A 6-Week, Randomized Study to Evaluate the Potential of MC2-01 Cream to Induce Photoallergic Skin Reaction in Healthy Subjects, Using a Controlled Photopatch Test Design
Phase: PHASE1
Conditions: Photoallergy
Sponsor: MC2 Therapeutics

 
Drug Delivery Solutions Ltd.  
(Part of MC2 Therapeutics) 
C/O: Agern Allé 24-26, 2970 Hørsholm, 
Denmark 
 
 
 
Clinical Study Protocol 
MC2-01 Cream (Calcipotriene/Betamethasone Dipropionate 0.005/0.064 w/w%) 
Sponsor Protocol No. MC2-01-C10 
TKL Study No. PB710518 
 
 
A 6-Week, Randomized Study to Evaluate the Potential of  
MC2-01 Cream to Induce a Photoallergic Skin Reaction  
in Healthy Subjects, Using a Controlled Photopatch Test Design 
 
 
Author: 
 
 
 
Allyson Marshall, PhD  
Document type: 
 
 
Clinical Study Protocol 
Development Phase:  
 
1 
IND Number:  
 
 
127152 
Document Date: 
 
 
10-January-2019  
Document Status 
 
 
Final v1.0 
Number of Pages:  
 
 
46 
 
 
 
Property of MC2 Therapeutics 
Confidential 
The confidential information provided in this document is for use by parties directly involved in this investigation. 
This document is delivered in confidence that such information will not be copied or made available to any third 
party without the written consent of MC2 Therapeutics.   
 
 
 

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Clinical Study Protocol 
Synopsis 
Study Title: 
A 6-Week, Randomized Study to Evaluate the Potential of MC2-01 Cream to Induce a 
Photoallergic Skin Reaction in Healthy Subjects, Using a Controlled Photopatch Test 
Design  
TKL Study Number: 
PB710518 
Sponsor Protocol Number: 
MC2-01-C10 
Sponsor: 
Drug Delivery Solutions Ltd.  
(Part of MC2 Part of MC2 Therapeutics) 
C/O: Agern Allé 24-26, 2970 Hørsholm, Denmark 
Development Phase: 
1 
IND Number: 
127152 
Study Objectives: 
The primary objective of this study will be to determine the photoallergic potential of 
MC2-01 Cream when topical application to healthy skin is followed by light exposure. 
In addition, safety will be assessed by evaluation of any AEs reported during the study. 
Study Design: 
During the 3-week Induction Phase, MC2-01 Cream and MC2-01 Vehicle, will each be 
applied 2 times per week (Monday and Thursday) to 2 sites on the infrascapular area of 
the back under semi-occlusive patch conditions for approximately 24 hours (± 4 hours). 
Minimal erythema dose (MED) irradiation will also be performed for each subject on 
Day 1.  After approximately 24 hours (± 4 hours) patches are removed, all application 
sites will be evaluated, and one application site of each study product will be irradiated 
with 2 times the subject’s MED using the full Xenon lamp spectrum.  All sites will be 
evaluated post irradiation at approximately 48 hours later when irradiated on Tuesdays 
and 72 hours later when irradiated on Fridays.  If a subject misses an irradiation session 
during the Induction Phase, an additional application of study product may be applied 
on the Monday of the rest period (week 4) and an additional irradiation approximately 
24 hours (± 4 hours) after application has occurred.  At Challenge, MC2-01 Cream and 
MC2-01 Vehicle will each be applied once to 2 naïve sites on the infrascapular area of 
the back under semi-occlusive patch conditions for approximately 24 hours (± 4 hours). 
After patch removal, all application sites will be evaluated, and one site of each test 
product will be irradiated with 6 J/cm2 of Ultraviolet A (UVA) followed by 0.5 times 
the subject’s MED of UVA/Ultraviolet B (UVB).  An additional untreated site will also 
be irradiated at Challenge and will serve as an untreated control.  Each site, including 
the untreated control site, will be evaluated again at approximately 24 hours, 48 hours, 
and 72 hours following irradiation. A Rechallenge will be performed if a cutaneous 
response observed during the Challenge Phase indicates possible photosensitization or 
at the discretion of the Investigator.   
Planned Sample Size: 
50 evaluable subjects 
Study Population: 
Healthy adult male and female volunteer subjects 
Investigational Products: 
MC2-01 Cream  
MC2-01 Vehicle 
Control: 
An untreated irradiated control site. 

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Efficacy Evaluation 
Criteria: 
Not applicable 
Safety Evaluation 
Criteria: 
The safety endpoints for this study are irritation responses during the Induction Phase, 
positive responses at Challenge (ie, reactions indicative of a sensitization response) 
and adverse events.  All local and systemic adverse events (AEs) observed by or 
reported to the Investigator throughout the study will be evaluated.  The intensity, 
duration, and causal relationship to the investigational products (IPs) are to be rated for 
all AEs. 
Statistical Methods: 
The focus of the statistical analysis will be the comparison with controls of the 
photoallergic response to the study products. The diagnosis of photosensitization 
response will be made by the Investigator based on review of the observed skin 
responses after Challenge. 
The mean score by subject and treatment, including all scores assigned during 
Induction, will be analyzed using Fisher’s least significant differences in the analysis 
of variance (ANOVA) with factors subject and treatment. All pairwise comparisons 
will be performed: MC2-01 Cream on both the irradiated and non-irradiated sites, and 
MC2-01 Vehicle on both the irradiated and non-irradiated sites. 
Number of Study 
Centers: 
Single Center 

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Clinical Study Protocol 
Investigators and study administrative structure  
Name 
Affiliation / Address 
Responsibility 
MC2 Therapeutics 
 
C/O: Agern Allé 24-26, 2970 Hørsholm, Denmark 
Sponsor 
TKL Research, Inc. 
 
