Conditions: Healthy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: yes

Brief summary:
This study was designed to assess the phototoxic potential of diacerein 1% ointment when application is followed by light exposure.

Detailed description:
This was a single-center, randomized, within-subject comparison of diacerein 1% ointment and vehicle ointment applied to 2 sites on opposite sides of the the infrascapular area of the back under occlusive patch conditions for approximately 24 (±2) hours. Product was applied according to the randomization scheme in an amount of 0.2 mL, once during the study.

Patches were removed and 1 of the skin sites for each product was irradiated and 1 remained non-irradiated. The irradiated and non-irradiated sites were compared with each other and with an untreated irradiated control site.

Arms:
arm 1: Single cohort received diacerein 1% ointment

Interventions: intervention 1: Diacerein 1% ointment
Intervention descriptions: intervention 1: Diacerein 1% ointment and vehicle ointment were applied on Day 1 at two randomly assigned skin sites on each side of the lower thoracic area of the back according to a randomization scheme. One side of the back was irradiated on Day 2, including an untreated irradiated control site, and the other side was to remain non-irradiated.

Protocol document:
Prot_SAP_000.pdf: 
6 Century Drive, 2nd Floor  
Parsippany, NJ 07054 
 
 
 
 
Clinical Study Protocol 
CCP-020 (Diacerein 1%) Topical Ointment 
Sponsor Protocol No. CCP-020-104 
TKL Study No. PB610317 
 
 
A 4 Day, Randomized Study to Evaluate the Potential of  
CCP-020 (Diacerein 1%) Topical Ointment 
to Induce a Phototoxicity Skin Reaction 
in Healthy Subjects, Using a Controlled Photopatch Test 
 
 
Author: 
 
 
 
 
Document type: 
 
 
Clinical Study Protocol 
Development Phase:  
 
1 
Document Date: 
 
 
23-October-2017 
Document Status 
 
 
Amendment 1 
Number of Pages:  
 
 
38 
 
 
 
Property of Castle Creek Pharmaceuticals, LLC. 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Castle Creek Pharmaceuticals, LLC. 
 
 


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Clinical Study Protocol 
Synopsis 
Study Title: 
A 4 Day, Randomized Study to Evaluate the Potential of CCP-020 (Diacerein 1%) 
Topical Ointment to Induce a Phototoxicity Skin Reaction in Healthy Subjects, Using 
a Controlled Photopatch Test  
TKL Study Number: 
PB610317 
Sponsor Protocol Number: 
CCP-020-104 
Sponsor: 
Castle Creek Pharmaceuticals, LLC 
Development Phase: 
1 
Study Objectives: 
To determine the potential of CCP-020 (Diacerein 1%) Topical Ointment and vehicle 
ointment to cause irritation when topical application to skin is followed by light 
exposure. 
Study Design: 
On Day 1, CCP-020 (Diacerein 1%) Topical Ointment and vehicle ointment will each 
be applied to 2 sites on the lower thoracic area of the back under fully occlusive 
patches for approximately 24 (±2) hours.  This will be the only application during the 
study.  Minimal erythema dose (MED) irradiation will also be performed for each 
subject on Day 1.  After patch removal on Day 2, all application sites will be 
evaluated and one application site of each study product will be irradiated with 
16 J/cm2 of Ultraviolet A (UVA) followed by 0.5 times the MED of UVA/Ultraviolet 
B (UVB) irradiation.  An additional site will also be irradiated with 16 J/cm2 of UVA 
followed by 0.5 times the MED of UVA/UVB and will serve as an untreated control. 
On Day 3, approximately 24 hours (±4 hours) after irradiation and Day 4, 
approximately 48 hours (±4 hours) after irradiation, all application sites and the 
untreated control site will be evaluated. 
Planned Sample Size: 
30 evaluable subjects 
Study Population: 
Healthy adult male and female volunteer subjects 
Investigational Products: 
Each study product, CCP-020 (Diacerein 1%) Topical Ointment and vehicle ointment 
will be applied in an amount of 0.2 mL under occlusive patch conditions to 2 sites 
(2 cm x 2 cm each) on the infrascapular area of the back once for approximately 
24 hours (±2 hours).  
Control: 
An untreated irradiated non-occlusive (open) control site. 
Efficacy Evaluation 
Criteria: 
Not applicable 


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Clinical Study Protocol 
 
 
Safety Evaluation 
Criteria: 
Phototoxic potential of the study products will be evaluated for all subjects 
completing the study.   
All local and systemic adverse events (AEs) observed by or reported to the 
Investigator will be evaluated.  The intensity, duration, and causal relationship to the 
study products are to be rated for all AEs. 
Statistical Methods: 
Selected pairwise comparisons will be performed on the mean of the Day 3 and Day 4 
response scores in the context of the analyses of variance (ANOVA).  Pairs to be 
compared are: each test sample irradiated versus non-irradiated and all pairwise 
comparisons on each side (CCP-020 (Diacerein 1%) Topical Ointment versus vehicle 
ointment on both the irradiated and non-irradiated sides and CCP-020 (Diacerein 1%) 
Topical Ointment versus untreated and vehicle ointment versus untreated on the 
irradiated side). 
Number of Study 
Centers: 
Single Center 
Planned Dates of Study 
November 2017 – December 2017 






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Clinical Study Protocol 
 
Investigators and study administrative structure  
Name 
Affiliation / Address 
Responsibility 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
                                       
 
 
 
 
 
 
 
 
   
  
                                       
 
 
 
 
 
 
 
 
  
 
 
 
                           
 
  
 
 
 
 
 
  
  
                                       
 
 
 
 
 
 
 
  
 
  
                                       
 
 
 
 
  


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Clinical Study Protocol 
 
Table of Contents 
Synopsis 
 ......................................................................................................................................2 
Signature page ..................................................................................................................................4 
Signature page for the Principal Investigator...................................................................................5 
Investigators and study administrative structure..............................................................................6 
Table of Contents .............................................................................................................................7 
List of Tables ...................................................................................................................................9 
List of Abbreviations  ....................................................................................................................10 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Background Information .............................................................................................11 
2. 
STUDY OBJECTIVES ..............................................................................................12 
3. 
INVESTIGATIONAL PLAN .....................................................................................13 
3.1. 
Study Design ...............................................................................................................13 
3.2. 
Discussion of Design ..................................................................................................13 
3.3. 
Study Population .........................................................................................................14 
3.3.1. 
Subject Population ......................................................................................................14 
3.3.2. 
Inclusion and Exclusion Criteria ................................................................................14 
3.3.3. 
Interruption or Discontinuation of Treatment .............................................................15 
3.3.4. 
Withdrawals ................................................................................................................16 
3.4. 
Treatments ..................................................................................................................16 
3.4.1. 
Investigational Products and Control ..........................................................................16 
3.4.2. 
Description of Investigational Products ......................................................................18 
3.4.3. 
Description of Patch Conditions .................................................................................18 
3.4.4. 
Packaging/Labeling ....................................................................................................18 
3.4.5. 
Assignment to Treatment ............................................................................................18 
3.4.5.1. 
Randomization ............................................................................................................18 
3.4.5.2. 
Blinding ......................................................................................................................19 
3.4.6. 
Prior and Concomitant Therapy ..................................................................................19 
3.4.7. 
Treatment Compliance ................................................................................................20 
3.5. 
Visit Schedule and Assessments .................................................................................20 
3.5.1. 
Study Procedures and Visit Schedule .........................................................................20 


