Conditions: Atopic Dermatitis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: yes

Brief summary:
Primary Objective:

\- Evaluate changes in skin barrier function with transepidermal water loss (TEWL) assessed after skin tape stripping (STS) in pre-defined lesional skin in participants with moderate to severe atopic dermatitis (AD) treated with dupilumab.

Secondary Objectives:

* Evaluate changes in skin barrier function with TEWL assessed after STS in pre-defined lesional and non-lesional skin in participants with moderate to severe AD treated with dupilumab in reference to normal skin of healthy volunteers.
* Evaluate time course of skin barrier function with TEWL assessed before and after STS in pre-defined lesional and non-lesional skin in participants with moderate to severe AD treated with dupilumab in reference to normal skin of healthy volunteers.

Detailed description:
The duration for each participant was a total of approximately 24 weeks.

Arms:
arm 1: Healthy volunteers with age, gender, location of targeted skin lesion area and study site matched to a selected atopic dermatitis (AD) participants, received no treatment, but were monitored in similar way as like enrolled AD participants. arm 2: Participants with moderate to severe AD and aged 18 years and older received dupilumab 600 milligrams (mg) (loading dose) subcutaneous (SC) injection on Day 1, followed by dupilumab 300 mg SC injection every 2 weeks (Q2W) through Week 14 (i.e., at Day 15, 29, 43, 57 and 85).

Participants aged greater than or equal to (\>=) 12 to less than (\<) 18 years received treatment based on their body weight: \<60 kilograms (kg) and \>=60 kg - received dupilumab 400 mg and 600 mg (loading dose) SC injection on Day 1, respectively, followed by dupilumab 200 mg and 300 mg SC injection Q2W through Week 14 (i.e., at Day 15, 29, 43, 57 and 85).

Interventions: intervention 1: Dupilumab SAR231893
Intervention descriptions: intervention 1: Pharmaceutical form:solution for injection Route of administration: subcutaneous

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 
Protocol title: 
Open label exploratory study to evaluate the effect of 
dupilumab on skin barrier function in patients with 
moderate to severe atopic dermatitis 
Protocol number: 
LPS15991 
Amendment number: 01 
Compound number 
(INN/Trademark): 
SAR231893/REGN668 
dupilumab/Dupixent 
Study phase: 
Phase 4 
Short title: 
Dupilumab skin BArrier function and LIpidomics STudy in 
Atopic Dermatitis - BALISTAD 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1, Avenue Pierre Brossolette 
91380 Chilly-Mazarin Cedex  
France 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
Regulatory agency identifier number(s): 
IND: 
107969 
EudraCT: 
2020-000314-15 
NCT: 
Not applicable 
WHO: 
U1111-1244-1409 
EUDAMED 
Not applicable 
Other: 
Not applicable 
NCT04447417


Amended Clinical Trial Protocol 01  
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Page 2 
 
 
TABLE OF CONTENTS  
 
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 8 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) / AD PATIENTS ................................................................... 20 
1.4 
SCHEDULE OF ACTIVITIES (SOA) / HEALTHY VOLUNTEERS ................................................ 24 
2 
INTRODUCTION ............................................................................................................................ 27 
2.1 
STUDY RATIONALE...................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
2.3.1 
Risk assessment ............................................................................................................................ 29 
2.3.2 
Benefit assessment ........................................................................................................................ 30 
2.3.3 
Benefit/risk related to Coronavirus Disease 2019 (COVID-19) ..................................................... 30 
2.3.4 
Overall benefit: risk conclusion ...................................................................................................... 31 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 32 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 36 
4.2.1 
Participant input into design ........................................................................................................... 37 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 37 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 37 
5 
STUDY POPULATION .................................................................................................................. 38 


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5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 39 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 41 
5.4 
SCREEN FAILURES...................................................................................................................... 42 
6 
STUDY INTERVENTION ............................................................................................................... 43 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 43 
6.1.1 
Devices .......................................................................................................................................... 44 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 44 
6.2.1 
Storage and handling ..................................................................................................................... 44 
6.2.2 
Responsibilities .............................................................................................................................. 45 
6.3 
MEASURES TO MINIMIZE BIAS .................................................................................................. 45 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 46 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 46 
6.5.1 
Rescue medicine ............................................................................................................................ 47 
6.5.1.1 
Prohibited medications and procedures......................................................................................... 47 
6.5.1.2 
Permitted medications.................................................................................................................... 48 
6.6 
DOSE MODIFICATION .................................................................................................................. 48 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 48 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 49 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 49 
7.1.1 
Definitive discontinuation ............................................................................................................... 49 
7.1.2 
Temporary discontinuation ............................................................................................................. 49 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 49 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 50 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 52 
8.1 
PROCEDURES PERFORMED ONLY AT THE SCREENING/BASELINE VISIT.......................... 52 
8.2 
EFFICACY ASSESSMENTS ......................................................................................................... 53 
8.2.1 
Transepidermal water loss assessment and skin tape stripping ................................................... 53 
8.2.1.1 
Transepidermal water loss assessment......................................................................................... 53 
8.2.1.2 
Skin tape stripping and collection of skin tapes ............................................................................. 53 
8.2.2 
Standardized photographs ............................................................................................................. 55 


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8.2.3 
Questionnaires and patient reported outcome assessments (PROs) ........................................... 56 
8.2.4 
Investigator’s Global Assessment (IGA) ........................................................................................ 56 
8.2.5 
Individual Signs Score (ISS) .......................................................................................................... 56 
8.2.6 
Eczema Area and Severity Index (EASI) ....................................................................................... 57 
8.2.7 
Severity Scoring of Atopic Dermatitis (SCORAD) .......................................................................... 57 
8.2.8 
Patient Oriented Eczema Measure (POEM) .................................................................................. 57 
8.2.9 
Dermatology life quality index / Children's dermatology life quality index ..................................... 57 
8.2.10 
Peak Pruritus Numerical Rating Scale (Peak Pruritus NRS) ......................................................... 58 
8.2.11 
Quality of Sleep NRS ..................................................................................................................... 58 
8.3 
SAFETY ASSESSMENTS ............................................................................................................. 58 
8.3.1 
Physical examinations ................................................................................................................... 58 
8.3.2 
Vital signs ....................................................................................................................................... 59 
8.3.3 
Laboratory testing .......................................................................................................................... 59 
8.3.4 
Electrocardiograms ........................................................................................................................ 59 
8.3.5 
Clinical safety laboratory assessments .......................................................................................... 59 
8.3.6 
Suicidal ideation and behavior risk monitoring .............................................................................. 59 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 59 
8.4.1 
Time period and frequency for collecting Adverse Events (AE) and Serious Adverse Events 
(SAE) information ........................................................................................................................... 59 
8.4.2 
Method of detecting AEs and SAEs ............................................................................................... 60 
8.4.3 
Follow-up of AEs and SAEs ........................................................................................................... 60 
8.4.4 
Regulatory reporting requirements for SAEs ................................................................................. 60 
8.4.5 
Pregnancy ...................................................................................................................................... 61 
8.4.6 
Cardiovascular and death events .................................................................................................. 61 
8.4.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 61 
8.4.8 
Adverse event of special interest ................................................................................................... 61 
8.4.9 
Guidelines for reporting product complaints .................................................................................. 63 
8.5 
TREATMENT OF OVERDOSE ...................................................................................................... 63 
8.6 
PHARMACOKINETICS .................................................................................................................. 63 
8.7 
PHARMACODYNAMICS ............................................................................................................... 63 
8.8 
GENETICS ..................................................................................................................................... 63 
8.9 
BIOMARKERS ............................................................................................................................... 64 
8.9.1 
Lipidomics assessment .................................................................................................................. 64 
8.9.1.1 
Filaggrin breakdown products ........................................................................................................ 64 
8.9.1.2 
Analysis of stratum corneum lipids ................................................................................................ 65 


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8.9.1.3 
Quantification of protein bound ceramides .................................................................................... 65 
8.9.2 
Proteomics ..................................................................................................................................... 65 
8.9.3 
Transcriptomics .............................................................................................................................. 66 
8.9.4 
Optional samples for biomarker research ...................................................................................... 66 
8.10 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 67 
8.11 
HEALTH ECONOMICS .................................................................................................................. 67 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 68 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 68 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 68 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 69 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 69 
9.4.1 
Subject description ......................................................................................................................... 69 
9.4.1.1 
Disposition of subjects ................................................................................................................... 69 
9.4.2 
Protocol deviations ......................................................................................................................... 69 
9.4.3 
Analysis population ........................................................................................................................ 70 
9.4.4 
Demographic and baseline characteristics .................................................................................... 70 
9.4.4.1 
Subject demographic characteristics, medical history and diagnoses .......................................... 70 
9.4.4.2 
Baseline efficacy parameters ......................................................................................................... 70 
9.4.4.3 
Baseline safety parameters ........................................................................................................... 70 
9.4.5 
Extent of study treatment exposure and compliance ..................................................................... 71 
9.4.5.1 
Extent of investigational medicinal product exposure .................................................................... 71 
9.4.5.2 
Compliance .................................................................................................................................... 71 
9.4.6 
Prior/Concomitant medication/Therapy.......................................................................................... 71 
9.4.7 
Efficacy analyses ........................................................................................................................... 72 
9.4.7.1 
Description of efficacy variables .................................................................................................... 72 
9.4.8 
Safety analyses .............................................................................................................................. 76 
9.4.8.1 
Adverse events .............................................................................................................................. 76 
9.4.8.2 
Vital signs ....................................................................................................................................... 78 
9.5 
INTERIM ANALYSES .................................................................................................................... 78 
9.6 
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD ................................. 79 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 80 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ...... 80 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 80 
10.1.2 
Financial disclosure........................................................................................................................ 81 
10.1.3 
Informed consent process .............................................................................................................. 81 


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10.1.4 
Data protection ............................................................................................................................... 82 
10.1.5 
Dissemination of clinical study data ............................................................................................... 82 
10.1.6 
Data quality assurance .................................................................................................................. 83 
10.1.7 
Source documents ......................................................................................................................... 84 
10.1.8 
Study and site start and closure ..................................................................................................... 84 
10.1.9 
Publication policy ........................................................................................................................... 85 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 85 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 85 
10.3.1 
Definition of AE .............................................................................................................................. 85 
10.3.2 
Definition of SAE ............................................................................................................................ 87 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 88 
10.3.4 
Reporting of SAEs.......................................................................................................................... 89 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 90 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 92 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 93 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................... 93 
11 
REFERENCES ............................................................................................................................... 95 
 


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Page 7 
LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 32 
Table 2 - Overview of study interventions administered ............................................................................... 43 
Table 3 - Populations for analyses ................................................................................................................ 69 
Table 4 - Efficacy analyses ........................................................................................................................... 72 
Table 5 - Protocol-required laboratory assessments .................................................................................... 85 
Table 6 - Highly effective contraceptive methods ......................................................................................... 91 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
Figure 2 - Example of selection of skin spots within lesional and non-lesional skin ..................................... 54 
Figure 3 - TEWL assessment and STS in lesional and non-lesional skin of AD patients and in normal 
skin of HV ...................................................................................................................................................... 55 
 


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Page 8 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
Document 
Country/Countries 
impacted by 
amendement 
Date, version 
Amended Clinical Trial Protocol 01 
All 
28 July 2020, version 1 (electronic 1.0) 
Original Clinical Trial Protocol 
All 
17 March 2020, version 1 (electronic 4.0) 
AMENDED PROTOCOL 01 (28 July 2020)  
This amended protocol 01 is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
To further characterize the treatment effect of dupilumab in adolescent and adult patients with 
moderate to severe atopic dermatitis in reference to match healthy controls, proteomics 
assessment and transcriptomics assessment from skin tape strips has been added.  
These assessments will allow to better assess the mechanism of dupilumab in atopic dermatitis. 
To have comparable data in lesional skin (LS) and non-lesional skin (non-LS) of AD patients as 
well as in normal skin of healthy volunteers the number of skin tape strips collected has been set 
to 20 for each skin area.  
A statement concerning the risk-benefit assessment due to COVID-19 has been added. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Throughout the 
document 
Inconsistencies and clarification were added to 
increase clarity of the protocol 
Correct inconsistencies 
1.1 Synopsis, 
Secondary 
endpoints 
Additional secondary endpoints for TEWL 
assessment for lesional, non-lesional and normal 
skin added 
Number of STS assessments in lesional skin increased 
from 10 to 20, therefore more TEWL assessments are 
to be conducted. Endpoint assessment in lesional, non-
lesional and normal skin has been aligned. 
1.1 Synopsis, 
Tertiary 
objectives and 
endpoints  
“Proteomics in STS” added 
Proteomics will provide additional mechanistic insight in 
treatment-related effect 
1.1 Synopsis, 
Tertiary 
objectives and 
endpoints 
“Transcriptomics in STS” added 
Transcriptomics will provide additional mechanistic 
insight in treatment-related effect 


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Section # 
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities / AD 
patients 
Line added with proteomics assessment 
schedule 
Implementation of specimen sampling for proteomics 
1.3 Schedule of 
activities / AD 
patients 
Line added with transcriptomics assessment 
schedule 
Implementation of specimen sampling for 
transcriptomics 
1.3 Schedule of 
activities / AD 
patients 
Footnotes and annotations were added and 
modified 
Increase in clarity and precision 
1.4 Schedule of 
activities / 
Healthy 
volunteers 
Line added with proteomics assessment 
schedule 
Implementation of specimen sampling for proteomics 
1.4 Schedule of 
activities / 
Healthy 
volunteers 
Line added with transcriptomics assessment 
schedule 
Implementation of specimen sampling for proteomics 
1.4 Schedule of 
activities / 
Healthy 
volunteers 
Footnotes and annotations were added and 
modified 
Increase in clarity and precision 
Multiple 
locations in 
protocol 
Proteomics and transcriptomics were added, 
whenever applicable 
Adding proteomics and transcriptomics requires 
adaptation of multiple sections 
2.1 Study 
rationale 
Text added for rationale of the study 
Proteins and gene expression changes in AD patients 
as reason for amendment 
2.2 Background  Reference to methods for proteomics and 
transcriptomics methods 
Explanation of methods used 
2.3.2 
Benefit/risk 
related to 
COVID-19 
Benefit/risk assessment due to COVID-19 
pandemic 
Specific section concerning COVID-19 added 
3 Objectives 
and endpoints 
Adapted objectives and endpoints due to more 
STS and TEWL timepoints and due to 
transcriptomics/proteomics assessment 
Number of STS increased, proteomics and 
transcriptomics added  
5.1 Inclusion 
criteria 
For several inclusion criteria the specification has 
been added for which population this would be 
applicable. The criteria remain unchanged. 
Clarity and precision 
5.4 Screen 
failures 
Re-screening of participants is allowed once 
To reduce risk of not including participants with 
temporary reasons for ineligibility 
6.1 Study 
interventions 
administered 
A monitoring period of at least 30 minutes after 
study drug administration added. Self-injection 
training modified. 
Monitoring period for adverse symptoms specified. Self-
injection training modified for more flexibility at the study 
site. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
6.2.1 Storage 
and handling of 
IMP 
AD patients to inform study site in case of issues 
with storing IMP  
Tracking of adequate storage of IMP provided to 
patients for self-administration 
8 Study 
assessments 
and procedures 
Monitoring of COVID-19 situation and 
implementation of alternative methods for patient 
follow-up described 
COVID-19 specific text to describe mechanisms by 
which the sponsor will react to the pandemic or other 
public health emergencies 
8.2.2 
Standardized 
photographs 
Separate ICF for photographs mentioned 
Study participants will need to separately consent to 
publication of photos taken during the study 
8.2.3 
Questionnaires 
Sentence added that patients will bring diary to 
the site at each visit for review 
Clarity and precision 
8.9.2 
Proteomics 
Description of proteomics assessment 
Proteomics is an additional study objective 
8.9.3 
Transcriptomics 
Description of transcriptomics assessment 
Transcriptomics is an additional study objective 
8.9.4 Optional 
samples for 
biomarker 
research 
Section has been re-numbered 
Due to inclusion of new sections for proteomics and 
transcriptomics 
9.4.7.1 
Description of 
efficacy 
variables 
Biostatistical analysis of additional endpoints 
To address additional TEWL and STS endpoints. To 
address addition of proteomics and lipidomics analysis 
9.4.8.1.1 
Definitions 
Grading of adverse events by NCI CTCAE 
criteria had been deleted 
Grading of non-serious adverse events will be in three 
categories (mild, moderate, severe) and not in five 
(mild, moderate, severe, life-threatening, death). The 
latter two would be documented as serious adverse 
events 
10.1.3 Informed 
consent 
process 
Separate ICF for agreement to publication of 
photos taken during the study added 
Consistency and clarity to Section 8.2.2 
 
 
 


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Page 11 
1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Open label exploratory study to evaluate the effect of dupilumab on skin barrier 
function in patients with moderate to severe atopic dermatitis 
Short title: 
Dupilumab skin BArrier function and LIpidomics STudy in Atopic Dermatitis - 
BALISTAD 
Rationale: 
To assess the effect of dupilumab on skin barrier function measured as transepidermal water loss 
(TEWL) and on skin lipidomics in conjunction with skin tape stripping (STS) in atopic dermatitis 
(AD) patients. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Evaluate changes in skin barrier function with 
transepidermal water loss (TEWL) assessed after 
skin tape stripping (STS) in pre-defined lesional skin 
in patients with moderate to severe atopic dermatitis 
(AD) treated with dupilumab. 
• 
Percent change from baseline in TEWL after 5 STS 
assessed on lesional skin at Week16 in AD 
patients. 
Secondary 
• 
Evaluate changes in skin barrier function with TEWL 
assessed after STS in pre-defined lesional and non-
lesional skin in patients with moderate to severe AD 
treated with dupilumab in reference to normal skin 
of healthy volunteers. 
 
• 
Change (percent and absolute) from baseline in 
TEWL after 20 STS assessed on lesional skin at 
Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in 
TEWL after 20 STS assessed on non-lesional skin 
at Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in 
TEWL after 20 STS assessed on normal skin at 
Week16 in healthy volunteers.  
• 
Change (percent and absolute) from baseline in 
TEWL after 15 STS assessed on lesional skin at 
Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in 
TEWL after 15 STS assessed on non-lesional skin 
at Week16 in AD patients. 
• 
Change (percent and absolute) from baseline in 
TEWL after 15 STS assessed on normal skin at 
Week16 in healthy volunteers. 
• 
Change (percent and absolute) from baseline in 
TEWL after 10 STS assessed on lesional skin at 
Week16 in AD patients.  