 
TKL Research, Inc. 
One Promenade Blvd., Suite 1101/1201  
Fair Lawn, NJ 07410 
CRO 
Lærke K. Kyhl, MD 
MC2 Therapeutics 
C/O: Agern Allé 24-26, 2970 Hørsholm, Denmark 
 +45 29246928 
e-mail: lky@mc2therapeutics.com 
Senior Medical Adviser 
Birgitte Vestbjerg  
MC2 Therapeutics  
C/O: Agern Allé 24-26, 2970 Hørsholm, Denmark 
  +45 20772575 
e-mail:bve@mc2therapeutics.com 
Director Clinical 
Operation 
Jonathan S. Dosik, MD 
TKL Research, Inc.  
One Promenade Blvd., Suite 1201                                       
Fair Lawn, NJ 07410 
 (201) 587-0500, ext. 2562 
 (201) 773-7371 
e-mail: jdosik@tklresearch.com 
Principal Investigator 
Michael Tuley, PhD   
TKL Research, Inc.  
One Promenade Blvd., Suite 1201                                       
Fair Lawn, NJ 07410 
 (201) 587-0500, ext. 2608 
 (551) 497-6696 
e-mail: mtuley@tklresearch.com 
Senior Director, 
Biostatistics and Data 
Management  
Maureen Damstra 
TKL Research, Inc. 
One Promenade Boulevard, Suite 1201 
Fair Lawn, NJ  07410                           
 (201) 587-0500, ext.2229  
 (201) 773-7371 
e-mail: mdamstra@tklresearch.com 
Director of Clinical 
Studies 
Kathy Oneglia  
TKL Research, Inc. 
1 Promenade Boulevard, Suite 1201 
Fairlawn, NJ 07410 
 (201) 587-0500, ext.2526  
 (201) 773-7371 
e-mail: koneglia@tklresearch.com 
Associate Clinical 
Research Coordinator 
Allyson Marshall, PhD  
TKL Research, Inc.  
One Promenade Blvd., Suite 1201                                       
Fair Lawn, NJ 07410 
 (201) 587-0500, ext. 2522 
 (201) 296-66660 
e-mail: amarshall@tklresearch.com 
Sr. Medical Writer  

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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 .................................................................................................................................10 
List of Abbreviations .....................................................................................................................11 
1. 
INTRODUCTION ......................................................................................................12 
1.1.1. 
The MC2-01 Cream Formulation ...............................................................................12 
1.1.2. 
MC2-01 Cream – Non-clinical Data ...........................................................................13 
1.1.3. 
MC2-01 Cream – Clinical Data ..................................................................................13 
2. 
STUDY OBJECTIVES ..............................................................................................15 
3. 
INVESTIGATIONAL PLAN .....................................................................................16 
3.1. 
Study Design ...............................................................................................................16 
3.2. 
Discussion of Design ..................................................................................................17 
3.3. 
Study Population .........................................................................................................17 
3.3.1. 
Subject Population ......................................................................................................17 
3.3.2. 
Inclusion and Exclusion Criteria ................................................................................17 
3.3.3. 
Interruption or Discontinuation of Treatment .............................................................19 
3.3.4. 
Withdrawals ................................................................................................................20 
3.4. 
Treatments ..................................................................................................................21 
3.4.1. 
Investigational Products and Control ..........................................................................21 
3.4.2. 
Description of Investigational Products ......................................................................21 
3.4.3. 
Description of Patch Conditions .................................................................................22 
3.4.4. 
Packaging/Labeling ....................................................................................................22 
3.4.5. 
Assignment to Treatment ............................................................................................22 
3.4.5.1. 
Randomization ............................................................................................................22 
3.4.5.2. 
Blinding ......................................................................................................................23 
3.4.6. 
Prior and Concomitant Therapy ..................................................................................23 
3.4.7. 
Treatment Compliance ................................................................................................24 

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3.5. 
Visit Schedule and Assessments .................................................................................24 
3.5.1. 
Study Procedures and Visit Schedule .........................................................................24 
3.5.2. 
Visit Schedule .............................................................................................................28 
3.5.3. 
Definition of Minimal Erythemal Dose ......................................................................30 
3.5.4. 
Light source ................................................................................................................30 
3.5.5. 
Background Information .............................................................................................30 
3.5.6. 
Efficacy Assessments .................................................................................................30 
3.5.7. 
Safety Assessments .....................................................................................................30 
3.5.7.1. 
Patch Test Site Evaluations ........................................................................................30 
3.6. 
Adverse Events ...........................................................................................................32 
3.6.1. 
Method of Determining Adverse Events ....................................................................32 
3.6.2. 
Adverse Event Definitions ..........................................................................................33 
3.6.2.1. 
Adverse Events ...........................................................................................................33 
3.6.2.2. 
Serious Adverse Events ..............................................................................................33 
3.6.2.3. 
Severity of Adverse Events ........................................................................................34 
3.6.2.4. 
Relationship of Adverse Events to Study Treatments ................................................34 
3.6.3. 
Reporting Adverse Events ..........................................................................................35 
3.6.4. 
Adverse Event Follow-up ...........................................................................................35 
3.6.5. 
Pregnancy reporting ....................................................................................................35 
3.6.6. 
Expected Adverse Events ...........................................................................................36 
3.7. 
Instructions for Rapid Notification of Serious Adverse Events .................................36 
3.7.1. 
Safety Contact person and number .............................................................................36 
3.7.2. 
Reporting Responsibility ............................................................................................36 
3.7.3. 
Reporting procedures ..................................................................................................36 
3.8. 
Appropriateness of Safety Measurements ..................................................................37 
4. 
STATISTICAL METHODS .......................................................................................38 
4.1. 
General Considerations for Data Analysis .................................................................38 
4.2. 
Sample Size and Power Considerations .....................................................................38 
4.3. 
Subject Populations for Analysis ................................................................................38 
4.3.1. 
Background and Demographic Characteristics ..........................................................38 
4.3.2. 
Study Product/Visit Compliance ................................................................................38 

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4.4. 
Prior and Concomitant Medications ...........................................................................39 
4.5. 
Efficacy Evaluation ....................................................................................................39 
4.6. 
Safety Evaluation ........................................................................................................39 
4.6.1. 
Assessment of Responses ...........................................................................................39 
4.6.2. 
Photosensitivity...........................................................................................................39 
4.6.3. 
Adverse Events ...........................................................................................................39 
4.7. 
Other topics .................................................................................................................39 
4.8. 
Interim analyses ..........................................................................................................40 
4.9. 
Special Methods ..........................................................................................................40 
5. 
ADMINISTRATIVE PROCEDURES .......................................................................41 
5.1. 
Ethics and Good Clinical Practice ..............................................................................41 
5.2. 
Institutional Review Board .........................................................................................41 
5.3. 
Informed consent ........................................................................................................41 
5.4. 
Declaration of Helsinki ...............................................................................................42 
5.5. 
Changes in Planned Study Conduct ............................................................................42 
5.5.1. 
Protocol amendments ..................................................................................................42 
5.5.2. 
Other changes in study conduct ..................................................................................42 
5.5.3. 
Termination or suspension of study ............................................................................42 
5.6. 
Data handling and record keeping ..............................................................................43 
5.6.1. 
Recording of data ........................................................................................................43 
5.6.2. 
Retention of documents ..............................................................................................43 
5.7. 
Product handling and accountability ..........................................................................43 
5.8. 
Quality control and quality assurance .........................................................................44 
5.8.1. 
Monitoring procedures ................................................................................................44 
5.8.2. 
Auditing procedures ....................................................................................................44 
5.9. 
Confidentiality and publication policies .....................................................................44 
5.9.1. 
Disclosure and confidentiality ....................................................................................44 
5.9.2. 
Communication and publication of results .................................................................45 
6. 
REFERENCES ...........................................................................................................46 
 