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3.5.2. 
Visit Schedule .............................................................................................................23 
3.5.3. 
Definition of minimal erythemal dose ........................................................................23 
3.5.4. 
Light source ................................................................................................................23 
3.5.5. 
Background information .............................................................................................23 
3.5.6. 
Efficacy Assessments .................................................................................................24 
3.5.7. 
Safety Assessments .....................................................................................................24 
3.5.7.1. 
Patch Test Site Evaluations ........................................................................................24 
3.6. 
Adverse Events ...........................................................................................................25 
3.6.1. 
Method of Determining Adverse Events ....................................................................25 
3.6.2. 
Adverse Event Definitions ..........................................................................................26 
3.6.2.1. 
Adverse Events ...........................................................................................................26 
3.6.2.2. 
Serious Adverse Events ..............................................................................................27 
3.6.2.3. 
Severity of Adverse Events ........................................................................................27 
3.6.2.4. 
Relationship of Adverse Events to Study Treatments ................................................28 
3.6.3. 
Reporting Adverse Events ..........................................................................................28 
3.6.4. 
Adverse Event Follow-up ...........................................................................................28 
3.6.5. 
Pregnancy reporting ....................................................................................................29 
3.6.6. 
Expected Adverse Events ...........................................................................................29 
3.7. 
Instructions for Rapid Notification of Serious Adverse Events .................................29 
3.7.1. 
Contact person and number ........................................................................................29 
3.7.2. 
Reporting Responsibility ............................................................................................29 
3.7.3. 
Reporting procedures ..................................................................................................30 
3.8. 
Appropriateness of Safety Measurements ..................................................................30 
4. 
STATISTICAL METHODS .......................................................................................31 
4.1. 
General Considerations for Data Analysis .................................................................31 
4.2. 
Sample Size and Power Considerations .....................................................................31 
4.3. 
Subject Populations for Analysis ................................................................................31 
4.3.1. 
Background and Demographic Characteristics ..........................................................31 
4.3.2. 
Study Product/Visit Compliance ................................................................................31 
4.4. 
Prior and Concomitant Medications ...........................................................................31 
4.5. 
Efficacy Evaluation ....................................................................................................31 
4.6. 
Safety Evaluation ........................................................................................................31 


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4.6.1. 
Local Tolerability Assessment ...................................................................................31 
4.6.2. 
Adverse Events ...........................................................................................................32 
4.7. 
Other topics .................................................................................................................32 
4.8. 
Interim analyses ..........................................................................................................32 
4.9. 
Special Methods ..........................................................................................................32 
5. 
ADMINISTRATIVE PROCEDURES .......................................................................33 
5.1. 
Ethics and Good Clinical Practice ..............................................................................33 
5.2. 
Institutional Review Board .........................................................................................33 
5.3. 
Informed consent ........................................................................................................33 
5.4. 
Declaration of Helsinki ...............................................................................................34 
5.5. 
Changes in Planned Study Conduct ............................................................................34 
5.5.1. 
Protocol amendments ..................................................................................................34 
5.5.2. 
Other changes in study conduct ..................................................................................34 
5.5.3. 
Termination or suspension of study ............................................................................35 
5.6. 
Data handling and record keeping ..............................................................................35 
5.6.1. 
Recording of data ........................................................................................................35 
5.6.2. 
Retention of documents ..............................................................................................35 
5.7. 
Product handling and accountability ..........................................................................35 
5.8. 
Quality control and quality assurance .........................................................................36 
5.8.1. 
Monitoring procedures ................................................................................................36 
5.8.2. 
Auditing procedures ....................................................................................................36 
5.9. 
Confidentiality and publication policies .....................................................................37 
5.9.1. 
Disclosure and confidentiality ....................................................................................37 
5.9.2. 
Communication and publication of results .................................................................37 
6. 
REFERENCES ...........................................................................................................38 
 
List of Tables 
Table 1: 
Fitzpatrick Skin Types ................................................................................................21 
Table 2: 
Visit Schedule and Assessments .................................................................................23 
Table 3: 
Response Scores .........................................................................................................24 
Table 4: 
Notations .....................................................................................................................25 
Table 5: 
Relationship of AE to Study Drug ..............................................................................28 


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List of Abbreviations  
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DMP 
Data Management Plan 
EBS 
Epidermolysis bullosa simplex 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product 
IRB 
Institutional Review Board  
MED 
Minimal Erythemal Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NF 
National Formulary 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
OA 
Osteoarthritis 
OTC 
Over-the-counter 
PI 
Principal Investigator 
PMD 
Primary Medical Doctor 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOPs 
Standard Operating Procedures 
TKL 
TKL Research, Inc. 
UPT 
Urine pregnancy test 
USP 
United States Pharmacopeia 
UV 
UVA 
UVB 
Ultraviolet 
Ultraviolet A 
Ultraviolet B 


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Clinical Study Protocol 
1. 
INTRODUCTION 
Because CCP-020 (Diacerein 1%) Topical Ointment is formulated for topical use and has shown 
to absorb light within the range of natural sunlight (290-400 nm), it is necessary to determine the 
potential of this product to cause a phototoxic reaction after topical application and irradiation to 
the skin.  This study investigates the phototoxic potential of CCP-020 (Diacerein 1%) Topical 
Ointment under standardized conditions compared with an untreated control site.   
The study will be conducted in compliance with Food and Drug Administration (FDA) 
regulations, the ethical principles of the Declaration of Helsinki concerning medical research in 
humans (Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects, Helsinki 1964 and amendments 2013), the International Conference on Harmonization 
(ICH) – Good Clinical Practice (GCP) Guidelines as currently amended, and all applicable 
standard operating procedures (SOPs) of TKL Research, Inc. (TKL). 
1.1. 
Background Information 
CCP-020 (previously developed as AC-203) 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 by Castle Creek 
Pharmaceuticals for the treatment of epidermolysis bullosa simplex (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 the 
dermis following administration.  Diacerein and rhein have been shown to inhibit the in vitro and 
in vivo production and activity of interleukin (IL)-1β and other proinflammatory 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.   
For the development of CCP-020, a total of 10 animal studies have been conducted with CCP-
020 ointment 1%, including one skin penetration study, three acute dermal toxicity studies, one 
phototoxicity study, three pharmacokinetic studies, and two sub-chronic juvenile toxicity studies.  
CCP-020 was well-tolerated in these studies and no untoward adverse effects (AEs) were noted.  
To date, two clinical studies of CCP-020 have been completed in patients with epidermolysis 
bullosa simplex (EBS).  These include a Phase one pilot study in five patients and a Phase 2, 
multiple-site study in 17 patients in Europe.  The Phase 2 study demonstrated CCP-020 was 
well-tolerated and no treatment-related AEs were reported.  The Investigator’s Brochure should 
be consulted for summaries of the results of these studies.1 
This Phase 1 study will assess the phototoxicity potential of CCP-020 (Diacerein 1%) topical 
ointment. 


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Clinical Study Protocol 
2. 
STUDY OBJECTIVES  
The objective of this study is to determine the phototoxic potential of CCP-020 (Diacerein 1%) 
Topical Ointment and vehicle ointment when topical application to skin is followed by light 
exposure.   
In addition, safety will be assessed by evaluation of any adverse events (AEs) reported during the 
study. 


