Clinical trial NCT03025282
Conditions: Psoriasis Vulgaris
Sponsor: Galderma R&D
Start date: 2016-11-03; Completion date: 2017-03-24
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was an exploratory, single-center, investigator blinded, randomized, controlled, intra-individual study, involving participants with psoriasis vulgaris.

The objective was to evaluate, in a modified Dumas-Scholtz psoriasis mini-zone test, the safety and efficacy of CD10367 solution at 1% and 3% after a 3-week treatment period of once daily application.

Detailed description:
Study drugs would be applied in each participant once daily, 5 days a week during the first 2 weeks and for 4 days the third week on 6 mini-zones located on at least 2 psoriatic plaques as described below:

* on 2 mini-zones pretreated by a keratolytic product, would be tested:

  * CD10367 3% solution
  * CD10367 solution placebo
* on 4 mini-zones non-pretreated, would be tested:

  * CD10367 3% solution
  * CD10367 1% solution
  * CD10367 solution placebo
  * Betneval 0.1% ointment

Arms: arm 1: None arm 2: None arm 3: CD10367 solution placebo serves as negative control. arm 4: This comparator containing Betamethasone valerate 0.1% serves as positive control. arm 5: None arm 6: None
Interventions: intervention 1: CD10367 3% Solution - Non-desquamated zone intervention 2: CD10367 1% Solution - Non-desquamated zone intervention 3: CD10367 solution placebo - Non-desquamated zone intervention 4: Betneval ointment - Non-desquamated zone intervention 5: CD10367 3% Solution - Desquamated zone intervention 6: CD10367 solution placebo - Desquamated zone
Intervention descriptions: intervention 1: Once daily application for 3 weeks intervention 2: Once daily application for 3 weeks intervention 3: Once daily application for 3 weeks intervention 4: Once daily application for 3 weeks intervention 5: Once daily application for 3 weeks intervention 6: Once daily application for 3 weeks

Protocol documents:
Prot_000.pdf: 
GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 1 of 85 
 
CLINICAL TRIAL PROTOCOL 
PROTOCOL NUMBER: RD.03.SPR.112075 
CONFIDENTIAL 
This document contains confidential, proprietary information 
All the information provided to the Investigator and his/her staff and all data obtained through 
this GALDERMA clinical trial protocol are confidential.  The Sponsor reserves all proprietary 
rights. No information may be disclosed to any third party without prior written consent from 
GALDERMA. 
 
CONFIDENTIAL  GALDERMA                  
Internally Approved
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 2 of 85 
TITLE PAGE 
Title 
EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF CD10367 IN SUBJECTS 
WITH PSORIASIS 
Project Name or CD number:  
Project Number: 
Clinical Trial Phase: 
CD10367 
315 
Phase 2a 
EUDRACT NUMBER 2016-002774-12 
Version Number: 01  
SPONSOR: 
Name: 
GALDERMA R&D, SNC 
Address: 
Les Templiers 
2400 route des Colles 
06410 BIOT France 
Telephone: 
+33 (0)4 93 95 70 70 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 3 of 85 
For any safety questions, please contact the Clinical Safety Officer (CSO) using the contact 
details provided in Section 7.2.6.2.2. 
For any medical questions related to the clinical trial protocol, please contact the Medical Expert 
(see contact details in study team contact list). 
This clinical trial will be performed in compliance with applicable regulatory requirements and 
Good Clinical Practice (GCP), 
.  This clinical trial protocol follows guidelines outlined by the International Conference on 
Harmonisation (ICH) and the GALDERMA template. 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 4 of 85 
Table of Contents 
TITLE PAGE ............................................................................................................................................... 2 
SYNOPSIS ................................................................................................................................................. 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................ 18 
1 
BACKGROUND AND RATIONALE ........................................................................................... 23 
1.1 
Medical background and Short rationale for the clinical trial .............................................. 23 
1.2 
Psoriasis ...................................................................................................................................... 23 
1.3 
Drug profile ................................................................................................................................ 24 
1.4 
Risk/Benefit assessment ............................................................................................................. 24 
2 
CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS ..................................... 27 
2.1 
Clinical trial objectives .............................................................................................................. 27 
2.2 
Clinical hypothesis ..................................................................................................................... 27 
3 
OVERALL CLINICAL TRIAL DESCRIPTION ........................................................................ 27 
3.1 
Overall description ..................................................................................................................... 27 
3.2 
Discussion of study design ......................................................................................................... 29 
3.2.1 
The modified Dumas-Scholtz psoriasis mini-zone model .................................................. 29 
3.2.2 
Pretreatment: Keratolytic agent .......................................................................................... 30 
3.2.3 
Control groups ...................................................................................................................... 30 
3.2.5 
Choice of concentrations ...................................................................................................... 30 
3.2.6 
Treatment application .......................................................................................................... 31 
3.2.7 
Evaluation of CD10367 efficacy ........................................................................................... 31 
3.2.9 
Safety monitoring .................................................................................................................. 31 
4 
CLINICAL TRIAL DURATION AND TERMINATION .......................................................... 32 
5 
SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION .......................... 32 
5.1 
Number of subjects .................................................................................................................... 32 
 
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Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 5 of 85 
5.2 
Clinical trial population characteristics ................................................................................... 32 
5.3 
Inclusion criteria ........................................................................................................................ 32 
5.4 
Exclusion criteria ....................................................................................................................... 33 
5.5 
Previous and concomitant therapies......................................................................................... 36 
5.5.1 
Definition ............................................................................................................................... 36 
5.5.2 
Categories .............................................................................................................................. 36 
5.5.3 
Recording ............................................................................................................................... 37 
5.5.4 
Authorized concomitant therapies ...................................................................................... 37 
5.5.5 
Prohibited concomitant therapies........................................................................................ 37 
5.6 
Procedures/Reasons for subject discontinuation ..................................................................... 37 
6 
CLINICAL SUPPLIES ................................................................................................................... 40 
6.1 
Clinical supply identification and use ...................................................................................... 40 
6.1.1 
Study drug(s) description ..................................................................................................... 40 
6.1.2 
Subject Identification Number (SIN) .................................................................................. 41 
6.1.3 
Method of treatment assignment ......................................................................................... 41 
6.1.4 
Randomization number ........................................................................................................ 41 
6.1.5 
Instructions for use and administration .............................................................................. 41 
6.1.5.1 
Selection of target plaque(s) and mini-zones ................................................................. 42 
6.1.6 
Other supplies........................................................................................................................ 43 
6.2 
Study drug(s) packaging and labeling ...................................................................................... 43 
6.3 
Supplies management ................................................................................................................ 43 
6.3.1 
Accountability ....................................................................................................................... 43 
6.3.2 
Storage of study drug(s) ....................................................................................................... 44 
6.3.3 
Dispensing and return .......................................................................................................... 44 
6.3.4 
Treatment compliance management and record ............................................................... 44 
6.4 
Dose modification ....................................................................................................................... 44 
6.5 
Blinding ....................................................................................................................................... 45 
6.5.1 
Verification of blinding ......................................................................................................... 45 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
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6.5.2 
Un-blinding during the clinical trial .................................................................................... 45 
7 
CLINICAL TRIAL ASSESSMENT .............................................................................................. 46 
7.1 
Efficacy assessments .................................................................................................................. 46 
7.1.1 
Efficacy measurements ......................................................................................................... 46 
7.1.1.1 
Individual clinical scores ................................................................................................. 46 
7.1.1.2 
Clearing score ................................................................................................................... 47 
7.1.2 
Efficacy endpoints ................................................................................................................. 47 
7.1.2.1 
Primary Criterion ............................................................................................................ 47 
7.1.2.2 
Secondary Criteria ........................................................................................................... 47 
7.2 
Safety assessment ....................................................................................................................... 48 
7.2.1 
Physical examination and vital signs ................................................................................... 48 
7.2.1.1 
Physical examination and vital signs .............................................................................. 48 
7.2.2 
Laboratory safety tests ......................................................................................................... 49 
7.2.3 
12-lead electrocardiogram .................................................................................................... 50 
7.2.4 
Ophthalmic examination ...................................................................................................... 51 
7.2.5 
Local tolerability assessment................................................................................................ 51 
7.2.6 
Adverse Events ...................................................................................................................... 52 
7.2.6.1 
Definitions ......................................................................................................................... 53 
7.2.6.1.1 
Adverse events (AE) ...................................................................................................... 53 
7.2.6.1.2 
Serious Adverse events (SAE) ....................................................................................... 53 
7.2.6.1.3 
Adverse Events of Special Interest (AESIs) .................................................................. 54 
7.2.6.1.4 
Unexpected adverse drug reaction ............................................................................... 55 
7.2.6.1.5 
Adverse event reporting period .................................................................................... 55 
7.2.6.1.6 
Severity ......................................................................................................................... 55 
7.2.6.1.7 
Relationship to the study drug(s) and/or clinical trial procedure ................................ 55 
7.2.6.2 
Reporting procedures ...................................................................................................... 56 
7.2.6.2.1 
Procedures for reporting Adverse Events ..................................................................... 56 
7.2.6.2.2 
Procedure for reporting a Serious Adverse Event ........................................................ 58 
7.2.6.2.3 
Procedure for reporting an Adverse Event of Special Interest ..................................... 60 
 
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Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 7 of 85 
7.2.6.2.4 
Procedures for reporting pregnancies .......................................................................... 63 
7.4 
Pharmacokinetic assessments ................................................................................................... 64 
7.4.1 
Plasma concentration ............................................................................................................ 64 
7.5.4 
Quality of Life Assessment ................................................................................................... 66 
7.6 
Appropriateness of measurements ........................................................................................... 66 
8 
CLINICAL TRIAL VISITS DESCRIPTIONS AND PROCEDURES ...................................... 67 
8.1 
Description of clinical trial visits .............................................................................................. 67 
8.1.1 
Screening visit (up to 5 weeks before Baseline visit) .......................................................... 67 
8.1.2 
Baseline visit [Day 1] ............................................................................................................. 68 
8.1.3 
Interim visits (from Day 2 to Day 18) .................................................................................. 70 
8.1.4 
Final/ Early Termination visit (Day 19 visit) ...................................................................... 70 
8.1.5 
Follow-up visit (D26 2 visit) ............................................................................................... 71 
8.2 
Subject instructions (other than study drug(s) administration) ............................................ 72 
9 
STATISTICAL METHODS PLANNED ...................................................................................... 73 
9.1 
Statistical and analytical plans .................................................................................................. 73 
9.1.1 
Data transformations ............................................................................................................ 73 
9.1.2 
Populations analyzed and evaluability ................................................................................ 73 
 
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Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
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9.1.3 
Data presentation and graphics ........................................................................................... 74 
9.1.4 
Inferential statistical analyses .............................................................................................. 75 
9.2 
Sample size determination ......................................................................................................... 75 
9.2.3 
Sample size calculation ......................................................................................................... 76 
10 
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ........... 76 
10.1 
Personnel training ...................................................................................................................... 76 
10.2 
Clinical monitoring .................................................................................................................... 77 
10.3 
Data management ...................................................................................................................... 77 
10.4 
Quality assurance / audit / inspection....................................................................................... 77 
10.5 
Changes in clinical trial conduct / amendments ...................................................................... 78 
10.5.1 
Clinical trial conduct ............................................................................................................ 78 
10.5.2 
Amendments .......................................................................................................................... 78 
11 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS ................ 78 
11.1 
Independent Ethics Committee (IEC) ...................................................................................... 78 
11.2 
Ethical conduct of the clinical trial ........................................................................................... 78 
11.3 
Subject information and consent .............................................................................................. 78 
11.4 
Contractual requirements ......................................................................................................... 79 
11.5 
Data collection and archiving .................................................................................................... 79 
11.5.1 
Data collection ....................................................................................................................... 79 
11.5.2 
Source documentation .......................................................................................................... 79 
11.5.3 
Archives ................................................................................................................................. 79 
11.6 
Insurance .................................................................................................................................... 80 
11.7 
Investigator and Administrative Structure ............................................................................. 80 
12 
LITERATURE REFERENCE LIST ............................................................................................. 80 
12.1 
Literature references ................................................................................................................. 80 
13 
APPENDICES ................................................................................................................................. 83 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
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13.1 
Classification of CYP Inhibitors ............................................................................................... 83 
13.2 
Summary of blood sample volumes .......................................................................................... 85 
 
List of Tables 
Table 1 
Clinical trial schematic ............................................................................................... 16 
Table 2 
Schedule of Assessments ........................................................................................... 17 
Table 3  
Prohibited therapies .................................................................................................... 34 
Table 4 
 Description and usage of the study drug(s) ............................................................... 40 
Table 5 
Individual clinical scores ........................................................................................... 46 
Table 6 
Clearing Score ............................................................................................................ 47 
Table 7 
Local tolerance 4-point scales .................................................................................... 52 
 
 
CONFIDENTIAL  GALDERMA                  
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 10 of 85 
SYNOPSIS 
Clinical Trial Title: EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CD10367 IN SUBJECTS WITH PSORIASIS 
Short Title: EXPLORATORY STUDY TO EVALUATE CD10367 IN PSORIASIS 
 
Clinical Trial phase:  
Clinical Trial Population: subjects with psoriasis vulgaris 
Phase 2a 
 
Clinical Trial objectives: 
Primary objectives:  
To evaluate, in a modified Dumas-Scholtz psoriasis mini-zone test, the 
safety and efficacy of CD10367 solution at 1% and 3% after a three 
weeks treatment period of once daily application. 
Clinical Trial design: 
Exploratory, single-centre, investigator blinded, randomized, controlled, 
intra-individual study (Dumas-scholtz design).  
 
 
Total number of subjects 
(Planned):  
As a screen failure rate of approximately 40% percent is expected, 
approximately 40 subjects may have to be screened in order to obtain 24 
subjects randomized. 
Number of clinical trial 
centers (Planned):  
1 site. 
Region(s) / country(ies) 
involved (Planned): 
France 
Clinical trial duration: 
The planned clinical trial duration (from FSFV to LSLV) is approximately 5 
months. 
 
The planned duration of recruitment (from FSFV to LSFV) is 
approximately 3.5 months. 
Duration of subject 
participation:  
Clinical trial participation for each subject is approximately 9 weeks 
including screening period. 
Key Inclusion criteria 
 
Adult male or female aged at least 18 and up to 70 years old 
inclusive at screening visit. 
 
Female of non-childbearing potential (postmenopausal [absence 
of menstrual bleeding for 1 year prior to screening, without any 
 
CONFIDENTIAL  GALDERMA                  
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 11 of 85 
SYNOPSIS 
Clinical Trial Title: EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CD10367 IN SUBJECTS WITH PSORIASIS 
other medical reason], hysterectomy or bilateral oophorectomy). 
 
Subject has a skin phototype I to IV on Fitzpatrick’s scale. 
(Screening visit). 
 
The subject has a clinical diagnosis of stable plaque psoriasis, 
defined as no flare during the month before Screening visit and 
no change between Screening visit and Baseline visit, of mild to 
moderate severity. (Screening visit and Baseline Visit). 
 
The subject presents with at least six eligible mini-zones, on at 
least two psoriasis plaques (Screening visit and verified also at 
Baseline Visit) with specific severity grades defined in the 
protocol (Screening and Baseline Visit) 
 
Subject agrees not to wear his/her contact lenses from the 
Baseline visit till the D19 visit,  
Key Exclusion criteria 
 
The subject presents guttate, erythrodermic, exfoliative, inverse, 
pustular, 
palmo 
plantar, 
infected 
or 
ulcerated 
psoriasis 
(Screening visit).  
 
Any uncontrolled or serious disease, or any medical or surgical 
condition, that may either interfere with the interpretation of the 
clinical trial results, and/or put the subject at significant risk 
(according to Investigator’s judgment) if he/she participates in the 
clinical trial (e.g. history of on-going gastric or duodenal ulcer, 
clinically significant lung disease, etc.). 
 
Known or suspected allergies or sensitivities to any components 
of the study drugs or of the keratolytic product (see Investigator’s 
Brochure/Product label) .  
 
Subject with known history of adverse drug reaction or 
hypersensitivity to a product with the same mode of action 
 
Subject with any abnormal clinically significant findings according 
to the ophthalmologist, at the ophthalmological exam at 
Screening, 
 
The subject presents any abnormal laboratory tests defined in 
the protocol  (blood sampling and urinalysis done at Screening 
visit), 
 
QTc interval >450msec or any abnormal ECG value considered 
as clinically significant by the cardiologist at Screening, 
 
The subject has received, applied or taken specific treatments 
within the time frame defined in the protocol  prior to the Baseline 
 
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Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 12 of 85 
SYNOPSIS 
Clinical Trial Title: EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CD10367 IN SUBJECTS WITH PSORIASIS 
visit. 
Investigational product: 
NA 
 
Name: 
NA 
Internal code [if 
applicable]: 
CD10367  
Pharmaceutical form: 
Solution 
[Strength/Concentration]: 1% 
Dosage (total daily dose): 50µl  
Route: 
Topical 
Duration of 
administration: 
Five consecutive days a week for two weeks and four consecutive days 
in the third week (14 applications)  
Dose regimen: 
Once daily 
Location of treated area: 
Mini-zones on upper and/or the lower extremities (elbows, knees and 
shin area excluded) and/or on the trunk 
Investigational product: 
NA 
 
Name: 
NA 
Internal code [if 
applicable]: 
CD10367  
Pharmaceutical form: 
Solution 
[Strength/Concentration]: 3% 
Dosage (total daily dose): 100µl  
(50µl on each mini-zone) 
Route: 
Topical 
Duration of 
administration: 
Five consecutive days a week for two weeks and four consecutive days 
in the third week (14 applications)  
Dose regimen: 
Once daily 
Location of treated area: 
Mini-zones on upper and/or the lower extremities (elbows, knees and 
shin area excluded) and/or on the trunk 
Investigational product: 
NA 
 
Name: 
NA 
Internal code [if 
applicable]: 
CD10367 placebo 
Pharmaceutical form: 
Solution 
[Strength/Concentration]: NA 
Dosage (total daily dose): 100µl  
(50µl on each mini-zone) 
Route: 
Topical 
Duration of 
administration: 
Five consecutive days a week for two weeks and four consecutive days 
in the third week (14 applications)  
Dose regimen: 
Once daily 
Location of treated area: 
Mini-zones on upper and/or the lower extremities (elbows, knees and 
 
CONFIDENTIAL  GALDERMA                  
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 13 of 85 
SYNOPSIS 
Clinical Trial Title: EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CD10367 IN SUBJECTS WITH PSORIASIS 
shin area excluded) and/or on the trunk 
Comparator: 
Betneval 
Name: 
Betamethasone valerate 0.1%  
Internal code: 
NA 
Pharmaceutical form: 
Ointment  
[Strength/Concentration]: 0.1% 
Dosage (total daily dose): 50µl 
Route: 
Topical 
Duration of 
administration: 
Five consecutive days a week for two weeks and four consecutive days 
in the third week (14 applications)  
Dose regimen: 
Once daily 
Location of treated area: 
Mini-zones on upper and/or the lower extremities (elbows, knees and 
shin area excluded) and/or on the trunk 
Efficacy assessment: 
 
 
Efficacy endpoints: 
The individual scores and clearing scores will be assessed twice weekly 
by the investigator. 
 
