Conditions: Dermatitis Atopic
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
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 predefined lesional skin in pediatric 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 predefined lesional and non-lesional skin in pediatric participants with moderate to severe AD treated with dupilumab in reference to normal skin of healthy volunteers.
* Evaluate time course of change in skin barrier function with TEWL assessed before and after STS in predefined lesional and non-lesional skin in pediatric participants with moderate to severe AD during dupilumab treatment phase and follow-up period in reference to normal skin of healthy volunteers.

Detailed description:
Total study duration including screening and follow-up was 32 weeks.

Arms:
arm 1: Pediatric participants with moderate-to-severe atopic dermatitis (AD) and with baseline body weight more than or equal to (\>=) 15 kilograms (kg) and less than (\<) 30 kg received a subcutaneous (SC) loading dose of dupilumab 600 milligrams (mg) (2 injections of dupilumab 300 mg) on Day 1 (Week 0) followed by dupilumab 300 mg SC injection every 4 weeks (Q4W), from Week 4 to Week 12. Pediatric participants with body weight \>=30 kg and \<60 kg received SC loading dose of dupilumab 400 mg (2 injections of dupilumab 200 mg) on Day 1 (Week 0), followed by dupilumab 200 mg SC injection every 2 weeks (Q2W), from Week 2 to Week 14. arm 2: Healthy volunteers with age, gender, location of targeted skin lesion area and study site matched to selected AD participants, received no treatment, but were monitored in a similar way as AD participants.