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Clinical Study Protocol 
3. 
INVESTIGATIONAL PLAN  
3.1. 
Study Design  
This is a single-center, randomized, within-subject comparison study of CCP-020 (Diacerein 
1%) Topical Ointment and vehicle ointment.  CCP-020 (Diacerein 1%) Topical Ointment and 
vehicle ointment will each be applied to 2 sites, one which will be irradiated and one which will 
remain non-irradiated.  The irradiated and non-irradiated sites will be compared with each other 
and with an untreated irradiated control.  
A total of 4 application sites (2 cm x 2 cm each) will be marked on the subject’s lower thoracic 
area of the back:  2 sites on each side of the back – 2 sites for CCP-020 (Diacerein 1%) Topical 
Ointment and 2 sites for vehicle ointment.  Each study product will be applied according to the 
randomization scheme in an amount of 0.2 mL under occlusive patch conditions once during the 
study. 
Approximately 24 (±2) hours post study product application, the patches will be removed by 
study staff.  The sites will then be graded for cutaneous reactions by a trained evaluator and the 
designated sites, including the untreated site, will be exposed to irradiation. One side of the back 
will be designated for irradiation and the other side will remain non-irradiated.  An additional 
site will be marked on the “irradiated side” of the back which will receive no treatment, but will 
receive irradiation to serve as an untreated irradiated control.   The sites and control will be 
examined at approximately 24 and 48 hours post irradiation and graded for reactions.  Cutaneous 
reactions at the application sites will be evaluated using a visual scale that rates the degree of 
erythema, edema, and other signs of cutaneous irritation (see Table 3 and Table 4). 
Safety evaluations include collection of adverse events (AEs). 
3.2. 
Discussion of Design 
Results are interpreted according to working criteria which are based upon published works, as 
well as the clinical experience of TKL Research, Inc.  These working criteria are periodically 
reviewed and amended subject to new information which becomes available. 
This phototoxicity study is designed to detect the ability of the CCP-020 (Diacerein 1%) Topical 
Ointment and vehicle ointment to cause topical skin irritation when exposed to light.  Each 
subject is to receive applications of CCP-020 (Diacerein 1%) Topical Ointment and vehicle 
ointment to 2 separate sites.  One will be irradiated and one will remain non-irradiated. An 
untreated control will also be irradiated.  This design provides built-in controls for the test 
product (CCP-020 (Diacerein 1%) Topical Ointment) under both irradiated and non-irradiated 
conditions.   


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3.3. 
Study Population 
3.3.1. 
Subject Population 
A sufficient number of subjects will be enrolled in order to provide 30 completed subjects 
evaluable for analysis; an individual subject will be allowed to participate in the study one time 
only.   
A rationale for the choice of sample size is provided in Section 4.2 of this protocol. 
3.3.2. 
Inclusion and Exclusion Criteria  
Inclusion Criteria  
A subject will be considered eligible for participation in the study if all of the following inclusion 
criteria are satisfied prior to randomization: 
1. Is a healthy male or female (to be confirmed by medical history);  
2. Is 18 years of age or older;  
3. In the case of a female of childbearing potential, is using two acceptable forms of birth 
control (oral/implant/injectable/transdermal contraceptives, intrauterine device, condom 
with spermicide, diaphragm with spermicide, abstinence, partner’s vasectomy, tubal 
ligation). Abstinence or vasectomies are acceptable if the female subject agrees to 
implement two of the other acceptable methods of birth control if her lifestyle/partner 
changes; 
4. In the case of a female of childbearing potential, has a negative urine pregnancy test 
(UPT) at Day 1 and are willing to submit to a UPT at the end of study (EOS); 
5. Is free of any systemic or dermatological disorder, which, in the opinion of the 
Investigator, will interfere with the study results or increase the risk of AEs; 
6. Has uniformly-colored skin on the lower thoracic area of the back which will allow 
discernment of erythema, and has Fitzpatrick Skin Types I, II, or III (see Table 1); 
7. Complete a medical screening procedure; and 
8. Read, understand, and sign an informed consent. 
Exclusion criteria 
A subject who has any of the following will be excluded from the study: 
1. Has a history of photosensitivity or photoallergy; 
2. Has any visible skin disease at the application site which, in the opinion of the 
Investigator, will interfere with the evaluation of the test site reaction; 
3. Is using systemic/topical corticosteroids within 3 weeks prior to and/or during the study, 
or systemic/topical antihistamines 72 hours prior to and during the study; 


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4. Is not willing to refrain from using systemic/topical anti-inflammatory analgesics such as 
aspirin (81 mg daily aspirin will be allowed), Aleve, Motrin, Advil, or Nuprin for 72 
hours prior to and during the study (occasional use of acetaminophen will be permitted); 
5. Is taking medication known to cause phototoxic reactions (eg, tetracyclines, thiazides, 
nonsteroidal anti-inflammatory drugs [NSAIDs]); 
6. Is using medication which, in the opinion of the Investigator, will interfere with the study 
results (e.g. anti-inflammatory medications, antipsychotics, anticonvulsants with potential 
pain relief effects, immunomodulatory medications, and others); 
7. Is unwilling or unable to refrain from the use of sunscreens, cosmetics, creams, 
ointments, lotions or similar products on the back during the study; 
8. Has psoriasis and/or active atopic dermatitis/eczema; 
9. Has a known sensitivity or allergy to constituents of the materials being evaluated 
including diacerein, mineral oil, petrolatum, cetyl alcohol, D&C Yellow #10 and/or ethyl 
paraben; 
10. Is a female who is pregnant, plans to become pregnant during the study, or is breast 
feeding a child; 
11. Has damaged skin in or around the test sites, including sunburn, excessively deep tans, 
uneven skin tones, tattoos, scars, excessive hair, numerous freckles, or other 
disfigurations of the test site; 
12. Has received treatment for any type of internal cancer within 5 years prior to study entry; 
13. Has a history of, or is currently being treated for skin cancer and/or hepatitis; 
14. Has a history of, or is currently being treated for diabetes; 
15. Has any condition that might compromise study results; 
16. Is currently or expects to sunbathe or use tanning salons during the study; 
17. Has a history of adverse response (eg, blistering, sun poisoning) to ultraviolet (UV) sun 
lamps/sunlight exposure; 
18. Is currently participating in any clinical testing; 
19. Has any known sensitivity to adhesives; and/or 
20. Has received any investigational drug(s) within 4 weeks prior to study entry. 
3.3.3. 
Interruption or Discontinuation of Treatment  
In accordance with legal requirements and ICH-GCP guidelines, every subject or his/her legal 
representative has the right to refuse further participation in the study at any time and without 
providing reasons (see also Section 5.3).  A subject's participation is to be terminated 
immediately upon his/her request.  The Investigator should seek to obtain the reason and record 
this on the case report form (CRF).  


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If at the time of refusal a study product has already been administered, the subject should be 
advised on follow-up safety investigations.  
If a subject develops a serious adverse event (SAE), his/her termination from the study will be 
considered by the Investigator.  Similarly, if the subject develops conditions over the course of 
the study which would have excluded his/her entry in the study according to the safety-related 
medical exclusion criteria, he/she must be withdrawn immediately.    
The subject may be withdrawn from the study at any time at the discretion of the Investigator for 
medical reasons and/or due to non-adherence to the treatment scheme and other duties stipulated 
in the study protocol.  The reasons are to be documented on the CRF. 
In addition, the Sponsor retains the right to end the study at any time if the study cannot be 
carried out as agreed upon in the protocol.  In case of premature termination or suspension of the 
study, the Sponsor’s study manager will promptly inform the Investigator/institutions and 
regulatory authorities of the termination or suspension and the reason for that.  It is the 
responsibility of the Principal Investigator (PI) to notify the Institutional Review Board (IRB) in 
the case of premature termination/suspension. 
3.3.4. 
Withdrawals  
The following medical and other reasons justify a premature termination (by subject or 
Investigator) of any of the study investigational products (IPs).  
• Adverse Event/Serious Adverse Event 
• Death  
• Protocol Violation (e.g. non-compliance) 
• Investigator Judgment  
• Pregnancy  
• Lost to Follow-up  
• Withdrawal by Subject 
• Study Terminated by Sponsor  
• Other  
If a subject withdraws from the study, all efforts will be made to complete a final evaluation, if 
possible.  Subjects discontinued for having experienced an AE will be followed until the AE is 
resolved, a reasonable explanation is provided for the event, or the subject is referred to his/her 
own primary medical doctor (PMD).  The specific AE in question will be recorded on the 
appropriate CRF. 
3.4. 
Treatments  
3.4.1. 
Investigational Products and Control  
Investigational Product(s): 


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CCP-020 Topical Ointment 
CCP-020 is a topical ointment, 1% (w/w).  All excipients used in the topical formulation meet 
United States Pharmacopeia (USP)/ National Formulary (NF) criteria and are commonly used in 
The CCP-020 topical ointment and vehicle ointment will be applied topically, under occlusive 
patch conditions once over a 4-day period.  Each product will be applied to 2 sites (one irradiated 
site and one non-irradiated site) on the lower thoracic area of each subject’s back for 
approximately 24 (+/- 2) hours.  An amount of investigational product sufficient to cover an area 
of the back approximately 2 cm x 2 cm will be applied (approximately 0.2 mL).   
CCP-020 topical ointment and vehicle ointment should be stored at room temperature 
(15°C/59°F to 30°C/86°F).  The PI will be responsible for the suitable storage of the IPs in 
compliance with the storage instructions and must restrict access to the investigative personnel 
only.   
Lot numbers will be given in the clinical study report. 
Manufacturer:  
 
 
 
TWi Pharmaceuticals will be responsible for the manufacturing and filling into the primary 
package; aluminum tubes.  TWi Pharmaceuticals will be responsible to package and distribute to 
TKL.  CCP will be responsible for final release of the product.  TKL will be responsible for 
labeling the product upon site delivery. 
Control 
An untreated irradiated non-occlusive (open) 2 cm x 2 cm site will serve as a control.   


