment for the treatment of 
subjects with EBS. Subjects at least 4 years of age with a genetic confirmation of EBS (based on 
either existing documentation or results from a sample collected as part of the study) who meet 
all the inclusion criteria and none of the exclusion criteria at Visit 1 will be eligible for 
enrollment in the study. 
Eligible subjects will be randomized in a 1:1 ratio to either receive 8 weeks of once-daily 
application of Diacerein 1% Ointment or Control Ointment to all EBS lesions.  Approximately 
80 subjects will be randomized at approximately 22 international investigational centers. The 
randomization will be stratified by genotype (KRT5 and/or KRT14 versus other genotypes) and 
age group (<8 and ≥8 years old). Subjects/caregivers will apply the assigned study medication to 
all EBS lesions, including any new EBS lesions that develop, once daily, every evening during 
the 8-week treatment period. No study medication applications will be made to any lesion that 
becomes infected until the infection resolves with appropriate investigational center specific 
medical care. 


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Subjects/caregivers will be instructed on the use of the electronic diary (eDiary) to record patient 
reported outcomes of pruritus, pain and mobility and to document bandage use, blister lancing 
compliance, new lesions that develop in between study visits, routine cleanser use and study 
medication applications. Adverse events, clinical laboratory data, pharmacokinetic (PK) 
sampling, efficacy evaluations and determination of study medication use will be routinely 
collected. 
The duration of study participation is anticipated to be a maximum of 158 days per subject (~22 
weeks). This includes the up to 6-week screening period, an 8-week treatment period and an 8- 
week no-treatment follow-up period. 
Study visits are summarized as follows: 
• Visit 1 (Week -6/Day -42 to 0) enrollment, start randomization eligibility assessment 
period 
• Visit 2 (Week 0/Day 1) randomization; first study medication application 
• Visit 3 (Week 1/Day 8) treatment period follow-up 
• Visit 4 (Week 4/Day 29) treatment period follow-up 
• Visit 5 (Week 6/Day 43) treatment period follow-up 
• Visit 6 (Week 8/Day 57) end of the treatment period 
• Visit 7 (Week 12/Day 85) no treatment follow-up 
• Visit 8 (Week 16/Day 113) no treatment follow-up, end of study 
A detailed schedule of procedures is provided in Table 1. 


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Table 1: Study Flow Chart 
 


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3. 
STUDY ENDPOINTS 
3.1. 
Efficacy Variables 
3.1.1. 
Primary Endpoint 
The proportion of subjects who achieve ≥ 60% reduction in BSA of EBS lesions within the 
Assessment Area from Baseline to Visit 6 (Week 8). 
 
3.1.2. 
Key Secondary Endpoint 
The proportion of subjects achieving success on the IGA of the Assessment Area, where success 
is defined as at least a 2-point reduction, from Baseline to Visit 6 (Week 8). 
 
3.1.3. 
Other Secondary Endpoints 
The other secondary endpoints are as follows: 
• The percent change in Reference Lesion Surface Area from Baseline to Visit  6 
(Week 8). 
• The proportion of subjects who achieve ≥ 60% reduction in BSA of EBS lesions within 
the Assessment Area from Baseline to Visit 8 (Week 16) 
• The proportion of subjects achieving success on the IGA of the Assessment Area, 
where success is defined as at least a 2-point reduction, from Baseline to Visit 8 (Week 
16). 
 
3.1.4. 
Exploratory Endpoints 
The exploratory endpoints are as follows: 
• The percent change in Reference Lesion Surface Area from Baseline to Visit  8 
(Week 16). 
• The proportion of subjects with a reduction in overall pain intensity from Baseline to 
Visit 6 (Week 8). 
• The proportion of subjects with a reduction in overall pruritus intensity from Baseline 
to Visit 6 (Week 8). 
• The proportion of subjects with a reduction in overall pain intensity from Baseline to 
Visit 8 (Week 16). 
• The proportion of subjects with a reduction in overall pruritus intensity from Baseline 
to Visit 8 (Week 16). 
 