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Objectives 
Endpoints 
• 
Change (percent and absolute) from baseline in 
TEWL after 10 STS assessed on non-lesional skin 
at Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in 
TEWL after 10 STS assessed on normal skin at 
Week16 in healthy volunteers.  
• 
Absolute change from baseline in TEWL after 
5 STS assessed on lesional skin at Week16 in AD 
patients. 
• 
Change (percent and absolute) from baseline in 
TEWL after 5 STS assessed on non-lesional skin at 
Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in 
TEWL after 5 STS assessed on normal skin at 
Week16 in healthy volunteers. 
• 
Evaluate time course of skin barrier function with 
TEWL assessed before and after STS in  
pre-defined lesional and non-lesional skin in 
patients with moderate to severe AD treated with 
dupilumab in reference to normal skin of healthy 
volunteers. 
• 
Change (percent and absolute) from baseline in 
TEWL before STS on lesional skin in AD patients 
over time.  
• 
Change (percent and absolute) from baseline in 
TEWL before STS on non-lesional skin in AD 
patients over time. 
• 
Change (percent and absolute) from baseline in 
TEWL before STS on normal skin in healthy 
volunteers over time. 
• 
Change (percent and absolute) in TEWL area under 
the curve (TEWL AUC: a composite measure 
before and after 5, 10,15 and 20 STS) for skin 
barrier function in lesional skin in AD patients over 
time. 
• 
Change (percent and absolute) in TEWL AUC (a 
composite measure before and after 5, 10, 15, and 
20 STS) for skin barrier function in non-lesional skin 
in AD patients over time. 
• 
Change (percent and absolute) in TEWL AUC (a 
composite measure before and after 5, 10, 15, and 
20 STS) for skin barrier function in normal skin in 
healthy volunteers over time. 
• 
Change (percent and absolute) from baseline in 
TEWL after STS assessed on lesional skin in AD 
patients over time. 
• 
Change (percent and absolute) from baseline in 
TEWL after STS assessed on non-lesional skin in 
AD patients over time. 
• 
Change (percent and absolute) from baseline in 
TEWL after STS assessed on normal skin in 
healthy volunteers over time. 


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Objectives 
Endpoints 
Tertiary/exploratory 
• 
Evaluate dupilumab treatment effect on skin 
lipidomics using STS samples in both pre-defined 
lesional and non-lesional skin in patients with 
moderate to severe AD in reference to normal skin 
of healthy volunteers.  
• 
Changes (percent and absolute) in lipidomics 
parameters in lesional and non-lesional skin 
including the ratio of highly hydrophobic ω-esterified 
fatty acid sphingosine ceramides (EOS CER) and 
non-hydroxy fatty acid sphingosine ceramides (NS 
CER), and filaggrin (FLG) breakdown products of 
urocanic acid (UCA) and pyroglutamic acid (PCA) 
concentrations at Week 8 and Week 16, 
respectively.  
• 
Global characterization of protein-bound ceramides 
over time. 
• 
Evaluate dupilumab treatment effect on skin 
proteomics using STS samples in both predefined 
lesional and non-lesional skin in patients with 
moderate-to-severe AD in reference to normal skin 
of healthy volunteers. 
• 
Changes (percent and absolute) in the expression 
of proteins associated with skin barrier function 
including keratin intermediate filaments, proteins 
associated with inflammatory response, and 
glycolysis and oxidative stress response proteins in 
STS protein extracts over time. 
• 
Evaluate dupilumab treatment effect on skin 
transcriptome using STS samples in both 
predefined lesional and non-lesional skin in patients 
with moderate-to-severe AD in reference to normal 
skin of healthy volunteers. 
• 
Changes in expression of genes associated with 
epidermal differentiation, barrier and lipid 
metabolism, and Type 2 inflammation over time. 
• 
Explore the association of skin barrier function 
measured by TEWL with disease severity assessed 
by standard AD severity assessments (Eczema 
Area and Severity Index (EASI), SCORing Atopic 
Dermatitis (SCORAD), local lesion severity on target 
lesion), patient reported outcomes (PRO) (Patient 
Oriented Eczema Measure (POEM), Dermatology 
Life Quality Index (DLQI) / Children Dermatology 
Life Questionnaire Index (CDLQI), peak pruritus 
Numerical Rating Scale (NRS), and quality of sleep 
NRS), standardized photos, and the biomarker 
profiles of lipidomics, proteomics, and 
transcriptomics assessed in the STS sample. 
• 
Change (percent and absolute) from baseline in 
EASI over time. 
• 
Change (percent and absolute) from baseline in 
SCORAD over time. 
• 
Change (percent and absolute) from baseline in 
Individual Signs Score (ISS) for target lesion over 
time. 
• 
Change (percent and absolute) from baseline in 
PRO (POEM) over time. 
• 
Change (percent and absolute) from baseline in 
PRO of DLQI in patients 18 years of age and older / 
CDLQI in patients ≥12 and <18 years of age over 
time. 
• 
Change (percent and absolute) from baseline in 
PRO of peak pruritus NRS over time. 
• 
Change (percent and absolute) from baseline in 
PRO of quality of sleep NRS over time. 
• 
Change (percent and absolute) from baseline in 
photograph outputs (eg, severity score) obtained 
from skin imaging over time. 
• 
Correlation between baseline values of TEWL 
before STS and TEWL AUC in lesional and non-
lesional skin of AD patients with the following 
baseline measures: 
- 
Local target lesion erythema and 
edema/papulation; ISS 
- 
EASI, SCORAD 


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Objectives 
Endpoints 
- 
PRO measures (POEM, DLQI, CDLQI, peak 
pruritus NRS, and quality of sleep NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS 
CER) 
- 
Filaggrin breakdown products of UCA and 
PCA concentrations in STS 
- 
Key components of skin proteomics in STS 
(expression of proteins associated with skin 
barrier function) 
- 
Key components of gene expression from 
transcriptomics 
- 
Image-derived severity score in targeted 
lesional skin 
• 
Correlation between percent change from baseline 
in TEWL before STS and TEWL AUC in lesional 
and non-lesional skin of AD patients at Week 8 and 
Week 16 with corresponding change from baseline 
in the following measures: 
- 
Local target lesion erythema and 
edema/papulation; ISS 
- 
EASI, SCORAD 
- 
PRO measures (POEM, DLQI, CDLQI, peak 
pruritus NRS, and quality of sleep NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS 
CER) 
- 
Filaggrin breakdown products of UCA and 
PCA concentrations in STS 
- 
Key components of skin proteomics in STS 
(expression of proteins associated with skin 
barrier function) 
- 
Key components of gene expression from 
transcriptomics 
- 
Image-derived severity score in targeted 
lesional skin 
Overall design: 
• Phase IV. 
• Two study sites (Dr Leung, Denver, USA; Dr Bissonnette, Innovaderm, Montreal, 
Canada). 
• Open-label, exploratory study. 
• Approximately 24 patients with moderate to severe AD will be enrolled to achieve 
20 evaluable patients. 
• Approximately 24 evaluable healthy volunteers matched for age, gender, location of skin 
area, and study site will serve as a reference comparator for skin barrier function. 


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This is a 16-week, open label, exploratory study designed to investigate dupilumab’s effect on 
skin barrier function as measured by TEWL before and after skin tape stripping in approximately 
10 adolescent and approximately 10 adult patients with moderate to severe AD (not more than  
12 of either group). During the first 2 treatment weeks, patients will have 2 on-site visits/week, 
followed by one on-site visit/week up to Week 4, one on-site visit every two weeks from Week 4 
to Week 8, and one on-site visit every 4 weeks up to Week 16 End of Treatment phase visit (EoT) 
thereafter.  
A follow-up visit by phone 4 weeks after the last study assessment at Week 16 will end the study 
for each participant (End of Study: EoS). The maximum duration of the study per participant will 
be 24 weeks. 
Lesional and non-lesional skin areas for TEWL assessment and STS will be identified on the 
upper limbs or lower limbs at baseline ("predefined skin area"). TEWL and STS-assessment at 
pre-defined non-lesional (normal looking) skin area in AD patients should be made about 4 cm 
from the edge of the lesional area. 
Within the predefined lesional skin (LS) and non-lesional skin (non-LS) areas three closely 
adjacent spots will be identified for subsequent skin barrier function assessment (3 spots on 
lesional skin, 3 spots on non-lesional skin). These spots must not overlap with each other once 
skin tapes are applied. 
The skin barrier function without and before STS will be assessed using TEWL measurement on 
each of the three spots within these pre-defined skin areas at each visit.  
Repeated TEWL assessment in pre-defined lesional and non-lesional skin areas of AD patients 
after STS for lipidomics, proteomics and transcriptomics analysis in STS samples will be 
conducted at baseline (Week 0, Day 1), Week 2 (Day 15), Week 4 (Day 29), Week 8 (Day 57), 
Week, 12 (Day 85), and at EoT at Week 16 (Day 113). 
In order to allow the skin to recover from the STS, the skin barrier function assessment with STS 
will be performed as follows: STS assessment on baseline (Week 0), Week 8 and Week 16 will be 
conducted on the first spot within the predefined lesional and non-lesional skin area. STS 
assessment on Week 2 will be conducted on the second spot. STS assessment on Week 4 and 
Week 12 will be conducted on the third spot.  
TEWL will be measured before and after 5, 10, 15, and 20 STS (5 TEWL assessments per visit) 
on targeted, predefined lesional, non-lesional skin in AD patients at baseline, Week 2, Week 4, 
Week 8, Week 12, and Week 16 on the predefined first, second or third spot, respectively.  
Skin barrier function in approximately twenty healthy volunteers matched for age, gender, 
location of targeted lesion area, and study site to the AD cases will be assessed in a similar 
manner at baseline, twice a week during the first two weeks, once a week during Week 3 to  
Week 4, every two weeks from Week 4 to Week 8, and every four weeks up to Week 16 
thereafter, serving as a reference comparator for skin barrier function. 


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Within the targeted skin area of healthy volunteers -the predefined skin location for TEWL and 
STS must be identical to the lesional area of the patient to which a healthy volunteer is matched- 
three closely adjacent spots without an overlap for the skin tapes will be identified for subsequent 
skin barrier function assessment.  
The skin barrier function without and before STS will be assessed using TEWL measurement on 
each of the three spots at each visit.  
On normal skin in healthy volunteers at each visit at baseline, Week 2, Week 4, Week 8, Week 12, 
and Week 16, TEWL will be measured before and after 5, 10, 15, and 20 STS on the predefined 
first, second or third spot respectively for skin barrier function assessment (5 TEWL assessments 
per visit in normal skin) at the same location as for the lesional skin in the matching AD patient 
and as described above.  
In particular, STS assessment on baseline (Week 0, Day 1), Week 8 (Day 57) and Week 16 
(Day 113) will be conducted on the first spot within the location-matched, normal skin. STS 
assessment on Week 2 (Day 15) will be conducted on the second spot. STS assessment on Week 4 
(Day 29) and Week 12 (Day 85) will be conducted on the third spot. 
Study drug will be administered on-site by study site staff at baseline, Week 2, 4, 6, 8 and 
Week 12, after the TEWL assessment has been completed. Study drug will be self-administered at 
home by AD patients at Week 10 and 14. 
Intervention groups and duration: 
This is a 16-week, open-label study of dupilumab in moderate to severe AD patients. Age-, 
gender-, targeted lesion area- and study-site-matched healthy volunteers will be included for a 
non-treatment, 16-week evaluation period. Total study duration including screening and follow-up 
phone call will be 24 weeks.  
Study intervention(s) 
Investigational medicinal product(s) 
Dupilumab 200 mg 
• Formulation: a 175 mg/mL dupilumab solution in a pre-filled syringe to deliver 200 mg in 
a 1.14 mL subcutaneous injection. 
• Route(s) of administration: subcutaneous injection (SC).  
Dupilumab 300 mg 
• Formulation: a 150 mg/mL dupilumab solution in a pre-filled syringe to deliver 300 mg in 
a 2 mL subcutaneous injection. 
• Route(s) of administration: subcutaneous injection (SC). 
• Dose regimen  


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- 
For AD patients aged ≥12 to <18 years the dose regimen will be based on body weight 
on Day 1. No change in dosing will be made if body weight increases or decreases 
during the study. Dose allocation will be according to the following table: 
 
Body Weight  
Loading Dose on Day 1  
Subsequent Doses (Q2W) a 
less than 60 kg  
400 mg (two 200 mg injections)  
200 mg  
60 kg or more  
600 mg (two 300 mg injections)  
300 mg  
a Every second week (Q2W) 
- 
AD patients age 18 years and older will receive a SC loading dose of 600 mg on 
Day 1, followed by 300 mg Q2W SC through Week 14. Drug will be administered by 
study site staff at baseline, Week, 2, 4, 6, 8 and 12. Drug will be self-administered by 
AD patients at home at Week 10 and 14. 
Post-trial access to study medication 
• After the study is completed, patients will not be provided with any further study 
medication as part of this protocol. 
Duration of study period (per participant)  
Study participation for each patient and healthy volunteer will be a total of approximately 
24 weeks including: 
• Screening period: Up to 4 weeks from signed informed consent. 
• Open label dupilumab treatment (AD patients) and observation period (healthy 
volunteers): 16 weeks from baseline on Day 1. 
• Follow-up period: 4 weeks after the EOT visit at Week 16. 
Statistical considerations: Analyses will be descriptive and explorative. 
After all patients and healthy volunteers have completed the Week 16 assessments, the data up to 
this time will be cleaned, and locked; all endpoints relating to Week 16 will be analyzed and 
reported at this time. 
• Sample size calculations 
- 
Sample size for this exploratory study was based on medical/clinical judgement and is 
consistent with the sample size from similar studies in the literature (1). No formal 
sample size calculation was performed. TEWL data collected in similar settings as 
planned for this study were not available: ie, TEWL values after 5 STS, and pre- and 
post-dupilumab treatment are unknown. 
• Analysis of primary, secondary and exploratory endpoints: 
- 
This is an exploratory study. No formal statistical testing will be conducted.  
- 
Descriptive statistics will be generated by group, time point and type of skin area 
(lesional or non-lesional, if applicable) for selected parameters of interest. Raw data 


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and changes from baseline: ie, absolute and percent changes, for selected parameters 
will be summarized in descriptive statistics and summary plots. 
- 
Evolution over time of TEWL before STS and TEWL AUC by type of skin area will 
be analyzed. Matched healthy subjects will provide normal reference values. 
• Safety/other analysis: 
- 
The safety evaluation will be conducted on all AD patients who receive at least one 
dose of dupilumab or had at least one TEWL/STS assessment performed, and on all 
healthy volunteers, who had at least one TEWL/STS assessment. The analysis will be 
based on descriptive statistics providing summary statistics for vital signs parameters 
(including summary of Potentially Clinically Significant Abnormalities (PCSAs)) and 
reported adverse event.  
Data Monitoring Committee: None 


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Page 19 
1.2 
SCHEMA  
Figure 1 - Graphical study design  
 


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Page 20 
1.3 
SCHEDULE OF ACTIVITIES (SOA) / AD PATIENTS  
Phase  
Screening Baseline 
Treatment Phase 
EoT 
EoSa 
Un-
scheduled 
Visit 
Premat
ure 
EoT 
Day 
D-28 to 
D-1 
D 1 
D4 
±2 
days 
D8 
±2 
days 
D11 
±2 
days 
D15 
±2 
days 
D22 
±2 
days 
D29 
±2 
days 
D43 
±2 
days 
D57 
±3 
days 
D85 
±3 
days 
D113 
±3 
days 
D141 
±3 days 
UNSCH 
 
Week 
 
W0 
W1 
W2 
W3 
W4 
W6 
W8 
W12 
W16 
W20 
 
 
Visits 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
V12 
V13 
 
 
Informed consent / 
assent form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history / 
IGA / Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications / procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm emollient and 
washing compliancej 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SC administration of 
dupilumabb 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
(X) 
 
Study drug self-
administration training by 
site staffo 
 
 
 
 
 
 
 
 
 
X 
 
 
 
(X) 
 
Study drug will be 
handed out at V10 
(Week 8) for self-
administration at Week 
10 and at V11 (Week 12) 
for self-administration at 
Week 14 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
(X) 
 
Compliance check of 
self-administrated study 
drug at Week 10 and 
Week 14 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
(X) 
X 


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Page 21 
Phase  
Screening Baseline 
Treatment Phase 
EoT 
EoSa 
Un-
scheduled 
Visit 
Premat
ure 
EoT 
Day 
D-28 to 
D-1 
D 1 
D4 
±2 
days 
D8 
±2 
days 
D11 
±2 
days 
D15 
±2 
days 
D22 
±2 
days 
D29 
±2 
days 
D43 
±2 
days 
D57 
±3 
days 
D85 
±3 
days 
D113 
±3 
days 
D141 
±3 days 
UNSCH 
 
Week 
 
W0 
W1 
W2 
W3 
W4 
W6 
W8 
W12 
W16 
W20 
 
 
Visits 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
V12 
V13 
 
 
Skin barrier function 
test in lesional and 
non-lesional skinc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TEWL at baseline/ 
before STSl,m 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
TEWL after STS 
assessmenth 
 
Xi 
 
 
 
Xi 
 
Xi 
 
Xi 
Xi 
Xi 
 
(X)n 
Xn 
Lipidomics, filaggrin 
(FLG) breakdown 
products, proteomics, 
and transcriptomics 
assessment from skin 
tape stripi 
 
Xi 
 
 
 
Xi 
 
Xi 
 
Xi 
Xi 
Xi 
 
(X)n 
Xn 
Standardized 
photographs of lesional 
and non-lesional skin 
areas used for TEWLl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
Standardized full body 
photographs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
EASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
ISS on lesion erythema 
and edema/papulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
SCORAD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
Patient reported 
outcomes (PRO)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
POEM 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
DLQI/CDLQIf 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
Peak pruritus NRSg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 


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28-Jul-2020 
SAR231893/REGN668-LPS15991 - dupilumab 
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Page 22 
Phase  
Screening Baseline 
Treatment Phase 
EoT 
EoSa 
Un-
scheduled 
Visit 
Premat
ure 
EoT 
Day 
D-28 to 
D-1 
D 1 
D4 
±2 
days 
D8 
±2 
days 
D11 
±2 
days 
D15 
±2 
days 
D22 
±2 
days 
D29 
±2 
days 
D43 
±2 
days 
D57 
±3 
days 
D85 
±3 
days 
D113 
±3 
days 
D141 
±3 days 
UNSCH 
 
Week 
 
W0 
W1 
W2 
W3 
W4 
W6 
W8 
W12 
W16 
W20 
 
 
Visits 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
V12 
V13 
 
 
Quality of sleep NRSg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Vital signsd 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
(X) 
X 
Physical examination 
X 
Xk 
 
 
 
 
 
 
 
 
 
Xk 
 
 
Xk 
Pregnancy test (urine), 
WOCBP onlye 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
DNA sampling for 
filaggrin gene 
sequencing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA sampling for future 
research 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker research 
samples (serum and 
plasma) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
a EoS safety follow-up by phone. 
b Loading dose dupilumab arm 600 mg (300 mg x 2 ie, two 300 mg syringes) for all adult patients and for those adolescents weighing 60 kg and above, and 400 mg (200 mg x 2 ie. two 200 mg syringes) for 
adolescent patients below 60 kg, followed by bi-weekly SC dosing of 300 mg dupilumab to adults and adolescents weighing 60 kg and above and bi-weekly SC dosing of 200 mg to adolescents weighing below  
60 kg. Dupilumap administration on following days: D1 (V02,W0) baseline,  D15±2days (V06, W2), D29±2days (V08, W4), D43±2days (V09, W6), D57±3days (V10, W8), D71±3days (W10; self-administration of 
dupilumab at home), D85±3days V11, W12), D99±3days (W14; self-administration of dupilumab at home). 
c Assessments on treatment days are to be conducted before administration of dupilumab. 
d Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured at Screening, Baseline at Week 0, Week 8, and 
Week 16 (EoT). Height (cm) will be measured at Baseline only. Body weight (kg) will be measured at Baseline, and Week 16 (EoT). 
e Only for women of childbearing potential. Pregnancy will lead to definitive treatment discontinuation in all cases. 
f 
DLQI will be used for adults; CDLQI will be used for adolescents. 