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3.4.2. 
Description of Investigational Products  
The IPs (CCP-020 [Diacerein 1%] topical ointment and vehicle ointment) will be supplied in 
aluminum tubes for the clinical study. CCP-020 (Diacerein 1%) topical ointment and vehicle 
ointment were manufactured and packaged in accordance with good manufacturing practice 
(GMP).   
3.4.3. 
Description of Patch Conditions  
The IP and vehicle will be evaluated under occlusive patch conditions is applied to a 2 cm x 2 
cm Webril pad attached to a non-porous, plastic film adhesive bandage (medical tape).  The 
patch is secured with hypoallergenic tape (Micropore), as needed. 
3.4.4. 
Packaging/Labeling  
The study medication tube label will show at least the following: 
• Protocol number 
• Storage conditions 
• Instructions for use 
• Expiration date 
• Sponsor information 
• Investigational drug warning 
• Space to enter lot number. 
A full product description can be found in the Investigator’s Brochure (IB).1 
All study IPs should be stored at room temperature (15°C/59°F to 30°C/86°F). 
3.4.5. 
Assignment to Treatment  
3.4.5.1. 
Randomization 
Each subject who signs an informed consent and successfully completes the screening 
procedures will be enrolled in the study.  Upon enrollment, each subject will be assigned a 
unique number, which will correspond to the subject number on the randomization code 
indicating application placement of the study materials.  Each subject in this study will serve as 
his or her own control. 
For each subject, one side of the back will be designated for irradiated sites and the other side 
will be for non-irradiated sites. On each side one application site will be assigned to the CCP-020 
[Diacerein 1%] topical ointment and one will be assigned to the vehicle ointment according to 
the randomization schedule.  On the irradiated side only one additional site will be assigned to 
the untreated irradiated control. 


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3.4.5.2. 
Blinding 
Investigative personnel who are involved in the preparation/application and removal of the 
treatments (CCP-020 [Diacerein 1%] topical ointment and vehicle ointment) will be unblinded 
and will not perform the evaluation of skin responses.  The trained evaluator who will be 
evaluating skin responses will be blinded to IPs and the treatment allocation; however, because 
of the demarcations/skin coloration remaining on the skin following patch removal, complete 
blinding of the evaluators cannot be completely assured. 
Investigative personnel, including the Investigator and the trained evaluator involved in the 
evaluation of responses, will remain blinded during the course of the study until Database Lock 
and finalization of the Statistical Analysis Plan (SAP). 
In the event of an emergency, if possible, the Investigator or designee will contact the Sponsor 
with notification of the intent to unblind the treatment codes prior to the actual unblinding.  If it 
is not possible to notify the Sponsor prior to the unblinding, the Investigator or designee will 
contact the Sponsor immediately following the unblinding procedure and follow with a written 
notification to document the exact manner in which the code was broken and the justification for 
the unblinding. The Investigator will communicate the treatment identification to only the 
investigative personnel who require the information to manage the emergency.  Unblinding will 
happen on site at TKL. 
3.4.6. 
Prior and Concomitant Therapy  
All medications, including over the counter (OTC) drugs and vitamins, taken within 28 days 
prior to the start of the study will be recorded at Screening.  Thereafter, a record of all 
medications taken during the course of the study will be made.  Information regarding the total 
daily dose, route of administration, start and discontinuation dates, and indication are to be 
captured on the subject’s CRF.  
The following prohibitions will apply for the duration of the study:  
• There will be no use of systemic/topical anti-inflammatory analgesics which in the 
opinion of the investigative personnel will interfere with the study results, including 
anti-inflammatory medications such as aspirin (81 mg aspirin will be allowed at the 
discretion of the Investigator), Aleve, Motrin, Advil, or Nuprin for 72 hours prior to 
and during the study (occasional use of acetaminophen will be permitted); 
• There will be no use of systemic/topical corticosteroids within 3 weeks prior to and/or 
during the study; 
• There will be no use of systemic/topical antihistamines 72 hours prior to and during 
the study; 
• There will be no use of medication known to cause phototoxic reactions (e.g., 
tetracyclines, thiazides, nonsteroidal anti-inflammatory drugs (NSAIDs)); 
• There will be no use of medication which, in the opinion of the Investigator, will 
interfere with the study results (e.g. anti-inflammatory medications, antipsychotics, 
anticonvulsants with potential pain relief effects, immunomodulatory medications, 
and others); 


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• There will be no use of sunbeds or sunlamps or deliberate exposure of the test sites to 
natural sunlight or to other sources of UV light; 
• There will be no participation in any other clinical study;  
• There will be no soaking of test areas; and/or 
• There will be no application of any product to the test areas. 
The use of or change in the dose of any and all concomitant medication, either prescription or 
OTC, during the study will be recorded.  The reason for use or change of dose of a concomitant 
therapy may need to be reported as an AE.  Therapies (medication and non-medication therapies) 
not restricted by the protocol may be used.  Non-prohibited chronic therapies being used at 
Baseline may be continued.   
All topical or systemic medication listed in the exclusion criteria are prohibited during this study.  
See the IB for information about possible drug-drug interactions.1 
3.4.7. 
Treatment Compliance 
All patches will be applied and removed by investigative personnel.  Whereas bathing will be 
allowed (low tub bath/frontal showers), the patched areas are not to be soaked and are to be kept 
as dry as possible, per the instructions to be given to each subject.  Subjects will be instructed to 
contact the Investigator before starting any medication, including OTC remedies.  In the case of 
an emergency treatment, the Investigator must be informed as soon as possible.  A trained, 
experienced evaluator will assess study compliance.   
Records of patch applications and visit schedule compliance will be recorded on the subjects’ 
CRFs. 
3.5. 
Visit Schedule and Assessments  
3.5.1. 
Study Procedures and Visit Schedule 
Screening  
At Screening, the subjects will receive any necessary written and verbal information, and the 
informed consent of each subject will be obtained.  Demographic data (including Fitzpatrick skin 
type) will be recorded, a medical history will be taken, and previous and concomitant 
medications will be reviewed.  Eligibility will be determined by review of the 
inclusion/exclusion criteria.   
• Any written and verbal information 
• Informed consent 
• Demographics 
• Previous/concomitant medication 
• Review of inclusion and exclusion criteria 
• Medical history (including lifestyle and habits) 


