Clinical trial NCT03758365
Conditions: Vasoconstriction
Sponsor: MC2 Therapeutics
Start date: 2018-11-05; Completion date: 2018-11-23
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this trial is to compare the vasoconstriction potential

Detailed description:
The objective of this trial is to compare the vasoconstriction potential (skin blanching effect) of MC2-01 cream with 5 comparators and MC2-01 vehicle using the human skin blanching test (McKenzie-Stoughton's test).

Arms: arm 1: Single application of MC2-01 (calcipotriene/betamethasone dipropionate, w/w 0.005%/0.064%) cream arm 2: Single application of Clobetasol propionate 0.05%, arm 3: Single application of Betamethasone dipropionate 0.05%, arm 4: Single application of Triamcinolone acetonide 0.1%, arm 5: Single application of Hydrocortisone Butyrate 0.1% Cream arm 6: Single application of Desonide 0.05% arm 7: Single application of Vehicle
Interventions: intervention 1: MC2-01 Cream intervention 2: Clobetasol Propionate 0.05% Lotion intervention 3: Betamethasone Dipropionate 0.05% Cream intervention 4: Triamcinolone Acetonide 0.1% Cream intervention 5: Hydrocortisone Butyrate 0.1% Cream intervention 6: Desonide 0.05% Cream intervention 7: Vehicle
Intervention descriptions: intervention 1: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation intervention 2: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation intervention 3: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation intervention 4: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation intervention 5: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation intervention 6: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation intervention 7: Single application, visual evaluation of skin blanching and local tolerability, physical examination and safety evaluation

Protocol documents:
Prot_000.pdf: 
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1 TITLE PAGE 
CLINICAL TRIAL PROTOCOL 
A RANDOMISED, EVALUATOR BLINDED, WITHIN SUBJECT, SINGLE-CENTRE EVALUATION OF THE 
VASOCONSTRICTION PROPERTIES OF MC2-01 CREAM, COMPARED TO 5 OTHER 
CORTICOSTEROIDS IN HEALTHY SUBJECTS 
 
Eudract number: 2018-001673-24 
 
Sponsor Trial Code: MC2-01-C4 
CPCAD number: CPC-3530 
Final Approved Version 20 August 2018 
 
SPONSOR: 
Dorte ALMSTRUP 
Clinical Project Manager 
Drug Delivery Solutions Aps (DDS) 
c/o MC2 Therapeutics A/S 
Agern Allé 24-26  
DK-2970 Hørsholm,  
Denmark 
Tel  : +45 61.60.63.00  
dal@mc2therapeutics.com 
INVESTIGATOR:  
Dr Catherine QUEILLE-ROUSSEL, MD 
Investigator 
Centre de Pharmacologie Clinique Appliquée 
à la Dermatologie, C P C A D  
Hôpital L'Archet 2 
151, route de St Antoine  
BP 3079, 06202 NICE Cedex 3 - France 
Tel : +33 492.03.62.40  
Fax : +33 492.03.62.39 
catherine.queille-roussel@skinpharma.fr 
 
This Trial Protocol is the property of the sponsor (DDS Ltd) and is a confidential document. It is not 
to be copied or distributed to other parties without written approval from sponsor. 
 


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2 CLINICAL TRIAL PROTOCOL APPROVAL 
The following persons have approved this Clinical Trial Protocol, on behalf of DDS, by manually signing in the 
Table below: 
Name & Title 
Date & Signature 
Johan SELMER, MD 
 
VP Medical Affairs 
 
 
 
 
 
 
It is the responsibility of the Investigator to approve the Clinical Trial Protocol comprising any subsequent 
amendment(s).  
The Principal Investigator has approved this Clinical Trial Protocol by manually signing in the Table below: 
Name & Title 
Date & Signature 
Catherine QUEILLE-ROUSSEL, MD 
 
Investigator 
 
 
 
 
 
 
 


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3 TRIAL SYNOPSIS 
Clinical Trial Title: A Randomized, Evaluator Blinded, Within Subject, Single-Centre evaluation of the 
Vasoconstriction Properties of MC2-01 cream, compared to 5 Other Corticosteroids in Healthy Subjects.  
Short Title : 
A vasoconstriction test trial with a MC2-01 cream (ranking trial). 
Sponsor Trial Number:  
MC2-01-C4 
Clinical Trial Phase:  
Phase 1 
Investigator:  
Dr Catherine QUEILLE-ROUSSEL 
Co-Investigator:  
Dr Bernard WAVRANT 
Clinical Trial Population:  
Healthy subjects, males and females, aged 18 to 50 years old. 
Clinical Trial Objectives:  
The objective of this trial is to compare the vasoconstriction potential (skin 
blanching effect) of MC2-01 cream with Clobex 0.05% (clobetasol propionate) 
lotion,   Betamethasone Dipropionate  (Augmented)  0.05% (betamethasone 
dipropionate) cream, Triamcinolone Acetonide 0.1% (triamcinolone acetonide) 
cream, Locoid® 0.1% (hydrocortisone butyrate) cream, Desowen® 0.05% 
(desonide) cream and MC2-01 vehicle using the human skin blanching test 
(McKenzie-Stoughton’s test). 
Background: 
Topically applied corticosteroids elicit a pharmacologic activity (blanching) 
viewed by many as being "vasoconstrictive" in nature. The skin blanching effect 
was first described by Mc Kenzie and Stoughton (1) in 1962. This 
pharmacodynamic response has been correlated with the clinical efficacy of the 
product in psoriasis (2) and used for years to determine the clinical potency of 
topical corticosteroid formulations and to classify them within the US topical 
steroid potency classification. 
MC2 Therapeutics has developed an innovative dermal pharmaceutical 
formulation containing calcipotriol (CAL) 0.005 % w/w (50 µg/g) and 
betamethasone dipropionate (BDP) 0.064 % w/w (0.5 mg/g as betamethasone), 
MC2-01 cream to ease local application of pharmaceuticals and to significantly 
enhance local cutaneous penetration of the active ingredients. 
Currently marketed products are restricted to non- oil-based formulations as 
calcipotriol and betamethasone are characterized by having a potential 
incompatibility to exist together in an environment, since calcipotriol requires 
basic conditions to maintain stability while betamethasone requires acidic 
conditions. 


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MC2-01 cream has been formulated using the PAD™ Technology allowing 
sufficient protection of the drug substances from degradation during storage.  
Clinical Hypothesis: 
The blanching effect of the MC2-01 cream is expected to be lower than Clobex, 
not significantly different from Betamethasone Dipropionate (Augmented) 
cream and higher than the other references.  
Clinical Trial Design:  
A single center, single application, randomized, investigator blinded, active and 
vehicle controlled, intra-individual comparison in healthy volunteers.  
The subjects will be screened within 2 weeks prior to the Day 1 and then receive 
a single application of investigational and reference products. All applications 
will be done on site by a qualified person. The Investigational products will be 
tested under non-occlusive condition for 16 hours.  
Clobex lotion (Galderma Labs LP),  Betamethasone Dipropionate (Augmented) 
cream (Taro Pharmaceuticals), Locoid cream (Precision dermatology), 
Desowen® cream (Galderma Labs LP) and Triamcinolone Acetonide (Ascend 
Laboratories LLC) will be used as positive controls. The MC2-01 matching 
vehicle will be used as negative control. 
Hence, the seven treatments will be randomly allocated to seven test sites of 
2.2 cm diameter on the anterior surface of the forearms (from the antecubital 
fossa to the wrist).  
The skin blanching will be assessed by visual scoring. 
Methodology: 
The trial will consist of a screening phase, a test phase of 2 days, and, if 
applicable, a follow-up phase. 
Screening Phase (Day-15 to Day-1): 
Within 15 days before treatment a screening visit for trial eligibility of the 
subjects will take place: 
Medical history and concomitants therapies 
Physical examination, record of vital signs  
Urine pregnancy test for female subjects of child-bearing potential 
Check of inclusion/exclusion criteria 
Pre-test of blanching response 
 
Test Phase (Day 1 to Day 2): 
Subjects will receive investigational and reference products (matching vehicle 
and positive references) on Day 1.  
 
 


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At Day 1: 
Will be performed: 
  
- 
Re-check of inclusion/exclusion criteria 
- 
Urine pregnancy test for female subjects of child-bearing potential 
- 
Selection of seven tests sites 
- 
Application of the products under non-occluded conditions for 16 
hours. 
 
At Day 2: 
- 
Removal of the products 
- 
Visual assessments of the skin blanching by 2 trained observers 2 hours 
after the removal. 
- 
Assessment of the local tolerability. 
During the treatment phase local and systemic adverse events will be reported 
on an ongoing basis. 
Follow-up: 
If an adverse event (serious or non-serious), classified as reasonable possible 
related to the trial medication is ongoing at the subject’s last visit, a follow-up 
visit/contact will take place 14 (±2) days after that visit.  
Total number of subjects 
(Planned):  
60 subjects will be screened in order to have 36 subjects randomized and at 
least 30 subjects completed.  
Number of clinical trial centers 
(Planned):  
Single center 
Region / country involved 
(Planned):  
France 
Clinical trial duration:  
2 months 
Duration of subject 
participation:  
 
Two days (plus the screening period and the follow-up phase). 


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Inclusion criteria: 
 
1. 
Male or female subjects, aged 18 years to 50 years old, having signed 
and dated an informed consent, 
2. 
Non-smoker subjects, 
3. 
Subjects 
demonstrating 
adequate 
vasoconstriction 
to  
Betamethasone Dipropionate  (Augmented) cream within 15 days 
prior to dosing (unoccluded application of Betamethasone 
Dipropionate  (Augmented) cream for 4-6 hours must show a visual 
score of skin blanching of at least one unit (visual scale (0-4)), 
4. 
Subjects 
without 
any 
signs 
of 
skin 
irritation/disease/disorders/symptoms or blemishes on test sites (e.g. 
erythema, dryness, roughness, scaling, scars, moles, sunburn), 
5. 
Female subject of non-child bearing potential, defined as surgically 
sterile or post-menopausal (at least one year post cessation of 
menses), 
6. 
Female of childbearing potential who has been, in the opinion of the 
Investigator, using an approved method of birth control (e.g. oral 
contraception pill or patch, intra-uterine devices, contraceptive 
implants or vaginal rings, condoms, bilateral tubal ligation) at trial 
entry and agree to continue until the end of last trial visit. 
7. 
Female subjects of childbearing potential must have a negative urine 
pregnancy test at screening visit and at Day 1 to continue, 
8. 
Subjects willing and able to follow all the trial procedures and 
complete the whole trial, 
9. 
Subjects affiliated to a social security system 
 
Exclusion criteria: 
1. Female subjects who are breastfeeding, 
2. Use of topical corticosteroids on the test areas (forearms) within 4 
weeks prior to the screening phase, 
3. Use of systemic drugs which may interfere with the blanching reaction 
including, but not limited to, corticosteroids and other vasoactive 
drugs (nitrates derivatives, antihypertensive, phenylpropanolamine, 
diphenhydramine, pseudo-ephedrine, antihistamines, non-steroidal 
anti-inflammatory drug and aspirin/acetylsalicylic acid), within two 
weeks prior to screening visit, 
4. Use of any other medication would interfere with the trial results, in 
particular topical drugs applied on the test area within two weeks prior 
to screening visit, 
5. Subject’s caffeine (i.e. coffee, cola, soft-drinks containing caffeine) 
intake greater than 500mg per day (1 cup of coffee contains 


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approximately 85mg of caffeine) within one day prior to screening visit 
and until the end of the last visit of the test phase, 
6. Subject with a history of drug or alcohol abuse/addiction. 
7. Subject with a history of  calcium metabolism  disorders, 
8. Abnormal pigmentation of the skin or skin type, that could, in any way, 
confound interpretation of the trail results (skin type V to VI on the 
Fitzpatrick scale), 
9. Subjects with obvious difference in skin color between arms, 
10. Subjects with any of the following conditions present on the test areas: 
viral (e.g. herpes or varicella) lesions of the skin, fungal and bacterial 
skin infections, parasitic infections, atrophic skin, and striae 
atrophicae, fragility of skin veins, ichthyosis and ulcers, 
11. Any current systemic or cutaneous disease that could in any way 
confound interpretation of the trial results (e.g. atopic dermatitis, 
contact eczema, or psoriasis), 
12. Known or suspected hypersensitivity to any component(s) of IMP, 
13. Subjects with current participation in any other interventional clinical, 
based on interview of the subject, 
14. Subjects who have received treatment with any non-marketed drug 
substance (i.e. an agent which has not yet been made available for 
clinical use following registration) within the last 4 weeks prior to 
screening phase, 
15. Previously enrolled in this clinical trial, 
16. Subject who do not accept to avoid strenuous physical activity nor 
alcohol intake during the study. 
17. In the opinion of the (sub)investigator, subjects who are unlikely to 
comply with the Clinical Trial Protocol (e.g. alcoholism, drug 
dependency or psychotic state), 
18. Subjects in close affiliation with the trial personnel (e.g. immediate 
family member or subordinate), subjects being a member of the 
clinical trial personnel, or being an employee of the sponsor or a CRO 
involved in the trial, 
19. Subjects impossible to contact in case of emergency, 
20. Subjects who are in an exclusion period in the National Biomedical 
Research Register of the French Ministry of Health at randomization, 
21. Subject under guardianship or hospitalized in a public or private 
institution, for a reason other than the research or subject deprived of 
freedom or under the protection of justice. 


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Investigational Product 1: 
Name / Internal code: 
Pharmaceutical form: 
Strength/Concentration: 
 
Route of administration: 
Dosage: 
 
MC2-01  
Cream 
Calcipotriol 0.005 % w/w (50 µg/g) and betamethasone dipropionate 0.064 % 
w/w (0.5 mg/g as betamethasone) 
Topical 
Twenty (20) μL / 2.2-cm diameter site 
Investigational Product 2: 
Name / Internal code: 
Pharmaceutical form: 
Strength/Concentration: 
Route of administration: 
Dosage: 
 
MC2-01 Vehicle 
Cream 
NA 
Topical 
Twenty (20) μL / 2.2-cm diameter site 
Reference Product 1: 
Name / Internal code: 
Pharmaceutical form: 
Strength/Concentration: 
Route of administration: 
Dosage: 
 
Clobex® 
lotion 
Clobetasol propionate 0.05%   
Topical.  
Twenty (20) μL / 2.2-cm diameter site 
Reference Product 2: 
Name: 
Pharmaceutical form: 
Strength/Concentration: 
Route of administration: 
Dosage: 
 
Betamethasone Dipropionate  (Augmented) 
Cream 
Betamethasone dipropionate 0.064% (equivalent to 0.05% betamethasone) 
Route of administration and dosage: Topical.  
Twenty (20) μL / 2.2-cm diameter site 
Reference Product 3: 
Name: 
Pharmaceutical form: 
Strength/Concentration: 
Route of administration: 
Dosage: 
 
Locoid 
Cream 
Hydrocortisone butyrate 0.1%  
Topical.  
Twenty (20) μL / 2.2-cm diameter site 
Reference Product 4: 
Name: 
Pharmaceutical form: 
Strength/Concentration: 
Route of administration: 
Dosage: 
 
Triamcinolone Acetonide 
Cream 
Triamcinolone acetonide  0.1% 
Topical  
Twenty (20) μL / 2.2-cm diameter site 
Reference Product 5: 
Name: 
Pharmaceutical form: 
Strength/Concentration: 
Route of administration: 
Dosage: 
 
Desowen 
Cream 
Desonide 0.05% 
Topical  
Twenty (20) μL / 2.2-cm diameter site 


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Evaluation criteria: 
 
The following evaluations will be performed during the trial: 
 
Visual assessment of skin blanching: 
The visual assessment will be performed by two trained readers on Day 2 (2 
hours after removal of products). 
 