3.2. 
Safety Variables 
3.2.1. 
Adverse Events 
Adverse events (AEs), which include clinical laboratory test variables, will be monitored and 
documented from the time of the first study medication application until the subject’s study 
participation is complete (Week 16). Beginning with the start of the first study medication 


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application, investigators should make an assessment for adverse events at each visit and record 
the event on the appropriate AE electronic Case Report Form (eCRF). All AEs that occur after 
the first study medication application and up to 30 days after the subject’s last study medication 
application will be considered treatment-emergent adverse events (TEAEs). 
In concert with system-organ classification (SOC) defined by MedDRA the following AEs will 
be categorized as AEs of special interest (AESIs) in this study: 
• All gastrointestinal (GI) disorders defined by MedDRA SOC 
• Hepatic Injury 
• Pancreatitis 
• Urticaria/angioedema 
• Epidermal necrolysis 
• Drug reaction with eosinophilia and systemic symptoms (DRESS) 
• Purpura/cutaneous vasculitis 
• Jaundice 
 
Each AE shall be evaluated for the severity, seriousness, duration, resolution, action taken and its 
relationship with the study medication. 
3.2.2. 
Safety Laboratory Evaluations 
At Visits 1, 2, 4, 6 and 8 a qualified staff member will collect blood and urine samples for 
clinical laboratory analysis. At Visit 2 (Week 0) the samples must be collected prior to the first 
study medication application. The following tests will be performed: 
 
Chemistry Panel 
Complete Blood Count 
Albumin 
Hematocrit 
Alkaline phosphatase (ALP) 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet count 
Amylase 
Red blood cell morphology 
Aspartate aminotransferase (AST) 
Red blood cell count 
Blood urea nitrogen (BUN) 
White blood cell count 
Bicarbonate 
White blood cell differential 
Chloride 
% and absolute: 
Creatinine 
Basophils 
Gamma-GT 
Eosinophils 
Glucose 
Lymphocytes 
HbA1c 
Monocytes 
Lactate dehydrogenase (LDH) 
Neutrophils 
Lipase 
Potassium 
Sodium 
Complete Urinalysis 
Total bilirubin 
Total protein 
Uric acid 


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3.2.3. 
Vital Signs 
At Visits 1-8 a qualified staff member will measure each subject’s vital signs. At Visit 1 (Week - 
6) these measurements will be part of the physical examination. The following items will be 
measured: 
• Body temperature 
• Pulse rate 
• Respiration rate 
• Blood pressure (systolic and diastolic) after the subject sits quietly for at least 5 minutes 
• Height (at Visit 1, 6 and 8) 
• Weight (at Visit 1, 6 and 8) 
3.2.4. 
Physical Examination 
At Visit 1 (Week -6) and Visit 6 (Week 8), 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 (excluding EBS lesions) 
• Cardiovascular system 
• Respiratory system 
• Head, eyes, ears, nose and throat 
• Lymph nodes 
• Gastrointestinal/Hepatobiliary (specifically assess for the presence of hepatomegaly and 
splenomegaly) 
• Vital signs 
3.2.5. 
Electrocardiogram (ECG) Monitoring 
Single 12 lead ECGs will be performed as outlined in the Study Flow Chart using sensitive 
electrodes ensuring the subject’s skin is not harmed from the procedure (e.g. SofTouch™ 
Electrodes). The ECGs will be performed on subjects in supine position. The following ECG 
data will be collected: 
• Heart rate 
• PR interval 
• QRS duration 
• QT interval 
• RR interval 
• Overall Interpretation 
3.2.6. 
Pharmacokinetic Variables 
Blood draws for population PK analysis will be drawn at protocol specific timepoints. 


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4. 
ANALYSIS POPULATIONS 
4.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population will consist of all randomized subjects who are dispensed 
study medication. All efficacy analyses will be conducted using the ITT population. Subjects 
will be included in the treatment group to which they were randomized. 
4.2. 
Safety Population 
The Safety Population will consist of all subjects who receive at least one application of study 
drug. All safety summaries and analyses will be conducted using the Safety Population. 
Subjects will be included in the treatment group based on the treatment that was received (if 
different from the subject’s randomized treatment assignment). 
4.3. 
Per Protocol Population 
The Per Protocol (PP) Population will consist of all ITT subjects with a BSA and IGA of EBS 
lesions at Week 8 and without a major protocol deviation as defined by International Conference 
of Harmonisation (ICH) E3 (Structure and Content of Clinical Study Reports) that may interfere 
with the assessment of drug safety, efficacy and overall integrity of the data. Before data are 
released for statistical analysis, a blinded review of all data will be performed by the Sponsor’s 
clinical team to identify protocol deviations that may potentially affect the results. At this time, 
it will be determined if patients and/or data should be excluded from the PP Population. The list 
of subjects or observations to be excluded from the PP Population, along with the reason for 
exclusion, will can be finalized prior to database unblinding. 
 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
Medpace is responsible for the statistical analyses for this trial. The statistical planning and 
conduct of analyses of the data from this trial will follow the principles defined in relevant ICH- 
E9 guidelines and Medpace’s Biostatistics SOPs. All tables, figures, and listings will be 
generated with SAS® (SAS Institute Inc. Cary, North Carolina, USA) Version 9.3 or higher and 
printed using a Rich Text Format (RTF) file format. 
 