Primary efficacy endpoint(s) or co-primary endpoint(s) 
 
Area Under the Curve (AUC) of Total Sum Score (sum of erythema, 
scaling and induration scores) from Day 1 to Day 19. 
 
 
Secondary efficacy endpoint(s) 
 
 
AUC of individual clinical scores (erythema, scaling and 
induration) from Day 1 to Day 19. 
 
TSS and percentage change from baseline at each visit. 
 
Erythema, Scaling and Induration score and their change from 
baseline at each visit. 
 
Success rate (defined as a clearing score of 0 or 1) at each 
evaluation visit and the time to first success. 
Safety assessment: 
 
A safety assessment will be conducted for all subjects at screening visit 
(from the Informed consent signature) and every subsequent visit. 
 
Safety endpoints [only 
when applicable]: 
 
Local tolerance assessed twice weekly by the Investigator using 
a 4-point scale for each mini-zone 
 
Physical examination at Screening, and Day 19 (or Early 
Termination visit if any); 
 
Record of vital signs at Screening, Baseline and Day 19 (or Early 
Termination visit if any); 
 
Ophtalmic examination at Screening, and Day 19 (or Early 
 
CONFIDENTIAL  GALDERMA                  
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 14 of 85 
SYNOPSIS 
Clinical Trial Title: EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CD10367 IN SUBJECTS WITH PSORIASIS 
Termination visit if any); 
 
ECG at Screening, and Day 19 (or Early Termination visit if any); 
 
Blood samplings for laboratory safety tests at Screening and Day 
19 (or Early Termination visit if any); 
 
Urinalysis at Screening and Day 19 (or Early Termination visit if 
any); 
 
Monitoring and recording of AEs to be recorded as specified in 
Section 7.2.6. 
 
Sample size: 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
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SYNOPSIS 
Clinical Trial Title: EXPLORATORY STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CD10367 IN SUBJECTS WITH PSORIASIS 
Therefore 24 subjects are planned to be randomized. 
This sample size is sufficient to assess also local tolerance in standard 
tolerance topical studies. 
 
 
CONFIDENTIAL  GALDERMA                  
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 16 of 85 
Table 1 
Clinical trial schematic 
Screening 
(Approximately 40 subjects) 
 
1 week pre-treatment with keratolytic product twice Daily at home on one or two psoriasis plaque(s) 
(extend one more week if Scaling score ≥2 at the end of one week) 
 
 
Treatment 
(Approximately 24 subjects randomized) 
  
 
 
Treated conditions: 
Desquamated plaque(s) 
Non desquamated plaque(s) 
CD10367 
3 % 
solution 
CD10367 
Solution 
Placebo 
 
CD10367 
3 % 
Solution 
CD10367 
1 % 
solution 
CD10367 
Solution 
Placebo 
 
Positive control: 
Betneval 0.1% 
Ointment 
 
 
Final Visit (D19) / ET 
 
 
Follow up Visit (D26+/-2) 
 
 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 17 of 85 
Table 2 
Schedule of Assessments 
  
Screening period 
Pre-treatment period 
Treatment Period 
Follow-up period 
Up to 3 weeks before 
pre-treatment period 
1 or 2 weeks a before 
treatment period 
Week 1 
Week 2 
Week 3 
Week 4 to 5 
D1 
D2 &D3 
D4 
D5 
D8 D9 & D10 D11 D12 D15 
D16&D17&D18 
Final visit D19 /ET  
D26 +/- 2 
Informed Consent Form 
X 
 
Demographics and Medical history 
X 
 
Previous treatments and procedures 
X 
 
Physical examination 
X 
 
X 
Vital signs 
X 
 
X 
X 
ECG 
X b 
X 
Ophthalmic examination 
X b 
X 
Inclusion Criteria and Exclusion Criteria 
X 
 
X 
Selection of target sites  
X 
 
X 
Urinalysis 
X 
 
X 
Safety tests Blood sampling 
X 
 
X 
Randomization 
 
X 
Local Tolerance c 
 
D2 only 
X 
 
X 
X 
 
X 
X 
Individual clinical scores 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Clearing score                                                     
 
X 
 
X 
X 
 
X 
X 
 
Keratolytic product application of selected plaque at home daily 
X 
Products application 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood sampling 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Concomitant treatments and Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exit form e 
 
X f 
X 
a. if the scaling score did not reach 0 or 1 after 1 week of pre-treatment, the pre-treatment period can be extended to 2 weeks, otherwise the subjects will start D1 visit immediately. b ECG and ophthalmic exams should be 
done as close as possible to baseline visit. c Local tolerance 
of the concerned zone must be taken at any visit in case of AE in a treatment zone. d Adverse Events have to be collected from the ICF signature. e 
Exit form should be signed after subject data collection has been completed. f Exit form should be completed at ET visit only if no follow-up visit is planned (discontinuation)  
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 18 of 85 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ACE 
Angiotensin-converting-enzyme 
AE  
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT/ALAT (SGPT) 
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) 
AST/ASAT (SGOT) 
Aspartate Aminotransferase (Serum Glutamic Oxaloacetic 
Transaminase) 
AUC  
Area under Curve  
AZ 
AstraZeneca 
BID  
Twice Daily (Latin: bis in die) 
CA 
Competent Authorities  
CRA 
Clinical Research Associate 
CRF/eCRF 
Case Report Forms/electronic Case Report Forms 
CRO 
Contract Research Organization 
CSO 
Clinical Safety Officer 
DMP 
Data Management Plan 
DS 
Drug substance 
ECG  
Electrocardiogram 
 
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Abbreviation 
Term 
e.g.  
For Example (Latin: exempli gratia) 
ET 
Early Termination 
etc 
Et cetera 
EU 
European Union 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit (date of first subject included i.e., informed 
consent signature) 
GCP  
Good Clinical Practice  
GLP 
Good laboratory practice 
GRD 
GALDERMA R&D 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
 
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Abbreviation 
Term 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
ID 
Identity 
i.e.  
That is (Latin: id est) 
IEC 
Independent Ethics Committee  
IHC   
immunohistochemistry 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LOCF 
Last Observation Carried Forward 
LOQ 
Limit of Quantification 
LSFV 
Last Subject First Visit (date of last subject included i.e., informed 
consent signature) 
LSLV 
Last Subject Last Visit (date of last subject’s last study visit) 
MALDI-FTICR-MS 
Matrix Assisted Laser Desorption Ionization 
MCV 
mean cell volume 
MD 
Medical Doctor 
 
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Abbreviation 
Term 
ME 
Medical Expert 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
N or n 
Number 
N/A 
Not Applicable 
NOAEL 
No-observed-adverse-effect level 
OTC 
Over-the-counter 
p 
Page(s) 
PE 
Physical Examination 
PK 
Pharmacokinetics 
Plt 
Platelets 
PO  
 Per os (Oral administration) 
PP 
Per-Protocol 
PT 
Preferred terms 
QD  
Once Daily (Latin: quaque die) 
RBC 
Red blood cell 
 
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Abbreviation 
Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
TESS 
Treatment Emergent Signs and Symptoms 
TOC 
Table of Contents 
TSS   
Total Sum Score 
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
UV 
ultraviolet 
WBC 
White Blood Cell 
 
 
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1 BACKGROUND AND RATIONALE 
1.1 
Medical background and Short rationale for the clinical trial 
1.2 
Psoriasis 
Psoriasis is a common, genetically determined, inflammatory and proliferative disease of the skin 
affecting 1.5% to 3% of the general population. The most characteristic lesions consist of 
chronic, sharply demarcated, dull-red scaly plaques, particularly on extensor parts of limbs. It can 
affect any body area including the face, palms, soles, folds, scalp and nails leading to erythema, 
scaling and thickening of the skin. 
Genetic-environmental interaction is usually considered for the causation of psoriasis. Smoking, 
alcohol consumption, diet, psychological stress, infections and physical trauma have been 
suggested as factors which may influence the onset of the disease and/or may affect severity or 
the response to treatment. 
The clinical course is unpredictable but in the majority of cases psoriasis is a chronically 
remitting and relapsing disease. Chronic stable plaque psoriasis (psoriasis vulgaris) is the most 
common form of the disease, accounting for 85% to 90% of cases. The circumscribed infiltrated 
skin lesions are scaly and erythematous and often symmetrically distributed over the body. Most 
of the patients suffer from mild to moderate plaque psoriasis with a body surface involvement of 
less than 10%. The majority of these patients can be treated with topical treatments, which 
generally provide both efficacy and safety (Menter et al., 2007). 
Psoriasis principal histological features are: thickening of the epidermis, parakeratosis, elongated 
rete ridges, and a mixed cellular infiltrate in the dermis (Griffiths and Barker, 2007).  The 
inflammatory infiltrate consists mainly in the dermis of dendritic cells, mast cells, macrophages, 
natural killer cells and different T-cell types such as CD4+ helper cells, CD8+ cytotoxic cells 
(Jullien, 2006). 
Keratinocytic hyperproliferation is mediated by pro-inflammatory cytokines produced by T-cells 
and dendritic cells that accumulate in diseased skin. Several inflammatory cytokines (e.g. 
interleukin 1 (IL-1), IL-6, IL-8, interferon-γ, and tumor necrosis factor-α (TNF-α)) are known to 
trigger epidermal hyperplasia through direct or indirect pathways (Jullien, 2006). 
Although there is no cure for psoriasis, a variety of treatments is available to reduce the severity 
of symptoms and lessen their impact on the patient’s quality of life. 
For patients with less than 20% body surface involvement, topical therapy is the most appropriate 
choice for the initial treatment. Commonly used topical therapies include corticosteroids, 
calcipotriol (a vitamin D analogue), tazarotene (the first topical retinoid approved for the 
treatment of psoriasis) and anthralin. Each of these treatments is effective in mild to moderate 
psoriasis, but each is also associated with varying degrees of safety and tolerability concerns. 
 
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For patients with more severe, recalcitrant, or extensive psoriasis, phototherapy and systemic 
therapies are available. These therapies are more effective than topical therapy, but are also 
associated with significant cutaneous and systemic adverse effects. 
Epidermal growth factor receptor (EGFR) is normally expressed in the skin, primarily in the 
proliferating undifferentiated keratinocytes of the basal cell layers of the epidermis and plays a 
key role in cellular proliferation, survival and differentiation. EGFR over-expression or over-
activity was associated with a number of cancers (e.g. lung, anal, head and neck, etc), but  recent 
data also showed an overexpression of EGFR ligands in lesional psoriasis skin (Johnston et al, 
2011). Varani et al showed in an in vitro study that psoriatic plaque skin incubated for eight days 
in the presence of a potent EGFR tyrosine kinase antagonist reverted to a normal histological 
appearance (Varani et al, 2005). 
There are also several case reports of patients with cancer treated by EGFR inhibitors showing an 
improvement of their psoriasis (Overbeck and Griesinger, 2012). 
. This outcome was already 
described in a mouse model by El-Abaseri (El- Abaseri 2013). 
Therefore the purpose of this study is to evaluate the safety, efficacy, 
 of CD10367 
topical solution in psoriasis.  
 
1.3 
Drug profile 
CD10367 is a potent and selective inhibitor of the tyrosine-kinase domain of the epidermal 
growth factor receptor (EGFR-TKI). This compound was initially developed as an oral 
formulation by AstraZeneca (AZ) for the treatment of solid tumors (including non-small cell lung 
cancer). 
  
 
 
 
 The compound is currently evaluated by GALDERMA R&D for the topical treatment 
of several indications such as psoriasis. 
 
1.4 
Risk/Benefit assessment 
This is an exploratory study to evaluate on psoriasis mini-zones the safety, efficacy, 
 
of CD10367 topical solution at 1% and 3%.  As only mini-zones will be treated in this study no 
individual benefit is expected for the subjects who will participate to the study. 
 
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All investigational medicinal product (IMP) will be applied on mini-zones, located on psoriatic 
plaques, and the quantity applied will be under the control of the qualified staff who will perform 
all the applications at the site and no IMP will be given to the subjects for applications at home.  
In order to improve the drug penetration, in this study, one or two psoriasis plaque(s) will be 
desquamated using a marketed cosmetic keratolytic agent 
 containing 
urea and low concentration of salicylic acid prior to application of CD10367 and its placebo on 
mini-zones. In clinical practice, urea and salicylic acid-based products are usually associated with 
local psoriasis treatments in order to increase and fasten their efficacy.   Only mild irritation has 
been reported as the most common side effect, making urea a safe and well-tolerated topical drug 
(Pan, 2013; Jacobi, 2015). This keratolytic product will be applied twice daily by the subjects at 
home. 
 
 The safety ratios calculation for the current study were estimated using two approaches: 1) in 
accordance with regulatory guidance (FDA Guidance for Industry July 2005), 
 
. 
 
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Considering the estimated safety ratios for the proposed study and the short treatment duration, 
these safety risks are not expected to occur. However, appropriate inclusion/ exclusion criteria 
and safety follow-up measures have been planned. 
Regarding the ocular toxicity risk, even if clinical studies done by AZ and GRD did not confirm 
this risk in human being, specific inclusion/exclusion criteria have been defined to minimize this 
risk for the subjects, e.g. exclusion of subjects with abnormal ophthalmic examination according 
to the ophthalmologist at Screening, etc.  
As to the cardiac risk, an ECG is planned at screening with exclusion of subjects with any 
clinically significant ECG findings; an ECG monitoring is planned during the study. 
 
Other toxicities have been reported for marketed oral or injectable EGFR inhibitors such as 
acneiform skin rash, gastrointestinal side effects (diarrhea), interstitial lung disease, 
hepatotoxicity or renal toxicity (MacDonald JB et al. 2015, Gillespie et al. 2009).   
As mentioned above for the ocular toxicity risk and the cardiac risk, these potential reactions are 
not expected to occur in the proposed study, considering the limited quantity of product applied 
and the short treatment duration.  
During the study, subjects safety will be closely monitored on a daily basis during product 
application period and at the follow-up visit taking into account data generated during the 
development of the oral route by AZ and the GRD studies for the topical route. 
 
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Local tolerance during the drug application period will be assessed systematically in order to 
evaluate any potential irritancy, sensitization reaction or papulo-pustular eruption. 
 
In conclusion, based on the current non-clinical and clinical data presented above and detailed in 
the Investigator’s Brochure, 
, the Sponsor considers 
that CD10367 topical solution at 1% and 3% does not raise any safety concerns when applied 
under the defined clinical study conditions. 
2 CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS 
2.1 
Clinical trial objectives 
The purpose of this study is to evaluate, in a modified Dumas-Scholtz psoriasis mini-zone test, 
the safety and efficacy of CD10367 solution at 1% and 3% after a three weeks treatment period 
of once daily application. 
2.2 
Clinical hypothesis 
The hypothesis of the study is that the CD10367 solutions at 3% and/or at 1% applied once daily 
during 3 weeks in patients with psoriasis are well tolerated and significantly superior in efficacy 
to their vehicle when applied in the same conditions (once daily on desquamated plaques or not). 
3 OVERALL CLINICAL TRIAL DESCRIPTION 
3.1 
Overall description 
This is an exploratory, single-centre, investigator blinded, randomized, controlled, intra-
individual study, involving approximately 24 subjects with psoriasis vulgaris meeting specific 
inclusion/exclusion criteria. 
The study will be conducted in France and consists of: 
 a screening period (within 3 weeks before pretreatment period); 
 
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 A pretreatment period 1 week before Baseline visit in order to decrease the scaling on selected 
target psoriasis plaque(s), before treatment with IMPs. This period can be extended to 2 
weeks if sufficient desquamation does not occur and the scaling score does not reach 0 or 1 
(none or mild scaling). During this period, the subjects will apply a keratolytic product at 
home twice a day on the selected plaque(s). 
 a 3-week treatment period during which the treatments will be applied on mini-zones 
according to the randomization list, 
 
 
 
 a final visit at Day 19 (or early termination visit if any), to evaluate safety and efficacy of the 
treatments, 
; 
 
 
 
In total, for each subject six-treatment mini-zone will be tested: 
- 
on one or more psoriatic plaque, four mini-zones will be tested: 
o CD10367 3% solution 
o CD10367 1% solution 
o CD10367 solution placebo 
o Betneval 0.1% ointment 
- 
on one or two desquamated psoriatic plaque (pre-treated), two mini-zones will be tested: 
o CD10367 3% solution 
o CD10367 solution placebo 
 
Figure 1: Schematics of the treated mini-zones 
 
 
 
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Local tolerance assessments will be performed twice a week from Day 2 to Day 19/ET visit and 
at any visit if a cutaneous AE occur on a treated zone.  
Psoriasis severity scores will be performed at screening visit before desquamation, then two times 
a week from Day 1 to Day 19/ET.  
All samples will be shipped to GALDERMA R&D or its contractors at the end of the study. 
 