Local tolerance / Systemic safety: 
- 
Local tolerability will be assessed by the Investigator at Day 2. 
- 
Daily record of AE.  
Principal statistical methods: 
 
MC2-01 cream will be compared with Clobex lotion,  Betamethasone 
Dipropionate  (Augmented) cream, Locoid® cream, Triamcinolone Acetonide 
cream, Desowen cream and MC2-01 cream vehicle in terms of visual score of 
skin blanching 2 hours after a 16-hour application, using an ANOVA having 
subjects and treatments as factors. Estimates of treatment effect and 95% 
confidence interval of differences between MC2-01 cream and the reference 
products will be calculated from the model without correction for multiplicity 
in the primary analysis. Correction for multiplicity using Dunnett’s test will be 
used as secondary analysis. 
Subject Number Calculation: 
In total 36 subjects will be randomized in the trial in order to have 30 completed 
evaluable subjects. Each subject will receive the MC2-01 cream, the 5 steroid-
containing treatments and the MC2-01 cream vehicle on 7 different test sites. 
For details of calculation see section 12.5.  
Trial dates:  
First Subject In: Late August - Early September 2018 
Last Subject Out: October 2018  


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Table 1 - Schedule of Assessments 
Trial Phases: 
Screening 
Test 
Follow-up(2) 
 Trial Days : 
Day-15 to 
Day-1 
Day1 
Day2 
Day15 
(±2days) 
Informed Consent Form 
 
 
 
 
Demographics/Medical history 
 
 
 
 
Previous treatments/procedures 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
Selection of test sites 
 
 
 
Physical exam, vital signs 
 
 
 
 
Urine pregnancy test(1) 
 
 
 
 
Screening test for blanching response 
 
 
 
 
Randomization 
 
 
 
 
Local tolerance(2) 
 
 
 
 
Application of IMPs 
 
 
 
 
Product excess removal(3) 
 
 
 
 
Measurement of skin blanching by 2 
trained evaluators(4) 
 
 
 
Concomitant treatments 
 
 
 
 
Adverse events 
 
 
 
 
End of treatment 
 
 
 
 
End of study 
 
 
 
 
1: For female subject of childbearing potential. Result must be negative to continue the trial. 
2: For subjects with a local tolerability scores >0 at Day 2 or if a non-serious adverse event classified as reasonably possibly 
related to the investigational products or an SAE is ongoing once a subject has completed the test phase (Day 2), a follow-
up visit/contact (telephone contact or visit according to the investigator’s discretion) will take place up to 14 (±2) days after 
the end of test phase (D2). AEs and SAEs assessed reasonably possibly related to the trial medication must be follow until 
it is resolved or until the medical condition of the subject is stable. 
3: 16 hours +/- 30 min after IMP application 
4: 2 hours +/- 30 min after IMP removal 
 
 
 


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TABLE OF CONTENTS 
 
1 
TITLE PAGE ....................................................................................................................................... 1 
2 
CLINICAL TRIAL PROTOCOL APPROVAL ........................................................................................... 2 
3 
TRIAL SYNOPSIS ............................................................................................................................... 3 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................ 15 
5 
BACKGROUND AND RATIONALE .................................................................................................... 16 
5.1 
Background ............................................................................................................................ 16 
5.2 
Rationale for the trial ............................................................................................................ 16 
5.2.1 
Rational for the trial design ........................................................................................... 16 
5.2.2 
Rational for the reference products .............................................................................. 17 
5.3 
Risk/benefit ratio assessment ............................................................................................... 18 
6 
CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS .............................................................. 18 
6.1 
Clinical trial objectives ........................................................................................................... 18 
7 
OVERALL CLINICAL TRIAL DESCRIPTION ........................................................................................ 19 
7.1 
Overall trial design ................................................................................................................. 19 
7.1.1 
Screening Phase ............................................................................................................. 19 
7.1.2 
Test Phase (Day 1 to Day 2) ........................................................................................... 20 
7.1.3 
Follow-up Phase ............................................................................................................ 21 
7.2 
Discussion of the trial design ................................................................................................. 22 
8 
CLINICAL TRIAL DURATION AND TERMINATION ........................................................................... 22 
9 
SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION .................................................. 22 
9.1 
Number of subjects ............................................................................................................... 22 
9.2 
Clinical trial population characteristics ................................................................................. 22 
9.2.1 
Inclusion criteria ............................................................................................................ 23 
9.2.2 
Exclusion criteria ........................................................................................................... 23 
9.2.3 
Previous and concomitant therapies ............................................................................. 24 
9.2.4 
Authorized concomitant therapies ................................................................................ 25 
9.2.5 
Prohibited concomitant therapies ................................................................................ 25 
9.3 
Withdrawal Criteria ............................................................................................................... 26 
9.4 
Stopping rules ........................................................................................................................ 26 
10 
CLINICAL SUPPLIES ..................................................................................................................... 28 


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10.1 
Clinical supply identification and use .................................................................................... 28 
10.1.1 
Trial drug(s) description ................................................................................................ 28 
10.1.2 
Subject Identification Number ...................................................................................... 29 
10.1.3 
Method of treatment assignment ................................................................................. 29 
10.1.4 
Randomization number ................................................................................................. 30 
10.1.5 
Instructions for use and administration ........................................................................ 30 
10.1.6 
Location of test sites ...................................................................................................... 30 
10.1.7 
Application procedure ................................................................................................... 30 
10.1.8 
Subject Treatment Instructions ..................................................................................... 31 
10.1.9 
Trial drug(s) packaging and labelling ............................................................................. 31 
10.2 
Supplies management ........................................................................................................... 32 
10.2.1 
Accountability ................................................................................................................ 32 
10.2.2 
Storage of clinical trial drug(s) ....................................................................................... 33 
10.2.3 
Dispensing and return ................................................................................................... 33 
10.2.4 
Treatment compliance management and record ......................................................... 33 
10.2.5 
Dose modification ......................................................................................................... 33 
10.3 
Blinding .................................................................................................................................. 33 
10.3.1 
Verification of blinding .................................................................................................. 33 
10.3.2 
Unblinding during the clinical trial ................................................................................ 34 
11 
CLINICAL TRIAL ASSESSMENT .................................................................................................... 34 
11.1 
Pharmacodynamic (Skin blanching) assessments ................................................................. 34 
11.1.1 
Visual Assessment of Skin Blanching ............................................................................. 34 
11.1.2 
Assessment of Local Tolerability ................................................................................... 35 
11.2 
Safety assessment ................................................................................................................. 35 
11.2.1 
Systemic safety assessment .......................................................................................... 36 
11.2.2 
Adverse Events .............................................................................................................. 36 
11.2.3 
Pregnancy ...................................................................................................................... 41 
11.3 
Other assessments ................................................................................................................ 41 
11.4 
Appropriateness of measurements ....................................................................................... 41 
12 
CLINICAL TRIAL VISITS DESCRIPTIONS AND PROCEDURES ........................................................ 42 
12.1 
Description of Clinical Trial Visits .......................................................................................... 42 
12.1.1 
Screening Phase ............................................................................................................. 42 
12.1.2 
Test Phase ...................................................................................................................... 43 
12.1.3 
Follow-up Phase ............................................................................................................ 44 


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12.1.4 
Subject instructions ....................................................................................................... 44 
13 
Statistical Analysis ..................................................................................................................... 44 
13.1 
Trial population ..................................................................................................................... 44 
13.1.1 
Baseline characteristics ................................................................................................. 45 
13.2 
Analysis of pharmacodynamic effect (blanching) ................................................................. 45 
13.2.1 
Primary pharmacodynamic criterion ............................................................................. 45 
13.2.2 
Secondary pharmacodynamic criterion ........................................................................ 45 
13.3 
Analysis of Safety ................................................................................................................... 46 
13.3.1 
Local safety .................................................................................................................... 46 
13.3.2 
Adverse events .............................................................................................................. 46 
13.4 
General principles .................................................................................................................. 46 
13.5 
Number of subjects calculation ............................................................................................. 47 
14 
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ............................. 47 
14.1 
Personnel training ................................................................................................................. 47 
14.2 
Clinical monitoring................................................................................................................. 47 
14.3 
Data management ................................................................................................................. 48 
14.4 
Quality assurance / audit / inspection .................................................................................. 48 
14.5 
Changes in clinical trial conduct / amendments ................................................................... 48 
14.5.1 
Clinical trial conduct ...................................................................................................... 48 
14.5.2 
Amendments ................................................................................................................. 48 
15 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS ....................................... 49 
15.1 
Independent Ethics Committee (IEC) .................................................................................... 49 
15.2 
Ethical conduct of the clinical trial ........................................................................................ 49 
15.3 
Subject information and consent .......................................................................................... 49 
15.4 
Protection of Personal Data .................................................................................................. 49 
15.5 
Regulatory Authority ............................................................................................................. 50 
15.6 
Contractual requirements ..................................................................................................... 50 
15.7 
Data collection and archiving ................................................................................................ 50 
15.7.1 
Data collection ............................................................................................................... 50 
15.7.2 
Source documentation .................................................................................................. 50 
15.7.3 
Archives ......................................................................................................................... 50 
15.8 
Insurance ............................................................................................................................... 51 
15.9 
Investigator and Administrative Structure ............................................................................ 51 
16 
REFERENCES .............................................................................................................................. 52 


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17 
APPENDICES ............................................................................................................................... 54 
 
 
Tables Index 
Table 1 - Schedule of Assessments ........................................................................................................ 10 
Table 2 - Description and usage of the investigational and reference products .................................. 28 
Table 3 - Skin blanching visual scale ...................................................................................................... 34 
Table 4 - Local tolerability scale ............................................................................................................ 35 
 
 
Figure Index 
Figure 1- Example of test sites location ................................................................................................ 21 
Figure 2- Model of label (in French) ...................................................................................................... 32 
 
 
 


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4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BDP 
Betamethasone Dipropionate 
CAL 
Calcipotriol 
CPCAD 
Centre de Pharmacologie Clinique Appliquée à la Dermatologie = name of 
the trial site [ for Clinical Pharmacologie Center Applied to Dermatology] 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Safety Responsible 
DDS 
Drug Delivery Solutions Aps 
EU 
European Union 
FDA 
Food and Drug Administration 
FSI 
First Subject In 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LSO 
Last Subject Out 
RDC 
Remote Data Capture 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
 


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5 BACKGROUND AND RATIONALE 
5.1 
Background 
Psoriasis is a common, immune-mediated, inflammatory skin disease that is found world-wide. There 
is no cure for psoriasis. The goal of treatment is to reduce or eliminate its signs and symptoms. Mild to 
moderate disease is often treated with topical therapies. Among topical therapies, a combination 
treatment of a Vitamin D analog and a topical glucocorticosteroid has become especially popular. 
Several studies show that the combination of calcipotriol (CAL) and betamethasone dipropionate (BDP) 
is superior to each of the single agent (3) (4) (5). There is strong scientific rationale for the combination 
of vitamin D and glucocorticosteroids both with respect to efficacy and safety (6) (7) (8), and 
combination treatment with a Vitamin D analog and a topical corticosteroid is recommended in both 
American and European guidelines (9) (10) (11) (12). 
Calcipotriol and betamethasone are incompatible in an environment, since CAL requires basic 
conditions to maintain stability while betamethasone requires acidic conditions. Currently marketed 
products are therefore restricted to non-, oil-based formulations. 
Sponsor has developed the MC2-01 cream containing the fixed dose combination 0.005 w/w% CAL (as 
anhydrate) and 0.064 w/w% BDP using the proprietary PADTM Technology which protects the drug 
substances from degradation 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 and it is expected that MC2-01 cream will differentiate from marketed 
formulations of CAL/BDP by patient preference for the cream. 
The investigational products (IMP) in the present trial are: 
- 
MC2-01 cream (0.005% w/w CAL, 0.064% w/w BDP), 
- 
MC2-01 cream vehicle. 
The dosage of the active agents of the presently tested formulation are 0.005% w/w for calcipotriol 
and 0.064% w/w for betamethasone (as dipropionate). These concentrations are similar to the ones 
of the commercially available formulations of calcipotriol and betamethasone dipropionate or the 
combination of both. 
5.2 
Rationale for the trial 
5.2.1 
Rational for the trial design 
The human skin blanching assay (vasoconstriction test) described by R. Stoughton and A.W. McKenzie 
in 1962 (1) has been used for many years by pharmaceutical companies and was accepted by the FDA 
as a mean to assess the clinical potency of topical corticosteroid formulations. The assay is typically 
performed with healthy volunteers and with intraindividual comparisons and is based on the ability of 
corticosteroids to produce skin blanching i.e., vasoconstriction in the dermal microvasculature. The 


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degree of skin blanching is a measure of inherent potency of the drug and its capacity to diffuse 
through the stratum corneum. 
The original human skin blanching assay (1) used a 16-hour application and visual assessments of the 
degree of vasoconstriction. Since then, numerous attempts to refine this assay have been done, e.g., 
by changing the application time and by including colorimetric assessments of the skin color.  
The most comprehensive comparison of the vasoconstrictor assay with clinical potency was in the trial 
by Cornell and Stoughton (2) of over twenty glucocorticoid formulations which involved the 
comparison of 2 formulations in both the vasoconstrictor assay and double-blind clinical studies in 
psoriasis. Thirty subjects in each vasoconstrictor and 30 or more subjects in each clinical trial/group 
(psoriasis) paired comparison was used. In all but two, the comparisons directly agreed with the clinical 
potency as determined by the bilateral, paired, double-blind studies in psoriasis. All these correlations 
were done with the single reading (at least 2h after the product removal procedure) after 16h of 
exposure under a guard (13). 
Ranking of the clinical potencies of USA glucocorticoid topical formulations has been based on the 
Stoughton’s skin blanching assay. 
5.2.2 
Rational for the reference products 
In the US potency ranking of commonly used corticosteroids, Group I is the super-potent category. 
Potency descends with each group to group VII, which is the least potent.  
In a ranking assay, the active reference products must be selected to ensure an adequate bracketing 
to determine the topical corticosteroid potency class of the MC2-01 cream (CA/BDP). It should also 
demonstrate that the IMP is not different from the target class representative. 
The active reference products are listed below including their steroid potency description and Group 
and Class according to the 7-point US classification system. Several US classification charts (13) (14) 
(15) (16) and the WHO classification (17) have been used for reference and selection. 
Generic name 
Group 
/Class 
Potency 
Brand name 
Rational 
Clobetasol 
propionate 0.05% 
I 
Ultra 
High/Super 
potent 
Clobex® lotion 
Highest potent 
Betamethasone 
dipropionate 0.05 
% 
II 
High/Potent 
Betamethasone 
Dipropionate  
(Augmented) 
cream 
Representative of the 
target potency group and 
matching steroid for the 
IMP 
Triamcinolone 
acetonide 0.1% 
IV 
Medium 
Triamcinolone 
Acetonide cream 
Representative of a 
medium group 
Hydrocortisone-17-
butyrate 0.1% 
V 
Medium 
Locoid® cream 
Representative of a lower 
medium group 
Desonide 0.05% 
VI 
Low 
Desowen® cream  
Lowest potency used in 
psoriasis (face or folds) 


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Group: From Stoughton (13), the American Academy of Family Physicians (16) and World Health 
Organization Classification of Topical Corticosteroids (17). 
Class: Potency of Topical Corticosteroids (USA classification) (14). 
 