5.1. 
Evaluation of Center Effect 
Due to the design, objectives, and sample size of the trial, center effects will not be evaluated. 
 
5.2. 
Assessment Windows 
In the descriptive statistics of safety and efficacy endpoints, only measurements from scheduled 
visits will be used if values are available. If no values from a scheduled visit are available but 
values from unscheduled visits are available, the values from the unscheduled visit closest to the 
target date for that visit will be used for the summary statistics. The date of an unscheduled visit 
will be used to assign the unscheduled visit to the nearest scheduled visit date. 


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For analysis purposes, if the event date is on or after the first treatment date, the study day is 
defined as follows: 
Study Day = Event date – First treatment date + 1 
Therefore, the day of the first treatment will be Day 1. If the event date is prior to the first 
treatment date, the addition of 1 will not be included in the calculation; thus, there will be no 
Day 0. 
5.3. 
Handling of Dropouts and Missing Data 
5.4. 
Date Values 
In cases of incomplete dates (e.g. AE, concomitant medication, and medical history start and/or 
stop dates), the missing component(s) will be assumed as the most conservative value possible. 
For example, adverse events with missing start dates will be considered as treatment-emergent 
unless the partial date excludes that possibility, e.g. the adverse event month is prior to the 
treatment infusion month. Otherwise, the first day of the month will be used to impute missing 
start days and January will be used to impute missing start months. If day is missing for an end 
date, the last day of the month will be imputed. 
Date imputation will only be used for computational purposes such as treatment-emergent status, 
etc. Actual date values, as they appear in the original CRFs, will be presented within the data 
listings. 
5.5. 
Non-Date Values 
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been enrolled. 
For the primary analysis of the primary efficacy endpoint (proportion of subjects who achieve ≥ 
60% reduction in BSA of EBS lesions with the Assessment Area from Baseline to Visit 6/Week 
8), subjects whose status at Week 8 is unknown will be defined to be a non-success/non- 
responder. 
For sensitivity analysis of this endpoint, the following analyses will be performed: 
1. Subjects with missing values at Week 8 in the Diacerein treatment group will be imputed 
as a success, while all subjects in the Placebo treatment group will imputed as a non- 
success. 
2. Subjects with missing values at Week 8 in the Diacerein treatment group will be imputed 
as a non-success, while all subjects in the Placebo treatment group will imputed as a 
success. 
3. Subjects with missing values at Week 8 will be imputed using multiple imputation (MI) 
under the assumption of missing at random (MAR). Based on the imputed value at Week 
8, the subjects will be assigned accordingly as either a success or non-success. 
Missing values for the BSA of EBS lesions within the Assessment Area will be imputed 
using multiple imputation methodology in two steps. Initially, ten datasets will be 
generated containing imputed values for non-monotone missing values in the original 
dataset. The variables used to guide this imputation will include the following: treatment 
group, age group (<8 and >=8 years old), genotype (KRT5/KRT14 and Other), and BSA 


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of EBS lesions in the Assessment Area at Baseline, Week 1, Week 4, Week 8, and Week 
16. In this step it will be assumed that any intermediate missing data points are MAR. In 
the second step, the remaining monotone missing values will be imputed. The same 
variables will be used to guide the imputation as in the first step. 
For each imputation dataset, the proportion of subjects who achieve success will be 
analyzed using the Cochran-Mantel-Haenszel test described in Section 7.1 below. A log 
transformation will be performed to normalize the relative risk estimates and the standard 
error of the transformed estimate will be obtained from the log-transformed confidence 
limits for the relative risk estimate. The results from these ten analyses will be combined 
and then back-transformed to the original log scale. The corresponding relative risk 
estimate and confidence interval will be presented. 
For the key secondary endpoint, the same imputation methods will be employed as with the 
primary endpoint. No imputation will be performed on the other secondary or exploratory 
endpoints. 
 