 
 
 
  
 
3.2 
Discussion of study design 
3.2.1 
The modified Dumas-Scholtz psoriasis mini-zone model 
The method of the psoriasis plaque test first described by Dumas and Scholtz (Scholtz J.R. and 
Dumas K.J 1968, Dumas K.J. and Scholtz J.R 1972) and modified by Baadsgaard (Baadsgaard,. 
1995) allows multiple intra-individual comparisons in the targeted pathology.  This method has 
been used to test the efficacy of corticosteroids (Scholtz J.R. and Dumas K.J 1968), 
immunomodulating molecules (Remitz, 1999) and vitamin D derivatives (Baadsgaar, 1995). 
The pertinence of this test in the assessment of the anti-psoriatic activity has been already 
validated several times with Betneval® 
 chosen in this 
study as positive control or with other products from the therapeutic arsenal of psoriasis, 
 
 
.  
 
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3.2.2 
Pretreatment: Keratolytic agent 
In this study, one or two psoriasis plaque(s) will be desquamated prior to application of CD10367 
3% and its vehicle with a marketed cosmetic keratolytic agent. The purpose is to remove  a part 
of superficial layers in order to eliminate any potential penetration issues linked to the barrier 
effect created by the squames.  
In order to avoid any potential interaction with the other mini-zones tested under normal 
conditions, the desquamation will be done on one or two entire psoriasis plaque(s) separated from 
the other ones to be used for the standard application zones. These plaques should be big enough 
to include two mini-zones (one zone for CD10367 solution 3% and one zone for its vehicle). 
 
 
 
The cosmetic product used as keratolytic agent will be 
 extreme cream from 
 
 (tube 50ml) with 50% of urea and 2% of salicylic acid (other components: serine, 
histidine, glycenin, protease, fragrance free and paraben free).  
Urea is a moisturizer and keratolytic agent usually used in the treatment of psoriasis as adjuvant. 
Different cosmetics are available on the market with variable concentrations in urea. A high 
content of urea is responsible for its keratolytic properties.  
Salicylic acid acts as a keratolytic agent as well and enhances the keratolytic effect produced by 
urea. 
3.2.3 
Control groups 
In this study, CD10367 solution will be tested on once daily application under normal psoriatic 
skin condition and on desquamated psoriatic skin condition.  The vehicle, tested in both 
corresponding skin conditions, will be used as negative control for efficacy objective.  
Betneval® 0.1% ointment (Betamethasone Valerate 0.1%) was chosen as positive control to 
validate the study.  As mentioned in section 3.2.1, this active was successfully used in a previous 
Dumas-Scholtz design study. 
3.2.5 
Choice of concentrations 
Two concentration of CD10367 solution will be applied in this study for a better understanding of 
the local tolerability and efficacy. The choice of concentration of CD10367 is based on the 
maximal concentration of the molecule to be formulated (3%) and a lower intermediary 
concentration (1%). 
 
 In the clinical phototoxicity study performed last year with  
three concentrations (0.1%, 1% and 3%) the reduction of UV induced erythema was in a dose 
proportional manner and statistically different from vehicle for the 1% and 3% solutions.   
 
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3.2.6 
Treatment application 
According to the modified Dumas-Scholtz psoriasis mini-zone test, the application of CD10367 
will be limited to mini-zones of about 3 cm².  Sixteen (16) mg/cm² i.e. 50 µL of each product will 
be applied once daily on each mini-zone, according to the application instructions.  As all 
products applications will be carried out in the site by a qualified person, the applied amounts 
will be secured. 
3.2.7 
Evaluation of CD10367 efficacy 
In order to evaluate the efficacy of CD10367 the primary criteria will be based on clinical 
evaluations. 
 
3.2.9 
Safety monitoring 
The Subjects safety will be closely monitored 5 days a week during the treatment period with the 
daily seeking of Adverse Events.  The inclusion to the study will be conditional to a normal 
medical exam including a physical exam, the check of the vital signs, a blood test and a 
urinalysis, a normal ECG exam, and a normal Ophthalmic exam. At the end of the treatment 
period the same medical exams will be performed. 
Local tolerance will be assessed twice weekly by the Investigator using a 4-point scale for each 
mini-zone (see section 7.2.5). 
 
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4 CLINICAL TRIAL DURATION AND TERMINATION 
The planned clinical trial duration (from FSFV to LSLV) is approximately 5 months. The date of 
end of the clinical trial is defined as the date of the last visit of the last subject. 
The planned duration of recruitment (from FSFV to LSFV) is approximately 3.5 months. 
Clinical trial participation for each subject is approximately 9 weeks including screening period. 
GALDERMA may decide to prematurely terminate or suspend the participation of a particular 
clinical trial center (for example, for lack of subject enrollment or non-compliance with clinical 
trial protocol, regulation, or GCP) or prematurely suspend the clinical trial (for example, for 
safety, study drug(s) quality, regulatory, efficacy, or logistical reasons) at any time with 
appropriate notification. 
5 SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION 
5.1 
Number of subjects 
As a screen failure rate of approximately 40% percent is expected, approximately 40 subjects 
may have to be screened in order to obtain 24 subjects randomized. 
5.2 
Clinical trial population characteristics 
In order to be eligible for the clinical trial, subjects must fulfill all of the following criteria (when 
applicable). These criteria are applicable at both screening and baseline unless specified.  
5.3 
Inclusion criteria 
1. Adult male or female aged at least 18 and up to 70 years old inclusive at screening visit. 
2. Female of non-childbearing potential (postmenopausal [absence of menstrual bleeding for 
1 year prior to screening, without any other medical reason], hysterectomy or bilateral 
oophorectomy). 
3. Subject has a skin phototype I to IV on Fitzpatrick’s scale. (Screening visit). 
4. The subject has a clinical diagnosis of stable plaque psoriasis, defined as no flare during the 
month before Screening visit and no change between Screening visit and Baseline visit, of 
mild to moderate severity. (Screening visit and Baseline Visit). 
5. The subject presents with at least six eligible mini-zones, on at least two psoriasis plaques 
(Screening visit and verified also at Baseline Visit) which: 
 
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5.1. are located on the upper and/or lower extremities (anterior crest of tibia, apex of knees 
and apex of elbows excluded) and/or on the trunk.  Plaques on the face, scalp, hands, feet 
and folds will not be eligible as test areas. 
5.2. have a Total Sum Score (TSS = erythema + induration + scaling) ≥ 6 before 
desquamation; each item separately being ≥2, 
5.3. have identical severity (i.e. identical TSS or variation of ±1 grade) before desquamation, 
5.4. are approximately 2 cm in diameter and at least 2 cm apart from each other. 
5.5. for the two desquamated zones at Baseline visit:   
5.5.a. 
have a scaling score of 0 or 1, 
5.5.b. 
have identical severity between the zones or variation of ±1 grade for the sum of 
induration and erythema scores, each item separately being ≥2   
6. Subject agrees not to wear his/her contact lenses from the Baseline visit till the D19 visit, 
(Screening visit) 
7. Subject is willing and able to comply with all of the time commitments and procedural 
requirements of the clinical trial protocol.  (Screening visit) 
8. Subject understands and signs an Informed Consent Form (ICF) at screening, prior to any 
investigational procedures being performed. (Screening visit) 
9. The subject is covered by a National Social Security System (Screening visit) 
Rationale:  
Criterion 
Rationale  
1 
To ensure appropriate age requirements for adults  
2 
No reproduction toxicity studies conducted with this IMP to date.  
3  
To allow proper assessment of clinical and biophysical skin imaging evaluation 
4, 5 
To ensure that the subjects have a stable psoriatic skin condition, which is comparable for each tested 
condition 
6 
To ensure no issue related to ocular toxicity risk 
7 & 8 
To ensure that all Subjects are fully informed and comply with the study requirements. Only the Subjects 
providing written consent are allowed to participate into the clinical trial, to be compliant with ICH, local 
regulations and GCP. 
9 
To be compliant with country regulation 
 
5.4 
Exclusion criteria 
Any subject who is meeting one or more of the following criteria at Screening and/or Baseline 
visits will not be included in this study: 
1. The subject presents guttate, erythrodermic, exfoliative, inverse, pustular, palmo plantar, 
infected or ulcerated psoriasis (Screening visit).  
2. The subjects has any uncontrolled or serious disease, or any medical or surgical condition, 
that may either interfere with the interpretation of the clinical trial results, and/or put the 
 
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subject at significant risk (according to Investigator’s judgment) if he/she participates in the 
clinical trial (e.g. history of on-going gastric or duodenal ulcer, clinically significant lung 
disease, etc.) (Screening visit). 
3. The subjects has known or suspected allergies or sensitivities to any components of the study 
drugs or of the keratolytic product (see Investigator’s Brochure/Product label). (Screening 
visit). 
4. The subjects has known history of adverse drug reaction or hypersensitivity to a product with 
the same mode of action 
5. The subject presents with presumed drug or alcohol abuse (based on medical history or 
present clinical symptoms) (Screening visit). 
6. The subjects has any abnormal clinically significant findings according to the 
ophthalmologist, at the ophthalmological exam at Screening visit, 
7. The subjects has any of the following laboratory test results (blood samplings and urinalysis 
done at Screening visit): 
7.1. Positive serology (HbsAg, HCV, HIV 1 or 2) 
7.2. ALT, AST, ALP or total bilirubin > 1.5ULN - Gilbert’s disease is accepted,  
7.3. Creatinine clearance <60mL/min/1.73m2 calculated with the CKD-EPI formula (Levey 
et al., 2009)  
7.4. Any other lab test parameter or urinalysis outside the normal ranges defined by the 
laboratory and these results are judged clinically significant by the investigator 
8. The subjects has QTc interval >450msec or any abnormal ECG value considered as clinically 
significant by the cardiologist (Screening visit). 
9. The subject has received, applied or taken the following treatments within the specified time 
frame prior to the Baseline visit: 
Table 3  
Prohibited therapies 
Treatment name/type 
Wash-out period 
Topical treatments on all psoriatic areas: 
 
Corticosteroids 
(use of corticoids on the face for short course therapy ,up to 5 days is 
authorized) 
4 weeks 
Retinoids 
2 weeks 
Vitamin D analogs 
2 weeks 
Immunomodulators 
2 weeks 
Antracen derivatives, tar and salicylic acid preparations 
2 weeks 
Topical treatment on treated areas: 
 
Other topical products, including emollients 
2 days 
Systemic treatments: 
Wash-out period 
 
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Anti-histaminic drug 
1 week 
Corticosteroids (inhaled products are authorized) 
2 weeks or 5 half-lives 
(whichever is longer)   
Immunosuppressive drugs 
3 month or 5 half-lives 
(whichever is longer)  
Biotherapies 
3 months or 5 half-lives 
(whichever is longer)   
Drugs with known ocular toxicity according to ophthalmologist 
5 half-lives 
Drugs that can prolong the QT interval as defined in the Crediblemeds.org 
list: http://www.crediblemeds.org/everyone/composite-list-all-
qtdrugs/?rf=All 
5 half-lives 
Strong CYP inhibitors as defined in the below reference, Table 5 strong 
inhibitors of CYP enzymes: (see list in appendix) 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc
es/DrugInteractionsLabeling/ucm093664.htm 
5 half-lives 
Retinoids, isotretinoin 
6 months 
Any systemic treatment that may impair hemostasis (anti-coagulant, 
antiplatelet, etc.)  
4 weeks 
Other treatments 
Wash-out period 
Phototherapy 
3 months 
 
10. The subject  is under the following systemic treatments (unless they have been on a stable 
dose of medication for at least 3 months prior to Screening (Screening visit)): 
10.1. 
Antimalarials 
10.2. 
Lithium 
10.3. 
ACE (angiotensin-converting-enzyme) inhibitors  
10.4. 
Beta blockers 
10.5. 
Indomethacin and other non-steroidal anti-inflammatory drugs (except sporadic 
intake of no more than 3 consecutive days). 
11. The subject is planning to sunbathe or to overexpose to UV-light (Screening visit). 
13. Current participation in any other clinical trial of a drug or device OR participated within 
1 month prior to baseline OR is in an exclusion period from a previous clinical trial (when 
possible). (Screening visit). 
 
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14. The subject is vulnerable as defined in French law “Code de la Santé Publique” (Screening 
Visit) such as: 
14.1. 
an adult under guardianship, or hospitalized in a public or private institution for a 
reason other than the Research, or deprived of freedom;  
14.2. 
a subject unable to communicate or cooperate with the Investigator due to 
language problems, poor mental development, or impaired cerebral function. 
Rationale: 
Criterion 
Rationale  
1, 2,  
To ensure that no medical or skin condition will interfere with study protocol results interpretation  
2, 3, 4, 5, 6, 7, 8 To ensure safe medical conditions at inclusion concerning potential identified IMP risks 
9, 10, 11, 13 
To ensure no interference with the study product and misinterpretations of the results 
14 
To be compliant with ICH-GCP and country regulation 
 
5.5 
Previous and concomitant therapies 
5.5.1 
Definition 
Previous therapies are defined as therapies that have been stopped within 6 months preceding the 
screening visit. Only relevant therapies (i.e. therapies that may have an impact on study 
assessments) will be recorded. 
Concomitant therapies are defined as follows: 
 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   
5.5.2 
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. 
 
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5.5.3 
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.  
The subjects may use a moisturizer on the psoriasis plaques, except the plaques that will be  
treated with the study products. They may use their own moisturizer or 
 
 which is provided by the sponsor. 
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. 
5.5.4 
Authorized concomitant therapies 
Unless listed under the exclusion criteria (Section 5.4) or in prohibited concomitant therapies 
(see Section 5.5.5), all therapies are authorized. 
5.5.5 
Prohibited concomitant therapies 
The following therapies are prohibited because they may interfere with the efficacy and/or safety 
(for example interaction with the study drug(s) metabolism) assessment of the study drug(s): 
 Listed in Section 5.4  
For topical products: No other topical medication, or product (including emollient) other than the 
study drugs, will be permitted on the treated areas from the start of the pretreatment procedure on 
the selected pre-treated plaques and from 2 days before Baseline visit until the end of the study 
on all plaques selected for application of the study drugs.  
If a prohibited therapy becomes a necessary treatment for the safety or best interest of the 
subject, GALDERMA should be notified to discuss possible alternatives prior to administration 
of a prohibited therapy. 
If a subject receives a prohibited therapy during the clinical trial, GALDERMA should be 
notified to discuss the pertinence and the modalities for the subject to continue in the clinical 
trial. 
5.6 
Procedures/Reasons for subject discontinuation 
An Investigator may decide to discontinue a subject from the clinical trial for safety reasons. 
 
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Although the importance of completing the entire clinical trial should be explained to the subject 
by the clinical trial personnel, any subject is free to discontinue participation in this clinical trial 
at any time and for whatever reason, specified or unspecified, and without any prejudice.  No 
constraints are to be imposed on the subject, and when appropriate, a subject may be treated with 
other conventional therapy when clinically indicated.  
When a subject does not complete the clinical trial, he/she will be fully assessed, if such 
assessment is possible.  The procedures designated for the Early Termination visit should be 
completed for all subjects discontinuing the clinical trial and the appropriate Case Report Form 
(CRF) should be completed. The Follow up visit should then occur approximately one week after 
the Early Termination visit. 
All discontinuations and the reason for discontinuation are to be documented by the Investigator 
on the Exit Form.  
For discontinuation due to an AE, the Adverse Event Form is to be completed. The Investigator 
should also ensure that the subject receives suitable therapy for the AE. 
A subject who has been randomized and assigned a randomization number cannot be replaced by 
another subject if he/she discontinues the clinical trial for any reason. Additional subjects could 
be enrolled (randomized/assigned to treatment) in order to attain the number of evaluable 
subjects. 
GALDERMA may also decide to prematurely terminate or suspend a subject’s participation in 
the clinical trial. 
Potential reasons for discontinuation, as listed on the Exit Form, are defined below: 
 Adverse Event: 
Complete an Adverse Event Form. 
 Withdrawal by 
Subject: 
Includes consent withdrawal, subject relocation, schedule conflicts, 
etc.  Does not include AE. Explain the reason for withdrawal in the 
comment section of the CRF Exit Form. 
 Protocol Deviation:  Explain the deviation in the comment section of the CRF Exit Form. 
 Lost to Follow-up: 
Confirmed with two documented phone calls and a certified letter 
(delivery receipt requested) without answer.  Explain in the comment 
section of the CRF Exit Form. 
 Other: 
This category is to be used for a subject who discontinues due to a 
reason other than as specified in the predefined categories above.  
Explain the reason for discontinuation in the comment section of the 
CRF Exit Form. 
If reason for discontinuation is “withdrawal by subject” or “other”, the subject will be questioned 
to rule out the possibility of an AE and this should be documented. If the AE led to 
 
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discontinuation, then “adverse event” should be chosen as the reason for discontinuation, rather 
than “withdrawal by subject” or “other”. 
 
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6 CLINICAL SUPPLIES 
6.1 
Clinical supply identification and use 
6.1.1 
Study drug(s) description 
Table 4 
 Description and usage of the study drug(s) 
 
Investigational 
product 
Investigational 
product 
Vehicle 
Reference 
Trade Name or 
Equivalent 
NA 
NA 
NA 
Betneval 
Name of drug 
substance 
NA 
NA 
NA 
Betamethasone 
valerate 0.1%  
Internal Code  
CD10367  
CD10367  
CD10367 
placeboa  
NA 
Pharmaceutical 
Form 
Solution 
Solution 
Solution 
Ointment  
Concentration 
1% 
3% 
NA 
0.1% 
Dosage (total 
maximal daily 
dose) 
50µl  
100µl 
(50µl on each mini-
zone) 
100µl 
(50µl on each 
mini-zone) 
50µl 
Route 
Topical 
Dose Regimen  
Once daily 
Duration of 
administration 
Five consecutive days a week for two weeks and four consecutive days in the 
third week (14 applications) 
Location of 
Treated Area 
Mini-zones on upper and/or the lower extremities (elbows, knees and shin 
area excluded) and/or on the trunk 
a CD10367 solution placebo is the same vehicle solution as the CD10367 solution but without the 
active ingredient  
b The most restrictive storage conditions will be applied. 
 
 
 
 
 
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6.1.2 
Subject Identification Number (SIN)  
Upon signature of the ICF, each subject will be assigned a Subject Identification Number (SIN). 
The SIN 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 SIN for all 
documentation and discussion. 
6.1.3 
Method of treatment assignment 
Prior to the start of the study, a randomization list will be generated by a statistician from 
GALDERMA R&D and will be transmitted to the assigned clinical packaging organization.  
 