5.3 
Risk/benefit ratio assessment 
The MC2-01 cream contains two well-known active compounds (CAL/BDP) in a novel topical 
formulation. The efficacy and safety profile of the combination is well established and have proven to 
be safe and efficacious, and available data for MC2-01 cream suggest a very benign safety profile 
resembling that known from the approved CAL/BDP products. 
The subject population in MC2-01-C4 will be healthy adult subjects. The products to be tested will be 
applied to circular test sites (2.2 cm diameter) on the flexor surface of each forearm between the wrist 
and elbow and removed after 16 hours in order to visually assess, vasoconstriction. 
Based on the extensive clinical experience available for the CAL/BDP combination, and in light of the 
fact that the healthy subjects in the vasoconstriction trial will be exposed to a very limited dose of 
MC2-01 cream, it is considered that the benefit of obtaining clinical data to evaluate the potency of 
MC2-01 cream relative to marketed corticosteroids outweighs any potential risks. 
6 CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS 
6.1 
Clinical trial objectives 
Primary objective: 
The objective of this trial is to compare the vasoconstriction potential (skin blanching effect) of MC2-
01 cream with Clobex 0.05% (clobetasol propionate) lotion, Betamethasone Dipropionate  
(Augmented) 0.05% (betamethasone dipropionate) cream, triamcinolone Acetonide 0.1% 
(triamcinolone Acetonide) cream, Locoid® 0.1% (hydrocortisone butyrate) cream, Desowen® 0.05% 
(desonide) cream and MC2-01 vehicle using the human skin blanching test (McKenzie-Stoughton’s 
test). 
Secondary objectives: 
To assess the local tolerability of MC2-01 cream and the matching vehicle. 


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7 OVERALL CLINICAL TRIAL DESCRIPTION 
7.1 
Overall trial design 
This is a single center, investigator blinded, active - and vehicle-controlled, single application, intra-
individual comparisons on mini-test sites (n=7), involving 36 healthy subjects meeting specific 
inclusion/exclusion criteria. 
Eligible subjects will receive a single application of each of the followings: 
- 
MC2-01 cream containing calcipotriol and betamethasone dipropionate, w/w 0.005% / 
0.064%. 
- 
Clobex lotion containing clobetasol propionate 0.05% 
- 
Betamethasone Dipropionate (Augmented) cream containing betamethasone dipropionate 
0.05% 
- 
Triamcinolone Acetonide containing triamcinolone acetonide 0.1% 
- 
Locoid® cream containing hydrocortisone-17-butyrate 0.1% 
- 
Desowen® cream containing desonide 0.05% 
- 
MC2-01 cream vehicle 
The trial will employ an unoccluded McKenzie-Stoughton trial design based on topical application of a 
corticosteroid-containing formulation for a period of 16 hours in healthy human volunteers followed 
by visual estimation of the degree of blanching on a multiple unit scale (0 to 4) by two independent 
trained observers 2 hours after the end of the application period. 
The trial will be conducted with three successive individual phases: 
- 
Screening phase with a screening blanching test. 
- 
Test phase 
- 
Follow-up phase. For subjects with a local tolerability scores >0 at Day 2 or if a non-serious 
adverse event classified as reasonably possibly related to the investigational products or an 
Serious Adverse Event (SAE) is ongoing once a subject has completed the test phase (Day 2), a 
follow-up visit/contact will take place up to 14 (±2) days after the end of test phase (D2). SAEs 
will be monitored until the Investigator and Sponsor agree that the event is satisfactorily 
resolved; Telephone contact or visit according to the investigator’s discretion. 
7.1.1 
Screening Phase 
A medical screening-examination will be performed at screening which will take place 1 to 15 days 
before the start of Day 1.  


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Before any trial related procedure, the subjects will receive the necessary written and verbal 
information and instructions including informed consent form (written informed consent) and the 
written subject information sheet. Each subject will receive a unique Subject Identification Number 
and eligibility will be determined by clinical examination and confirmation of in/exclusion criteria.  
During screening procedure general data such as demographics, vital signs (blood pressure and heart 
rate sitting after 5 minutes at rest), concomitant medication, concurrent diagnoses, sex and skin type 
will be recorded. Female subjects of childbearing potential will undergo a urine pregnancy test that 
also must be negative.  
A screening test for blanching response will be performed and the subject should have a visual score 
(single reading) of skin blanching of at least one unit (visual scale (0-4)) after an unoccluded application 
of Betamethasone Dipropionate (Augmented) cream (20 μL for 4-6 hours), on a forearm test site of 
2.2 cm in diameter which will not be used during the test phase. 
7.1.2 
Test Phase (Day 1 to Day 2) 
The start of the treatment phase is defined as Day 1 (Visit 2, baseline). A re-check of all in/exclusion 
criteria will be performed in subjects who were suitable based on previous examinations. Concomitant 
medication will be reviewed. Female subjects of childbearing potential will undergo a urine pregnancy 
test that must be negative.  
If all inclusion and exclusion criteria are met, the subject will continue the trial and receive a unique 
randomization number which determines the application scheme of investigational and reference 
products for the individual subject (see Section 10.1.4). 
 
Location of test sites 
Seven circular sites (2.2 cm diameter) will be outlined on the anterior surface of the forearms (4 sites 
on one arm and 3 sites on the other). A number will identify them: 1 to 4 on one arm and 5 to 7 on the 
other arm (from the antecubital fossa to the wrist). The test sites will be delimited using a disposable 
circular device and a marker pen. 
The distal part of the wrist, the veins, and hair covered areas should be avoided. Test sites should be 
no closer than 3 cm to the antecubital fossa or to the wrist. The distance between two test sites must 
be at least 2.5 cm center to center (i.e. at least 0.3 cm between site perimeters) and might be in straight 
line or staggered pattern, depending on the surface suitability (e.g., vascularity, nevi, etc.) and arm 
length. 


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Figure 1- Example of test sites location  
Product application 
The products will be allocated to each test site according to a pre-determined randomization scheme. 
The specified dose of each product will be applied to the delimited area and gently massaged into the 
skin using a gloved finger. Each product will be applied using a different gloved finger.  
The test sites will be protected by a plastic ring and covered with a non-occlusive gauze dressing to 
avoid any lateral spreading of the product from the application site. 
At the end of the application period (16 hours after application), any remaining topical product will be 
gently removed from the skin by 3 consecutive swabbings with dry paper tissue swabs (no washing). 
During the application phase, the temperature of the room will be kept constant at 22-24 °C. 
Visual assessment of skin blanching 
Visual assessments of the skin blanching will be made independently by 2 trained observers 2 hours 
after the removal of the products, according to a grading scale (0 to 4). During the assessments, the 
temperature of the room will be kept constant at 22-24°C. 
Assessment of local tolerability 
At Day 2, the (sub)investigator will assess each test site for local tolerability according to a graded scale. 
Local and systemic adverse events (AE) will be assessed at each visit. 
7.1.3 
Follow-up Phase 
A follow-up visit/contact (telephone contact or visit according to the investigator’s discretion) will take 
place up to 14 (±2) days after Day 2 if any of the below conditions apply when the subject has 
completed the trial:  
- The subject has a local tolerability score >0, 
5 
6 
7 


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- The subject has an ongoing non-serious adverse event classified as reasonably possibly related to the 
investigational products, 
- The subject has an ongoing SAE.  
7.2 
Discussion of the trial design 
Please see 5.2.1. Rational for the trial design. 
8 CLINICAL TRIAL DURATION AND TERMINATION 
The planned clinical trial duration (from FSI to LSO) is approximately 2 months. The date of end of the 
clinical trial is defined as the date of the last visit of the last subject who participates in the clinical trial. 
The planned duration of recruitment (i.e. From FSI to LSI) is approximately 1 month. 
Clinical trial participation for each subject is of 2 days plus the screening phase and a possible follow-
up phase. 
The sponsor may decide to prematurely terminate or suspend the trial (for example, for non-inclusion 
or non-compliance with clinical trial protocol, regulation, or GCP) or prematurely suspend the clinical 
trial (for example, for safety, trial drug(s) quality, regulatory, efficacy, or logistical reason(s) at any time 
with appropriate notification. 
The date of end of the trial will be the date of the last visit of the last Subject undergoing the trial. 
9 SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION 
The volunteers will be recruited via the CPCAD Volunteer Database or from those who spontaneously 
come to the CPCAD or if needed, via press advertising after approval by the Ethics Committee. 
9.1 
Number of subjects 
Approximately 60 subjects will be pretested in order to get 36 subjects randomized and 30 subjects 
completed. 
9.2 
Clinical trial population characteristics 
In order to be eligible for the clinical trial, subjects must fulfil all of the following criteria.  Some criteria 
are to be checked during the Screening Phase and/or at Baseline, as specified. 


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9.2.1 
Inclusion criteria 
1. 
Male or female subjects aged 18 years to 50 years old having signed and dated an informed 
consent, 
2. 
Non-smoker subjects, 
3. 
Subjects demonstrating adequate vasoconstriction to Betamethasone Dipropionate  
(Augmented) cream within 15 days prior to dosing (unoccluded application of Betamethasone 
Dipropionate  (Augmented) cream for 4-6 hours must show a visual score of skin blanching of 
at least one unit (visual scale (0-4)), 
4. 
Subjects without signs of skin irritation/disease/disorders/symptoms or blemishes on test sites 
(e.g. erythema, dryness, roughness, scaling, scars, moles, sunburn), 
5. 
Female subject of non-child bearing potential defined as surgically sterile or post-menopausal 
(at least one year post cessation of menses), 
6. 
Female of childbearing potential who has been, in the opinion of the Investigator, using an 
approved method of birth control (e.g. oral contraception pill or patch, intra-uterine devices, 
contraceptive implants or vaginal rings, condoms, bilateral tubal ligation) at trial entry and 
agree to continue until the end of the last trial visit, 
7. 
Female subjects of childbearing potential must have a negative urine pregnancy test at 
screening visit and at Day 1 to continue, 
8. 
Subjects willing and able to follow all the trial procedures and complete the whole trial, 
9. 
Subjects affiliated to a social security system. 
9.2.2 
Exclusion criteria 
1. 
Female subjects who are breastfeeding, 
2. 
Use of topical corticosteroids on the test areas (forearms) within 4 weeks prior to the screening 
phase, 
3. 
Use of systemic drugs which may interfere with the blanching reaction including, but not 
limited to, corticosteroids and other vasoactive drugs (nitrates derivatives, antihypertensive, 
phenylpropanolamine, diphenhydramine, pseudo-ephedrine, antihistamines, non-steroidal 
anti-inflammatory drug and aspirin/acetylsalicylic acid), within two weeks prior to screening 
visit, 
4. 
Use of any other medication would interfere with the trial results, in particular topical drugs 
applied on the test area within two weeks prior to screening visit, 
5. 
Subject’s caffeine (i.e. coffee, cola, soft-drinks containing caffeine) intake greater than 500mg 
per day (1 cup of coffee contains approximately 85mg of caffeine) within one day prior to 
screening visit and until the end of the last visit of the test phase, 
6. 
Subject with a history of drug or alcohol abuse/addiction, 


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7. 
Subject with a history of  calcium metabolism disorders, 
8. 
Abnormal pigmentation of the skin or skin type, that could, in any way, confound 
interpretation of the trail results (skin type V to VI on the Fitzpatrick scale), 
9. 
Subjects with obvious difference in skin color between arms, 
10. 
Subjects with any of the following conditions present on the test areas: viral (e.g. herpes or 
varicella) lesions of the skin, fungal and bacterial skin infections, parasitic infections, atrophic 
skin, and striae atrophicae, fragility of skin veins, ichthyosis and ulcers, 
11. 
Any current systemic or cutaneous disease that could in any way confound interpretation of 
the trial results (e.g. atopic dermatitis, contact eczema, or psoriasis), 
12. 
Known or suspected hypersensitivity to any component(s) of IMP, 
13. 
Subjects with current participation in any other interventional clinical, based on interview of 
the subject, 
14. 
Subjects who have received treatment with any non-marketed drug substance (i.e. an agent 
which has not yet been made available for clinical use following registration) within the last 4 
weeks prior to screening phase, 
15. 
Previously enrolled in this clinical trial, 
16. 
Subject who do not accept to avoid strenuous physical activity nor alcohol intake during the 
study. 
17. 
In the opinion of the (sub)investigator, subjects who are unlikely to comply with the Clinical 
Trial Protocol (e.g. alcoholism, drug dependency or psychotic state), 
18. 
Subjects in close affiliation with the trial personnel (e.g. immediate family member or 
subordinate), subjects being a member of the clinical trial personnel, or being an employee of 
the sponsor or a CRO involved in the trial, 
19. 
Subjects impossible to contact in case of emergency, 
20. 
Subjects who are in an exclusion period in the National Biomedical Research Register of the 
French Ministry of Health at randomization, 
21. 
Subject under guardianship or hospitalized in a public or private institution for a reason other 
than the research, subject deprived of freedom or under the protection of justice. 
 
9.2.3 
Previous and concomitant therapies 
Definition 
Previous therapies are defined as therapies that have been stopped within the six (6) months preceding 
the screening visit. 
Concomitant therapies are defined as follows: 


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 
any existing therapies ongoing at the time of the screening visit, 
 
any changes to existing therapies (such as changes in dose or formulation) during the course 
of the clinical trial, or 
 
any new therapies received by the subject since the screening visit. 
Categories 
The following two categories are to be considered for previous and concomitant therapies:  
- 
Drugs/therapies including but not limited to, prescription, over-the-counter (OTC), birth 
control pills/patches/hormonal devices, vitamins, moisturizers, sunscreens, herbal 
medicines/supplements, and homeopathic preparations. 
- 
Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers, X-rays, etc. 
Recording 
Previous and concomitant therapies are to be recorded on the Drugs/Therapies form (for 
drugs/therapies) and/or on the Medical and Surgical Procedures form (for medical/surgical 
procedures) in the CRF. 
Concomitant therapies are to be recorded, reviewed, and updated at each visit. 
Any new concomitant therapy or modification of an existing therapy may be linked to an adverse event 
(AE).  A corresponding Adverse Event Form must be completed to account for the change in therapy, 
except in some cases such as therapy used for prophylaxis, dose modification for a chronic condition, 
etc. 
9.2.4 
Authorized concomitant therapies 
Unless listed under the exclusion criteria (Section 9.2.2, items 2 and 3) or in prohibited concomitant 
therapies (see Section 9.2.5), all therapies are authorized. 
9.2.5 
Prohibited concomitant therapies 
The following therapies are prohibited because they may interfere with the efficacy and/or safety (for 
example interaction with the trial drug(s) metabolism) assessment of the trial drug(s): 
Listed in Section 9.2.2 items 2 and 3. 
If prohibited therapies become a necessary treatment for the safety or best interest of the subject, the 
sponsor should be notified to discuss possible alternatives prior to administration of a prohibited 
therapy. 
If a subject receives prohibited therapy during the clinical trial, sponsor should be notified to discuss 
the pertinence and the modalities for the subject to continue in the clinical trial. 