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List of Tables 
Table 1: 
Fitzpatrick Skin Types ................................................................................................25 
Table 2: 
Visit Schedule and Assessments .................................................................................29 
Table 3: 
Response Scores .........................................................................................................31 
Table 4: 
Notations .....................................................................................................................31 
Table 5: 
Relationship of AE to Study Drug ..............................................................................35 
 
 

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List of Abbreviations  
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
API 
Active Pharmaceutical Ingredients 
B17P 
Betamethasone 17-Propionate 
BDP 
Betamethasone Dipropionate  
CAL 
Calcipotriene, Anhydrate  
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DMP 
Data Management Plan 
EEC 
European Ethics Committee 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
Investigational Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IEC 
International Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board  
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
MC2-01 
Calcipotriene/Betamethasone Dipropionate 0.005/0.064 w/w% 
MED 
Minimal Erythemal Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over-the-counter 
PAD™ 
Polyaphron Dispersion Technique 
PI 
Principal Investigator 
PMD 
Primary Medical Doctor 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOPs 
Standard Operating Procedures 
TEAE 
Treatment-emergent Adverse Event 
TKL 
TKL Research, Inc. 
UBC 
United BioSource Corporation 
UPT 
Urine pregnancy test 
US 
United States 
UV 
UVA 
UVB 
Ultraviolet 
Ultraviolet A 
Ultraviolet B 

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1. 
INTRODUCTION 
This study evaluates the potential of MC2-01 (Calcipotriene/betamethasone dipropionate 
0.005/0.064 w/w%) Cream to induce a photoallergic skin reaction using a controlled photopatch 
test design.  Because MC2-01 Cream 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 photoallergic reaction after application to the skin.   
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 
MC2-01 Cream contains two active pharmaceutical ingredients (APIs): the vitamin D3 analogue 
calcipotriene 0.005% as anhydrate (CAL) and the glucocorticosteroid betamethasone 0.064% as 
betamethasone dipropionate (BDP).  Use of the combination of vitamin D and corticosteroids for 
the treatment of plaque psoriasis has proven very effective and safe both for acute treatment and 
for long-term maintenance therapy.1,2  This combination is today approved in different 
formulation worldwide, including an ointment, a gel-topical suspension and a foam, under 
different brand names.  A combination of CAL/BDP is recommended by both European 
guidelines3-5, the Canadian Dermatology Association6, and by the American Academy of 
Dermatology7 as a first line treatment of mild to moderate plaque psoriasis.8   
This Phase I study will assess the photosensitization potential of MC2-01 Cream. 
1.1.1. 
The MC2-01 Cream Formulation 
The currently marketed products of this drug combination are restricted to non-aqueous oil-based 
formulations that are sticky and inconvenient to many patients9, as it has not previously been 
possible to co-formulate CAL and BDP in an aqueous formulation due to very different pH 
requirements for long-term stability of the two compounds.  
The MC2-01 Cream is an aqueous formulation designed for patient-friendly treatment of 
psoriasis vulgaris.  The cream has been developed using the Polyaphron Dispersion Technique™ 
(PAD™) Technology which protects the drug substances from degrading during storage.  The 
MC2-01 Cream is easy to apply, and the cosmetic appearance is that of a white, easily-
spreadable cream that absorbs completely into the skin a few minutes after application. 
The concentrations of CAL and BDP in the MC2-01 cream are identical to the concentrations in 
already-marketed CAL/BDP medicinal products, which have been found to be efficacious and 
safe.8  

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1.1.2. 
MC2-01 Cream – Non-clinical Data  
The safety profiles of topical applied CAL and BDP has, in numerous preclinical studies, been 
found benign.  The systemic absorption of CAL and BDP through intact skin of rats, minipigs, 
and humans from the marketed products is very small.  The main adverse local effects identified 
in non-clinical toxicology studies with topical products containing CAL and BDP are skin 
irritation due to the CAL component and skin atrophy due to the BDP component.  
In vitro skin penetration studies comparing MC2-01 Cream with the marketed Daivobet® 
Ointment (in US marketed as Taclonex® Ointment) and Daivobet® Gel (in US marketed as 
Taclonex® Topical Suspension) indicate that the transdermal penetration of CAL and BDP from 
the MC2-01 Cream is in the same range as that seen with Daivobet® Ointment and Daivobet® 
Gel.   
A 4-week local tolerance study conducted with MC2-01 Cream in minipigs showed that this 
formulation was well tolerated and without systemic effects.  There was no obvious difference 
with respect to the local skin tolerance between MC2-01 Cream and the reference Daivobet® 
Gel.  
In an 8-week study in minipigs, the toxicological profile, safety, as well as the pharmacokinetic 
profile of MC2-01 Cream and Daivobet® Ointment was investigated after daily applications on 
10% of the surface area of the animals.  None of the animals showed signs of systemic toxicity, 
and the study showed that the MC2-01 Cream had a higher local tolerance compared to 
Daivobet® Ointment.  Very few samples had quantifiable plasma concentrations of the parent 
compounds BDP and CAL.  The majority of animals had measurable levels of the BDP 
metabolite betamethasone 17-propionate (B17P), and the pre-dose plasma levels of B17P at Day 
22 were essentially similar between the two treatment groups.8  
1.1.3. 
MC2-01 Cream – Clinical Data  
The marketed formulations of the CAL/BDP combination are known as efficacious and safe 
drugs for the treatment of plaque psoriasis. According to the USPI for Taclonex® Topical 
Suspension, only a limited number of adverse reactions has been reported. There were no 
adverse reactions reported that occurred in ≥1% of subjects treated with Taclonex® Topical 
Suspension and at a rate higher than in subjects treated with vehicle. Similar safety profiles are 
reported with Taclonex® Ointment and Enstilar® Foam. 
Available data on MC2-01 cream suggest that MC2-01 cream displays a similar safety profile as 
the approved CAL/BDP topical products. A Phase 3 trial with MC2-01 cream has been 
completed. The Phase 3 trial including 794 subjects was a randomized, investigator-blind, 
multicentre, vehicle and comparator controlled, parallel-group, 3-arm trial, designed to show 
therapeutic non-inferiority of MC2-01 cream to Taclonex® Suspension in subjects with mild-to-
moderate psoriasis vulgaris. The primary objective of demonstration of non-inferiority of MC2-
021 compared to Taclonex® Suspension was met. The PGA treatment success was higher in the 
MC2-01 cream group (40.1% of subjects achieved treatment success; 95% CI 34.5, 45.6) 
compared with the active comparator group (24.0% of subjects achieved treatment success; 95% 
CI 19.0, 29.0). A subsequent post hoc analysis of treatment efficacy of MC2-01 cream compared 
to active comparator was performed on the PGA and other disease activity measures based on 