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

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ....................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
1 
PROTOCOL SUMMARY ................................................................................................................. 8 
1.1 
SYNOPSIS ....................................................................................................................................... 8 
1.2 
SCHEMA ........................................................................................................................................ 17 
1.3 
SCHEDULE OF ACTIVITIES/AD PEDIATRIC PATIENTS ............................................................ 18 
1.4 
SCHEDULE OF ACTIVITIES/HEALTHY VOLUNTEERS.............................................................. 22 
2 
INTRODUCTION ............................................................................................................................ 25 
2.1 
STUDY RATIONALE...................................................................................................................... 25 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
2.3.1 
Risk assessment ............................................................................................................................ 28 
2.3.2 
Benefit assessment ........................................................................................................................ 29 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 30 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 31 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 34 
4 
STUDY DESIGN ............................................................................................................................ 35 
4.1 
OVERALL DESIGN ........................................................................................................................ 35 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 35 
4.2.1 
Participant input into design ........................................................................................................... 36 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 36 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 36 
5 
STUDY POPULATION .................................................................................................................. 37 
5.1 
INCLUSION CRITERIA .................................................................................................................. 37 
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5.2 
EXCLUSION CRITERIA ................................................................................................................ 38 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 41 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 41 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 41 
5.3.3 
Activity ............................................................................................................................................ 41 
5.4 
SCREEN FAILURES...................................................................................................................... 41 
6 
STUDY INTERVENTION ............................................................................................................... 42 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 42 
6.1.1 
Devices .......................................................................................................................................... 43 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 43 
6.2.1 
Storage and handling ..................................................................................................................... 43 
6.2.2 
Responsibilities .............................................................................................................................. 44 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 44 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 45 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 45 
6.5.1 
Rescue medicine ............................................................................................................................ 46 
6.5.1.1 
Prohibited medications and procedures......................................................................................... 46 
6.5.1.2 
Permitted medications.................................................................................................................... 47 
6.6 
DOSE MODIFICATION .................................................................................................................. 47 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 47 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 48 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 48 
7.1.1 
Definitive discontinuation ............................................................................................................... 48 
7.1.2 
Temporary discontinuation ............................................................................................................. 48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 48 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 50 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 51 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 52 
8.1.1 
Transepidermal water loss assessment and skin tape stripping ................................................... 52 
8.1.1.1 
Transepidermal water loss assessment......................................................................................... 52 
8.1.1.2 
Skin tape stripping and collection of skin tapes ............................................................................. 52 
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8.1.2 
Standardized photographs ............................................................................................................. 56 
8.1.3 
Clinician-reported outcome assessments (ClinROs) and patient reported outcome 
assessments (PROs) ..................................................................................................................... 57 
8.1.4 
Eczema area and severity index (EASI) ........................................................................................ 57 
8.1.5 
Individual signs score ..................................................................................................................... 57 
8.1.6 
Worst itch numerical rating scale ................................................................................................... 58 
8.1.7 
Sleep disturbance numerical rating scale ...................................................................................... 58 
8.1.8 
Skin pain numerical rating scale .................................................................................................... 58 
8.1.9 
Patient oriented eczema measure (POEM) ................................................................................... 58 
8.1.10 
Children's dermatology life quality index (CDLQI) ......................................................................... 59 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 59 
8.2.1 
Physical examinations ................................................................................................................... 59 
8.2.2 
Vital signs ....................................................................................................................................... 59 
8.2.3 
Laboratory testing .......................................................................................................................... 59 
8.2.4 
Electrocardiograms ........................................................................................................................ 59 
8.2.5 
Clinical safety laboratory assessments .......................................................................................... 60 
8.2.6 
Suicidal ideation and behavior risk monitoring .............................................................................. 60 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 60 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 60 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 60 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 61 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 61 
8.3.5 
Pregnancy ...................................................................................................................................... 61 
8.3.6 
Cardiovascular and death events .................................................................................................. 62 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 62 
8.3.8 
Adverse event of special interest ................................................................................................... 62 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 63 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 63 
8.5 
PHARMACOKINETICS .................................................................................................................. 64 
8.6 
PHARMACODYNAMICS ............................................................................................................... 64 
8.7 
GENETICS ..................................................................................................................................... 64 
8.8 
BIOMARKERS ............................................................................................................................... 64 
8.8.1 
Lipidomics assessment .................................................................................................................. 64 
8.8.1.1 
Filaggrin breakdown products ........................................................................................................ 65 
8.8.1.2 
Analysis of stratum corneum lipids ................................................................................................ 65 
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8.8.1.3 
Quantification of protein bound ceramides .................................................................................... 65 
8.8.2 
Proteomics assessment ................................................................................................................. 66 
8.8.3 
Skin tape transcriptome ................................................................................................................. 66 
8.8.4 
Optical coherence tomography (OCT) ........................................................................................... 66 
8.8.5 
Attenuated total reflectance (ATR) Fourier-transform infrared (FTIR) spectroscopy .................... 67 
8.8.6 
Optional samples for biomarker research ...................................................................................... 68 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 68 
8.10 
HEALTH ECONOMICS .................................................................................................................. 68 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 69 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 69 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 69 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 70 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 70 
9.4.1 
Subject description ......................................................................................................................... 70 
9.4.1.1 
Disposition of subjects ................................................................................................................... 70 
9.4.2 
Protocol deviations ......................................................................................................................... 70 
9.4.3 
Analysis population ........................................................................................................................ 71 
9.4.4 
Demographic and baseline characteristics .................................................................................... 71 
9.4.4.1 
Subject demographic characteristics, medical history, and diagnoses ......................................... 71 
9.4.4.2 
Baseline efficacy parameters ......................................................................................................... 71 
9.4.4.3 
Baseline safety parameters ........................................................................................................... 71 
9.4.5 
Extent of study treatment exposure and compliance ..................................................................... 72 
9.4.5.1 
Extent of investigational medicinal product exposure .................................................................... 72 
9.4.5.2 
Compliance .................................................................................................................................... 72 
9.4.6 
Prior/Concomitant medication/therapy ........................................................................................... 72 
9.4.7 
Efficacy analyses ........................................................................................................................... 73 
9.4.7.1 
Description of efficacy variable(s) .................................................................................................. 73 
9.4.8 
Safety analyses .............................................................................................................................. 77 
9.4.8.1 
Adverse events .............................................................................................................................. 77 
9.4.8.2 
Vital signs ....................................................................................................................................... 79 
9.5 
INTERIM ANALYSES .................................................................................................................... 79 
9.6 
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD ................................. 80 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 81 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 81 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 81 
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10.1.2 
Financial disclosure........................................................................................................................ 82 
10.1.3 
Informed consent process .............................................................................................................. 82 
10.1.4 
Data protection ............................................................................................................................... 83 
10.1.5 
Dissemination of clinical study data ............................................................................................... 83 
10.1.6 
Data quality assurance .................................................................................................................. 84 
10.1.7 
Source documents ......................................................................................................................... 85 
10.1.8 
Study and site start and closure ..................................................................................................... 85 
10.1.9 
Publication policy ........................................................................................................................... 86 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 86 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 86 
10.3.1 
Definition of AE .............................................................................................................................. 86 
10.3.2 
Definition of SAE ............................................................................................................................ 88 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 89 
10.3.4 
Reporting of SAEs.......................................................................................................................... 90 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 91 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 93 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 93 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................... 93 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY .................................................................. 95 
11 
REFERENCES ............................................................................................................................... 96 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 31 
Table 2 - Overview of study interventions administered ............................................................................... 42 
Table 3 - Populations for analyses ................................................................................................................ 70 
Table 4 - Efficacy analyses ........................................................................................................................... 73 
Table 5 - Protocol-required laboratory assessments .................................................................................... 86 
Table 6 - Highly effective contraceptive methods ......................................................................................... 91 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 17 
Figure 2 - Example of selection of skin spots within lesional and non-lesional/healthy skin ........................ 53 
Figure 3 - TEWL assessment and STS in lesional skin of AD patients ........................................................ 54 
Figure 4 - TEWL assessment and STS in non-lesional skin of AD patients and in normal skin of 
healthy volunteers ......................................................................................................................................... 55 
Figure 5 - STS assessment in 3 spots within the predefined lesional and non-lesional skin area in AD 
patients and in normal skin area in healthy children ..................................................................................... 56 
Figure 6 - OCT and FTIR assessments in lesional and non-lesional skin of AD patients and in normal 
skin of healthy volunteers .............................................................................................................................. 67 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Open-label exploratory study to evaluate the effect of dupilumab on skin barrier 
function in pediatric patients with moderate-to-severe atopic dermatitis. 
Short title: 
Dupilumab-PEdiatric skin barrier function and LIpidomics STudy in patients with 
Atopic Dermatitis - PELISTAD 
Rationale: 
There is a growing body of literature to suggest that patients with early-onset atopic dermatitis 
(AD) have a higher risk of developing other Type 2 comorbidities (the atopic march). The early 
optimal and successful treatment of AD may prevent or attenuate the development other atopic 
conditions (1, 2). Literature indicates that samples acquired using a non-invasive skin tape 
stripping (STS) can be reliably used for analyzing transepidermal water loss (TEWL), TEWL area 
under the curve (AUC) responses, lipidomics, filaggrin (FLG) breakdown products, proteomics, 
and transcriptomics. Results from these analyses demonstrated that children with AD pediatric 
and food allergy exhibit elevated epidermal barrier defects even in non-lesional skin (3). The 
proposed study will evaluate the effect of dupilumab treatment on the skin barrier in a pediatric 
population with early-onset moderate-to-severe AD using non-invasive methodologies such as 
TEWL, STS for skin barrier function assessment, Optical Coherence Tomography (OCT), and 
Fourier-Transform Infrared (FTIR) spectroscopy for skin barrier structure evaluation. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Evaluate changes in skin barrier function with 
transepidermal water loss (TEWL) assessed after skin 
tape stripping (STS) in predefined lesional skin in 
pediatric 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 Week 16 in AD 
patients. 
Secondary 
• 
Evaluate changes in skin barrier function with TEWL 
assessed after STS in predefined lesional and 
non-lesional skin in pediatric 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 
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 healthy volunteers. 
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Objectives 
Endpoints 
• 
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 healthy volunteers. 
• 
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 healthy volunteers. 
• 
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 healthy volunteers. 
• 
Evaluate time course of change in skin barrier function 
with TEWL assessed before and after STS in 
predefined lesional and non-lesional skin in pediatric 
patients with moderate-to-severe AD during dupilumab 
treatment phase and follow-up period in reference to 
normal skin of healthy volunteers. 
• 
Change (percent and absolute) in TEWL before 
STS on lesional skin in AD patients over time. 
• 
Change (percent and absolute) in TEWL before 
STS on non-lesional skin in AD patients over time. 
• 
Change (percent and absolute) 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) in TEWL after STS 
assessed on lesional skin in AD patients over time. 
• 
Change (percent and absolute) in TEWL after STS 
assessed on non-lesional skin in AD patients over 
time. 
• 
Change (percent and absolute) 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 predefined lesional and 
non-lesional skin in pediatric patients with moderate-to-
severe AD during dupilumab treatment phase and 
follow-up period 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 
omega-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 over time. 
• 
Global characterization of protein-bound CER over 
time. 
• 
Evaluate dupilumab treatment effect on skin 
proteomics using STS samples in both predefined 
lesional and non-lesional skin in pediatric patients with 
moderate-to-severe AD during dupilumab treatment 
phase and follow-up period 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 epidermal 
hypertrophy and structure of skin barrier changes 
measured by Optical Coherence Tomography (OCT) 
and Fourier-Transform Infrared (FTIR) spectroscopy in 
both predefined lesional and non-lesional skin in 
pediatric patients with moderate-to-severe AD during 
dupilumab treatment phase and follow-up period in 
reference to normal skin of healthy volunteers. 
• 
Change (percent and absolute) in epidermal 
hypertrophy parameters including epidermal 
thickness (µm), superficial plexus depth (µm), blood 
vessel diameter (µm) and density (segments/mm2) 
measured by OCT over time. 
• 
Change (percent and absolute) in stratum corneum 
lipid structure measured by FTIR spectroscopy in 
conjunction with tape-stripping over time. 
• 
Evaluate dupilumab treatment effect on skin 
transcriptome using STS samples in both predefined 
lesional and non-lesional skin in pediatric patients with 
moderate-to-severe AD during dupilumab treatment 
phase and follow-up period 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 impact  assessed by 
standard AD severity assessments (Eczema Area and 
Severity Index [EASI], and Individual Signs Score 
[ISS]), patient reported outcomes (PRO) (Patient 
Oriented Eczema Measure [POEM], Children 
Dermatology Life Questionnaire Index [CDLQI], worst 
itch Numerical Rating Scale [NRS], sleep disturbance 
NRS, skin pain NRS), standardized photos, the 
biomarker profiles of lipidomics, proteomics, and 
transcriptomics assessed in the STS sample, and the 
skin barrier hypertrophy and structure profiles 
assessed by OCT and FTIR. 
• 
Change (percent and absolute) in EASI over time. 
• 
Change (percent and absolute) in ISS for target 
lesion over time. 
• 
Change (percent and absolute) in POEM over time. 
• 
Change (percent and absolute) in CDLQI over time. 
• 
Change (percent and absolute) in assessment of 
worst itch NRS over time. 
• 
Change (percent and absolute) in sleep disturbance 
NRS over time. 
• 
Change (percent and absolute) in skin pain NRS 
over time. 
• 
Change (percent and absolute) in photograph 
outputs (eg, severity score) obtained from skin 
imaging over time. 
• 
Correlation between baseline values of TEWL 
before and after STS, and TEWL AUC in lesional 
and non-lesional skin of AD patients with the 
following baseline measures: 
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Objectives 
Endpoints 
- 
EASI 
- 
Targeted lesion ISS 
- 
PRO measures (POEM, CDLQI, worst itch 
NRS, sleep disturbance NRS, and skin pain 
NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS 
CER) 
- 
Filaggrin breakdown products of UCA and PCA 
concentrations in STS 
- 
Image-derived severity score in targeted 
lesional skin 
- 
Key components of skin proteomics in STS 
(expression of proteins associated with skin 
barrier function) 
- 
Quantified epidermal hypertrophy and structure 
changes in OCT and FTIR 
- 
Key components of gene expression form 
transcriptomics 
• 
Correlation between percent change from baseline 
in TEWL before and after STS, and TEWL AUC in 
lesional and non-lesional skin of AD patients at 
Week 8, Week 16 and Week 28 with corresponding 
change from baseline in the following measures: 
- 
EASI  
- 
Targeted lesion ISS 
- 
PRO measures (POEM, CDLQI, worst itch 
NRS, sleep disturbance NRS, and skin pain 
NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS 
CER) 
- 
Filaggrin breakdown products of UCA and PCA 
concentrations in STS 
- 
Image-derived severity score in targeted 
lesional skin 
- 
Key components of skin proteomics in STS 
(expression of proteins associated with skin 
barrier function) 
- 
Quantified epidermal hypertrophy and structure 
changes in OCT and FTIR 
- 
Key components of gene expression from 
transcriptomics 
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Overall design: 
• Phase 4. 
• Two study sites (Dr Leung, Denver, USA; Dr Cork, Michael J, EU [UK]). Patients with 
moderate-to-severe AD will be included in the US site and patients with severe AD will be 
included in the EU site (UK). More study sites could be initiated if recruitment at 1 or both 
of above-mentioned study sites is insufficient. 
• Open-label, exploratory study. 
• Approximately 24 pediatric patients with moderate-to-severe AD will be enrolled to 
achieve 20 evaluable patients. These enrolled AD patients will receive Investigational 
medicinal product (IMP) dupilumab treatment during the study. 
• Approximately 24 healthy volunteers will be enrolled to achieve 20 evaluable subjects. 
These enrolled healthy volunteers will not receive any IMP treatment during the study.  
This is a 32-week, open-label, exploratory study with a 4-week screening period, 16-week 
treatment phase designed to investigate dupilumab’s effect on skin barrier function as measured 
by TEWL before and after STS in approximately 20 pediatric patients with moderate-to-severe 
AD (not more than 24 patients aged ≥6 and <12 years old), and a 12-week follow-up period. 
Patients will have 1 on-site visit/week, up to Week 4, 1 on-site visit every 2 weeks from 
Week 4 to Week 8, and 1 on-site visit every 4 weeks from Week 8 to Week 16 End of Treatment 
(EoT) phase visit, and every 6-weeks thereafter during the follow-up period and by this will end 
the study for each participant (End of Study [EoS]). The maximum duration of the study 
per participant will be 32 weeks (including screening period).  
Lesional and non-lesional skin areas for TEWL assessment and STS will be identified on the 
upper limbs or lower limbs (including trunk, if needed) at baseline ("predefined skin area"). These 
predefined, lesional and non-lesional skin areas for skin barrier assessment should be separated by 
a distance of about 4 cm. 
Within these predefined skin areas 3 closely adjacent spots without an overlap for the skin tapes 
will be identified for subsequent skin barrier function assessment (3 spots on lesional skin, 3 spots 
on non-lesional skin). 
The skin barrier function without and before STS will be assessed using TEWL measurement on 
each of the 3 spots within these predefined skin areas at each visit except Weeks 10 and 14, for 
which there will be no study assessments, and only study drug administration. 
Repeated TEWL assessment in predefined lesional and non-lesional skin areas of AD patients 
after STS and lipidomics, proteomics, and transcriptomics analysis in STS samples will be 
conducted at baseline (Week 0, Day 1), Week 2, Week 4, Week 8, Week 12, EoT at Week 16, and 
Follow-ups at Week 22 and Week 28. 
In order to allow the skin to recover from the STS, the skin barrier function assessment with STS 
will be performed within the predefined lesional and non-lesional skin area as follows: STS 
assessment on baseline (Week 0), Week 8, Week 16, and Week 28 will be conducted on the 
first spot; STS assessment on Week 2 will be conducted on the second spot; and STS assessment 
on Week 4, Week 12, and Week 22 will be conducted on the third spot. 
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TEWL will be measured before STS (on each of the 3 spots) and after 5, 10, 15, and 20 STS (on 
the spot defined for the visit) (5 TEWL assessments per visit) on targeted, predefined lesional skin 
in AD patients at baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 22 and Week 28 
on the predefined first, second or third spot, respectively.  
TEWL will be measured before (on each of the 3 spots) and after 5, 10, 15, and 20 STS (on spot 
defined for the visit) (5 TEWL assessments per visit) on targeted, predefined non-lesional skin in 
AD patients at baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 22, and Week 28 on 
the predefined first, second or third spot, respectively (see Figure 3 and Figure 5 in  
Section 8.1.1.2).  
Skin barrier function in approximately 20 healthy volunteers (not more than 24 healthy 
participants aged ≥6 and <12 years old) matched for age (match on age ±2 years), gender, location 
of targeted lesion area, and study site to the AD cases will be assessed in a similar manner at 
baseline, and will have 1 on-site visit/week, up to Week 4, 1 on-site visit every 2 weeks from 
Week 4 to Week 8, and 1 on-site visit every 4 weeks from Week 8 to Week 16 EoT phase visit, 
and every 6-weeks thereafter during the follow-up period, serving as a reference comparator for 
skin barrier function. 
Within the targeted skin area of healthy volunteers-the location of it to be identical to the lesional 
area of the patient to which a healthy volunteer is matched-3 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 3 spots at each visit, except Weeks 10 and 14. 
On normal skin in healthy volunteers at each visit at baseline (Week 0), Week 2, Week 4, Week 8, 
Week 12, Week 16, Week 22, and Week 28 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 (See Figure 4 and Figure 5 in  
Section 8.1.1.2).  
In particular, STS assessment on baseline (Week 0, Day 1), Week 8, Week 16, and Week 28 will 
be conducted on the first spot within the location-matched, normal skin. STS assessment on 
Week 2 will be conducted on the second spot. STS assessment on Week 4, Week 12, and 
Week 22 will be conducted on the third spot. 
Study drug will be administered on-site by study site staff at baseline (Week 0, Day 1), Weeks 4, 
8, and 12 for dose regimen 1; and at baseline (Week 0, Day 1), Weeks 2, 4, 6, 8, 10, 12, and 14 for 
dose regimen 2, after the TEWL assessment has been completed. 
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Intervention groups and duration: 
The study is an open-label study of dupilumab with a 16-week treatment phase in moderate-to-
severe AD pediatric 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 will be 32 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 injection. 
• Route(s) of administration: subcutaneous (SC) injection.  
Dupilumab 300 mg 
• Formulation: a 150 mg/mL dupilumab solution in a pre-filled syringe to deliver 300 mg in 
a 2 mL injection. 
• Route(s) of administration: SC injection. 
Dose regimen  
Dose regimen 1: 
• Children with baseline 15 kg ≤ body weight <30 kg will receive an SC loading dose of 
dupilumab 600 mg (2 injections of dupilumab 300 mg) on Day 1 (Week 0), followed by 
every 4-week SC dosing of dupilumab 300 mg from Week 4 to Week 12. The IMP will be 
administered by study site staff at baseline (Week 0, Day 1), Weeks 4, 8, and 12. 
Dose regimen 2: 
• Children with baseline 30 kg ≤ body weight <60 kg will receive a SC loading dose of 
dupilumab 400 mg (2 injections of dupilumab 200 mg) on Day 1 (Week 0), followed by 
bi-weekly SC dosing of dupilumab 200 mg from Week 2 to Week 14. The IMP will be 
administered by study site staff at baseline (Week 0, Day 1), Weeks 2, 4, 6, 8, 10, 12, 
and 14. 
Post-trial access to study medication 
• After the study treatment phase is completed, patients will stop the study medication. 
Rescue treatment with dupilumab for AD may be provided to patients during follow-up 
period. Investigators will be required to perform an Investigator Global Assessment (IGA) 
evaluation prior to starting rescue treatment and initiate rescue treatment only in patients 
who either have an IGA score of 4, or have intolerable symptoms. After the study is 
completed at Week 28, patients will not be provided with any further study medication as 
part of this protocol. 
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Duration of study period (per participant) 
Study duration for each AD patient and healthy volunteer will be approximately 32 weeks 
including: 
• Screening period: Up to 4 weeks (Day -28 to Day -1) from signing the informed consent. 
• Open-label dupilumab treatment (AD patients) and observation period (healthy volunteers) 
for 16 weeks from baseline on Day 1 (Week 0). 
• Follow-up period for 12 weeks after the EoT visit (Week 16). Dupilumab may be used as a 
rescue therapy for AD patients, if needed during follow-up period. 
Statistical considerations: Analyses will be descriptive and explorative. 
A first analysis (treatment phase), will be performed 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. A second analysis 
(follow-up period) will be run once all patients and healthy volunteers have completed the 
Week 28 assessments. The analysis of the follow-up period will be based on all participants and 
all data. 
• Sample size calculations 
- 
Sample size for this exploratory study was based on medical/clinical judgment and is 
consistent with the sample size from similar studies in the literature (4). 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. 
- 
Allowing for drop-out rate of 15%, a total of approximately 24 pediatric 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 Week 16, 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 minimal. Any drop-out healthy volunteer for whom the matched patient 
is considered as evaluable will not be replaced. 
• 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 
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 participants will provide normal reference values. 
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• Safety/other analysis: 
- 
The safety evaluation will be conducted on all AD patients who receive at least 1 dose 
of dupilumab or had at least 1 TEWL/STS assessment performed, and on all healthy 
volunteers, who had at least 1 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 [PCSA]) and reported 
adverse event (AE).  
Data Monitoring Committee: None 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
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a For the purpose of this study, any female who has had her first menstrual period (menarche) and is sexually active will be considered to be of childbearing potential. Female patients who are not of childbearing 
potential at the start of the study but have the onset of menarche during the course of the study and are sexually active will also have to follow adequate birth control methods to continue participation in the study. 
These females must have a negative urine β-HCG pregnancy test at screening and at each visit (except patients who assigned to dose regimen 1 will not attend visits V9 (W10) and V11 (W14), therefore there’s no 
pregnancy test for these patients on both visits). Pregnancy will lead to definitive treatment discontinuation in all cases. 
b Emollients should NOT be applied from Day -7 to the EoS (Week 28) to the targeted, predefined 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. 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 provided by the study site. 
c Dose regimen 1: Children with baseline 15 kg ≤ body weight <30 kg will receive a SC loading dose of dupilumab 600 mg (2 injections of dupilumab 300 mg) on Day 1 (V02), followed by every 4-week SC dosing of 
dupilumab 300 mg until Week 12 (at Week 0 [(Day 1], Weeks 4, 8, and 12).  
Dose regimen 2: Children with baseline 30 kg ≤ body weight <60 kg will receive a SC loading dose of dupilumab 400 mg (2 injections of dupilumab 200 mg) on Day 1 (V02), followed by bi-weekly SC dosing of 
dupilumab 200 mg until Week 14 (at Week 0 (Day 1), Weeks 2, 4, 6, 8, 10, 12, and 14). 
d Assessments on treatment days have to be conducted before administration of dupilumab. 
e Predefined lesional and non-lesional skin areas. TEWL will be measured at each of the 3 closely adjacent spots within the predefined skin areas at all visits without STS and before STS at visits with STS. 
f 
TEWL will be conducted before STS and then after 5, 10, 15, and 20 STS in lesional skin and non-lesional skin. 
g At Weeks 0, 8, 16, and 28, 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 Weeks 4, 12, and 
22 STS will be conducted on the third spot within the predefined skin area. TEWL will be assessed in lesional skin and non-lesional skin before STS and after 5, 10, 15, and 20 STS. All skin tape strips should be 
collected and stored. 
h In case STS assessment is to be conducted at an unscheduled visit or at a premature EoT 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. 
i 
OCT will be done before STS/TWL, and FTIR will be done before and during STS. 
j 
Worst itch NRS, Sleep disturbance NRS and Skin pain NRS will be assessed daily from Day -7 to Day -1; daily from Day 1 to Week 4 and then 7 days prior to Week 6, Week 8, Week 12, Week 16, Week 22, and 
to Week 28 by e-diary. 
k eDiary will be dispensed to the patients at screening (Visit 01) and will be collected on Week 28 (Visit 14). The PROs will be administered to patients via eDiary. Patients will bring the eDiary to the site at each visit, 
and it will be reviewed for any questionnaires omission and dispensed back to patients at each visit. 
l 
Vital signs, including heart rate, systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured. 
m Limited to skin-related physical examination at baseline, EoT visit (Week 16) and EoS (Week 28). 
n Saliva swab samples for DNA isolation should be collected on Day 1/Baseline (predose) for FLG gene sequencing analysis, but may be collected at any study visit. 
o Please refer to Section 8.8.6 for details. 
AE = Adverse Events; AD = Atopic Dermatitis; CDLQI = Children's Dermatology Life Quality Index; D= Day; EASI = Eczema Area and Severity Index; EoT = End of Treatment; EoS = End of Study; FLG = Filaggrin; 
IGA = Investigator Global Assessment; ISS = Individual Signs Score; NRS = Numerical Rating Scale; POEM = Patient Oriented Eczema Measure; SAE = Serious Adverse Events; SC = Subcutaneous; STS = Skin 
Tape Stripping; TEWL = Transepidermal Water Loss; UNSCH = unscheduled; V = Visit; W = Week; W = Women of Childbearing Potential.
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b Emollients should NOT be applied from Day -7 to the EoS (Week 28) to the targeted, predefined skin areas that will be used for TEWL assessment. Participants should not take showers or soak in a bathtub within 
6 hours before TEWL assessment. 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 provided by the study site. 
c TEWL will be measured at each of the 3 closely adjacent spots within the predefined skin areas at all visits without STS and before STS at visits with STS. 
d TEWL will 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 Weeks 0, 8, 16, and 28, 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 Weeks 4, 12, and 
22 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 should be collected and stored. 
f 
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. 
g OCT will be done before STS/TWL, and FTIR will be done before and during STS. 
h Vital signs, including heart rate, systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured.  
i 