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9.3 
Withdrawal Criteria 
Subjects may withdraw for any of the following reasons: 
1. 
Unacceptable treatment efficacy: the investigator is free to withdraw the subject at any time 
for medical reasons. 
2. 
Unacceptable adverse events: any adverse event that the investigator or the subject considers 
unacceptable. 
3. 
Exclusion criteria: any exclusion criteria which emerge/become apparent during the subject’s 
participation in the clinical trial. 
4. 
Voluntary withdrawal: subjects will be free to withdraw from the clinical trial at any time and 
for any reason. 
5. 
Other reasons: other reasons than stated above which requires the subject to (be) withdraw(n) 
should be specified. 
Subjects who are discovered, after enrolment/randomization, not to have fulfilled all in/exclusion 
criteria at time of enrolment, should be withdrawn from treatment unless the investigator, based on 
clinical and ethical evaluation, finds withdrawal inappropriate. Such deviation(s) from the Clinical Trial 
Protocol must be reported to (and IEC/IRB, as appropriate) and recorded in the Clinical Trial Report. 
The assessments at the early withdrawal visit should be attempted to be completed for all subjects 
who withdraw from the treatment for any reasons. The ultrasound measurement should be performed 
at this early withdrawal visit. 
In case of early withdrawal from the trial, a follow-up visit/contact should be planned 14 (+/- 2) days 
after the last visit for those subjects having an adverse event classified as reasonably possibly related 
to the trial medication, unless final outcome of the event has been determined in the meantime. 
Reason(s) for withdrawal will be recorded in the CRF. Subjects withdrawn will not be substituted. 
9.4 
Stopping rules 
The “Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials 
with investigational medicinal products“ (EMEA/CHMP/SWP/28367/07 Rev. 1) indicates that the 
protocol should define unambiguous stopping rules which result in an immediate stop to dosing. It 
should further be specified in the rule if the stop is a final end of dosing or a temporary halt. Restart is 
possible without a substantial amendment if review leads to a conclusion which is fully within 
predefined conditions for the relevant stopping criterion.  
Any submitted substantial amendment should include a rationale for the proposed dosing and for the 
continuation of the trial and details of any adjustments to the protocol including additional safety 
monitoring, if applicable.  
Stopping rules should be defined for each of the following:  
• final stop to dosing and termination of the trial;  


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• stopping for an individual subject, at any time in the trial;  
• stopping within a cohort  
− when subjects in a cohort are dosed staggered;  
− during multiple dosing;  
• progression to the next part of the trial;  
• any dose escalation parts of the trial.  
Separate rules can be in place for each of the bullet points above, or it may be appropriate to use the 
same criteria for several areas of the protocol. For example, stopping rules for dose escalation could 
be the same as those for within a cohort or those for individual subjects. Integrated protocols should 
clearly outline decision points and criteria for the situation where stopping rules are met.  
Stopping rules for healthy volunteer trials should include, but not be limited to:  
• a ‘serious’ adverse reaction (i.e. a serious adverse event considered at least possibly related to 
the IMP administration) in one subject;  
• ‘severe’ non-serious adverse reactions (i.e. severe non-serious adverse events considered as, at 
least, possibly related to the IMP administration) in two subjects in the same cohort, independent 
of within or not within the same system-organ-class.  
 Consideration should be given to stopping criteria based on a rolling review of the data that takes 
account of ‘moderate’ non-serious adverse reactions (i.e. moderate adverse events at least possibly 
related to the IMP administration) in blinded or unblinded fashion and their relation to PD effects, the 
number of subjects in which they occur, concurrency of more than one within the same subject and 
potential safety signals identified for other IMPs in the same class (mechanistic and/or chemical). 
Changes from baseline measurements should also be considered, and not just absolute cut-offs based 
on upper or lower limits of normal that might apply for healthy volunteers.  
A dose stopping criterion comprising a maximum clinical exposure (Cmax or AUC) should generally be 
included. When reviewing emerging data in relation to this criterion, the maximum exposure observed 
in individual subjects within a cohort rather than the mean exposure should be taken into account.  


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10 CLINICAL SUPPLIES 
10.1 Clinical supply identification and use 
10.1.1 
Trial drug(s) description 
 
Table 2 - Description and usage of the investigational and reference products 
 
Investigational 
product 1 
Investigational 
product 2 
Reference 
product 1 
Reference product 
2 
Trade Name or 
Equivalent 
MC2-01 
MC2-01 vehicle 
Clobex 
(Galderma Labs 
LP) 
Betamethasone 
Dipropionate  
(Augmented) 
(Taro 
Pharmaceuticals) 
Name of Drug 
Substance 
Calcipotriol + 
Betamethasone 
dipropionate 
NA 
Clobetasol 
propionate 
Betamethasone 
dipropionate 
Pharmaceutical 
Form 
cream 
cream 
lotion 
cream 
Concentration 
0.005% + 0.064% 
NA 
0.05% 
0.064% w/w 
(equivalent to 
0.05% 
betamethasone) 
Package 
60 g aluminum tubes 
60 g aluminum tubes 
Bottle 59ml 
15 g aluminum 
tubes 
Storage 
conditions 
Store between 2-8°C between treatment days 
– May be store at room temperature below 
25°C at the day of treatment application 
Store below 30°C 
Do not store above 
25°C 
Dosage (per site) 
20 µL 
20 µL 
20 µL 
20 µL 
Route 
Topical (Cutaneous to the skin) 
Dose Regimen 
A single application of each IMP 
Duration of 
administration 
Contact duration of 16 hours (+/- 30 min) 
Location of 
Treated Area 
Area of 2.2 cm diameter 


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Table 2 (continued) 
Description and usage of the investigational and reference products 
 
Reference product 3 
Reference product 4 
Reference product 5 
Trade Name or 
Equivalent 
Triamcinolone 
Acetonide 
(Ascend Laboratories LLC) 
Locoid 
(Precision Dermatology) 
Desowen 
(Galderma Labs LP) 
Name of Drug 
Substance 
Triamcinolone 
acetonide 
Hydrocortisone butyrate 
Desonide 
Pharmaceutical 
Form 
cream 
cream 
cream 
Concentration 
0.1% 
0.1% 
0.05% 
Package 
30 g tube 
30 g aluminum tube 
60 g tube 
Storage 
conditions 
Store at 20- 25°C 
Do not store above 25°C.  
Do not refrigerate or freeze 
Store between 2° and 30°C 
Dosage (per site) 
20 µL 
20 µL 
20 µL 
Route 
Topical (Cutaneous to the skin) 
Dose Regimen 
A single application of each IMP 
Duration of 
administration 
Contact duration of 16 hours (+/- 30 min) 
Location of 
Treated Area 
Area of 2.2 diameter 
10.1.2 
Subject Identification Number  
Upon signature of the ICF, each subject will be assigned a Subject Identification Number. 
This Subject Identification Number will be allocated in ascending sequential order to each subject. For 
the duration of the entire clinical trial, the subject will be identified using the Subject Identification 
Number for all documentation and discussion. 
10.1.3 
Method of treatment assignment 
Prior to the start of the trial, a randomization list will be generated by a statistician from CPCAD and 
will be transmitted to the person in charge of the products application.   


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The list will indicate the assignment of the seven products to the seven different test sites (1-7) of each 
Subject, according to a Latin squares design. The order of applications will be 1 to 7 for all Subjects. 
10.1.4 
Randomization number 
At Day 1, each Subject who fulfils all inclusion/non-inclusion criteria will be assigned a Randomization 
Number.  This three-digit Randomization Number will be dispensed in the chronological order of 
his/her inclusion in the trial and no number should be omitted or skipped.  The date and time of 
randomization define this number, independently of the Subject Identification Number that was 
initially assigned at the Screening visit. 
10.1.5 
Instructions for use and administration 
All applications will be performed at the trial center by a person from the investigational team other 
than the two independent trained readers. Application will be supervised by a second person also 
other than the two independent trained readers. 
All trial drugs will be accounted for and in no case used in any unauthorized situation.  All used and 
unused trial drugs will be appropriately inventoried and disposed of by the trial center. 
10.1.6 
Location of test sites 
Seven circular sites (2.2 cm diameter) will be outlined on the anterior surface of the forearms. A 
number will identify them: 1 to 4 on one arm and 5 to 7 on the other arm (from the antecubital fossa 
to the wrist). The test sites will be delimited using a disposable circular device. 
The distal part of the wrist, the veins, and hair covered areas should be avoided. Test sites should be 
no closer than 3 cm to the antecubital fossa or to the wrist. The distance between two test sites must 
be at least 2.5 cm center to center (i.e. at least 0.3 cm between site perimeters) and might be in straight 
line or staggered pattern, depending on the surface suitability (e.g., vascularity, nevi, etc.) and arm 
length. 
As assessment will be visual no untreated control site is required. 
10.1.7 
Application procedure 
The seven tested products will be randomly allocated to 7 sites. The 7 test sites will be numbered from 
1 to 7. The treatments will be applied at the investigational site center by a qualified person, using a 
marker pen to define the areas of products application. A transparent sheet will be used to landmark 
the test sites location on each forearm.  
The person in charge of applications will use a calibrated Eppendorf system with appropriate combitips 
to dose 20µL of the tested product. One system will be dedicated to one tested product. Before the 
study start, every system will be checked according to CPCAD SOP PT 013 06 2018 01 18 - Eppendorf 
multipette. The check form will be retained in the study file. The combitip is filled by removing the 
plunger, filling the combitip and putting the plunger in place before connecting the combitip to the 
Eppendorf multipette. 


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The 20µL of products will be applied to each test site and gently massaged into the skin using a gloved 
finger. Each product will be applied using a different gloved finger. 
After application and rubbing in, the test sites will be protected by a non-occlusive device. At the end 
of the application period (16 hours after application), remaining topical product will be gently removed 
from the skin by 3 consecutive swabbings with dry paper tissue swabs (no washing). 
10.1.8 
Subject Treatment Instructions 
At screening phase (visit 1) and Day 1 (visit 2), an instruction sheet will be handed out to the subject. 
The instructions will apply throughout the trial. 
According to this the subject will be instructed that: 
 
No occlusive dressing is permitted 
 
The devices should remain in place during the treatment period (16 hours) 
 
Bathing (bathtub, lake/sea), swimming and sauna is not permitted during Day 1 and Day 2 
before the clinical evaluation 
 
Washing and direct showers on the test sites (forearms) are not allowed during Day 1 and Day 
2 before the clinical evaluation 
 
No excessive sun exposure, as well as any kind of sun exposure of test sites is allowed. 
 
No sun cream or oil application on the test sites during Days 1 and 2. 
 
Subjects will abstain from strenuous physical activity and alcohol intake during Day 1 and Day 
2 before the clinical evaluation. 
10.1.9 
Trial drug(s) packaging and labelling 
MC2-01 / MC2-01 vehicle will be dispensed in 60 g aluminum tubes. The labels will be printed in French. 
The text of the labels will detail the information requested by Good Manufacturing Practice and local 
regulations.  


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Figure 2- Model of label (in French) 
 
Commercially available reference products will be used from their commercial packaging and packed 
in a uniform outer package, in order to blind the product. 
The products will be coded A, B, C, D, E, F and G. 
10.2 Supplies management 
10.2.1 
Accountability 
Upon receipt of the trial drug(s), the designee product manager will maintain accurate records of the 
trial drug(s) delivery to the clinical trial center, the inventory at the clinical trial center, the 
reconciliation of all trial drug(s) received from the Sponsor, and the return to the Sponsor or alternative 
disposal of used and unused trial drug(s). 
The designee product manager is required to sign and return the original “Receipt of Clinical Supplies” 
Form (or any acknowledgment of receipt) upon receipt and inspection of the supplies, fax the signed 
copy to sponsor and retain a copy within the clinical trial file. 
All used and unused clinical trial drug(s) will be appropriately inventoried by the monitor and returned 
to the Sponsor for destruction as instructed by the sponsor. 
All clinical trial drug(s) sent to the Investigator/Institution will be accounted for and no unauthorized 
use is permitted. 


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10.2.2 
Storage of clinical trial drug(s) 
Trial drug(s) must be stored in a safe and secure area with restricted access, under the storage 
conditions specified by sponsor (see Table 2 - Description and usage of the investigational and 
reference products). 
10.2.3 
Dispensing and return  
No drug will be dispensed directly to the subject.  Trial drugs will be applied at the clinical center on 
Day 1. The person in charge of product applications will not be the Investigator/evaluator.   
In the event of early termination/suspension of the clinical trial, a rapid recall of trial drug(s) will be 
initiated. 
10.2.4 
Treatment compliance management and record 
Since product applications will be performed by a qualified person and verified by a second individual, 
who will not be the investigator/evaluator, treatment compliance will be ensured and documented 
appropriately by trial staff. 
10.2.5 
Dose modification  
Not applicable 
10.3 Blinding 
10.3.1 
Verification of blinding 
The trial will be performed as an investigator-blinded trial since the following procedures will be 
followed in order to prevent the Investigator and/or other Evaluator(s) from coming into contact with 
the trial materials thereby compromising the blinding of the trial. 
All applications will be performed by designated trial personnel at the trial site. The trained observers 
performing the clinical assessments must not perform the application of the investigational products. 
Likewise, the site personnel performing the applications will be the only persons at the site having 
access to the randomization schedule. 
The packaging and labelling of the investigational products will allow to distinguish their identity. 
The subjects may be able to distinguish between the various applied formulations. They will therefore 
be instructed not to reveal any information about the trial medications to the (sub)investigator and/or 
trained observers performing the clinical assessments. 
The tubes will be labeled with a letter A, B, C, D, E, F or G by IMP Pharmaceutical Services. IMP 
Pharmaceutical Services will furthermore create a document, listing which reference product is A, B 
etc. CPCAD will receive a copy of this document, sealed in an envelope, to be used in case of 
emergency. Access to the identification of treatment codes will be limited to the designated personnel. 