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Page 23 
g Peak puritus NRS and quality of sleep NRS will be assessed daily from Day-7 to Day -1; daily from Day 1 to Day 29 and then for the 7 days prior to Week 6, Week 8, to Week 12 and to Week 16 by e-diary. 
Patients will bring the eDiary to the site at each visit. eDiary will be reviewed for any questionnaires omission and dispensed back to patients at each visit. 
h TEWL to be conducted before STS and then after 5, 10, 15, and 20 STS in pre-defined lesional and non-lesional skin. All skin tape strips will be collected and stored. 
i 
At Week 0, 8 and 16 STS will be conducted on the first spot within the predefined skin area. At Week 2 STS will be conducted on the second spot within the predefined skin area. At Week 4 and 12 STS will be 
conducted on the third spot within the predefined skin area. TEWL will be assessed in lesional and non-lesional skin before STS and after 5, 10, 15, and 20 STS. All skin tape strips will be collected and stored for 
lipidomics, proteomics, and transcriptomics analyses. 
j 
Emollients should NOT be applied from Day -7 to the EoT (Week 16, Day 113) to the targeted, pre-defined skin areas that will be used for TEWL assessment. Participants should not take showers or soaking in a 
bathtub within 6 hours before TEWL assessment. Compliance must be documented in participant’s source data. Emollients for use during the study will be provided by the study site to study participants. Use of 
emollients should be documented in a diary. 
k Limited to skin-related physical examination at baseline and EoT visit. 
l 
Pre-defined lesional (3 spots) and non-lesional skin areas (3 spots), whereby the assessment spots on non-lesional skin are located about 4 cm apart from the edge of the AD lesion. 
m TEWL will be measured at each of the three closely adjacent spots within the predefined skin areas at all visits as baseline assessment; if there is STS, subsequent TEWL assessment will only be done at the 
lesional and no-lesional spot, at which STS is performed.  
n In case STS assessment is to be conducted at an unscheduled visit or at a premature end of treatment visit the assessment should be conducted at that spot of the skin area, for which the period passed since the 
last STS assessment is the longest. 
o Study participants may by trained for study drug self-administration starting from D1 (Visit 2). Training should be completed and documented at Week 8 (Visit 10). Site staff has to verify patients’ injection technique 
before they are allowed to self-inject at home. On-site injections may be performed by either site staff or AD patient or caregiver/parent/legal representative if previously trained on self-injection technique 
EASI = Eczema Area and Severity Index; EoT = End of Treatment Phase; EoS = End of Study; IGA = Investigator Global Assessment; SCORAD = SCORing Atopic Dermatitis; STS = Skin Tape Stripping; 
TEWL = Transepidermal Water Loss; V = Visit; W = Week; WOCBP = Women of Childbearing Potential 
 


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Page 24 
1.4 
SCHEDULE OF ACTIVITIES (SOA) / HEALTHY VOLUNTEERS  
Phase  
Screening 
Baseline 
Observation Period 
EoT 
EoSa 
Un-
scheduled 
Visit 
Premat
ure 
EoT 
Day 
D-28 to 
D-1 
D 1 
D4 
±2 
days 
D8 
±2 
days 
D11 
±2 
days 
D15 
±2 
days 
D22 
±2 
days 
D29 
±2 
days 
D43 
±2 
days 
D57 
±3 
days 
D85 
±3 
days 
D113 
±3 
days 
D141 
±3 
days 
 
 
Week 
 
W0 
W1 
W2 
W3 
W4 
W6 
W8 
W12 
W16 
W20 
 
 
Visits 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
V12 
V13 
 
 
Informed consent/ assent 
form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Matching by age and genderi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history / 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications / procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm emollient and 
washing compliancef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Skin barrier function test 
in pre-defined normal skin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TEWL at baseline/ before 
STSh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
TEWL after STS 
assessmentd 
 
Xe 
 
 
 
Xe 
 
Xe 
 
Xe 
Xe 
Xe 
 
(X)j 
Xj 
Lipidomics, FLG breakdown 
products, proteomics, and 
transcriptomics assessment 
from skin tape stripk 
 
Xe 
 
 
 
Xe 
 
Xe 
 
Xe 
Xe 
Xe 
 
(X)j 
Xj 
Standardized photographs of 
healthy skin area used for 
TEWL 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 
Standardized full body 
photographs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
X 


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Phase  
Screening 
Baseline 
Observation Period 
EoT 
EoSa 
Un-
scheduled 
Visit 
Premat
ure 
EoT 
Day 
D-28 to 
D-1 
D 1 
D4 
±2 
days 
D8 
±2 
days 
D11 
±2 
days 
D15 
±2 
days 
D22 
±2 
days 
D29 
±2 
days 
D43 
±2 
days 
D57 
±3 
days 
D85 
±3 
days 
D113 
±3 
days 
D141 
±3 
days 
 
 
Week 
 
W0 
W1 
W2 
W3 
W4 
W6 
W8 
W12 
W16 
W20 
 
 
Visits 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
V12 
V13 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Vital signsb 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
 
(X) 
X 
Physical examination 
X 
Xg 
 
 
 
 
 
 
 
 
 
Xg 
 
 
Xg 
Pregnancy test (urine), 
WOCBP onlyc 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
DNA sampling for filaggrin 
gene sequencing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA sampling for future 
research 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker research samples 
(serum and plasma) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
a EoS safety follow-up by phone. 
b Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured at Screening, Baseline at Week 0, Week 8, and 
Week 16 (“EoT”). Height (cm) will be measured at Baseline only. Body weight (kg) will be measured at Baseline and at Week 16 (“EoT”).  
c Only for women of childbearing potential. Pregnancy in a healthy volunteer will lead to definitive discontinuation of the study in all cases. 
d TEWL to be conducted before STS and then after 5, 10, 15, and 20 STS for skin barrier function assessment in normal skin and at the same location as for the lesional skin in the matching AD patient. All skin tape 
strips will be collected and stored. 
e At Week 0, 8 and 16 STS will be conducted on the first spot within the predefined skin area. At Week 2 STS will be conducted on the second spot within the predefined skin area. At Week 4 and 12 STS will be 
conducted on the third spot within the predefined skin area. TEWL will be assessed in normal skin before STS and 5, 10, 15, and 20 STS. All skin tape strips will be collected and stored for lipidomics, proteomics, 
and transcriptomics analyses. 
f 
Emollients should NOT be applied from Day -7 to EoT (Week 16, Day 113) to the targeted, pre-defined skin areas that will be used for TEWL assessment. Participants should not take showers or soaking in a 
bathtub within 6 hours before TEWL assessment. Compliance must be documented in participant’s source data. Emollients for use during the study will be provided by the study site to study participants. Use of 
emollients should be documented in a diary. 
g Limited to skin-related physical examination at baseline and end-of-study visit. 
h TEWL will be measured at each of the three closely adjacent spots within the predefined skin areas at all visits as baseline assessment; if there is STS, subsequent TEWL assessment will only be done at the spot, 
at which STS is performed. 


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i 
Age- and gender-matched to a selected AD patient by study site. Adolescents aged 12 to 17 years will be matched by puberty status. Adults will be matched by age as close as possible within a range of 10 years 
above or below the age of the matched AD patient.  
j 
In case STS assessment is to be conducted at an unscheduled visit or at a premature end of treatment visit the assessment should be conducted at that spot of the skin area, for which the period passed since the 
last STS assessment is the longest. 
k First spot to be assessed by STS at Baseline, Week 8 and Week 16, second spot to be assessed by STS at Week 2, third spot to be assessed by STS at Week 4 and Week 12 
EoT = End of Treatment Phase; for healthy volunteers this is the end of the “Observation Period”; EoS = End of Study; STS = Skin Tape Stripping; TEWL = Transepidermal Water Loss; V = Visit; W = Week; WOCBP 
= Women of Childbearing Potential  


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2 
INTRODUCTION  
Dupilumab is a human monoclonal antibody (2, 3) that blocks the shared receptor subunit for 
interleukin (IL)-4 and IL-13, thus inhibiting signaling of both IL-4 and IL-13, cytokines that are 
key drivers of type 2 inflammatory diseases (4). 
Dupilumab is the first targeted biologic agent approved in the United States of America for 
subcutaneous administration every 2 weeks (Q2W) for the treatment of patients aged ≥12 years 
with moderate-to-severe atopic dermatitis (AD) inadequately controlled with topical prescription 
therapies or when those therapies are not advisable, for the treatment of adult AD patients not 
adequately controlled with existing therapies in Japan, and for use in adults and adolescents with 
moderate-to-severe AD who are candidates for systemic therapy in the European Union.  
Recently Guttman et al (5) demonstrated that dupilumab-mediated inhibition of interleukin-(IL)-4 
and IL-13 signaling through IL-4 receptor α blockade significantly  suppressed cellular and 
molecular cutaneous markers of type 2 inflammation and systemic type 2 inflammation mediators 
like thymus and activation-regulated chemokine (TARC) and IgE, and reversed AD-associated 
epidermal phenotype abnormalities; namely significantly reduced epidermal hyperplasia 
proliferation measured by Keratin-16 and Ki-67, significantly increased the expression of 
epidermal differentiation, lipid metabolism and barrier junction genes measured by filaggrin 
(FLG) , loricrin, claudins, and elongation of very long chain fatty acids protein (ELOVL3), and 
significantly reduced lesional epidermal thickness (5, 6). This evidence supports the hypothesis 
that blockade of type 2 inflammation, achieved with dupilumab treatment, can repair skin barrier 
function. It is well known that an intact skin barrier is critical and its impairment leads to 
downstream signals that aim to restore barrier homeostasis (7). 
2.1 
STUDY RATIONALE  
The objective of this study is to assess dupilumab treatment effect on skin barrier function 
measured by TEWL and measurement of lipids, proteins and gene expression associated with skin 
barrier function from skin tape stripping in patients with moderate to severe atopic dermatitis, and 
to evaluate the relationship between skin barrier function and disease activity measured by clinical 
assessments and patient reported outcomes, as well as high definition standard photography. 
TEWL is one of the most broadly used, non-invasive methods for measuring the function of the 
skin barrier. The first measurement approaches were described in 1911, and today this parameter 
is regarded as the standard in a variety of dermatological and skin research contexts. TEWL is 
influenced by many environmental and individual factors, including age, sex, race, anatomical 
region, skin temperature, environmental conditions, season, smoking status, measurement 
technique and many others (8). Therefore, including a ‘normal’ TEWL from an age-, gender-, 
targeted lesion area- and study site-matched healthy volunteers cohort assessed at the same time in 
the same measurement conditions on the same anatomical region with reference thresholds of skin 
barrier function evaluation indicating pathological relevance is important (8, 9). For this reason, 
an age-, gender-, targeted lesion area- and study-site-matched healthy volunteer cohort is included 
as a reference that could help with interpreting study results. 


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2.2 
BACKGROUND  
Atopic dermatitis (AD) is a chronic systemic inflammatory skin disease with a prevalence of up to 
25% in children and up to 7% in adults. A large proportion of patients experience sleep 
disturbance and impaired quality of life (10). AD is caused by the complex interplay between 
epithelial dysfunction and dysregulated/over-activated type 2 immune response in the skin, with a 
special role for IL-4/IL-13–driven signaling in AD pathogenesis (11). This type 2 hyperactivation 
blocks terminal differentiation of skin keratinocytes and formation of a mature stratum corneum 
that is mainly responsible for the skin barrier function (12). 
Clinical manifestations and skin pathology in AD are driven by impaired skin barrier and Type 2–
skewed immune responses. Impaired skin barrier function is caused by changes in the expression 
of key structural cornified barrier proteins and skin barrier lipids. Filaggrin mutations are the most 
profound single-gene defects involved in AD (13). FLG deficiency promotes inflammation and 
inflammatory cell infiltration in the skin. Changes in FLG expression alter skin acidification, 
which, in turn, supports activation of skin proteases that alter skin barrier homeostasis by 
interfering with lipid lamellae assembly and support the onset of type 2 inflammatory responses. 
Type 2–skewed immune responses in AD favor epidermal barrier disruption by inhibiting the 
expression of FLG and other structural proteins in skin. Type 2 cytokines also inhibit production 
of skin barrier lipids in the skin. These changes are already present in non-lesional, normal-
appearing AD skin, and are further aggravated in AD lesional skin (14). 
Healthy epidermis has lipids that are mostly composed of ceramides (CER), free fatty acids, and 
cholesterol (15, 16), with very little presence of other lipids. A very specific, highly hydrophobic 
group of CER, called esterified omega-hydroxy sphingosine (EOS) ceramides, is present only in 
the skin. Fatty acids are also unique in skin ceramides, as they are unusually very long (up to C38) 
and hydrophobic; this also contributes to the overall requirement for a highly rigid and 
hydrophobic structure to provide an efficient barrier. Several groups of investigators have already 
reported that lesional and non-lesional skin of AD patients has decreased proportion of EOS 
ceramides and other ceramides with very long–chain fatty acids (C22–C30), and short-chain  
non-hydroxy fatty acids sphingosine ceramides (C16–C20). Ultralong-chain lipids, such as EOS 
CER, control water retention in the skin and prevent allergen penetration. Such changes in skin 
lipid composition result in aberrant lipid organization in the lipid layers and positively correlate 
with the degree of transepidermal water loss in AD skin (12). The greatest decrease in the ratio 
between EOS CER and non-hydroxy fatty acid sphingosine (NS) CER indicates the maximum 
loss of skin hydrophobicity due to a decline of highly hydrophobic EOS CER and the increase in 
short-chain NS CER. This suggests the entire skin surface of AD is at risk for allergen penetration 
(17). 
Leung et al have pioneered novel methods to profile skin through STS analysis combined with 
lipidomics, proteomics and transcriptomics (17). Using an STS protein mass spectrometry 
analysis, AD skin exhibits significantly lower expression of skin barrier proteins (FLG2, 
corneodesmosin, DSG1, DSC1, and TGM3) and enzymes (arginase-1, caspase-14, and γ-glutamyl 
cyclotransferase) involved in generating NMF. The transcriptome sequencing together with 
lipidomics and proteomics has proven a powerful technique for diagnostic examination of 
genomic, lipidomic, and proteomic expression profiles in non-lesional and lesional AD skin (10). 


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2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has demonstrated a positive benefit-risk profile and is approved for treatment in 
patients with moderate to severe AD aged 12 years and above in the United States, Canada and 
the European Union. Dupilumab dose in this study is consistent with the approved label. The 
safety data observed so far in completed and currently ongoing studies in atopic dermatitis has 
demonstrated a satisfactory safety profile.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of dupilumab may be found in the Investigator’s Brochure. 
2.3.1 Risk assessment  
Risks Associated with Skin Barrier TEWL Measurement  
There are no known risks associated with this non-invasive skin measurement.  
Risks Associated with Skin Tape Strip Collection  
Risks associated with STS, theoretically, include the rare possibility of an allergic reaction to the 
tape or a skin infection. Since the tape is removed immediately after application, the risk of an 
allergic reaction is low.  
In previous and ongoing studies involving tape stripping, it has been noted that a mild erythema 
may develop immediately after a series of tape strips on one localized area of skin, presumably 
due to the mild mechanical disturbance. The erythema is expected to resolve within 12 hours 
without sequelae.  
The risk of skin infection is very low since only superficial skin layers are removed. A bandage 
will be applied to the area of tape stripping to reduce the small likelihood of an infection.  
Possible bleeding and/or bruising may also occur at the area. Participants with a history of 
moderate to severe and serious life-threatening reaction to tape or adhesives known to be used 
will be excluded from participating, per study exclusion criteria. 
Risks Associated with Health Questionnaires 
There is a possibility that participants may find questions too personal. Participants may refuse to 
answer any questions that make them feel uncomfortable. 
Risks Associated with Stopping the Use of Protocol Prohibited Medications/Procedures  
Risks associated with stopping the use of protocol-prohibited medications/procedures may include 
worsening of the condition being treated and will be reported as such. In an effort to minimize 
these risks, participants with severe AD or severe asthma who may have difficulty tolerating 
periods without medication/procedure use will be excluded from participating, per study exclusion 
criteria. 


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Risks Associated with Blood Collection 
Risks associated with drawing blood include possible pain when the needle is inserted, as well as 
bleeding, bruising and/or infection at the puncture site. Some people may experience 
lightheadedness, nausea, or fainting. A topical anesthetic (eg, topical lidocaine/prilocaine cream) 
may be placed on the skin before the blood draw to reduce the pain of the stick. Side effects from 
this cream (mainly skin rash) may occur. Institution-specific guidelines for blood collection 
(amount and frequency based on age) will be followed. 
2.3.2 Benefit assessment  
There may or may not be any direct benefits for the participants who elect to enroll in this study. 
Participants with AD disease in the AD cohort will receive a total of 16 weeks of dupilumab 
treatment during study, and health volunteer’s cohort will receive no treatment during study.  
One potential benefit for participants in the AD cohort is that their AD may improve and their itch 
may be reduced while on dupilumab; however, there is no guarantee that the product will help the 
participant’s condition. The participant’s skin condition may even get worse by withholding 
his/her previous/regular AD treatment. 
Healthy volunteers are given the same test and procedure for skin barrier function assessment that 
the patient group receives. Investigators learn about the disease process by comparing the patient 
group to the clinical research volunteers. Participants in the healthy volunteers’ cohort will not 
benefit directly from participation in this study, other than the nominal reimbursements provided 
for completing study procedures and visits.  
Although the results of this study may be of commercial value, it will be explained to participants 
that they will not have ownership of these results, and will not benefit financially from 
participation in this study, other than the nominal reimbursements provided for completing study 
procedures and visits. However, the results obtained from healthy volunteers in comparison to AD 
patients will allow the Sponsor to better understand the immune, epidermal, and barrier defects 
observed in AD patients.  
The potential benefit to society is significant if it improves our understanding of what affects AD 
disease severity and skin barrier function. Therefore, the expectation is that the results will benefit 
others in the future. Information obtained from these studies will improve our understanding of 
the immune, epidermal, and barrier defects observed in study participants. 
2.3.3 Benefit/risk related to Coronavirus Disease 2019 (COVID-19)  
Dupilumab has shown clinical benefit in several type-2 driven immunological disorders, such as 
AD, asthma, chronic rhinosinusitis with nasal polyposis. In asthma and AD clinical benefit has 
also been established in certain pediatric patients (for asthma in adolescents and for AD in 
6-18 year olds) and a similar benefit-risk profile to adults has been observed. 