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the ITT population. The PGA treatment success rate was found to be statistically significantly 
higher in the MC2-01 cream group compared to the active comparator at Weeks 4 (24.18 vs. 
12.9, p=0.0001), Week 6 (32.95 vs. 20.16, p<0.0001), and Week 8 (37.38 vs. 22.75 p<0.0001). 
Similar statistical superiority of MC2-01 cream over Taclonex® Suspension was demonstrated 
for the modified PASI score (excluding the face). 
The type and incidence of AEs were as expected based on the known safety profile as the 
marketed products containing CAL/BDP at identical concentrations (w/w 0.005%/0.064%). 
The incidence of treatment emergent adverse events (TEAEs), related TEAEs, and lesional and 
lesional/perilesional AEs was low and comparable between MC2-01 cream and Taclonex® 
Suspension. TEAEs were most frequently reported in the SOC “infections and infestations” but 
with no difference in incidence between MC2-01 cream, Taclonex® Suspension, and vehicle. 
Furthermore, most of these TEAEs were judged not to be related to trial medication. Also, the 
incidence of TEAEs related to “General disorders and administration site reactions” were low 
and similar between the three trial arms. Finally, the trial did not indicate a significant effect of 
MC2-01 cream or Taclonex® Suspension on calcium homeostasis.  

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2. 
STUDY OBJECTIVES  
The primary objective of this study will be to determine the photoallergic potential of MC2-01 
Cream when topical application to healthy skin is followed by light exposure.   
In addition, safety will be assessed by evaluation of any AEs reported during the study. 

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3. 
INVESTIGATIONAL PLAN  
3.1. 
Study Design  
This will be a randomized, double-blind, single-center, controlled, within-subject comparison 
study of the investigational products (IPs), MC2-01 Cream, MC2-01 Vehicle, and an untreated 
irradiated control site in healthy volunteer subjects.  A total of 8 application sites (2 cm x 2 cm 
each) will be marked on the subject’s back and distributed so that 4 sites are on one side of the 
back for induction, and 4 sites are on the other side for challenge patches.  The IPs will be 
applied in two sets. One set of patches on the back will be designated for irradiation after 
approximately 24 hours (± 4 hours) of study product application and the other set will remain 
non-irradiated.  An additional site will be marked on the back during Challenge.  The site will 
receive no treatment but will be irradiated at Challenge to serve as an untreated irradiated 
control.   
A defined area (approximately 50 cm2) on the infrascapular region of each subject’s back will be 
irradiated to determine the minimal erythemal dose (MED) of ultraviolet (UV) light. 
During the 3-week Induction Phase of the study, 0.2 g of each study product will be applied to 
2 sites twice each week (Monday and Thursday) for approximately 24 hours (± 4 hours) under 
semi-occlusive patch conditions (6 applications).  After patch removal, all application sites will 
be evaluated, and one application site of each study product will be irradiated with 2 times the 
subject’s MED using the full Xenon lamp spectrum.  The sites will be evaluated by a trained 
evaluator.  All sites will be reevaluated post irradiation, at approximately 48 hours later when 
irradiated on Tuesdays and at approximately 72 hours later when irradiated on Fridays except 
when irradiated on the last Friday of the Induction Phase or after the last make-up visit (if 
required), the sites will not be evaluated because these readings are not used for determination of 
photosensitization and any response will have subsided by Monday.  These procedures will be 
performed each week for 3 weeks of the Induction Phase.  Dermal 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). 
 
At the end of the Induction Phase, the subjects will enter a Rest Period of 10-17 days and then a 
Challenge Phase.  One application/irradiation session may be missed during the Induction Phase.  
If a subject misses an irradiation session during the Induction Phase, an additional 
application/irradiation session will be scheduled the Monday of rest period (week 4).  
 
At Challenge, each study product will be applied in an amount of 0.2 g to 2 naive sites once for 
approximately 24 hours (±4 hours) under semi-occlusive patches.  After 24 hours (±4 hour) of 
product application, all sites will be evaluated, and one application site of each product and the 
additional untreated site will be irradiated.  The sites will be examined for dermal reactions at 
approximately 24 hours (±4 hours), 48 hours (±4 hours), and 72 hours (±4 hours) 
post-irradiation.  A Rechallenge should be performed if a cutaneous response observed during 
the Challenge Phase indicates possible photosensitization or at the discretion of the Investigator.   
The safety endpoints for this study are irritation responses during the Induction Phase, positive 
responses at Challenge (ie, reactions indicative of a sensitization response) and AEs.   