 
 
 
   
Coding of the study products will be defined independently by the Pharmaceutical Unit at 
GALDERMA.  
6.1.4 
Randomization number 
At Baseline visit (Day 1), each Subject who fulfills all inclusion/non-inclusion criteria will be 
assigned a Randomization Number. The randomization number will be allocated in ascending 
sequential order 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 Screening visit.  
6.1.5 
Instructions for use and administration 
The keratolytic product will be supplied by GRD, and distributed to the subjects by the 
investigational centre. They will be applied by the subjects at home during the pre-treatment 
period. 
From Baseline visit, all study drugs applications will be performed by a person from the 
investigational team other than the Investigator at the study centre to make sure the investigator 
remains blinded. 
All study drugs will be accounted for and in no case used in any unauthorized situation.  All used 
and unused study drugs will be appropriately inventoried by the study centre. 
 
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6.1.5.1 
Selection of target plaque(s) and mini-zones 
During Baseline visit, validation of the stability of the psoriatic plaques selected at Screening 
will be checked by the Investigator.   
At Baseline visit, the selected target mini-zones for standard psoriatic skin conditions (n=4) 
should:  
 be located on the upper and/or lower extremities (anterior crest of tibia, apex of knees and 
apex of elbows excluded) and/or on the trunk.  Plaques on the face, scalp, hands, feet and 
folds will not be eligible as test areas. 
 have a Total Sum Score (TSS = erythema + induration + scaling)  6; each item separately 
being  2 (see Table 5),  
 have identical severity (i.e. identical baseline TSS or variation of  1 grade), 
 be approximately 2 cm in diameter and be at least 2 cm apart from each other in order to avoid 
any interference between products. 
Target mini-zones previously selected at Screening visit for desquamated psoriatic skin 
conditions (n=2) should at Baseline visit:  
 be located on the upper and/or lower extremities (anterior crest of tibia, apex of knees and 
apex of elbows excluded) and/or on the trunk.  Plaques on the face, scalp, hands, feet and 
folds will not be eligible as test areas. 
 have a scaling score of 0 or 1,  
 have identical severity between the two zones or variation of ±1 grade for the sum of 
induration and erythema scores, each item separately being ≥2   
 are approximately 2 cm in diameter and at least 2 cm apart from each other. 
If the scaling score is not at 0 or 1 after 2 weeks of pre-treatment period, they will not be 
randomized in the study. 
 
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6.1.6 
Other supplies 
Galderma R&D will provide keratolytic product (
 
 
), and emollient 
.  
These supplies will be monitored during the study to be sure the site has always enough supplies to 
conduct the study in compliance with the protocol requirements. 
6.2 
Study drug(s) packaging and labeling 
The investigational products will be supplied by GALDERMA R&D (see Table 4). 
The labels will be printed in the local language. The text of the label will detail the information 
requested by Good Manufacturing Practice and local regulations. 
6.3 
Supplies management 
6.3.1 
Accountability 
Upon receipt of the study drug(s), the Investigator or designee will maintain accurate records of 
the study drug(s) delivery to the clinical trial center, the inventory at the clinical trial center, the 
use by each subject, the reconciliation of all study drug(s) received from the Sponsor, and the 
return to the Sponsor or alternative disposal of used and unused study drug(s). 
The Investigator or designee is required to sign the appropriate form upon receipt and inspection 
of the supplies, fax the signed copy to GALDERMA or the Depot and retain the receipt within 
the clinical trial file. 
All used and unused study drug(s) will be appropriately inventoried by the monitor and returned 
to the Sponsor for for destruction as instructed by GALDERMA/CRO. 
 
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All study drug(s) sent to the Investigator/Institution will be accounted for and no unauthorized 
use is permitted. 
6.3.2 
Storage of study drug(s) 
Study drug(s) must be stored in a safe and secure area with restricted access, under the storage 
conditions specified by GALDERMA (see Table 4). 
6.3.3 
Dispensing and return  
Each subject will receive the keratolytic and the emollient products at Screening visit. 
Subjects will be instructed by the investigator on the importance of being compliant with the use 
of the keratolytic product throughout the week(s) proceeding Baseline visit. 
From Baseline, no drug will be dispensed directly to the subject. 
 
 
 
 
As this study is an Investigator/evaluator blinded study, the Investigator should not have access 
to the study drugs. The person in charge of product applications will not be the 
Investigator/evaluator. 
In the event of Screen failure (e.g. due to abnormal laboratory results), the Investigator or 
designee must immediately instruct the subjects to stop the keratolytic product regimen.  
In the event of early termination/suspension of the clinical trial, a rapid recall of study drug(s) to 
Galderma will be initiated.   
6.3.4 
Treatment compliance management and record 
Since product applications will be performed by a qualified person, treatment compliance will be 
ensured and documented appropriately by study staff. 
In case of missed visit corresponding to clinical evaluation visit; clinical evaluations will be 
performed on the following visit. 
6.4 
Dose modification  
In case of significant irritation on one mini-zone according to investigator’s judgment, the 
dosage regimen may be temporarily discontinued on this mini-zone to allow the irritation to 
subside.   
When a study drug dosage modification has been required, the investigator should attempt to 
return the subject to the pre specified dosage regimen as soon as possible.  The other mini-zones 
on that same subject should continue to be treated with the planned treatment. 
 
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All temporary and permanent treatment discontinuations must be documented and justified.  In 
the case of permanent treatment interruptions for safety reasons, an AE form should be filled in 
and considered as an AESI if there is a relationship between this AE and the study treatment. 
6.5 
Blinding 
6.5.1 
Verification of blinding 
This study design is not considered double-blind since study products and the comparator 
(Betneval®) are different in appearance (formulation and packaging). 
However, the design is considered Investigator-blind since the following procedures will be 
followed in order to prevent the Investigator and/or other Evaluator(s) from coming into contact 
with the study materials thereby compromising the blinding of the study:  
 The study materials will be applied according to the randomisation list by a designated 
person other than the Investigator or other Evaluator(s).  Additionally, both the person in 
charge of drug applications and the Subject will be instructed not to discuss the study 
materials with the Investigator or other Evaluator(s). 
 Sealed envelopes will contain the description of test medications.  Access to the 
identification of treatment codes will be limited to the designated personnel directly 
responsible for packaging and labelling of study materials. 
6.5.2 
Un-blinding during the clinical trial 
Emergency un-blinding 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 Investigators.  At the clinical trial center, the blinded 
label (sealed envelopes) containing the identification of the assigned study drug(s) will be 
revealed in emergency situations only.  In such an emergency, the Investigator will only break 
the blind for the treated zone involved.  
The Investigator must notify the Sponsor’s CSO immediately in the event of such an emergency 
(see contact details in Section 7.2.6.2.2).  If possible, 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 un-blinding on the appropriate form (provided by 
the Sponsor) and fax the completed form to the CSO immediately. 
 
 
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7 CLINICAL TRIAL ASSESSMENT 
7.1 
Efficacy assessments 
7.1.1 
Efficacy measurements 
Throughout the study, the individual clinical scores and the clearing score for each individual 
mini-zone will be performed, to the extent possible, by the same Investigator.  In the event there 
is a change in the assigned Investigator for a given Subject, the reason for change must be 
documented.  If it is not possible to use the same Investigator for 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. 
7.1.1.1 
Individual clinical scores 
The status of the psoriasis for each mini zone will be evaluated by recording Individual clinical 
scores (erythema, scaling and induration) at screening and twice weekly during the treatment 
period from Day 1 visit (before treatment application) to Day 19/ET visit using the following 5-
point scale.  
However, data collected during the Screening visit will be used for the pre-selection of the mini-
zones only and not for data analysis.  
Table 5 
Individual clinical scores 
ERYTHEMA 
0 
None 
No detectable erythema. 
1 
Mild 
Slight pinkness present 
2 
Moderate 
Definite redness, easily recognized. 
3 
Severe 
Intense redness 
4 
Very Severe 
Very intense redness 
SCALING 
0 
None 
No shedding 
1 
Mild 
Barely perceptible shedding, noticeable only on light scratching or 
rubbing. 
2 
Moderate 
Obvious but not profuse shedding 
3 
Severe 
Heavy scale production 
4 
Very Severe 
Very thick scales 
INDURATION 
 
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0 
None 
Normal skin thickness.  No elevation of skin 
1 
Mild 
Barely perceptible elevation (by touching) of the psoriasis plaques. 
2 
Moderate 
Obvious elevation above the normal skin level; moderate thickening 
3 
Severe 
Definite thick elevation above normal skin level 
4 
Very Severe 
Very thick elevation 
Evaluations will be done for the entire treatment period of the study even if a mini zone clears. 
In case of treatment discontinuation (on one or several zones) for poor local tolerance, the 
individual clinical scores will continue to be assessed. 
7.1.1.2 
Clearing score 
The clearing score evaluation will be done for each individual mini-zone from Day 4 visit and 
then twice weekly during the treatment period (before treatment application) up to Day 19/ET 
visit, using the following 3-point scale. 
Table 6 
Clearing Score 
CLEARING SCORE 
0 
Complete 
clearing 
No scaling and no infiltration even on palpation. Post inflammatory 
hypopigmentation or hyperpigmentation may be present. 
1 
Almost clear 
Residual erythema with some induration / infiltration (not clinically visible but 
palpable) without scaling, or residual erythema and residual scaling with no 
infiltration. 
2 
Unchanged  
No change or less than almost clear. 
 
7.1.2 
Efficacy endpoints 
7.1.2.1 
Primary Criterion 
Area Under the Curve (AUC) of Total Sum Score (sum of erythema, scaling and induration 
scores) from Day 1 to Day 19. 
7.1.2.2 
Secondary Criteria 
 AUC of individual clinical scores (erythema, scaling and induration) from Day 1 to Day 
19. 
 TSS and percentage change from baseline at each visit. 
 Erythema, Scaling and Induration score and their change from baseline at each. 
 
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 Success rate (defined as a clearing score of 0 or 1) at each evaluation visit and the time to 
first success. 
7.2 
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: 
 Physical examination at Screening, and Day 19 (or Early Termination visit if any); 
 Record of vital signs at Screening, Baseline and Day 19 (or Early Termination visit if 
any); 
 Blood samplings for laboratory safety tests at Screening and Day 19 (or Early 
Termination visit if any); 
 Urinalysis at Screening and Day 19 (or Early Termination visit if any); 
 ECG at Screening, and Day 19 (or Early Termination visit if any); 
 Ophtalmic examination at Screening, and Day 19 (or Early Termination visit if any); 
 Local tolerance assessed twice weekly by the Investigator using a 4-point scale for each 
mini-zone 
 Monitoring and recording of AEs to be recorded as specified in Section 7.2.6. 
7.2.1 
Physical examination and vital signs 
7.2.1.1 
Physical examination and vital signs 
A standard physical examination will be performed at Screening and Day 19 / ET visits and it 
will be noted as “normal” or “abnormal” by the Investigator. Abnormalities will be recorded on 
the CRF. 
Vital signs will be evaluated at the screening visit, at baseline visit and at Day 19 / ET. Vital 
signs will include systolic and diastolic blood pressure and pulse rate and will be measured after 
the subject has been sitting for at least 5 minutes.  
The Investigator may choose to investigate any sign that he/she observes during the examination 
and should assess all abnormal findings for clinical significance.  
All clinically significant abnormal findings at the screening visit will be recorded in the Medical 
History. 
For any clinically significant changes from the screening visit, an AE is to be recorded. 
 
 
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7.2.2 
Laboratory safety tests 
The following laboratory safety tests will be performed at the screening visit, and the D19/ET 
visit: 
The following laboratory safety tests will be performed: 
 Haematology: 
White blood cell (WBC) count with differential, red blood cell (RBC) count, haemoglobin (Hb), 
haematocrit (hct), mean cell volume (MCV), and platelet count (Plt) 
 Blood chemistry: 
Creatinine, uric acid, urea nitrogen, alkaline phosphatase (ALP), aspartate aminotransferase 
(ASAT=SGOT), alanine aminotransferase (ALAT=SGPT), and bilirubin (total and conjugated), 
Sodium (Na+), Potassium (K+) and Chlorides (CL-). 
Creatinine clearance will be calculated with the CKD-EPI formula. 
 Virology only at Screening 
HBsAg, HCV, and HIV antibodies 
 Urinalysis: 
A semi-quantitative urinalysis using dipsticks will be performed at Screening and Day 19 (or ET 
visit).  The following parameters will be evaluated: blood, proteins, leukocytes, glucose, ketones, 
nitrites, bilirubin, urobilinogen, pH, and specific gravity.  
The screening visit laboratory values must be available prior to the Baseline visit. 
The Investigator or another medically qualified Sub-Investigator must review and evaluate 
laboratory values for each subject in a timely manner.  The Investigator or designee will initial 
and date all laboratory reports and note directly on the report whether or not each out-of-range 
laboratory value is clinically significant. An out of range laboratory value should be considered 
as clinically significant if either of the following conditions is met: 
- 
The abnormality suggests a disease and/or organ toxicity 
- 
The abnormality is of a degree that requires additional active management, e.g., change 
of dose, discontinuation of the drug, close observation, more frequent follow-up 
assessments, or further diagnostic investigation 
In case of clinically significant out-of-range laboratory values for blood and/or urine samples 
collected at Screening, the subject will not be included in the study.  
All clinically significant out-of-range laboratory values for blood and/or urine samples 
collected after screening, are to be reported as an AE if this abnormality was not present at 
 
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the screening visit or is assessed as having worsened since the screening visit (i.e., there is a 
significant change from screening).  
If the Investigator observes a clinically relevant laboratory test value, the laboratory tests will be 
repeated as soon as possible and monitored until the values have returned to normal and/or an 
adequate explanation for the abnormality is found. This does not apply to screening laboratory 
test values. No retest at screening is allowed. 
An out-of-range laboratory value that is identified as clinically significant and related to the 
study drug(s) is considered by the Sponsor to be an Adverse Event of Special Interest (AESI) 
(see Section 7.2.6.1.3). 
In instances when a laboratory abnormality is reported as an AE or AESI, whenever possible, the 
Investigator is to provide a diagnosis rather than reporting individual laboratory abnormalities. 
A summary of sample volumes and the number of blood samples is detailed in Appendix (section 
13.2). 
7.2.3 
12-lead electrocardiogram 
A single standard 12-lead ECG will be conducted during Screening period (as close as possible 
to Baseline visit), and at Day 19 or early termination visit. 
To participate in the study, the subject should not present: 
 QTc interval >450msec  
 And/or any abnormal ECG value considered as clinically significant by the investigator 
The subject should be kept in the supine and resting position for at least 10 minutes prior to 
obtaining the ECG in order to achieve a steady heart rate. 
The ECG reading will be performed in a real time by the investigator or a cardiologist. 
Any abnormal ECG result will be assessed by the investigator or a cardiologist for clinical 
significance.  
If an ECG abnormality at Day 19 was not present at Screening or is assessed as having worsened 
compared to Screening ECG, the Investigator is to report it as an Adverse Event. 
Any increase of QTc interval from Baseline superior to 60msec or a value >500msec at the Day 
19 / ET visit and assessed as related to the study drug is considered as an Adverse Event of 
Special Interest (see section 7.2.6.1.3). 
 
 
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7.2.4 
Ophthalmic examination 
The ophthalmic examination will be performed by an ophthalmologist during Screening period 
(as close as possible to Baseline visit), and at Day 19 or earlier in case of study discontinuation 
(ET). 
The examination will consist of visual acuity measurement, slit lamp exam with fluorescein and 
Tear Film break-up time.  
The global ophthalmic examination will be scored with a ‘normal’ / ‘abnormal’ answer system. 
In addition, subjective ophthalmologic symptoms will be also asked and recorded as comments if 
any. 
In case of abnormal clinically significant findings at Screening, the subject will be not included 
in the study and the information will be recorded in the Medical History form. 
For any abnormal clinically significant changes from Screening, an AE is to be recorded. 
A treatment-emergent abnormal ophthalmic examination result that is identified as clinically 
significant and related to the study drug is considered as an Adverse Event of Special Interest 
(see section 7.2.6.1.3). 
7.2.5 
Local tolerability assessment 
Local tolerability assessment will be performed using the following twice a week from Day2 to 
Day 19/ET visits scales two times per week during the treatment period. If at any visit, a 
treatment leads to discontinue applications either temporarily or permanently, an AE must be 
declared, and local tolerability assessments and photos of the concerned zone must be performed 
even if it was not planned in study flowchart for this visit. Grading for local tolerability 
assessments will take into consideration the time period from the last local tolerability 
assessment up to the current visit. The worst severity since the previous visit will be recorded. 
Local tolerability (Irritation, stinging/burning, pruritus) will be assessed separately on each mini-
zone using the following scales: 
 
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Table 7 
Local tolerance 4-point scales 
Irritation 
Skin irritation Assessment  
0 
None: 
No signs of irritation  
1 
Mild: 
Slight signs of irritation 
2 
Moderate: 
Moderate signs of irritation: Obvious increase in redness as compared 
to the non-treated surrounding area 
3 
Severe: 
Severe signs of irritation  
Stinging/ 
Burning 
Prickling pain sensation  
0 
None: 
No stinging/burning 
1 
Mild: 
Slight warm, tingling/stinging sensation; not really bothersome 
2 
Moderate: 
Definite 
warm, 
tingling/stinging 
sensation 
that 
is 
somewhat 
bothersome 
3 
Severe: 
Hot, tingling/stinging sensation that causes severe discomfort 
Pruritus 
Itch sensation 
0 
None: 
No itching 
1 
Mild: 
Itching is noticeable but not really bothersome 
2 
Moderate: 
Definite itching that is somewhat bothersome 
3 
Severe: 
Marked itching, urge to scratch and causes definite discomfort 
 
Irritation, will be clinically evaluated by the Investigator. The Investigator will record 
stinging/burning and pruritus after discussion with the subject. The severity of stinging/burning 
sensation occurring after the last drug application before the visit will be asked. The Investigator 
will ask an open-ended question, taking care not to influence the subject’s answer, such as “Have 
you experienced any sensations such as stinging/burning?” 
An Adverse Event page must be completed if the severity of the signs and symptoms is such that: 
 The subject temporary or permanently discontinues the treatment at his/her request or at 
the Investigator’s request.   
 The subject requires concomitant treatment, including OTC products (other than 
moisturizer). 
 