Limited to skin-related physical examination at baseline, EoT visit (Week 16), and EoS (Week28). 
j 
Saliva swab samples for DNA isolation should be collected on Day 1/Baseline (predose) for FLG gene sequencing analysis, but may be collected at any study visit. 
k Please refer to Section 8.8.6 for details. 
AE = Adverse Events; AD = Atopic Dermatitis; CDLQI = Children's Dermatology Life Quality Index; D = Day; EASI = Eczema Area and Severity Index; EoT = End of Treatment; EoS = End of Study; FLG = Filaggrin; 
IGA = Investigator Global Assessment; NRS = Numerical Rating Scale; POEM = Patient Oriented Eczema Measure; SAE = Serious Adverse Events; SC = Subcutaneous; STS = Skin Tape Stripping; 
TEWL = Transepidermal Water Loss; V = Visit; W = Week; W = Women of Childbearing Potential. 
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2 
INTRODUCTION  
Dupilumab is a human monoclonal antibody (5, 6) 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 (7). 
Dupilumab is recently approved in the US for SC administration Q2W/Q4W (depends on the 
body weight) for the treatment of pediatric patients ≥6 and <12 years of age with moderate-to-
severe AD whose disease is not adequately controlled with topical prescription therapies or when 
those therapies are not advisable. 
For adults and adolescents, dupilumab was already approved in the US for SC administration 
Q2W for the treatment of patients aged ≥12 years with moderate-to-severe 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 (8) demonstrated that dupilumab-mediated inhibition of 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 immunoglobulin (Ig) E, 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 
FLG, loricrin, claudins, and elongation of very long-chain fatty acids protein (ELOVL3), and 
significantly reduced lesional epidermal thickness (8, 9). 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 permeability of skin barrier is critical, and its impairment leads to 
downstream signals that aim to restore barrier homeostasis (10). 
2.1 
STUDY RATIONALE  
Literature shows that patients with early-onset AD have a higher risk of developing other 
Type 2 comorbidities (the atopic march). It has been suggested that early optimal and successful 
treatment of AD may prevent or attenuate the development of other atopic conditions (1, 2). 
Leung et al used a non-invasive STS sampling technique can be reliably analyzing TEWL, TEWL 
AUC responses, lipidomics, FLG breakdown products, proteomics, and transcriptomics. Results 
from these analyses demonstrated that children with AD and food allergy exhibit elevated 
epidermal barrier defects even in non-lesional skin (3). The proposed study will evaluate the 
effect of dupilumab on the skin barrier in a pediatric population with early-onset moderate-to-
severe AD using non-invasive methodologies such as TEWL, STS, OCT, and FTIR spectroscopy 
for skin barrier structure evaluation. The effect of dupilumab treatment on skin barrier function 
will be evaluated using TEWL in conjugation with STS, lipidomics, proteomics, and 
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transcriptomics using tape stripping samples. Skin barrier structure changes will be evaluated 
using OCT and FTIR spectroscopy in both predefined lesional and non-lesional areas in pediatric 
patients.  
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 (11). 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 (11, 12). 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. 
2.2 
BACKGROUND  
Atopic dermatitis 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 (QOL) (13). Additionally, AD places a heavy economic 
burden on patients and their family (14, 15). Atopic dermatitis 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 (16). 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 (17). 
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 (18). Filaggrin 
mutations are the most profound single-gene defects involved in AD (19). Filaggrin 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 (18). 
Healthy epidermis has lipids that are mostly composed of ceramides (CER), free fatty acids, and 
cholesterol (20, 21), with very little presence of other lipids. A very specific, highly hydrophobic 
group of CER, called esterified omega-hydroxy sphingosine (EOS) CER, is present only in the 
skin. Fatty acids are also unique in skin CER, 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 CER and other 
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CER with very long–chain fatty acids (C22-C30), and short-chain non-hydroxy fatty acids 
sphingosine CER (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 TEWL in 
AD skin (17). 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 (3). 
Leung et al have pioneered novel methods to profile skin through STS analysis combined with 
lipidomics, proteomics and transcriptomics (3). 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 agnostic examination of genomic, lipidomic, and 
proteomic expression profiles in non-lesional and lesional AD skin (14). 
Optical coherence tomography (OCT) is a non-invasive, depth resolved imaging modality 
conceptually similar to ultrasound, but using near-infrared light (22); as it can image down to 
1 to 2 mm depth, it is ideal for studying epithelial tissues including skin. It has become the 
established method of choice for imaging the retina and is emerging strongly into coronary 
vascular imaging and dermatology. Angiographic OCT is used to measure epidermal hypertrophy 
and dermal vascular changes as non-invasive biomarkers of sub-clinical AD.  
Attenuated Total Reflectance (ATR) FTIR spectroscopy is a form of molecular spectroscopy 
useful for the analysis of surfaces, including skin. It has proved valuable for quantifying the lipid, 
water, and carboxylate content of the skin barrier and for analyzing lipid arrangement/structure 
(23, 24, 25, 26, 27). 
Therefore, the proposed study will use these non-invasive innovative technologies to assess skin 
barrier function change over in pediatric patients with moderate-to-severe AD. 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has demonstrated a positive benefit-risk profile and is approved for treatment of 
moderate-to-severe AD in pediatric patients, ≥6 and <12 years of age in the US. 
The safety profile in the pediatric population (≥6 and <12 years of age) was comparable to that 
previously observed in adult and adolescent patients with AD for whom the drug is already 
approved. Dupilumab dose in this study is consistent with the approved label. 
The safety of dupilumab with concomitant topical corticosteroid (TCS) was assessed in a study of 
367 subjects ≥6 and <12 years of age with severe AD. The safety profile of dupilumab + TCS in 
these subjects through Week 16 was similar to the safety profile from studies in adults and 
adolescents with AD. 
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The long-term safety of dupilumab + TCS was assessed in an open-label extension study of 
368 subjects ≥6 and <12 years of age with AD. The safety profile of dupilumab + TCS in subjects 
followed through Week 52 was similar to the safety profile observed at Week 16. The long-term 
safety profile of dupilumab + TCS observed in pediatric patients was consistent with that seen in 
adults and adolescents with AD. 
In the US, Dupilumab is approved for the treatment of patients ≥6 and <12 years of age with 
moderate-to-severe AD whose disease is not adequately controlled with topical prescription 
therapies or when those therapies are not advisable. Dupilumab can be used with or without TCS, 
whereby in the EU dupilumab is under review for the treatment of severe AD in children ≥6 and 
<12 years of age who are candidates for systemic therapy. Therefore, in this study a pediatric 
population with moderate-to-severe AD will be included in the US and severe AD patients in the 
EU.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dupilumab may be found in the Investigator’s Brochure (28). 
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 a 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 1 localized area of skin, presumably due 
to the mild mechanical disturbance. The erythema is expected to resolve within 12 hours without 
sequelae. Skin tape stripping should be ceased, if the skin is broken (ie, bleeding), which is very 
rare based on investigator’s experience. 
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 OCT and FTIR  
There are no known risks associated with this non-invasive OCT and FTIR spectroscopy 
assessments. 
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Risks Associated with Health Questionnaires 
There is a possibility that participants or their parents may find questions too personal. 
Participants including their parents 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 very severe AD who may have difficulty tolerating periods without 
medication/procedure use will be excluded from participating, per study exclusion criteria. 
Risks Associated with Blood Collection 
Risks associated with drawing blood (if any) 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 needle insertion. 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 dupilumab treatment for a total of 
16 weeks, and participants in the health volunteer’s cohort will receive no treatment during the 
study. 
One potential benefit for participants in the AD cohort is that their AD may be improved and itch 
may be reduced while on dupilumab treatment; 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 will receive 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. 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 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. 
Although the results of this study may be of commercial value, it will be explained to participants 
that they will not have ownership of the study results, and will not be benefited financially from 
participation in this study, other than the nominal reimbursements provided for completing study 
procedures and visits. 
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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 to 
18-year-old) and a similar benefit-risk profile to adults has been observed. 
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 LPS16764 is pediatric patients with moderate-to-severe 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. Literature shows that children with AD and food allergy exhibit elevated 
epidermal barrier defects even in non-lesional skin.  
Based on the aforementioned potential benefits to patients participating in LPS16764, 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 a pediatric population 
with early-onset moderate-to-severe AD. The efficacy and safety of dupilumab were confirmed 
based on data that includes a pivotal Phase 3 trial in which dupilumab was used in combination 
with TCS and compared to TCS alone in children with severe AD. In the trial, children treated 
with dupilumab and TCS experienced significant improvements in overall disease severity, skin 
clearance and quality of life. Therefore, the operation of LPS16764 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). 
2.3.3 Overall benefit: risk conclusion  
Taking into account the measures taken to minimize the risk to participants in this study, the 
potential risks identified in association with dupilumab, TEWL and STS are justified by the 
anticipated benefits that may be afforded to participants with AD. 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 
Estimands/Endpoints 
Primary 
• 
Evaluate changes in skin barrier function 
with transepidermal water loss (TEWL) 
assessed after skin tape stripping (STS) in 
predefined lesional skin in pediatric 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 Week 16 in AD patients. 
Secondary 
• 
Evaluate changes in skin barrier function 
with TEWL assessed after STS in 
predefined lesional and non-lesional skin in 
pediatric 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 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 healthy 
volunteers.  
• 
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 healthy 
volunteers. 
• 
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 healthy 
volunteers. 
• 
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 healthy 
volunteers. 
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Objectives 
Estimands/Endpoints 
• 
Evaluate time course of change in skin 
barrier function with TEWL assessed 
before and after STS in predefined lesional 
and non-lesional skin in pediatric patients 
with moderate-to-severe AD during 
dupilumab treatment phase and follow-up 
period in reference to normal skin of 
healthy volunteers. 
• 
Change (percent and absolute) in TEWL before STS on 
lesional skin in AD patients over time. 
• 
Change (percent and absolute) in TEWL before STS on 
non-lesional skin in AD patients over time. 
• 
Change (percent and absolute) 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) in TEWL after STS assessed 
on lesional skin in AD patients over time. 
• 
Change (percent and absolute) in TEWL after STS assessed 
on non-lesional skin in AD patients over time. 
• 
Change (percent and absolute) 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 
predefined lesional and non-lesional skin in 
pediatric patients with moderate-to-severe 
AD during dupilumab treatment phase and 
follow-up period 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 omega-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 over 
time. 
• 
Global characterization of protein-bound CER over time. 
• 
Evaluate dupilumab treatment effect on 
skin proteomics using STS samples in both 
predefined lesional and non-lesional skin in 
pediatric patients with moderate-to-severe 
AD during dupilumab treatment phase and 
follow-up period 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 
epidermal hypertrophy and structure of skin 
barrier changes measured by Optical 
Coherence Tomography (OCT) and 
Fourier-Transform Infrared (FTIR) 
spectroscopy in both predefined lesional 
and non-lesional skin in pediatric patients 
with moderate-to-severe AD during 
dupilumab treatment phase and follow-up 
period in reference to normal skin of 
healthy volunteers. 
• 
Change (percent and absolute) in epidermal hypertrophy 
parameters including epidermal thickness (µm), superficial 
plexus depth (µm), blood vessel diameter (µm) and density 
(segments/mm2) measured by OCT over time. 
• 
Change (percent and absolute) in stratum corneum lipid 
structure measured by FTIR spectroscopy in conjunction with 
tape-stripping over time. 
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Objectives 
Estimands/Endpoints 
• 
Evaluate dupilumab treatment effect on 
skin transcriptome using STS samples in 
both predefined lesional and non-lesional 
skin in pediatric patients with moderate-to-
severe AD during dupilumab treatment 
phase and follow-up period 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 
impact  assessed by standard AD severity 
assessments (Eczema Area and Severity 
Index [EASI], and Individual Signs Score 
[ISS]), patient reported outcomes (PRO) 
(Patient Oriented Eczema Measure 
[POEM], Children Dermatology Life 
Questionnaire Index [CDLQI], worst itch 
Numerical Rating Scale [NRS], sleep 
disturbance NRS, skin pain NRS), 
standardized photos, the biomarker profiles 
of lipidomics, proteomics, and 
transcriptomics assessed in the STS 
sample, and the skin barrier hypertrophy 
and structure profiles assessed by OCT 
and FTIR. 
• 
Change (percent and absolute) in EASI over time. 
• 
Change (percent and absolute) in ISS for target lesion over 
time. 
• 
Change (percent and absolute) in POEM over time. 
• 
Change (percent and absolute) in CDLQI over time. 
• 
Change (percent and absolute) in assessment of worst itch 
NRS over time. 
• 
Change (percent and absolute) in sleep disturbance NRS over 
time. 
• 
Change (percent and absolute) in skin pain NRS over time. 
• 
Change (percent and absolute) in photograph outputs 
(eg, severity score) obtained from skin imaging over time. 
• 
Correlation between baseline values of TEWL before and after 
STS, and TEWL AUC in lesional and non-lesional skin of AD 
patients with the following baseline measures: 
- 
EASI  
- 
Targeted lesion ISS 
- 
PRO measures (POEM, CDLQI, worst itch NRS, sleep 
disturbance NRS, and skin pain NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS CER) 
- 
Filaggrin breakdown products of UCA and PCA 
concentrations in STS 
- 
Image-derived severity score in targeted lesional skin  
- 
Key components of skin proteomics in STS (expression of 
proteins associated with skin barrier function) 
- 
Quantified epidermal hypertrophy and structure changes 
in OCT and FTIR 
- 
Key components of gene expression from transcriptomics 
• 
Correlation between percent change from baseline in TEWL 
before and after STS, and TEWL AUC in lesional and 
non-lesional skin of AD patients at Week 8, Week 16, and 
Week 28 with corresponding change from baseline in the 
following measures: 
- 
EASI  
- 
Targeted lesion ISS 
- 
PRO measures (POEM, CDLQI, worst itch NRS, sleep 
disturbance NRS, and skin pain NRS) 
- 
Lipidomics in STS (ratio of EOS CER to NS CER) 
- 
Filaggrin breakdown products of UCA and PCA 
concentrations in STS 
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Objectives 
Estimands/Endpoints 
- 
Image-derived severity score in targeted lesional skin 
- 
Key components of skin proteomics in STS (expression of 
proteins associated with skin barrier function) 
- 
Quantified epidermal hypertrophy and structure changes 
in OCT and FTIR 
- 
Key components of gene expression from transcriptomics 
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 and TEWL AUC after various numbers of STS. The stratum 
corneum provides skin barrier protection and controls transcutaneous water loss. TEWL 
measurement, which quantifies water diffusion across the stratum corneum, is commonly used for 
the physiologic assessment of skin barrier function (29). 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 STS to measure skin barrier integrity (10). 
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 after 5, 10, 15, and 
20 skin tape strips. TWEL after 5 tape strips in the lesional skin causes a mild perturbation of the 
skin barrier, is tolerable for patients, and therefore chosen as the primary endpoint. The AUC for 
TEWL measurements (TEWL AUC) done over a defined number of STS is used to reflect the 
overall integrity of the stratum corneum. Skin barrier dysfunction and increased TEWL are major 
pathologic features of AD (18, 30, 31). TEWL has been shown to correlate with AD severity 
(32, 33, 34). 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 4 open-label, exploratory study in 2 sites evaluating the effect of dupilumab on 
skin barrier function in pediatric patients aged between ≥6 and <12 years old with moderate-to-
severe AD with a healthy volunteer cohort as a reference comparator. Patients with moderate-to-
severe AD will be included in the US site and patients with severe AD will be included in the EU 
site (UK). More study sites could be initiated if recruitment at 1 or both of above-mentioned study 
sites is insufficient. 
The maximum study duration per participant will be 32 weeks. The study will comprise of: 
• Screening period 1 (Day -28 to Day -1): Participants will be evaluated according to 
inclusion and exclusion criteria. 
• Baseline visit (Week 0, Day 1): Participants who remain eligible will be enrolled. 
• A 16-week treatment phase for AD patients and a 16-week observation period for healthy 
volunteers. 
• A 12-week follow-up period.  
The overall study schema is provided in Section 1.2. TEWL and STS procedures are detailed in 
Section 1.1 and Section 8.1. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The study design includes 2 parallel study cohorts: the AD patients cohort with open-label 
dupilumab treatment for 16-weeks, and follow-up period for 12 weeks, and the healthy volunteers 
cohort without any treatment for the whole study duration, 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, lipidomics, proteomics, and 
transcriptomics from STS samples, OCT and FTIR, standardized full body photographs, 
photographs from the targeted lesional and non-lesional areas, clinical disease severity, and 
patient reported outcomes (PRO).  
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 controlled skin barrier perturbation using STS to measure skin barrier 
function and integrity (10). 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 the 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 (35, 36). Through 
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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 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 in 
interpreting study assessment results (11, 12). 
4.2.1 Participant input into design  
Not applicable. 
4.3 
JUSTIFICATION FOR DOSE  
The dose (2 dose regimens based on body weight) selected in this study is the dose approved for 
the treatment of moderate-to-severe pediatric (≥6 and <12 years of age) AD patients for 
dupilumab in the US and is under review for the treatment of severe pediatric (≥6 and <12 years 
of age) AD patients for dupilumab in the 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 EoS visit as shown in the Schedule of Activities (SoA) in Section 1.3. 
The EoS is defined as the date of the last visit of the last participant in the study as shown in the 
SoA for the last participant in the study. 
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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 ≥6 to <12 years, with moderate-to-
severe AD.  
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 ≥6 to <12 years of age (inclusive), at the time of signing the 
informed consent.  
Type of participant and disease characteristics 
Atopic dermatitis patients: 
I 02. Male or female pediatric patients. 
I 03. Patients with AD diagnosis according to Hanifin and Rajka criteria at least 1 year before 
screening. 
I 04. Investigator Global Assessment  score of ≥3 (for US patients) or IGA ≥4 (for EU patients) 
at screening (on the 0 to 4 scale) depending on approved label indication in the country.  
I 05. Patients with moderate-to-severe AD are eligible to be treated with dupilumab according to 
product label. 
I 06. Patients with AD must have active lesions on the upper limbs or lower limbs (including 
trunk, if needed), with severity for lesion erythema or edema/papulation ≥2 at screening on 
the 0 to 3 scale of the ISS. 
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. 
I 08. Willing to refrain from applying any topical medications on the target assessment areas 
(including lesional and non-lesional) throughout the study until EoS unless necessary to 
alleviate intolerable symptoms.  
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I 09. Willing to refrain from showers or soak 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 Week 28 (EoS). 
I 11. Willing and able to comply with all clinic visits and study-related procedures. 
Healthy volunteers: 
I 12. Age and gender matched (match on age ±2 years) to a selected AD patient by study site.  
I 13. No current dermatologic or systemic condition that could interfere with the assessments. 
Weight  
I 14. 15 kg ≤ body weight <60 kg. 
Sex 
I 15. Male or female 
Contraceptive use by female of childbearing potential and sexually active should be 
consistent with local regulations regarding the methods of contraception for those 
participating in clinical studies. 
Informed consent 
I 16. 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. Participant’s legally authorized 
representative must provide signed informed consent. Participant must also provide 
separate informed assent to enroll in the study, and sign and date either a separate informed 
assent form (IAF) or the ICF signed by the parent/legally authorized representative 
(as appropriate based on local regulations and requirements).  
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, tinea infection, 
contact dermatitis). 
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E 03. Cracked, crusted, oozing, or bleeding AD lesions in the designated lesional assessment 
area leaving insufficient skin that is adequate for TEWL assessments. 
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 individuals with ocular conditions that require the use of 
ocular corticosteroids or cyclosporine. 
E 06. Systemic AD treatment, cyclosporine A (CsA), systemic corticosteroids, azathioprine 
(AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or Janus kinase (JAK) 
inhibitors 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 endoparasitic infections, short life expectancy, uncontrolled diabetes (hemoglobin 
A1c ≥9%), 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, 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 form [eCRF], screening logs, etc). 
E 09. History of hypersensitivity reaction to tape or adhesives used in desquamme discs. 
Prior/concomitant therapy  
E 10. Treatment with an investigational medication within 16 weeks or within 5 half-lives 
(if known) prior to Day 1, whichever is longer. 
E 11. Patients who received a live vaccine within 4 weeks of baseline. 
Prior/concurrent clinical study experience 
E 12. Current participation in another investigational or interventional clinical study. 
Diagnostic assessments 
Not applicable. 
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 Other exclusions 
E 13. Individuals (including parents or legal guardians) accommodated in an institution because 
of regulatory or legal order; prisoners or participants who are legally institutionalized. 
E 14. Participants (including parents or legal guardians) are dependent or relative of the Sponsor 
or Investigator (in conjunction with Section 1.61 of the International Council for 
Harmonisation (ICH)-Good Clinical Practice [GCP] Ordinance E6). 
E 15. Individuals (including parents or legal guardians) directly involved in the conduct of the 
study, or immediate family members of such individuals. 
E 16. Any specific situation during study implementation/course that may raise ethical 
considerations. 
E 17. Planned or anticipated major surgical procedure during the patient’s participation in this 
study. 
E 18. Healthy volunteers with a personal history of an atopic condition. 
E 19. Healthy volunteers with use of any topical treatment anywhere except Cetaphil®, 
Vanicream™, E45 cream or the preferred moisturizer not containing additives on 
non-targeted skin areas. 
E 20. Female of childbearing potential* and sexually active, who is unwilling to use highly 
effective methods of contraception prior to the initial dose, during the study and for at least 
12 weeks after the last dose of study drug. Highly effective contraceptive measures include 
stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, vaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, 
implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles 
prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
bilateral tubal ligation; vasectomized partner; and or sexual abstinence**. 
* For the purpose of this study, any female who has had her first menstrual period 
(menarche) and is sexually active will be considered to be of childbearing potential. 
Female patients who are not of childbearing potential at the start of the study but have the 
onset of menarche during the course of the study and are sexually active will also have to 
follow adequate birth control methods to continue participation in the study. 
** 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 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
NOTE: Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception. 
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5.3 
LIFESTYLE CONSIDERATIONS  
• Study participants should not take a shower or a bath within 6 hours before assessment of 
TEWL. 
• Participants should apply Cetaphil, Vanicream, E45 cream or preferred same emollients 
not containing additives except at the predefined skin assessment areas up to 2 times daily 
from Day -7 to Week 16 (EoT). 
• Participants should not apply any emollients on or within 5 cm of the predefined skin 
assessment areas during the entire study period from Day -7. 
• 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 provided by the study site. 
5.3.1 Meals and dietary restrictions  
Patients with a known food allergy should not consume any foods from an outside home provider 
on the day of the dupilumab injection. 
5.3.2 Caffeine, alcohol, and tobacco  
Not applicable. 
5.3.3 Activity  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
subsequently found to be not eligible to enroll 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 AE (SAE). 
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 pediatric patients with moderate-to-severe AD will receive dupilumab. 
• Dose regimen 1: children with baseline 15 kg ≤ body weight <30 kg will receive an SC 
loading dose of dupilumab 600 mg (2 injections of dupilumab 300 mg) on Day 1 
(Week 0), followed by every 4-week SC dosing of dupilumab 300 mg from Week 4 to 
Week 12. 
• Dose regimen 2: children with baseline 30 kg ≤ body weight <60 kg will receive an SC 
loading dose of dupilumab 400 mg (2 injections of dupilumab 200 mg) on Day 1 
(Week 0), followed by bi-weekly SC dosing of dupilumab 200 mg from Week 2 to 
Week 14. 
Note: Treatment regimen will be applied based on the approved label for the study 
population. 
• One kit number list by dosage strength is generated centrally by Sanofi and IMPs are 
packaged in accordance with these lists. The treatment will be given to the pediatric 
patient (≥6 and <12 years of age) depending on their 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 injection 
A 150 mg/mL dupilumab solution in a 
pre-filled syringe to deliver 300 mg in 
2 mL injection 
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 28 ±2 or 3 days after an 
initial loading dose of 600 mg 
Route of administration 
Subcutaneousa 
Subcutaneousa 
Use 
Experimental 
Experimental 
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ARM name 
Dupilumab 200 
Dupilumab 300 
IMP  
IMP 
IMP 
Storage  
2°C to 8°C 
2°C to 8°C 
Packaging and labeling 
One glass pre-filled syringe packed in a 
patient kit box. Both 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 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 the study site staff and/or by a 
trained person 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 as per the clinical procedures 
and blood collection (if any) should be performed. 
The IMP will be administered on-site by study site staff at baseline (Day 1, Week 0), Weeks 4, 8, 
and 12 for AD patients who receives dose regimen 1 and at baseline (Day 1, Week 0), Weeks 2, 4, 
6, 8, 10, 12, and 14 for AD patients who receives dose regimen 2, after the TEWL assessment has 
been completed. No IMPs will be administered to healthy volunteers.  
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, dupilumab may be supplied from the site to the participant 
(patient, parent, caregiver or legal guardian) via a Sponsor-approved courier company where 
allowed by local regulations and agreed by the parent or legal guardian. In this case the injections 
will be administered by a qualified site personnel, a home nurse, a trained caregiver or by a 
trained parent/legal guardian. 
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 that 2°C to 8°C 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 authorized site staff may supply or administer study intervention. At study site, 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. 
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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).  
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 8.3.9). 
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 study protocol, or dispose of IMP in any 
other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
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. 
• Efficacy data (TEWL and OCT) 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 in 2 study centers which has experience in conducting studies.  
• One central laboratory for lipidomics, proteomics, and transcriptomics analysis to reduce 
skin barrier assessment variabilities. 
• One central center for image and spectra processing and analysis. 
• Standardized study assessment procedures, including TEWL, STS, OCT, FTIR in skin 
barrier function assessments. 
• Standardized photography for targeted lesional and non-lesional areas, and clinical disease 
severity and PRO 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:  
• 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 and source documents.  
Participants will receive the study intervention (see Section 1.3) 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 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. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, [live vaccine is prohibited]) 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 g/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. 
Cetaphil, Vanicream, E45 cream, or the preferred 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 up to 2 times daily from Day -7 to Week 16 (EoT). 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 healthy volunteers 
for TEWL assessments from Day -7 to Week 28 (EoS). 
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6.5.1 Rescue medicine  
During treatment phase, 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 (ie, topical treatment with high potency TCS). Investigators should 
make every attempt to conduct efficacy and safety assessments (eg, disease severity scores, safety 
laboratory assessments) immediately before administering any rescue treatment. An unscheduled 
visit may be used for this, if necessary. Rescue treatment with dupilumab for AD may be provided 
to patients during follow-up period (Weeks 17 to 28). Investigators will be required to perform an 
IGA evaluation prior to starting rescue treatment and initiate rescue treatment only in patients who 
either have an IGA score of 4, or have intolerable. The date and time of rescue medication 
administration as well as the name and dosage regimen of the rescue medication must be recorded 
in the eCRF. 
6.5.1.1 Prohibited medications and procedures  
Treatment with the following concomitant medications and procedures is prohibited until the 
Week 16 (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, cyclosporine A (CsA), azathioprine 
(AZA), methotrexate (MTX), mycophenolate mofetil (MMF), Interferon gamma (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  
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8. In addition, participants will be asked to abstain from live (attenuated) vaccinations 
through Week 28. If a participant requires a vaccination prior to 28-weeks after 
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 should be avoided until Week 28. Moisturizers other than Cetaphil, 
Vanicream, E45 cream, or the preferred 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 nasal and 
inhaled corticosteroids, and oral antihistamines. The use of these medications should be recorded. 
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 and lipidomics, proteomics, 
transcriptomics, OCT, and FTIR spectroscopy. See the SoA (Section 1.3 and Section 1.4) 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 eCRF 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: 
For example, temporary intervention discontinuation decided by the Investigator corresponds to 
first 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. 
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• At the time of discontinuation from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3 and Section 1.4). For data to be 
collected at the time of study discontinuation and follow-up, and for any further 
evaluations that need to be completed, as shown in SoA (Section 1.3 and Section 1.4). 
• 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 
patients may withdraw from treatment with the IMP, if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
The Investigators should discuss with them about the key visits to be attended. 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. Preferably the patient should withdraw consent in writing and, if the patient or the 
patient’s representative refuses or is physically unavailable, the site should document and sign the 
reason for the patient’s failure to withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF 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. Patients requesting withdrawal should be informed that withdrawal of 
consent for follow-up may jeopardize the public health value of the study. 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.  
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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 
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. 
• At the first contact during screening, the study will be explained to the patient’s parents or 
legal guardian (hereinafter the “parent”). The parent will receive verbal information 
concerning the aims and methods of the study, its constraints and risks, and the study 
duration. Written informed consent must be signed by the parent prior to any 
investigations. In addition, provision of assent form will be signed by minor patients or 
ICF will be signed by emancipated or mature minors (defined by local laws). 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3 and Section 1.4), 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 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 (Section 1.3 and Section 1.4). The participants may be 
rescreened once during the open screening period and 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. 
• 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 provided by the 
study site. The medication log might look different for AD patients and healthy volunteers. 
• The maximum amount of blood collected from each participant, if any, 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. 
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Procedures Performed at the Screening/Baseline Visit 
Assessments performed at the screening and/or baseline visit include informed consent/assent 
form, medical/surgical history, medication history, IGA, demographics, prior/concomitant 
medication/procedure, confirm emollient and washing compliance, and diagnosis of chronic AD. 
Atopic dermatitis disease characteristics are assessed by clinical evaluations and PROs. Baseline 
skin barrier function and structure evaluated by TEWL, STS, OCT, and FTIR. 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Transepidermal water loss assessment and skin tape stripping  
8.1.1.1 Transepidermal water loss assessment  
TEWL is a skin barrier function test that measures perspiration or water loss through the skin. 
TEWL is generally higher in AD skin compared with normal skin as the barrier is disrupted 
allowing water to evaporate more readily. If the barrier improves with dupilumab treatment, then 
TEWL will 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. Participants 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°C to 23°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 to Week 28 (EoS). 
The first TEWL assessment at each visit will be conducted each of the 3 × 2 spots in predefined 
lesional and non-lesional areas. After start of STS all subsequent TEWL assessments at each visit 
will be done on the single lesional and non-lesional spot respectively (see also Figure 3 and 
Figure 4).  
8.1.1.2 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 in the predefined skin areas. 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 AUC for TEWL measurements over a defined number of 
STS reflects the overall function of the stratum corneum. 
This procedure involves the defined, non-invasive application of a commercially available 
adhesive sheet on the surface of the skin at predefined areas and then peeling it off the skin 
(= the STS 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. 
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 STS.  
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Healthy volunteers will undergo skin barrier function tests at time points according to Section 1.4 
before, and after STS. 
Specifically, lipidomics, proteomics, and transcriptomics samples will be collected by STS at 
baseline, and Weeks 2, 4, 8, 12, 16, 22, and 28. A total 20 skin tapes will be collected in lesional, 
non-lesional, and normal skin at each STS visit. 
In order to allow the skin to recover from STS, 3 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 at least 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/healthy skin  
 