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To date, more than 8000 subjects have been treated with dupilumab during the clinical 
development program in several indications, of which atopic dermatitis, asthma and chronic 
rhinosinusitis with nasal polyposis are licensed in some countries.  
Currently, we do not have sufficient data in patients with COVID-19 who are being treated with 
dupilumab. Thus, the safety and efficacy of dupilumab in COVID-19 patients is unknown. During 
the course of the clinical trial program, respiratory infections including viral infections were 
monitored and these events are not listed as adverse drug reactions with dupilumab. 
The target population of LPS15991 is adult and adolescent patients with moderate-to-severe 
Atopic Dermatitis (AD) and healthy volunteers as reference. AD, the most common form of 
eczema, is a chronic inflammatory disease that often appears as a rash on the skin. Moderate-to-
severe AD is characterized by rashes that can potentially cover much of the body and can include 
intense, persistent itching, skin lesions and skin dryness, cracking, redness or darkness, crusting 
and oozing. Itch is one of the most burdensome symptoms for patients and can be debilitating. 
Skin barrier dysfunction is a major pathogenic factor in AD.  
Based on the aforementioned potential benefits to patients participating in LPS15991, the Sponsor 
assessment is that the benefit-risk remains favorable for patient to participate in this trial. The 
proposed study will evaluate the effect of dupilumab on the skin barrier in adult and adolescent 
population with moderate-to-severe AD. The efficacy and safety of dupilumab were confirmed 
based on data that included in pivotal Phase 3 trials in which dupilumab were used alone or in 
combination with topical corticosteroids (TCS) and compared to placebo or TCS alone in patients 
with moderate to severe AD. In the trials, patients treated with dupilumab alone or in combined 
with TCS experienced significant improvements in overall disease severity, skin clearance and 
quality of life. Therefore, the operation of LPS15991 will allow enrolled AD patients the 
opportunity to receive a therapy which may provide benefit in improving their skin barrier 
function, overall disease severity, and quality of life.  Participants in the healthy volunteers’ 
cohort will not benefit directly from participation in this study, other than the nominal 
reimbursements provided for completing study procedures and visits. However, the results 
obtained from healthy volunteers in comparison with AD patients will allow the Sponsor to better 
understand the immune, epidermal, and barrier defects observed in AD patients. The Sponsor also 
recognizes that the “Coronavirus Disease 2019” (COVID-19) pandemic may have an impact on 
the conduct of clinical trials.  The Sponsor will monitor the situation closely and ensure the 
integrity of the trial conduct and data (see Section 8). 
2.3.4 Overall benefit: risk conclusion  
Taking into account the measures taken to minimize risk to participants participating in this study, 
the potential risks identified in association with dupilumab, TEWL and skin tape stripping are 
justified by the anticipated benefits that may be afforded to participants with atopic dermatitis. For 
healthy volunteers no benefit is expected, but there is also no relevant risk identified for those 
participants. 


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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Evaluate changes in skin barrier function 
with transepidermal water loss (TEWL) 
assessed after skin tape stripping (STS) in 
pre-defined lesional skin in patients with 
moderate to severe AD treated with 
dupilumab. 
• 
Percent change from baseline in TEWL after 5 STS 
assessed on lesional skin at Week 16 in AD patients. 
Secondary 
• 
Evaluate changes in skin barrier function 
with TEWL assessed after STS in pre-
defined lesional and non-lesional skin in 
patients with moderate to severe AD 
treated with dupilumab in reference to 
normal skin of healthy volunteers. 
 
• 
Change (percent and absolute) from baseline in TEWL after 
20 STS assessed on lesional skin at Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
20 STS assessed on non-lesional skin at Week16 in AD 
patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
20 STS assessed on normal skin at Week16 in healthy 
volunteers.  
• 
Change (percent and absolute) from baseline in TEWL after 
15 STS assessed on lesional skin at Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
15 STS assessed on non-lesional skin at Week16 in AD 
patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
15 STS assessed on normal skin at Week16 in healthy 
volunteers. 
• 
Change (percent and absolute) from baseline in TEWL after 
10 STS assessed on lesional skin at Week16 in AD patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
10 STS assessed on non-lesional skin at Week16 in AD 
patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
10 STS assessed on normal skin at Week16 in healthy 
volunteers.  
• 
Absolute change from baseline in TEWL after 5 STS 
assessed on lesional skin at Week16 in AD patients. 
• 
Change (percent and absolute) from baseline in TEWL after 
5 STS assessed on non-lesional skin at Week16 in AD 
patients.  
• 
Change (percent and absolute) from baseline in TEWL after 
5 STS assessed on normal skin at Week16 in healthy 
volunteers. 


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Objectives 
Endpoints 
• 
Evaluate time course of improvement in 
skin barrier function with TEWL assessed 
before and after STS in pre-defined 
lesional and non-lesional skin in patients 
with moderate to severe AD treated with 
dupilumab in reference to normal skin of 
healthy volunteers. 
• 
Change (percent and absolute) from baseline in TEWL 
before STS on lesional skin in AD patients over time.  
• 
Change (percent and absolute) from baseline in TEWL 
before STS on non-lesional skin in AD patients over time. 
• 
Change (percent and absolute) from baseline in TEWL 
before STS on normal skin in healthy volunteers over time. 
• 
Change (percent and absolute) in TEWL area under the 
curve (TEWL AUC: a composite measure before and after 5, 
10, 15 and 20 STS) for skin barrier function in lesional skin 
in AD patients over time. 
• 
Change (percent and absolute) in TEWL AUC (a composite 
measure before and after 5, 10, 15, and 20 STS) for skin 
barrier function in non-lesional skin in AD patients over time. 
• 
Change (percent and absolute) in TEWL AUC (a composite 
measure before and after 5, 10, 15, and 20 STS) for skin 
barrier function in normal skin in healthy volunteers over time. 
• 
Change (percent and absolute) from baseline in TEWL after 
STS assessed on lesional skin in AD patients over time. 
• 
Change (percent and absolute) from baseline in TEWL after 
STS assessed on non-lesional skin in AD patients over time. 
• 
Change (percent and absolute) from baseline in TEWL after 
STS assessed on normal skin in healthy volunteers over 
time. 
Tertiary/exploratory 
 
• 
Evaluate dupilumab treatment effect on 
skin lipidomics using STS samples in both 
pre-defined lesional and non-lesional skin 
in patients with moderate to severe AD in 
reference to normal skin of healthy 
volunteers.  
• 
Changes (percent and absolute) in lipidomics parameters in 
lesional and non-lesional skin including the ratio of EOS 
CER and NS CER, and FLG breakdown products of UCA 
and PCA concentrations at Week 8 and Week 16, 
respectively.  
• 
Global characterization of protein-bound ceramides over 
time. 
• 
Evaluate dupilumab treatment effect on 
skin proteomics using STS samples in both 
predefined lesional and non-lesional skin in 
patients with moderate-to-severe AD in 
reference to normal skin of healthy 
volunteers. 
• 
Changes (percent and absolute) in the expression of 
proteins associated with skin barrier function including 
keratin intermediate filaments, proteins associated with 
inflammatory response, and glycolysis and oxidative stress 
response proteins in STS protein extracts over time. 
• 
Evaluate dupilumab treatment effect on 
skin transcriptome using STS samples in 
both predefined lesional and non-lesional 
skin in patients with moderate-to-severe 
AD in reference to normal skin of healthy 
volunteers. 
• 
Changes in expression of genes associated with epidermal 
differentiation, barrier and lipid metabolism, and Type 2 
inflammation over time. 
• 
Explore the association of skin barrier 
function measured by TEWL with disease 
severity assessed by standard AD severity 
assessments (Eczema Area and Severity 
Index (EASI), SCORing Atopic Dermatitis 
(SCORAD), local lesion severity on target 
• 
Change (percent and absolute) from baseline in EASI over 
time. 
• 
Change (percent and absolute) from baseline in SCORAD 
over time. 


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Objectives 
Endpoints 
lesion), patient reported outcomes (PRO) 
(Patient Oriented Eczema Measure 
(POEM), Dermatology Life Quality Index  
(DLQI) / Children Dermatology Life 
Questionnaire Index (CDLQI), peak 
pruritus Numerical Rating Scale (NRS), 
and quality of sleep NRS), standardized 
photos, and the biomarker profiles of 
lipidomics, proteomics, and transcriptomics 
assessed in the STS sample. 
• 
Change (percent and absolute) from baseline in Individual 
Signs Score (ISS) for target lesion over time. 
• 
Change (percent and absolute) from baseline in PRO POEM 
over time. 
• 
Change (percent and absolute) from baseline in PRO of 
DLQI in patients 18 years of age and older / CDLQI in 
patients ≥12 and <18 years of age over time. 
• 
Change (percent and absolute) from baseline in PRO of 
peak pruritus NRS over time. 
• 
Change (percent and absolute) from baseline in PRO of 
quality of sleep NRS over time. 
• 
Change (percent and absolute) from baseline in photograph 
outputs (eg, severity score) obtained from skin imaging over 
time. 
• 
Correlation between baseline values and change from 
baseline of TEWL before STS and TEWL AUC in lesional 
and non-lesional skin of AD with the following measures: 
- 
Local target lesion erythema and edema/papulation; 
ISS 
- 
EASI, SCORAD 
- 
PRO measures (POEM, DLQI, CDLQI, peak pruritus 
NRS, and quality of sleep NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS CER) 
- 
FLG breakdown products of UCA and PCA 
concentrations in STS 
- 
Key components of skin proteomics in STS (expression 
of proteins associated with skin barrier function) 
- 
Key components of gene expression from 
transcriptomics 
- 
Image-derived severity score in targeted lesional skin 
• 
Correlation between percent change from baseline in TEWL 
before STS and TEWL AUC in lesional and non-lesional skin 
of AD patients at Week 8 and Week 16 with corresponding 
change from baseline in the following measures: 
- 
Local target lesion erythema and edema/papulation; 
ISS 
- 
EASI, SCORAD 
- 
PRO measures (POEM, DLQI, CDLQI, peak pruritus 
NRS, and quality of sleep NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS CER) 
- 
Filaggrin breakdown products of UCA and PCA 
concentrations in STS 
- 
Key components of skin proteomics in STS (expression 
of proteins associated with skin barrier function) 
- 
Key components of gene expression from 
transcriptomics 
- 
Image-derived severity score in targeted lesional skin 


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3.1 
APPROPRIATENESS OF MEASUREMENTS  
The primary endpoint is percent change from baseline in TEWL after 5 tape strips assessed on 
lesional skin at Week 16 in AD patients, and key secondary endpoints include TEWL changes 
over time measured by TEWL AUC after various number of STS.  The stratum corneum (SC) 
provides skin barrier protection and controls transcutaneous water loss. TEWL measurement, 
which quantifies water diffusion across the SC, is commonly used for the physiologic assessment 
of skin barrier function (18). In addition to basal TEWL to assess the undisturbed permeability of 
the skin barrier, TEWL measurements have also been conducted together with controlled skin 
barrier perturbation using skin tape stripping (STS) to measure skin barrier integrity (7). Healthy 
skin is not highly sensitive to STS, and can withstand mild perturbation, while disrupted skin and 
skin with low structural integrity exhibit greater changes in TEWL.  The area under the curve 
(AUC) for TEWL measurements (TEWL AUC) done over a defined number of STS is used to 
reflect the overall integrity of the SC. Skin barrier dysfunction and increased TEWL are major 
pathologic features of AD (14, 19, 20). TEWL has been shown to correlate with AD severity  
(21, 22, 23). Therefore, this study has selected TEWL in conjunction with STS, and TEWL AUC 
as the key primary and secondary endpoints.  


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a phase IV open-label, exploratory study evaluating the effect of dupilumab on skin barrier 
function in adolescent and adult patients with moderate to severe AD with a healthy volunteer 
cohort as a reference comparator in two study sites. 
The maximum study duration per participant will be 24 weeks. The study will comprise of: 
• Screening Period 1 (Day -28 to -1): Subjects will be evaluated according to inclusion and 
exclusion criteria. 
• Baseline Visit (Day 1): Subjects who remain eligible will be enrolled. 
• 16-week treatment period for AD patients and a 16-week observation period for healthy 
volunteers. 
• 4-week safety follow-up period.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The study design includes two parallel study cohorts: the AD patient’s cohort with open-label 
dupilumab treatment for 16-weeks, and the healthy volunteer’s cohort without any treatment, 
which serves as a reference comparator group for the skin barrier assessment parameters. The 
study applies comprehensive skin barrier function assessments including TEWL in conjunction 
with STS, and lipidomics, proteomics and transcriptomics from STS samples, standardized full 
body photographs and photographs from the targeted lesional and non-lesional areas, and clinical 
disease severity and patient reported outcomes.  
TEWL is commonly used for physiologic assessment of skin barrier function. In addition to basal 
TEWL to assess the undisturbed permeability of skin barrier, recently TEWL measurements have 
also been combined with skin barrier perturbation using STS to measure skin barrier function and 
integrity (7). So far, most studies investigating epidermal biomarkers have used skin biopsies for 
studies on immunological parameters as well as skin barrier function. The STS technique uses a 
standardized tape for removing of epidermis layer by layer. Advantages of this technique are: it is 
non-invasive, causes no pain in the patients and leave no scars. With this technique it is possible 
to follow reactions within the same skin area over time, and to study precisely in which depth of 
the epidermis the different substances are located (24, 25). Through these assessments, the study 
will explore the interplay between skin barrier function kinetics and clinical disease severity and 
therapeutic response. 
TEWL can be influenced by many environmental and individual factors, including age, sex, race, 
anatomical region, skin temperature, environmental conditions, season, smoking status, 
measurement technique and many others. Therefore, including an age-, gender-, targeted lesion 
area-, and study site-matched healthy volunteers’ cohort assessed at the same time in the same 
measurement conditions with reference thresholds of skin barrier function evaluation indicating 
pathological relevance is important in interpreting study assessment results (8, 9).  


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4.2.1 Participant input into design  
Not applicable. 
4.3 
JUSTIFICATION FOR DOSE  
The dose selected in this study is the dose approved for the treatment of moderate to severe AD 
for Dupixent in US, Canada, EU. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including end of study visit (EoS) as shown in the Schedule of Activities in Section 1.3. 
The end of the study is defined as the date of the last visit of the last participant in the study 
shown in the Schedule of Activities for the last participant in the trial globally. 


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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The purpose of this study is to understand the effect of dupilumab treatment on well-described 
pathophysiological features of AD (eg, barrier, epidermal activation, epidermal lipids, etc). This 
study will be limited to male and female participants aged 12 to 65 years, with moderate to severe 
AD, because dupilumab as approved in patients ≥12 years with moderate to severe AD. An upper 
age limit has been put on the study population because skin barrier function /structure deteriorates 
in elderly individuals, and we want to minimize the effect of this confounding variable would 
have on our study interpretations.  
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be between 12 to 65 years of age (inclusive), at the time of signing the 
informed consent.  
Type of participant and disease characteristics 
Atopic dermatitis patients and healthy volunteers: 
I 02. Male or female patients. 
I 03. Patients with AD diagnosis according to Hanifin and Rajka criteria at least 1 year before 
screening. (AD patients only) 
I 04. Investigator Global Assessment (IGA) score of ≥3 at screening (on the 0-4 scale). (AD 
patients only) 
I 05. Patients with moderate to severe atopic dermatitis that are eligible to be treated with 
dupilumab according to product monograph. (AD patients only) 
I 06. Patients with AD must have active lesions on the upper limbs or lower limbs, with severity 
for lesion erythema or edema/papulation ≥2 at screening on the 0-3 scale of the ISS. (AD 
patients only) 
I 07. Participants should have a non-lesional (normal looking) skin area 4 cm from the edge of 
the lesional area. If unable to identify non-lesional skin 4 cm from the lesional area, it is 
acceptable to identify normal looking skin as close to the lesion as possible. (AD patients 
only) 
I 08. Willing to refrain from applying any topical medication products on the target assessment 
areas (including lesional and non-lesional) throughout the study until the EoT visit unless 
necessary to alleviate intolerable symptoms.  


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I 09. Willing to refrain taking showers or soaking in a bathtub with soaps and body washes 
within 6 hours before TEWL assessments. 
I 10. Willing to NOT apply any moisturizers to the areas of the skin that are targeted assessment 
areas (lesional and non-lesional) during the entire study from Day -7 to the EoT visit. 
I 11. Willing and able to comply with all clinic visits and study-related procedures. 
Healthy volunteers only: 
I 12. Age and gender matched to a selected AD patient by study site. Adolescents aged 12 to  
17 years will be matched by post puberty status, and adults aged 18 to 65 years will be 
matched by age as close as possible within 10 years of age. 
I 13. No current dermatologic or systemic condition that could interfere with the assessments. 
Weight  
Not applicable. 
Sex 
I 14. Male or Female 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. See Section 10.4. 
Informed Consent 
I 15. Capable of understanding and giving signed informed consent/assent as will be described 
in the protocol, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. For adolescents ≥12 and <18 years 
of age a specific ICF must also be signed by the participant’s legally authorized 
representative. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Previous treatment with dupilumab within 6 months prior to screening. 
E 02. Skin conditions other than AD that can confound assessments in the area of TEWL 
assessments in the opinion of the investigator (ie, skin atrophy, ichthyosis, Netherton 
syndrome, severe photo damage). 
E 03. Cracked, crusted, oozing, or bleeding AD lesions in the designated lesional assessment 
area leaving insufficient skin that is adequate for TEWL assessments. 


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E 04. Hypersensitivity to the active substance or to any of the excipients of dupilumab. 
E 05. Ocular disorder that in the opinion of the investigator could adversely affect the 
individual’s risk for study participation. Examples include -but are not limited to- 
individuals with a history of active cases of herpes keratitis; Sjogren’s syndrome, 
keratoconjunctivitis sicca or dry eye syndrome that require daily use of supplemental 
lubrication; or individuals with ocular conditions that require the use of ocular 
corticosteroids or cyclosporine. 
E 06. Systemic AD treatment or phototherapy within 4 weeks of baseline. 
E 07. Topical AD treatment within 1 week of baseline. Face and neck may be treated with 
topical steroids during the washout period if approved by the investigator. 
E 08. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect 
the patient’s participation in the study. Examples include, but are not limited to patients 
with short life expectancy, patients with uncontrolled diabetes (hemoglobin A1c ≥9%), 
patients with cardiovascular conditions (eg, Class III or IV cardiac failure according to the 
New York Heart Association classification), severe renal conditions (eg, patients on 
dialysis), hepato-biliary conditions (eg, Child-Pugh class B or C), neurological conditions 
(eg, demyelinating diseases), active major autoimmune diseases (eg, lupus, inflammatory 
bowel disease, rheumatoid arthritis, etc), other severe endocrinological, gastrointestinal, 
metabolic, pulmonary, psychiatric (known suicidal intentions) or lymphatic diseases. The 
specific justification for patients excluded under this criterion will be noted in study 
documents (chart notes, electronic case report forms [eCRF], screening logs, etc). 
E 09. History of hypersensitivity reaction to tape or adhesives. 
Prior/concomitant therapy  
E 10. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known) 
prior to Day 1, whichever is longer. 
Prior/concurrent clinical study experience 
E 11. Current participation in another investigational clinical study. 
Diagnostic assessments 
Not applicable. 
 Other exclusions 
E 12. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized. 
E 13. Participants are dependent on the Sponsor or Investigator (in conjunction with section 1.61 
of the ICH-GCP Ordinance E6). 


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E 14. Individuals directly involved in the conduct of the study, or immediate family members of 
such individuals. 
E 15. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 16. Planned or anticipated major surgical procedure during the patient’s participation in this 
study. 
E 17. Pregnant or breast-feeding women, or were planning to become pregnant or breastfeed 
during the subject’s participation in this study. 
E 18. Women unwilling to use adequate birth control, if of reproductive potential* and sexually 
active. Adequate birth control is defined as agreement to consistently practice an effective 
and accepted method of contraception throughout the duration of the study and for 
12 weeks after last dose of study drug. These include condom with spermicide, hormonal 
contraceptives, intrauterine device, or double barrier contraception (ie, condom + 
diaphragm) or a male partner with documented vasectomy. Additional requirements for 
acceptable contraception may apply in certain countries, based on local regulations. 
Investigators in these countries will be notified accordingly in a protocol clarification 
letter. 
*For females, menopause is defined as at least 12 consecutive months without menses; if 
in question, a follicle stimulating hormone (FSH) level of ≥25 mU/mL must be 
documented. Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be 
documented, as applicable; if documented, women with these conditions are not required 
to use additional contraception. 
E 19. Healthy volunteers with a personal history of an atopic condition. 
E 20. Healthy volunteers with use of any topical treatment anywhere except Cetaphil, 
Vanicream, or the preferred moisturizer not containing additives on non-targeted skin 
areas. 
5.3 
LIFESTYLE CONSIDERATIONS  
• Study participants should not take a shower or soaking in a bath within 6 hours before 
assessment of TEWL. 
• Emollients for use during the study will be provided by the study site to study participants. 
• Participants should apply Cetaphil, Vanicream, or preferred same emollients not 
containing additives except at the pre-defined skin assessment areas up to two times daily 
from Day -7 to the EoT visit.  
• Participants should not apply any emollients on or within 5 cm of the pre-defined skin 
assessment areas during the entire study period from Day-7 until the EoT visit. 
• The type, amount (number of fingertip units), and frequency of topical products used 
during the study will be recorded at home in a medication log/diary. 