In case of permanent treatment discontinuation, skin sensitization or papulo-pustular reaction an 
AESI must be declared (see section 7.2.6.1.3). 
7.2.6 
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. 
 
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7.2.6.1 
Definitions 
7.2.6.1.1 
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 unfavorable and 
unintended sign (including an abnormal laboratory value), 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, 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.) from the screening visit 
should be reported as a new AE. 
Notes: 
 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 or 
abnormal laboratory values 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, signs, or laboratory values should be used to describe the AE. 
 The “date of onset” should be the date that the first symptom occurred. 
7.2.6.1.2 
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. 
 
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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 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). 
7.2.6.1.3 
Adverse Events of Special Interest (AESIs) 
An AESI is a noteworthy event for the particular study drug that can be appropriate to monitor 
closely.  It could be serious or non-serious and AESIs could include events that might be 
potential precursors or prodromal symptoms for more serious medical conditions in susceptible 
individuals. 
The AESIs for this protocol have been pre-defined as follows: 
- 
Suspected sensitization or photosensitization 
- 
Any non-dermatological treatment-emergent related adverse events (AE), including: 
o Increase in QTc interval from Baseline >60msec or a value>500msec at D19/ET 
ECG assessed as related to the study drug   
o Out-of-range laboratory results that are identified as both clinically significant and 
related to the study drug(s)  
o Any treatment-emergent signs/symptoms suggestive of keratitis or corneal 
ulceration (e.g. pain of the eye, injected/red eye, blurred vision, etc.), or 
treatment-emergent 
keratitis 
or 
corneal 
ulceration 
diagnosed 
at 
the 
ophthalmological 
examination, 
or 
any 
other 
treatment-emergent 
acute 
ophthalmological findings assessed as related to the study drug   
- 
Any dermatological treatment-emergent related adverse events (AE) leading to 
permanent treatment discontinuation on any zone 
- 
Treatment-emergent skin rash assessed as related to the study drug, defined as a 
papulopustular eruption commonly described as acneiform eruption 
For AESIs, the Investigator is required to complete the Adverse Event Form on the CRF and 
follow the AESI reporting procedures in Section 7.2.6.2.3 even if the event is considered 
non-serious according to the usual regulatory criteria. 
 
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7.2.6.1.4 
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 study drug information 
(e.g., Investigator’s Brochure for an unapproved investigational product or the package 
insert/summary of product characteristics for an approved product). 
7.2.6.1.5 
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 do not appear until 
a medication has been discontinued. 
7.2.6.1.6 
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 clinical trials conducted or sponsored by GALDERMA.  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 
 
7.2.6.1.7 
Relationship to the study drug(s) and/or clinical trial 
procedure 
The Investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE and exposure to the study drug(s) and/or clinical trial procedure (for 
example, moisturizer, or keratolytic use). AE reporting for moisturizer use should be detailed, 
taking into account whether moisturizer use is recommended or mandatory. Medical judgment 
should be used to determine the relationship, considering all relevant factors including the 
pattern of reaction, temporal relationships, positive dechallenge or rechallenge, relevant medical 
history, and confounding factors such as co-medication or concurrent diseases. 
 
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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 conducted or sponsored by GALDERMA: 
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 study drug (investigational product, active comparator, or vehicle, etc.) and the AE,  
 The clinical trial protocol procedure (such as 
, 
, blood test or 
intraocular pressure measurement, ancillary products provided by the sponsor, such as 
moisturizers, keratolytic, etc.) and the AE.  
 
The Investigator has to complete these 2 causality assessments on the AE form. 
No Reasonable Possibility: 
No suggestive evidence or arguments can be identified regarding a causal relationship between 
the study drug or the clinical trial protocol procedure and the AE. 
7.2.6.2 
Reporting procedures 
7.2.6.2.1 
Procedures for reporting Adverse Events 
The collection of AEs is from the time that a subject signs the ICF to their final visit. 
At each post-enrollment 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 study 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 study drug(s), and 
outcome, without omitting any requested and known information.  Additional information will 
be requested under certain circumstances.   
Adverse Events (AEs) assessed as related to the treatment or study procedure will be monitored 
until they have resolved or reached a stable condition.  Other AEs will be monitored until the last 
visit if they have not resolved or reached a stable condition.  
 
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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. 
For SAEs (see Section 7.2.6.2.2), AESIs (see Section 7.2.6.2.3), the CSO is to be informed 
immediately by e-mail/fax.  The event must be reported by fax or sent by e-mail to the CSO 
within 24 hours of receipt of the information (contact details in Section 7.2.6.2.2). 
 
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7.2.6.2.2 
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: 
1. 
Take prompt and appropriate medical action, if necessary.  The safety of the subject is the 
first priority. 
2. 
Ensure that the event is classified as an SAE. Immediately inform the CSO of the event by 
e-mail/fax and discuss further actions to be taken. 
Investigator contact: 
Local Clinical Safety Officer 
E-mail: pharmacovigilance@galderma.com 
 
Phone: +33 (4) 92 95 29 69 – Fax: +33 (4) 93 95 70 92 
Additional contact details are provided in the Investigator’s site file. 
3. 
Complete the Adverse Event Form provided in the CRF as fully as possible. 
4. 
Complete the Serious Adverse Event Form provided by the Clinical Research Associate 
(CRA) at the start of the clinical trial.  Fax or send by e-mail the completed form 
accompanied by demographics, medical history, Drugs/Therapies form, Medical and 
Surgical Procedures form, and adverse event pages of the CRF, and any other relevant 
information or medical records (e.g., laboratory test results) within 24 hours of receipt of 
the information to the GALDERMA CSO.   
5. 
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, fax or send by 
e-mail all additional follow-up information on the SAE to the GALDERMA CSO within 
24 hours of receipt of the updated information.  Serious Adverse Events (SAEs) will be 
monitored until the Investigator and Sponsor agree that the event is satisfactorily resolved. 
6. 
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. 
7. 
Inform the CSO of the final outcome of the event.  Send a revised or updated Serious 
Adverse Event Form and Adverse Event Form, if appropriate. 
 
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8. 
Prompt notification of SAEs by the investigator to GALDERMA is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
GALDERMA has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. 
GALDERMA will comply with country specific regulatory requirements relating to safety 
reporting to regulatory authorities, IECs and investigators. Investigator safety reports are 
prepared for Suspected Unexpected Serious Adverse Reactions (SUSARs) according to 
local regulatory requirements and GALDERMA policy and are forwarded to investigators 
as necessary. An investigator who receives an investigator safety report describing an 
SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from 
GALDERMA will file it with the Investigator’s Brochure (IB) and will notify the IEC, if 
appropriate according to local requirements. 
9. 
Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to 
the Independent Ethics Committee (IEC). 
 
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7.2.6.2.3 
Procedure for reporting an Adverse Event of Special 
Interest 
For any AESI (see Section 7.2.6.1.3) occurring during the period of the clinical trial, whether 
related to the treatment or not, and whether expected or not, the Investigator is to do the 
following: 
1. 
Take prompt and appropriate medical action, if necessary.  The safety of subjects is the 
first priority. 
2. 
Ensure that the event is classified as an AESI. Immediately inform the CSO by e-mail/fax 
of the event and discuss further actions to be taken. 
3. 
Investigator contact: Refer to Section 7.2.6.2.2 
4. 
Complete the Adverse Event Form provided in the CRF as fully as possible. 
5. 
Fax or send by e-mail the completed form accompanied by demographics, medical history, 
Drugs/Therapies form, Medical and Surgical Procedures form, and adverse event pages of 
the CRF, and any other relevant information or medical records (e.g., laboratory test 
results) within 24 hours of receipt of the information to the GALDERMA CSO.   
6. 
Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae.  For all the additional follow-up evaluations, fax or 
send the additional follow-up information by e-mail to the GALDERMA CSO within 
24 hours of receipt of the updated information.  AESIs will be monitored until the 
Investigator and Sponsor agree that the event is satisfactorily resolved.  
7. 
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 
information such as anonymized medical records. 
8. 
Inform the CSO of the final outcome of the event.  Send a revised or updated Adverse 
Event Form, if appropriate. 
 
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7.2.6.2.3.1 
Procedure for suspected allergic contact reaction 
This is a general procedure and any other details might be discussed with the sponsor. 
 Stop the study product. 
 Take a picture of the affected area and the non-affected surrounding skin 
 Document the event as an Adverse Event of Special Interest, e-mail/fax the CSO 
immediately, and report the event within 24 hours of receipt of the information to the 
CSO as described in section ‎7.2.6.2.3 
a. In case of suspicion of allergic contact dermatitis  
1. After all signs and symptoms of AESI have resolved and after a minimum of two 
weeks from last dose application, perform a re-challenge test with the assigned 
study product.  
2. Ensure the subject has not been under any treatment with corticosteroids or 
antihistamines, regardless of the route of administration, the week before testing. 
3. Ensure that the skin on the back has not been exposed to the sun or artificial 
ultraviolet sources the week before testing. 
4. Apply an appropriate quantity of the assigned study product to fill in the cupule of 
the test chamber on the skin of the upper back on either the right or left side of the 
centre line (or the inner forearm if the back cannot be tested). If no test chamber is 
available on-site, patch test units will be provided. It may be preferable to perform 
the test under semi-occlusive conditions depending on the irritant potential of the 
study product and the intensity of the reaction that was observed. The method to 
be used should be discussed with the sponsor. 
Choose a skin site that was not previously involved in the inflammatory skin 
reaction. Cover it for 48 hours with a hypoallergenic tape. 
5. Patient should be informed about avoiding exercise, showers, application of 
toiletries products, etc. to keep the test system dry 
6. After 48 hours, remove the tests and evaluate the site: 
 
at approximately 30 minutes after patch test removal (1st reading) and, 
 
24 to 48 hours later (i.e. 72 or 96 hours after application) (2nd reading).   
 
A facultative 3rd reading must be performed 96 to 120 hours later (i.e. 6 to 7 
days after application of the patch) if the overall assessment so far is 
equivocal or if asked by the sponsor. 
 
Pictures of the tested areas will be taken systematically at each reading and 
properly documented. 
 
 
Duration of study 
product application 
1st Reading 
2nd  Reading 
3rd reading  
(optional) 
 
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48 hours 
48 hours after study product 
application (30 minutes 
after patch test removal) 
 72 to 96 hours after study 
product application (24 to  48  
hours after patch test removal) 
6 or 7 days after study product 
application (96 to 120 hours after 
patch removal) 
  
7. Refer to the scoring system (Spiewak – 2008) used by the International Contact 
Dermatitis Research Group (ICDRG) to assign a score at each reading:  
 
Score 
Morphology 
Interpretation 
- 
No skin changes in the tested area 
Negative 
? 
Faint, non-palpable erythema  
Doubtful reaction 
+ 
Palpable erythema (moderate oedema or infiltrate), 
papules not present or scarce, vesicles not present  
Weak positive reaction 
++ 
Strong infiltrate, numerous papules, vesicles present 
Strong positive reaction 
+++ 
Erythema, infiltration, confluent vesicles, bullae or 
ulceration 
Extreme positive reaction 
ir 
Inflammation sharply limited to the exposed area, lack of 
infiltrate, small petechiae, pustules, and efflorescences 
other than papules and vesicles 
Irritant reaction 
Nt 
 
Not tested 
 
 
8. At last reading, the investigator will provide an assessment regarding a possible 
sensitization reaction using the following scale: 
Sensitization Reaction 
0 
Negative (absence of reaction or might be irritant reaction) 
1 
Equivocal 
2 
Positive 
 
9.  Report the results from the re-challenge test as directed by the sponsor and 
document with photographs. 
10. In case of absence of reaction, the subject may resume treatment if appropriate 
11. If the re-challenge is positive or equivocal, notify the CSO immediately. Except 
specific situations, a new series of patch test will be initiated as directed by the 
sponsor (with individual ingredients at different concentrations if applicable, and 
possibly negative and positive controls) after a minimum of additional two weeks 
(but not later than 6 months) and after all signs and symptoms have resolved. The 
patch tests will be placed on the subject’s back (or the inner forearm if the back 
cannot be tested) distant from the site of the re-challenge test (e.g., the left upper 
back skin if the re-challenge test was done on the right side). Follow the same 
procedure for the patch test as for the re-challenge.  
 
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b. In case of suspicion of immediate contact skin reaction (such as 
urticaria) 
A case by case approach will be applied and the procedure to follow will be discussed with the 
sponsor 
7.2.6.2.4 
Procedures for reporting pregnancies 
Not Applicable 
 
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7.4 
Pharmacokinetic assessments 
7.4.1 
Plasma concentration  
All subjects will have blood samples performed to quantify the concentration of CD10367 in 
plasma at visits D5, D19/ET and D26. 
The detail of the procedures for PK samples and storage conditions will be described in an 
operational manual provided by the Sponsor.  
 
 CD10367 plasma concentrations will be determined by GALDERMA R&D Sophia 
Antipolis France, using an LC MS/MS method developed for the purpose of the method. 
 
 
 
 
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7.5.4 
Quality of Life Assessment 
Not applicable. 
7.6 
Appropriateness of measurements 
Efficacy is evaluated by dermatologists using appropriate scorings 
 
. 
Safety is documented by the recording of adverse events, the local tolerance scales, the physical 
examination, the vital signs assessments, the ophthalmic examination, the ECG, and the 
laboratory tests. 
 
 
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8 CLINICAL TRIAL VISITS DESCRIPTIONS AND PROCEDURES 
8.1 
Description of clinical trial visits 
Please refer to the Schedule of Assessments table in the Synopsis (Table 2). 
A written, signed ICF must be obtained prior to performing any clinical trial-related evaluations 
and/or procedures. The subject must be provided with a fully completed, dated and signed copy. 
The Investigator representative will review and explain the nature of the study to the Subject and 
particularly the prohibited activities and the constraints of the study.  A copy of the signed and 
dated ICF will be provided to the Subject, another copy will be filed in the Investigator site file. 
8.1.1 
Screening visit (up to 5 weeks before Baseline visit) 
A maximum of 5 weeks is allowed between Screening and the first study drug administration at 
Baseline, including 3 weeks of screening period and up to 2 weeks of pre-treatment period. The 
minimum time period between Screening and Baseline is the amount of time necessary for the 
Investigator to receive laboratory test results from the Screening visit and allow at least one week 
of pre-treatment. The Screening period may be performed using several visits during this 
screening period, especially ECG and ophthalmic exam should be performed as close as possible 
to Baseline visit, which may be performed during the pretreatment period. 
At the Screening visit, the Investigator or designee will: 
1. Review and explain the nature of the study in detail to the Subject, particularly the 
prohibited activities and constraints (e.g., restrictions in the use of topical and systemic 
medications). 
2. Ensure that the Subject reads, date and signs the Informed Consent Form(s); provide a fully 
completed dated and signed copy to the subject. 
3. Assign to the Subject a Subject identification Number and give the Subject card. 
4. Collect information regarding demographics, relevant medical history, previous 
medications/procedures and concomitant therapies/procedures. 
5. Confirm clinical diagnosis of psoriasis vulgaris 
6. Collect urine for a semi-quantitative (“dipstick”) urinalysis. 
7. Perform a physical examination (PE) and check vital signs. 
8. Preselect six (6) target mini-zones, on two or more psoriasis plaques which: 
 are located on the upper and/or lower extremities (anterior crest of tibia, apex of knees and 
apex of elbows excluded) and/or on the trunk.  Plaques on the face, scalp, hands, feet and 
folds will not be eligible as test areas. 
 
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 have a Total Sum Score (TSS = erythema + induration + scaling)  6; each item separately 
being  2, 
 have identical severity (i.e. identical baseline TSS or variation of  1 grade), 
 are approximately 2 cm in diameter and at least 2 cm apart from each other. 
 include two mini-zones for the desquamation pre-treatment located on one or two plaque(s) 
isolated from the other plaques intended to be used for normal applications. 
9. Perform a 12-lead electrocardiogram (should be done as close possible to Baseline visit)  
10. Perform an ophthalmic examination (should be done as close possible to Baseline visit)  
11. Check that the subject meets inclusion/exclusion criteria. 
12. Perform clinical evaluations by measuring the individual clinical scores of psoriasis 
(erythema, scaling and induration) on each individual target mini-zones. 
13. Collect a blood sample for hematology, biochemistry, and virology. 
14. Complete the Subject Screening & Enrolment log.  
15. Record any AEs on the CRF. 
16. Explain to the subject how, where, when to apply the keratolytic product. Distribute one tube 
of the keratolytic product to the subject and explain instructions for application at home only 
on the plaque(s) selected for desquamation according to the protocol. Also, distribute one 
tube of emollient if necessary. Explain to the subject that no application must be done at 
home the of Day 1 visit before visiting the site. 
17. Give the Subject an appointment for the Day 1 visit. (and additional screening visits if 
applicable) 
 
8.1.2 
Baseline visit [Day 1] 
At the Baseline visit, the Investigator or designee will: 
1. Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate, on the 
corresponding CRF form(s). 
2. Check laboratory results hematology, biochemistry, virology, urinalysis from the 
Screening visit. 
3. Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes in the source document 
and the CRF. 
4. Check vital signs  
5. Confirm the six target mini-zones according to the inclusion criteria, 
 
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6. 
 
 
7. Perform clinical evaluations by measuring the intensity of the erythema, scaling and 
induration on each mini-zone using the individual clinical score, and record scores in the 
source document and CRF.. 
For non-desquamated zones TSS (erythema + induration + scaling) should be superior 
or equal to 6 on a 13 point scale (0 to 12), with individual score of erythema, induration 
and scaling separately being  2. The zones must present a similar severity, i.e.: identical 
Baseline TSS or variation of  1 grade. 
For desquamated zones scaling score should be equal to 0 or 1 on a 5 point scale (0 to 
4), and individual score of erythema, and induration separately being  2. The zones 
must present a similar severity, i.e.: identical Baseline sum of erythema and induration or 
variation of  1 grade. 
8. Confirm subject meets inclusion/exclusion criteria. 
9. Assign a randomization number to the Subject (this number will be assigned to 
randomized Subjects in increasing order and no numbers will be omitted). 
10.
A member of staff other than the Investigator will: 
11. Apply 50µl of the tested products on the Subject’s selected mini-zones according to the 
randomization list generated by the sponsor and in compliance with the operational 
manual. 
12. Instruct the Subject to avoid wetting areas (swimming, bath, sauna, hammam are not 
allowed).  However, showers are permitted at least eight hours following applications. 
13. Complete the Subject Enrollment Log and subject identification code list. 
14. Schedule the next visits (D2 to D19). 
 