6. 
ANALYSIS OF DISPOSITION AND SUBJECT 
CHARACTERISTICS 
6.1. 
Disposition and Analysis Populations 
Subject disposition information will be summarized. Counts (number and percent) of subjects 
who are randomized, who are treated with study medication, 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 Safety Population will be used as the denominator for the percentage 
calculations. Subject disposition, inclusion/exclusion criteria, and comments will be listed. The 
number and percent of patients in each analysis population will also be tabulated. 
6.2. 
Protocol Deviations 
A listing of all major protocol deviations will be provided. 
 
6.3. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment for each of the 
analysis populations. Demographic and baseline characteristics include the following: age at 
informed consent, sex, race, ethnicity, genotype, IGA score at baseline, BSA of assessment area 
at baseline BSA of treatment area at baseline, total BSA of all EBS lesions at baseline, pruritus 
severity at baseline, pain severity at baseline, and mobility score at baseline. Unless otherwise 
stated, all continuous variables will be represented by n, mean, standard deviation, minimum, 
median, and maximum. All categorical variables will be presented as counts and percentages. 
Demographic characteristics will also be listed. 
Baseline for all analysis variables will be the last measurement prior to the first application study 
medication, unless otherwise stated. For data collected from the eDiary, Baseline will be the 
value recorded from the first day that the subject received study medication. 


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Medical history will be summarized for the number and percentage of patients for each medical 
term. Medical history information will be listed. A listing of concomitant therapies/procedures 
will be provided. 
 
6.4. 
Concomitant Medications 
All medications administered during the study will be listed including the reported term, start 
and stop dates, and other relevant data will be provided. Concomitant medications include all 
medications taken on or after the date of the first treatment of study medication. Prior 
medications include all medications taken before the date of the first treatment of study 
medication and discontinued before the first treatment of study medication. All medications will 
be coded using the World Health Organization (WHO) Drug Sept 2016E B2 version. 
 
7. 
ANALYSIS OF EFFICACY 
Descriptive summaries of efficacy endpoints will be presented by treatment group and visit. All 
efficacy endpoints will be based on the Assessment Area, defined in the protocol, unless 
otherwise stated. The ITT population and PP population will be used for this analysis. A by- 
subject listing of efficacy endpoints will be provided. 
 
7.1. 
Primary Efficacy Analysis 
Descriptive summaries of the proportion of subjects who achieve ≥ 60% reduction in BSA of 
EBS lesions will be presented by treatment group at each visit. 
The primary endpoint is the proportion of subjects who achieve ≥ 60% reduction in BSA of EBS 
lesions from Baseline to Visit 6 (Week 8). Subjects whose status at Visit 6 is unknown will be 
defined to be nonresponders. The primary analysis will be conducted using the Cochran-Mantel- 
Haenszel (CMH) test, stratified by genotype (KRT5/KRT15 and Other) and age group (<8 and 
≥8 years old). Estimated relative risk, associated 95% confidence interval (CI), and p-values will 
be provided. 
At the final analysis, the treatment groups will be compared using a two-sided test at the 
alpha=0.049 level of significance in order to account for the alpha spent in the Interim Analysis 
as described in Section 10 below. 
7.2. 
Key Secondary Efficacy Analysis 
The key secondary endpoint is the proportion of subjects achieving success on the IGA of the 
Assessment Area, where success on the IGA is defined as at least a 2-point reduction from 
Baseline to Visit 6 (Week 8). Subjects whose status at Visit 6 is unknown will be defined as 
non-responders. The key secondary endpoint will be analyzed using the CMH test, as described 
for the primary analysis. However, if the primary analysis is not statistically significant, then the 
results for the key secondary endpoint will be exploratory rather than confirmatory. This fixed 
sequence testing procedure maintains the overall level of significance for the primary and key 
secondary endpoints. 