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• Evaluation of application site area 
Table 1: 
Fitzpatrick Skin Types  
I 
Always burns easily, never tans 
II 
Always burns easily, tans minimally 
III 
Burns moderately, tans gradually  
IV 
Burns minimally, always tans well  
V 
Rarely burns, tans very well  
VI 
Never burn, deeply pigmented4,5 
Day 1 
On Day 1, all subjects will be questioned regarding the entry criteria and female subjects of 
childbearing potential will undergo a UPT.  If the subject fulfills all the inclusion and none of the 
exclusion criteria, he/she will be allowed to participate in the study.  Concomitant medications 
and AEs will be reviewed and recorded at this visit. 
Upon enrollment, each subject will be assigned a consecutive, unique 3-digit subject number 
starting with 001, which will correspond to the subject number on the randomization code 
indicating application placement of the study products.  
A baseline evaluation of the patch sites will be performed immediately prior to application of the 
patches to ensure that no conditions, markings, or coloration of the skin will interfere with 
interpretation of the study results. 
A total of 4 application sites (2 cm x 2 cm each) will be marked on each subject’s back, placing 2 
sites on opposite sides of the back.  Of the 4 sites, 2 will be designated as “irradiated sites” and 2 
will be designated as “non-irradiated sites”. The CCP-020 [Diacerein 1%] topical ointment and 
its vehicle ointment will then each be applied to its designated “irradiated site” and its “non-
irradiated site” under occlusive conditions. The distance between the patches will be no less than 
one centimeter.  The numbering of the test sites will remain the same throughout the study.  The 
sites will be marked with an indelible, surgical marker.  
Minimal Erythema Dose (MED) Determination 
On Day 1, subjects will have an area of skin on their back, approximately 50 cm2, divided into 
6 equal sites marked with a surgical marker.  Each of the sites will be irradiated with full 
spectrum UV light (UVA/UVB), with each exposure differing from the previous by a factor of 
1.25 (ie, each irradiated site will be exposed to a 25% greater dose of UV irradiation than the 
previous site).2 
The areas involved in MED determination will be different from the study product application 
sites.  Evaluation of the exposed sites will be performed on Day 2.3 
Day 2 
On Day 2, a trained evaluator will examine the 6 irradiated sites and determine the MED for each 
subject. To determine the MED the sites are read and scored by the trained evaluator for the 
presence of erythema. There will be a main evaluator for the study; a backup evaluator will also 
be assigned in the event that an emergency occurs and the main evaluator is unable to attend the 


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study visit. The lowest exposure dose of the 6 irradiated sub-sites showing an erythema response 
is selected as the minimal erythema dose (see Section 3.5.7 for scoring scale). 
The clinical staff will remove the patches approximately 24 (± 2) hours after application and 
evaluate the application sites according to the criteria in Table 3 and Table 4 (Section 3.5.7).  
Evaluations will be recorded on the appropriate CRF.  The timing of the UVA and UVA/UVB 
irradiation will be calculated based on the output of the solar simulator.  The solar simulator 
output will be measured prior to each irradiation.   Details of the UV irradiation including output 
of the simulator, time of exposure, equipment used, and staff performing irradiations will be 
documented.  The sites designated for irradiation will receive 16 J/cm2 of UVA radiation 
followed by 0.5 times the MED of UVA/UVB irradiation, using a filtered light source (see 
Section 3.5.4).  One additional site (untreated) will be irradiated with 16 J/cm2 of UVA radiation 
followed by 0.5 times the MED of UVA/UVB radiation, using a filtered light source and will 
serve as an untreated control.   
In addition, AEs and concomitant medications will be reviewed and recorded, as appropriate. 
Day 3 
On Day 3, approximately 24 (±4) hours after irradiation (ie, approximately 48 (±4) hours 
following product application) all application sites and the untreated control site will be 
evaluated.  In addition, AEs and concomitant medications will be reviewed and recorded. 
Day 4/End of Study 
On Day 4, approximately 48 (±4) hours after irradiation (ie, approximately 72 (±4) hours 
following product application), all application sites and the untreated control site will be 
evaluated.  Adverse events and concomitant medications will be reviewed and recorded, as 
appropriate.  A UPT will be performed for female subjects of childbearing potential. 
Retest 
Although not all observations of erythema and edema are associated with phototoxicity, 
erythema and edema must be observed for a reaction to be suspected of being a positive 
phototoxic reaction. An increase in the intensity of the reaction over time further supports an 
assessment of phototoxicity. If a reaction is observed at both the irradiated and non-irradiated 
product sites (ie, if contact sensitization or irritation may have occurred), the reaction upon retest 
must be at least one grade more intense at the irradiated site than at the non-irradiated site for the 
reaction to be suspected of being a phototoxicity reaction (refer to Section 3.5.7 for response 
grades and notations).   
If it is determined by the Investigator that a retest should be performed, then the retest patches 
will be applied as soon as the original reactions have resolved.  The Investigator will determine 
the patch conditions to use during the Retest (see Section 3.4.3).  The study material will be 
applied to naive sites on the back, using appropriate patches to further discriminate a phototoxic 
reaction from an irritation reaction.  Identical patches will be applied to sites previously 
unexposed to the study material. Approximately 24 (± 2) hours later one site will be irradiated 
with 16 J/cm2 of UVA followed by ½ MED of UVB radiation using a filtered light source. An 
additional untreated site will be irradiated with 16 J/cm2 of UVA followed by ½ MED of UVB 
radiation using a filtered light source and serve as an untreated irradiated control.  All sites will 


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be evaluated upon patch removal and approximately 24, 48, and 72 hours after irradiation. 
Concomitant medications and AEs will also be reviewed. 
 
In some cases the retest may be done on the individual ingredients of the products. 
3.5.2. 
Visit Schedule  
A summary of the visit schedule and assessments is presented in Table 2. 
Table 2: 
Visit Schedule and Assessments  
 
Dosing Phase 
 
 
 
Day 1 
Screening 
Day 2 
Day 3 
Day 4  
EOS 
Informed consent 
X 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
Medical history 
X 
 
 
 
Demographic information 
X 
 
 
 
MED irradiation/evaluation 
X 
X 
 
 
Randomization (if applicable) 
Xa 
 
 
 
Product application  
X 
 
 
 
Patch Removal 
 
X 
 
 
Application site evaluations 
X 
X 
X 
X 
Application site and untreated control 
site irradiation  
 
X 
 
 
Untreated control evaluation 
 
X 
X 
X 
Review of concomitant medications 
X 
X 
X 
X 
Review of adverse events 
 
X 
X 
X 
Urine Pregnancy Test  
X 
 
 
X 
a The randomization will be performed on Day 1 of the study. 
Note:  The visit schedule may be revised if necessary. 
3.5.3. 
Definition of minimal erythemal dose 
Minimal erythemal dose (MED) is defined as the length (in time) of light exposure required to 
produce a minimal erythema reaction 16 - 24 hours after irradiation using a standardized filtered 
UV light source that emits UVB (290-320 nm) as part of its emission spectrum.2 
3.5.4. 
Light source 
The light source will be a Xenon Arc Solar Simulator (150 W), with UV-reflecting dichroic 
mirror, UVC-blocking filter, and visible/infrared blocking filter to generate a continuous 
emission spectrum in the UVA and UVB range (290 to 400 nm).2 An additional filter is added 
during irradiation of the application sites to block UVB radiation allowing only UVA irradiation 
of the sites.  The output is measured daily prior to irradiation using a radiometer/photometer.  
3.5.5. 
Background information 
Date of birth, gender, race, Fitzpatrick skin type (see Table 1), and a significant medical history 
of each subject will be recorded at Screening. 