 
 
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8.1.3 
Interim visits (from Day 2 to Day 18)   
At each of the following visits, Subjects will be asked to return to the clinical centre every day 
(except Saturdays and Sundays) for study drug applications and site evaluations. 
At each visit, the Investigator or the designated study person will:  
1. 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. 
2. 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 will: 
3. Apply 50 µl of the tested products on the Subject’s selected mini-zones according to the 
randomization list and in compliance with the operational manual 
4. Instruct the Subject to avoid wetting areas (swimming, bath, sauna, hammam are not 
allowed).  However, showers are permitted at least eight hours following applications. 
5. Schedule an appointment for the next Visit 
Moreover at Day 2, the Investigator, before any applications will: 
6. Assess local cutaneous tolerance of each mini-zone.  
Also at Day 4, Day 8, Day 11, Day 15 the Investigator, before any applications will:  
7. Assess local cutaneous tolerance of each mini-zone.  
8. Perform clinical evaluations of efficacy by measuring the intensity of the erythema, scaling 
and induration on each individual mini-zone. 
9. Perform clinical evaluations of the clearing score for each mini-zone 
Moreover at Day 5 visit: 
10. Collect a blood sample for plasma PK analysis. 
8.1.4 
Final/ Early Termination visit (Day 19 visit) 
At the Day 19/ET visit, the Investigator or designee will: 
 
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1. Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate, on the 
corresponding CRF form(s). 
2. Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes in the source document 
and the CRF.  
3. Perform a PE and vital signs measurements. 
4. Collect urine for a semi-quantitative (“dipstick”) urinalysis. 
5. Collect a blood sample for hematology and biochemistry and for plasma PK analysis.  
6. Assess local cutaneous tolerance of each mini-zone.  
7. Perform clinical evaluations of efficacy by measuring the intensity of the erythema, 
scaling and induration on each individual mini-zone. 
8. Perform clinical evaluations of the clearing score for each mini-zone 
9. 
10. Perform a 12-lead electrocardiogram (before keratolytic product application)  
11. Perform an ophthalmic examination  
12.
16. Give the Subject an appointment for the Day 262 visit. 
8.1.5 
Follow-up visit (D26 2 visit) 
The Investigator will: 
 
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1. 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 page(s) 
2. 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 
3. Check the results of the laboratory tests performed at Day 19  
4. 
5. 
6. Remove the suture (if applicable) 
7. Complete the Exit Form. 
8.2 
Subject instructions (other than study drug(s) administration) 
Each subject will receive specific requirements or instructions to follow until the end of the 
study. 
During the study, the Subject will be allowed to use, if needed, all types of therapies excluding 
those listed in the 5.5.5 Prohibited concomitant therapies. 
Subjects will be instructed not to apply any treatment oremollient to the target psoriasis plaques 
receiving the pre-treatment or the treatments during the study.  Subjects may treat the other 
psoriasis plaques (other than the one(s) with selected mini-zones) only with their regular 
emollient, or using the emollient provided by the Sponsor. 
Scalp psoriasis may be treated with non-steroid shampoo. 
The Subject will be instructed to apply the keratolytic product at home every day two times per 
day, preferably after washing, from 7 days before the planned Baseline visit appointment on the 
plaque(s) selected by the investigator only and not on the other plaques. No application should be 
performed the day of Baseline visit. This period may be extended to one more week based on 
investigator judgment.  
If a Subject needs 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 will be 
allowed at least eight hours after the applications.  Some additional gauze may be used to protect 
the treated areas from getting wet (i.e use of “Cellofrais”).  Bathing (swimming, bath, sauna, 
hammam) will be prohibited during the duration of the study.  In addition, the Subject will be 
instructed to avoid excessive sun exposure and vigorous exercise that may result in excessive 
sweating during the study. 
The subjects should never  remove the bandages on treated zones. 
 
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The contact lens wearing is prohibited during the treatment period. 
 
The Subject should come to the site each day for study procedures and study drugs applications 
except on Saturdays and Sundays. 
The Subject will be instructed not to discuss the study materials with the Investigator or other 
Evaluator(s). 
For safety precautions, participation in any other clinical trial is prohibited during the course of 
the study and for the following month. 
9 STATISTICAL METHODS PLANNED 
9.1 
Statistical and analytical plans 
9.1.1 
Data transformations 
Baseline assessments are accounted for deriving specific criteria (Change and percent changes). 
Concentrations data will logarithmically transformed before analysis. 
9.1.2 
Populations analyzed and evaluability  
The intent-to-treat efficacy population (ITT) consists of the entire randomized population.  
The ITT population will be analyzed for TSS, clinical scores and their percent change and 
change from baseline. A last visit for treatment period will be created, Endpoint, containing the 
last observation carried forward LOCF. Only Baseline and Endpoint/LOCF will be descriptively 
summarized.  
The per-protocol efficacy population (PP) consists of all randomized subjects, except some 
subjects considered as not evaluable due to major deviations from the protocol. 
Major deviations will be defined after data entry and before breaking the treatment blind, and 
may include: inclusion criteria not respected, interfering therapy, protocol deviation, poor 
compliance to study treatment administration or protocol requirements, unblinding. The decision 
on determining whether a subject is excluded from the PP population will be made during a blind 
review meeting. 
The per-protocol population as defined above will be analyzed for efficacy at each evaluation 
visit during treatment period. 
All Subjects having received a treatment at least once will be included in the safety population. 
If applicable, an additional safety population will be defined for the pretreatment period with 
keratolitic. 
 
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9.1.3 
Data presentation and graphics 
The subject disposition, demographics, baseline characteristics, previous therapies, concomitant 
therapies will be summarized by descriptive statistics. 
All efficacy variables will also be summarized by treatment (treatment / pre-treatment) at each 
visit.  The categorical variables will be summarized by frequency and percentage for each 
response category (N, %).  The continuous variables will be summarized using means, medians, 
minimum, maximum, and standard deviations for the data collected at each visit. 
The area under the curve of the TSS (sum of individual clinical scores erythema, 
induration/plaque elevation and scaling), as well as those of each individual clinical score will be 
calculated from Day 1 (before application) up to Day 19 by subject and by treatment, using the 
trapezoidal rule. 
The time to success (defined as a clearing score of 0 or 1) will be summarized by treatment.  Only 
the earliest day of success will be considered in defining the time to partial clearing, 
independently of the subsequent days. 
The local tolerance scores will be summarized using frequency and percentage by visit and study 
product. The worst scores will also be summarized. 
Adverse Events will be tabulated by study treatment.  Adverse Events will be tabulated in 
frequency tables by System Organ Class (SOC) and Preferred Term (PT) based on the MedDRA 
dictionary.  Additional summary tables will be provided for Adverse Events that will be 
considered as severe, serious (SAEs) and Adverse Events leading to discontinuation.  Any AE 
and related AE will be summarized for each category.  Analyses of adverse events will be based 
on Treatment Emergent Signs and Symptoms (TESS) i.e. adverse events occurring on the day of, 
or after, treatment application (Baseline). 
Events having occurred before the day of treatment application (i.e. before Baseline) will be 
listed only. 
Due to the intra-individual study design and whenever possible (known from e-CRF), AE will be 
imputed to the treated area, when not possible then the AE will be imputed to all treated area. 
Physical examination, vital signs, ECG and ophthalmic examination will be summarized by 
descriptive statistics. 
Shift tables for the laboratory data (and urinalysis) will be tabulated for each laboratory 
parameter. 
 
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Pharmacokinetics parameters will be descriptively summarized. 
9.1.4 
Inferential statistical analyses 
 
For all zones, TSS and percent change from baseline, Clinical scores and their change from 
baseline will be descriptively summarized by visit and by treatment received.  
 
9.2 
Sample size determination 
 
 
 
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Therefore 24 subjects are planned to be randomized. 
This sample size is sufficient to assess also local tolerance in standard tolerance topical studies. 
10 TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE 
10.1 
Personnel training 
A study initiation visit will be conducted by the Sponsor with the Investigators and the study 
teams.  During this visit, an extensive review and discussion of the protocol, procedures, CRF, 
and any other study material will be conducted.  Sponsor’s monitoring visits will be performed. 
 
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Clinical Research Associates (CRAs) and other applicable personnel will be trained prior to 
study initiation to familiarize CRAs with the disease, the Standard Operating Procedures (SOP), 
the protocol and other study specific items.  Team organization, communication and operational 
issues will also be discussed. 
10.2 
Clinical monitoring 
The conduct of the clinical trial will be closely monitored by representatives of GALDERMA 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, study drug(s) dispensing 
records, and any other documents considered source documentation.  Additionally, the 
CRO/Sponsor representative is to have access to the study drug(s) storage area and clinical trial 
facilities. 
The Investigator also agrees to assist the representative if required. 
10.3 
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 (CRF), and whether the data management activities are performed internally or 
outsourced.  Computerized edit checks and review processes will be performed on an ongoing 
basis as outlined in the DMP until all data clarifications are resolved.  The data will be exported 
to be stored in SAS datasets.  After all data clarifications are resolved, coding is approved, 
SAE/pregnancy reconciliation has been completed (if applicable) and subject’s evaluability is 
determined, the database will be locked. 
10.4 
Quality assurance / audit / inspection 
The clinical trial is conducted under the sponsorship of GALDERMA 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 GALDERMA 
and/or the Contract Research Organization (CRO). 
Audits of clinical trial centers 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, GALDERMA auditors, audit certificate(s) will be 
provided by Quality Assurance. 
 
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10.5 
Changes in clinical trial conduct / amendments 
10.5.1 
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/favorable 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. 
10.5.2 
Amendments 
The Sponsor may modify the clinical trial protocol at any time for ethical, medical, or scientific 
reasons. Any amendments will be handled according to applicable local regulations. 
The Sponsor does not have to notify non-substantial amendments to the competent authorities or 
the Ethics Committees. However, non-substantial amendments should be recorded and detailed 
in subsequent submissions e.g., in the subsequent notification of a substantial amendment. 
11 ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS 
11.1 
Independent Ethics Committee (IEC) 
This clinical trial protocol and all amendments will be reviewed and approved by the appropriate 
IEC. 
11.2 
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.  
11.3 
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, federal regulations, and guidelines and in 
accordance with local requirements.   
The ICF approved by an IEC, will be fully explained to the subject. An additional ICF will also 
be approved relating to the long term research program (see section 7.3.3).  
 
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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). 
11.4 
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. 
11.5 
Data collection and archiving 
11.5.1 
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. 
11.5.2 
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 Form.  All AEs must be thoroughly documented. 
Results of any diagnostic tests conducted during the clinical trial should also be included in the 
source documentation. 
11.5.3 
Archives 
All pertinent data, samples, photographs, 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. 
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. 
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. 
 
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11.6 
Insurance 
A certificate attesting Third Party coverage of CRO/Sponsor will be provided upon request. 
11.7 
Investigator and Administrative Structure  
Designation of a Coordinating Investigator (CI) will be done pursuant to the European Agency 
for the Evaluation of Medicinal Products (EMA) guidance on “Coordinating Investigator 
Signature of Clinical Study Reports”. 
12 LITERATURE REFERENCE LIST 
12.1 
Literature references 
Baadsgaard O and al. Optimal concentration of tacalcitol in once daily treatment of psoriasis. 
Journal of Dermatological Treatment 1995; 145-150 
Bangha E, Elsner P. Evaluation of topical antipsoriatic treatment by chromametry, visiometry 
and 20-MHz ultrasound in the psoriasis plaque test. Skin Pharmacol. 1996, 9(5):298-306. 
Beutner K. AN2728 demonstrates significant efficacy in three phase Ib psoriasis microplaque 
trials. JAAD, 2009, 60(3), supp 1: AB168. 
Buder, K., Wozel, G. Evaluation of Methylprednisolone Aceponate, Tacrolimus, and 
Combination Thereof in the Psoriasis Plaque Test by Sum Score, 20-Mhz Ultrasonography, and 
Optical Coherence Tomography. Basic Clin Pharmacol Toxicol 2009: 104(6): 494 
Dumas KJ, Scholtz JR. The psoriasis bioassay for topical corticosteroid activity. Acta Derm 
Stock 1972; 52, 43-48.  
El-Abaseri TB, Hammiller B, Repertinger SK, Hansen LA. The epidermal growth factor receptor 
increases cytokine production and cutaneous inflammation in response to ultraviolet irradiation. 
ISRN Dermatol. 2013;2013:848705. 
Griffiths CE, Barker JN.  Pathogenesis and clinical features of psoriasis. Lancet. 2007 Jul 21; 
370(9583):263-71. 
Gillespie Theresa W., Carney Pamela H., Knoop Teresa J. Caring for Oncology Patients: Tips 
and Tools for Managing Targeted Therapy Side Effects eHandbook 2009; Chapter 2: 2-5   
Jacobi A, Mayer A, Augustin M. Keratolytics and Emollients and Their Role in the Therapy of 
Psoriasis: a Systematic Review. Dermatol Ther (Heidelb), 2015, 5(1):1-18. 
Johnston Andrew, Gudjonsson Johann E., Aphale Abhishek, Guzman Andrew M., Stoll Stefan 
W., and Elder James T. EGFR and IL-1 signaling synergistically promote keratinocyte 
antimicrobial defenses in a differentiation-dependent manner. J Invest Dermatol. 2011 February; 
131(2): 329–337. doi:  10.1038/jid.2010.313. 
 
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Jullien D. Psoriasis physiopathology. JEADV. 2006. 20 (suppl. 2); 10-23. 
Levey AS, MD; Stevens LA., MD, MS; Schmid CH., PhD; Zhang Y(L), MS; Castro III AF., 
MPH; Feldman HI., MD, MSCE; Kusek JW., PhD; Eggers P, PhD; Van Lente F, PhD; Greene T, 
PhD; and Coresh J, MD, PhD, MHS. A New Equation to Estimate Glomerular Filtration Rate, 
Annals of Internal Medicine 2009;150(9):604-613  
Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of 
targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol. 2015 
Feb;72(2):203-18 
Menter A, Griffiths CE.  Current and future management of psoriasis. Lancet. 2007 Jul 
21;370(9583):272-84. 
Morsy Hanan, Kamp Soren, Thrane Lars, Behrendt Nille, Saunder Birgit, Zayan Hisham, Ensaf 
Abd Elmagid, Jemec Gregor B. E. Optical coherence tomography imaging of psoriasis vulgaris: 
correlation with histology and disease severity. Archives of Dermatological Research March 
2010, Volume 302, Issue 2, pp 105-111. 
Overbeck Tobias R. Griesinger Frank. Two Cases of Psoriasis Responding to Erlotinib: Time to 
Revisiting Inhibition of Epidermal Growth Factor Receptor in Psoriasis Therapy? Dermatology 
2012; 225:179–182 DOI: 10.1159/000342786 
Pan M, Heinecke G, Bernardo S, Tsui C, Levitt J. Urea: a comprehensive review of the clinical 
literature. Dermatology Online Journal, 2013, 19(11). 
Remitz A et al. Tacrolimus ointment improves psoriasis in a microplaque assay. British Journal 
Dermatology 1999; 141: 103-107.  
Scholtz JR, Dumas KJ. Standards for clinical evaluation of topical steroids. 13th Int Congr. 
Derm. 1968, vol 2, 179- 181.  
Varani J., Lateef H., Fay K., Elder J.T., Antagonism of Epidermal Growth Factor Receptor 
Tyrosine Kinase Ameliorates the Psoriatic Phenotype in Organ-Cultured Skin. Skin Pharmacol 
Physiol 2005; 18:123–131. DOI: 10.1159/000084909 
 
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13 APPENDICES 
13.1 
Classification of CYP Inhibitors 
From FDA site: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInterac
tionsLabeling/ucm093664.htm 
Classification of In Vivo Inhibitors of CYP Enzymes(1) (7/28/2011) Drug Development and 
Drug Interactions. (Table 5 on the website) 
CYP Enzymes   
Strong 
Inhibitors(2)  
≥ 5-fold increase in AUC 
or > 80% decrease in CL  
Moderate 
inhibitors(3)  
≥ 2 but < 5-fold increase in 
AUC 
or 50-80% decrease in CL  
Weak 
inhibitors(4)  
≥ 1.25 but < 2-fold increase in 
AUC 
or 20-50% decrease in CL  
CYP1A2 
Ciprofloxacin, 
enoxacin,
fluvoxamine 
Methoxsalen, 
mexiletine,
oral 
contraceptives, 
phenylpropanolamine, 
thiabendazole, zileuton 
Acyclovir, allopurinol, caffeine, 
cimetidine, 
Daidzein,(5), 
disulfiram, 
Echinacea,(5) 
famotidine, 
norfloxacin, 
propafenone, 
propranolol, 
terbinafine, 
ticlopidine, verapamil 
CYP2B6 
 
 
Clopidogrel, 
ticlopidine 
prasugrel 
CYP2C8 
Gemfibrozil(6) 
 
Fluvoxamine, 
ketoconazole, 
trimethoprim 
CYP2C9 
 
Amiodarone, 
fluconazole,
miconazole, oxandrolone 
Capecitabine, 
cotrimoxazole,
etravirine, 
fluvastatin, 
fluvoxamine, 
metronidazole, 
sulfinpyrazone, 
tigecycline,
voriconazole, zafirlukast 
CYP2C19 
Fluconazole,(7) 
Fluvoxamine,(8) 
ticlopidine(9) 
Esomeprazole, 
fluoxetine, 
moclobemide, 
omeprazole, voriconazole 
Allicin 
(garlic 
derivative), 
armodafinil, 
carbamazepine,
cimetidine, 
etravirine, 
human growth hormone (rhGH),
felbamate, 
ketoconazole, 
oral contraceptives(10) 
CYP3A 
Boceprevir, 
clarithromycin, 
conivaptan,
grapefruit 
juice,(11) 
indinavir, 
itraconazole, 
ketoconazole,  
lopinavir/ritonavir, 
mibefradil, 
(12)
nefazodone, 
nelfinavir,
posaconazole, 
ritonavir, 
saquinavir,  
telaprevir, 
telithromycin, 
voriconazole 
Amprenavir, 
aprepitant,
atazanavir, 
ciprofloxacin,
darunavir/ritonavir, 
diltiazem, 
erythromycin, 
fluconazole, 
fosamprenavir, 
grapefruit 
juice,(11) 
imatinib, verapamil 
Alprazolam, 
amiodarone, 
amlodipine, 
atorvastatin, 
bicalutamide, 
cilostazol, 
cimetidine, 
cyclosporine, 
fluoxetine, 
fluvoxamine, 
ginkgo,(5) 
goldenseal,(5) 
isoniazid, 
nilotinib,
oral contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, zileuton 
 
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CYP2D6 
Bupropion, 
fluoxetine,
paroxetine, quinidine 
Cinacalcet, 
duloxetine,
terbinafine 
Amiodarone, 
celecoxib,
cimetidine, 
desvenlafaxine, 
diltiazem, 
diphenhydramine, 
Echinacea,(5) 
escitalopram,
febuxostat, 
gefitinib,
hydralazine, hydroxychloroquine,
imatinib, 
methadone,
oral 
contraceptives, 
propafenone, 
ranitidine,
ritonavir, 
sertraline,
telithromycin, verapamil 
1. Please note the following:  This is not an exhaustive list.  For an updated list, see the 
following link 
2. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
substrate for that CYP by equal or more than 5-fold. 
3. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of 
a sensitive substrate for that CYP by less than 5-fold but equal to or more than 2-fold. 
4. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a 
sensitive substrate for that CYP by less than 2-fold but equal to or more than 5-fold. 
5. Herbal product. 
6. Gemfibrozil also inhibits OATP1B1. 
7. Fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, 
which is also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
8. Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, but also inhibits CYP2C8/2C9 and 
CYP3A; 
9. Ticlopidine strongly inhibits CYP2C19, but also inhibits CYP3A, CYP2B6, and CYP1A2. 
10. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
11. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent.  Studies have shown that it can be classified as a “strong CYP3A 
inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a 
“moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single 
strength). 
12. Withdrawn from the United States market because of safety reasons. 
 