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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
subsequently found not to be eligible to be enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any serious adverse event (SAE). Subjects, who do not meet the 
criteria for participation in this study (screen failure) may be rescreened once. In such a case all 
the screening procedures will be repeated; a different patient identification number will be issued. 
There is no requirement for a waiting period between the screen failure date and the rescreening 
date. Participants that are rescreened must sign a new consent form and all Visit 1 procedures 
must be repeated. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless otherwise specified by the protocol. 


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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Study participants will be assigned to study intervention as described below:  
• Up to 24 adolescent and adult moderate to severe AD patients will receive dupilumab. 
• For AD patients aged ≥12 to <18 years the dose regimen will follow the table below and 
based on the body weight on Day 1 (the dose will not be changed during the study): 
Body Weight  
Loading Dose on Day 1 
Subsequent Doses (Q2W) 
less than 60 kg 
400 mg (two 200 mg injections) 
200 mg 
60 kg or more 
600 mg (two 300 mg injections) 
300 mg 
• AD patients age 18 years and older will receive a SC loading dose of 600 mg on Day 1, 
followed by 300 mg Q2W SC through Week 14. Drug will be administered by study site 
staff at baseline, Weeks 2, 4, 6, 8, 12. Drug will be self-administered by AD patients at 
Week 10 and 14. 
One kit number list by dosage strength is generated centrally by Sanofi and IMP are packaged in 
accordance with these lists. The treatment will be given to the patient depending on their age and 
body weight.  
Study intervention will be dispensed at the study visits summarized in SoA (see Section 1.3). 
Returned study intervention should not be re-dispensed to the participants.  
Table 2 - Overview of study interventions administered  
ARM name 
Dupilumab 200 
Dupilumab 300 
Intervention name 
Dupilumab 200 mg 
Dupilumab 300 mg 
Type  
Biological/Vaccine 
Biological/Vaccine 
Dose formulation 
A 175 mg/mL dupilumab solution in a 
pre-filled syringe to deliver 200 mg in 
1.14 mL 
A 150 mg/mL dupilumab solution in a 
pre-filled syringe to deliver 300 mg in  
2 mL 
Unit dose strength(s) 
200 mg 
300 mg 
Dosage level(s) 
200 mg every 14 ±2 or 3 days after an 
initial loading dose of 400 mg 
300 mg every 14 ±2 or 3 days after an 
initial loading dose of 600 mg 
Route of administration 
Subcutaneousa 
Subcutaneousa 
Use 
Experimental 
Experimental 
IMP  
IMP 
IMP 


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ARM name 
Dupilumab 200 
Dupilumab 300 
Packaging and labeling 
One glass pre-filled syringe packed in a 
patient kit box. Both the glass pre-filled 
syringe and the box will be labeled as 
required per country requirement. 
One glass pre-filled syringe packed in a 
patient kit box. Both the glass pre-filled 
syringe and the box will be labeled as 
required per country requirement. 
[Current/Former name(s) or alias(es)] 
Dupixent®  
Dupixent® 
a Subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same 
site is not injected twice during consecutive administrations. Injection in the upper arms can only be done by a trained person (parent/legally 
authorized representative/caregiver trained by Investigator or Delegate) or health care professional but not the participant themselves.  
IMP: investigational medicinal product 
Investigational medicinal product(s) 
When the participant has a study visit, the IMP will be administered following clinical procedures 
and blood collection (if any). AD patients will be monitored for at least 30 minutes after each 
injection. Patients should monitor themselves for at least 30 minutes after performing self-
injection at home. 
Study participants may by trained for study drug self-administration starting from D1 (Visit 2). 
Training should be completed and documented at Week 8 (Visit 10). Site staff has to verify 
patients injection technique before they are allowed to self-inject at home. On-site injections may 
be performed by either site staff or AD patient or caregiver/parent/legal representative if 
previously trained on self-injection technique. 
Between the protocol-scheduled on-site visits, participants are allowed to self-inject IMP at home. 
Patient should also be trained by the site staff to recognize potential signs and symptoms of 
hypersensitivity reaction in order to self-monitor at home. In case of hypersensitivity symptoms 
the patient should contact healthcare provider/emergency. The training must be documented in the 
participant’s study file. Participants will be dispensed an adequate amount of IMP for home 
administration to last through the next scheduled study visit. Participants who prefer to have a 
healthcare professional administer the IMP may choose to have injections administered at the 
study site. 
6.1.1 Devices  
No devices for administration of study drug will be used in this study. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Storage and handling  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
2. Only participants enrolled in the study (or their legal representatives, parents, or guardians in 
case of adolescents) may receive study intervention and only authorized site staff may supply 


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or administer study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). Study medication may be dispensed 
to study participants for self-administration at Week 10 and/or Week 14. In this case study 
participants need to inform the site is there are any issues with temperature storage during 
transport, storage at home, or any other issues with IMP. 
6.2.2 Responsibilities  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.4.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for Direct to 
patient [DTP] shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
6.3 
MEASURES TO MINIMIZE BIAS  
The study is open label study without a treatment control group in patients. To control bias, the 
following measures are taken: 
• Age-, gender-, targeted lesion area-, and study site-matched healthy volunteers will serve 
as a reference comparator cohort for interpreting study results. 
• PROs will be collected by electronic data capture. 
• Efficacy data (TEWL) will be measured by the same device model. 
• Biomarker data (lipidomics, proteomics, and transcriptomics) will be measured by an 
experienced, central laboratory. 
• Study is limited to 2 very experienced study centers 
• One central laboratory for lipidomics, proteomics and transcriptomics analyses to reduce 
skin barrier assessment variabilities. 
• Standardized study assessment procedures, including TEWL and STS skin barrier function 
• Standardized photography for targeted lesional and non-lesional areas, and clinical disease 
severity and patient reported outcome evaluations. 
• Reason for screen failures (if any) will be documented. 


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6.4 
STUDY INTERVENTION COMPLIANCE  
Investigator or his/her delegate must ensure that IMP will be administered to each participant 
according to the labeling instructions.  
IMP accountability:  
• Intervention units are returned by the participant at the next study visit.  
• The Investigator counts the number of remaining unused kits/pre-filled syringes, and fills 
in the IMP accountability and inventory forms.  
• The Investigator or his/her delegate records the dosing information on the appropriate 
page(s) of the eCRF.  
• The monitor in charge of the study then checks the eCRF data by comparing them with the 
IMP which he/she has retrieved and source documents.  
When participants are dosed at the site (see Section 1.3), they will receive study intervention 
directly from the Investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents and recorded in the 
eCRF. The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the study 
intervention.  
When participants self-administer study intervention(s) at home (see Section 1.3) , they will 
document compliance on a home dosing diary. Compliance with study intervention will be 
assessed at each visit. Deviation(s) from the prescribed dosage regimen should be recorded in the 
eCRF. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Participants must abstain from taking prohibited prescription drugs within 7 days (or 14 days if 
the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of 
study intervention until completion of the follow-up visit, unless, in the opinion of the Investigator 
and Sponsor, the medication will not interfere with the study. 
Paracetamol/acetaminophen, at doses of 2 grams/day, is permitted for use any time during the 
study. Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor, if required. 


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Cetaphil, Vanicream, or the preferred same moisturizer not containing additives will be dispensed 
by the study site and its use is allowed on all body areas except the targeted assessment areas. No 
moisturizers or emollients are allowed at any time during the study for the targeted lesional and 
non-lesional skin areas including a buffer zone of 5 cm in AD patients and the targeted skin areas 
in HV for TEWL assessments from Day -7 to Day 113 (Week 16, EoT). 
6.5.1 Rescue medicine  
If absolutely medically necessary (ie, to control intolerable AD symptoms on face and genital 
areas), rescue treatment for AD may be provided to study patients at the discretion of the 
investigator. Investigators should make every attempt to conduct efficacy and safety assessments 
(eg, disease severity scores, safety labs) immediately before administering any rescue treatment. 
An unscheduled visit may be used for this, if necessary.  
6.5.1.1 Prohibited medications and procedures  
Treatment with the following concomitant medications and procedures is prohibited until the EoT 
visit: 
1. Medications used for the treatment of AD or for super-infection: 
- 
Topical calcineurin inhibitors (tacrolimus or pimecrolimus)  
- 
Topical phosphodiesterase inhibitors (crisaborole)  
- 
Topical corticosteroids 
2. Topical antibiotics 
3. Vitamins and dietary or herbal supplements (unless approved by the investigator) 
4. Use of any moisturizers other than those approved and dispensed by the study staff. 
5. Systemic treatment for AD with an immunosuppressive/immunomodulating agent 
(including, but not limited to, systemic corticosteroids, CsA, AZA, MTX, MMF, IFN-γ, or 
other biologics)  
6. Treatment with immune modulating biologics including, but not limited to, the following:  
- 
Any cell-depleting agents (eg, rituximab)  
- 
Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, or 
anakinra  
7. Procedures used for the treatment of AD (these are considered rescue procedures):  
- 
Phototherapy (such as ultraviolet B (UVB), narrowband UVB (NBUVB), ultraviolet 
A1 (UVA1), or psoralen-UVA (PUVA))  
- 
Bleach baths  
- 
Use of a tanning booth/parlor  
8. In addition, participants will be asked to abstain from live (attenuated) vaccinations 
through Week 16. If a participant requires a vaccination prior to 16 weeks after 


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discontinuing treatment with dupilumab, titers should be checked post-vaccination. Live 
(attenuated) vaccinations include but are not limited to the following:  
- 
Bacillus Calmette-Guérin (BCG) 
- 
Chickenpox (Varicella)  
- 
FluMist-Influenza  
- 
Intranasal influenza  
- 
Measles (Rubeola)  
- 
Measles-mumps-rubella (MMR) combination  
- 
Measles-mumps-rubella-varicella (MMRV) combination  
- 
Mumps  
- 
Oral polio (Sabin)  
- 
Oral typhoid  
- 
Rotavirus  
- 
Rubella  
- 
Smallpox (Vaccinia)  
- 
Varicella Zoster (shingles)  
- 
Yellow fever  
9. Taking showers or soaking in a bathtub with soaps and body washes within 6 hours before 
TEWL assessments is to be avoided. Moisturizers other than Cetaphil, Vanicream, or the 
preferred same moisturizer not containing additives are prohibited. 
6.5.1.2 Permitted medications  
Other than the prohibited medications and procedures listed in Section 6.5.1.1, treatment with 
concomitant medications and procedures is permitted during the study. This includes treatment 
with contraceptives, nasal and inhaled corticosteroids, and oral antihistamines. 
6.6 
DOSE MODIFICATION  
No change in IMP dose is allowed. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
Any intervention after the EOS Visit will be at the discretion of investigator or treating physician.  
 


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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for TEWL, lipidomics, proteomics and 
transcriptomics. See the SoA for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
Pregnancy in a female participant will lead to definitive intervention discontinuation in all cases. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. For all temporary intervention discontinuations, duration should be recorded by 
the Investigator in the appropriate pages of the eCRF.  
The following definition can be considered: 
Eg, temporary intervention discontinuation decided by the Investigator corresponds to one dose 
not administered to the participant. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 


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study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 


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necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  


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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA, Section 1.3 and Section 1.4. 
Protocol waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• The type, amount (number of fingertip units), and frequency of topical products (see also 
Section 6.5) used during the study will be recorded in a medication log. The medication 
log might look different for AD patients and healthy volunteers. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 50 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• In light of the public health emergency related to COVID-19 (or in case of any other 
public health emergency), the continuity of clinical study conduct and oversight may 
require implementation of temporary or alternative mechanisms, such as phone contact, 
virtual visits, online meetings, use of local clinic or laboratory locations, and home visits 
by skilled staff. Implementation of such mechanisms may differ country by country, 
depending on country regulations and local business continuity plans. Additionally, no 
waivers to deviate from protocol enrollment criteria due to COVID-19 (or any other 
pandemic) will be granted. All temporary mechanisms utilized, and deviations from 
planned study procedures are to be documented as being related to COVID-19 (or any 
other public health emergency) and will remain in effect only for the duration of the public 
health emergency. 
8.1 
PROCEDURES PERFORMED ONLY AT THE SCREENING/BASELINE VISIT  
Assessments performed only at the screening and/or baseline visit include medical history, 
medication history, IGA, demographics, and diagnosis of chronic AD. AD disease characteristics 
are assessed by clinical and patient reported outcomes. 


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8.2 
EFFICACY ASSESSMENTS  
8.2.1 Transepidermal water loss assessment and skin tape stripping  
8.2.1.1 Transepidermal water loss assessment  
Transepidermal water loss is a skin barrier function test that measures perspiration or water loss 
through the skin. Transepidermal water loss is generally higher in AD skin compared to normal 
skin as the barrier is disrupted allowing water to evaporate more readily. If the barrier improves 
with dupilumab treatment, TEWL would be expected to decrease. 
TEWL assessment will be conducted in a quiet environment with temperature and humidity being 
documented. TEWL measurements will be conducted in the same room throughout the study 
where possible. Subjects will be acclimated to the room for a minimum of 20 minutes prior to 
TEWL measurements. Room temperature will be set to be within 19.0°C to 23.0°C. Humidity will 
be set to be below 60% as the maximum allowed humidity. To further control TEWL readout, 
moisturizers will be standardized for all study participants starting from Day -7 until Day 113 
(Week 16). The first TEWL assessment at each visit will be conducted at each of the three spots 
in predefined lesional and non-lesional areas respectively. After start of STS all subsequent 
TEWL assessments at each visit will be done on the single lesional and non-lesional spot 
respectively at which the STS is performed (see also Figure 3).  
8.2.1.2 Skin tape stripping and collection of skin tapes  
In addition to TEWL measurements at the skin surface, TEWL measurements can be combined 
with STS to measure skin barrier function. With STS, the uppermost layers of the skin are peeled 
away using adhesive discs. Skin with compromised skin barrier exhibits greater changes in 
TEWL. The area under the curve for TEWL measurements over a defined number of STS reflects 
the overall function of the SC. 
This procedure involves the defined, non-invasive application of a commercially available 
adhesive sheet on the surface of the skin at predefined areas. A dedicated instrument (eg, D-
SQUAME Pressure Instrument D500) is used to apply a defined pressure onto the skin tape strip 
for 5 to 10 seconds. Thereafter the skin tape strip will be peeled off the skin in a ripping motion 
using a forceps (= the skin tape-stripping method).  
This procedure will be repeated up to 20 times sequentially, interrupted every 5 STS by TEWL to 
collect samples from the stratum corneum. The samples will be collected for lipidomics, 
proteomics and transcriptomics assessment.  
Lesional and non-lesional areas of skin will be tested. Patients will undergo skin barrier function 
tests at time points according to Section 1.3 before, and after skin tape stripping.  
Healthy volunteers will undergo skin barrier function tests at time points according to Section 1.4 
before, and after skin tape stripping. 


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Specifically, lipidomic, proteomic and transcriptomics samples will be collected by STS at 
baseline, Week 2, 4, 8, 12, and 16. A total 210 skin tapes will be collected in lesional, non-
lesional or normal skin, respectively. 
In order to allow the skin to recover from STS three closely adjacent spots (without an overlap for 
the skin tapes) will be identified for subsequent skin barrier function assessment within lesional, 
non-lesional and normal skin area (Figure 2). STS assessments from the same spot will be 
separated by 8 weeks. In case of STS assessment at an unscheduled visit or at a premature end of 
treatment visit the assessment should be conducted at that spot of the skin area, for which the time 
period passed since the last STS assessment is the longest. 
Figure 2 - Example of selection of skin spots within lesional and non-lesional skin  
 
TEWL assessment in lesional, non-lesional and normal skin will be done before, and after skin 
tape stripping according to the attached Figure 3. All skin tape strips will be collected, stored, and 
analyzed for lipidomics, proteomics and transcriptomics according to Section 8.9.  
 
 
 


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Figure 3 - TEWL assessment and STS in lesional and non-lesional skin of AD patients and in 
normal skin of HV  
 
The detailed procedure for TEWL, skin tape stripping, collecting and storing skin tapes for 
lipidomic, proteomic and transcriptomic analysis will be provided in the study reference manual. 
Details about lipidomic, proteomic and transcriptomic analyses by time point will be provided in 
the SAP. 
8.2.2 Standardized photographs  
In AD patients photographs will be taken of a representative area of AD involvement (the lesional 
area used for TEWL assessments) as well of a representative area without AD involvement (the 
non-lesional areas used for TEWL assessments) on day 1/baseline (pre dose). Subsequent 
photographs of the same area will be taken at each visit until Week 16 in AD patients.  
In healthy volunteers photographs will be taken of a skin area corresponding to the lesional area 
of the AD patients, to which this healthy volunteer is matched on Day 1 at baseline. Subsequent 
photographs of the same area will be taken at each visit until Week 16 in HV. 
For each image of each targeted lesional, non-lesional and healthy skin area morphologic 
parameters will be assessed by a validated method. The parameters may include size, color and 
other parameters. In addition each image will be scored by a blinded expert reader to grade the 
severity of skin findings. 


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Full body photographs will be taken for documentation purposes.  
All photographs should be taken before the first TEWL assessment at each visit.  
A separate photography ICF will be signed by study participants to confirm agreement to 
photography publication. Photographs are mandatory to be taken in all subjects, but agreement to 
their publication is only mandatory for AD patients. Healthy volunteers can decline consent for 
photography publication but still participate in the study. 
Further instructions for taking the photographs and additional information on the parameters to be 
analyzed will be provided in the study reference manual. 
8.2.3 Questionnaires and patient reported outcome assessments (PROs)  
Questionnaires and patient-reported assessments will only be conducted in AD patients. Patient 
reported outcomes will be collected in an appropriate form, for which the respective device, diary 
and/or instruction is handed out to the patient at the screening (or baseline) visit. The electronic 
diary will be only used by the subset of patients who speak fluently the language in which 
adequate translations (ie, validated translations where applicable) are available. These Patient-
Reported Outcome (PRO) questionnaires and NRS should be completed by the patients before the 
TEWL assessment at each visit and in a quiet place. The questionnaires should be completed by 
the patients themselves, independently from their physician, the study nurse or any other medical 
personnel and without any help from friends or relatives.  
Patients will bring the diary to the site at each visit. Diary will be reviewed for any questionnaires 
omission and dispensed back to patients at each visit. 
8.2.4 Investigator’s Global Assessment (IGA)  
The IGA is an assessment scale used in clinical studies to determine severity of AD and clinical 
response to treatment based on a 5-point scale ranging from 0 (clear) to 4 (severe). The IGA score 
will be assessed at time points according to Section 1.3. IGA will be required for inclusion 
decision and is only be collected at screening. 
The IGA will be provided in the study reference manual. 
8.2.5 Individual Signs Score (ISS)  
The ISS -also called Global Individual Signs Score (GISS)- is an assessment scale used to 
evaluate individual components of the AD lesions (erythema, edema/papulation, excoriations, and 
lichenification) by the investigator based on a 4-point scale ranging from 0 (none) to 3 (severe). 
The ISS score on erythema and edema/papulation will be assessed at time points according to 
Section 1.3. 
The ISS will be provided in the study reference manual. 