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10.3.2 
Unblinding during the clinical trial 
Emergency unblinding during the clinical trial may be required for therapeutic or for regulatory reasons 
(for expedited safety reporting). 
A blind break system will be available for the investigator. At the clinical center, a sealed document, 
containing the identification of tubes of trial medication, may be revealed in emergency situation only. 
This list will be compared with the sequence of applications done for the subject in question by the 
person in charge of the applications or a designated person different from the investigator/readers. 
The information will be transmitted to the investigator only for the subject involved and documented.  
The Investigator must notify the Sponsor’s Clinical Safety Responsible immediately in the event of such 
an emergency (see contact details in Section 11.2.2.2.  The Investigator should notify the Sponsor 
before breaking the blind in order to discuss this decision with the Sponsor.  The Investigator is 
required to document each case of emergency unblinding on the randomization disclosure form 
(provided by the Sponsor) and fax the completed form to the CSR immediately. 
 
11 CLINICAL TRIAL ASSESSMENT 
11.1 Pharmacodynamic (Skin blanching) assessments 
Throughout the trial, the assessment of the blanching response for each individual test site (mini test 
site) will be performed to the extent possible by the same 2 trained evaluators. In the event there is a 
change in the assigned readers for a given Subject, the reason for change must be documented.  If it is 
not possible to use the same reader to follow a given Subject, the Sponsor recommends that 
evaluations between the primary and subsequent evaluator overlap (both evaluators should examine 
the Subject together and discuss findings) for at least one visit. 
11.1.1 
Visual Assessment of Skin Blanching 
Visual assessment of blanching will be made independently by two trained readers on Day 2 (2 hours 
after removal of products, following 16 hours application time) according to the following scale: 
Table 3 - Skin blanching visual scale 
Score* 
Description 
0 
No change in color skin 
1 
Slight (barely visible) blanching 
2 
Obvious blanching 
3 
Intense blanching 
4 
Blanching judged to be maximal 
*Intermediate scores (half units) may be used when needed (e.g. 0.5 for a doubtful blanching). 


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Two visual score values (one per trained evaluator) will be recorded for each test site. 
 
11.1.2 
Assessment of Local Tolerability 
At Day 2, the (sub)investigator will assess each test site for local tolerability according to the scale in 
Table 4. 
 
Table 4 - Local tolerability scale 
Score* 
Description 
0 
No reaction 
0.5 
Only slight erythema 
1 
Only erythema 
2 
Erythema with papules or oedema 
3 
Erythema, oedema with papules, oedema with vesicle 
4 
Blisters 
IR 
Irritant reaction including: miliaria (sweet rash), follicular pustules, burn-like 
reactions, dry scales 
 
Subjects with a local tolerability score >0 will be re-assessed at a follow-up visit. 
Cutaneous reactions scored as local tolerability will be reported as local AEs. 
 
11.2 Safety assessment 
A safety assessment will be conducted for all subjects at the screening visit (from the Informed consent 
signature) and every subsequent visit.  The safety parameters are AEs, to be recorded as specified in 
Section 11.2.2.1, global cutaneous tolerance assessments, physical examination and vital signs 
assessments (Screening visit only). 
Adverse events will be reported individually on an ongoing basis. 
All clinical medical events, whether observed by the Investigator or reported by the Subject will be 
considered adverse events and recorded on the appropriate Adverse Event form. Assessment of 
severity and causality will be based on specific definitions. 


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11.2.1 
Systemic safety assessment 
11.2.1.1 General Physical examination 
The following body systems should be evaluated as “normal” or “abnormal” by the Investigator, at the 
screening visit: Skin, Lungs, Abdomen, Eyes/ears/nose/throat, Musculoskeletal system, Lymph nodes, 
Cardiovascular system. 
The Investigator may choose to further investigate any other sign that he/she observes during the 
physical examination. 
All abnormal findings at the screening visit identified as clinically significant by the Investigator, will be 
recorded in the Medical History form. 
For any clinically significant changes from the screening visit, an AE is to be recorded. 
 
11.2.1.2 Vital signs  
Evaluation of vital signs will be performed after 5 minutes rest in the sitting position at the screening 
visit.  It will include measurement of systolic and diastolic blood pressure and pulse rate in the supine 
position. 
All abnormal values at the screening visit identified as clinically significant by the Investigator, will be 
recorded in the Medical History form. 
For any clinically significant changes from the screening visit, an AE is to be recorded. 
For AEs, whenever possible, the Investigator is to provide a diagnosis rather than to report individual 
laboratory abnormalities. 
 
11.2.2 
Adverse Events 
Adverse events (AEs) are to be monitored throughout the course of the clinical trial.  All AEs are to be 
reported on the Adverse Event Form of the CRF with complete information as required.  If AEs occur, 
the main concern will be the safety of the subjects.  At the time of the ICF signature, each subject must 
be provided with the name and phone number of clinical trial center personnel for reporting AEs and 
medical emergencies. 
11.2.2.1 Definitions 
Adverse events (AE) 
According to ICH E2A, an AE is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended sign, 


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symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
Thus, any new sign or symptom or disease, or any clinically significant worsening of an existing sign, 
symptom or disease compared to the condition at the first visit (including disease treated), should be 
considered as an AE.  Lack of efficacy is not considered as an AE. 
Each new episode of a chronic disease (e.g., hay fever, allergy, etc...) should be reported as a new AE. 
Any new sign or symptom reported by the subject that appears after accidental or intentional overdose 
or misuse should also be reported as an AE. 
There should be an attempt to report a diagnosis rather than the signs, symptoms associated with the 
report of an AE.  However, a diagnosis should be reported only if, in the Investigator’s judgment, it is 
relatively certain.  Otherwise, symptoms or signs should be used to describe the AE. 
Serious Adverse events (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, 
• 
Is life threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the 
safety of the subject, and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasia, or convulsions that do not result in hospitalization. 
Note: The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it was 
more severe. 
Inpatient hospitalization is considered to have occurred if the subject has had to stay for a night at the 
hospital.  The criterion for prolongation of hospitalization is also defined as an extra night at the 
hospital.  Hospitalization may not constitute sufficient grounds to be considered as an SAE if it is solely 
for the purpose of a diagnostic tests (even if related to an AE), elective hospitalization for an 
intervention that was already planned before subject enrolment in the clinical trial, admission to a day 
care facility, social admission (e.g., if the subject has no place to sleep), or administrative admission 
(e.g., for a yearly examination). 
Unexpected adverse drug reaction 
According to ICH E6, an unexpected adverse drug reaction is defined as an adverse reaction, the nature 
or severity of which is not consistent with the applicable trial drug information (e.g., Investigator’s 


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Brochure for an unapproved investigational product or the package insert/summary of product 
characteristics for an approved product). 
Adverse event reporting period 
The clinical trial period during which AEs must be reported is the period from when the subject signed 
the Informed Consent Form to the end of the subject’s participation. 
The Sponsor should be informed if the Investigator becomes aware of any unusual safety information 
or any safety information that appears to be drug related involving a subject who has participated in a 
clinical trial, even after a subject has completed the clinical trial.  The Investigator should be diligent in 
looking for possible latent safety effects that may not appear until a medication has been discontinued. 
Severity 
Severity is a clinical determination of the intensity of an AE and not of a disease. 
The Investigator is to classify the intensity of AEs using the following definitions as a guideline for all 
AEs occurring during the conducted clinical trial.  For this classification, the Investigator will take into 
account the possible range of the intensity of the event and report the grade of intensity which is the 
most appropriate according his medical judgment. 
 
Mild 
 
Awareness of signs or symptom, but easily tolerated. 
 
Moderate 
Discomfort, enough to cause interference with usual activity 
 
Severe  
Incapacitating with inability to work or perform usual activity 
 
Relationship to the trial drug(s) 
The Investigator is to determine whether there is a reasonable causal relationship between the trial 
drug(s) and the AE.  Medical judgment should be used to determine the relationship, considering all 
relevant factors including the pattern of reaction, temporal relationships, positive challenge or re-
challenge, relevant medical history, and confounding factors such as co medication or concurrent 
diseases. 
The expression “reasonable causal relationship” is meant to convey in general that there are facts or 
arguments to suggest a causal relationship (ICH E2A, Section IIIA 1). 
The relationship assessment for an AE is to be completed using the following definitions as a guideline 
for all AEs occurring during clinical trials: 
 
Reasonable Possibility: 
According to the reporting Investigator, there is a reasonable possibility (i.e., suggestive evidence or 
arguments) that there is a causal relationship irrespective of the dose administered between: 
The trial drug (investigational product, active reference, or vehicle, etc.) and the AE,  
The clinical trial protocol procedure (e.g. product application, etc.) and the AE. 
 
No Reasonable Possibility: 


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No suggestive evidence or arguments can be identified regarding a causal relationship between the 
trial drug or the clinical trial protocol procedure and the AE. 
11.2.2.2 Reporting procedures 
Procedures for reporting Adverse Events 
The collection of AEs is from the time that subjects signs the ICF to their final visit. 
At each post enrolment visit, the Investigator (or sub-Investigator) will question the subject about AEs 
using an open non-persuasive question to elicit reporting of AEs, for example “Have you noticed any 
change in your health since the last visit?”  Directed questioning and examination will then be 
performed as appropriate.  
Any AE occurring during the AE reporting period, whether it is related to the trial drug(s) or not, will 
be recorded immediately in the source document, and described on the Adverse Event Form of the 
[CRF along with the date of onset, severity, relationship to the trial drug(s), and outcome, without 
omitting any requested and known information.  Additional information may be requested under 
certain circumstances.  Adverse Events (AEs) assessed as related to the treatment will be monitored 
until they are completely or satisfactorily resolved.  Other AEs will be monitored until the last visit if 
they are not resolved or satisfactorily resolved. 
The Investigator will obtain and maintain in the subject’s files all pertinent medical records, 
information and medical judgment from colleagues who assisted in the treatment and follow up of the 
subject.  If necessary, the Investigator will contact the subject’s personal physician or hospital staff to 
obtain further details. 
Procedure for reporting a Serious Adverse Event 
For an SAE occurring during the period of the clinical trial, regardless of whether it is related to the 
treatment or not, and of whether it is expected or not, the Investigator must do the following: 
 
Take prompt and appropriate medical action, if necessary.  The safety of the subject is the first 
priority. 
 
Immediately inform the Clinical Safety Responsible (from the UBC Company) designated by Drug 
Delivery Solutions Aps (DDS) c/o MC2 Therapeutics A/S of the event by email or Fax and discuss 
further actions to be taken. 
Email: EUSafety@ubc.com 
Fax number:  +41 225 964 446 
Additional contact details are provided in the Investigator’s site file. 
 
Complete the Adverse Event Form provided in the eCRF as fully as possible. 
 
Ensure that the event is classified as an SAE. 
 
Complete the standard Serious Adverse Event Form.  Fax or scan and send by e-mail the 
completed form accompanied by demographics, medical history, previous and concomitant 


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therapies and adverse event pages of the CRF, and any other relevant information or medical 
records (e.g., laboratory test results) within 24 hours to UBC.   
 
Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae.  For all additional follow-up evaluations, first inform the 
CSR of the outcome by telephone, then fax or scan and send by e-mail all additional follow-up 
information to the UBC within 24 hours.  Serious Adverse Events (SAEs) will be monitored until 
the Investigator and Sponsor agree that the event is satisfactorily resolved. 
 
Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject.  If 
necessary, contact the subject’s personal physician or hospital staff to obtain further details. 
 
Inform the CSR of the final outcome of the event.  Send a revised or updated Serious Adverse 
Event Form and Adverse Event Form, if appropriate. 
 
Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to the 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC). 
Responsibilities of the Sponsor: 
For Suspected Unexpected Serious Adverse Events (SUSAR): 
For the researches mentioned in n°1 of the article L. 1121-1 of the Public Health Book concerning drugs 
and cells therapies, the Sponsor has to declare to the competent authority any suspicion of unexpected 
Serious Adverse Events (SUSAR) occurring in France and outside the national territory within the 
following deadlines: 
1. 
In the case of suspected unexpected Serious Adverse Events having caused death or having 
endangered life, without delay starting from when the Sponsor has been informed; 
2. 
In the case of the others unexpected Serious Adverse Events, at the latest within fifteen days 
starting from when the Sponsor has been informed. 
The Sponsor declares in the form of a follow-up report to the ANSM the relevant further information 
concerning the unexpected Serious Adverse Events. In the case of suspicion of unexpected Serious 
Adverse Events having caused death or having endangered life, these further information are notified 
within eight days starting from the declaration mentioned in 1 °. In the other cases of suspicion of 
unexpected Serious Adverse Events and in case of new fact mentioned in the article L. 1123-10, the 
relevant further information are transmitted within a new deadline of eight days starting from the 
deadline mentioned in 2 °. 
> Each SUSAR must be reported in an individual email message and should be sent to: 
declarationsusars@ansm.sante.fr. A declaration should be also sent to the Eudravigilance: (clinical 
trials module) https://eudravigilance.ema.europa.eu. 
The subject line should be written as follows: SUSAR_yyyymmdd_name of substance (or trial code 
no.)_Worldwide unique case identification number_CT,  
Ex: SUSAR_20140115_SUBSTANCE_123456789_CT.  


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to any third party without sponsors written consent 
 Particular case:  SUSARs regarding a clinical trial on medicinal products involving healthy volunteers 
(whatever the clinical trial phase): the subject line should be written as follows: EC‐VS‐
SUSAR_yyyymmdd_name of substance (or trial code no.)_Worldwide unique case identification 
number_CT. 
The following document should be attached to the message: ‐ CIOMS form (PDF format) / File name 
labelled as follows:  yyyymmdd_name of substance (or trial code no.)_Worldwide unique case 
identification number_CT_C.  
Ex: 20140115_SUBSTANCE_123456789_CT_C. 
An acknowledgement of receipt will be automatically sent by return email. 
  
For Expected serious adverse reaction or other serious adverse event (clinical trials on a medicinal 
product involving healthy volunteers):  
The Sponsor has to declare without delay to the competent authority the expected Serious Adverse 
Events and all other Serious Adverse Events occurring in France and outside the national territory. 
> Each notification must be reported in an individual email message and should be sent to: 
declarationsusars@ansm.sante.fr   
    The subject line should be written as follows: EC‐VS‐EIGA yyyymmdd_name of substance (or trial 
code no.)_Worldwide unique case identification number_CT.  
The following document should be attached to the message: ‐ CIOMS form (PDF format) / File name 
labelled as follows:  yyyymmdd_name of substance (or trial code no.)_Worldwide unique case 
identification number_CT_C. 
An acknowledgement of receipt will be automatically sent by return email.  
  
For other serious adverse event which occurred in France:  The only difference compared to other SAEs 
is that the subject line should be written as follows: EC‐VS‐EVIG yyyymmdd_name of substance (or trial 
code no.)_Worldwide unique case identification number_CT.  
11.2.3 
Pregnancy 
Any pregnancy occurring from the date of the informed consent signature and until trial completion 
must be reported immediately of UBC as soon as it becomes known to the investigator and no longer 
than 24 hours after first knowledge of the occurrence of the pregnancy (11.2.2.2). 
11.3 Other assessments 
NA 
11.4 Appropriateness of measurements 
Visual assessment of the skin blanching used for US ranking trial (13).  