 
 
 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.112075 V01 16 Aug 2016 
Page 85 of 85 
 
13.2 
Summary of blood sample volumes  
 
Standard Analysis 
(Volumes in mL) 
Blood 
Sample 
Total 
Volume 
(mL) 
Screening 
 - Virology 
- Haematology  
- Biochemistry 
 
 
5 
3 
3 
 
 
11 
 
 
 
Day 5 visit 
- 
PK 
 
5 
 
5 
Day 19 or Early Termination 
- Biochemistry  
- Haematology 
- PK 
 
3 
3 
5 
 
11 
 
 
 
Day 25 visit 
- 
PK 
 
5 
 
5 
TOTAL AMOUNT 
 
32 
 
 
 
 
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SAP_001.pdf: 
Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 1 of 38
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 2 of 38
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviations
Terms
AEs
Adverse events
ATC
Anatomical Therapeutic Chemical
AUC
Area Under Curve
BLQ
Below Limit of Quantification
CV
Coefficient of variation
EGFR
Epidermal Growth Factor Receptor
ERK
Extracellular signal – Regulated Kinases
ET
Early Termination
FU
Follow Up
IHC
Immuno Histo Chemistry
ITT
Intent-To-Treat
Ln
Logarithmic
LOCF
Last Observation Carried Forward
LOQ
Limit Of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
N
Number
NA
Not Applicable
PK
PharmacoKinetic
PP
Per protocol
PT
Preferred Term
R&D
Research & Development
SAEs
Serious Adverse Events
SAS
Statistical Analyses System
SD
Standard deviation
SOC
System Organ Class
TSS
Total Sum Score
WHO
World Health Organization
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 3 of 38
TABLE OF CONTENTS
1.
STUDY OBJECTIVES............................................................................................................................6
2.
STUDY DESIGN....................................................................................................................................6
3.
EFFICACY AND SAFETY ASSESSMENT ...............................................................................................8
4.
EFFICACY AND SAFETY VARIABLES..................................................................................................9
4.1.
Efficacy variables............................................................................................................................9
4.2.
Safety variables.............................................................................................................................10
5.
POPULATIONS ANALYZED................................................................................................................11
5.1.
The Intent-to-treat (ITT) population..........................................................................................11
5.2.
The Per-Protocol (PP) efficacy population.................................................................................12
5.3.
The Safety population ..................................................................................................................12
7.
STATISTICAL METHODS AND DATA CONSIDERATIONS ..................................................................13
7.1.
Study subjects ...............................................................................................................................14
7.1.1.
Disposition of subjects ...............................................................................................................14
7.1.2.
Protocol deviations.....................................................................................................................14
7.2.
Efficacy analysis............................................................................................................................14
7.2.1.
Data sets analyzed......................................................................................................................14
7.2.2.
Demographic characteristics.....................................................................................................14
7.2.3.
Medical history, previous and concomitant therapies, medical and surgical 
procedures ..................................................................................................................................14
7.2.4.
Compliance.................................................................................................................................15
7.2.5.
Efficacy analysis.........................................................................................................................15
7.2.5.1
Primary and secondary efficacy analysis...................................................................................15
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 4 of 38
7.2.6.
Statistical and analytical issues.................................................................................................16
7.2.6.1
Adjustment for covariates..........................................................................................................16
7.2.6.2
Handling of dropouts or missing data........................................................................................16
7.2.6.3
Interim analyses and data monitoring........................................................................................16
7.2.6.4
Multicenter studies ....................................................................................................................16
7.2.6.5
Multiple comparison/multiplicity..............................................................................................16
7.2.6.6
Use of an efficacy subset of patients .........................................................................................16
7.2.6.7
Active-Control studies intended to show equivalence...............................................................16
7.2.6.8
Examination of Subgroups ........................................................................................................16
7.3.
Safety analysis...............................................................................................................................17
7.3.1.
Extent of exposure......................................................................................................................17
7.3.2.
Local tolerance ...........................................................................................................................17
7.3.3.
Adverse events............................................................................................................................17
7.3.4.
Physical examination, vital signs ..............................................................................................17
7.3.5.
Ophthalmic examination...........................................................................................................17
7.3.6.
12-lead electrocardiogram.........................................................................................................18
7.3.8.
Laboratory parameters .............................................................................................................18
7.4.1.
Plasma concentration.................................................................................................................18
7.5.
Analysis visit definition ................................................................................................................19
8.
CHANGES FROM THE PROTOCOL ANALYSIS PLAN .........................................................................19
9.
TABLES, FIGURES AND GRAPHS.......................................................................................................20
9.1.
Study subjects ...............................................................................................................................20
9.2.
Efficacy analyses...........................................................................................................................20
9.2.1.
Subjects characteristics .............................................................................................................20
9.2.2.
Baseline characteristics..............................................................................................................21
9.2.3.
Primary and secondary efficacy criteria..................................................................................22
9.3.
Safety analyses ..............................................................................................................................28
9.3.1.
Extent of exposure......................................................................................................................28
9.3.2.
Local tolerance ...........................................................................................................................30
9.3.3.
Adverse events............................................................................................................................31
9.3.4.
Vital Signs, Physical Findings...................................................................................................32
 
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Protocol No: RD.03.SPR.112075
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9.3.5.
Laboratory Parameters.............................................................................................................34
9.4.
Graphs ...........................................................................................................................................35
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 6 of 38
1.
STUDY OBJECTIVES
The primary objective is to evaluate, in a modified Dumas-Scoltz psoriasis mini-zone test, the 
safety and efficacy of CD10367 solution at 1% and 3% after a three weeks treatment period of 
once daily application.
2.
STUDY DESIGN
Phase IIa.
This is an exploratory, single-centre (France), investigator blinded, randomized, controlled, intra-
individual study (Dumas-scholtz design).
Approximately 40 male or female of at least 18 and up to 70 years old suffering from stable 
plaque psoriasis vulgaris will be screened to randomize 24 subjects.
The subjects will be screened within 3 weeks prior to the pre-treatment period of up to 2 weeks, 
followed by a treatment period of 3 weeks and a follow-up period of 1 week.
During the pre-treatment period, the subject will apply a keratolytic product at home twice a day 
on the selected plaques defined by the investigator. 
 extreme cream from 
 
 (tube 50ml) with 50% of urea and 2% of salicylic acid (other components: serine, 
histidine, glycenin, protease, fragrance free and paraben free) will be used as the keratolytic 
agent. On these target areas, the desquamation will be controlled by the dermatologist and if the 
scaling’s score is 0 or 1 (none or mild), the subject will be enrolled.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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A final visit at Day 19 (or early termination visit if any) will be performed to evaluate safety and 
efficacy of the treatments, 
 
.
 
The study is expected to last approximately 5 months from the first subject included in the study 
to the last visit of the last subject. The total maximum study duration for one subject will be 9
weeks.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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3.
EFFICACY AND SAFETY ASSESSMENT
Screening period
Pre-treatment period
Treatment Period
Follow-up period
Up to 3 weeks before 
pre-treatment period
1 or 2 weeks abefore 
treatment period
Week 1
Week 2
Week 3
Week 4 to 5
D1
D2 &D3
D4
D5
D8
D9 & D10
D11
D12
D15
D16&D17&D18
Final visit D19 /ET 
D26 +/- 2
Informed Consent Form
X
Demographics and Medical history
X
Previous treatments and procedures
X
Physical examination
X
X
Vital signs
X
X
X
ECG
X b
X
Ophthalmic examination
X b
X
Inclusion Criteria and Exclusion Criteria
X
X
Selection of target sites 
X
X
Urinalysis
X
X
Safety tests Blood sampling
X
X
Randomization
X
Local Tolerance c
D2 only
X
X
X
X
X
Individual clinical scores
X
X
X
X
X
X
X
Clearing score                                                    
X
X
X
X
X
Keratolytic product application of selected plaque at home daily
X
Products application
X
X
X
X
X
X
X
X
X
X
PK blood sampling
X
X
X
Concomitant treatments and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Exit form e
X f
X
a. if the scaling score did not reach 0 or 1 after 1 week of pre-treatment, the pre-treatment period can be extended to 2 weeks, otherwise the subjects will start D1 visit immediately. b ECG and ophthalmic exams should be 
done as close as possible to baseline visit. c Local tolerance
of the concerned zone must be taken at any visit in case of AE in a treatment zone. d Adverse Events have to be collected from the ICF signature. e
Exit form should be signed after subject data collection has been completed. f Exit form should be completed at ET visit only if no follow-up visit is planned (discontinuation)
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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4.
EFFICACY AND SAFETY VARIABLES
4.1.
Efficacy variables
Primary clinically efficacy criteria
Area Under the Curve (AUC) from Day 1 to Day 19 of Total Sum Score (TSS)
(sum of erythema, scaling and induration scores).
Secondary clinically efficacy criteria
- AUC of individual clinical scores (erythema, scaling and induration) from Day 1 
to Day 19.
Erythema is scored on the following 5-point scale:
0
None
No detectable erythema. 
1
Mild
Slight pinkness present
2
Moderate
Definite redness, easily recognized.
3
Severe
Intense redness
4
Very Severe
Very intense redness
Scaling is scored on the following 5-point scale:
0
None
No shedding
1
Mild
Barely perceptible shedding, noticeable only on light scratching or 
rubbing.
2
Moderate
Obvious but not profuse shedding
3
Severe
Heavy scale production
4
Very Severe
Very thick scales
Induration is scored on the following 5-point scale:
0
None
Normal skin thickness.  No elevation of skin
1
Mild
Barely perceptible elevation (by touching) of the psoriasis plaques.
2
Moderate
Obvious elevation above the normal skin level; moderate thickening
3
Severe
Definite thick elevation above normal skin level
4
Very Severe
Very thick elevation
- TSS at each visit (screening, end of pre-treatment period for Z1 and Z2, day 1, 
day 4, day 8, day 11, day 15 and day 19) and TSS percent change from baseline;
- Erythema, scaling and induration score at each visit: screening, end of pre-
treatment period for Z1 and Z2, day 1, day 4, day 8, day 11, day 15 and day 19)
and their change from day 1;
- Success rate (defined as a clearing score of 0 or 1) at each evaluation visit (day 
4, day 8, day 11, day 15 and day 19) and the time to first success.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 10 of 38
The clearing score is defined as: 
0
Complete 
clearing
No scaling and no infiltration even on palpation. Post inflammatory hypo- or 
hyperpigmentation may be present. 
1
Almost clear
Residual erythema with some induration/ infiltration (not clinically visible but 
palpable) without scaling, or residual erythema and residual scaling with no 
infiltration.
2
Unchanged
Unchanged or less than almost clear.
The time to partial clearing (clearing score of 0 or 1) is defined as:
0
No Success at any day
1
Success at Day 19 and not before
2
Success at Day 15 and not before
3
Success at Day 11 and not before
4
Success at Day 8 and not before
5
Success at Day 4 and not before
Only the earliest day of success will be considered in defining the time to partial clearing, 
independently of the subsequent days.
4.2.
Safety variables
- Local tolerance (irritation, stinging/burning, pruritus) twice weekly using a 4-point scale 
for each mini-zone:
Irritation
Skin irritation Assessment 
0
None:
No signs of irritation 
1
Mild:
Slight signs of irritation
2
Moderate:
Moderate signs of irritation: Obvious increase in redness as compared to the 
non-treated surrounding area
3
Severe:
Severe signs of irritation 
Stinging/ Burning
Prickling pain sensation 
0
None:
No stinging/burning
1
Mild:
Slight warm, tingling/stinging sensation; not really bothersome
2
Moderate:
Definite warm, tingling/stinging sensation that is somewhat bothersome
3
Severe:
Hot, tingling/stinging sensation that causes severe discomfort
Pruritus
Itch sensation
0
None:
No itching
1
Mild:
Itching is noticeable but not really bothersome
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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2
Moderate:
Definite itching that is somewhat bothersome
3
Severe:
Marked itching, urge to scratch and causes definite discomfort
- Incidence and multiplicity of Adverse Events (from informed consent signature to the end 
of the study);
- Ophtalmic examination at screening and day 19/ET
- Physical examination at screening and day 19/ET;
- Vital signs performed after 5 minutes rest in the sitting position (systolic blood pressure, 
diastolic blood pressure, pulse rate, vital signs evaluation) at screening, baseline and 
day 19/ET;
- 12-lead electrocardiogram during the screening period and at day 19/ET;
- Blood samplings for laboratory safety tests (haematology and blood chemistry) at 
screening and day 19/ET (Virology will be performed only at screening);
- Urinalysis at screening and day 19/ET;
5.
POPULATIONS ANALYZED
5.1.
The Intent-to-treat (ITT) population
The ITT Population is defined as comprising all subjects who are randomized.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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5.2.
The Per-Protocol (PP) efficacy population
This population will consist of ITT subjects, except some subjects considered as not evaluable 
due to major deviations from protocol.
Major deviations will be defined after data entry and before breaking the treatment blind, and 
may include: inclusion criteria not respected, interfering therapy, protocol deviation, poor 
compliance to study treatment administration or protocol requirements, unblinding. The decision 
on determining whether a subject is excluded from the per-protocol (PP) population will be made 
during the blind review meeting.  
If no patient has a major deviation, PP efficacy population will be the same as ITT population, 
and results will be presented on the ITT population only.
5.3.
The Safety population
Safety population corresponds to all subjects who received at least once the study treatment
during the treatment period.
In case of identical populations, only one safety population will be used for the analysis.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 13 of 38
7.
STATISTICAL METHODS AND DATA CONSIDERATIONS
SAS® version 9.3 will be used for the analysis. Graphics will be performed on SAS.
The categorical variables will be summarized by frequency and percentage for each response 
category (N, %). The continuous variables will be summarized using means, medians, minimum, 
maximum, and standard deviations. 
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 14 of 38
7.1.
Study subjects
7.1.1.
Disposition of subjects
Subject disposition will be summarized in the ITT population.
Normal completion as well as early discontinuation will be summarized using frequency 
distribution (n, %). All early discontinuations will be detailed in a subject-by-subject listing.
7.1.2.
Protocol deviations
All protocol deviations, including the decisions regarding major/minor protocol deviations, will 
be documented in the blind data review meeting and entered into a dataset.
Subjects with major protocol deviations will be excluded from the PP population. 
Major protocol deviations will be summarized using frequency distribution (n, %) and will be
detailed in a subject-by-subject listing.
7.2.
Efficacy analysis
7.2.1.
Data sets analyzed
Number of subjects included in each population (ITT population, PP population, safety
population, 
) will be summarized.
7.2.2.
Demographic characteristics
Frequency distribution (n, %), for qualitative criteria, will be used.
Usual descriptive statistics (n, mean, standard deviation, median, min, max), for quantitative 
criteria, will be used.
Analysis will be performed on ITT population and PP population (if the number of patients is too 
different).
7.2.3.
Medical history, previous and concomitant therapies, medical and surgical 
procedures
Medical history will be defined as any disease present before the Screening visit.
Frequency distribution of subjects with previous or/and concomitant disease(s) will be tabulated.
Previous and concomitant therapies will be coded using the World Health Organization (WHO) 
Drug Dictionary (version v032015).
Previous therapies are defined as therapies stopped within the 6 months preceding the screening 
visit. Frequency distribution of subjects with at least one previous therapy will be tabulated by 
Anatomical Therapeutic Chemical (ATC) classification.
Concomitant therapies are defined as any ongoing therapies at the time of the screening visit, and 
any new therapies started or changed since the screening visit. 
Frequency distribution of subjects with at least one concomitant therapy will be tabulated by 
ATC classification.
Previous and concomitant procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA version 18.0).
Previous procedures are defined as procedures stopped within 6 months preceding the screening 
visit.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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Frequency distribution of subjects with at least one previous procedure will be tabulated (n, %) 
by preferred term.
Concomitant procedures are defined as any ongoing procedures at the time of the screening visit, 
and any new procedures started or changed since the screening visit.
Frequency distribution of subjects with at least one concomitant procedure will be tabulated (n, 
%) by preferred term.
7.2.4.
Compliance
 extreme cream will be applied at home by the subject twice daily, up to 2 weeks 
before the treatment period upon the judgment of the dermatologist. The scaling score should be 
0 or 1 when the subject is enrolled.
All applications during the treatment period will be performed by a person from the
investigational team at the study centre, once daily during 3 weeks, 5 days a week except for the 
third week, for a total of 14 applications.
Subjects with a low compliance will be excluded from PP population during the data review.
7.2.5.
Efficacy analysis 
7.2.5.1
Primary and secondary efficacy analysis
Descriptive statistics will be done on observed cases for PP and ITT populations.
The Area Under the Curve (AUC) will be calculated from Day 1 (before application) to Day 19
by subject and by treatment/pre-treatment on the Z1-Z6 mini-zone, using the trapezoidal rule on 
ITT and PP population.
Dates of theorical visit will be used to perform AUC.
AUC of TSS will be submitted to an analysis of variance including subject and treatment/pre-
treatment as factors in the model, 
 