TEWL assessment in lesional, non-lesional, and normal skin (healthy subject) will be conducted 
before, and after STS (Figure 3 and Figure 4). A total of 20 tape strips for lesional and non-
lesional skin in AD patients and normal skin in healthy subjects will be collected, stored, and 
analyzed for lipidomics, proteomic, and transcriptomic analyses. 
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Figure 3 - TEWL assessment and STS in lesional skin of AD patients  
 
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Figure 4 - TEWL assessment and STS in non-lesional skin of AD patients and in normal skin of 
healthy volunteers  
 
 
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Figure 5 - STS assessment in 3 spots within the predefined lesional and non-lesional skin area in 
AD patients and in normal skin area in healthy children  
 
AD = Atopic Dermatitis; STS = Skin Tape Stripping. 
The detailed procedure for TEWL, STS, and collecting and storing skin tapes for lipidomic, 
proteomic, and transcriptomic analyses will be provided in the study reference manual. Details 
about lipidomic, proteomic, and transcriptomic analyses by time point will be provided in the 
statistical analysis plan (SAP). 
8.1.2 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 (predose). 
Subsequent photographs of the same area will be taken at each visit (except Weeks 10 and 14) 
until Week 16, and at follow-up visits at Week 22 and Week 28 and premature EoT.  
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 28 in healthy volunteers. 
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. 
Full body photographs will be taken for documentation purposes.  
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All photographs should be taken before the first TEWL assessment at each visit. Further 
instructions for taking the photographs and additional information on the parameters to be 
analyzed will be provided in the study reference manual. 
8.1.3 Clinician-reported outcome assessments (ClinROs) and patient reported outcome 
assessments (PROs)  
Patient reported outcome (PRO) assessments will only be conducted in AD patients. Patient 
reported outcome assessments 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/and or baseline visit. 
The electronic diary (eDiary) will be only used for PRO data collection. These PRO measures 
(questionnaires and Numerical Rating Scale [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. For the questionnaires 
completed by caregivers (eg, Patient Oriented Eczema Measure [POEM]), to ensure consistency 
in perception over longitudinal administration and to minimize respondent variability, it is 
important that the same caregiver complete the questionnaire at each time point. This should be 
communicated to caregivers during consent and prior to the first completion of the questionnaire. 
8.1.4 Eczema area and severity index (EASI)  
The Eczema Area and Severity Index (EASI) is a validated ClinRO measure used in clinical 
practice and clinical trials to assess the severity and extent of AD (37). 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 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 and 
neck, 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. 
8.1.5 Individual signs score  
The individual signs score (ISS) also called Global Individual Signs Score (GISS), is ClinRO 
assessment scale used to evaluate individual targeted 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 collected at time 
points according to Section 1.3. 
The ISS will be provided in the study reference manual. 
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8.1.6 Worst itch numerical rating scale  
The worst itch NRS includes 2 items asking about the “worst itching” experienced by the child: 
one that addresses the worst itching “last night” and one that addresses the worst itching “today.” 
Both items are rated by the child with AD using an 11-point NRS in which, 0 indicates no itching 
and 10 indicates the worst itching possible, with figures depicting the 0 and 10 anchors on each 
scale. 
The worst itch NRS will be administered via eDiary, at time points according to Section 1.3. 
8.1.7 Sleep disturbance numerical rating scale  
The Sleep disturbance numerical rating scale (NRS) consists in one item asking the patients to 
rate how their sleep has been affected last night, using a scale from 0 (Best possible sleep) to 
10 (Worst sleep possible). 
Patients will complete the rating scale daily from Day-7 until Week 4, and then until Week 28 
(EoS) at the week before the visits as indicated at Section 1.3. 
The sleep disturbance NRS will be provided in the study reference manual. 
8.1.8 Skin pain numerical rating scale  
Skin pain NRS includes 2 items asking about the “worst skin pain” experienced: one that 
addresses the worst skin pain “last night” and one that addresses the worst skin pain “today.” Both 
items are rated by the child with AD using an 11-point NRS in which 0 indicates “not at all” and 
10 indicates “worst pain possible”. 
The skin pain NRS will be administered via eDiary, at time points according to Section 1.3. 
8.1.9 Patient oriented eczema measure (POEM)  
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults (38). The format is a response to 7-items (dryness, 
itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency of these disease 
symptoms 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). Total scores range from 0 to 28, with higher scores indicating greater frequency 
of AD symptoms and sleep disturbance. 
Charman et al. (2013) proposed the following severity score bands for POEM scores, derived 
from analysis of data collected from 1000 children and adults with AD: 0 to 2 for clear or almost 
clear, 3 to 7 for mild AD, 8 to 16 for moderate AD, 17 to 24 for severe AD, and 25 to 28 for very 
severe AD (39). The proxy version will be used, ie, the questionnaire asks the caregiver to report 
their perception of patient’s AD symptoms. It is therefore completed by the caregiver.  
The questionnaire will be administered at time points according to Section 1.3. 
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8.1.10 Children's dermatology life quality index (CDLQI)  
Children's dermatology life quality index (CDLQI) is the respective, validated version of DLQI to 
be used in adolescents and younger children (cartoon version) (40). Waters et al. (2010) proposed 
the following severity bands for CDLQI scores: 0 to 1 for no effect on a child’s life, 2 to 6 for 
small effect on a child’s life, 7 to 12 for moderate effect on a child’s life, 13 to 18 for very large 
effect on a child’s life, and 19 to 30 for extremely large effect on a child’s life (41). 
The questionnaire will be administered at time points according to Section 1.3.  
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3 and 
Section 1.4). 
8.2.1 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 AE. 
8.2.2 Vital signs  
Vital signs, including heart rate, blood pressure, pulse rate, body temperature, and respiratory rate 
will be collected prior to TEWL assessments at time points according to Section 1.3 and 
Section 1.4. Heart rate, blood pressure, and respiratory rate will be measured with the patient in 
sitting position, after the patient has rested comfortably for at least 5 minutes. 
8.2.3 Laboratory testing  
Urinalysis for pregnancy testing will be performed for all female of childbearing potential. Urine 
pregnancy testing will be performed at time points according to Section 1.3 and Section 1.4. 
Please also refer to Section 8.7 for any laboratory testing. 
8.2.4 Electrocardiograms  
No electrocardiogram (ECG) assessments are required in this study. 
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8.2.5 Clinical safety laboratory assessments  
No clinical safety laboratory assessments are required in this study. 
8.2.6 Suicidal ideation and behavior risk monitoring  
Not applicable for this study. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse events 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 which 
cause the participant to discontinue the study intervention (see Section 7).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
according to the SoA (Section 1.3 and Section 1.4). 
All AEs 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 AEs 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 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. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs 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. 
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8.3.3 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, AESI 
(as defined in Section 8.3.8), 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). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification within 24 hours by the Investigator to the Sponsor of an SAE is 
essential so that legal obligations and ethical responsibilities toward 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 
(IRBs)/Independent Ethics Committees (IECs), 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 
- 
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 an 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. 
8.3.5 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 as SAEs. 
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8.3.6 Cardiovascular and death events  
Not applicable. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.8 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. 
• Keratitis. 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms). 
Patients who experience AESI related to eye disorders will also be referred to an ophthalmologist 
(preferably with expertise in treating pediatric patients or Cornea and External Eye Disease 
[“front-of-the-eye”] subspecialty expert). Further evaluation of these AESIs will be performed 
including any additional tests, if applicable, as per the discretion of the ophthalmologist.  
The following events also require reporting to the Sponsor within 24 hours of learning of the 
events: 
• Pregnancy of a female subject entered in the study as well as pregnancy occurring in a 
female partner of a male subject entered in the study. 
- 
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 1 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. 
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- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
• Significant alanine transaminase (ALT) elevation. 
- 
ALT >5 × the upper limit of normal (ULN) in participants with baseline ALT 
≤2 × ULN; 
or 
- 
ALT >8 × ULN if baseline ALT >2 × 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 AE forms. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
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. 
8.3.9 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. 
8.4 
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 eCRF. 
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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. 
8.5 
PHARMACOKINETICS  
Pharmacokinetic parameters are not evaluated in this study. 
8.6 
PHARMACODYNAMICS  
Pharmacodynamics parameters are evaluated using TEWL assessments as described in 
Section 8.1.1. 
8.7 
GENETICS  
A saliva swab sample for DNA isolation will be collected at baseline from all participants for 
FLG gene sequencing analysis. Saliva swab samples for DNA isolation should be collected on 
Day 1/Baseline (predose), but may be collected at any study visit.  
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 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.  
In the event of DNA isolation failure, a replacement genetic 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 5 (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 
in the study at a facility selected by the Sponsor. 
8.8 
BIOMARKERS  
Collection of skin samples for lipidomics, proteomics, and transcriptomics analyses is an 
important part of this study. 
8.8.1 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). 
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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. 
Skin lipidomics 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. 
8.8.1.1 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 (42). Filaggrin deficiency leads to impaired lipid profile 
and altered acidification pathways (43). Lipid abnormalities have been reported in patients with 
FLG mutations (44).  
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. 
8.8.1.2 Analysis of stratum corneum lipids  
It has been reported that lesional and non-lesional skin of AD patients has decreased EOS CER 
and other CER with very long-chain fatty acids (C22-C30), and increased short-chain fatty acids 
NS CER (C16-C22) (17). Highly hydrophobic omega-esterified acid sphingosine CER (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 (17). 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 Liquid Chromatography with tandem Mass 
Spectrometry (LC-MS/MS). All mass spectrometric data will be normalized to the total amount of 
hydrolyzed protein determined. 
EOS CER and NS CER will be identified and quantified using a targeted ultra-high performance 
liquid chromatography electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). 
8.8.1.3 Quantification of protein bound ceramides  
Protein bound ceramides are formed from EOS CER and represent a portion of EOS CER without 
linoleic acid, thus having a terminal hydroxyl group N-linked fatty acid. Protein-bound ceramides 
are released from proteins during protein hydrolysis. After protein determination in hydrolysates, 
freed omega-OH CER will be extracted and omega hydroxy fatty acid containing CER will be 
detected by the UHPLC-ESI-MS/MS. Values obtained will be normalized against protein content 
in the samples. 
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Detailed guidelines and requirements for samples preparation, handling of skin tapes after 
stripping, and storage and shipment of such skin tapes will be provided in the study reference 
manual. 
8.8.2 Proteomics assessment  
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: 
• 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. 
8.8.3 Skin tape transcriptome  
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 (3, 13) 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. 
8.8.4 Optical coherence tomography (OCT)  
Structural and Angiographic OCT scans using the Vivosight OCT machine  
Optical coherence tomography (OCT) is a non-invasive imaging modality conceptually similar to 
ultrasound but uses near-infrared radiation rather than sound. It has a 2 to 10 µ depth resolution 
compared with 100 to 1 000 µ typical for clinical ultrasound; and 1 to 2 mm imaging depth vs. 
10 to 100 mm for clinical ultrasound. It is thus ideal for imaging the surface layers of accessible 
tissues such as the skin. It is attracting interest throughout the medical community as a scanning 
tool and for diagnosis of illnesses such as epithelial cancer, connective tissue disorders, and 
atherosclerosis.  
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The Vivosight OCT device will be used to provide information for both structural and 
angiographic OCT outcomes. 
1. Structural OCT: With a depth focus of 1.0 mm and optical resolution of 7.5 × 5.0 µm the 
Vivosight provides structural images of the skin comparable to histology sections. From 
these images the thickness of the epidermis, the suprapapillary epidermis, and the papillary 
region can be extrapolated. Epidermal thickness has been identified using histology, as a 
useful biomarker of disease activity and treatment effects in AD.  
2. Angiographic OCT: Structural OCT performed at high image frame rates can map areas of 
temporal decorrelation due to moving red blood cells. Based on this, demonstrated that the 
Vivosight can acquire high-quality maps of the superficial vasculature in living 
participants and is an ideal tool to monitor and quantify erythema, hyperplasia, and 
TCS-induced tissue remodeling.  
The OCT assessments will be performed before STS/TEWL assessments at each designated visit 
from Week 0 to Week 28 (see Section 1.3, Section 1.4 and Figure 6). Two scans will be taken 
from each target area (separate, adjacent, sites for each scan) at each designated visit. All images 
will be checked for quality upon collection, and images with visible imaging artifacts will be 
re-captured. Any part of the device in contact with human skin (the stand-off) will be 
decontaminated between uses. 
Details of OCT operation and OCT data analysis will be provided in a separate study reference 
manual.  
Figure 6 - OCT and FTIR assessments in lesional and non-lesional skin of AD patients and in 
normal skin of healthy volunteers  
 
8.8.5 Attenuated total reflectance (ATR) Fourier-transform infrared (FTIR) spectroscopy  
Attenuated Total Reflectance (ATR) FTIR spectroscopy is a form of molecular spectroscopy 
useful for the analysis of surfaces, including the lipid, water, and carboxylate content of the skin 
barrier and for analyzing lipid arrangement/structure (23, 24, 25, 26, 27).  
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In this study the Agilent 4300 handheld FTIR spectrometer will be used. Measurements will be 
performed by gently but firmly placing the probe in contact with the skin. Duplicate 
measurements will be collected from each target site at the visits indicated in the schedule of 
events. The quality of spectra will be assessed at the point of collection, and any that do not meet 
the established quality parameters (signal to noise ratio) will be discarded. After use in each 
participant the ATR (probe head) will be decontaminated with 70% alcohol wipe. 
The FTIR assessments will be performed before and during the STS assessments at 
each designated visit (see Section 1.3, Section 1.4 and Figure 6).  
Detailed measurement and data collection from FTIR will be provided in a separate study manual. 
8.8.6 Optional samples for biomarker research  
The following optional serum and plasma samples for biomarker research should be collected 
from participants in the study, where possible: 
• Venous blood samples (not more than 12 mL in total) will be collected at baseline and 
EoT/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 intervention 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 Clinical Study 
Report (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 in the study at a facility selected by the Sponsor. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
No antibodies to dupilumab will be evaluated in this study.  
8.10 
HEALTH ECONOMICS  
Not applicable. 
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9 
STATISTICAL CONSIDERATIONS  
The statistical methodology presented in this section constitutes the SAP for the study. However, 
biomarkers’ analyses: ie, lipidomics, FLG genotyping, proteomics, and transcriptomics, will be 
detailed in a specific SAP. If the SAP 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 SAP or an appropriate statistical technical document (STD) reflecting the 
changes will be issued prior to database lock or any interim analysis. 
If no major changes to the statistical analysis planned in the present document are needed, a STD 
will be issued to document only technical conventions used for the analyses (and minor 
modifications from the planned analyses, if any). 
There will be 2 analyses, 1 for the treatment phase and 1 for the follow-up period. The analysis of 
the treatment phase will be based on all patients and performed on data collected until the EoT 
visit (Week 16). This will be done once the last evaluable participant has completed his/her EoT 
visit. The analysis of the follow-up period will be based on all participants and all data. 
The following definitions will be used in this section: 
• Cohort: the study includes 2 cohorts: patients with moderate-to-severe AD cohort and a 
healthy volunteers cohort. 
• Group: 3 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 judgment and is consistent 
with the sample size from similar studies in the literature (4). 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.  
Allowing for drop-out rate of 15%, a total of approximately 24 pediatric 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 Week 16, 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 minimal. 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 informed consent form (ICF) 
Intent-to-treat (ITT) 
The ITT population includes all enrolled patients, who received at least 1 dose of investigational 
medicinal product (IMP) and all enrolled healthy volunteers who have at least 1 transepidermal 
water loss (TEWL)/ skin tape stripping (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 atopic dermatitis 
(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 1 dose of IMP or had 
at least 1 TEWL/STS assessment and all healthy volunteers who have at least 1 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 intervention intake, will be fully 
documented in the body of the CSR. 
A listing of subjects with treatment discontinuation will be provided. 
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 
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. 
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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 CSR. 
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 modified 
intent-to-treat (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 PROs, and skin barrier function, will be 
presented along with the on-treatment summary statistics in the 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 Day 1 (Week 0), for patients and as the last available and evaluable value at Day 1 
(Week 0) 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, if so, the 3 spots will be analyzed separately. 
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 Day 1 
(Week 0) 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, IMP, and IMP batch number) will 
be sorted by patient. 
9.4.5.1 Extent of investigational medicinal product exposure  
Duration of IMP exposure is defined regardless of unplanned intermittent discontinuations as:  
• Dose regimen 1: the last dose date - first dose date + 28 days 
• Dose regimen 2: the last dose date - first dose date + 14 days. 
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 a significant number of patients 
using rescue therapy are observed during the study treatment phase, visit values removed due to 
use of rescue therapy will be imputed. The imputation methods applied will be described in the 
SAP. Rescue medication may be allowed during the study follow-up period at the discretion of the 
Investigator.  
9.4.7.1 Description of efficacy variable(s)  
Efficacy parameters are described in Section 8.1. 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 intent-to-treat (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, if deemed appropriate (eg, by FLG mutation status). 
TEWL data collected at the same visit from without and before STS measurement on each of the 
3 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 
1-sided paired t-test at a Type 1 error level of alpha=0.05 
(H0: 0 ≤ TEWLWeek 16-TEWLbaseline, Ha: 0 > TEWLWeek 16-TEWLbaseline).  
Point estimate, 2-sided 90% confidence interval and corresponding 1-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 healthy volunteers.  
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 healthy volunteers. 
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 healthy volunteers. 
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 healthy volunteers. 
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. 
Change (percent and absolute) in TEWL before STS 
on lesional skin in AD patients over time. 
Change (percent and absolute) in TEWL before STS 
on non-lesional skin in AD patients over time. 
Change (percent and absolute) in TEWL before STS 
on normal skin in healthy volunteers over time. 
Change (percent and absolute) in TEWL after STS 
assessed on lesional skin in AD patients over time. 
Change (percent and absolute) in TEWL after STS 
assessed on non-lesional skin in AD patients over 
time. 
Change (percent and absolute) 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. For follow-up period data, change from Week16 (or last visit prior to 
use of rescue treatment) will also be reported.Profiles over study days will 
be generated for individual values and group means for raw data and 
absolute change from baseline/Week 16. 
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. 
Additional analyses using linear mixed model to explore the evolution of 
TEWL over time in the different conditions might be performed. 
As an exploratory analysis, the time to improvement of skin barrier function for 
lesional and non-lesional skin area measured by TEWL will be summarized for 
the treatment phase. Improvement is defined as time to the first post-baseline 
day for which at least 1 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. 
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Endpoint 
Statistical analysis methods 
Change (percent and absolute) in 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. 
As all TEWL values are expected to be positive, area under the TEWL 
curve will be calculated using the trapezoidal method over the 20 STS 
(measurement at every 5 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. For 
follow-up period data, change from Week16 (or last visit prior to use of 
rescue treatment) will also be reported.  
Profiles over study days will be generated for individual values and group 
means for raw data and absolute change from baseline/Week 16. 
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 for the treatment phase. 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 
over time. 
Global characterization of protein-bound CER over 
time. 
Lipidomics data will be summarized with descriptive statistics. Multivariate 
unsupervised and supervised analyses will be performed as appropriate. 
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. 
Change (percent and absolute) in epidermal 
hypertrophy parameters including epidermal 
thickness (µm), superficial plexus depth (µm), blood 
vessel diameter (µm) and density (segments/mm2) 
measured by OCT over time. 
Change (percent and absolute) in stratum corneum 
lipid structure measured by FTIR spectroscopy in 
conjunction with tape-stripping 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 and time points. For 
follow-up period data, change from Week16 (or last visit prior to use of 
rescue treatment) will also be reported.  
Profiles over study days will be generated for individual values and group 
means for raw data and absolute change from baseline/Week 16. 
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. 
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Endpoint 
Statistical analysis methods 
Change (percent and absolute) in CDLQI over time.  
Change (percent and absolute) in EASI over time. 
Change (percent and absolute) in ISS for target 
lesion over time. 
Change (percent and absolute) in POEM over time. 
Change (percent and absolute) in assessment of 
worst itch NRS over time. 
Change (percent and absolute) in sleep disturbance 
NRS over time. 
Change (percent and absolute) in skin pain NRS over 
time. 
Change (percent and absolute) in photograph outputs 
(eg, severity score) obtained from skin imaging 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 and time points. For 
follow-up period data, change from Week16 (or last visit prior to use of 
rescue treatment) will also be reported. 
Correlation between baseline values of TEWL before 
and after STS, and TEWL AUC in lesional and 
non-lesional skin of AD patients with the following 
baseline measures: 
• 
EASI  
• 
Targeted lesion ISS 
• 
PRO measures (POEM, CDLQI, worst itch 
NRS, sleep disturbance NRS, and skin pain 
NRS) 
• 
Lipidomics in STS (ratio of EOS CER to NS 
CER) 
• 
FLG breakdown products of UCA and PCA 
concentrations in STS 
• 
Image-derived severity score in targeted 
lesional skin 
• 
Key components of skin proteomics in STS 
(expression of proteins associated with skin 
barrier function) 
• 
Quantified epidermal hypertrophy and 
structure changes in OCT and FTIR 
measures 
• 
Key components of gene expression from 
transcriptomics 
Correlation between percent change from baseline in 
TEWL before and after STS, and TEWL AUC in 
lesional and non-lesional skin of AD patients at Week 
8,Week 16 and Week 28 with corresponding change 
from baseline in the following measures: 
• 
EASI  
• 
Targeted lesion ISS 
• 
PRO measures (POEM, CDLQI, worst itch 
NRS, sleep disturbance NRS, and skin pain 
NRS) 
Scatterplot to visualize the form of the relationship between variables will 
be produced for patients’ cohort at specific time points: ie, baseline, 
Week 8, Week 16 and Week 28, based on the mITT population. 
 