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7.3. 
Other Secondary Efficacy Analyses 
All other secondary endpoints will be analyzed using two-sided tests at the alpha=0.05 level of 
significance, with no adjustment for multiplicity. 
7.3.1. 
Percent Change in Reference Lesion Surface Area (LSA) 
Descriptive statistics of the percent change in Reference Lesion surface area from Baseline to 
Visit 6 (Week 8) will be presented by treatment. An Analysis of Covariance (ANCOVA) model 
with treatment, genotype, and age group as fixed effects and baseline surface area of the 
Reference Lesion as a covariate will be used to analyze the data. Treatment differences in the 
percent change from baseline between Diacerein 1% Ointment and Control Ointment will be 
evaluated by the least-squares mean, standard error, 2-tailed 95% confidence interval, and a 2- 
sided p-value. 
 
7.3.2. 
BSA success at Visit 8 (Week 16) 
The proportion of subjects who achieve ≥ 60% reduction in BSA of EBS lesions from Baseline 
to Visit 8 (Week 16) will be analyzed using the CMH test, as described for the primary efficacy 
endpoint. 
 
7.3.3. 
IGA Success at Visit 8 (Week 16) 
The proportion of subjects achieving success on the IGA of the Assessment Area, where success 
on the IGA is defined as at least a 2-point reduction from Baseline to Visit 8 (Week 16), will be 
analyzed using the CMH test, as described for the primary efficacy endpoint. 
 
7.4. 
Exploratory Efficacy Analyses 
Descriptive statistics for the exploratory endpoints will be presented by treatment group at each 
visit. All exploratory efficacy analyses will be conducted using two-sided tests at the alpha=0.05 
level of significance, with no adjustment for multiplicity. 
7.4.1. 
Reduction in Pain Intensity at Visit 6 (Week 8) and Visit 8 (Week 16) 
The proportion of subjects with a reduction in overall pain intensity from Baseline to Visit 6 
(Week 8) and Baseline to Visit 8 (Week 16) will be analyzed in the same manner as described 
previously for the IGA success at Visit 6 (Week 8). The overall pain intensity at a given visit 
will be based on the average of the subject’s reported pain intensity from the 7 days prior to the 
visit assessment, based on the data collected from the subject’s eDiary. 
7.4.2. 
Reduction in Pruritus Intensity at Visit 6 (Week 8) and Visit 8 (Week 16) 
The proportion of subjects with a reduction in overall pruritus intensity from Baseline to Visit 6 
(Week 8) and Baseline to Visit 8 (Week 16) will be analyzed in the same manner as described 
previously for the IGA success at Visit 6 (Week 8). The overall pruritus intensity at a given visit 
will be based on the average of the subject’s reported pruritus intensity from the 7 days prior to 
the visit assessment, based on the data collected from the subject’s eDiary. 


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8. 
ANALYSIS OF SAFETY 
Safety will be assessed using the Safety Population. The assessment of safety will include 
adverse events, clinical laboratory assessments, ECGs, physical examinations, and vital signs. 
The safety analysis will be based primarily on the frequency of new or worsening adverse events, 
laboratory abnormalities, and serious adverse events (SAEs). Other safety data will be 
summarized as appropriate. 
8.1. 
Extent of Exposure 
Amount of study drug used will be summarized by treatment group for the Safety Population 
using descriptive statistics. Study drug usage is based on data collected from the Drug 
Accountability eCRF where drug usage is calculated as the amount of study drug dispensed 
minus the amount of study drug returned, in grams. 
Percent compliance with the study medication will be summarized by treatment group for the 
Safety Population using descriptive statistics. Compliance with study medication application is 
based on data collected from the subject’s eDiary. The analysis will include listings for drug 
exposure and compliance. 
 
8.2. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.0 and summarized by treatment group, system organ class, and preferred term. 
A summary overview of TEAEs will be provided which presents the number and percentage of 
patients in each treatment group satisfying each of the following categories: 
• All TEAEs, 
• Drug-related TEAEs, 
• Maximum severity of TEAEs, 
• Maximum severity of drug-related TEAEs, 
• All AESIs, 
• Drug-related AESIs, 
• Maximum severity of AESIs, 
• All treatment-emergent SAEs, 
• Drug-related treatment-emergent SAEs, 
• Death due to TEAEs, 
• TEAEs leading to study drug discontinuation, and 
• Drug-related TEAEs leading to study drug discontinuation. 
The numbers and percentages of patients with TEAEs will be summarized by MedDRA 
preferred term within system organ class, by treatment group and overall. For the summaries by 
treatment group, multiple AEs with the same MedDRA preferred term within system organ class 
from the same patient within a given treatment will only be counted once. For overall 
summaries, multiple AEs with the same MedDRA preferred term within system organ class from 
the same patient will only be counted once. 
All TEAEs related to study drug, AESIs, SAEs, and AEs leading to study drug discontinuation 
will be summarized in the same manner. Summaries will also be provided for the numbers and 