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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.  These working criteria are periodically reviewed and 
amended subject to new information that becomes available. 
This photoallergy study is designed to detect the ability of the MC2-01 Cream and MC2-01 
Vehicle to cause photoallergic skin reactions when exposed to sunlight.  Each subject is to 
receive applications of the MC2-01 Cream and MC2-01 Vehicle to 2 separate sites.  One will be 
irradiated, and one will remain non-irradiated. An untreated site will also be irradiated at 
Challenge.  This design provides built-in controls for the test product (MC2-01 Cream) under 
both irradiated and non-irradiated conditions. 
3.3. 
Study Population 
3.3.1. 
Subject Population 
A sufficient number of subjects will be enrolled in order to provide 50 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. Agree not to participate in any clinical or patch test studies at Day 1 through study 
completion; 
4. Females of childbearing potential must use a highly effective method of contraception 
(ie, a method with a failure rate of less than 1% per year when used consistently and 
correctly) for one month prior to Screening and until the end of study (EOS) visit has 
been performed.  Highly effective contraception is defined as follows:  
a. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibitor of ovulation (oral, injectable, implantable, transdermal, intravaginal) 
b. Intrauterine device (IUD) 
c. Intrauterine hormone-releasing system (IUS) 
d. Bilateral tubal occlusion  
e. Vasectomized partner (Provided that is the sole sexual partner of the subject and that 
the vasectomized partner has received medical assessment of the surgical success) 

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f. Sexual abstinence (if in line with the preferred and usual lifestyle of the subject and 
defined as refraining from heterosexual intercourse during the entire period of the 
trial 
*Periodic methods of abstinence (e.g. calendar, ovulation, symptothermal, post ovulation 
methods) are not accepted methods of contraception). 
5. In the case of a female of childbearing potential, has a negative urine pregnancy test 
(UPT) on Day 1 prior to randomization and are willing to submit to a UPT at the EOS; 
6. In the case of a female of non-childbearing potential, has had a hysterectomy or is 
postmenopausal (at least 1 year with no menses prior to enrollment); 
7. 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; 
8. Has uniformly-colored skin on the infrascapular region of the back which will allow 
discernment of erythema, and has Fitzpatrick Skin Types I, II, or III (see Table 1); 
9. Complete a medical screening procedure; and 
10. 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. Current or past history of hypercalcemia, vitamin D toxicity, severe renal insufficiency, 
or severe hepatic disorders; 
4. 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; 
5. 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); 
6. Are taking medication known to cause phototoxic reactions (eg, tetracyclines, thiazides, 
nonsteroidal anti-inflammatory drugs [NSAIDS]); 
7. 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); 
8. Is unwilling or unable to refrain from the use of sunscreens, cosmetics, creams, 
ointments, lotions or similar products on the back during the study; 
9. Has psoriasis and/or active atopic dermatitis/eczema; 
10. Has a known sensitivity or allergy to constituents of the materials being evaluated; 

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11. Is a female who is pregnant, plans to become pregnant during the study, or is breast 
feeding a child; 
12. 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; 
13. Has received treatment for any type of internal cancer within 5 years prior to study entry; 
14. Has a history of, or are currently being treated for skin cancer and/or hepatitis; 
15. Has a history of, or is currently being treated for diabetes; 
16. Has any condition that might compromise study results; 
17. Is  expected to sunbathe or use tanning salons during the study; 
18. Has a history of adverse response (eg, blistering, sun poisoning) to UV sun 
lamps/sunlight exposure; 
19. Is currently participating in any clinical testing; 
20. Has any known sensitivity to adhesives; and/or 
21. Has received any investigational drug(s) within 28 days from Day 1. 
3.3.3. 
Interruption or Discontinuation of Treatment  
A reaction of at least moderate erythema (2) accompanied with mild, but definite edema (1) to a 
study product observed after the first patch application/irradiation sequence of the Induction 
Phase may indicate the subject to be pre-sensitized and may cause the discontinuation of the 
subject from the study. 
After the second reading of the Induction Phase, either of the following conditions will require 
that the study product be applied to a naïve patch site under open patch conditions: 
 Reaction of >50% “p” or “p” with no erythema, mild but definite erythema, moderate or 
severe erythema; or “D” (see Table 3 and Table 4); 
 Any reaction of definite erythema (mild, moderate or severe) with definite edema. 
Study product may not be relocated more than twice.   
If the reactions noted above occur on an irradiation day during the Induction Phase, the sites will 
not be able to be irradiated.  Patches will be relocated at the subject’s next visit.     
The 3 weeks of continuous patch contact during the Induction Phase frequently results in 
tape-related irritation that is exacerbated by warm weather, but which occurs among some 
individuals irrespective of the season.  Tape-related irritation will not be graded as a 
photosensitivity response at the patch site but will be noted separately on the case report form 
(CRF).  Severe tape-related irritation will necessitate a change in the application site.  As above, 
the application site will only be changed twice and then the subject must be discontinued. 
One application/irradiation session may be missed during the Induction Phase. In case of a 
missed application/irradiation, an additional application/irradiation during Week 4 must be 

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performed.  In this case, no evaluation will be required following irradiation.  Only one missed 
patch application or irradiation is allowed.  A subject must be discontinued and considered not 
complete if more than one application or irradiation is missed. 
In accordance with legal requirements and ICH-GCP guidelines, every subject 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 CRF.  
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 withdraws from the study, all efforts will 
be made to complete a final evaluation if possible. Subjects experiencing 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. 
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 PI.  
• 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  

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•
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 PMD.  The specific AE in question will be recorded on the appropriate CRF. 
3.4. 
Treatments 
3.4.1. 
Investigational Products and Control 
Investigational Products: 
MC2-01 Cream 
MC2-01 cream contains 0.005% w/w CAL (as anhydrate) and 0.064% w/w% BDP and is filled 
in sealed, collapsible aluminum tubes as primary packaging material.  The MC2-01 cream 
formulation contains 70% oil and 30% aqueous external phase at approximately neural pH.  The 
oil fully solubilizes the drug substances and provides semi-occlusiveness important for skin 
penetration, while the aqueous external phase contributes to the skin feel.  The cosmetic 
appearance is a white easily spreadable cream with high oil content that absorbs completely into 
the skin within few minutes of application.8 
MC2-01 Vehicle 
MC2-01 Vehicle contains no active components. 
MC2-01 Cream and MC2-01 Vehicle will each be applied in an amount of 0.2 g to 2 sites (2 cm 
x 2 cm) on the infrascapular area of the subjects’ backs for 24 hours (±4 hours) under semi-
occlusive patch conditions (Webril®).  The patches will be secured to the skin with airtight 
nonporous Blenderm® tape.  This will be repeated twice each week during the 3-week Induction 
Phase, once on Monday during rest week 4 as applicable (if a subject misses a visit and doesn’t 
apply the IPs) and once at Challenge.  One application site of each study product will be 
irradiated and the other will remain non-irradiated. 
Lot numbers will be given in the clinical study report. 
Manufacturer: DPT Laboratories, Ltd. 
307 E. Josephine St. 
San Antonio, Texas 78215 
Control 
An untreated irradiated site will serve as a control. 
3.4.2. 
Description of Investigational Products 
The IPs (MC2-01 Cream and MC2-01 Vehicle) will be supplied in collapsible aluminum tubes 
for the clinical study. MC2-01 Cream and MC2-01 Vehicle were manufactured and packaged in 
accordance with good manufacturing practice (GMP).   