Pearson correlation will be assessed at each defined time points for EASI, 
ISS, POEM, CDLQI, worst itch NRS, sleep disturbance NRS, skin pain 
NRS, photograph outputs, OCT outputs:ie, epidermal thickness, 
supervidial plexus depth, blood vessel diameter and density, FTIR 
measures and key components of protein and gene expression. 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 an exploratory analysis repeated measures correlation method might 
be used to assess the overall correlation pooling data from baseline, Week 
8, Week 16 and Week 28 (45). 
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Endpoint 
Statistical analysis methods 
• 
Lipidomics in STS (ratio of EOS CER to NS 
CER) 
• 
FLG breakdown products of UCA and PCA 
concentrations in STS 
• 
Image-derived severity score in targeted 
lesional skin 
• 
Key components of skin proteomics in STS 
(expression of proteins associated with skin 
barrier function) 
• 
Quantified epidermal hypertrophy and 
structure changes in OCT and FTIR 
measures 
• 
Key components of gene expression from 
transcriptomics 
AD = Atopic dermatitis; AE = Adverse Events; AD = Atopic Dermatitis; AUC = area under curve; CDLQI = Children's Dermatology Life Quality 
Index; EASI = Eczema Area and Severity Index; EoT = End of Treatment Phase; EoS = End of Study; EOS CER = E for esterified/O for 
omega-hydroxy/S for sphingosin ceramides; FLG = Filaggrin; FTIR = Fourier-transform infrared spectroscopy; IGA = Investigator Global 
Assessment; ISS = Individual Signs Score; mITT = modified intention-to-treat; NRS = Numerical Rating Scale; NS CER = non-hydroxy fatty acid 
sphingosine ceramides; OCT = optical coherence tomography; PCA = pyrrolidone carboxylic acid; PRO = patient reported outcome; 
POEM = Patient Oriented Eczema Measure; SAE = Serious Adverse Events; SC = Subcutaneous; SD = standard deviation; STS = Skin Tape 
Stripping; TEWL = Transepidermal Water Loss; UCA = urocanic acid; UNSCH = unscheduled; V = Visit; W = Week 
9.4.8 Safety analyses  
The safety evaluation will be based on the review of vital signs parameters and reported AEs. The 
safety analysis will be conducted according to the Sponsor’s document “Analysis and reporting of 
safety data from Clinical Trials through the CSR” (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 EoT 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 (including the follow-up period). 
Treatment-emergent AEs 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 EoS 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 1 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 healthy 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, 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 Day 1 (Visit 02, Week 0) 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 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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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. 
As it is an open-label study with no predefined hypothesis testing there is no issue regarding 
blinding or multiplicity adjustment.  
There will be 2 analyses, 1 for the treatment phase and 1 for the follow-up period. None of these 
will be considered as interim analysis. 
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 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 and the parents, or guardians of participants must be informed that their 
participation is voluntary. The parents, or guardians of participants 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.  
• For the children participation, local law must be observed in deciding whether 1 or both 
parents/guardians consent is required. If only 1 parent or guardian signs the consent form, 
the Investigator must document the reason for only 1 parent or guardian’s signature. 
• 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. 
• The parents, or guardians of 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.  
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The ICF will contain a separate section that addresses 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 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. 
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.  
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 (46) 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 and the parents, or guardians of participants 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 and the parents, or guardians of participants 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 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
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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 eCRF 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 eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• 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 eCRF 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 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 female of childbearing 
potential)a  
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 fulfill 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, electrocardiogram, 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 fulfill the definition of 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. 
• 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. 
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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 1 of the 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. 
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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 eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE eCRF 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. 
• 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. 
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• The Investigator will also consult the Investigator’s Brochure 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 1 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 eCRF. 
• 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 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. 
• 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 or to the Sponsor by 
telephone. 
• Contacts for SAE reporting can be found in the study reference manual. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A female in this study is considered fertile following menarche. 
If fertility is unclear and a menstrual cycle cannot be confirmed before first dose of study 
intervention, additional evaluation should be considered. 
Females in premenarchal are not considered WOCBP 
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 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. 
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. 
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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 
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 8.3.5.  
• 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. 
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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 saliva 
swab sample will be collected for DNA analysis from consenting participants. 
• For all participants, a saliva swab sample will be collected for FLG gene sequencing 
analysis. 
• For participants, who consent to optional genetic research, a saliva swab sample will be 
collected and isolated DNA will be stored for broad genetic analysis, which may include, 
but is not limited to, whole genome or exome sequencing. 
• 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 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 events 
AESI: 
adverse events of special interest 
ALT: 
alanine transaminase 
ATR: 
attenuated total reflectance 
AUC: 
area under the curve 
BMI: 
body mass index 
CER: 
ceramides 
COVID-19: 
coronavirus disease 2019 
CSR: 
clinical study report 
EASI: 
eczema area and severity index 
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eCRF: 
electronic case report form 
eDiary: 
electronic diary 
EoS: 
end of study 
EOS: 
E for esterified/O for omega-hydroxy/S for sphingosin 
EoT: 
end of treatment 
FLG: 
filaggrin 
FTIR: 
fourier transform infrared spectroscopy 
GCP: 
Good Clinical Practice 
ICF: 
informed consent form 
ICH: 
International Council for Hormonisation 
IEC: 
Independent Ethics Committees 
IGA: 
Investigator Global Assessment 
IL: 
interleukin 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
ISS: 
individual signs score 
ITT: 
intent-to-treat 
LC-ESI-MS/MS: liquid chromatography electrospray ionization tandem mass spectrometry 
LC-MS/MS: 
liqulid chromatography with tandem mass spectrometry 
mITT: 
modified intent-to-treat 
NRS: 
numerical rating scale 
NS: 
non-hydroxy fatty acid sphingosine  
OCT: 
optical coherence tomography 
PCA: 
pyrrolidone carboxylic acid 
PCSA: 
potentially clinically significantly abnormalities 
POEM: 
patient oriented eczema measure 
PRO: 
patient reported outcome 
PT: 
preferred term 
QOL: 
quality of life 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SD: 
standard deviation 
SoA: 
schedule of activities 
SOC: 
system organ class 
STD: 
statistical technical document 
SUSAR: 
suspected unexpected serious adverse reactions 
TCS: 
topical corticosteroid 
TEAE: 
treatment emergent adverse events 
TEWL: 
transepidermal water loss 
UHPLC-ESI-MS/MS: 
ultra-high performance liqulid chromatography electrospray 
ionization mass spectroscopy 
ULN: 
upper limit of normal 
 
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10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY  
Not applicable. 
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11 
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27. Takada S, Naito S, Sonoda J, Miyauchi Y. Noninvasive in vivo measurement of natural 
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29. Fluhr JW, Feingold KR, Elias PM. Transepidermal water loss reflects permeability barrier 
status: validation in human and rodent in vivo and ex vivo models. Exp Dermatol. 
2006;15(7):483-92. 
30. Elias PM. Skin barrier function. Curr Allergy Asthma Rep. 2008;8(4):299-305. 
31. 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(6):1333-6. 
32. 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(10):2224-33. 
33. Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler AJ, Fluhr JW, 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(2):198-208. 
34. 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(2):345-50. 
35. Clausen ML, Slotved HC, Krogfelt KA, Agner T. Tape stripping technique for stratum 
corneum protein analysis. Sci Rep. 2016;28(6):19918. 
36. Koppes SA, Brans R, Ljubojevic Hadzavdic S, Frings-Dresen 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(3):187-93. 
37. 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):11-18. 
38. 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(12):1513-9. 
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39. Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Translating Patient-Oriented Eczema 
Measure (POEM) scores into clinical practice by suggesting severity strata derived using 
anchor-based methods. Br J Dermatol. 2013;169(6):1326-32. 
40. Lewis-Jones MS, Finlay AY. The children's dermatology life quality index (CDLQI): initial 
validation and practical use. Br J Dermatol. 1995;132(6):942-9. 
41. Waters A, Sandhu D, Beattie P, Ezughah F, Lewis-Jones S. Severity stratification of 
Children’s Dermatology Life Quality Index (CDLQI) scores. Br J Dermatol. 2010;163 (Suppl 
1):121. 
42. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic 
diseases. N Eng J Med. 2011;365(14):1315-27. 
43. 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(3):746-53. 
44. 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(5):2252-63. 
45. Bakdash JZ, Marusich LR. Repeated measures correlation. Front Psychol. 2017;8:456. 
46. 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(6):595-605. 
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SAP_001.pdf: 
            16.1.9 Statistical analysis plan
Page 1


Table of Contents
16.1.9 Statistical analysis plan ..........................................................................................................
16.1.9.1 Statistical analysis plan ..........................................................................................................
16.1.9.2 Statistical analysis plan - Biomarker .....................................................................................
1
3
42
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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 
According to template: QSD-004258 VERSION N°4.0 (20-FEB-2019) 
Page 1 
STATISTICAL ANALYSIS PLAN 
OPEN-LABEL EXPLORATORY STUDY TO EVALUATE THE EFFECT OF 
DUPILUMAB ON SKIN BARRIER FUNCTION IN PEDIATRIC PATIENTS WITH 
MODERATE-TO-SEVERE ATOPIC DERMATITIS 
STUDY NUMBER: LPS16764 
STUDY NAME: PELISTAD 
COMPOUND: SAR231893/REGN668 
SANOFI STATISTICIAN: 
 
SERVICE PROVIDER STATISTICIAN: 
) 
DATE OF ISSUE: 13-Dec-2022 
VERSION: 1 
Total number of pages: 
38 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 4 
1 
OVERVIEW AND STUDY PLAN ..................................................................................................... 5 
1.1 
STUDY DESIGN .............................................................................................................................. 5 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objective .............................................................................................................................. 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.2.3 
Tertiary/exploratory objectives ......................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 7 
1.5 
MODIFICATIONS FROM THE PROTOCOL ................................................................................... 8 
1.6 
MODIFICATIONS FROM THE APPROVED STATISTICAL ANALYSIS PLAN .............................. 9 
2 
COLLECTED DATA ...................................................................................................................... 10 
3 
GENERAL STATISTICAL APPROACH ....................................................................................... 11 
4 
ANALYSIS OF PATIENT DATA ................................................................................................... 12 
4.1 
ANALYSIS VARIABLES ................................................................................................................ 12 
4.1.1 
Baseline variables .......................................................................................................................... 12 
4.1.2 
Main evaluation variable(s) ............................................................................................................ 12 
4.1.3 
Secondary evaluation variable(s) ................................................................................................... 12 
4.1.4 
Tertiary/exploratory evaluation variable(s) ..................................................................................... 13 
4.2 
ANALYSIS POPULATIONS ........................................................................................................... 14 
4.2.1 
Enrolled population ........................................................................................................................ 14 
4.2.2 
Intent-to-treat population ................................................................................................................ 14 
4.2.3 
Modified Intent-to-treat population ................................................................................................. 15 
4.2.4 
Safety population ........................................................................................................................... 15 
4.3 
STATISTICAL METHODS ............................................................................................................. 15 
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Statistical Analysis Plan  
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4.3.1 
Disposition of patients .................................................................................................................... 15 
4.3.1.1 
Participant disposition .................................................................................................................... 15 
4.3.1.2 
Protocol deviations ......................................................................................................................... 16 
4.3.1.3 
Analysis populations ...................................................................................................................... 16 
4.3.2 
Analyses of baseline characteristics .............................................................................................. 16 
4.3.2.1 
Participant demographic characteristics, medical history, and diagnoses .................................... 16 
4.3.2.2 
Baseline efficacy parameters ......................................................................................................... 16 
4.3.2.3 
Baseline safety parameters ........................................................................................................... 17 
4.3.2.4 
Extent of study treatment exposure and compliance ..................................................................... 17 
4.3.2.5 
Prior/Concomitant medication/therapy ........................................................................................... 18 
4.3.3 
Analyses of evaluation variables .................................................................................................... 18 
4.3.3.1 
Analysis of main evaluation variable(s).......................................................................................... 18 
4.3.3.2 
Analyses of secondary evaluation variables .................................................................................. 19 
4.3.3.3 
Analyses of tertiary/exploratory evaluation variables ..................................................................... 21 
4.3.4 
Additional exploratory analyses ..................................................................................................... 21 
4.3.5 
Analyses of safety parameters ....................................................................................................... 22 
4.3.5.1 
Adverse events .............................................................................................................................. 22 
4.3.5.2 
Vital signs ....................................................................................................................................... 23 
4.3.5.3 
Clinical laboratory parameters ....................................................................................................... 24 
5 
DATA HANDLING CONVENTIONS .............................................................................................. 25 
5.1 
DATA HANDLING CONVENTIONS FOR PATIENT DATA ........................................................... 25 
5.2 
DATA HANDLING CONVENTIONS FOR PATIENT REPORTED OUTCOMES .......................... 25 
5.3 
MISSING DATA ............................................................................................................................. 25 
5.4 
DEFINITION OF REGIONS ........................................................................................................... 25 
5.5 
WINDOWS FOR TIME POINTS .................................................................................................... 25 
5.6 
STATISTICAL TECHNICAL ISSUES ............................................................................................. 26 
6 
INTERIM ANALYSIS ..................................................................................................................... 27 
7 
SOFTWARE DOCUMENTATION ................................................................................................. 28 
8 
LIST OF APPENDICES ................................................................................................................. 29 
8.1 
APPENDIX A GRAPHICAL STUDY DESIGN ............................................................................... 29 
8.2 
APPENDIX B SCHEDULE OF ACTIVITIES IN PEDIATRIC PATIENTS ...................................... 30 
8.3 
APPENDIX C SCHEDULE OF ACTIVITIES IN HEALTHY VOLUNTEERS .................................. 34 
8.4 
APPENDIX D POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) 
CRITERIA ...................................................................................................................................... 37 
9 
REFERENCES ............................................................................................................................... 38 
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Statistical Analysis Plan  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AD: 
atopic dermatitis 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AUC: 
area under the curve 
BMI: 
body mass index 
CDLQI: 
children's dermatology life quality index 
CI: 
confidence interval 
ClinRO: 
clinical-reported outcome 
DBP: 
diastolic blood pressure 
EASI: 
eczema area and severity index 
EoS: 
end of study 
EoT: 
end of treatment 
FLG: 
filaggrin 
FTIR: 
fourier-transform infrared 
HLGT: 
high level group term 
HLT: 
high level term 
ICH: 
international conference on harmonization 
IMP: 
investigational medicinal product (synonymous with study drug) 
ISS: 
individual signs score 
ITT: 
intention-to-treat 
LOCF: 
last observation carried forward 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified intention-to-treat 
NRS: 
numerical rating scale 
OCT: 
optical coherence tomography 
POEM: 
patient oriented eczema measure 
PRO: 
patient reported outcome 
PT: 
preferred term 
SAP: 
statistical analysis plan 
SAS: 
statistical analysis system® 
SBP: 
systolic blood pressure 
SC: 
subcutaneous 
SD: 
standard deviation 
SEM: 
standard error of the mean 
SOC: 
system organ class 
STS: 
skin tape stripping 
TEAE: 
treatment-emergent adverse event 
TEWL: 
transepidermal water loss 
V: 
visit 
W: 
week 
WHO-DD: 
world health organisation drug dictionary 
 
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Statistical Analysis Plan  
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1 
OVERVIEW AND STUDY PLAN 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical technique to be used to realize the analysis of data for study LPS16764 (short title: 
Dupilumab-pediatric skin barrier function and lipidomics study in patients with atopic dermatitis – 
PELISTAD). It is applicable for the analysis for the treatment phase and the analysis for the 
follow-up period. 
The analyses described are based upon the final clinical study protocol V1.0 dated 13 July 2020 
and will be prepared in accordance with the international conference on harmonization (ICH) E9 
Step 4 version dated 05 February 1998 (1).  
Objectives, endpoints and statistical analyses related to biomarkers (ie, lipidomics, Filaggrin 
(FLG) genotyping, proteomics, and transcriptomics) will be detailed in a specific dedicated SAP. 
The statistical analyses (except biomarkers analyses) will be performed by the Biostatistics 
department of BIOTRIAL BIOMETRICS in agreement with the Sponsor. 
The clinical SAP will be validated and signed before the study database for the treatment phase 
analysis is locked.  
1.1 
STUDY DESIGN 
Study design 
This is a Phase 4 open-label, exploratory study in three sites evaluating the effect of dupilumab on 
skin barrier function (as measured by transepidermal water loss (TEWL) before and after skin 
tape stripping [STS]) in pediatric patients aged between ≥6 and <12 years old with moderate-to-
severe atopic dermatitis (AD) with a healthy volunteer cohort as a reference comparator. Patients 
with moderate-to-severe AD will be included in the US site and patients with severe AD will be 
included in the EU site (UK). One more US site was initiated because the recruitment at the first 
US site was insufficient. 
Sample size 
Approximately 24 pediatric patients with moderate-to-severe AD will be enrolled. An 
approximately equal number of age, gender, location of targeted lesion area and site matched 
healthy volunteers serving as a reference comparator cohort will also be enrolled. 
Randomization 
Not applicable. 
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Treatment received 
Study participants will be assigned to study intervention as described below: 
• Up to 24 pediatric patients with moderate-to-severe AD will receive dupilumab. 
• Dose regimen 1: children with baseline 15 kg ≤body weight <30 kg will receive a 
subcutaneous (SC) loading dose of dupilumab 600 mg (2 injections of dupilumab 300 mg) 
on Day 1 (Week 0), followed by every 4-week SC dosing of dupilumab 300 mg from 
Week 4 to Week 12. 
• Dose regimen 2: children with baseline 30 kg ≤body weight <60 kg will receive a SC 
loading dose of dupilumab 400 mg (2 injections of dupilumab 200 mg) on Day 1 
(Week 0), followed by bi-weekly SC dosing of dupilumab 200 mg from Week 2 to 
Week 14. 
The treatment will be given to the pediatric patient (≥6 and <12 years of age) depending on its 
body weight. 
Duration of study period 
This is a 32-week study with a 4-week screening period, 16-week treatment phase designed to 
investigate dupilumab’s effect on skin barrier function in approximately 20 pediatric patients with 
moderate-to-severe AD, and a 12-week follow-up period. 
The graphical study design is detailed in Section 8 (Appendix A).  
1.2 
OBJECTIVES 
1.2.1 Primary objective 
The primary objective of this study is to evaluate changes in skin barrier function with TEWL 
assessed after STS in predefined lesional skin in pediatric patients with moderate-to-severe AD 
treated with dupilumab. 
1.2.2 Secondary objectives 
The secondary objectives are:  
1. To evaluate changes in skin barrier function with TEWL assessed after STS in predefined 
lesional and non-lesional skin in pediatric patients with moderate-to-severe AD treated 
with dupilumab in reference to normal skin of healthy volunteers. 
2. To evaluate time course of change in skin barrier function with TEWL assessed before and 
after STS in predefined lesional and non-lesional skin in pediatric patients with moderate-
to-severe AD during dupilumab treatment phase and follow-up period in reference to 
normal skin of healthy volunteers. 
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1.2.3 Tertiary/exploratory objectives 
The clinical tertiary/exploratory objectives are:  
1. To evaluate dupilumab treatment effect on epidermal hypertrophy and structure of skin 
barrier changes measured by optical coherence tomography (OCT) and fourier-transform 
infrared (FTIR) spectroscopy in both predefined lesional and non-lesional skin in pediatric 
patients with moderate-to-severe AD during dupilumab treatment phase and follow-up 
period in reference to normal skin of healthy volunteers. 
2. To explore the association of skin barrier function measured by TEWL with disease 
impact assessed by standard AD severity assessments (Eczema area and severity index 
[EASI], and individual signs score [ISS]), patient reported outcomes (PRO) (patient 
oriented eczema measure [POEM], children dermatology life questionnaire index 
[CDLQI], worst itch numerical rating scale [NRS], sleep disturbance NRS, skin pain 
NRS), standardized photos, and the skin barrier hypertrophy and structure profiles 
assessed by OCT and FTIR. 
1.3 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculation was performed for this exploratory study. It was based on 
medical/clinical judgment and is consistent with the sample size from similar studies in the 
literature (2). 
Allowing for drop-out rate of 15%, a total of approximately 24 pediatric patients with moderate-
to-severe AD will be enrolled to achieve 20 evaluable patients. 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. Any drop-out healthy volunteer for whom the 
matched patient is considered as evaluable will not be replaced. 
1.4 
STUDY PLAN 
The study will comprise of: 
• Screening period: Up to 4 weeks (Day -28 to Day -1) from signing the informed consent. 
• Baseline visit (Week 0, Day 1): Participants who remain eligible will be enrolled. 
• A 16-week open-label treatment phase for AD patients and a 16-week observation period 
for healthy volunteers. 
• Follow-up period for 12 weeks after the end of treatment (EoT) visit (Week 16). 
Dupilumab may be used as a rescue therapy for AD patients, if needed during follow-up 
period. 
Schedule of activities in pediatric patients and healthy volunteers are detailed in Section 8 
(Appendix B and Appendix C). 
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1.5 
MODIFICATIONS FROM THE PROTOCOL 
The following changes are added compared to the planned analysis detailed in the study protocol: 
• Overall addition: additional information to display on standard TFLs due to COVID19 
flags. 
• Addition of listing of participants and visits with reasons of exclusion for mITT population 
(see Section 4.3.1.3). 
• Removing of the listing of other baseline characteristics (see Section 4.3.2.1). 
• Due to strong variability between the 3 adjacent spots in a similar study conducted by the 
Sponsor, the mean of the 3 adjacent spots will not be appropriated. The analysis will be 
performed for each spot separately at a visit before/without STS measurement 
(see Section 4.3.2.2 and Section 4.3.3.2). 
• Update in the Baseline definition for efficacy: the value at Day 1 will be considered as 
baseline value (or value at Screening if the one at Day 1 is not available). For participants 
with a value at Day 1 collected after and close to the investigational medicinal product 
(IMP), the value at this visit could be considered as baseline (judged by clinicians without 
impact on statistical analysis) (see Section 4.3.2.2). 
• If a change in spot anatomical location changed versus Day 1 is identified and assessed by 
the study team as having a significant impact on skin barrier, only visits prior to the 
location change will be considered in the statistical analysis of TEWL data (see 
Section 4.3.3.1 and Section 4.3.3.2). 
• Use of a repeated measures mixed model to analyze primary and main secondary 
endpoints (see Section 4.3.3.1). 
• Addition of descriptive statistics on TEWL conditions (see Section 4.3.3.2). 
• Except for AUC derivation, TEWL data performed at unplanned number of STS will not 
be used (see Section 4.3.3.2). 
• Tertiary/exploratory endpoints will be analyzed also on the ITT population (see 
Section 4.3.3.2). 
• The following analyses will be added on ITT population only (see Section 4.3.4): 
- 
The comparison in TEWL between Day 1 and Week 16 will be performed by skin 
group (lesional and non-lesional skin area only), STS and spot using a non-parametric 
Wilcoxon signed-rank test. 
- 
The comparison in TEWL AUC between Day 1 and Week 16 will be performed by 
skin group (lesional and non-lesional skin area only) and spot using a non-parametric 
Wilcoxon signed-rank test. 
- 
The comparison AD participants (lesional skin area/non-lesional skin area) versus 
Healthy participants will be performed on TEWL data at Week 16 using a non-
parametric Wilcoxon signed-rank test. 
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- 
The comparison AD participants (lesional skin area/non-lesional skin area) versus 
Healthy participants will be performed on TEWL AUC data at Week 16 using a non-
parametric Wilcoxon signed-rank test. 
• Additional statistical analyses could be envisaged as the correlation analysis between the 
primary endpoint and quantitative global scores of standard AD severity assessments and 
PRO and the investigation of centre effect due to differences in clinical conditions 
observed in the similar study conducted by the Sponsor (see Section 4.3.4). 
1.6 
MODIFICATIONS FROM THE APPROVED STATISTICAL ANALYSIS PLAN 
Not applicable. 
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2 
COLLECTED DATA 
Data collected on AD patients and healthy volunteers at screening and baseline are:  
• Informed consent/assent form.  
• Inclusion and exclusion criteria. 
• Demographic data (age, sex, race and ethnicity). 
• Medical/surgical history. 
• Prior medications/procedures. 
• Physical measurements (height and body weight). 
• Urine pregnancy test for females with childbearing potential only. 
• AD disease characteristics are assessed by clinical-reported outcome assessments 
(ClinROs) (EASI and ISS) and PROs via eDiary (POEM, CDLQI and Worst itch/Sleep 
disturbance/Skin pain NRS). 
• Skin barrier function and structure evaluated by TEWL, STS, OCT, FTIR, and 2D and 3D 
photographs. 
• Safety will be assessed by adverse events, vital signs (including heart rate, systolic and 
diastolic blood pressure, pulse rate, body temperature, and respiratory rate), physical 
examination. 
• For AD patients only: attribution of the dose regimen for study treatment administration 
according to approved label. 
• Standardized photographs of (predefined lesional/non-lesional or healthy) skin area used 
for TEWL and standardized full body photographs. 
Data collected on AD patients and healthy volunteers after baseline (treatment phase (if 
applicable) and follow-up) are: 
• Urine pregnancy test for females with childbearing potential only. 
• Concomitant medications/procedures. 
• Safety will be assessed by adverse events, vital signs (including heart rate, systolic and 
diastolic blood pressure, pulse rate, body temperature, and respiratory rate) and physical 
examination. 
• AD disease characteristics are assessed by ClinROs (EASI and ISS) and PROs via eDiary 
(POEM, CDLQI and Worst itch/Sleep disturbance/Skin pain NRS). 
• Skin barrier function and structure evaluated by TEWL, STS, OCT, FTIR, and 2D and 3D 
photographs. 
• For AD patients only: study treatment administration according to approved label. 
• Standardized photographs of (predefined lesional/non-lesional or healthy) skin area used 
for TEWL and standardized full body photographs. 
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3 
GENERAL STATISTICAL APPROACH 
Two final analyses will be performed:  
• One for the treatment phase: based on all patients and performed on data collected until 
the EoT visit (Week 16). This will be done once the last evaluable participant has 
completed his/her EoT visit. 
• One for the follow-up period: based on all participants and all data. 
The quantitative variables will be summarized using the following parameters: 
• Number of non-missing data. 
• Mean. 
• Standard deviation (SD). 
• Standard Error of the Mean (SEM). 
• Median. 
• Minimum. 
• Maximum. 
The qualitative variables will be summarized using the following parameters: 
• Number of non-missing data, 
• Counts and percentages. 
Missing data or unknown responses will not be counted in the percentages. 
The following definitions will be used in this document: 
• Cohort: the study includes 2 cohorts: patients with moderate-to-severe AD cohort and a 
healthy volunteers cohort. 
• Group: 3 groups are identified: patients’ lesional skin area group, patients’ non-lesional- 
skin area group, and healthy volunteers’ normal skin group. 
 