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percentages of patients by system organ class, preferred term, and maximum severity, for 
TEAEs, AESIs, and drug-related TEAEs. 
All AEs will be included in by-patient listings containing additional information of interest such 
as onset and resolution times, maximum severity, causal relationship to study medication, and 
action taken. Specific by-patient listings of AESI, SAEs, and TEAEs leading to study 
discontinuation will be provided. 
 
8.3. 
Safety Laboratory Parameters 
Clinical laboratory results will be summarized with descriptive statistics by treatment and visit. 
Change from baseline will also be summarized. Laboratory values will also be listed by visit, 
within patient. 
 
8.4. 
Vital Signs 
Vital signs and the change from baseline will be summarized descriptively by treatment and 
visit. The count and percentage of subjects with abnormal values will be summarized by 
treatment and visit. Abnormal blood pressure measurements for subjects age 17 and younger 
will be defined as either systolic or diastolic measurements above the 95th percentile, according 
to height, sex, and age. Abnormal blood pressure measurements for subjects age 18 and older 
will consist of either a systolic blood pressure >140mm Hg or a diastolic blood pressure >90mm 
Hg. Abnormal weight measurements for subjects age 18 and older will be defined as 
measurements > 300 pounds (>118 kilograms). Abnormal BMI measurements for subjects age 
17 and younger will be defined as measurements above the 95th percentile, according to sex and 
age. Abnormal values will be defined as clinically relevant (CR) or not clinically relevant 
(NCR) on the eCRFs. Vital sign data will also be listed by visit, within patient. 
 
8.5. 
ECG Parameters 
Electrocardiogram results will be summarized by treatment and visit. Electrocardiogram results 
will also be listed. 
 
8.6. 
Physical Examinations 
Physical examinations and the change from baseline will be summarized by treatment and visit. 
Physical examination results will also be listed by visit, within patient. 
 
8.7. 
Pharmacokinetic Analysis 
Blood draws for PK sampling and modeling will be obtained at the timepoints listed in the Study 
Flow Chart (see Table 1). Quantification of diacerein and its active metabolite, rhein in patient 
plasma will be performed using a validated bioanalytical assay. Data permitting, population PK 
and pharmacokinetic/pharmacodynamic (PK/PD) analyses will be performed. A separate 
Pharmacokinetic Analysis Plan will be prepared describing the details regarding the PK analysis, 
including the data handling and methods for the analysis. 


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9. 
DATA MONITORING COMMITTEE 
An independent data monitoring committee (DMC) will monitor the safety of subjects over the 
course of the study. An interim analysis will also be conducted by the DMC. Details related to 
the DMC responsibilities, authorities, and procedures will be documented in the DMC charter. 
After each meeting, the DMC will advise whether any changes to the conduct of the study are 
necessary. 
 
10. 
INTERIM ANALYSIS 
An interim analysis of the two confirmatory endpoints (primary endpoint, key secondary 
endpoint) for efficacy, futility, and sample size re-estimation will be conducted by an 
independent data monitoring committee (DMC) when 40 subjects (50% of the planned total 
sample size) have completed Visit 6 (Week 8). The Sponsor and the study investigators will 
remain blinded. Following the interim analysis, the DMC will make one of the following four 
recommendations to the Sponsor: 
• Terminate the study for futility. 
• Continue the study as planned. 
• Increase the sample size to n=XXX subjects, where the maximum value of XXX is equal 
to 200. 
• Terminate the study on the basis of having demonstrated overwhelming evidence of 
efficacy. 
Based on the Lan-DeMets method for group sequential trials using O’Brien-Fleming boundaries 
(Reboussin, 2000), the levels of significance for the interim and final analyses corresponding to a 
single interim analysis at the 50% information fraction are alpha=0.00305 and alpha=0.049, 
respectively. 
If the two-sided p-values at the interim analysis for both the primary efficacy endpoint and the 
key secondary endpoint are less than 0.00305, then the DMC may recommend to the sponsor that 
the trial be terminated early for efficacy. 
If the DMC does not recommend early termination for efficacy, then the conditional power 
(Jennison, 2000) for the final analysis of the primary endpoint will be computed under the 
assumption that the treatment difference and variability observed at the interim analysis represent 
the true values of the unknown parameters. If the estimated conditional power for the final 
analysis of the primary endpoint is less than 10%, then the DMC may recommend to the sponsor 
that the trial be terminated early for futility. 
If the DMC does not recommend early termination (for efficacy or futility), then for each of the 
two endpoints (primary endpoint, key secondary endpoint), the sample size required to achieve 
80% power at the final analysis will be re-estimated based on the treatment difference and 
variability observed at the interim analysis. The DMC may then recommend that the sample size 
be increased to the larger of the two sample size estimates in order to maintain 80% power. 
Due to the sample size re-estimation component of the interim analysis, the final analysis will be 
conducted using the approach of Cui, Hung, and Wang. (Cui, 1999) 