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3.4.3. 
Description of Patch Conditions  
Material evaluated under semi-occlusive patch conditions is applied to a 2 cm x 2 cm Webril® 
pad.  The pad is affixed to the skin with hypoallergenic tape (Micropore). 
Material evaluated under open (non-occlusive) conditions is applied directly to a 2 cm x 2 cm 
area of the skin, which is then loosely covered by gauze secured on 2 sides with Micropore tape. 
3.4.4. 
Packaging/Labeling  
The study product tubes labels will contain, at a minimum, the following information: 
• Name and address of the Sponsor  
• Protocol number 
• Name and address of manufacturer  
• Date of manufacture  
• Lot / batch number  
• Tube contents   
• Storage conditions  
• Caution statements: 
−  “New Drug – Limited by Federal Law to Investigational Use” 
−  “Flammable” 
− “Keep out of reach of children” 
A full product description can be found in the Investigator’s Brochure (IB).8 
MC2-01 Cream and MC2-01 Vehicle must be stored at 2°-8°C (36°-46°F) in a temperature-
controlled cabinet at the clinical site.  MC2-01 will not be dispensed to individual subjects during 
this clinical study but may be stored at temperatures below 25°C (77°F) during the product 
application visits.  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.   
3.4.5. 
Assignment to Treatment  
3.4.5.1. 
Randomization 
Each subject who signs an informed consent form (ICF) will be assigned a screening number.  If 
the subject meets all of the inclusion and none of the exclusion criteria, and successfully 
completes the screening procedures, they will be enrolled in the study.  Upon enrollment, each 
subject will be assigned a unique subject number and receive a randomization code, indicating 
application placement of the study materials.  Each subject in this study will serve as his or her 
own control.  All subjects will receive MC2-01 Cream and MC2-01 Vehicle at adjacent 
application sites, i.e. study product placement on the left side will be the same as on the right 
side. 

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The MC2-01 Cream and MC2-01 Vehicle will be assigned in a randomized sequence to the test 
sites. The same study material will be applied to the same test site throughout the Induction 
Phase and to a naïve site at Challenge and Rechallenge Phases (if applicable).   
3.4.5.2. 
Blinding 
The treatments (MC2-01 Cream and MC2-01 Vehicle) will not be blinded to investigative 
personnel involved in the preparation/application and removal of treatments.   
Investigative personnel who are involved in the preparation/application and removal of the 
treatments will be unblinded and will not perform the evaluation of skin responses.  The subjects 
and 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 who are blinded, including the Investigator and 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; 

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• There will be no use of medication known to cause phototoxic reactions (e.g., 
tetracyclines, thiazides, 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); 
• 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.8 
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. 
If individual patches become dislodged or are misplaced, such that continuous contact with the 
skin has been interrupted, the subject will be discontinued from further participation in the study.   
3.5. 
Visit Schedule and Assessments  
3.5.1. 
Study Procedures and Visit Schedule 
 
 

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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) 
• 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 burns, deeply pigmented10, 11 
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 of the inclusion and none of 
the exclusion criteria, he/she will be allowed participation in the study.  Concomitant 
medications and AEs will be reviewed and recorded at this visit. 
Upon enrollment, each subject will be assigned a unique subject number and receive a 
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 planned on each subject’s back.  Prior to 
patching, sites will be marked with site numbers.   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 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.  The duration of UVA/UVB irradiation for minimal 

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erythema dose (MED) exposure will be calculated based on subjects’ Fitzpatrick Skin Type and 
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. Each of the sites will be 
irradiated with full spectrum UV light (UVA/UVB), with each exposure differing from the next 
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).12 
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 2.12 
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 
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). 
Induction 
The Induction Phase consists of a series of 6 patch applications of the study products (twice a 
week [Monday and Thursday] and subsequent irradiation [Tuesday and Friday] and evaluations 
of the patch test sites [Thursday and Monday]) over a 3-week Induction Phase.   
Under semi-occlusive conditions, 0.2 g of each study product, MC2-01 Cream and MC2-01 
Vehicle will be applied to two Webril® patches. The patches will then be applied to their 
assigned sites on the back for Induction for 24 hours (±4 hours).  This process will be repeated 
twice each week (Mondays and Thursdays) during the 3-week Induction Phase.  The patches will 
be secured to the skin with airtight nonporous Blenderm® tape.  The same study product will be 
applied to the same test site throughout the Induction Phase.   
Application sites will be evaluated immediately prior to study product application. 
After 24 hours (±4 hours) of study product application (eg, Tuesday and Friday), all patches will 
be removed.  The sites will be evaluated using the scoring system detailed in Section 3.5.7.1.  
One set of patches will be assigned for irradiation and the other will remain non-irradiated, ie, 
only one application site of each study product will receive irradiation.  On all Tuesdays and 
Fridays, the sites designated for irradiation will be irradiated with 2 times the subject’s MED 
using the full Xenon lamp spectrum.   
Adverse events and concomitant medications will be reviewed at each visit and recorded as 
applicable.  
One application/irradiation session may be missed during the Induction Phase.  If a subject 
misses an irradiation session during the Induction Phase, an additional application/irradiation 
session will be scheduled the Monday of rest period (week 4).  
Rest Period (Weeks 4 and 5) 
During the Rest Period of approximately 10-17 days, subjects will not receive any application of 
study materials. An additional application of study product may be applied on the Monday of the 