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4 
ANALYSIS OF PATIENT DATA 
4.1 
ANALYSIS VARIABLES 
4.1.1 Baseline variables 
Baseline characteristics (demographics, medical history, prior medications, vital signs, physical 
examination and disease characteristics) are collected. 
No electrocardiogram and clinical safety laboratory assessments are required in this study. 
4.1.2 Main evaluation variable(s) 
The primary endpoint is the percent change from baseline in TEWL after 5 STS assessed on 
lesional skin at Week 16 in AD patients. 
4.1.3 Secondary evaluation variable(s) 
The secondary endpoints are:  
• Change (percent and absolute) from baseline in TEWL after 5, 10, 15, 20 STS assessed on 
lesional skin at Week 16 in AD patients. 
• Change (percent and absolute) from baseline in TEWL after 5, 10, 15, 20 STS assessed on 
non-lesional skin at Week 16 in AD patients. 
• Change (percent and absolute) from baseline in TEWL after 5, 10, 15, 20 STS assessed on 
normal skin at Week 16 in 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) from baseline 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) from baseline 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) from baseline 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. 
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• 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. 
4.1.4 Tertiary/exploratory evaluation variable(s) 
The tertiary/exploratory endpoints are: 
• Change (percent and absolute) from baseline in epidermal hypertrophy parameters 
including epidermal thickness, superficial plexus depth, blood vessel diameter and density 
measured by OCT over time. 
• Change (percent and absolute) from baseline in stratum corneum lipid structure measured 
by FTIR spectroscopy in conjunction with tape-stripping over time. 
• Change (percent and absolute) from baseline in EASI (total score) over time. 
- 
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 be assessed for severity by the Investigator or 
designee on a intensity 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 and neck, 
trunk, upper limbs, and lower limbs, and converted to a area score of 0 to 6. In each 
body region, the area score 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%). 
- 
Even if the EASI scores are available in the SDTM database, the intermediate and total 
EASI scores will be derived as follows. However, only the total EASI score will be 
analyzed. 
i. Severity scores: for each region (Head and neck, Trunk, Upper limbs and 
Lower limbs), the severity score will be derived as follows, ranging from 0 to 
12: 
Severity score R = Intensity score Erythema, R + Intensity score Edema/Papulation, R + 
Intensity score Excoriation, R + Intensity score Lichenification, R,  
where R = region. 
ii. Region scores: for each region, the region score will be derived as follows: 
Region score R = Severity score R * Area score R * Multiplier 
where R = region, Multiplier = 0.1 (or 0.2 for children <8 years) for Head and 
Neck region, 0.3 for Trunk, 0.2 for Upper Limbs, 0.4 (or 0.3 for children 
<8 years) with the age calculated at each visit. 
iii. Total EASI score will be derived as the sum of the 4 region scores, ranging 
from 0 to 72. 
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• Change (percent and absolute) from baseline in ISS (total score) over time: 
- 
Total ISS score will be derived as the sum of the four target lesions (Erythema, 
Infiltration/Papulation, Excoriations and Lichenification), ranging from 0 to 12. 
• Change (percent and absolute) from baseline in POEM (total score) over time. 
• Change (percent and absolute) from baseline in CDLQI (total score) over time. 
• Change (percent and absolute) from baseline in assessment of worst itch NRS (scale) over 
time. 
• Change (percent and absolute) from baseline in sleep disturbance NRS (scale) over time. 
• Change (percent and absolute) from baseline in skin pain NRS (scale) over time. 
• Change (percent and absolute) from baseline in photograph outputs (TiVi and skin 
roughness indexes) obtained from skin imaging over time. 
• Correlation between baseline values of TEWL before and after STS, and TEWL AUC in 
lesional and non-lesional skin of AD patients with the following baseline measures: 
- 
EASI. 
- 
Targeted lesion ISS. 
- 
Image-derived severity score in targeted lesional skin. 
- 
Quantified epidermal hypertrophy and structure changes in OCT and FTIR. 
• Correlation between percent change from baseline in TEWL before and after STS, and 
TEWL AUC in lesional and non-lesional skin of AD patients at Week 8, Week 16 and 
Week 28 with corresponding change from baseline in the following measures: 
- 
EASI. 
- 
Targeted lesion ISS. 
- 
Image-derived severity score in targeted lesional skin. 
- 
Quantified epidermal hypertrophy and structure changes in OCT and FTIR. 
4.2 
ANALYSIS POPULATIONS 
The following analysis populations will be defined: 
4.2.1 Enrolled population 
The enrolled population will be defined by all participants who sign the informed consent form. 
4.2.2 Intent-to-treat population 
The intent-to-treat (ITT) population will include all enrolled patients, who received at least 1 dose 
of investigational medicinal product (IMP) and all enrolled healthy volunteers who have at least 
1 TEWL/STS assessment performed, irrespective of compliance with the study protocol and 
procedures. 
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The ITT population will be used for efficacy analyses. 
4.2.3 Modified Intent-to-treat population 
The modified intent-to-treat population (mITT) will include all ITT participants. If prohibited 
therapies for atopic dermatitis (AD) 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. 
The mITT population will be used for efficacy analyses. 
4.2.4 Safety population 
The safety population will include all patients, who actually received at least 1 dose of IMP or had 
at least 1 TEWL/STS assessment and all healthy volunteers who have at least 1 TEWL/STS 
assessment performed. 
4.3 
STATISTICAL METHODS 
All analysis variables will be described according to the methods defined in Section 3 for the 
description of continuous and categorical variables. 
The reporting of the efficacy and safety statistical analyses will be programmed according to the 
recommendations and templates of the BTD-009094 “Summarizing and reporting standard Early 
Development clinical trial data (except oncology)” Version 4.0 dated 02-Feb-2021. 
4.3.1 Disposition of patients 
4.3.1.1 Participant disposition 
A detailed description of participant accountability including count of participants by analysis 
populations, screen failure participants with reasons for screen failure, participants who did not 
complete the study observation period along with the main reason for study discontinuation 
(including the relationship to COVID19 for the reasons “Other” if any), and participants who 
requested permanent treatment discontinuation with the main reason for permanent treatment 
discontinuation (including the relationship to COVID19 for reasons “Adverse event”, 
“Withdrawal by subject” and “Other” if any), will be generated by cohorts. 
Participant disposition by centre/site will also be performed. 
All withdrawals from the study, taking place on or after study intervention intake, will be listed 
(including the column “Related to COVID19” if applicable). 
A listing of patients with treatment discontinuation will be provided (including the column 
“Related to COVID19” if applicable). 
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4.3.1.2 Protocol deviations 
Individual deviations to inclusion and exclusion criteria as reported by the Investigator will be 
listed. Major and critical deviations, other than those involving inclusion/exclusion, will be listed 
by participant (including the column “Related to COVID19” if applicable). 
4.3.1.3 Analysis populations 
The number of participants included in each study population (safety population and efficacy 
populations (ITT and mITT) will be provided. Participants (and visits for mITT population) with 
reasons of exclusion will be listed. 
4.3.2 Analyses of baseline characteristics 
4.3.2.1 Participant demographic characteristics, medical history, and diagnoses 
Continuous variables (age, weight and body mass index [BMI]) and qualitative variables (gender, 
race, ethnicity, and BMI [<20 / ≥20]) 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).  
Medical/surgical histories will be coded using the version of medical dictionary for regulatory 
activities (MedDRAMedDRA) in effect at Sanofi at the time of each database lock. 
Medical/surgical histories will be summarized by cohort and by system organ class (SOC), high 
level term (HLT) and preferred term (PT) and listed.  
Disease characteristics (ie, years since AD diagnosis at baseline) will be summarized by 
descriptive statistics for the mITT population. 
Matched participants will be listed. 
4.3.2.2 Baseline efficacy parameters 
For efficacy parameters, baseline is defined as the last available and evaluable value at Day 1 
(Week 0) (or at Screening if the value at Day 1 is not available) for patients and healthy 
volunteers.  
For TEWL data, the baseline value will be defined for each skin group and each number of STS 
(before/without STS, after 5 STS, after 10 STS, after 15 STS and after 20 STS). In addition for 
before/without STS, a baseline will be defined for each spot, due to strong variability between the 
3 adjacent spots in a similar study conduct by the Sponsor.  
Baseline efficacy values will be presented along with the subsequent efficacy values assessed 
during the on-treatment period. 
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4.3.2.3 Baseline safety parameters 
For vital sign parameters, baseline 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 
Day 1 (Week 0) for healthy volunteers. 
Baseline safety values will be presented along with subsequent safety values assessed during the 
study. 
4.3.2.4 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. 
A listing of patients receiving IMP from specified batch (patient, IMP, and IMP batch number) 
will be performed by patient. 
Extent of IMP exposure 
Duration of IMP exposure is defined regardless of unplanned intermittent discontinuations as: 
• Dose regimen 1: the last dose date - first dose date +28 days. 
• Dose regimen 2: the last dose date - first dose date +14 days. 
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 as 
quantitative and qualitative variables (1 day / 2 to 15 days / 16 to 29 days / 30 to 43 days / 44 to 
57 days / 58 to 71 days / 72 to 85 days / 86 to 99 days / 100 to 113 days / 114 to 155 days / 156 to 
197 days). This description could be performed by trial impact (disruption) due to COVID19 
(without and with). 
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. 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 
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given, as well as the number and percentage of patients with 0, ]0, 20%], and >20% under planned 
dosing administrations. 
4.3.2.5 Prior/Concomitant medication/therapy 
All medications taken during the study will be coded using the version of world health 
organization drug dictionary (WHO-DD) in effect at Sanofi at the time of each database lock. 
Medications will be classified into three categories, prior, concomitant and post-treatment 
medications, according to the following rules: 
• Prior medications are those the participant used before the first IMP administration. Prior 
medications can be discontinued before the first IMP administration or can be ongoing 
during the treatment phase. 
• Concomitant medications are any medications received by the participant concomitantly to 
the IMP, from the first IMP administration to the last IMP administration + 28 and 14 days 
for regimen dose 1 and regimen dose 2 respectively. 
• Post-treatment medications are those the participant took in the period running from the 
end of the concomitant medications period up to the end of the study. 
A given medication can be classified simultaneously as a prior, concomitant and post-treatment 
medication. If a medication date or time is missing or partially missing and it cannot be 
determined whether it was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
For each category of medications, medications will be summarized by cohort according to the 
WHO-DD dictionary, considering the first digit of the anatomic therapeutic class (ATC) 
(anatomic category) and the first three digits of the ATC class (therapeutic category). All ATC 
codes corresponding to a medication will be summarized, and participants will be counted once in 
each ATC category (anatomic or therapeutic) linked to the medication. Therefore, participants 
may be counted several times for the same medication. Concomitant medications will be listed 
separately by participants.  
4.3.3 Analyses of evaluation variables 
4.3.3.1 Analysis of main evaluation variable(s) 
The primary endpoint will be analyzed on the mITT population. As a sensitivity analysis, it will 
also be analyzed based on the ITT population. 
The calculation of changes (absolute and percent) from baseline will be based on the same 
number of STS (ie, for absolute change from baseline after 5 STS at W16: Change TEWL at W16 
after 5 STS = TEWL value at W16 after 5 STS – TEWL value at baseline after 5 STS). 
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If a change in spot anatomical location changed versus Day 1 is identified and assessed by the 
study team as having a significant impact on skin barrier, only visits prior to the location change 
will be considered in the statistical analysis of TEWL data.Raw data and change (absolute and 
percent) from baseline will be summarized with descriptive statistics by timepoint. 
Profiles over time (from baseline to Week 16) will be generated for individual values (spaghetti 
plot). 
For information purpose as study is not powered (no multiplicity correction will be applied): 
• For each number of STS, the evolution of the percent change from baseline over time will 
be analyzed using a repeated measures analysis of variance with visit, type of skin, 
interaction between visit and type of skin, age, and baseline value as fixed effects and 
subject identifier as random effect, at a Type 1 error level of alpha=0.05. In case of 
heterogeneity at baseline, additional covariates (ie, site, race …) could be added in this 
statistical model. 
• The following covariance structures will be tested in the REPEATED statement of the 
PROC MIXED: un, vc and cs at least. The structure with the smallest Bayesian 
information criteria will be selected for the final model. 
• Point estimate and two-sided 95% confidence interval and corresponding two-sided 
p-value will be reported for each effect. No comparison will be performed. 
• If assumption of normal distribution is strongly violated, transformation method could be 
used: eg, log transformation; normality assumption will be assessed through quantile-
quantile plot and Shapiro-Wilk test at 5% Type I error. 
4.3.3.2 Analyses of secondary evaluation variables 
The secondary endpoints will be analyzed on the mITT populations. 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. 
Due to high variability between the 3 adjacent spots for TEWL data in a similar study conducted 
by the Sponsor, the average of these 3 adjacent spots will not be appropriated. Consequently, 
TEWL data collected at the same visit from without or before STS measurement on each of the 
3 spots within the predefined skin areas will be analyzed by spot separately. The calculation of 
changes (absolute and percent) from baseline at a visit before/without STS measurement will be 
based on the same spot (ie, for absolute change from baseline at W2 before STS in spot 1: Change 
TEWL at W2 before STS in spot 1 = TEWL value at W2 before STS in spot 1 – TEWL value at 
baseline before STS in spot 1). The calculation of changes (absolute and percent) from baseline at 
a visit after STS measurement will be based on the same number of STS, as for the primary 
endpoint. 
If a change in spot anatomical location changed versus Day 1 is identified and assessed by the 
study team as having a significant impact on skin barrier, only visits prior to the location change 
will be considered in the statistical analysis of TEWL data. 
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For the analysis of change (percent and absolute) from baseline in TEWL after 5, 10, 15 and 
20 STS assessed on each skin group at Week 16, the similar approach, as for the analysis of 
primary endpoint, will be used. For each number of STS, point estimate, two-sided 95% 
confidence interval and corresponding two-sided p-value will be reported for each effect. No 
comparison will be performed. 
For the analyses of change (percent and absolute) from baseline in TEWL before/without and 
after each planned number of STS on each skin group over time:  
• Raw data and change (absolute and percent) from baseline will be summarized with 
descriptive statistics by skin group, number of STS and spot (if applicable), and timepoint. 
For follow-up period data, change from Week 16 (or last visit prior to use of rescue 
treatment) will also be reported. 
• Profiles over time will be generated for individual values (spaghetti plot) and group means 
(±SEM) for raw data and absolute change from baseline/Week 16 by skin group, number 
of STS and spot (if applicable). 
• As an exploratory analysis, the time to improvement of skin barrier function for lesional 
and non-lesional skin area measured by TEWL will be summarized for the treatment 
phase. Improvement is defined as time to the first post-baseline day for which at least 
1 TEWL measure of a patient is equal or lower than the TEWL median in the matched 
heathy volunteers over time. Results might be reported through Kaplan-Meier plot in case 
of high number of events. Time to improvement of skin barrier function for lesional and 
non-lesional skin area will also be listed. 
For the analyses of change (percent and absolute) from baseline in TEWL AUC (a composite 
measure before and after 5, 10, 15, and 20 STS) for skin barrier function in each skin group 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 20 STS (measurement at every 5 STS and 
all other unplanned number of STS) at each visit. For AUC derivation only, TEWL data 
performed at unplanned number of STS will be used.  
• Raw data and change (absolute and percent) from baseline will be summarized with 
descriptive statistics by skin group and timepoints. For follow-up period data, change from 
Week 16 (or last visit prior to use of rescue treatment) will also be reported.  
• Box plots over time will be generated for absolute change from baseline/Week 16.  
• As exploratory analysis, time to improvement of skin barrier function for lesional and non-
lesional skin area measured by TEWL AUC will be summarized for the treatment phase. 
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 in case of high number of events. 
TEWL conditions (ie, room temperature and humidity, etc.) will be summarized with descriptive 
statistics by timepoint. 
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4.3.3.3 Analyses of tertiary/exploratory evaluation variables 
The tertiary/exploratory endpoints will be analyzed on the mITT and ITT populations. 
For the analysis of change (percent and absolute) from baseline in epidermal hypertrophy 
parameters and in stratum corneum lipid structure over time, raw data and change (absolute and 
percent) from baseline will be summarized with descriptive statistics by skin group and timepoint. 
For follow-up period data, change from Week 16 (or last visit prior to use of rescue treatment) 
will also be reported. Profiles over time will be generated for individual values and group means 
for raw data and absolute change from baseline. 
For the analysis of the change (percent and absolute) from baseline in CDLQI, EASI, ISS for 
target lesion, POEM, assessment of worst itch NRS, sleep disturbance NRS, skin pain NRS, and 
photograph outputs (TiVi and skin roughness indexes) obtained from skin imaging over time, raw 
data and change (absolute and percent) from baseline will be summarized with descriptive 
statistics by skin group and timepoint. For follow-up period data, change from Week 16 (or last 
visit prior to use of rescue treatment) will also be reported. Profiles over time will be generated for 
individual values (spaghetti plot only for PRO measures [POEM, CDLQI, worst itch NRS, sleep 
disturbance NRS, and skin pain NRS]) and group means for raw data and absolute change from 
baseline (only for ClinROs measures [EASI and ISS]). 
A correlation analysis will also be investigated between baseline values of TEWL (before and 
after each number of STS), and TEWL AUC in lesional and non-lesional skin of AD patients with 
the following baseline measures: EASI, targeted lesion ISS, image-derived severity score in 
targeted lesional skin, and quantified epidermal hypertrophy and structure changes in OCT and 
FTIR measures. For this analysis, scatterplot to visualize the form of the relationship between 
variables will be produced for patients’ cohort at specific time points: baseline, Week 8, Week 16 
and Week 28. Pearson correlation will be assessed at each defined time point for EASI, ISS, 
photograph outputs, OCT outputs: epidermal thiceasikness, supervidial plexus depth, blood vessel 
diameter and density, and FTIR measures. Pearson correlation coefficient and p-value will be 
reported. Spearman’s rank correlation will be assessed at each defined timepoint for ISS. 
Spearman correlation coefficient and p-value will be reported. As an exploratory analysis repeated 
measures correlation method might be used to assess the overall correlation pooling data from 
baseline, Week 8, Week 16 and Week 28 (3). 
The same approach will be used to investigate the correlation between percent change from 
baseline in TEWL (before and after each number of STS), and TEWL AUC in lesional and non-
lesional skin of AD patients at Week 8, Week 16 and Week 28 with corresponding change from 
baseline of the aforementioned measures (ie, EASI, targeted lesion ISS …). 
4.3.4 Additional exploratory analyses 
In a similar study conducted by the Sponsor, differences in clinical conditions were also identified 
between centres (ie, room temperature in a specific centre higher than required by the study 
protocol). Consequently, the centre effect will be investigated and some covariates (ie, room 
temperature …) could be included in the statistical models. 
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Additionally, the following comparisons will be investigated on ITT population only: 
• The comparison in TEWL between Day 1 and Week 16 will be performed by skin group 
(lesional and non-lesional skin area only), STS and spot using a non-parametric Wilcoxon 
signed-rank test. 
• The comparison in TEWL AUC between Day 1 and Week 16 will be performed by skin 
group (lesional and non-lesional skin area only) and spot using a non-parametric Wilcoxon 
signed-rank test. 
• The comparison between AD participants (lesional skin area/non-lesional skin area) and 
Healthy participants will be performed on TEWL data at Week 16 using a non-parametric 
Wilcoxon signed-rank test. 
• The comparison AD participants (lesional skin area/non-lesional skin area) versus Healthy 
participants will be performed on TEWL AUC data at Week 16 using a non-parametric 
Wilcoxon signed-rank test. 
4.3.5 Analyses of safety parameters 
All the safety analyses will be performed using the safety population. When applicable, results 
will be by cohort and overall. 
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 
Version 3.0 dated on 24 May 2014). 
4.3.5.1 Adverse events 
Adverse events will be coded to a lower level term (LLT), PT, HLT, high level group term 
(HLGT) and primary SOC using the version of MedDRA in effect at Sanofi at the time of each 
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. 
• 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 EoT 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 (including the follow-up period). 
Treatment-emergent AEs 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. 
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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 EoS visit (EoS included). 
All AEs reported in the study will be listed, sorted by participant, onset date and time. 
The following TEAEs summaries will be provided for the patients’ cohort of the safety 
population: 
• Overview of TEAEs: number and percentage of participants 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 healthy volunteers will be summarized separately. 
In addition, the following listings/summary will be provided:  
• Listing of any deaths and serious AEs. 
• Listing of any AEs leading to permanent treatment discontinuation. 
• Number (%) of patients experiencing treatment emergent adverse events of special interest 
(AESI) will be presented by AESI category and PT, sorted by decreasing incidence of PT 
within each AESI category. 
• Listing of AESIs. 
• Number (%) of patients experiencing at least one treatment emergent COVID19 related 
adverse event by primary SOC and PT. 
4.3.5.2 Vital signs 
Heart rate, 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 baseline will be the Day 1 (Visit 2, Week 0) predose assessment. If any 
of the scheduled baseline tests are repeated for any participant, the last rechecked values will be 
considered as baseline, provided, for patients, they were done before the IMP administration of 
the respective treatment phase, and in the same condition. 
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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 
participants with potentially clinically significant abnormal (PCSA) values 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 participants with post-baseline PCSAs will be provided; values 
will be flagged when reaching the PCSA criteria. 
PCSA criteria are detailed in Section 8 (Appendix D). 
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 for patients’ cohort and 
scheduled time of measurement. 
For body weight, raw data and percent change from baseline will be summarized in descriptive 
statistics by cohort and scheduled time of measurement. 
4.3.5.3 Clinical laboratory parameters 
Positive results as well as all individual data for urine pregnancy tests (for women with 
childbearing potential only) will be listed. 
 