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11. 
SAMPLE SIZE AND POWER CONSIDERATIONS 
The original sample size calculation was based on the endpoint of the proportion of subjects with 
≥ 40% reduction in BSA of EBS lesions at Week 16. The assumed true rates were 60% and 30% 
in the Diacerein 1% Ointment and Control Ointment groups, respectively. Based on a two-sided, 
two-sample comparison of proportions at the alpha=0.049 level of significance, a total sample 
size of 80 subjects provides 77% power. No data are available on which to base a sample size 
calculation for the primary endpoint, now defined at Week 8 and now based on the proportion of 
subjects with ≥ 60% reduction in BSA. 
 
12. 
CHANGES FROM THE PROTOCOL 
Reference is made to FDA Advice Letter dated 26 March 2018, whereby the Agency noted its 
position on IGA as the primary endpoint. The update to this SAP incorporates FDA guidance as 
it relates to consideration of IGA as a key secondary endpoint in addition to BSA as the primary 
endpoint. Additionally, CCP has implemented the FDA recommendation regarding the number 
of secondary endpoints; thus, this SAP has been updated to address multiplicity. Table 2 
summarizes the changes made to the SAP and the corresponding impacted section to the current 
CCP-020-301 (3a) protocol. The protocol will be amended at the time of the next major 
amendment or at the time of the IND annual reporting, whichever to occur first. 


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Table 2: Summary of Changes and Impact to Protocol (CCP-020-301; 3a) 
 
SAP 
Section 
SAP Section 
Description of Change 
Impacted Protocol (3a) Section 
2.1 
Objectives 
Change primary endpoint analysis to ≥ 
60% reduction from Visit 8 (week 16) 
to Visit 6 (Week 8) 
N/A 
Reduced number of secondary 
outcomes by removing “mobility” 
3.1.1 
Primary 
endpoints 
Primary endpoint to ≥ 60% reduction 
at Visit 6 (Week 8) versus Visit 8 
(Week 16) 
Note: in addition to increasing % 
reduction from 40 to 60, this change in 
assessment range merely moves a pre- 
specified secondary endpoint to the 
primary outcome 
5.1 Primary Endpoints 
3.1.2 
(NEW) 
Key 
secondary 
endpoint 
Promoted secondary endpoint to “Key 
secondary” assessing Baseline to Visit 
6 (Week 8). 
5.2 Key Secondary Endpoints 
3.1.3 
(Amended 
from 
version 
1.0) 
Other 
secondary 
endpoints 
Defined other secondary endpoints are 
as follows: 
• 
The percent change in Reference 
Lesion Surface Area from 
Baseline to Visit 6 (Week 8). 
• 
The proportion of subjects who 
achieve ≥ 60% reduction in BSA 
of EBS lesions from Baseline to 
Visit 8 (Week 16) 
• 
The proportion of subjects 
achieving success on the IGA of 
the Assessment Area, where 
success is defined as at least a 2- 
point reduction, from Baseline to 
Visit 8 (Week 16). 
Note: Reference lesion surface area 
(Baseline to Visit 6 (Week 8) has been 
reclassified from exploratory. 
Secondary outcomes for pain intensity 
and intensity of itch from Baseline to 
Visit 6 (Week 8) has been moved to 
Section 3.1.4 Exploratory endpoints. 
“Mobility” endpoint has been 
eliminated. 