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Safety is documented by the recording of adverse events, the global cutaneous tolerance, the physical 
examination and the vital signs assessments. 
 
12 CLINICAL TRIAL VISITS DESCRIPTIONS AND PROCEDURES 
12.1 Description of Clinical Trial Visits 
A written, signed Informed Consent Form (ICF) must be obtained prior to performing any trial related 
evaluations and/or procedures for this protocol.  The Investigator representative will review and 
explain the nature of the trial to the Subject and particularly the prohibited activities and the 
constraints of the trial.  A copy of the signed and dated ICF will be provided to the Subject, another 
copy will be filed in the Investigator site file.  
Visual assessments must be conducted by two trained readers for skin blanching response. 
Schedule of Assessments is described in Table 1.  
12.1.1 
Screening Phase 
The Screening period takes place within 15 days to 1 day prior to Day 1 visit. 
The Investigator or the designed trial person will: 
 
Review and explain the nature of the trial in detail to the Subject, particularly the prohibited 
activities and the constraints of the trial. 
 
Insure that the Subject read and sign the Informed Consent Form. Give a copy to the Subject. 
 
Perform a urinary pregnancy test for female subject of childbearing potential. 
 
Assign to the Subject a Subject identification number and give his/her a Subject card. 
 
Collect 
information 
regarding 
demographics, 
relevant 
medical 
history, 
previous 
medications/procedures use and concomitant therapies/procedures use. 
 
Check inclusion/exclusion criteria. 
 
Perform a physical examination of the Subject, check vital signs (blood pressure, pulse rate). 
 
Test for assessment of the blanching response with the reference product on healthy skin 
 
Complete the Subject Screening & Enrolment log. 
 
Give the Subject an appointment for the Day 1 visit. 


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12.1.2 
Test Phase 
12.1.2.1 Baseline visit (Day 1) 
The Investigator or the designated trial person will: 
• Re-check inclusion/exclusion criteria including concomitant therapies. 
• Ask the Subject about AEs by asking an open-ended question taking care not to 
influence the Subject’s answer, such as “Have you noticed any change in your health since 
the last visit?” Record all events, as appropriate on the corresponding CRF pages. 
• Ask the Subject whether there have been any changes to his/her concomitant 
therapies/procedures (added, removed, or changed) since the previous visit. Document all 
changes on the Concomitant Therapy form of the CRF. 
• Perform a urinary pregnancy test for female subject of childbearing potential. 
The test must be negative to continue the trial. 
• Preselect seven test sites, 2.2 cm in diameter on the anterior surface of the forearms 
(4 sites on one forearm and 3 on the other). Mark the selected sites with a cutaneous 
marker. 
• Number the selected test sites from 1 to 7 (Z1-Z7). 
• Assign a randomization number to the Subject (this number will be assigned to 
enrolled Subjects in a sequential order and no numbers will be omitted). 
• Complete the Subject Screening and enrolment log and the Subject Identification Code 
List form indicating the last name, first name and date of inclusion. 
• A member of staff other than the Investigator will: 
• Apply 20µL of the tested products on the Subject’s selected areas using gloves and a multi-
pipette Eppendorf.  
• Protect the test sites with a non-occlusive gaze dressing (for 16 hours). 
• Instruct the Subject to avoid wetting areas (showers, swimming, bath, sauna, Hamman are not 
allowed).  
• Schedule an appointment for the next Visit. 
12.1.2.2 Day 2 
At this visit, the Investigator or the designated trial person will:  
 
Ask the Subject about AEs by asking an open-ended question taking care not to influence the 
Subject’s answer, such as “Have you noticed any change in your health since the last visit?” 
Record all events, as appropriate on the corresponding CRF pages. 


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 
Ask the Subject whether there have been any changes to his/her concomitant 
therapies/procedures (added, removed, or changed) since the previous visit. Document all 
changes on the Concomitant Therapy form of the CRF. 
 
A member of staff other than the Investigator/trained readers will: 
 
Remove the dressings and the product excess on each test site. 
 
Two distinct trained readers will: 
 
Assess the skin blanching response (2 trained readers) on each test site 2 hours after removal 
of the products, 
 
Assess local tolerance by test site using a 4 point-scale for each site. 
12.1.3 
Follow-up Phase 
If an adverse event (serious or non-serious), classified as possible or probably related to the trial 
medication or not assessable in relation to the trial medication, is ongoing at the subject’s last visit, a 
follow-up visit/contact will take place 14 (±2) days after that visit. 
12.1.4 
Subject instructions 
During the trial, the Subject will be allowed to use, if needed, all types of therapies excluding those 
listed in the exclusion criteria (section 9.2.2).   
If a Subject need to take a concomitant treatment (topical or systemic), he/she should inform the 
Investigator of it as quickly as possible (at the latest, at the next visit). 
The Subject will be instructed to keep the treated areas as dry as possible.  Showers and baths are not 
allowed after the applications. In addition, the Subject will be instructed to avoid excessive sun 
exposure during the trial. During the trial, the Subject should avoid practicing strenuous exercises 
during the entire trial period. 
Participation in any other clinical trial is prohibited during the course of the trial and for the following 
month. 
13 Statistical Analysis 
13.1 Trial population 
All subjects recruited for the trial (i.e. signed informed consent obtained and a CRF Book started) will 
be accounted for in the trial report. 


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All randomized subjects who receive any trial medication and who contribute any efficacy data in the 
trial will comprise the full analysis set and will be analyzed for efficacy. 
A per protocol analysis set will be defined by exclusion of subjects from the full analysis set, who do 
not fulfil all of the inclusion criteria or who meet any of the exclusion criteria. 
Further subjects and/or subject data may be excluded from the per protocol analysis when agreed 
upon on the basis of the actual data obtained as evaluated before breaking the randomization code. 
All subjects who receive any treatment with trial medication and for whom the presence or confirmed 
absence of adverse events is available will be included in the safety analysis set and analyzed for safety. 
The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial analysis sets 
will be documented in the Statistical Analysis Plan Update before breaking the randomization code. 
13.1.1 
Baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for all 
randomized subjects. 
Summary statistics of demographics (age and sex) and of baseline characteristics (height, weight, skin 
type, heart rate, systolic and diastolic blood pressure, concurrent diagnoses and concomitant 
medication at baseline) will be tabulated for all randomized subjects. 
13.2 Analysis of pharmacodynamic effect (blanching) 
The statistical analysis of efficacy will be based on the defined response criteria. 
13.2.1 
Primary pharmacodynamic criterion 
The analysed variable will be the mean between the two readers at each evaluation time. 
The results will be expressed by the mean values obtained at each assessment time by product/site. 
MC2-01 cream will be compared with Clobex lotion, Betamethasone Dipropionate  (Augmented) 
cream, Triamcinolone Acetonide cream, Locoid® cream, DesOwen cream and MC2-01 cream vehicle in 
terms of visual score of skin blanching 2 hours after a 16 hours application, using an ANOVA with 
subjects and treatments as factors. The mean of visual assessments obtained at the same time points 
from 2 independent trained readers will be used. In case of a significant treatment effect, estimates of 
treatment effect and 95% confidence interval of differences between reference products and MC2-01 
cream will be calculated from the model without correction for multiplicity in the primary analysis. 
Correction for multiplicity using Dunnett’s test will be used as secondary analysis. In case of significant 
deviation to the normal assumption, a non-parametric approach with Kruskall-Wallis test for the 
overall product effect and Wilcoxon’s Sign Rank Test for the pairwise comparisons will be used. 
13.2.2 
Secondary pharmacodynamic criterion 
Not Applicable 


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13.3 Analysis of Safety 
13.3.1 
Local safety 
The local tolerance score will be summarized using frequency and percentage by visit and trial product.  
The worst score will also be summarized. 
13.3.2 
Adverse events 
Adverse events will be coded during the course of the trial and will be in accordance with the current 
version of the MedDRA dictionary. The adverse events will be tabulated by Preferred Terms and 
System Organ Class. 
The number of subjects experiencing each type of adverse event (according to MedDRA Preferred 
Terms and System Organ Class) will be tabulated regardless of the number of times each adverse event 
is reported by each subject. 
Adverse events where the investigator has not excluded a causal relationship to trial medication (i.e. 
not described relationship as “no reasonable possibility”, adverse drug reactions) will be evaluated 
separately. A table or a description of these ADRs will be produced depending on the number of ADRs. 
As with adverse events, the number of subjects affected, not the number of events, will be considered.  
The causal relationship of adverse events to trial medication and the intensity of adverse drug 
reactions will be tabulated or described. Where there are several recordings of causal relationship and 
intensity for the same event, causal relationship will be taken from the last report of the event (since 
that is when the investigator will be in possession of most information and so best able to judge causal 
relationship) and intensity will be taken as the worst ever recording. Adverse events observed on the 
application areas will be tabulated or described by treatment. 
13.4 General principles 
All significance tests will be two-sided and all confidence intervals will be presented with 95% degree 
of confidence.  
Categorical data will be summarized using the number and percentage of subjects in each category. 
Continuous data will be summarized using the mean, median, SD, minimum and maximum values. 
Very few missing values from primary response criterion are expected. Usually less than 10% of 
randomized subjects do not attend the last visit in this kind of studies. Drop-outs and missing values 
will be accounted for by the analysis of end of treatment values using a last observation carried forward 
approach and by the definition of the trial analysis sets prior to unblinding. All the pre-specified 
analyses will be reviewed in relation to the blinded data actually obtained and the Statistical Analysis 
Plan Update will be finalized before breaking the randomization code. 
 


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13.5 Number of subjects calculation 
The null hypothesis for each pairwise comparison will be no difference in the human skin blanching 
test : 
H0: Δ = 0, 
where Δ is the mean difference in visual score between test sites with the compared treatments. The 
standard assumptions of normality and independence will be used. 
According to previous vasoconstriction trial performed by CPCAD, a maximal standard deviation for 
the difference of 0.65 is assumed. 
Using a paired t-test, a two-sided significance level of 5%, with 30 complete subjects, the probability 
of detecting a difference of 0.5 units assuming a standard deviation for the difference of 0.65 is 98%. 
MC2-01 cream will be compared to the five steroid-containing reference products giving at least 92% 
(0.98) power to obtain 5 significant differences if the true difference with each reference product is at 
least 0.5 int. MC2-01 cream will also be compared to the matching MC2-01 cream vehicle, but that will 
have negligible impact on the overall power assuming a difference of at least 1 point between both 
products. 
A total of 36 subjects will be randomized in this trial in order to obtain at least 30 completed evaluable 
subjects. 
14 TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE 
14.1 Personnel training 
A trial initiation visit will be conducted by the Sponsor with the Investigator and the trial team.  During 
this meeting, an extensive review and discussion of the protocol, procedures, CRF and any other trial 
material will be conducted.  Sponsor’s monitoring visits will be performed. 
Clinical Research Associates (CRAs) and other applicable personnel will be trained prior to trial 
initiation to familiarize CRAs with the disease, the Standard Operating Procedures (SOP), the protocol 
and other trial specific items.  Team organization, communication and operational issues will also be 
discussed. 
14.2 Clinical monitoring 
The conduct of the clinical trial will be closely monitored by the sponsor’s designee (Adhoc Clinical, Te 
Warde 45,89 Ieper, Belgium) to verify adherence to the clinical trial protocol, ICH GCP guidelines, and 
applicable SOPs.   
The Investigator will allow the CRO/Sponsor’s representatives, to have direct access to all clinical trial 
records, CRFs, corresponding subject medical records, trial drug(s) dispensing records, trial drug(s) 
storage area, clinical trial facilities, and any other documents considered source documentation.   


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The Investigator also agrees to assist the representative if required. 
14.3 Data management 
All data management procedures will be detailed in a Data Management Plan (DMP).   
The DMP will describe the Clinical Data Management System (CDMS) that will be used to collect data. 
The study data will be collected on an electronic data capture (EDC) set up by the CRO.  Computerized 
edit checks and review processes will be performed on an ongoing basis until all data clarifications are 
resolved.  The data will be exported from MySQL database to be stored in appropriate format.  After 
all data clarifications are resolved, coding is approved, and subject’s evaluability is determined, the 
database will be locked. 
14.4 Quality assurance / audit / inspection 
The clinical trial is conducted under the sponsorship of DDS Ltd in compliance with the applicable 
international and local regulatory requirements as well as applicable ICH guidelines and in accordance 
with the SOPs for clinical trial conduct and monitoring from the assigned Contract Research 
Organization (CRO), Adhoc Clinical. 
Audits of the clinical trial center may be conducted by the Sponsor/CRO representatives, and 
inspection may be performed by Regulatory Authority inspectorates or IECs before, during, or after 
the clinical trial.   
The Investigator will allow and assist the CRO/Sponsor’s representatives, IECs and any regulatory 
agency to have direct access to all requested clinical trial-related records. 
For the audits performed by, or on behalf of, sponsors auditors, audit certificate(s) will be provided by 
Quality Assurance. 
14.5 Changes in clinical trial conduct / amendments 
14.5.1 
Clinical trial conduct 
With the exception of eliminating an immediate hazard to a subject, the Investigator should not 
deviate from the clinical trial protocol or implement any changes without written approval from the 
Sponsor and prior review and documented approval/favourable opinion from the IEC of a protocol 
amendment. 
Changes that involve only logistical or administrative changes to the clinical trial protocol are 
authorized.  The Investigator should document and explain any deviation from the clinical trial 
protocol. 
14.5.2 
Amendments 
The Sponsor may modify the clinical trial protocol at any time for ethical, medical, or scientific reasons. 


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Protocol change to be submitted (Changes as per Substantial amendment in EU): 
No amendment can be implemented at clinical trial center, unless to eliminate an immediate hazard 
to the subjects, without having obtained a favorable opinion from the appropriate Regulatory 
Authority and/or the IEC in compliance with applicable regulation(s). 
Protocol change not to be submitted (Non-substantial amendment for EU): 
An amendment will not be issued for modification(s) due to change in logistical or administrative 
aspects of the clinical trial (e.g., change in contact details for the Sponsor or Sponsor representative) 
or for non-substantial amendments for the clinical trial center within the European Union.  In such 
cases, these changes will be documented and communicated to clinical trial center in the most 
appropriate way depending on the nature of the change. 
 