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3.5.6. 
Efficacy Assessments 
No efficacy will be assessed in this study. 
3.5.7. 
Safety Assessments  
3.5.7.1. 
Patch Test Site Evaluations 
Assessment of the application sites will be done once daily, Days 1-4.  Assessment of the 
untreated irradiated control site will be done once daily on Days 2, 3 and 4.   
The symbols listed in Table 3 and their respective numerical equivalents will be used to express 
the response observed at the time of examination. Additional response notations are presented in 
Table 4. 
Table 3: 
Response Scores 
 
Response 
Symbol 
Numerical Equivalent 
Score 
Erythema 
 
 
No reaction 
- 
0 
Mild, but definite erythema 
+ 
1 
Moderate erythema 
++ 
2 
Marked/severe erythema 
+++ 
3 
Edema 
 
 
No reaction 
- 
0 
Mild, but definite edema 
** 
1 
Definite edema with erosion/vesiculation 
*** 
2 


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Table 4: 
Notations 
Response/Comment 
Notation 
Hyperpigmentation 
Hr 
Hypopigmentation 
Ho 
Vesiculation 
V 
Papular response 
p 
Papulovesicular response 
pv 
Damage to epidermis: oozing, crusting, and/or superficial erosions 
D 
Itching 
I 
Spreading of reaction beyond patch study site (ie, reaction where material 
did not contact skin) 
S 
Follicular irritation with or without pustule formation (folliculitis) 
f 
Subject absent 
X 
Patch dislodged 
PD 
Not patched 
NP 
No reaction 
0 
 
Before results are interpreted as indicative of phototoxicity, the subject(s) must first be retested 
to the product(s) to demonstrate that the results obtained are reproducible.  
 
If the non-irradiated study product sites give reactions indicative of significant primary irritancy 
or prior sensitization, it may not be possible to make any comments about phototoxic potential.  
In such situations, further routine patch evaluation might be recommended. 
 
Because of the relatively small number of subjects evaluated in this study, it will generally not be 
possible (except in extreme cases) to categorize a product as having mild, moderate or severe 
phototoxic potential. 
 
The readings will be made under a standardized white light source.  The numerical equivalent 
scores will be used for calculations. 
3.6. 
Adverse Events  
3.6.1. 
Method of Determining Adverse Events  
Safety assessments will include recording AEs reported spontaneously by the subject or collected 
by the Investigator.  AEs will be recorded at each visit throughout the study on the appropriate 
CRF.  Every attempt should be made to describe the AE in terms of a diagnosis.  If a clear 
diagnosis has been made, individual signs and symptoms will not be recorded unless they 
represent atypical or extreme manifestations of the diagnosis, in which case they should be 
reported as separate events.   


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Subjects should be asked whether, since the time of the last observation or visit, they had any of 
the following:  
• Experience any changes in well-being; 
• Used any new medications;  
• Changed medication regimens (both prescription and OTC); and/or 
• Were admitted to a hospital or had any accidents.  
All questions should be of a general nature and should not suggest symptoms.   
When an AE is suspected, all relevant evaluations will be carried out and appropriate treatment 
provided.  Additional follow-up will be done as necessary (Section 3.6.4) and recorded in the 
subject’s source documents, and the results will be provided to the Sponsor.   
For AE definitions and reporting requirements refer to Section 3.6.2 and Section 3.6.3.  
Note:  Any observed response which can be denoted using the irritation criteria summarized in 
Table 3 and Table 4 will not be considered an AE.  Likewise, any tape-related irritation will only 
be noted as an AE when all patches are discontinued due to tape reaction around all sites (see 
Section 3.6.6). 
3.6.2. 
Adverse Event Definitions 
3.6.2.1. 
Adverse Events  
Information about all local and systemic AEs, whether volunteered by the subject, discovered by 
Investigator questioning, or detected through other means, will be collected and recorded on the 
AE CRF and followed as appropriate.   
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product (or cosmetic product), which does not necessarily 
have a causal relationship with this treatment.  An AE can therefore, be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a medicinal 
investigational product, whether or not considered related to the medicinal investigational 
product.   
Adverse Events will be coded using an internationally recognized medical dictionary for 
regulatory activities (MedDRA). 
Medical conditions/diseases present before starting study treatment are considered AEs only if 
they worsen after starting study treatment (any procedures specified in the protocol).  Any AEs 
occurring before starting study treatment but after signing the ICF are recorded on the Medical 
History/Current Medical Conditions CRF.  
To the extent possible, each AE will also be described by: 
1. its duration (start and end dates), 
2. the severity grade (mild, moderate, severe),  
3. its relationship to the study drug, 


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4. the action(s) taken, and 
5. as relevant, the outcome. 
Note:  Any observed response which can be denoted using the irritation criteria summarized in 
Table 3 and Table 4 will not be considered an AE.  Likewise, any tape-related irritation will not 
be noted as an AE. 
3.6.2.2. 
Serious Adverse Events  
A “SAE” is any AE that: 
• Results in death; 
• Is life-threatening (Note: the term “life-threatening” refers to any AE that, as it 
occurs, puts the subject at immediate risk of death.  It does not refer to an AE that 
hypothetically might have caused death if it were more severe). 
• Results in hospitalization or prolongation of current hospitalization (not including 
hospitalization for a pre-existing condition that has not increased in severity or 
frequency from the subject’s underlying medical condition prior to entry into the 
study). 
• Is a congenital anomaly/birth defect in the offspring of a subject.  
• Is another serious (important medical events) event.  
• Results in persistent or significant disability/incapacity.  
(Note: Important medical events may not be immediately life-threatening or result in death or 
hospitalization but may be considered serious when, based on the appropriate medical judgment, 
they may jeopardize the subject or 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 hospitalization; or development of drug dependency or drug abuse.) 
3.6.2.3. 
Severity of Adverse Events 
“Severity” of the AE refers to the extent to which an AE affects the subject’s daily activities and 
differs from “Serious,” which is a regulatory classification.   
The Investigator is to classify the severity of an AE according to the following definitions: 
• Mild: The symptom has a negligible effect or no impairing effect on the subject’s 
normal function.  
• Moderate: The symptom impairs the subject’s normal function to some extent.  
• Severe: The symptom has an obvious, significantly impairing effect on the subject’s 
normal function.  


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3.6.2.4. 
Relationship of Adverse Events to Study Treatments 
The Investigator is to classify the drug relationship of an AE according to the definitions outlined 
in Table 5.  
Table 5: 
Relationship of AE to Study Drug 
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). 
3.6.3. 
Reporting Adverse Events 
Adverse events that occur from first dose through completion of the last study visit should be 
reported.  All SAEs, 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 TKL 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 occurring after the 30-day follow-up period AND 
considered related to study drug must also be reported to the Sponsor.  
Every attempt should be made to describe the AE in terms of a diagnosis.  If a clear diagnosis 
has been made, individual signs and symptoms will not be recorded unless they represent 
atypical or extreme manifestations of the diagnosis, in which case they should be reported as 
separate events.  If a clear diagnosis cannot be established, each sign and symptom must be 
recorded individually.  
Any SAEs occurring in a subject receiving study drug must be reported to the Sponsor within 24 
hours of the site being informed of the event, even if the event does not appear to be drug-
related.  The report must be made by sending a completed SAE Report form to the Sponsor.  Any 
pertinent follow-up information should be provided in a similar manner.  Contact information is 
provided in Section 3.7.1. 
3.6.4. 
Adverse Event Follow-up 
Any ongoing AE at the time of study completion or withdrawal will be followed until the AE is 
resolved or the subject is referred to his/her own PMD.  The Investigator and the Sponsor will 


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decide if longer follow-up is appropriate on a case-by-case basis.  Subjects who experience any 
clinically significant AE will remain under medical supervision until the Investigator or the 
Sponsor’s Medical Monitor deems the AE to be resolved, stabilized, or no longer serious enough 
to warrant follow-up.   
3.6.5. 
Pregnancy reporting  
Prior to study enrollment, females of childbearing potential must be advised of the importance of 
avoiding pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy.  The signed Informed Consent Form must document this discussion.   
A UPT will be performed on all females of childbearing potential at Day 1 (day of first patch 
application) and EOS.  All women of childbearing potential will receive a UPT prior to the first 
study drug administration and the study drug must be withheld until the results of laboratory 
pregnancy testing are available.  If pregnancy is confirmed, the subject must not receive any 
study drug and must not be enrolled in the study.  
3.6.6. 
Expected Adverse Events  
Any observed response in the patch test area that can be denoted using the irritation criteria 
summarized in Table 3 and Table 4 will not be considered an AE.   
Tape related reactions will only be recorded as AEs when the subject is discontinued due to tape 
reaction around all sites.  When 1 or 2 sites are experiencing severe tape related reactions, the 
application site will be stopped and the subject will continue on the study.   
3.7. 
Instructions for Rapid Notification of Serious Adverse Events 
3.7.1. 
Contact person and number  
Serious adverse events must be reported immediately (i.e., not later than 24 hours after first 
knowledge) by e-mail with the scanned TKL SAE report form to: 
 