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8.2.6 Eczema Area and Severity Index (EASI)  
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (26). The EASI is a composite index with scores ranging from 0 to 72. Four AD 
disease characteristics (erythema, thickness [induration, papulation, and edema], scratching 
[excoriation], and lichenification) will each be assessed for severity by the investigator or 
designee on a scale of “0” (absent) through “3” (severe). In addition, the area of AD involvement 
will be assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and 
converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 
2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). The 
EASI will be collected at time points according to Section 1.3. 
The EASI assessment tool will be provided in the study reference manual. 
8.2.7 Severity Scoring of Atopic Dermatitis (SCORAD)  
The SCORAD is a validated tool used in clinical research and clinical practice that was developed 
to standardize the evaluation of the extent and severity of AD (27). The extent of AD is assessed 
as a percentage of each defined body area and reported as the sum of all areas, with a maximum 
score of 100% (assigned as “A” in the overall SCORAD calculation). The severity of 6 specific 
symptoms of AD is assessed using the following scale: none (0), mild (1), moderate (2), or severe 
(3) (for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation). 
Subjective assessment of itch and sleeplessness is recorded for each symptom by the patient or 
relative on a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst 
imaginable itch (or sleeplessness), with a maximum possible score of 20. This parameter is 
assigned as “C” in the overall SCORAD calculation. 
The SCORAD is calculated as: A/5 + 7B/2 + C. Patients will undergo this assessment at time 
points according to Section 1.3. 
The SCORAD assessment tool will be provided in the study reference manual. 
8.2.8 Patient Oriented Eczema Measure (POEM)  
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
frequency of disease symptoms in children and adults (28). The format is a response to 7 items 
(dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency during 
the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) 
with a scoring system of 0 to 28; the total score reflects disease-related severity. The questionnaire 
will be administered at time points according to SoA (Section 1.3). 
The POEM will be provided in the study reference manual. 
8.2.9 Dermatology life quality index / Children's dermatology life quality index  
The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to 
assess the impact of AD disease symptoms and treatment on Quality of Life (QOL) (29). The 


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format is a simple response to 10 items, which assess QOL over the past week, with an overall 
scoring system of 0 to 30; a high score is indicative of a poor QOL. The questionnaire is adapted 
to patient age and will be administered at time points according to Section 1.3. CDLQI is the 
respective, validated version of DLQI to be used in adolescents (30). 
The DLQI/CDQLI will be provided in the study reference manual. 
8.2.10 Peak Pruritus Numerical Rating Scale (Peak Pruritus NRS)  
The Peak Pruritus NRS is a simple assessment tool that patients will use to report the intensity of 
their pruritus (itch) during a daily recall period. Patients will be asked the following questions: 
 “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable’, how 
would you rate your itch at the worst moment during the previous 24 hours?” 
Patients will complete the rating scale daily from Day-7 until Day 29, and then until Day 113 
(EoT) at the week before the visits as indicated at Section 1.3. 
The Peak Pruritus NRS will be provided in the study reference manual. 
8.2.11 Quality of Sleep NRS  
Quality of Sleep NRS to collect information on patient-reported quality of sleep. Numerical rating 
scale range is from 0 (“worst possible sleep”) to 10 (“best possible sleep”). 
Patients will complete the rating scale daily from Day-7 until Day 29, and then until Day 113 
(EoT) at the week before the visits as indicated at Section 1.3. 
The Quality of Sleep NRS will be provided in the study reference manual. 
8.3 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA. 
8.3.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the skin, the 
cardiovascular, respiratory, and neurological systems. Height and weight will also be 
measured and recorded.  
• Signs and symptoms of hypersensitivity reaction (if any) will be documented. 
• A skin focused physical examination will be performed prior to TEWL assessments at 
time points according to Section 1.3 and Section 1.4.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new adverse 
event. 


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8.3.2 Vital signs  
Vital signs, including heart rate, blood pressure, body temperature, and respiration rate, will 
collected prior to TEWL assessments at time points according to Section 1.3 and Section 1.4. 
Heart rate, respiratory rate and blood pressure will be measured with the patient in sitting position, 
after the patient has rested comfortably for at least 5 minutes. 
8.3.3 Laboratory testing  
Urinalysis for pregnancy testing 
Pregnancy testing will be performed for all women of childbearing potential. Urine pregnancy 
testing will be performed at time points according to Section 1.3 and Section 1.4. 
8.3.4 Electrocardiograms  
No ECG assessments will be required in this study. 
8.3.5 Clinical safety laboratory assessments  
No clinical safety laboratory assessments are required in this study. 
8.3.6 Suicidal ideation and behavior risk monitoring  
Not applicable for this study.  
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).  
8.4.1 Time period and frequency for collecting Adverse Events (AE) and Serious Adverse 
Events (SAE) information  
All SAEs will be collected from the signing of the informed consent form (ICF) until the follow-
up visit at the time points specified in the SoA (Section 1.3 and Section 1.4). 
All AE will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3 and Section 1.4). 
All SAEs and adverse events of special interest (AESI) will be recorded and reported to the 
Sponsor or designee immediately and under no circumstance should this exceed 24 hours, as 


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indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.4.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.4.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, AEs of 
special interest (as defined in Section 8.4.8), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.4.4 Regulatory reporting requirements for SAEs  
• Prompt notification within 24 hours by the Investigator to the Sponsor of a SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days 


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- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor 
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
8.4.5 Pregnancy  
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 12 weeks after EoS. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.6 Cardiovascular and death events  
Not applicable. 
8.4.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.4.8 Adverse event of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
The following events are AESIs and require reporting to the Sponsor within 24 hours of learning 
of the event: 
• Anaphylactic reactions. 
• Systemic hypersensitivity reactions. 
• Helminthic infections. 
• Any severe type of conjunctivitis or blepharitis. 


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• Keratitis. 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms). 
The following events also require reporting to the Sponsor within 24 hours of learning of the 
event: 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP. 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria 
- 
In the event of pregnancy in a female participant, investigational medical product 
(IMP) should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined  
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs 
• Significant alanine transaminase (ALT) elevation 
- 
ALT >5 x the upper limit of normal (ULN) in participants with baseline ALT ≤2 x 
ULN;  
or 
- 
ALT >8 x ULN if baseline ALT >2 x ULN 
• Symptomatic overdose (serious or nonserious) with IMP  
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the intended dose during an interval of less than 11 days. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate adverse event forms. 
The definitions of an AE or SAE can be found in the study protocol. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study procedures, or that caused the participant 
to discontinue the study (see study protocol).  


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8.4.9 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.5 
TREATMENT OF OVERDOSE  
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab can no longer be detected systemically (at least 28 days). 
3. Document appropriately in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.6 
PHARMACOKINETICS  
PK parameters are not evaluated in this study. 
8.7 
PHARMACODYNAMICS  
Pharmacodynamics is evaluated using TEWL assessments as described Section 8.2.1. 
8.8 
GENETICS  
A blood sample for DNA isolation will be collected at baseline from all participants for filaggrin 
gene sequencing analysis. Blood for DNA isolation should be collected on Day 1/Baseline (pre-
dose) but may be collected at any study visit.  
Participants who provide a blood sample may agree to broader genetic analysis, in addition to the 
mandatory filaggrin gene sequencing analysis. Optional broad genetic analysis may include, but is 
not limited to, whole exome or whole genome sequencing. Participants will be required to 
separately agree to this optional genetic research within the informed consent form (ICF) to 
consent to broad genetic analysis. Participants who do not wish to participate in optional broad 
genetic research may still participate in the study.  


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In the event of DNA isolation failure, a replacement genetic blood sample may be requested from 
the participant. Signed informed consent will be required to obtain a replacement sample unless 
replacement collection was included in the original consent. 
Details on processes for collection, storage, shipment and destruction of these samples can be 
found in the study reference manual. See Appendix (Section 10.5) for information regarding 
genetic research. 
DNA samples may be stored for a maximum of 15 years following the last participant’s last visit 
for the study at a facility selected by the Sponsor. 
8.9 
BIOMARKERS  
Collection of serum, plasma and skin samples for potential, future biomarker research is also part 
of this study. 
8.9.1 Lipidomics assessment  
Samples for skin lipidomic assessment are required and will be collected from all participants in 
this study as specified in the SoA (Section 1.3 and Section 1.4). 
Targeted skin lipidomics will be performed by means of a validated mass spectrometry method 
from skin tapes that have been collected during tape stripping at the TEWL assessment. 
Lipidomics in skin will be assessed in skin tapes from skin tapes obtained from lesional skin, non-
lesional skin and normal skin. 
Skin tape strip samples may be stored for a maximum of 5 years following the last participant’s 
last visit for the study at a facility selected by the Sponsor. 
8.9.1.1 Filaggrin breakdown products  
Filaggrin is a structural protein that plays an important role in controlling water retention in the 
skin, and the hygroscopic properties of FLG breakdown products have an important role as 
natural moisturizing factor ingredients (31). Filaggrin deficiency leads to impaired lipid profile 
and altered acidification pathways (32). Lipid abnormalities have been reported in patients with 
FLG mutations (33).  
Filaggrin breakdown products, cis/trans-urocanic acid (total UCA) and pyrrolidone carboxylic 
acid (PCA), also known as pyroglutamic acid, will be quantified via a liquid chromatography 
electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) approach in the same tape 
strips that are used for lipidomics assessment. 


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8.9.1.2 Analysis of stratum corneum lipids  
It has been reported that lesional and non-lesional skin of AD patients has decreased EOS 
ceramides and other ceramides with very long–chain fatty acids (C22–C30), and increased short-
chain fatty acids NS CER (C16–C20) (12). Highly hydrophobic ω-esterified acid sphingosine 
ceramides (EOS CER) and NS CER will be analyzed as follows. 
STS processing for lipid extraction 
STS will be processed through a Bligh and Dyer procedure as previously described (12). The 
bottom chloroform layer from the skin tape extraction will be used for lipid analyses while upper 
water-methanol phase will be used for polar component analyses by the LC-MS/MS. A fixed 
amount of internal standards (N-palmitoyl-D-erythro-sphingosine (d7), (d7)NS CER and 
d18:1/26:0/18:1(d9) or (d9)EOS CER) will be added at the beginning of the extraction process. 
Protein interphase formed during extraction process will be hydrolyzed with 1N NaOH (80°C x 
3h), neutralized with 1N HCl and protein content will be measured using BCA (bicinchonic acid) 
protein assay. All mass spectrometric data will be normalized to the total amount of hydrolyzed 
protein determined as described above. 
EOS CER and NS CER will be identified and quantified using a targeted UHPLC-ESI-MS/MS. 
8.9.1.3 Quantification of protein bound ceramides  
Protein bound ceramides are formed from EOS CER and represent a portion of EOS CER without 
linoleic acid and thus having a terminal hydroxy group in N-linked fatty acid. Protein-bound 
ceramides are released from proteins during protein hydrolysis procedure (see above). Therefore, 
after protein determination in hydrolysates, freed omega-OH ceramides will be extracted using 
Bligh and Dyer procedure as described above with the addition of fixed amount of (d7)NS CER to 
ensure ceramide quantitation. Omega hydroxy fatty acid containing ceramides will be detected by 
the UHPLC-ESI-MS/MS as described above using appropriate transitions from corresponding 
molecular ions to the m/z 264, 292, and 320. As most standards of omega hydroxy fatty acid 
containing ceramides are not available, quantitation will be performed against standard curves of 
NS-ceramides. Obtained values will be normalized against protein content in the samples. 
Detailed guidelines and requirements for samples preparation, handling of skin tapes after 
stripping, storage and shipment of such skin tapes will be provided in the study reference manual. 
8.9.2 Proteomics  
Proteomics in skin will be assessed in skin tapes obtained from lesional skin, non-lesional skin 
and normal skin. 
Protein extracts will be prepared from STS samples by LC-MS/MS.  
The following 3 major functional groups of proteins associated with skin barrier function will be 
examined: 


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• Keratin intermediate filaments 
• Proteins associated with inflammatory response (S100 proteins, alarmins, protease 
inhibitors) 
• Glycolysis and oxidative stress response proteins (glycolytic enzymes, oxidative stress 
response enzymes) 
Skin proteomics samples may be stored for a maximum of 5 years following the last participant’s 
last visit in the study at a facility selected by the Sponsor. 
Detailed sample preparation for proteomic analysis will be provided in a separate study reference 
manual. 
8.9.3 Transcriptomics  
Transcriptomics in skin will be assessed in skin tapes obtained from lesional skin, non-lesional 
skin and normal skin. 
Skin tapes will be collected and stabilized in RLT buffer with DTT and stored frozen at -80°C for 
transcriptomic analysis. Skin tape transcriptome samples will be shipped to National Jewish 
Health, where total RNA will be isolated and RNA sequencing will be performed using qualified 
methods (10, 17) to support whole transcriptome analysis and data generation. 
Skin transcriptomics samples and any RNA isolated from the samples may be stored for a 
maximum of 5 years following the last participant’s last visit in the study at a facility selected by 
the Sponsor. 
Transcriptome sample preparation and analysis details will be provided in a separate study 
reference manual. 
8.9.4 Optional samples for biomarker research  
Optional serum and plasma samples for biomarker research that should be collected from 
participants in the study, where possible, are the following: 
• Venous blood samples will be collected at baseline and end of treatment/end of 
observation at Week 16 to obtain serum and plasma to be stored for possible future 
research related to response, disease activity, safety, the Type 2 inflammation pathway, 
and for assessing the effects of the study drug on modulation of IL-4 receptor and on 
atopic disease processes, as well as to study biomarkers that may have predictive utility for 
response to dupilumab treatment. 
• The results of exploratory research testing will not be included in this CSR. 
Details on collection, storage and shipment of these samples will be provided in the study 
reference manual. 
Plasma and serum samples may be stored for a maximum of 5 years following the last 
participant’s last visit for the study at a facility selected by the Sponsor. 


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8.10 
IMMUNOGENICITY ASSESSMENTS  
No antibodies to dupilumab will be evaluated in this study.  
8.11 
HEALTH ECONOMICS  
Not applicable. 


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9 
STATISTICAL CONSIDERATIONS  
The material in Section 9 of the clinical trial protocol constitutes the statistical analysis plan for 
the study. However, biomarkers’ analyses: ie, lipidomics, proteomics, transcriptomics, and 
filaggrin genotyping, will be detailed in a specific statistical analysis plan. If the statistical 
analysis plan in the present document needs revision during the study to provide further details or 
adapt to unexpected issues in study execution and data that affect planned analyses, a statistical 
analysis plan or an appropriate statistical technical document (STD) reflecting the changes will be 
issued prior to database lock or any interim analysis. 
If no major adaptation to the statistical analysis planned in the present document is needed, a STD 
will be issued to document only technical conventions used for the analyses (and minor 
modifications from the planned analyses, if any). 
The following definitions will be used in Section 9: 
• Cohort: the study includes two cohorts: patients with moderate to severe AD cohort and 
healthy volunteers cohort. 
• Group: three groups are identified: patients’ lesional skin area group, patients’ non-
lesional skin area group and healthy volunteers’ normal skin group. 
9.1 
STATISTICAL HYPOTHESES  
No hypothesis testing is predefined in this exploratory study. 
9.2 
SAMPLE SIZE DETERMINATION  
Sample size for this exploratory study was based on medical/clinical judgement and is consistent 
with the sample size from similar studies in the literature (1). No formal sample size calculation 
was performed. TEWL data collected in similar settings as planned for this study were not 
available: ie, TEWL values after 5 skin tape strips, and pre- and post-dupilumab treatment are 
unknown.  
 
Allowing for drop-out rate of 15%, a total of approximately 24 patients with moderate to severe 
AD will be enrolled to achieve 20 evaluable patients: ie, patients with no major or critical 
deviations related to IMP and/or TEWL measurements, for whom the TEWL data for primary 
analysis: ie, TEWL at baseline and Week16, are considered sufficient and interpretable. An 
approximately equal number of age, gender, location of targeted lesion area and site matched 
healthy volunteers serving as a reference comparator cohort will be enrolled. Drop-out rate in 
healthy volunteers is expected to be zero. Any drop-out healthy volunteer for whom the matched 
patient is considered as evaluable will not be replaced.   


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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 3): 
Table 3 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF 
Intent-to-treat (ITT) 
The ITT population includes all enrolled patients, who received at least one dose of 
IMP and all enrolled healthy volunteers who have at least one TEWL/STS 
assessment performed, irrespective of compliance with the study protocol and 
procedures. 
Modified Intent-to-treat (mITT) 
The mITT population includes all ITT participants. If prohibited therapies for AD (see 
Section 6.5.1) are used and assessed by the study team as having a significant 
impact on skin barrier only visits prior to rescue treatment use are considered.   
Efficacy 
The mITT and ITT populations 
Safety 
The safety population includes all patients, who actually received at least one dose 
of IMP or had at least one TEWL/STS assessment and all healthy volunteers who 
have at least one TEWL/STS assessment performed. 
9.4 
STATISTICAL ANALYSES  
9.4.1 Subject description  
9.4.1.1 Disposition of subjects  
A detailed description of participant accountability including count of participants by analysis 
populations (Table 3), screen failure participants with reasons for screen failure, participants who 
did not complete the study observation period along with the main reason for permanent treatment 
discontinuation, and participants who requested permanent treatment discontinuation, will be 
generated by cohorts.   
All withdrawals from the study, taking place on or after study drug intake, will be fully 
documented in the body of the Clinical Study Report (CSR).  
A listing of subjects with treatment discontinuation will be provided. 
A listing of all comments related to IMP compliance and dosing, safety (AEs, vital signs), or other 
comments will be provided by cohorts, participants, visit and examination type in chronological 
order. 
9.4.2 Protocol deviations  
During the review of the database, compliance with the protocol will be examined with regard to 
inclusion and exclusion criteria, treatment compliance, prohibited therapies, and timing and 


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availability of planned assessments. Protocol deviations will be identified by the study team 
before database lock and listed in the Data Review and Surveillance Report, including missing 
data and study drug discontinuations, and classified as critical, major or minor deviations. 
Individual deviations to inclusion and exclusion criteria as reported by the Investigator will be 
listed. 
If any, major and critical deviations other than those involving inclusion/exclusion will be listed 
by participant and/or described in the body of the clinical study report. 
9.4.3 Analysis population  
The number of participants included in each study population (safety population and efficacy 
populations (Intent-to-treat and modified-Intent-to-treat)) will be provided. All exclusion from 
any analysis population will be fully documented in the CSR. 
9.4.4 Demographic and baseline characteristics  
9.4.4.1 Subject demographic characteristics, medical history and diagnoses  
Continuous variables (age, weight) and qualitative variables (gender, race and body mass index 
[BMI]) will be summarized by cohorts, by descriptive statistics (summary tables) for the mITT 
population and for additional population if relevant (eg, if many participants from the mITT 
population are not part of the safety population). 
Specific medical/surgical history will be listed. Other baseline characteristics will be listed. 
Disease characteristics at baseline: ie, clinical and patient reported outcomes, and skin barrier 
function, will be presented along with the on-treatment summary statistics in the efficacy  
Section 9.4.7. 
9.4.4.2 Baseline efficacy parameters  
Baseline is defined as the last available and evaluable value before and closest to the first dose of 
the IMP: ie, at D1 (V02, W0), for patients and as the last available and evaluable value at D1 
(V02, W0) for healthy volunteers. For TEWL data, the average of the values of the 3 spots within 
each predefined skin area will be used as baseline, unless a large difference between the spots is 
observed. 
9.4.4.3 Baseline safety parameters  
Baseline for safety parameters will be defined as the last available and evaluable value before and 
closest to the first dose of IMP for patients and as the last available and evaluable value at D1 
(V02, W0) for healthy volunteers, for vital sign parameters. 
Baseline safety values will be presented along with subsequent safety values assessed during the 
study. 