15 ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS 
15.1 Independent Ethics Committee (IEC) 
This clinical trial protocol and all amendments will be reviewed and approved by the appropriate IECs. 
15.2 Ethical conduct of the clinical trial 
This clinical trial will be conducted in accordance with the protocol, the HELSINKI declaration (1964) 
and subsequent amendments, and the ICH GCP, and in compliance with applicable regulatory 
requirements.  
15.3 Subject information and consent 
All subjects who participate in this clinical trial are required to be fully informed about the clinical trial 
in accordance with GCPs guidelines and in accordance with local requirements.   
All subjects recruited for this clinical trial will be registered in the National File of Persons Participating 
in Research involving the Human Person. 
The ICF, approved by an IEC, will be fully explained to the subject.   
Prior to enrolment into the clinical trial, the subject will sign and date the consent form(s).  The 
Investigator is responsible for maintaining each subject’s consent form(s) in the Investigator’s site file 
and providing each subject, with a copy of the signed and dated consent form(s). 
15.4 Protection of Personal Data  
CPCAD is registered by the French Commission Nationale de l'Informatique et des Libertés (CNIL) as 
complying with the MR-001 Reference Methodology for processing clinical trial data (Declaration 


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number 1246487). CPCAD also complies with the local French GDPR (General Data Protection 
Regulation) law that entered into force on 25 May 2018. The GDPR allows the subject to exercise 
his/her rights of rectification, opposition, deletion, portability and limitation of the procession of 
his/her personal data. To assert this right, the volunteer can contact the Investigator. 
15.5 Regulatory Authority 
The written authorization of the clinical trial by the regulatory authorities (ANSM) will be required prior 
to the trial implementation. 
15.6 Contractual requirements 
A contractual agreement will be signed between the CRO/Sponsor and each Investigator/Institution.  
This document will contain supplementary information, including financial terms, confidentiality, the 
clinical trial schedule, third party responsibility, and publication rights. 
15.7 Data collection and archiving 
15.7.1 
Data collection 
The Investigator must maintain all required records for all subjects.  Data for this clinical trial will be 
recorded in the subject’s source documents and on the CRFs provided by the Sponsor.  All data should 
be recorded on the CRFs completely and promptly, and legibly using black ink.  A complete set of copies 
will remain at the clinical trial center with the related data clarification forms.  
15.7.2 
Source documentation 
The Investigator must keep accurate separate records (other than the CRFs) of all subject visits, being 
sure to include all pertinent clinical trial-related information.  A statement should be made indicating 
that the subjects have been included in this clinical trial and have provided signed written Informed 
Consent.  All AEs must be thoroughly documented. 
Results of any diagnostic tests conducted during the clinical trial should also be included in the source 
documentation.   
15.7.3 
Archives 
All pertinent data, correspondence, and reports, the original or amended clinical trial protocol, and all 
other material relating to the clinical trial will be maintained securely in Sponsor/CRO/Investigator/ 
Institution archives for the legally required duration for archiving (15 years after the end of the 
research or after its premature termination). 
The Investigator/Institution should maintain the essential clinical trial documents as specified in 
Section 8 of ICH GCP, and according to the applicable regulatory requirements. 


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The Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents. 
If the Principal Investigator retires, relocates, or withdraws from the responsibility of keeping the 
clinical trial records for any other reasons, custody must be transferred to a person who will accept 
the responsibility.  The Sponsor/CRO must be notified in writing of the name and address of the new 
custodian. 
15.8 Insurance 
A certificate attesting Third Party coverage of CRO/Sponsor will be provided upon request. 
15.9 Investigator and Administrative Structure  
Not applicable 
 
 


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16 REFERENCES 
1. McKenzie AW, Stoughton RB. Method for comparing percutaneous absorption of steroids. Arch 
Dermatol 1962; 86: 608-610. .  
2. Cornell RC and Stoughton RB. . Correlation of the vasoconstriction assay and clinical activity in 
psoriasis. . Arch Dermatol. 1985; 121; 63-67.  
3. Fleming C, Ganslandt C, Guenther L, Johannesson A, Buckley C, Simon JC, et al. Calcipotriol plus 
betamethasone dipropionate gel compared with its active components in the same vehicle and the 
vehicle alone in the treatment of psoriasis vulgaris: a randomied, parallel group, double-blind, 
exploratory study. . Eur J Dermatol. 2010;20(4):465-71.  
4. Kaufmann R, Bibby AJ, Bissonnette R, Cambazard F, Chu AC, Decroix J, et al. A new 
calcipotriol/betamethasone dipropionate formulation (Daivobet) is an effective once-daily treatment 
for psoriasis vulgaris. Dermatology. 2002;205(4):389-93.  
5. Lebwohl M, Tyring S, Bukhalo M, Alonso-Llamazares J, Olesen M, Lowson D, et al. Fixed 
Combination Aerosol Foam Calcipotriene 0.005% (Cal) Plus Betamethasone Dipropionate 0.064% (BD) 
is More Efficacious than Cal or BD Aerosol Foam Alone for Psoriasis Vulgaris: A Randomized, Double-
blind, Multicenter, Three-arm, Phase 2. Study. J Clin Aesthet Dermatol. 2016;9(2):34-41.  
6. Lovato P, Norsgaard H, Tokura Y, Ropke M. Calcipotriol and betamethasone dipropionate exert 
additive inhibitory effects on the cytokine expression of inflammatory dendritic cell-Th17 cell axis in 
psoriasis. J Dermatol Sci. 2016;81(3):153-64.  
7. Gniadecki R, Gniadecka M, Serup J. Inhibition of glucocorticoid-induced epidermal and dermal 
atrophy with KH 1060--a potent 20-epi analogue of 1,25-dihydroxyvitamin D3. . Br J Pharmacol. 
1994;113(2):439-44.  
8. Norsgaard H, Kurdykowski S, Descargues P, Gonzalez T, Marstrand T, Dunstl G, et al. Calcipotriol 
counteracts betamethasone-induced decrease in extracellular matrix components related to skin 
atrophy. . Arch Dermatol Res. 2014;306(8):719-29.  
9. Menter A, Korman NJ, Elmets CA, Feldman S, Gelfand JM, Gordon KB, et al. Guidelines of care for 
the management of psoriasis and psoriatic arthritis Section 3. Guidelines of care for the management 
and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60(4):643-59.  
10. Samarasekera E, Sawyer L, Parnham J, Smith CH. Assessment and management of psoriasis: 
summary of NICE guidance. BMJ. 2012;345:e6712.  
11. Dauden E, Bewley A, Lambert J, Girolomoni G, Cambazard F, Reich K. Expert recommendations: 
the use of the fixed combination calcipotriol and betamethasone dipropionate gel for the topical 
treatment of psoriasis. . J Eur Acad Dermatol Venereol. 2014;28 Suppl 2:22-32.  
12. Hendriks AG, Keijsers RR, de Jong EM, Seyger MM, van de Kerkhof PC. Efficacy and safety of 
combinations of first-line topical treatments in chronic plaque psoriasis: a systematic literature review. 
. J Eur Acad Dermatol Venereol. 2013;27(8):931-51.  


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13. Stoughton RB. Vasoconstriction Assay - Specific Applications. [book auth.] Surber C (eds) Maibach 
HI. Topical Corticosteroids. Basel : Karger, 1992 pp 42-53. 
14. 
Potency 
of 
Topical 
Corticosteroids 
(USA 
Classification). 
http://www.resourceclinical.com/clinical-tables/topical-corticosteroids-potency-USA-
classification.pdf. [Online]  
15. Foundation, National Psoriasis. Just looking for the Topical Steroids Potency Chart? 
https://www.psoriasis.org/about-psoriasis/treatments/topicals/steroids/potency-chart. [Online]  
16. Ference JD, Last AR. Choosing Topical Corticosteroids. Am Fam Physician (2009) 79(2):135-140.  
17. 
World 
Health 
Organization 
Classification 
of 
Topical 
Corticosteroids. 
https://emedicine.medscape.com/article/2172256-overview. [Online]  
 
 
 


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17 APPENDICES 
Appendix 1: Summary of Product Characteristics (SmPC)/ Product Monographs for Investigational 
Products – Clobex® lotion 
Appendix 2: Summary of Product Characteristics (SmPC)/ Product Monographs for Investigational 
Products – Betamethasone Dipropionate (Augmented) 
Appendix 3: Summary of Product Characteristics (SmPC)/ Product Monographs for Investigational 
Products – Triamcinolone Acetonide cream 
Appendix 4: Summary of Product Characteristics (SmPC)/ Product Monographs for Investigational 
Products – Locoid® cream 
Appendix 5: Summary of Product Characteristics (SmPC)/ Product Monographs for Investigational 
Products – DesOwen® cream  

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A RANDOMISED, EVALUATOR BLINDED, WITHIN SUBJECT, 
SINGLE CENTRE EVALUATION OF THE VASOCONSTRICTION 
PROPERTIES OF MC2-01 CREAM, COMPARED TO 5 OTHER 
CORTICOSTEROIDS IN HEALTHY SUBJECTS 
 
 
SPONSOR N° 
MC2-01-C4 
CPCAD N° 
CPC-3530 
EUDRACT N° 
2018-001673-24 
 
Sponsor 
Investigator 
BIRGITTE VESTBJERG 
 
DRUG DELIVERY SOLUTIONS APS (DDS) C/O 
MC2 THERAPEUTICS A/S 
AGERN ALLÉ 24-26 
DK-2970 HØRSHOLM 
DENMARK 
CATHERINE QUEILLE-ROUSSEL 
 
CPCAD 
HOPITAL L’ARCHET 2 
151 ROUTE DE SAINT-ANTOINE DE 
GINESTIERE 
FR-06202 NICE 
FRANCE 
 
 
 
Version number 
Date 
#2.0 
05-Dec-2018 
 
 


Statistical Analysis Plan 
 
 
MC2-01-C4 / CPCAD CPC-3530 
Version 2.0 dated 05-Dec-2018 
Page 2/16 
 
 
 
 
VERSION HISTORY 
 
Version 
Date of Issue 
Reason for change 
Version #1.0 
30-Oct-2018 
Anne-Claire Cathelineau issued the first version. 
Version #2.0 
05-Dec-2018 
Anne-Claire Cathelineau implemented the changes 
required by Irene Sandholdt and Morten Præstegaard 
and issued the second version. 
 
 


Statistical Analysis Plan 
 
 
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Version 2.0 dated 05-Dec-2018 
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SAP APPROVALS 
 
The following persons have approved this Statistical Analysis Plan by manually signing in 
the Tables below: 
On behalf of DDS 
Name & Title 
Date & Signature 
Johan SELMER, MD 
 
VP Medical Affairs 
 
 
 
 
 
CPCAD 
Name & Title 
Date & Signature 
Catherine QUEILLE-ROUSSEL, MD 
 
Investigator 
 
 
 
Anne-Claire CATHELINEAU, MSc 
 
Biostatistician 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
 
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Version 2.0 dated 05-Dec-2018 
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Table of contents 
 
1 
List of Abbreviations and definitions of terms ................................................................. 5 
2 
Study objectives ................................................................................................................ 6 
2.1 
Primary study objective ............................................................................................. 6 
2.2 
Secondary study objectives ....................................................................................... 6 
3 
Study design ...................................................................................................................... 6 
3.1 
Study type .................................................................................................................. 6 
3.2 
Study duration............................................................................................................ 7 
3.3 
Study schedule ........................................................................................................... 7 
3.4 
Population characteristics .......................................................................................... 8 
3.5 
Study treatments ........................................................................................................ 8 
4 
Study evaluation ................................................................................................................ 9 
4.1 
Visual assessment of skin blanching ......................................................................... 9 
4.2 
Assessment of local tolerability ................................................................................. 9 
4.3 
Safety assessment .................................................................................................... 10 
5 
Statistical methods .......................................................................................................... 10 
5.1 
Trial Population ....................................................................................................... 10 
5.1.1 
Definition ......................................................................................................... 10 
5.1.2 
Baseline characteristics .................................................................................... 12 
5.2 
. Analysis of pharmacodynamic effect (blanching) ................................................. 13 
5.2.1 
Primary pharmacodynamic criterion ................................................................ 13 
5.2.2 
Secondary pharmacodynamic criterion ............................................................ 14 
5.3 
Analysis of local tolerance / Systemic safety .......................................................... 14 
5.3.1 
Local safety ...................................................................................................... 14 
5.3.2 
Adverse events (AEs) ....................................................................................... 15 
5.4 
General principles .................................................................................................... 15 
5.4.1 
Handling of missing values .............................................................................. 15 
5.4.2 
Data presentation and graphics ........................................................................ 16 
 
List of Tables 
Table 1 –Study flow chart ........................................................................................................ 7 
Table 2 – Study treatments ....................................................................................................... 8 
Table 3 - Skin blanching visual scale ....................................................................................... 9 
Table 4 - Local tolerability scale .............................................................................................. 9 
 
List of Figures 
Figure 1: Disposition of subjects ......................................................................................... 11 
 
 
 


Statistical Analysis Plan 
 
 
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1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BDP 
Betamethasone dipropionate 
CPCAD 
Centre de Pharmacologie Clinique Appliquée à la Dermatologie = name of 
the trial site 
FAS 
Full Analysis Set 
IMP 
Investigational Medicinal Product 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N 
Number of subjects 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class 
 
 
 
 


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2 STUDY OBJECTIVES 
2.1 
Primary study objective 
The objective of this trial is to compare the vasoconstriction potential (skin blanching effect) 
of MC2-01 cream with Clobex® 0.05% (clobetasol propionate) lotion, Betamethasone 
Dipropionate (Augmented) cream, Triamcinolone Acetonide 0.1% (triamcinolone acetonide) 
cream, Locoid® 0.1% (hydrocortisone butyrate) cream, Desowen® 0.05% (desonide) cream 
and MC2-01 vehicle using the human skin blanching test (McKenzie-Stoughton’s test). 
 
2.2 
Secondary study objectives 
The objective of this trial is to assess the local tolerability of MC2-01 cream and the 
matching vehicle. 
 
3 STUDY DESIGN 
3.1 
Study type 
This is a single center, investigator blinded, active - and vehicle-controlled, single 
application, intra-individual comparisons on mini-test sites (n=7), involving 36 healthy 
subjects meeting specific inclusion/exclusion criteria. 
Eligible subjects will receive a single application of each of the following: 
- 
MC2-01 cream containing calcipotriol and betamethasone dipropionate, w/w 
0.005% / 0.064%. 
- 
MC2-01 cream vehicle 
- 
Clobex® lotion containing clobetasol propionate 0.05% 
- 
Betamethasone Dipropionate (Augmented) cream  
- 
Triamcinolone Acetonide containing triamcinolone acetonide 0.1% 
- 
Locoid® cream containing hydrocortisone-17-butyrate 0.1% 
- 
Desowen® cream containing desonide 0.05% 
The trial will employ an unoccluded McKenzie-Stoughton trial design based on topical 
application of a corticosteroid-containing formulation for a period of 16 hours in healthy 
human volunteers followed by visual estimation of the degree of blanching on a multiple 
unit scale (0 to 4) by two independent trained observers 2 hours after the end of the 
application period. The trial will be conducted with three successive individual phases: 
- 
Screening phase with a screening blanching test. 
- 
Test phase 
- 
Follow-up phase. For subjects with a local tolerability scores >0 at Day 2 or if a 
non-serious adverse event classified as reasonably or possibly related to the 
investigational products or a Serious Adverse Event (SAE) is ongoing once a subject 
has completed the test phase (Day 2), a follow-up visit/contact will take place up to 
14 (±2) days after the end of test phase (Day 2). SAEs will be monitored until the 


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Investigator and Sponsor agree that the event is satisfactorily resolved; telephone 
contact or visit according to the investigator’s discretion. 
 
3.2 
Study duration 
Clinical trial participation for each subject is of 2 days plus the screening phase and a 
possible follow-up phase. 
 