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Table 2: Summary of Changes and Impact to Protocol (CCP-020-301; 3a) (Continued) 
 
SAP 
Section 
SAP Section 
Description of Change 
Impacted Protocol (3a) Section 
3.1.4. 
(Amended 
from 
version 
1.0) 
Exploratory 
endpoints 
Redefined “exploratory endpoints” as 
follows: 
• 
The percent change in Reference 
Lesion Surface Area from 
Baseline to Visit 8 (Week 16). 
• 
The proportion of subjects with a 
reduction in overall pain intensity 
from Baseline to Visit 6 (Week 8). 
• 
The proportion of subjects with a 
reduction in overall pruritus 
intensity from Baseline to Visit 6 
(Week 8). 
• 
The proportion of subjects with a 
reduction in overall pain intensity 
from Baseline to Visit 8 (Week 
16). 
• 
The proportion of subjects with a 
reduction in overall pruritus 
intensity from Baseline to Visit 8 
(Week 16).” 
Note: “Mobility” outcomes has been 
removed; expanded exploratory 
analysis to include pain intensity and 
intensity of itch from Baseline to Visit 
6 (Week 8) 
5.3 Exploratory Endpoints 
3.2 
Adverse 
Events 
AEs of special interest (AESIs) have 
been updated to include all 
gastrointestinal (GI) disorders defined 
by MedDRA SOC 
10.4.3. Adverse Events of Special 
Interest 
4.1.1 
Intent-to- 
Treat 
Population 
Intent-to-Treat Population (ITT) was 
clarified to include all randomized 
subjects who are dispensed study 
medication (per FDA Advice Letter 
26-March 2018 
11.1 Analysis Populations 
4.1.3 
Per Protocol 
Population 
Editorial update to clarify a major 
protocol deviation as defined by ICH 
E3 (Structure and Content of Clinical 
Study Reports) that may interfere with 
the assessment of drug safety, efficacy 
and overall integrity of the data. 


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Table 2: Summary of Changes and Impact to Protocol (CCP-020-301; 3a) (Continued) 
 
SAP 
Section 
SAP Section 
Description of Change 
Impacted Protocol (3a) Section 
5.3.3 
Data 
imputation 
Incorporated guidance from FDA 
Advice Letter dated 26 March 2018: 
“Missing data for the placebo arm will 
be considered as success while 
missing data for the diacerein arm will 
be imputed as failure.” 
11.2.1 Missing Data Handling 
Methods 
7.1 
Primary 
Efficacy 
Analysis 
Updated: changed to ≥ 60% reduction 
in BSA and assessment period from 
Baseline to Visit 6 (Week 8) 
11.2.3 Analysis of Efficacy 
7.2 
(Amended 
from 
version 
1.0) 
Key 
Secondary 
Efficacy 
Analysis 
Defined hierarchical statistical 
approach to key secondary endpoint: 
“The key secondary endpoint is the 
proportion of subjects achieving 
success on the IGA of the Assessment 
Area, where success on the IGA is 
defined as at least a 2-point reduction 
from Baseline to Visit 6 (Week 8). 
Subjects whose status at Visit 6 is 
unknown will be defined as non- 
responders. The key secondary 
endpoint will be analyzed using the 
CMH test, as described for the 
primary analysis. However, if the 
primary analysis is not statistically 
significant, then the results for the key 
secondary endpoint will be 
exploratory rather than confirmatory. 
This fixed sequence testing procedure 
maintains the overall level of 
significance for the primary and key 
secondary endpoints.” 
10 (NEW) 
Interim 
Analysis 
Greater specificity provided per DMC 
possible recommendations; e.g. 
maximum re-estimation of sample size 
has been set at 200 
11.3 Interim Analysis 


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13. 
REFERENCES 
Cui L, Hunt HM, Wang SJ. (1999) Modification of sample size in group sequential clinical 
trials. Biometrics, 55:853-857. 
Jennison C, Turnbull BW. (2000) Group sequential methods with applications to clinical trials. 
Boca Raton: Chapman & Hall/CRC 
Reboussin DM, D. D. (2000) Computations for group sequential boundaries using the Lan- 
DeMets spending function method. Controlled Clinical Trial, 21:190-207.