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9.4.5 Extent of study treatment exposure and compliance  
The extent of study treatment exposure and compliance will be assessed and summarized for 
patients´ cohort within the safety population. 
The following listings will be provided: 
• Patients receiving IMP from specified batch; (patient, drug product batch number, drug 
product) will be sorted by patient. 
9.4.5.1 Extent of investigational medicinal product exposure  
Duration of IMP exposure is defined as: last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations. 
If the patient’s date of last dose is unknown, his/her last IMP dispensing date will be used in its 
place. 
Duration of exposure will be summarized in patients’ cohort using descriptive statistics such as 
mean, standard deviation (SD), median, minimum and maximum. 
9.4.5.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Percentage of compliance for a patient will be defined as the number of administrations the 
patient was compliant divided by the total number of administrations the patient was planned to 
take (the number of doses missed due to interruptions at investigators' judgment will not be 
subtracted) on or before the last IMP administration date.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, mean, SD, median, minimum, and maximum). The percentage of patients with 
compliance <80% will be summarized. In addition, number and percentage of patients with at 
least 1 above-planned dosing administration will be given, as well as the number and percentage 
of patients with 0, (0, 20%], and >20% under-planned dosing administrations. 
9.4.6 Prior/Concomitant medication/Therapy  
Medications will be coded according to the World Health Organization Drug Dictionary (WHO 
Drug Dictionary, last available version before database lock). Concomitant medications with the 
IMP will be listed separately by participants. 


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9.4.7 Efficacy analyses  
The efficacy evaluation will be based upon the review of the individual values (graphics), 
descriptive statistics (summary tables, graphics) and, where applicable, exploratory statistical 
analysis. 
Due to the small sample size and the exploratory characteristics of the study missing or 
incomplete data of efficacy marker will not be imputed. In case an important number of patients 
using rescue therapy is observed, visit values removed due to use of rescue therapy will be 
imputed. The imputation methods applied will be described in an SAP. 
9.4.7.1 Description of efficacy variables  
Efficacy parameters are described in Section 8.2. The derivation of baseline results is described in 
Section 9.4.4.2. 
The analysis of the efficacy marker will be based on the mITT population. As a sensitivity 
analysis, the primary endpoint will also be analyzed based on the ITT population. Secondary 
endpoints analysis might be run on the ITT population as sensitivity analysis in case an important 
number of patients using rescue therapy is observed. 
Sub-analysis might be done for adolescents and adults, if deemed appropriate. 
TEWL data collected at the same visit from without and before STS measurement on each of the 
three spots within the predefined skin areas will be averaged, unless a large difference between 
spots is observed. 
Analysis  
Table 4 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
Percent change from baseline in TEWL after 
5 STS assessed on lesional skin at Week 16 in 
AD patients 
 
 
Raw data and change from baseline; ie, absolute and percentage changes, 
will be summarized with descriptive statistics (such as mean, median, SD, 
minimum, and maximum) based on the mITT and ITT populations. 
Profiles for baseline and Week 16 time points will be generated for 
individual values: eg, spaghetti plot and boxplot, and patients’ cohort 
means. 
For information purpose as study is not powered (no multiplicity correction 
will be applied): 
Difference between baseline and Week 16 values will be tested through 
one-sided paired t-test at a Type 1 error level of alpha=0.05  
(H0: 0 ≤ TEWLWeek16-TEWLbaseline, Ha: 0 > TEWLWeek16-TEWLbaseline).  
Point estimate, two-sided 90% confidence interval and corresponding one-
sided p-value will be reported.  
If assumption of normal distribution is strongly violated, non-parametric 
methods: eg, Wilcoxon signed-rank test, will be used; normality 
assumption will be assessed through quantile-quantile plot and 
Shapiro-Wilk test at 5% Type I error.  


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Endpoint 
Statistical Analysis Methods 
Secondary 
 
Change (percent and absolute) from baseline in 
TEWL after 20 STS assessed on lesional skin at 
Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 20 STS assessed on non-lesional 
skin at Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 20 STS assessed on normal skin at 
Week 16 in HV 
Change (percent and absolute) from baseline in 
TEWL after 15 STS assessed on lesional skin at 
Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 15 STS assessed on non-lesional 
skin at Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 15 STS assessed on normal skin at 
Week 16 in HV 
Change (percent and absolute) from baseline in 
TEWL after 10 STS assessed on lesional skin at 
Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 10 STS assessed on non-lesional 
skin at Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 10 STS assessed on normal skin at 
Week 16 in HV 
Absolute change from baseline in TEWL after 
5 STS assessed on lesional skin at Week 16 in 
AD patients 
Change (percent and absolute) from baseline in 
TEWL after 5 STS assessed on non-lesional skin 
at Week 16 in AD patients 
Change (percent and absolute) from baseline in 
TEWL after 5 STS assessed on normal skin at 
Week 16 in HV 
The similar approach as for the analysis of primary endpoint will be used. 
 
In addition, percentage change relative to the healthy volunteers’ cohort 
will be calculated as a ratio of means by number of STS, at baseline and 
Week 16 for lesional and non-lesional skin groups. 
 


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Endpoint 
Statistical Analysis Methods 
Change (percent and absolute) from baseline in 
TEWL before STS on lesional skin in AD patients 
over time 
Change (percent and absolute) from baseline in 
TEWL before STS on non-lesional skin in AD 
patients over time 
Change (percent and absolute) from baseline in 
TEWL before STS on normal skin in healthy 
volunteers over time 
Change (percent and absolute) from baseline in 
TEWL after STS assessed on lesional skin in AD 
patients over time 
Change (percent and absolute) from baseline in 
TEWL after STS assessed on non-lesional skin 
in AD patients over time 
Change (percent and absolute) from baseline in 
TEWL after STS assessed on normal skin in 
healthy volunteers over time 
 
Raw data and change from baseline; ie, absolute and percentage changes, 
will be summarized with descriptive statistics (such as mean, median, SD, 
minimum, and maximum) by groups, number of STS and time point. 
Profiles over study days will be generated for individual values and group 
means for raw data and absolute change from baseline. 
Percentage change relative to the healthy volunteers’ cohort will be 
calculated as a ratio of means by number of STS and time point for 
lesional and non-lesional skins groups. 
As exploratory analysis time to improvement of skin barrier function for 
lesional and non-lesional skin area measured by TEWL will be 
summarized. Improvement is defined as time to the first post-baseline day 
for which at least one TEWL measure of a patient is equal or lower than 
the median, of the corresponding TEWL measured in his/her matched 
heathy volunteer over time. Results might be reported through Kaplan-
Meier plot. 
 
Change (percent and absolute) in TEWL area 
under the curve (TEWL AUC: a composite 
measure before and after 5, 10, 15 and 20 STS) 
for skin barrier function in lesional skin in AD 
patients over time 
Change (percent and absolute) in TEWL area 
under the curve (TEWL AUC: a composite 
measure before and after 5, 10, 15, and 20 STS) 
for skin barrier function in non-lesional skin in AD 
patients over time 
Change (percent and absolute) in TEWL area 
under the curve (TEWL AUC: a composite 
measure before and after 5, 10, 15, and 20 STS) 
for skin barrier function in normal skin in healthy 
volunteers over time 
 
As all TEWL values are expected to be positive, area under the TEWL 
curve will be calculated using the trapezoidal method over the 10 or 
20 STS (measurement at every five STS) at each visit. 
Raw data and change from baseline; ie, absolute and percentage changes, 
will be summarized with descriptive statistics (such as mean, median, SD, 
minimum, and maximum) by groups and time points. 
Profiles over study days will be generated for individual values and group 
means for raw data and absolute change from baseline. 
Percentage change relative to the healthy volunteers’ cohort will be 
calculated as a ratio of means by time point for lesional and non-lesional 
skins groups. 
As exploratory analysis time to improvement of skin barrier function for 
lesional and non-lesional skin area measured by TEWL AUC will be 
summarized. Improvement is defined as time to the first post-baseline day 
for which TEWL AUC of a patient is equal or lower than the median, of the 
corresponding TEWL AUC computed in his/her matched heathy volunteer 
over time. Results might be reported through Kaplan-Meier plot. 
Tertiary/exploratory 
 
Change (percent and absolute) in lipidomics 
parameters in lesional and non-lesional skin 
including the ratio of EOS CER and NS CER, 
and FLG breakdown products of UCA and PCA 
concentrations at Week 8 and Week 16, 
respectively 
Global characterization of protein-bound 
ceramides over time 
Lipidomics data will be summarized with descriptive statistics. Multivariate 
unsupervised and supervised analyses will be performed as appropriate.  
 


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Endpoint 
Statistical Analysis Methods 
Changes (percent and absolute) in the 
expression of proteins associated with skin 
barrier function including keratin intermediate 
filaments, proteins associated with inflammatory 
response, and glycolysis and oxidative stress 
response proteins in STS protein extracts over 
time. 
Proteomics data will be summarized with descriptive statistics. Multivariate 
unsupervised and supervised analyses will be performed as appropriate. 
Changes in expression of genes associated with 
epidermal differentiation, barrier and lipid 
metabolism, and Type 2 inflammation over time. 
Skin transcriptome phenotype data will be summarized with descriptive 
statistics. Multivariate unsupervised and supervised analyses will be 
performed as appropriate. 
Change (percent and absolute) from baseline in 
EASI over time 
Change (percent and absolute) from baseline in 
SCORAD over time 
Change (percent and absolute) from baseline in 
ISS over time 
Change (percent and absolute) from baseline in 
POEM over time 
Change (percent and absolute) from baseline in 
DLQI in patients 18 years of age and CDLQI in 
patients ≥12 and <18 years of age over time 
Change (percent and absolute) from baseline in 
peak pruritus NRS over time 
Change (percent and absolute) from baseline in 
quality of sleep NRS over time 
Change (percent and absolute) from baseline in 
photograph outputs (eg, severity score) obtained 
from skin imaging over time 
EASI, SCORAD, POEM, DLQI/CDLQI, peak pruritus NRS, and quality of 
sleep NRS, photograph outputs: 
• 
Raw data and change from baseline; ie, absolute and 
percentage changes, will be summarized with descriptive 
statistics (such as mean, median, SD, minimum, and maximum) 
by time points based on patients from mITT population. 
 
• 
Mean plots (mean ± SEM) on raw data and absolute change 
from baseline over time for patients’ cohort will be produced. 
 
ISS: 
• 
Number and percentage of patients by severity will be reported 
by time points based on the patients from mITT population. 
 
• 
Barplot (percentages of patients by severity grade) over time for 
patients’ cohort will be produced. 
 
Correlation between baseline values of TEWL 
before STS and TEWL AUC in lesional and non-
lesional skin of AD patients with the following 
baseline measures: 
• 
Local target lesion erythema and 
edema/papulations; ISS 
• 
EASI, SCORAD 
• 
POEM, DLQI, CDLQI, peak pruritus 
NRS, and quality of sleep NRS 
• 
Lipidomics in STS (ratio of EOS CER 
to NS CER) 
• 
FLG breakdown products of UCA and 
PCA concentrations in STS 
• 
Key components of skin proteomics in 
STS (expression of proteins associated 
with skin barrier function) 
• 
Key components of gene expression 
from transcriptomics 
• 
Image-derived severity score in 
targeted lesional skin 
Scatterplot to visualize the form of the relationship between variables will 
be produced for patients’ cohort at specific time points: ie, baseline,  
Week 8 and Week 16, based on the mITT population. 
 
Pearson correlation will be assessed at each defined time points for EASI, 
SCORAD, POEM, DLQI/CDLQI, peak pruritus NRS, quality of sleep NRS, 
and photograph outputs. Pearson correlation coefficient and p-value will be 
reported.  
 
Spearman’s rank correlation will be assessed at each defined time points 
for ISS. Spearman correlation coefficient and p-value will be reported.  
 
As exploratory analysis repeated measures correlation method might be 
used to assess the overall correlation pooling data from baseline, Week 8 
and Week 16 (34). 


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Endpoint 
Statistical Analysis Methods 
Correlation between percent change from 
baseline in TEWL before STS and TEWL AUC in 
lesional and non-lesional skin of AD patients at 
Week 8 and Week 16 with corresponding change 
from baseline in the following measures: 
• 
Local target lesion erythema and 
edema/papulations; ISS 
• 
EASI, SCORAD 
• 
POEM, DLQI, CDLQI, peak pruritus 
NRS, and quality of sleep NRS 
• 
Lipidomics in STS (ratio of EOS CER 
to NS CER) 
• 
FLG breakdown products of UCA and 
PCA concentrations in STS 
• 
Key components of skin proteomics in 
STS (expression of proteins associated 
with skin barrier function) 
• 
Key components of gene expression 
from transcriptomics 
• 
Image-derived severity score in 
targeted lesional skin 
9.4.8 Safety analyses  
The safety evaluation will be based on the review of vital signs parameters and reported adverse 
events. The safety analysis will be conducted according to the sponsor’s document “Analysis and 
reporting of safety data from Clinical Trials through the Clinical Study Report” (BTD-009536). 
All the safety analyses will be performed using the safety population. When applicable, results 
will be by cohorts and overall. 
9.4.8.1 Adverse events  
9.4.8.1.1 Definitions  
Adverse events will be coded to a “Preferred Term (PT)” and “High Level Group Term (HLGT)”, 
“High Level Term (HLT)” and primary “System Organ Class (SOC)” using the Medical 
Dictionary for Regulatory Activities (MedDRA, version currently in use by the sponsor at the 
time of database lock). 
For patients’ cohort, they will be classified into predefined standard categories according to 
chronological criteria: 
• Pre-treatment AEs: AEs that occurred, worsened or became serious during the pre-
treatment period defined as the time between informed consent signature and the first IMP 
administration. 


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• Treatment emergent AEs (TEAEs): AEs that occurred, worsened or became serious during 
the TEAE period defined as the time from the first IMP administration up to the end of 
treatment visit (EoT included). 
• Post-TEAEs: AEs that occurred, worsened or became serious during the post-TEAE period 
defined as the time starting after the TEAE period. 
TEAEs will be assigned to the treatment received at the time of the AE onset.  
If the onset date (or time) of an AE (occurrence, worsening or becoming serious) is incomplete or 
missing, then the AE will be considered as a TEAE unless a partial date (or time) shows it as a 
pre- or post-treatment event. 
For all healthy volunteers, safety data will be considered as part of a single period starting with 
the signature of the informed consent and ending with the end of study visit (EoS included). 
All AEs reported in the study will be listed, sorted by subject/patient, onset date and time. 
9.4.8.1.2 Treatment-emergent adverse events  
The following TEAEs summaries will be provided for the patients’ cohort of the safety 
population: 
Overview of TEAEs: number and percentage of subjects with any TEAE, any serious TEAE, any 
TEAE leading to death (if any occurred), any TEAE leading to permanent treatment 
discontinuation, and any TEAE of special interest. 
• Summary of TEAEs by primary SOC and PT: 
- 
Number and percentage of patients with at least one TEAE; 
- 
Number of occurrences of TEAEs. 
Patients presenting TEAEs will be listed sorted by primary SOC and PT. By definition, no TEAEs 
summary will be displayed for healthy volunteers. 
AEs that occur outside the treatment emergent period or in heathy volunteers will be summarized 
separately. 
9.4.8.1.3 Deaths, serious, and other significant adverse events  
Any deaths, serious and other significant AEs will be listed. 
9.4.8.1.4 Adverse events leading to treatment discontinuation  
Any AEs leading to permanent treatment discontinuation will be listed. 


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9.4.8.1.5 Adverse events of special interest (AESI)  
Number (%) of subjects experiencing treatment emergent AESI will be presented by AESI 
category and PT, sorted by decreasing incidence of PT within each AESI category. 
9.4.8.2 Vital signs  
Heart rate (HR), systolic and diastolic blood pressures (SBP and DBP), body temperature and 
respiratory rate will be analyzed as raw parameter value and change from baseline. 
Body weight will be analyzed as raw parameter value and percent change from baseline. BMI will 
be analyzed as raw parameter value. 
Baseline definition 
The values to be used as baselines will be the D1 (V02, W0) predose assessment. If any of the 
scheduled baseline tests are repeated for any subject/patients, the last rechecked values will be 
considered as baselines, provided, for patients, they were done before the IMP administration of 
the respective treatment phase, and in the same condition.  
Abnormalities analyses 
For vital sign parameters, analysis will be performed using all post-baseline assessments done 
during the TEAE period/safety period, including all unplanned and rechecked values. Counts of 
subjects with Potentially Clinically Significant Abnormality (PCSAs) will be presented by cohort, 
regardless of the baseline status. PCSA values are defined as abnormal values considered 
medically important by the sponsor according to predefined criteria/thresholds based on literature 
review and defined by the sponsor. 
A listing of individual data from subjects/patients with post-baseline PCSAs will be provided; 
values will be flagged when reaching the PCSA criteria. 
Descriptive statistics and plots 
For heart rate, blood pressures, body temperature and respiratory rate, raw data and absolute 
changes from baseline will be summarized in descriptive statistics (such as mean, median, SD, 
minimum, and maximum) for patients’ cohort and scheduled time of measurement.  
For body weight, raw data and percent change from baseline will be summarized in descriptive 
statistics (such as mean, median, SD, minimum, and maximum) by cohort and scheduled time of 
measurement. 
9.5 
INTERIM ANALYSES  
A data quality control interim analysis for data quality purposes will be conducted after 
10 patients are included and have completed the TEWL assessments at Day 1.  