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5 
DATA HANDLING CONVENTIONS 
5.1 
DATA HANDLING CONVENTIONS FOR PATIENT DATA 
In all tables, figures, listings and in-texts, the following cohort labels will be used: 
• Healthy Participant. 
• AD Participant. 
5.2 
DATA HANDLING CONVENTIONS FOR PATIENT REPORTED OUTCOMES 
When multiple answers are reported by the patient, the data will be considered as missing. 
5.3 
MISSING DATA 
Missing data imputation (last observation carried forward (LOCF) method or another complex 
method) could be envisaged due to a high number of missing data and high variability. Sensitivity 
analyses could also be planned. 
5.4 
DEFINITION OF REGIONS 
Not applicable. 
5.5 
WINDOWS FOR TIME POINTS 
Except for the baselines, only observations from visits and/or timepoints planned in the protocol 
will be used in descriptive statistics. Usually, all timepoints planned in the protocol should be 
described. 
All the data collected from eDiary (Patient-reported outcome) were linked to a unique 
unscheduled visit in the SDTM database. To perform the analysis by visit, the following visit 
window algorithm is defined. 
 
VISIT WINDOW ALGORITHM 
Patient-Reported Outcomes 
Planned visits in the 
protocol 
Time interval for analysed visits 
Worst itch NRS 
Sleep disturbance NRS 
Skin pain NRS 
D1 
-1 to 1 day before the first IMP administration 
From D2 to D28 
x days after the first IMP administration for each Dx 
D36 
29 to 39 days after the first IMP administration 
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VISIT WINDOW ALGORITHM 
Patient-Reported Outcomes 
Planned visits in the 
protocol 
Time interval for analysed visits 
D43 
40 to 50 days after the first IMP administration 
D57 
51 to 71 days after the first IMP administration 
D85 
72 to 99 days after the first IMP administration 
D113 
100 to 134 days after the first IMP administration 
D155 
135 to 176 days after the first IMP administration 
D197 
177 to 200 days after the first IMP administration 
 
If more than one record occurs within the same visit window where only one assessment is 
expected, then the following rule will be applied: for D1, the last non-missing result prior to study 
drug administration will be used; for post-treatment assessments the closest non-missing result to 
the scheduled visit will be used.  
5.6 
STATISTICAL TECHNICAL ISSUES 
No hypothesis testing is predefined in this exploratory study. 
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6 
 INTERIM ANALYSIS 
An analysis of the primary and secondary endpoints was performed after the inclusion of 10 AD 
patients who have completed the TEWL assessments at Day 1. Descriptive statistics and plots 
were provided only. 
The interim analysis was 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 were analyzed. 
As it is an open-label study with no predefined hypothesis testing there is no issue regarding 
blinding or multiplicity adjustment. 
As specified in Section 3, two analyses will be conducted (one for the treatment phase and one for 
the follow-up period) but none of these will be considered as interim analysis. The analysis for the 
treatment phase will be descriptive and will include the following analyses: 
• Disposition of patients: participant disposition, analysis population, participant 
demographic characteristics, medical history, and diagnoses. 
• Efficacy analysis: descriptive statistics and the repeated measures mixed model of primary 
endpoint and secondary endpoints, and tertiary/exploratory endpoints [ClinROs (EASI and 
ISS) and PROs via eDiary (POEM, CDLQI and Worst itch/Sleep disturbance/Skin pain 
NRS) only]. 
• Safety analysis: TEAEs summaries only. 
 
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7 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS® software Version 9.4 (SAS 
institute Inc. Cary NC USA). 
 
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a 
For the purpose of this study, any female who has had her first menstrual period (menarche) and is sexually active will be considered to be of childbearing potential. Female patients who are not of 
childbearing potential at the start of the study but have the onset of menarche during the course of the study and are sexually active will also have to follow adequate birth control methods to continue 
participation in the study. These females must have a negative urine β-HCG pregnancy test at screening and at each visit (except patients who assigned to dose regimen 1 will not attend visits V9 (W10) 
and V11 (W14), therefore there’s no pregnancy test for these patients on both visits). Pregnancy will lead to definitive treatment discontinuation in all cases. 
b 
Emollients should NOT be applied from Day -7 to the EoS (Week 28) to the targeted, predefined 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. 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 provided by 
the study site. 
c 
Dose regimen 1: Children with baseline 15 kg ≤ body weight <30 kg will receive a SC loading dose of dupilumab 600 mg (2 injections of dupilumab 300 mg) on Day 1 (V02), followed by every 4-week SC 
dosing of dupilumab 300 mg until Week 12 (at Week 0 [(Day 1], Weeks 4, 8, and 12).  
Dose regimen 2: Children with baseline 30 kg ≤ body weight <60 kg will receive a SC loading dose of dupilumab 400 mg (2 injections of dupilumab 200 mg) on Day 1 (V02), followed by bi-weekly SC dosing of 
dupilumab 200 mg until Week 14 (at Week 0 (Day 1), Weeks 2, 4, 6, 8, 10, 12, and 14). 
d 
Assessments on treatment days have to be conducted before administration of dupilumab. 
e 
Predefined lesional and non-lesional skin areas. TEWL will be measured at each of the 3 closely adjacent spots within the predefined skin areas at all visits without STS and before STS at visits with STS. 
f 
TEWL will be conducted before STS and then after 5, 10, 15, and 20 STS in lesional skin and non-lesional skin. 
g 
At Weeks 0, 8, 16, and 28, 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 Weeks 4, 12, and 
22 STS will be conducted on the third spot within the predefined skin area. TEWL will be assessed in lesional skin and non-lesional skin before STS and after 5, 10, 15, and 20 STS. All skin tape strips 
should be collected and stored. 
h 
In case STS assessment is to be conducted at an unscheduled visit or at a premature EoT 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. 
i 
OCT will be done before STS/TWL, and FTIR will be done before and during STS. 
j 
Worst itch NRS, Sleep disturbance NRS and Skin pain NRS will be assessed daily from Day -7 to Day -1; daily from Day 1 to Week 4 and then 7 days prior to Week 6, Week 8, Week 12, Week 16, Week 
22, and to Week 28 by e-diary. 
k 
eDiary will be dispensed to the patients at screening (Visit 01) and will be collected on Week 28 (Visit 14). The PROs will be administered to patients via eDiary. Patients will bring the eDiary to the site at 
each visit, and it will be reviewed for any questionnaires omission and dispensed back to patients at each visit. 
l 
Vital signs, including heart rate, systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured. 
m 
Limited to skin-related physical examination at baseline, EoT visit (Week 16) and EoS (Week 28). 
n 
Saliva swab samples for DNA isolation should be collected on Day 1/Baseline (predose) for FLG gene sequencing analysis, but may be collected at any study visit. 
o 
Please refer to Section 8.8.6 of protocol for details. 
AE = Adverse Events; AD = Atopic Dermatitis; CDLQI = Children's Dermatology Life Quality Index; D= Day; EASI = Eczema Area and Severity Index; EoT = End of Treatment; EoS = End of Study; FLG = Filaggrin; 
IGA = Investigator Global Assessment; ISS = Individual Signs Score; NRS = Numerical Rating Scale; POEM = Patient Oriented Eczema Measure; SAE = Serious Adverse Events; SC = Subcutaneous; STS = Skin 
Tape Stripping; TEWL = Transepidermal Water Loss; UNSCH = unscheduled; V = Visit; W = Week; W = Women of Childbearing Potential.
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a 
For the purpose of this study, any female who has had her first menstrual period (menarche) and is sexually active will be considered to be of childbearing potential. Female patients who are not of 
childbearing potential at the start of the study but have the onset of menarche during the course of the study and are sexually active will also have to follow adequate birth control methods to continue 
participation in the study. These females must have a negative urine ß-HCG pregnancy test at screening and at each visit. Pregnancy will lead to definitive treatment discontinuation in all cases. 
b 
Emollients should NOT be applied from Day -7 to the EoS (Week 28) to the targeted, predefined skin areas that will be used for TEWL assessment. Participants should not take showers or soak in a bathtub 
within 6 hours before TEWL assessment. 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 provided by the study 
site. 
c 
TEWL will be measured at each of the 3 closely adjacent spots within the predefined skin areas at all visits without STS and before STS at visits with STS. 
d 
TEWL will 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 Weeks 0, 8, 16, and 28, 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 Weeks 4, 12, and 
22 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 should be collected and 
stored. 
f 
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. 
g 
OCT will be done before STS/TWL, and FTIR will be done before and during STS. 
h 
Vital signs, including heart rate, systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured.  
i 
Limited to skin-related physical examination at baseline, EoT visit (Week 16), and EoS (Week28). 
j 
Saliva swab samples for DNA isolation should be collected on Day 1/Baseline (predose) for FLG gene sequencing analysis, but may be collected at any study visit. 
k 
Please refer to Section 8.8.6 of protocol for details. 
AE = Adverse Events; AD = Atopic Dermatitis; CDLQI = Children's Dermatology Life Quality Index; D = Day; EASI = Eczema Area and Severity Index; EoT = End of Treatment; EoS = End of Study; FLG = Filaggrin; 
IGA = Investigator Global Assessment; NRS = Numerical Rating Scale; POEM = Patient Oriented Eczema Measure; SAE = Serious Adverse Events; SC = Subcutaneous; STS = Skin Tape Stripping; 
TEWL = Transepidermal Water Loss; V = Visit; W = Week; W = Women of Childbearing Potential. 
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8.4 
APPENDIX D POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA 
Table 3 - PCSA criteria for vital signs parameters for studies in children (24 May 2014) 
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  
 
6 to <12 years old (Children) 
80 mmHg and decrease from baseline 20 mmHg  
108 mmHg 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 
12 to 16/18 years old (Adolescents) 
90 mmHg and decrease from baseline 20 mmHg  
119mmHg and increase from baseline 20 mmHg 
DBP 
 
6 to <12 years old (Children) 
48 mmHg and decrease from baseline 10 mmHg  
72mHg and increase from baseline 10 mmHg  
12 to 16/18 years old (Adolescents) 
54 mmHg and decrease from baseline 10 mmHg  
78mHg and increase from baseline 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 
6 to <12 years old (Children) 
<18 per minutes  
>30 per minutes 
Based on normal range 
12 to 16/18 years old (Adolescents) 
<12 per minutes  
>20 per minutes 
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 
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9 
REFERENCES 
1. International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human use. ICH Harmonised tripartite guideline. Statistical Principles for 
Clinical Trials E9 – Current step 4 dated 5 February 1998. 
2. 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 
Dermatol. 2011;165(2):329-34. 
3. Bakdash JZ, Marusich LR. Repeated measures correlation. Front Psychol. 2017;8:456. 
 
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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 
 
According to template: QSD-004258 VERSION N°4.0 (20-FEB-2019) 
Page 1 
STATISTICAL ANALYSIS PLAN 
FOR TRANSLATIONAL RESEARCH 
PEdiatric skin barrier function and LIpidomics Study in patients with Atopic 
Dermatitis - PELISTAD 
 
Open label exploratory study to evaluate the effect of dupilumab on skin barrier 
function in pediatric patients with moderate to severe atopic dermatitis 
STUDY NUMBER: LPS16764 
STUDY NAME: PELISTAD 
COMPOUND: SAR231893/REGN668 
SANOFI STATISTICIAN: 
 