3.3 
Study schedule 
Table 1 –Study flow chart 
Trial Phases: 
Screening 
Test 
Follow-up(2) 
 Trial Days : 
Day-15 to Day-
1 
Day1 
Day2 
Day15 (±2days)
Informed Consent Form 
 
Demographics/Medical history 
 
 
 
 
Previous treatments/procedures 
 
 
 
 
Inclusion/exclusion criteria 
 
 
Selection of test sites 
 
Physical exam, vital signs 
 
Urine pregnancy test(1) 
 
 
Screening test for blanching response 
 
 
 
 
Randomization 
 
Local tolerance(2) 
 
 
Application of IMPs 
 
 
 
 
Product excess removal(3) 
 
 
 
 
Measurement of skin blanching by 2 trained 
evaluators(4) 
 
 
 
 
Concomitant treatments 
 
 
 
 
Adverse events 
 
 
 
 
End of treatment 
 
End of study 
 
 
 
 
1: For female subject of childbearing potential. Result must be negative to continue the trial. 
2: For subjects with a local tolerability scores >0 at Day 2 or if a non-serious adverse event classified as reasonably or 
possibly related to the investigational products or an SAE is ongoing once a subject has completed the test phase (Day 2), a 
follow-up visit/contact (telephone contact or visit according to the investigator’s discretion) will take place up to 14 (±2) 
days after the end of test phase (Day 2). AEs and SAEs assessed as reasonably or possibly related to the trial medication 
must be followed until resolved or until the medical condition of the subject is stable. 
3: 16 hours +/- 30 min after IMP application 
4: 2 hours +/- 30 min after IMP removal 


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3.4 
Population characteristics 
Approximately 60 subjects will be pretested in order to have 36 subjects randomized and at least 30 subjects completed. 
3.5 
Study treatments 
Table 2 – Study treatments 
 
Investigational  
product 1 
Investigational 
product 2 
Reference 
product 1 
Reference  
product 2 
Reference 
product 3 
Reference  
product 4 
Reference 
product 5 
Trade Name or 
Equivalent 
MC2-01 
MC2-01 vehicle 
Clobex® 
(Galderma Labs 
LP) 
Betamethasone 
Dipropionate 
(Augmented) 
(Taro 
Pharmaceuticals) 
Triamcinolone 
Acetonide 
(Ascend 
Laboratories 
LLC) 
Locoid 
(Precision Dermatology) 
Desowen 
(Galderma 
Labs LP) 
Name of Drug 
Substance 
Calcipotriol + 
Betamethasone dipropionate 
NA 
Clobetasol 
propionate 
Betamethasone 
dipropionate 
Triamcinolone 
acetonide 
Hydrocortisone butyrate 
Desonide 
Pharmaceutical 
Form 
cream 
cream 
lotion 
cream 
cream 
cream 
cream 
Concentration 
0.005% + 0.064% 
NA 
0.05% 
0.064% w/w 
(equivalent to 
0.05% 
betamethasone) 
0.1% 
0.1% 
0.05% 
Package 
60 g aluminium tubes 
60 g aluminium 
tubes 
Bottle 59ml 
15 g aluminium 
tubes 
30 g tube 
30 g aluminium tube 
60 g tube 
Storage 
conditions 
Store between 2-8°C between treatment days – 
May be store at room temperature below 25°C at 
the day of treatment application 
Store below 30°C 
Do not store above 
25°C 
Store at 20- 
25°C 
Do not store above 25°C.  
Do not refrigerate or 
freeze 
Store between 
2° and 30°C 
Dosage  
(per site) 
20 µL 
20 µL 
20 µL 
20 µL 
20 µL 
20 µL 
20 µL 
Route 
Topical (Cutaneous to the skin) 
Dose Regimen 
A single application of each IMP 
Duration of 
administration 
Contact duration of 16 hours (+/- 30 min) 
Location of 
Treated Area 
Area of 2.2 cm diameter 


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4 STUDY EVALUATION 
4.1 
Visual assessment of skin blanching 
Visual assessment of blanching will be made independently by two trained readers on Day 2 
(2 hours after removal of products, following 16 hours application time) according to the 
following scale: 
Table 3 - Skin blanching visual scale 
Score* 
Description 
0 
No change in skin color 
1 
Slight (barely visible) blanching 
2 
Obvious blanching 
3 
Intense blanching 
4 
Blanching judged to be maximal 
*Intermediate scores (half units) may be used when needed (e.g. 0.5 for a doubtful 
blanching). 
Two visual score values (one per trained evaluator) will be recorded for each test site. 
 
4.2 
Assessment of local tolerability 
At Day 2, the (sub)investigator will assess each test site for local tolerability according to 
the scale in Table 4. 
Table 4 - Local tolerability scale 
Score* 
Description 
0 
No reaction 
0.5 
Only slight erythema 
1 
Only erythema 
2 
Erythema with papules or oedema 
3 
Erythema, oedema with papules, oedema with vesicle 
4 
Blisters 
IR 
Irritant reaction including: miliaria (sweat rash), follicular pustules, burn-like 
reactions, dry scales 
 
Subjects with a local tolerability score >0 will be re-assessed at a follow-up visit. 
Cutaneous reactions scored as local tolerability will be reported as local Adverse Events 
(AEs). 


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4.3 
Safety assessment 
A safety assessment will be conducted for all subjects at the screening visit (from the 
Informed Consent signature) and every subsequent visit.  The safety parameters are AEs, to 
be recorded as specified in the protocol, global cutaneous tolerance assessments, physical 
examination and vital signs assessments (Screening visit only). 
AEs will be reported individually on an ongoing basis. 
All clinical medical events, whether observed by the Investigator or reported by the Subject 
will be considered as adverse events and recorded on the appropriate Adverse Event form. 
Assessment of severity and causality will be based on specific definitions. 
 
5 STATISTICAL METHODS 
5.1 
Trial Population 
5.1.1 Definition 
A detailed counting of subjects included or excluded from analysis will be performed prior 
to any data review and analysis. All protocol deviations will be reported.  
All randomized subjects who receive any trial medication and who contribute any efficacy 
data in the trial will comprise the full analysis set (FAS) and will be analyzed for efficacy. 
A per protocol analysis set (PP) will be defined by exclusion of subjects from the FAS, 
who do not fulfil all of the inclusion criteria or who meet any of the exclusion criteria. 
Further subjects and/or subject data may be excluded from the per protocol analysis when 
agreed upon on the basis of the actual data obtained as evaluated before breaking the 
randomization code. 
All subjects who receive any treatment with trial medication and for whom the presence or 
confirmed absence of AEs is available will be included in the safety analysis set and 
analyzed for safety. 
 
 


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The following chart will be completed to describe the different populations: 
Figure 1: Disposition of subjects 
 
 
 
N=XX 
Subjects screened 
N=XX 
Subjects randomized 
N=XX 
Screening failures 
 
Reasons: 
 ….(n) 
 ….(n) 
N=XX 
Did not receive any 
treatment 
 
Reasons: 
 ….(n) 
 ….(n) 
N=XX 
Day 1 completed  
N=XX 
Major protocol deviations 
N=XX 
Day 2 completed  
N=XX 
 
Safety Analysis Set 
N=XX 
 
Per Protocol Analysis 
Set (PP) 
N=XX 
 
Full Analysis Set (FAS) 
N=XX 
Withdrawn 
 
Reasons: 

AE (n) 

Subject’s request (n) 


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A data blind review will be performed after the database lock and before breaking the 
randomization code. A listing of all protocol deviations will be provided, including the type 
(major/minor) and their consequences in terms of analysis, according to the decisions made 
by the reviewers. 
A major protocol deviation is any event likely to biase significantly the interpretation of the 
efficacy results and especially the primary ones. Then, this type of deviation will lead to 
subject exclusion from the PP population. All other protocol deviations will be considered as 
minor. 
A priori the following deviations will be considered as major: 
 Deviations in inclusion and non-inclusion criteria at screening, 
 Exclusion criteria during the study (pregnancy, health problems, protocol 
deviation / violation, consent withdrawal, intake of any product or treatment 
able to interfere with study results, onset of an intolerance to the study 
treatments), 
 Evaluation of primary criterion non-available. 
Other elements will be detailed to detect possible deviations: 
 
Consistency of the randomization scheme, 
 
Premature withdrawals from study, 
 
Medical and surgical history, 
 
Previous and concomitant treatments, 
 
Adverse events, 
 
Deviations in dates of visits. 
Number and percentage of subjects having at least one minor protocol deviation will be 
presented by type and deviation class. Major deviations will be listed. 
5.1.2 Baseline characteristics 
Summary statistics of subject characteristics (age, sex, skin type, height, weight and BMI) 
and of baseline characteristics (hormonal status, concurrent diagnoses and concomitant 
medication at baseline as well as screening test for skin blanching) will be tabulated. 
 
The results will be presented as follows: 
 
 
 
Full Analysis Set (N=XX) 
Quantitative 
variable 
N 
 
Mean±SD 
 
Median 
 
(Min,Max) 
 
Qualitative 
variable 
N 
 
Modality 1 
N (%) 
Modality 2 
N (%) 
Modality n 
N (%) 
 


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5.2 
. Analysis of pharmacodynamic effect (blanching) 
5.2.1 Primary pharmacodynamic criterion 
The analysed variable will be the mean between the two readers at each evaluation time. 
The results will be expressed by the mean values obtained at each assessment time by 
product/site. 
MC2-01 cream will be compared with Clobex® lotion, Betamethasone Dipropionate 
(Augmented) cream, Triamcinolone Acetonide cream, Locoid® cream, DesOwen® cream 
and MC2-01 cream vehicle in terms of visual score of skin blanching 2 hours after a 16 
hours application, using an ANOVA with subjects and treatments as factors.  
Some minor changes in the protocol statistical methods have been decided and reported in 
the SAP to improve the data analysis of the primary criterion. 
The protocol planned that In case of a significant treatment effect, estimates of treatment 
effect and 95% confidence interval of differences between reference products and MC2-01 
cream will be calculated from the model without correction for multiplicity in the primary 
analysis and that correction for multiplicity using Dunnett's test will be used as secondary 
analysis. In case of significant deviation to the normal assumption, a non-parametric 
approach with Kruskall-Wallis test for the overall product effect and Wilcoxon's Sign Rank 
Test for the pairwise comparisons will be used 
The present Statistical Analysis Plan states that In case of a significant treatment effect, the 
comparisons between reference products and MC2-01 cream will be done from the model 
with correction for multiplicity using Dunnett's test directly in the primary analysis.  For 
each fitted model, residual plots will be used to check the model assumptions. If there is an 
obvious deviation to these assumptions, the analysis will be done on the rank-transformed 
data. 
The data will be also presented graphically by treatment using boxplot of visual assessment 
of skin blanching. 


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The results will be presented as follows: 
 
MC2-01 cream 
(n=XX) 
Clobex® lotion 
(n=XX) 
Betamethasone 
Dipropionate 
(Augmented) 
cream (n=XX) 
Triamcinolone 
Acetonide 
cream (n=XX) 
Locoid® cream 
(n=XX) 
Desowen® 
cream (n=XX) 
MC2-01 cream 
vehicle (n=XX) 
N 
 
 
 
 
 
 
 
Mean±SD 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
(Min,Max) 
 
 
 
 
 
 
 
p-valuea (treatment 
comparison versus 
MC2-01 cream) 
- 
 
 
 
 
 
 
a: method used for multiple comparisons 
5.2.2 Secondary pharmacodynamic criterion 
Non Applicable 
5.3 
Analysis of local tolerance / Systemic safety 
5.3.1 Local safety 
The local tolerance score will be summarized using frequency and percentage by trial product. The worst score will also be summarized. 
The results will be presented as follows: 
 
MC2-01 cream 
(n=XX) 
Clobex® lotion 
(n=XX) 
Betamethasone 
Dipropionate 
(Augmented) 
cream (n=XX) 
Triamcinolone 
Acetonide 
cream (n=XX) 
Locoid® cream 
(n=XX) 
Desowen® 
cream (n=XX) 
MC2-01 cream 
vehicle (n=XX) 
N 
 
 
 
 
 
 
 
Modality 1 
Modality 2 
Modality n 
 
 
 
 
 
 
 


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5.3.2 Adverse events (AEs) 
An overview of all AEs occurred during the trial will be presented as follows: 
 
 
Safety Population (N=XX) 
 
n events 
n (%) subjects 
All AEs 
 
 
Related AEs 
 
 
All cutaneous AEs 
 
 
Related cutaneous AEs 
 
 
All serious AEs 
 
 
Related serious AEs 
 
 
Severe AEs 
 
 
Related severe AEs 
 
 
AEs of special interest 
 
 
AEs leading to discontinuation 
 
 
Related AEs leading to discontinuation 
 
 
Deaths 
 
 
 
Adverse events will be coded during the course of the trial and will be in accordance with 
the current version of the MedDRA dictionary. The adverse events will be tabulated by 
Preferred Terms and System Organ Class. 
The number of subjects experiencing each type of adverse event (according to MedDRA 
Preferred Terms and System Organ Class) will be tabulated regardless of the number of 
times each adverse event is reported by each subject. 
Adverse events where the investigator has not excluded a causal relationship to trial 
medication (i.e. not described relationship as "no reasonable possibility", adverse drug 
reactions (ADR)) will be evaluated separately. A table or a description of these ADRs will 
be produced depending on the number of ADRs. As with adverse events, the number of 
subjects affected, not the number of events, will be considered. 
The causal relationship of adverse events to trial medication and the intensity of adverse 
drug reactions will be tabulated or described. Where there are several recordings of causal 
relationship and intensity for the same event, causal relationship will be taken from the last 
report of the event (since that is when the investigator will be in possession of most 
information and so best able to judge causal relationship) and intensity will be taken as the 
worst ever recording. Adverse events observed on the application areas will be tabulated or 
described by treatment. 
 
5.4 
General principles 
All tests will be two-sided and the 0.05 probability level will be chosen to declare 
significance. The analysis will be performed using the R-Software version 3.3.2 
5.4.1 Handling of missing values 
It was assumed that only very few skin blanching scores would be missing for the primary 
endpoint. Drop-outs and missing values will be accounted for by the definition of the trial 


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analysis sets prior to unblinding. No particular treatment will be done on missing values. In 
case of missing data concerning the primary pharmacodynamic primary criterion, the subject 
will be excluded from the analysis.  
A last observation carried forward (LOCF) approach is not relevant as the study involves a 
single pharmacodynamic endpoint. 
 
5.4.2 Data presentation and graphics 
Continuous variables will be summarized using mean, median, minimum (Min), maximum 
(Max) and standard deviation (SD). Categorical variables will be summarized by counts (N) 
and percentages (%) for each response category. 
Subject disposition, demographic variables, baseline characteristics and concomitant 
treatments will be summarized for all randomized subjects. 
The number of decimals presented will refer to the original values. Min and Max will have 
as many decimals as the original values. 
The tables will be structured with a column for each study treatment and will be annotated 
with the total population size relevant to that treatment. 
AEs will be tabulated in frequency tables by System Organ Class (SOC) and Preferred Term 
(PT) based on the MedDRA dictionary.