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As it is an open-label study with no predefined hypothesis testing there is no issue regarding 
blinding or multiplicity adjustment.  
The interim analysis will be performed using the safety population for safety parameters, the 
mITT and ITT populations for TEWL parameters. Only primary and secondary objectives for 
which data are available will be analyzed as described in Section 9. 
9.6 
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD  
No DMC or other review board is planned for this study. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is 
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, and has analytical validity, and has clinical validity.  
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 


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- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial  that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told that 


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they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period.  
A separate consent will be required to document a participant's agreement to allow any remaining 
specimens to be used for exploratory research. Participants who decline to participate in this 
optional research will not provide this separate consent. 
A separate consent will be required to document a participant's agreement to allow publication of 
photos taken during the study. Participants who decline to agree to publication of photos taken 
during the study will not provide this separate consent. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (General Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because TEWL may be influenced by 
ethnicity (35) and could therefore substantially influence the results of this study. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 


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websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials.   Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com.  
10.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  


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10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the study reference manual. 
10.1.8 Study and site start and closure  
The signature of the informed consent by the first participant is considered the first act of 
recruitment and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 


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10.1.9 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• Pregnancy testing 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
Table 5 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Urine pregnancy test 
Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)a 
NOTES : 
a Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 


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Events meeting the AE definition 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE.” 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 


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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 


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other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested. In 
this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 


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• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report. However, it is very important that the 
Investigator always makes an assessment of causality for every event before the 
initial transmission of the SAE data. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 


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• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor by telephone. 
• Contacts for SAE reporting can be found in the study reference manual. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 


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CONTRACEPTION GUIDANCE: 
Recommended contraceptive methods are listed below in Table 6. 
Table 6 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
- 
oral 
- 
injectable 
Highly effective methods that are user independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not and less than 1 year after 
vasectomy, additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days.) 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies. 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive dupilumab. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 


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delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.4.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
• For all participants, a blood sample will be collected for mandatory filaggrin gene 
sequencing analysis.  
• For participants, who consent to optional genetic research, a DNA sample will be stored 
for broad genetic analysis, which may include, but is not limited to, whole genome or 
exome sequencing.  


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• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to dupilumab or study interventions of this class to understand 
study disease or related conditions.  
• The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples will be retained while research on dupilumab or study interventions of this 
class continues but no longer than 15 years or other period as per local requirements. 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.7 
APPENDIX 7: ABBREVIATIONS  
 
AD: 
atopic dermatitis  
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine transaminase 
AUC: 
area under the curve 
CDLQI: 
children dermatology life quality index 
CER: 
ceramides 
DLQI: 
dermatology life quality index 
EASI: 
eczema area and severity index 
EOS: 
E for esterified / O for omega-hydroxy / S for sphingosin 
EOS CER: 
highly hydrophobic omega-esterified fatty acid sphingosine ceramides 
EoT: 
end of treatment phase 
FLG: 
filaggrin 
ICF: 
informed consent form 
IGA: 
investigator global assessment 
IL: 
interleukin 
IMP: 
investigational medical product 
ISS: 
Individual Signs Score 
ITT: 
intent-to-treat 
LC-MS/MS: 
liqulid chromatography with tandem mass spectrometry 
mITT: 
modified intent-to-treat 
MKI67: 
antigen ki-67 
NRS: 
numerical rating scale 
NS: 
non-hydroxy fatty acid sphingosine  
NS CER: 
non-hydroxy fatty acid sphingosine ceramides 
PCA: 
pyroglutamic acid, also pyrrolidone carboxylic acid 
POEM: 
patient oriented eczema measure 


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PRO: 
patient reported outcomes 
Q2W: 
every second week 
QOL: 
quality of life 
SAE: 
serious adverse event 
SC: 
subcutaneous  
SCORAD: 
SCORing atopic dermatitis 
STS: 
skin tape stripping  
TEWL: 
transepidermal water loss 
UCA: 
urocanic acid 
ULN: 
upper limit of normal 
 


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11 
REFERENCES  
1. Danby SG, Al-Enezi T, Sultan A, Chittock J, Kennedy K, Cork MJ. The effect of aqueous 
cream BP on the skin barrier in volunteers with a previous history of atopic dermatitis. Br J 
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2. Macdonald LE, Karow M, Stevens S, Auerbach W, Poueymirou WT, Yasenchak J, et al. 
Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl 
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3. Murphy AJ, Macdonald LE, Stevens E, Karow M, Dore AT, Pobursky K, et al. Mice with 
megabase humanization of their immunoglobulin genes generate antibodies as efficiently as 
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proximal drivers in type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15:35-50. 
5. Guttman-Yassky E, Bissonnette R, Ungar B, Suárez-Farinas M, Ardeleanu M, Esaki H, et al. 
Dupilumab progressively improves systemic and cutaneous abnormalities in patients with 
atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155-72. 
6. Hamilton JD, Suárez-Farinas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab 
improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. 
J Allergy Clinical Immunol. 2014;134(6):1293-300. 
7. Alexander H, Brown S, Danby S, Flohr C. Research techniques made simple: transepidermal  
water loss measurement as a research tool. J Invest Dermatol. 2018;138(11):2295-300. 
8. Akdeniz M, Gabriel S, Lichterfeld-Kottner A, Blume-Peytavi U, Kottner J. Transepidermal 
water loss in healthy adults: a systematic review and meta‐analysis update. Br J Dermatol. 
2018;179(5):1049-55. 
9. Kottner J, Lichterfeld A, Blume-Peytavi U. Transepidermal water loss in young and aged 
healthy humans: a systematic review and meta-analysis. Arch Dermatol Res. 2013;305:315-
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10. Dyjack N, Goleva E, Rios C, Kim BE, Bin L, Taylor P, et al. Minimally invasive skin tape 
strip RNA sequencing identifies novel characteristics of type 2-high atopic dermatitis disease 
endotype. J Allergy Clin Immunol. 2018;141(4):1298-309. 
11. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its 
reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 
2017;139(4S):S65-S76. 
12. Berdyshev E, Goleva E, Bronova I, Dyjack N, Rios C, Jung J, et al. Lipid abnormalities in 
atopic skin are driven by type 2 cytokines. JCI Insight. 2018;3(4):e98006. 


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13. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic 
diseases. N Engl J Med. 2011;365(14):1315-27. 
14. Goleva E, Berdyshev F, Leung DY. Epithelial barrier repair and prevention of allergy. J Clin 
Invest. 2019;129(4):1463-74. 
15. Feingold KR, Elias PM. The important role of lipids in the epidermis and their role in the 
formation and maintenance of the cutaneous barrier. Biochim Biophys Acta. 2014;1841:279-
94. 
16. Li S, Ganguli-Indra G, Indra AK. Lipidomic analysis of epidermal lipids: a tool to predict 
progression of inflammatory skin disease in humans. Expert Rev Proteomics. 2016;13:451-6. 
17. Leung DYM, Calatroni A, Zaramela LS, LeBeau PK, Dyjack N, Brar K, et al.The nonlesional 
skin surface distinguishes atopic dermatitis with food allergy as a unique endotype. Sci Transl 
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18. Fluhr JW, Feingold KR, Elias PM. Transepidermal water loss reflects permeability barrier 
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19. Elias PM. Skin barrier function. Curr Allergy Asthma Rep. 2008;8:299-305. 
20. Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, et al. Filaggrin loss-
of-function mutations are associated with early-onset eczema, eczema severity and 
transepidermal water loss at 3 months of age. Br J Dermatol. 2010;163:1333-6. 
21. Simpson EL, Villarreal M, Jepson B, Rafaels N, David G, Hanifin J, et al. Patients with atopic 
dermatitis colonized with staphylococcus aureus have a distinct phenotype and endotype. J 
Invest dermatol. 2018;138:2224-33. 
22. Chamlin SL, Frieden IJ, Fowler A, Williams M, Kao J, Sheu M, et al. Ceramide-dominant 
barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a 
sensitive indicator of disease activity. J Am Acad Dermatol. 2002;47:198-208. 
23. Flohr C, Perkin M, Logan K, Marrs T, Radulovic S, Campbell LE, et al. Atopic dermatitis and 
disease severity are the main risk factors for food sensitization in exclusively breastfed infants. 
J Invest Dermatol. 2014;134:345-50. 
24. Clausen ML, Slotved HC, Krogfelt KA, Agner T. Tape stripping technique for stratum 
corneum protein analysis. Sci Rep. 2016;28:6:19918.  
25. Koppes SA, Brans R, Ljubojevic Hadzavdic S, Frings-Drese MH, Rustemeyer T, Kezic S. 
Stratum corneum tape stripping: Monitoring of inflammatory mediators in atopic dermatitis 
patients using topical therapy. Int Arch Allergy Immunol. 2016;170:187-93. 


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26. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10(1):11-8. 
27. Consensus Report of the European Task Force on Atopic Dermatitis. Severity Scoring of 
Atopic Dermatitis: The SCORAD Index. Dermatology. 1993;186:23-31. 
28. Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and 
initial validation of a new tool for measuing atopic dermatitis severity from the patients' 
perspective. Arch Dermatol. 2004;140:1513-9. 
29. Badia X, Mascaró JM, Lozano R. Measuring health-related quality of life in patients with mild 
to moderate eczema and psoriasis: clinical validity, realiability and sensitivity to change of the 
DLQI. The Cavide Research Group. Br J Dermatol. 1999;141(4):698-702. 
30. Lewis-Jones MS, Finlay AY. The children's dermatology life quality index (CDLQI): initial 
validation and practical use. Br J Dermatol. 1995;132:942-9. 
31. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic 
diseases. N Eng J Med. 2011;365:1315-27. 
32. Vávrová K, Henkes D, Strüver K, Sochorová M, Školová B, Witting MY, et al. Filaggrin 
deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin 
construct. J Invest Dermatol. 2014;134:746-53. 
33. Gruber R, Elias PM, Crumrine D, Lin TK, Brandner JM, Hachem JP, et al. Filaggrin genotype 
in ichthyosis vulgaris predicts abnormalities in epidermal structure and function.Am J Pathol. 
2011;178:2252-63. 
34. Bakdash JZ, Marusich LR. Repeated measures correlation. Front Psychol. 2017;8:456. 
35. Voegeli R, Rawlings AV, Seroul P, Summers B. A novel continuous colour mapping 
approach for visualization of facial skin hydration and transepidermal water loss for four 
ethnic groups. Int J Cosmetic Sci. 2015;37:595-605.  


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Page 1 
STATISTICAL TECHNICAL DOCUMENT 
SAR231893/REGN668 - LPS15991 
Open label exploratory study to evaluate the effect of dupilumab on skin barrier 
function in patients with moderate to severe atopic dermatitis 
STATISTICIAN: 
 
DATE OF ISSUE: 06-Jul-2021 
Total number of pages: 10 
NCT04447417


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TABLE OF CONTENTS 
STATISTICAL TECHNICAL DOCUMENT ..................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 3 
1 
STATISTICAL AND ANALYTICAL PROCEDURES ...................................................................... 4 
1.1 
INTRODUCTION .............................................................................................................................. 4 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL ............................ 4 
1.3 
DATA HANDLING CONVENTIONS ................................................................................................ 5 
2 
SOFTWARE DOCUMENTATION ................................................................................................... 7 
3 
LIST OF APPENDICES ................................................................................................................... 8 
3.1 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA – ADULT 
HEALTHY VOLUNTEERS ............................................................................................................... 8 
3.2 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALISTIES CRITERIA – ADULT 
ATOPIC DERMATITIS PATIENTS .................................................................................................. 8 
3.3 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA – MINOR 
PARTICIPANTS ............................................................................................................................... 9 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AD: 
atopic dermatits 
GISS: 
global individual signs score 
HV: 
healthy volunteer 
ISS: 
individual signs score 
MedDRA: 
medical dictionary for regulatory activities 
mITT: 
modified-Intent-to-treat 
SD: 
standard deviation 
STS: 
skin tape stripping 
TEAE: 
treatment-emergent adverse event 
TEWL: 
transepidermal water loss 
WHO-DD: 
World Health Organization Drug Dictionnary 
 


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1 
STATISTICAL AND ANALYTICAL PROCEDURES  
1.1 
INTRODUCTION  
The purpose of this document is to provide additional technical details. 
A comprehensive and detailed description of strategy and statistical technique used to perform the 
analysis of data was provided in Section 9 of the protocol (amendment 01, dated 28-Jul-2020). 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA version 24.0). 
Previous and concomitant medication records will be coded according to the World Health 
Organization Drug Dictionary (WHO-DD version March 2021).  
The definitions of potentially clinical significant abnormalities (PCSA list, BTD-009536 Version 
3.0, dated 24 May 2014) used in the statistical analysis of vital signs are provided in Section 3.1 
(for adult healthy volunteers), Section 3.2 (for adult atopic dermatitis patients) and Section 3.3 
(for minor participants). 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL  
This section describes the modifications and additional statistical analyses from the protocol.  
Due to unbalance between adults and adolescents atopic dermatitis (AD) patients, analyses based 
on age group (adult/adolescent) will only be performed for adverse event (AE) data reporting. 
The study objectives are exploratory. Sample size was not based on power requirements. No 
multiplicity correction will be used for the tests performed as part of the statistical analyses. 
Analysis population 
Any participant with major deviation impacting assessment of efficacy data (except for deviations 
concerning AD related prohibited therapy administration) will be excluded for the modified-
Intent-to-treat (mITT) population.  
Demographic and medication data 
Descriptive statistics for disease duration since AD diagnostic will be provided by cohort and age 
group (adults/adolescents).  
Medications (including rescue medications) administered during the follow-up period will be 
summarized, in addition to previous and concomitant medications.  
Efficacy analysis 
Change from baseline in TEWL data is defined as change versus Day 1 TEWL data at matched 
number of STS samples (eg, TEWL after 5 STS at Week 16 will be compared to TEWL after 
5 STS at Day 1). 


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Individual Signs Score (ISS) questionnaire was not done as planned per protocol. Instead, to 
assess lesion severity locally, Quantificare evaluation data will be used. Global Individual Signs 
Score (GISS) was evaluated during the study. Both Quantificare data and GISS data will be 
analyzed using descriptive statistics for raw data, absolute and percent by timepoints. For AD 
patients, on mITT population, correlation with TEWL data will be evaluated. Scatterplots will be 
provided to visualize the form of the relationship and Spearman’s rank correlation coefficient as 
well as p-values at specific timepoints (Baseline, Week 8 and Week 16) will be provided. 
Adverse event data 
All summary of AEs will be provided by cohort and age group. 
1.3 
DATA HANDLING CONVENTIONS  
This section describes the rules and conventions used in the presentation and analysis of data.  
In the statistical appendices and in-text tables, the following cohort label and group label will be 
used: 
• Cohort label: 
- 
AD patients 
- 
Healthy volunteers 
• Group label: 
- 
AD patients – lesional skin 
- 
AD patients – non-lesional skin 
- 
HV – healthy skin 
For parameters with evaluations before administration and in cases of rechecked value(s) for 
one subject, only the last observation will be used as baseline in descriptive statistics and 
derivations of other parameter values. After baseline, only observations planned in the protocol 
will be used in descriptive statistics. 
If not otherwise stated in the statistical section of the protocol: 
• 
Missing TEWL data (including data from visits excluded of the efficacy analyses after the 
use of prohibited medication) will be imputed using Last Observation Carried Forward 
(LOCF) imputation ; sensitivity analyses will be performed to assess the precision of 
LOCF imputation versus MMRM imputation. 
• 
Descriptive statistics for quantitative parameters will be provided using number of 
observations (N), mean, standard deviation (SD), standard error of the mean (SEM), 
minimum, maximum and median.  
• 
Descriptive statistics for qualitative parameters will be provided using frequencies (N) and 
percent (%). 


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Handling missing data for adverse events 
In case of missing or inconsistent information on the time of onset, an AE will be counted as a 
treatment-emergent adverse event (TEAE) unless it can clearly be ruled out that it is not a TEAE 
(eg, by partial dates or other information). 
 


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2 
SOFTWARE DOCUMENTATION  
The analysis of clinical data will be performed under the responsibility of Sanofi Biostatistics 
Department, using SAS® (SAS Institute, NC USA).  
 


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3 
LIST OF APPENDICES  
3.1 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA – ADULT 
HEALTHY VOLUNTEERS  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in healthy subjects only 
Parameter 
PCSA 
Comments 
Vital signs 
 
 
HR 
≤40 bpm and decrease from baseline ≥20 bpm 
≥100 bpm and increase from baseline ≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20 mmHg 
≥140 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥90 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic Hypotension 
Orthostatic SBP 
Orthostatic DBP 
 
≤-20 mmHg 
≤-10 mmHg 
- 
Weight 
≥5% increase from baseline 
≥5% decrease from baseline 
FDA Feb 2007. 
3.2 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALISTIES CRITERIA – ADULT 
ATOPIC DERMATITIS PATIENTS  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20 mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
 


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3.3 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA – MINOR PARTICIPANTS  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Vital Signs 
Ref. : Kidney Disease Outcomes Quality Initiatives 
(KDOQI) Guideline 13; 1996; The fourth report on 
the diagnosis, evaluation, and treatment of high 
blood pressure in children and adolescents, 
Pediatrics 2004; Bowman E & Fraser S Neonatal 
Handbook 2012;  Mulberg AE et al. Pediatric Drug 
Development Concepts and applications. John 
Wiley & sons, Inc. 2009; Pediatric respiratory rates 
http://www.health.ny.gov/ 
SBP  
 
Birth/0 to 27 days old (Neonates) 
60 mmHg and decrease from baseline 20 mmHg  
85 mHg and increase from baseline 20 mmHg 
Based on definition of Hypertension as average 
SBP or DBP ≥95th percentile for gender, age, and 
height on ≥3 occasions 
28 days/1 month to 23 months old (Infants) 
70 mmHg and decrease from baseline 20 mmHg  
98 mmHg and increase from baseline 20 mmHg 
24 months/2 years to <6 years old (Children) 
70 mmHg and decrease from baseline 20 mmHg  
101 mHg and increase from baseline 20 mmHg 
6 to <12 years old (Children) 
80 mmHg and decrease from baseline 20 mmHg  
108 mmHg and increase from baseline 20 mmHg 
12 to 16/18 years old (Adolescents) 
90 mmHg and decrease from baseline 20 mmHg  
119 mmHg and increase from baseline 20 mmHg 
DBP 
  
 
Birth/0 to 27 days old (Neonates) 
34 mmHg and decrease from baseline 10 mmHg  
50 mHg and increase from baseline 10 mmHg 
 
28 days/1 month to 23 months old (Infants) 
34 mmHg and decrease from baseline 10 mmHg  
54 mHg and increase from baseline 10 mmHg 


Statistical Technical Document  
06-Jul-2021 
SAR231893/REGN668 - LPS15991 - dupilumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 10 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
24 months/2 years to <6 years old (Children) 
34 mmHg and decrease from baseline 10 mmHg  
59 mHg and increase from baseline 10 mmHg  
6 to <12 years old (Children) 
48 mmHg and decrease from baseline 10 mmHg  
72 mHg and increase from baseline 10 mmHg  
12 to 16/18 years old (Adolescents) 
54 mmHg and decrease from baseline 10 mmHg  
78 mHg and increase from baseline 10 mmHg  
Orthostatic 
hypotension 
All age ranges 
SBP: St — Su ≤- 20 mmHg  
DBP: St — Su ≤- 10 mmHg  
 
Temperature 
All age ranges 
Rectal, ear or temporal artery: >100.4 °F/38.0 °C 
Oral or pacifier: >99.5 °F/37.5 °C 
Axillary or skin infrared: >99 °F/37.2 °C 
Ear temperature not accurate below 6 months of 
age 
Respiratory rate 
Birth/0 to 27 days old (Neonates) 
<30 per minutes  
>60 per minutes 
Based on normal range 
 
28 days/1 month to 23 months old (Infants) 
<24 per minutes  
>40 per minutes 
24 months/2 years to <6 years old (Children) 
<22 per minutes  
>34 per minutes 
6 to <12 years old (Children) 
<18 per minutes  
>30 per minutes 
12 to 16/18 years old (Adolescents) 
<12 per minutes  
>20 per minutes 
Sa02 
All age ranges 
<95 % 
 
Weight 
All ranges 
>5 % weight loss from baseline 
 
Based on identification of trends in the child’s 
growth with a series of visits 
WHO Multicentre Reference Study Group, 2006; 
Center for Disease Control. Growth chart 2007