 
 
3.7.2. 
Reporting Responsibility  
Any death, SAE, pregnancy, (see Section 3.6), or unusual frequency of AEs, must be reported 
immediately (i.e., not later than 24 hours after first learning of its occurrence) to the Sponsor’s 
study manager by the Investigator, even if the event(s) appear to be unrelated to study treatment.  
Follow-up information about a previously reported SAE or pregnancy must also be reported to 
the Sponsor within 24 hours of receiving it.  If the SAE has not been previously documented 
(i.e., is a new occurrence) and it is thought to be related to the IP (or therapy), the Sponsor may 
contact the Investigator to obtain further information.  If warranted, an investigator alert may be 


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issued to inform all Investigators involved in any study with the same product (or therapy) that 
this SAE has been reported.   
The IRB should also be notified of SAEs or pregnancies and of any follow-up information in 
writing, as is practical, and depending on local regulations.   
3.7.3. 
Reporting procedures 
For each SAE, the Investigator will complete a SAE Report Form in English and assess the 
relationship of each SAE to study treatment.  The completed form(s) should be sent by e-mail to 
the Sponsor within 24 hours of first knowledge of the SAE (as outlined in Section 3.7.1 and 
Section 3.7.2).  The initial SAE should be reported immediately, even if only preliminary 
information is available.  Follow-up information should be sent by the same Investigator, 
restating the date of the original report.  Either a new SAE form is sent (stating that it is a follow-
up), or the original one is resent (with the new information highlighted and a new date provided).  
The follow-up should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not, and whether the patient continued or discontinued 
study participation.  The form confirmation will be retained. 
Pregnancy follow-up (as outlined in Section 3.6.5) should be reported to the IRB within 24 hours 
of first knowledge on a Pregnancy Report Form.  Follow up will describe the outcome of the 
pregnancy, including any voluntary or spontaneous termination, details of the birth, and the 
presence or absence of any congenital abnormalities or birth defects.   
3.8. 
Appropriateness of Safety Measurements  
The safety assessments in the study are standard safety measures in clinical trials.  


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4. 
STATISTICAL METHODS  
4.1. 
General Considerations for Data Analysis  
The focus of the statistical analysis will be the comparison with controls of the phototoxic 
response to the study products.  The parameter for phototoxicity will be the mean of Day 3 and 4 
scores (sum of erythema and edema). 
 
All statistical processing will be performed using the SAS® system (version 9.2 or higher).  No 
interim or subgroup analyses are planned. 
4.2. 
Sample Size and Power Considerations 
The sample size of 30 evaluable subjects conforms to industry and regulatory standards for 
determination of irritation when topical application to skin is followed by light exposure. 
4.3. 
Subject Populations for Analysis 
All subjects who receive treatment will be evaluable for AEs.  The evaluation of phototoxicity 
potential of the study products will be assessed for all subjects completing the study. 
4.3.1. 
Background and Demographic Characteristics 
Descriptive statistics will be used to summarize demographic characteristics (age, gender, 
Fitzpatrick skin type, and race) and background characteristics for the randomized subject 
population.  Past/coexistent medical history information for all randomized subjects will be 
presented in a by-subject listing. 
4.3.2. 
Study Product/Visit Compliance 
Descriptive statistics will be used to summarize study product compliance for the randomized 
subject population. 
4.4. 
Prior and Concomitant Medications 
Prior and concomitant medication information for all randomized subjects will be presented in a 
by-subject listing. 
4.5. 
Efficacy Evaluation 
This section is not applicable to this study. 
4.6. 
Safety Evaluation 
4.6.1. 
Local Tolerability Assessment 
All assigned scores during the study for subjects who complete the study will be summarized 
using frequency counts by treatment for Days 2, 3 and 4. Selected pairwise comparisons will be 
performed on the mean of the Day 3 and Day 4 response scores (sum of erythema and edema 


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scores) in the context of the analyses of variance (ANOVA).  Pairs to be compared are: each 
study product irradiated versus non-irradiated and all pairwise comparisons on each side (CCP-
020 [Diacerein 1%] topical ointment versus vehicle ointment on both the irradiated and 
non-irradiated sides and CCP-020 [Diacerein 1%] topical ointment versus untreated and vehicle 
ointment versus untreated on the irradiated side).    
4.6.2. 
Adverse Events  
Adverse events will be summarized as an overall incidence of at least one event, incidence 
within body systems only, incidence by body system and preferred term, and by highest severity.  
Each subject will contribute only once (e.g., the first occurrence) to each of the rates, regardless 
of the number of occurrences (events) the subject experiences.   
Treatment-emergent AEs will be summarized and tabulated by the system organ class and 
preferred term, by severity (mild, moderate, severe) and by relationship to study product (not 
related, unlikely, possible, probable, and definite).   
Treatment-emergent will be defined as any AE with an onset date on or after the first study 
product administration date.  Any event with a missing onset date will be included as a 
treatment-emergent AE. 
Deaths and SAEs will be listed by subject. 
4.7. 
Other topics 
There are no other topics being evaluated. 
4.8. 
Interim analyses 
No interim analyses are anticipated. 
4.9. 
Special Methods 
This section is not applicable for this protocol. 


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5. 
ADMINISTRATIVE PROCEDURES 
5.1. 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and in accordance with TKL 
Research, Inc.’s standard operating procedures.  These are designed to ensure adherence to Good 
Clinical Practices guidelines, as described in:  
• ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.  Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
• United States (US) 21 Code of Federal Regulations (CFRs) dealing with clinical 
studies (including parts 50 and 56 concerning informed consent and IRB/IEC/EEC 
regulations). 
• Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 
1964 and amendments). 
The PI agrees, when signing the protocol, to adhere to the instructions and procedures described 
in it and thereby to adhere to the principles of GCP that it conforms to. 
5.2. 
Institutional Review Board 
Before implementing this study, the protocol, the ICF and other information to subjects, must be 
reviewed by a properly constituted IRB.  A signed and dated statement that the protocol and 
informed consent have been approved by the IRB must be given to Sponsor before study 
initiation.  This committee must also approve any amendments to the protocol, other than 
administrative ones, and a signed and dated statement of approval must be sent to the Sponsor 
prior to initiation of the amendment procedures.  The name and occupation of the chairman and 
the members of the IRB must also be supplied to Sponsor. 
5.3. 
Informed consent 
The Investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved, and any discomfort it may entail.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, and 
that withdrawal of consent will not affect his/her subsequent medical treatment or relationship 
with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language.  The subject should read and consider the statement before signing and 
dating it, and he/she should be given a copy of the signed document.  No subject can enter the 
study before informed consent has been obtained from him/her, or his/her legally authorized 
representative. 