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rest period (week 4) if the subject misses an irradiation session during the Induction Phase of the 
study. 
Challenge (Week 6) 
On Day 1 of the Challenge Phase, subjects who have completed the Induction Phase and the Rest 
Period will have study product applications to naïve sites in the same manner as applied during 
the Induction.  As in the Induction Phase, 0.2 g of MC2-01 Cream and MC2-01 Vehicle will 
each be applied to 4 assigned sites for Challenge for approximately 24 hours (±4 hours) under 
semi-occlusive patch conditions.  A baseline evaluation of the naïve 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. The clinical staff will 
then remove the patches and a trained evaluator will evaluate the test sites.  The designated sites 
and an additional untreated site will be irradiated with 6 J/cm2 of UVA (320-400 nm) followed 
by 0.5 times the MED of UVA/UVB (full-spectrum) irradiation, obtained by using a filtered light 
source (see Section 3.5.4).  Each site will be evaluated again at approximately 24 hours 
(±4 hours), 48 hours (±4 hours), and 72 hours (±4 hours) post irradiation.   
Adverse events and concomitant medications will be reviewed at each visit and recorded as 
applicable.   A UPT will be performed for female subjects of childbearing potential at the last 
study visit (if rechallenge is not required). 
Rechallenge  
A Rechallenge should be performed if a cutaneous response observed during the Challenge 
Phase indicates possible photosensitization or at the discretion of the Investigator.  If it is 
determined by the Investigator that a Rechallenge should be performed, the Rechallenge patches 
will be applied as soon as Challenge reactions have resolved.  Just as in the Challenge procedure 
0.2 g of each study product MC2-01 Cream and MC2-01 Vehicle will each be applied to 4 naïve 
sites for approximately 24 hours (±4 hours) using appropriate patches to further discriminate a 
photosensitization reaction from an irritation reaction.  A baseline evaluation of the naïve 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. 
Approximately twenty-four (24) hours (±4 hours) after study product application, the clinical 
staff will remove the patches and a trained evaluator will evaluate the test sites.  One site of each 
product and an additional untreated site will be irradiated with full spectrum UV light 
(UVA/UVB) using a filtered light source.  All sites (irradiated and non-irradiated) will be graded 
for dermal reactions at approximately 24 hours (±4 hours), 48 hours (±4 hours), and 72 hours 
(±4 hours) following irradiation.  Concomitant medications and AEs will also be reviewed. A 
UPT will be performed for female subjects of childbearing potential at the last study visit. 
End of Study  
At the EOS, all patches will be removed as described above, and the final evaluations of the test 
sites will be made.   
An EOS examination will be conducted and consist of the following: 
• Concomitant medication 

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• AEs 
• UPT in females of childbearing potential 
Concomitant medications and AEs will be reviewed and recorded during the whole study.  For a 
detailed listing of scheduled study time points refer to the Visit Schedule and Assessments 
(Table 2). 
3.5.2. 
Visit Schedule  
A summary of the visit schedule and assessments is presented in Table 2.  

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Table 2: 
Visit Schedule and Assessments  
Treatment Period 
 
Screening 
 
Day 
1a 
(M) 
Induction 
(Weeks 1-3) 
Rest 
(Weeks 
4-5) 
Challenge  
(Week 6) 
Study Days 
 
 
M 
 
8, 
15 
Tu 
2, 
9, 
16 
Th 
4, 
11, 
18 
F 
5. 
12, 
19 
 
M 
36 
Tu 
37 
W 
38 
Th 
39 
F 
40 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
Fitzpatrick Skin 
Typing 
X 
 
 
 
 
 
 
 
 
 
 
 
UPT 
 
X 
 
 
 
 
 
 
 
 
 
X 
MED 
irradiation/evaluation 
 
Xb 
 
Xc 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Product application  
 
X 
X 
 
X 
 
 
X 
 
 
 
 
Application site 
evaluations 
 
X 
X 
X 
X 
Xd 
 
X 
X 
X 
X 
X 
Application site 
irradiation  
 
 
 
X 
 
Xd 
 
 
X 
 
 
 
Untreated control site 
irradiation 
 
 
 
 
 
 
 
 
X 
 
 
 
Make-up evaluation/ 
application 
 
 
 
 
 
 
Xe 
 
 
 
 
 
Make-up evaluation/ 
irradiation 
 
 
 
 
 
 
Xe 
 
 
 
 
 
Review of 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
Xf 
X 
X 
X 
X 
X 
Review of AEs 
X 
X 
X 
X 
X 
X 
Xf 
X 
X 
X 
X 
X 
a  Screening and the first day of Induction (Day 1) may take place on the same day. 
b MED irradiation on Day 1. 
c MED evaluation on Day 2. 
d  Evaluations will not be conducted after irradiation on the last Friday of the Induction Phase.   
e Make-up evaluation/application and evaluation/irradiation are performed as necessary (see Section 3.5.1). 
f 
Concomitant medications and AEs will be reviewed only for subjects who are required to return to the test 
facility for make-up visits during Rest Period - Week 4.   
Note:  The visit schedule may be revised if necessary. 

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3.5.3. 
Definition of Minimal Erythemal Dose 
Minimal erythemal dose 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 UVA/UVB (full spectrum) irradiation as part of its emission spectrum.12 
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).12  An additional filter is added 
during irradiation of the 6 J/cm2 of UVA (320-400 nm) to the test 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. 
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 
For both Induction and Challenge Phases, after 24 hours (±4 hours) of product application, all 
sites will be evaluated, and one application site of each product and the additional untreated site 
will be irradiated.  The sites will be examined for dermal reactions at approximately 24 hours, 48 
hours, and 72 hours post-irradiation.   
The scores in Table 3 will be used to express the response observed at the time of examination 
and will be recorded on the subjects’ CRFs.  The score will be used for statistical analysis.  
Additional response notations are presented in Table 4. The same evaluator (where possible) 
should perform the assessment throughout (from Induction to Rechallenge) the study. 

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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 
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 
 
The readings will be made under a standardized white light source.   
The 3-week period of patch contact during the Induction Phase may result in tape-related irritation 
in some individuals.  Tape related irritation will not be graded as an irritant response at the patch 
site but will be noted separately on the CRF. 

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The Investigator will assess the reactions seen during the Challenge Phase and determine 
whether the subject is photosensitized or not.  The following guidelines are generally considered 
in this assessment.  Not all observations of erythema and edema are associated with 
photosensitivity; only if erythema and edema are observed can a reaction be suspected of being a 
positive photosensitivity reaction.  An increase in the intensity of the reaction over time further 
supports an assessment of photosensitivity.  If reactions are observed at both the irradiated and 
non-irradiated study product sites (ie, if contact sensitization may have occurred), the reaction at 
the irradiated site upon Rechallenge must be at least one grade more intense than at the 
non-irradiated site for the reaction to be suspected of being a photosensitivity reaction (refer to 
Section 3.5.7.1 for response scores and notations).   
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.  Adverse events will be collected during the period from the time of the 
signature of the informed consent form and first trial-related activity performed until the end of 
the trial.  Adverse events 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.   
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 other than those permitted in the inclusion criteria;  
• 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). 