AUC of individual clinical scores (erythema, scaling and induration) will be submitted to the 
same variance analysis.
TSS and TSS percent change from day 1 will be descriptively summarized by visit, as the 
individual score of erythema, scaling and induration and their respective change from day 1. The 
analysis will be performed on PP population and ITT population (baseline and Endpoint/LOCF)
Success will be presented in frequency tables (N,%) by treatment/pre-treatment and by visit.
The time to first success will be summarized by treatment/pre-treatment.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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7.2.6.
Statistical and analytical issues
7.2.6.1
Adjustment for covariates
Adjustments to baseline value, i.e., day 1 will be considered in the calculation of change and 
percent change.
7.2.6.2
Handling of dropouts or missing data
For evaluation by visit, on ITT population, a last visit named “Endpoint/LOCF” containing the 
last observation carried forward (LOCF) will be created.
For Area Under the Curves (of the TSS or for each individual clinical score), no imputation for 
missing assessment will be done and calculations will be done on observed data, nevertheless for 
the subjects who terminated earlier, the Final Visit will be imputed to the closest theoretical visit 
of the protocol.
For patients who have individual score assessments on unscheduled day, closest theoretical visit 
of the protocol will be used, for each evaluation overtime and AUC.
7.2.6.3
Interim analyses and data monitoring
Not Applicable (NA)
7.2.6.4
Multicenter studies
NA
7.2.6.5
Multiple comparison/multiplicity
7.2.6.6
Use of an efficacy subset of patients
NA
7.2.6.7
Active-Control studies intended to show equivalence
NA
7.2.6.8
Examination of Subgroups
NA
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 17 of 38
7.3.
Safety analysis
All safety data will be summarized based on the safety population.
7.3.1.
Extent of exposure
Number of days of keratolytic during the pre-treatment period in zone 1 and 2 will be 
summarized.
Study product application will be presented by treatment/pre-treatment and by visit.
Number of study products applications will be summarized by treatment/pre-treatment.
7.3.2.
Local tolerance
Local individual signs/symptoms (irritation, skinging/burning, pruritus) in term of frequency 
distribution and in quantitative description and the worst score (from Day 2 to Day 19/ET) over 
time of each individual sign/symptom will be calculated by study product.
7.3.3.
Adverse events
Adverse Events will be tabulated by study treatment/pre-treatment and in overall.
Occurrence of adverse events will be separated in two periods: the pre-treatment period from the 
beginning of the pre-treatment period to day 1 excluded, and the treatment period from the date 
of first application of study drugs to the end of the study.
For the pre-treatment period, only a table with the overview of the adverse events and a listing of 
the adverse events during this period will be performed.
For the treatment period, Adverse Events (AE) will be tabulated in frequency tables by System 
Organ Class (SOC) and Preferred Term (PT) based on MedDRA version 18.0. Additional
summary tables will be provided for Adverse Events that are considered serious (SAEs), related 
to study product, related to protocol procedure, related to the study (study product and/or 
protocol procedure), Adverse Events of special interest, and Adverse Events leading to 
discontinuation.  
Due to the intra-individual study design and whenever possible (known from CRF) AE will be 
imputed to the treated area, when not possible then the AE will be imputed to all treated zones.
AEs with an onset prior to the pre-treatment period will be listed separately.
7.3.4.
Physical examination, vital signs
Physical examination and vital signs evaluation will be summarized by visit using frequency 
tables (Normal/Abnormal and not clinically significant/Abnormal and clinically significant).
Shift table will be tabulated.
Systolic blood pressure, diastolic blood pressure and pulse rate will be summarized by visit in 
quantitative manner. Change from baseline will be calculated.
7.3.5.
Ophthalmic examination
Ophthalmic examination will be summarized by visit using frequency tables (Normal/Abnormal 
and not clinically significant/Abnormal and clinically significant).
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
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Shift table will be tabulated.
7.3.6.
12-lead electrocardiogram
Results of 12-lead electrocardiogram will be summarized by visit using frequency tables
(Normal/Abnormal and not clinically significant/Abnormal and clinically significant).
Shift table will be tabulated.
QTc interval and change from screening will be also summarized by visit.
7.3.8.
Laboratory parameters
Each hematology and biochemistry parameter will be subject to quantitative and qualitative 
analyses at screening and at day 19/ET.
Quantitative values in standard units will be summarized at screening and at Day 19/ET, as well 
as change from screening.
Frequency of subjects with low, normal, high values with respect to normal range will be 
summarized at screening and at day 19/ET.  
Shift tables will be displayed presenting data at screening and at day 19/ET.
Each urinalysis parameter will be subject to qualitative analyses at screening and at day 19/ET. 
Shift tables will also be displayed.
In case of urinalysis parameter in quantitative manner, results will be presented by summary 
statistics.
7.4.1.
Plasma concentration
Raw values of concentration of CD10367 will be summarized with geometric mean, arithmetic 
mean, standard deviation (SD), coefficient of variation (CV), median, minimum and maximum 
values by visit (day 5; day 19/ET and day 26).
Logarithmic values (ln) of concentration of CD10367 will be summarized with mean, standard 
deviation, median, minimum and maximum value by visit.
 
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Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 19 of 38
7.5.
Analysis visit definition
NA
8.
CHANGES FROM THE PROTOCOL ANALYSIS PLAN
NA
 
CONFIDENTIAL  GALDERMA                  
Internally Approved
01-Feb-2019
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 20 of 38
9.
TABLES, FIGURES AND GRAPHS
9.1.
Study subjects
Table. Enrollment by Center
Table. Subjects who discontinued treatment and reason for discontinuation
Table. Major protocol deviations
9.2.
Efficacy analyses
9.2.1.
Subjects characteristics
Table. Data sets analyzed
Table. Demographic data – ITT population
Including age (as quantitative data and by class 18-64, 65-84 and >=85), gender, race, phototype, subject of childbearing potential.
Table. Medical history – ITT population
Including duration of psoriasis and relevant or major illnesses present before the screening visit.
Table. Previous therapies by ATC term – ITT population
Table. Previous procedures by preferred term – ITT population
Table. Concomitant therapies by ATC term – ITT population
Table. Concomitant procedures by preferred term – ITT population
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 21 of 38
9.2.2.
Baseline characteristics
Table. Target location – ITT population
CD10367 placebo
pre-treated
CD10367 3% 
pre-treated
CD10367 
placebo
CD10367 1%
CD10367 3% 
Betneval 0.1%
Overall
N
Elbows
n(%)
Knees
n(%)
…
Table. Target location – PP population
Table. Pre-treatment clinical scores in mini-zones Z1 and Z2 – ITT population
CD10367 placebo 
pre-treated
CD10367 3% 
pre-treated
Overall
Erythema
N
2
3
4
Mean
SD
Median
(Min,Max)
Scaling
N
0
1
Mean
SD
Median
(Min,Max)
Induration…
…
TSS
…
Table. Pre-treatment clinical scores in mini-zones Z1 and Z2 – PP population
Table. Baseline clinical scores in mini-zones Z1 to Z6 – ITT population
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 22 of 38
Baseline corresponds to week 1 day 1.
Table. Baseline clinical scores in mini-zones Z1 to Z6 – PP population
Baseline corresponds to week 1 day 1.
9.2.3.
Primary and secondary efficacy criteria
Table. AUC of TSS – Treatment period - PP and ITT population
CD10367 
placebo 
pre-treated
CD10367 
3% 
pre-treated
CD10367 placebo
CD10367 1%
CD10367 3% 
Betneval 0.1%
AUC of TSS (PP)
N
Mean
SD
Median
(Min,Max)
AUC of TSS (ITT)
N
Mean
SD
Median
(Min,Max)
Table. Analysis of variance for AUC of TSS – Treatment period - PP population
LSmean(SE)
p-value*
Model Effects
Patient
-
Treatment
CD10367 placebo pre-treated
Treatment
CD10367 3% pre-treated
…
Contrast
CD10367 placebo – Betneval
…
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 23 of 38
Table. AUC of erythema – Treatment period - PP and ITT population
Table. Analysis of variance for AUC of erythema – Treatment period - PP population
Table. AUC of scaling – Treatment period - PP and ITT population
Table. Analysis of variance for AUC of scaling – Treatment period - PP population
Table. AUC of induration – Treatment period - PP and ITT population
Table. Analysis of variance for AUC of induration – Treatment period - PP population
Table. TSS and TSS percent change from day 1 – PP population
TSS
CD10367 
placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 
placebo
CD10367 1%
CD10367 
3% 
Betneval 
0.1%
Screening
N
Mean
SD
Median
(Min,Max)
End of pre-treatment period*
Day 1, Day 4
N
Mean
SD
Median
(Min,Max)
Percent change from Day 1 at Day 4
N
Mean
SD
Median
(Min,Max)
Day 8, Day 11, Day 15, Day 19
N
…
Percent change from Day 1 at  Day 
8, Day 11, Day 15, Day 19
N
…
*performed only in Z1 and Z2
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 24 of 38
Table. TSS and TSS percent change from day 1 – ITT population
ITT population and with only 2 visits: Day 1 and Endpoint/LOCF
Table. Erythema and change from day 1 – PP population
Table. Erythema and change from day 1 – ITT population
Table. Scaling and change from day 1 –PP population
Table. Scaling and change from day 1 –ITT population
Table. Induration and change from day 1 – PP population
Table. Induration and change from day 1 – ITT population
Table. Clearing score by visit – Treatment period - PP population
Clearing score
CD10367 placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
…
Day 4
N
0
1
2
Mean
SD
Median
(Min,Max)
Day 8, Day 11, Day 15, Day 19
…
Table. Clearing score by visit – Treatment period - ITT population
Same table as above but on ITT population and with the additional visit Endpoint/LOCF
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 25 of 38
Table. Success by visit – Treatment period - PP population
Success
CD10367 
placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
…
Day 4
N
No
Yes
Day 8, Day 11, Day 15, Day 19
N
No
Yes
Table. Success by visit – Treatment period - ITT population
Table. Time to first success – Treatment period - PP and ITT population
Time to first success
CD10367 
placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
…
PP
N
No success at any day
Success at Day 19 and not before
Success at Day 15 and not before
Success at Day 11 and not before
Success at Day 8 and not before
Success at Day 4 and not before
Mean
SD
Median
(Min,Max)
ITT
…
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 26 of 38
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 27 of 38
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 28 of 38
9.3.
Safety analyses
9.3.1.
Extent of exposure
Table. Pre-treatment duration of keratolytic product – Safety population
CD10367 placebo 
pre-treated
CD10367 3% 
pre-treated
Number of days of keratolytic product applications
N
4
5
6
7
N
Mean
SD
Median
(Min,Max)
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 29 of 38
Table. Study drug applications during the treatment period on mini-zones Z1 to Z6 – Safety population 
CD10367 
placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
…
Day 1
N
No
Yes
Day 2, 3 4, 5, 8, 9, 10, 11, 12, 15, 16, 
17,18
N
No
Yes
Day 2: reason for not applied
N
Temporarily 
discontinued due 
to irritation
Permanent 
discontinuation 
due to irritation
Other
…
Table. Number of applications during the treatment period on mini-zones Z1 to Z6 – Safety population
CD10367 placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
…
N
11
12
13
Mean
SD
Median
(Min,Max)
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 30 of 38
9.3.2.
Local tolerance
Table. Irritation in term of continuous data
0= None – 1=Mild – 2=Moderate – 3=Severe
Table. Irritation in term of frequency distribution
Irritation
CD10367 placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
Day 2
N
0- None
1- Mild
2- Moderate
3 – Severe
Day 2 …
Table. Stinging /Burning in term of continuous data
Table. Stinging /Burning in term of frequency distribution
Table. Pruritus in term of continuous data
Table. Pruritus in term of frequency distribution
Table. Worst Score in term of frequency distribution
Irritation
CD10367 placebo 
pre-treated
CD10367 3% 
pre-treated
CD10367 placebo
…
…
…
Day 2
N
xx
xx
xx
xx
xx
xx
Mean±sd
xx.x±xx.x
xx.x±xx.x
xx.x±xx.x
xx.x±xx.x
xx.x±xx.x
xx.x±xx.x
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
(Min,Max)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
Day 3…
…
Day 19
Day 19/ET
Follow-up
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 31 of 38
9.3.3.
Adverse events
Table. Overview of adverse events during the pre-treatment period – Safety population 
Table. Listing of adverse events during the pre-treatment period – Safety population 
Table. Listing of adverse events prior the pre-treatment period – Safety population 
†Or listing if few AE.
Table. Overview of adverse events during the treatment period – Safety population 
Table †. Summary of adverse events by Preferred Term – Safety population 
Table †. Summary of adverse events Related to the study drug by Preferred Term – Safety population
Table †. Summary of adverse events Related to the protocol procedure by Preferred Term – Safety population
Table †. Summary of adverse events Related to the study by Preferred Term – Safety population
Table . Summary of adverse events by System Organ Class and Preferred term – Safety population
Table †. Summary of adverse events Related to the study drug by System Organ Class and Preferred term – Safety population
Table †. Summary of adverse events Related to the protocol procedure by System Organ Class and Preferred term – Safety population
Table †. Summary of adverse events Related to the study by System Organ Class and Preferred term – Safety population
Table †. Summary of adverse events by severity by System Organ Class and by Preferred term – Safety population
Table †. Summary of adverse events Related to the study drug by severity by System Organ Class and by Preferred term – Safety population
Table †. Summary of adverse events Related to the protocol procedure by severity by System Organ Class and by Preferred term – Safety population
Table †. Summary of adverse events Related to the study by severity by System Organ Class and by Preferred term – Safety population
Table †. Summary of serious adverse events by System Organ Class and by Preferred term – Safety population
Table †. Summary of adverse events leading to discontinuation by System Organ Class and by Preferred term – Safety population
Table †. Summary of AESIs by System Organ Class and by Preferred term – Safety population
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 32 of 38
9.3.4.
Vital Signs, Physical Findings
Table. Physical examination – Safety population
Table. Shift table of Physical examination – Safety population
Day 19/ET
Screening
Normal
Abnormal and not clinically significant
Abnormal and clinically signficant
Normal
Abnormal and not clinically 
significant
Abnormal and clinically 
signficant
Table. Vital signs – Safety population
Median
(Min,Max)
Diastolic blood pressure (mmHg)
…
Pulse rate (bpm)
…
Vital signs evaluation
N
Normal 
Abnormal and Not clinically significant
Abnormal and Clinically significant
Screening
DAY 19/ET
Physical examination
N
Normal 
Abnormal and Not clinically significant
Abnormal and Clinically significant
Screening
Baseline
D19/ET
Change from 
baseline
Systolic blood pressure (mmHg)
N
Mean
SD
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 33 of 38
Table. Shift table of vital signs evaluation – Safety population
Day 19/ET
Baseline
Normal
Abnormal and not clinically significant
Abnormal and clinically signficant
Normal
Abnormal and not clinically 
significant
Abnormal 
and 
clinically 
signficant
Table. Ophthalmic examination – Safety population
Table. Shift table of ophthalmic examination – Safety population
Table. 12-lead ECG – Safety population
Table. Shift table for 12-lead ECG – Safety population
Screening
DAY 19/ET
ECG
N
Normal 
Abnormal and Not clinically significant
Abnormal and Clinically significant
QTC (ms)
N
Mean
SD
Median
(Min,Max)
QTC > 500 ms
N
No
Yes
Change in QTC (ms)
N 
Mean …
Change > 60 ms
N  No Yes
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 34 of 38
9.3.5.
Laboratory Parameters
Table. Haematology – Summary statistics – Safety population
Table. Haematology – Distribution by normality level – Safety population
Table. Haematology – Shift table – Safety population
Screening
D19/ET
Change from 
Screening
White blood cells (Giga/L)
N
Mean
SD
Median
(Min,Max)
…
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 35 of 38
Table. Blood chemistry – Summary statistics – Safety population
Table. Blood chemistry – Distribution by normality level – Safety population
Table. Blood chemistry – Shift table – Safety population
Table. Virology at screening – Safety population
Table. Urinalysis *– Summary statistics – Safety population
*: only for data in quantitative manner (like pH for exemple)
Table. Urinalysis – Distribution by normality level – Safety population
Table. Urinalysis – Shift table – Safety population
9.4.
Graphs
Graph. Mean TSS versus time per treatment -PP population
Graph. Median TSS percent change from day 1 by visit and by treatment -PP population
Graph. Mean Erythema versus time per treatment -PP population
Graph. Mean Erythema change from day 1 by visit and by treatment -PP population
Graph. Mean Scaling versus time per treatment -PP population
Graph. Mean Scaling change from day 1 by visit and by treatment -PP population
Graph. Mean Induration versus time per treatment -PP population
Graph. Mean Induration change from day 1 by visit and by treatment -PP population
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 36 of 38
Graph. Success by visit -PP population
Graph. Mean Irritation versus time per treatment -Safety population
Graph. Mean Stinging/burning versus time per treatment -Safety population
Graph. Mean Pruritus versus time per treatment -Safety population
Some other descriptive graphics could be performed upon request.
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI
CCI
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI


Protocol No: RD.03.SPR.112075
Statistical Analysis Plan 
Page 38 of 38
CONFIDENTIAL  GALDERMA 
Internally Approved
01-Feb-2019
CCI