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The ICF is considered to be part of the protocol, and must be submitted by the PI with it for IRB 
approval.  Any changes to the proposed ICF suggested by the PI must be agreed to by Castle 
Creek Pharmaceuticals, LLC before submission to the IRB and a copy of the approved version 
must be provided to Castle Creek Pharmaceuticals, LLC after IRB approval. 
5.4. 
Declaration of Helsinki 
The PI must conduct the study in accordance with the laws and regulations of the country in 
which the study is conducted, as outlined in the Declaration of Helsinki.  
5.5. 
Changes in Planned Study Conduct  
5.5.1. 
Protocol amendments 
With the exception of changes in the visit schedule and/or administrative changes, any changes 
or additions to this clinical study protocol require a written protocol amendment that must be 
approved by Castle Creek Pharmaceuticals, LLC and the PI before implementation.  
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study, require additional approval by the appropriate IRB.  A copy of the 
written approval of the IRB, which becomes part of the protocol, must be given to Castle Creek 
Pharmaceuticals, LLC.  Examples of amendments requiring such approval are: 
1. an increase in study product dosage or duration of product exposure of subjects, 
2. a significant change in the study design (e.g., addition or deletion of a control group), 
3. an increase in the number of invasive procedures to which subjects are exposed, and 
4. addition or deletion of a test procedure for safety monitoring. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the Investigator or the Sponsor in the interests of preserving the safety of all subjects 
included in the study.  If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons the study Sponsor should be 
notified and the IRB should be informed within 10 working days. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval, but the IRB must be kept informed of such administrative 
changes.  Examples of administrative changes not requiring formal protocol amendments and 
IRB approval that can be treated as administrative amendments include: 
1. changes in the staff used to monitor studies, and  
2. minor changes in the packaging or labeling of the study product. 
5.5.2. 
Other changes in study conduct 
Deviations from the planned study conduct are not permitted; any unforeseen changes in study 
conduct must be reported to the Sponsor and noted in the final clinical study report. 


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5.5.3. 
Termination or suspension of study 
Both the Sponsor and the PI reserve the right to terminate or suspend the study at any time.  If 
study termination is necessary, the procedures will be arranged on an individual study basis after 
review and consultation by both parties.  It is the responsibility of the PI to notify the IRB of the 
termination/suspension and the reason(s).  In terminating the study, the Sponsor and the PI will 
ensure that adequate consideration is given to the protection of the subjects’ interests.   
5.6. 
Data handling and record keeping 
5.6.1. 
Recording of data 
Case report forms will be designed to identify each subject by subject entry number and, where 
appropriate, subject's initials, the product being evaluated, and the results observed.  All entries 
to the CRFs must be made as instructed by the study Sponsor at study initiation.  Data on 
subjects collected on CRFs during the study will be documented in an anonymous fashion, and 
the subject will only be identified by the subject number, and by his/her initials, if also required.  
If, as an exception, it is necessary for safety or regulatory reasons to identify the subject, both the 
study Sponsor and the PI are bound to keep this information confidential.   
The PI must sign the designated page(s) of the CRFs, thereby stating that he/she takes 
responsibility for the accuracy of the data in the entire case record book.  All records will be kept 
in conformance to applicable national laws and regulations. 
The original signed ICF will be attached to each subject’s file.  When the study treatment is 
completed, the ICF will be kept in the appropriate file folder; otherwise a note indicating where 
the records can be located will be made.   
5.6.2. 
Retention of documents 
Storage is maintained for 5 years or until the Sponsor advises to release the archives at either the 
TKL facility at One Promenade Blvd. Suite 1101/1201, Fair Lawn, NJ 07410 in a secured room 
accessible only to TKL employees, or at an offsite location that provides a secure environment 
with burglar/fire alarm systems, camera detection, and controlled temperature and humidity.  
Originals or copies of the CRFs, source documents, correspondence, IRB documents, study 
reports, etc. will be available for the Sponsor's review on the premises of TKL or at a secure 
location off-site.  All database management activities can be found in the data management plan 
(DMP).   
5.7. 
Product handling and accountability 
All product supplies are to be used only for this clinical study and not for any other purpose.  
Study product supplies must be kept in an appropriate, secure area (e.g., locked cabinet) and 
stored according to the conditions specified on the product labels.   
The PI or a designee must maintain a full record of the shipment and application of study product 
in a product accountability ledger.  This log must be kept current and should contain the 
following information: 
• identification of the subject to whom the study product was dispensed, 


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• date(s) of the study product dispensed to the subject, and 
• initials of the study site representative(s) dispensing study product. 
The inventory must be available for inspection by the study monitor.  A product-inventory and 
storage-facility inspection will be conducted at appropriate time intervals throughout the clinical 
investigation, depending on enrollment and the length of the study.  Any discrepancy and/or 
deficiency must be accounted for by the PI or his/her designee. 
The PI must not destroy any product labels, or any partly used or unused product supply.  At the 
conclusion of the study and, as appropriate, during the course of the study, all study product 
supplies, including partially used or empty containers, must be returned according to the 
designation of the Sponsor.  Any missing supplies will be indicated on the inventory; the original 
inventory list will be retained in the PI’s records for this clinical study. 
5.8. 
Quality control and quality assurance 
5.8.1. 
Monitoring procedures 
During the study, the Sponsor may visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to ICH-GCP 
guidelines, the progress of enrollment, and also to ensure that study product is being stored, 
dispensed and accounted for according to specifications.  Key investigative personnel will be 
available to assist the field monitor during these visits. 
The data required by the protocol must be recorded on the appropriate CRFs.  The CRFs and any 
source documents will be available to the study monitor who will perform a 100% data check 
(comparison of the data recorded in the CRF with those in the source documents).  The CRFs 
and source data will also be available for an audit by the Sponsor or the FDA at any time.  
The Investigator will give the monitor access to relevant clinical records, to confirm their 
consistency with the CRF entries.  No information in these records about the identity of the 
subjects will leave the study center.  Additional checks of the consistency of the source data with 
the CRFs are performed according to the study-specific monitoring plan. 
5.8.2. 
Auditing procedures 
In addition to the routine monitoring procedures, a study center may be audited in depth for 
study quality assurance by the Sponsor, an external auditor on behalf of the Sponsor, and/or by 
regulatory authorities.  This audit may include a review of all source documents, drug records, 
and original CRFs the study site used in this study.  Patient confidentiality will be maintained at 
all times and consent for this will be obtained before entry of the patient into the clinical study 
(see Section 5.3).  If an inspection is requested by a regulatory authority, the PI must 
immediately inform the study Sponsor that this request has been made. 


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5.9. 
Confidentiality and publication policies 
5.9.1. 
Disclosure and confidentiality 
By signing the protocol, the PI agrees to keep all information provided by the Sponsor in strict 
confidence and to request similar confidentiality from his/her staff and the IRB.  Study 
documents provided by the Sponsor (protocols, IBs, CRFs and other material) will be stored 
appropriately to ensure their confidentiality.  The information provided by the Sponsor to the PI 
may not be disclosed to others without direct written authorization from the Sponsor, except to 
the extent necessary to obtain informed consent from subjects who wish to participate in the 
study.   
5.9.2. 
Communication and publication of results 
Any formal presentation or publication of data from this study will be considered as a joint 
publication by the Investigator(s) and appropriate Sponsor personnel.  Authorship will be 
determined by mutual agreement.   
Castle Creek Pharmaceuticals, LLC must receive copies of any intended communication in 
advance of publication (at least 15 working days for an abstract or oral presentation and 45 
working days for a journal submission).  The Sponsor will review the communications for 
accuracy (thus avoiding potential discrepancies with submissions to health authorities), verify 
that confidential information is not being inadvertently divulged and provide any relevant 
supplementary information. 


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6. 
REFERENCES 
1. Investigator’s Brochure. CCP-020 (Diacerein 1%) Topical Ointment. Castle Creek 
Pharmaceuticals, LLC. Version Number 1.0. 04 November 2016. 
2. Berger DS. Specification and design of solar ultraviolet simulators. Journal of 
Investigational Dermatology. 1969; 53:192-199. 
3. Final Monograph: 21 CFR Parts 310, 352, 700, 740.  Sunscreen drug products for 
over-the-counter human use.  Federal Register.  Vol 64/No. 98/Pages: 27666-27693. 
4. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. 
Arch.Dermatol. 1988; 124: 869-871. 
5. Sachdeva S. Fitzpatrick skin typing: Applications in dermatology. Indian J Dermatol 
Venereol Leprol 2009;75:93-6