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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 IP, whether or not 
considered related to the medicinal IP.   
Any AE that is considered related to the IP must be followed by the investigator until it is resolved 
or until the medical condition of the subject is stable; all relevant follow-up information will be 
reported to MC2 or designee. Adverse Events will be coded using the 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 study 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, 
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. 
The outcome of an AE will be classified as recovered, recovered with sequelae, 
recovering/resolving, ongoing, or death.  
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). 

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• 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 
The Investigator is to classify the severity (intensity) of an AE according to the following 
definitions: 
• Mild – The subject was aware of the signs and symptoms, but the signs and 
symptoms were easily tolerated and do not interfere with daily activity. 
• Moderate – The signs and symptoms were sufficient to restrict, but did not prevent, 
usual daily activity for the subject. The subject is still able to function.  
• Severe – The subject was unable to perform usual daily activity. 
The maximum intensity of an AE (mild, moderate, or severe) will be assessed taking into 
account the possible range of intensity of the symptom(s). 
3.6.2.4. 
Relationship of Adverse Events to Study Treatments 
The Investigator is responsible to assess the relationship of an AE to the IP treatment using good 
clinical judgment and definitions outlined in Table 5.  

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Table 5: 
Relationship of AE to Study Drug  
Association 
Definition 
Not related 
The AE is clearly explained by another cause not related to the IP administration; the 
temporal relationship of the AE to IP administration makes a causal relationship unlikely, 
or, concomitant medication, therapeutics interventions, or underlying condition provide a 
sufficient explanation for the observed AE 
 
 
Possibly Related  
The AE and administration of IP are temporally related, but the AE can be explained 
equally well by causes other than the IP administration 
 
 
Probably Related 
The AE and use of IP are temporally related, and the AE is more likely explained by IP 
administration than by other causes 
 
 
Definitely Related 
The AE and IP administration are related in time, and a direct association can be 
demonstrated. Concomitant medication, therapeutics interventions, or underlying 
conditions do not provide a sufficient explanation for the observed AE 
3.6.3. 
Reporting Adverse Events 
Adverse events that occur from the time of informed consent through completion of the last 
study visit should be reported.   
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 
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.  

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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.  
Pregnancy follow-up 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.   
3.6.6. 
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.   
3.7. 
Instructions for Rapid Notification of Serious Adverse Events 
3.7.1. 
Safety Contact person and number 
Serious adverse events and pregnancies must be reported immediately (i.e., not later than 24 
hours after first knowledge).  The SAE or pregnancy report should be e-mailed or faxed to 
United BioSource Corporation (UBC) using the following e-mail or fax-number: 
Email: EUSafety@ubc.com 
Fax: +41 225 964 446 
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 
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 

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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 photoallergic 
response to the study products.  The diagnosis of photosensitization response will be made by the 
Investigator based on review of the observed skin responses after Challenge. 
The mean score by subject and treatment, including all scores assigned during Induction, will be 
analyzed in the analysis of variance with factors subject and treatment. All pairwise treatment 
comparisons will be performed.  
The statistical analyses described below will be supplemented by a comprehensive SAP which 
will be finalized before the database is locked.  Any changes to the statistical plans will be 
described and justified in the final report. 
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 50 evaluable subjects conforms to industry and regulatory standards for 
determination of irritation/sensitization 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 analysis of local tolerability 
(photoirritation) will be based off all subjects who complete the Induction Phase of the study. 
Subjects who completed Induction are those who have received at least 6 applications/irradiation 
of study products, and at least 11 subsequent evaluations during Induction. The evaluation of 
photosensitization will be based on all subjects who complete the Challenge Phase of the study.  
Subjects who completed Challenge are those who have received at least 6 applications/irradiation 
of study products, and at least 11 subsequent evaluations during Induction, completed the Rest 
Phase and have received one application of study products at Challenge, subsequent irradiation 
and complete the 3 post-irradiation evaluations for that product.   
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. 

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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. 
Assessment of Responses 
All assigned scores during Induction and Challenge will be summarized by frequency counts by 
time point and treatment.  The incidence of reactions will be summarized by frequency counts 
for each treatment. The mean score by subject and treatment, including all scores assigned during 
Induction, will be analyzed using Fisher’s least significant differences in the analysis of variance 
(ANOVA) with factors subject and treatment. All pairwise comparisons will be performed: 
MC2-01 Cream on both the irradiated and non-irradiated sites, and MC2-01 Vehicle on both the 
irradiated and non-irradiated sites. 
4.6.2. 
Photosensitivity 
The determination of dermal photosensitization potential will be made by the Investigator based 
on specific scoring criteria derived from observations in the Challenge Phase of the study and 
confirmed in the Rechallenge Phase, if necessary. The incidence of photosensitization reactions 
will be summarized by frequency counts for each treatment.  If photosensitization occurs, the 
95% confidence interval for the proportion of subjects with photosensitization for each product 
will be calculated.  Photosensitivity will not be determined by statistical methods.   
4.6.3. 
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 adverse events (TEAEs) 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, possibly related, probably related, and definitely related).   
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. 

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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’s 
SOPs.  These are designed to ensure adherence to GCP guidelines, as described in:  
• ICH Harmonized Tripartite Guidelines for GCP 1996.  Directive 91/507/European 
Ethics Committee (EEC), The Rules Governing Medicinal Products in the European 
Community. 
• United States (US) 21 Code of Federal Regulations (CFR) dealing with clinical 
studies (including parts 50 and 56 concerning informed consent and IRB/International 
Ethics Committee (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 or designee must explain to each subject 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. 
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 Sponsor 
before submission to the IRB and a copy of the approved version must be provided to Sponsor 
after IRB approval. 

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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 Sponsor 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 Sponsor.  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. 
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 

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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 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, 
• date(s) of the study product dispensed to the subject, and 
• initials of the study site representative(s) dispensing study product. 

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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.  Subject confidentiality will be maintained at 
all times and consent for this will be obtained before entry of the subject 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. 
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 

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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.   
Sponsor 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. 
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