DATE OF ISSUE: 19-Dec-2022  
VERSION: 1.0 
 
 
Total number of pages: 
24 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
FOR TRANSLATIONAL RESEARCH ............................................................................................................ 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 5 
1.1 
INTRODUCTION .............................................................................................................................. 5 
1.2 
STUDY DESIGN .............................................................................................................................. 5 
1.2.1 
Graphical study design .................................................................................................................... 6 
1.3 
ANALYSIS ENDPOINTS ................................................................................................................. 6 
1.3.1 
Biomarkers ....................................................................................................................................... 6 
1.3.2 
Demographic and baseline characteristics ...................................................................................... 7 
1.3.3 
Efficacy endpoints ............................................................................................................................ 7 
1.4 
PATIENT AND SAMPLE DISPOSITION ......................................................................................... 9 
1.5 
ANALYSIS POPULATIONS ........................................................................................................... 10 
1.6 
BIOMARKER ANALYSIS OBJECTIVES ....................................................................................... 10 
1.7 
BIOMARKER ASSESSMENTS AND SCHEDULE ........................................................................ 10 
1.7.1 
Lipidomics, proteomics, and transcriptomics ................................................................................. 10 
1.7.2 
Optical coherence tomography (OCT) ........................................................................................... 11 
1.7.3 
Attenuated total reflectance (ATR) FTIR spectroscopy ................................................................. 11 
1.7.4 
Optional samples for biomarker research ...................................................................................... 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 12 
2.1 
PREPROCESSING AND QUALITY CONTROL ............................................................................ 12 
2.1.1 
Data normalization ......................................................................................................................... 12 
2.1.1.1 
Lipidomics ...................................................................................................................................... 12 
2.1.1.2 
Proteomics ..................................................................................................................................... 12 
2.1.1.3 
Transcriptomics .............................................................................................................................. 12 
2.1.2 
Missing data, outlier, and batch effect assessment ....................................................................... 13 
2.1.2.1 
Data imputation .............................................................................................................................. 13 
2.1.2.2 
Outlier detection ............................................................................................................................. 13 
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Page 3 
2.1.2.3 
Batch effect assessment ................................................................................................................ 14 
2.2 
DESCRIPTIVE STATISTICS AND VISUALIZATION .................................................................... 14 
2.2.1 
Descriptive statistics....................................................................................................................... 14 
2.2.2 
Data Visualization .......................................................................................................................... 14 
2.3 
CLUSTER ANALYSIS .................................................................................................................... 15 
2.3.1 
Patients clustering .......................................................................................................................... 15 
2.3.2 
Biomarker clustering at baseline .................................................................................................... 16 
2.4 
CORRELATION ANALYSIS .......................................................................................................... 16 
2.4.1 
Correlation between biomarker and TEWL .................................................................................... 16 
2.4.2 
Correlation between biomarker and clinical and disease parameters ........................................... 16 
2.4.3 
Intra-class Correlation Coefficient .................................................................................................. 16 
2.5 
IDENTIFICATION OF BIOMARKERS ........................................................................................... 17 
2.5.1 
Differentially expressed biomarkers ............................................................................................... 17 
2.5.2 
Discriminative biomarkers .............................................................................................................. 17 
2.5.3 
Predictive biomarkers..................................................................................................................... 17 
2.6 
MULTIPLICITY ISSUE ................................................................................................................... 18 
2.7 
BIOINFORMATICS METHODS AND RESULTS INTERPRETATION .......................................... 18 
2.7.1 
Analyses based on biomarkers regulated by treatment from longitudinal analysis of RNA-
seq.................................................................................................................................................. 18 
2.7.2 
Functional protein association networks ........................................................................................ 18 
3 
SOFTWARE DOCUMENTATION ................................................................................................. 19 
4 
SUPPLEMENTARY INFORMATION ............................................................................................ 20 
4.1 
DETAILED BIOMARKER ASSESSMENTS ................................................................................... 20 
4.1.1 
Lipidomics ...................................................................................................................................... 20 
4.1.1.1 
Filaggrin breakdown products ........................................................................................................ 20 
4.1.1.2 
Analysis of stratum corneum lipids ................................................................................................ 20 
4.1.1.3 
Quantification of protein bound ceramides .................................................................................... 20 
4.1.2 
Proteomics ..................................................................................................................................... 21 
4.1.3 
Transcriptomics .............................................................................................................................. 21 
4.1.4 
Optical coherence tomography ...................................................................................................... 21 
4.1.5 
ATR FTIR spectroscopy ................................................................................................................. 22 
4.1.6 
Optional samples for biomarker research ...................................................................................... 22 
5 
REFERENCES ............................................................................................................................... 24 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AD: 
atopic dermatitis 
ANOVA: 
analysis of variance 
ATR: 
attenuated total reflectance 
AUC: 
area under the curve 
BMI: 
body mass index 
CDLQI: 
children's dermatology life quality index 
ClinRO: 
clinician reported outcome assessments 
cpm: 
count per million 
CSR: 
clinical study report 
EASI: 
eczema area and severity index 
FLG: 
filaggrin 
FTIR: 
Fourier transform infrared 
IL: 
interleukin 
IPA: 
ingenuity pathway analysis 
IQR: 
interquartile range 
ISS: 
individual signs score 
LLOQ: 
lower limit of quantification 
MDS: 
multidimensional scaling 
NRS: 
numerical rating scale 
OCT: 
optical coherence tomography 
PCA: 
pyroglutamic acid, principal component analysis 
POEM: 
patient oriented eczema measure 
PRO: 
patient reported outcome 
SD: 
standard deviation 
SEM: 
standard error of mean 
STS: 
skin tape stripping 
TEWL: 
transepidermal water loss 
t-SNE: 
t-distributed stochastic neighbor embedding 
UCA: 
urocanic acid 
VST: 
variance stabilizing transformation 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
INTRODUCTION 
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. 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. 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. 
Dupilumab is a human monoclonal antibody 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. Dupilumab is recently approved in the US for the 
treatment of pediatric patients ≥6 and <12 years of age with moderate-to-severe AD whose 
disease is not adequately controlled with topical prescription therapies or when those therapies are 
not advisable. 
The LPS16764 study is an open label exploratory phase 4 study designed for assessing the effect 
of subcutaneous injection of dupilumab on skin barrier function measured as transepidermal water 
loss (TEWL) in AD pediatric patients. The effect of dupilumab treatment on skin barrier function 
is evaluated using TEWL in conjugation with skin lipidomics, proteomics, and transcriptomics 
generated from skin tape stripping (STS) samples. Skin barrier structure changes is evaluated 
using optical coherence tomography (OCT) and Fourier-Transform Infrared (FTIR) spectroscopy 
in both predefined lesional and non-lesional skin areas. 
This document provides a statistical analysis plan for all biomarker data repeatedly collected 
during the LPS16764 study. The term biomarker in this document will then refer to lipidomics, 
proteomics, transcriptomics, or filaggrin (FLG) breakdown products. TEWL may refer to a 
measurement before STS; after a given number of STS samplings or can be AUC (area under the 
curve) of TEWL before STS and after STSs performed at the specified STS visits. The term study 
group or group in general refers to lesional, non-lesional or normal health skin group. This 
biomarker statistical analysis plan is based on clinical trial protocol Version 1 (13-Jul-2020).  
1.2 
STUDY DESIGN 
LPS16764 is a Phase 4 open-label, exploratory study in two sites evaluating the effect of 
dupilumab on skin barrier function in pediatric patients aged between ≥6 and <12 years old with 
moderate-to-severe AD. A healthy volunteer cohort will be enrolled as a reference comparator 
matched to AD for age-, gender-, study-site and sampling will be matched on targeted lesion area. 
Approximately 24 pediatric patients with moderate-to-severe AD will be enrolled to 
achieve 20 evaluable patients. These enrolled AD patients will receive Investigational 
medicinal product (IMP) dupilumab treatment during the study. Approximately 24 healthy 
volunteers will be enrolled to achieve 20 evaluable subjects. These enrolled healthy volunteers 
will not receive any IMP treatment during the study. 
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The maximum study duration per participant will be 32 weeks. The study will comprise of: 
• Screening period 1 (Day -28 to Day -1): Participants will be evaluated according to 
• Inclusion and exclusion criteria. 
• Baseline visit (Week 0, Day 1): Participants who remain eligible will be enrolled. 
• A 16-week treatment phase for AD patients and a 16-week observation period for healthy 
volunteers. 
• A 12-week follow-up period. 
Biomarker assessment based on lipidomics, proteomics, and transcriptomics in STS samples will 
be conducted at baseline (Week 0, Day 1), Week 2, Week 4, Week 8, Week 12, EoT at Week 16, 
and Follow-ups at Week 22 and Week 28.  
1.2.1 Graphical study design 
 
1.3 
ANALYSIS ENDPOINTS 
1.3.1 Biomarkers 
The followings are the list of biomarkers to be explored: 
• Lipidomics. 
• Proteomics. 
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• Transcriptomics. 
• FLG breakdown products. 
1.3.2 Demographic and baseline characteristics 
Baseline is defined as the last available and evaluable value before and closest to the first dose of 
the IMP: i.e., at Day 1 (Week 0), for patients and as the last available and evaluable value at 
Day 1(Week 0) for healthy volunteers. For TEWL data, the average of the values of 3 spots within 
each predefined skin area will be used as baseline, unless a large difference between the spots is 
observed, if so, the 3 spots will be analyzed separately. 
Demographic characteristics 
• Age. 
• Weight. 
• Sex. 
• Race. 
• Body Mass Index (BMI). 
Disease characteristics 
• TEWL: 
- 
TEWL before STS at each study visit 
- 
TEWL AUC, a composite measure before and after 5, 10, 15, and 20 STS 
- 
TEWL after each set of 5 STSs for up to 20 STSs 
• Clinician-reported outcome assessments (ClinROs) and patient reported outcome 
assessments (PROs). 
• Eczema area and severity index (EASI). 
• Individual signs score (ISS). 
• Worst itch numerical rating scale. 
• Sleep disturbance numerical rating scale. 
• Skin pain numerical rating scale. 
• Patient oriented eczema measure (POEM). 
• Children’s dermatology life quality index (CDLQI). 
1.3.3 Efficacy endpoints 
Primary efficacy endpoint is percent change from baseline in TEWL after 5 STS assessed on 
lesional skin at Week 15 in AD patients. 
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Secondary efficacy endpoints are: 
• Change (percent and absolute) from baseline in TEWL after 20 STS (after 15 STS, after 
10 STS) assessed on:  
- 
Lesional/non-lesional skin at Week 16 in AD patients 
- 
Normal skin at Week 16 in healthy volunteers 
•  Change (percent and absolute) from baseline in TEWL after 5 STS assessed on: 
- 
Non-lesional skin at Week 16 in AD patients 
- 
Normal skin at Week 16 in healthy volunteers 
• Change (percent and absolute) in TEWL before STS (after STS) on: 
- 
Lesional/non-lesional skin in AD patients over time 
- 
Normal skin in healthy volunteers 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: 
- 
Lesional/non-lesional skin in AD patients over time 
- 
Normal skin in healthy volunteer over time 
Tertiary (Exploratory) efficacy endpoints are: 
• 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 over time. 
• Global characterization of protein-bound CER over time. 
• Change (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. 
• Change (percent and absolute) in epidermal hypertrophy parameters including epidermal 
thickness (μm), superficial plexus depth (μm), blood vessel diameter (μm) and density 
(segments/mm2) measured by OCT over time. 
• Change (percent and absolute) in stratum corneum lipid structure measured by 
FTIR spectroscopy in conjunction with tape-stripping over time. 
• Changes in expression of genes associated with epidermal differentiation, barrier and lipid 
metabolism, and Type 2 inflammation over time. 
• Change (percent and absolute) in CDLQI over time. 
• Change (percent and absolute) in EASI over time. 
• Change (percent and absolute) in ISS for target lesion over time. 
• Change (percent and absolute) in POEM over time. 
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• Change (percent and absolute) in assessment of worst itch NRS over time. 
• Change (percent and absolute) in sleep disturbance NRS over time. 
• Change (percent and absolute) in skin pain NRS over time. 
• Change (percent and absolute) in photograph outputs (eg, severity score) obtained from 
skin imaging over time. 
• Correlation between baseline values of TEWL before and after STS, and TEWL AUC in 
lesional and non-lesional skin of AD patients with the following baseline measures: 
- 
EASI, Targeted lesion ISS, PRO measures (POEM, CDLQI, worst itch numerical 
rating scale (NRS), sleep disturbance NRS, and skin pain NRS), Lipidomics in STS 
(ratio of EOS CER to NS CER), FLG breakdown products of Urocanic Acid (UCA) 
and Pyroglutamic Acid (PCA) concentrations in STS, Image-derived severity score in 
targeted lesional skin, Key components of skin proteomics in STS (expression of 
proteins associated with skin barrier function), Quantified epidermal hypertrophy and 
structure changes in OCT and FTIR measures, Key components of gene expression 
from transcriptomics. 
• Correlation between percent change from baseline in TEWL before and after STS, and 
TEWL AUC in lesional and non-lesional skin of AD patients at Week 8, Week 16 and 
Week 28 with corresponding change from baseline in the following measures: 
- 
EASI, Targeted lesion ISS, PRO measures (POEM, CDLQI, worst itch NRS, sleep 
disturbance NRS, and skin pain NRS), Lipidomics in STS (ratio of EOS CER to NS 
CER), FLG breakdown products of UCA and PCA concentrations in STS, 
Image-derived severity score in targeted lesional skin, Key components of skin 
proteomics in STS (expression of proteins associated with skin barrier function), 
Quantified epidermal hypertrophy and structure changes in OCT and Fourier-
transform infrared (FTIR) measures, Key components of gene expression from 
transcriptomics. 
1.4 
PATIENT AND SAMPLE DISPOSITION 
A detailed description of participant accountability including count of participants by analysis 
populations, 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 intervention intake, will be fully 
documented in the body of the clinical study report (CSR). 
A listing of subjects with treatment discontinuation will be provided. 
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1.5 
ANALYSIS POPULATIONS 
Table 1 - Populations for analyses 
Population 
Description 
Baseline biomarker 
All participants who were enrolled in the study, who had a sample drawn for 
biomarker measurement and successfully analyzed at baseline. 
Pharmacodynamic (PD) 
All participants who were enrolled in the study, who had a sample drawn for 
biomarker measurement and successfully analyzed at baseline and at any post-
baseline visit. 
1.6 
BIOMARKER ANALYSIS OBJECTIVES 
The followings are the analysis objectives of biomarkers (lipidomics, proteomics, transcriptomics, 
FLG): 
• Evaluate dupilumab treatment effect on skin biomarkers using STS samples in both 
predefined lesional and non-lesional skin in pediatric patients with moderate-to-severe AD 
during dupilumab treatment phase and follow-up period in reference to normal skin of 
healthy volunteers. 
• Explore the association of skin barrier function measured by TEWL with disease impact 
assessed by standard AD severity assessments (EASI, and ISS), PRO (POEM, CDLQI, 
worst itch NRS, sleep disturbance NRS, )patient reported outcomes (PRO) (Patient 
Oriented Eczema Measure [POEM], Children Dermatology Life Questionnaire Index 
[CDLQI], worst itch Numerical Rating Scale [NRS], sleep disturbance NRS, skin pain 
NRS), standardized photos, the biomarker profiles of lipidomics, proteomics, FLG, and 
transcriptomics assessed in the STS samples, and the skin barrier hypertrophy and 
structure profiles assessed by OCT and FTIR. 
1.7 
BIOMARKER ASSESSMENTS AND SCHEDULE 
1.7.1 Lipidomics, proteomics, and transcriptomics 
Samples for skin lipidomic assessment are required and will be collected from all participants in 
this study.  
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. The 
detailed assessment plan for lipidomics is listed in Section 4.1.1. 
Protein extracts will be prepared from STS samples by LC-MS/MS. The detailed assessment plan 
for proteomics is listed in Section 4.1.2.  
Skin tapes will be collected for transcriptomic analysis. The detailed assessment plan for 
transcriptomics is listed in Section 4.1.3. 
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For both AD pediatric patients and healthy volunteers, samples are collected at Week 0, 2, 4, 8, 12, 
16, and 22. All STS will be conducted on the predefined spots. TEWL will be assessed before 
STS and after 5, 10, 15, and 20 STS in lesional and non-lesional skin (AD patients) and normal 
skin (healthy volunteer). Weeks and spot on which STS is conducted are   
• At Weeks 0, 8, 16, and 28, STS conducted on the first spot. 
• At Week 2, STS conducted on the second spot. 
• At Weeks 4, 12, 22, STS conducted on the third spot. 
All skin tape strips should be collected and stored. 
1.7.2 Optical coherence tomography (OCT) 
OCT is a non-invasive imaging modality conceptually like ultrasound but uses near-infrared 
radiation rather than sound. The detailed assessment plan for OCT is in Section 4.1.4. For both 
AD pediatric patients and healthy volunteers, samples for OCT are generated at Week 0, 1, 2, 3, 4, 
6, 8, 12, 16, and 28. OCT will be done before STS/TEWL. 
1.7.3 Attenuated total reflectance (ATR) FTIR spectroscopy 
ATR FTIR spectroscopy is a form of molecular spectroscopy useful for the analysis of surfaces, 
including the lipid, water, and carboxylate content of the skin barrier and for analyzing lipid 
arrangement/structure. The detailed assessment plan for FTIR spectroscopy is in Section 4.1.5. 
For both AD pediatric patients and healthy volunteers, samples for FTIR spectroscopy are 
generated at Week 0, 8, 16 and 28. FTIR will be done before and during STS. 
1.7.4 Optional samples for biomarker research 
The following optional serum and plasma samples for biomarker research should be collected 
from participants in the study, where possible. The detailed collection plan for optional samples is 
in Section 4.1.6. For both AD pediatric patients and healthy volunteers, optional blood samples 
are collected at Week 0 and 16. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
PREPROCESSING AND QUALITY CONTROL 
2.1.1 Data normalization 
2.1.1.1 Lipidomics 
STS samples processing for lipid extraction will be done as described in Section 4.1.1. Lipidomic 
data will be provided as absolute concentration in pmol/mg protein or in ug/mg protein requiring 
no normalization step. Values below limit of quantification (LLOQ), missing values, and outliers 
will be treated as described in Section 2.1.2. 
2.1.1.2 Proteomics 
There is no normalization step performed after sample analyses as specified by National Jewish 
Health (NJH). Polar metabolite samples will be normalized based on sample protein values before 
running the assay then signal intensities are expressed relative to healthy volunteers’ group.  
2.1.1.3 Transcriptomics 
Raw sequencing data (fastq files) will be taken through successive steps to generate expression 
measures at gene level (counts): quality control, adapter trimming and filtering, mapping of reads 
to the human reference genome or pseudo-alignment to the transcriptome, quantification. These 
steps will be performed by NJH. The raw and the preprocessed transcriptomic data will be sent to 
Sanofi.  
Samples filtering 
Total RNA from the skin tapes will be normalized for cDNA generation and preparation of 
sequencing libraries. Both the cDNA and sequencing libraries generated will be quantified and 
qualified using the Bioanalyzer High-Sensitivity DNA chip. Samples that will yield low quality 
cDNA and sequencing libraries will not be sequenced.  
Gene filtering 
Genes having very low counts across all libraries will be filtered out. For this purpose, the count 
per million (cpm) values will be computed. Counts per million are counts scaled by the number of 
sequenced fragments in a sample (library size) times one million. Genes with less than 1 cpm in 
more than half of the samples will be filtered out. This filtering rule will be applied separately for 
count data matrices in HV and AD cohorts. Genes that successfully pass the filter in at least one 
data set will be kept. The specific threshold of 1 cpm may be adjusted depending on count 
distribution in the dataset. 
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Normalization and transformation of counts data 
Normalization is a process designed to remove systematic technical differences between samples 
to ensure that technical bias has minimal impact on the results. One can envisage within-sample 
and between-samples normalization. In this study since we are interested in differential expression 
between experimental conditions rather than comparing expression of different genes in a sample, 
only a between-sample normalization will be performed. Using the DESeq2 R package, variance 
stabilizing transformation (VST) will be applied for analyses other than differential testing, for 
example clustering of samples or other machine learning applications. For differential testing 
the DESeq function will be applied to raw counts.  
Included in VST, a log2 transformation is performed after addition of a small offset to avoid 
taking the log of zero. The quality of the normalization will be assessed by plotting the densities 
of variance-stabilized counts for the different samples. Since it is assumed that most of the genes 
are unaffected by the experimental conditions, a successful normalization should lead to 
overlapping densities. The mean-variance association will also be investigated before and after 
normalization. Samples boxplots will be plotted before and after normalization. 
2.1.2 Missing data, outlier, and batch effect assessment 
2.1.2.1 Data imputation 
For each biomarker, the number of values below LLOQ will be computed by group (lesional, 
non-lesional and healthy skin). Values below LLOQ will be imputed according to the following 
rules: 
• If for a given biomarker, less than 25% of all samples have values below LLOQ, all values 
below LLOQ will be imputed by a random number draw from a uniform distribution in 
[0, LLOQ]. The minimum computed across all samples will be used if the LLOQ is not 
provided. 
• If more than 50% of samples have values below LLOQ, the biomarker will be discarded 
from statistical analyses 
• If the percentage of values below LLOQ is between 25% and 50%, it will be checked if 
the values below LLOQ occur mostly in a specific study group. The Fisher test will be 
used to check the dependency between the occurrence of below LLOQ and group.  
• The biomarker will be discarded from statistical analysis if the LLOQ occurrence is group 
independent. Values below LLOQ will be imputed by the minimum computed across all 
samples, otherwise. 
Missing values not due to measurements being below LLOQ maybe be imputed by the mean 
value computed across all samples, as appropriate. 
2.1.2.2 Outlier detection 
Biomarker will be investigated for outliers regardless of group or visit. A value will be declared 
outlier if it falls out of the interval [Q1-3*IQR, Q3+3*IQR], where Q1 denotes the first quartile, 
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Q3 the third quartile and IQR the interquartile range. Outliers will be imputed by Q1-3*IQR and 
Q3+3*IQR, respectively. Samples will be investigated for possible contamination that may lead to 
sample being outlier. For this purpose, samples boxplots, principal component analyses (PCA) 
hierarchical cluster dendrogram will used. Outlier samples will be scrutinized and maybe 
discarded from the statistical analyses. 
The distribution of biomarkers will be assessed by histogram and QQ-plot. The values may be 
log-transformed to fit a Gaussian distribution prior to some statistical analyses. The 
standardization may be performed for multivariate analyses.  
2.1.2.3 Batch effect assessment 
Samples maybe analyzed or transferred to NJH in different batches. PCA will be computed and a 
visual inspection of the projection of the samples on the first principal components will enable a 
first view of the potential batch’s effect. The batch effect will be assessed using a linear model 
estimating a batch effect for each biomarker. This model will include the batch effect, the visit, 
the health status and interaction between visit and health status. The relevance of the correction 
for batch effect will be assessed by the p-values of the batch effect. 
2.2 
DESCRIPTIVE STATISTICS AND VISUALIZATION 
2.2.1 Descriptive statistics 
For lipidomics and proteomics, the summary statistics (min, Q1, mean, median, Q3, max, SD and 
SEM) will be computed by group (lesional, non-lesional and healthy skin) and by visit. The 
summary statistics will be computed by age categories as appropriate.  
For OCT, raw data and change from baseline (absolute and percent changes) will be summarized 
with descriptive statistics (mean, median, SD, min, max) by groups and time points. For follow-up 
period data, change from Week16 (or last visit prior to use of rescue treatment) will also be 
reported. 
For FTIR, profiles over study days will be generated for individual values and group means for 
raw and absolute change from baseline and Week 16. 
2.2.2 Data Visualization 
Spaghetti plots  
The biomarker profiles will be represented graphically using line plots (one line per subject). The 
lines will be colored by group. Additional plots will be generated by age categories as appropriate.   
Profile plots  
For each biomarker, the mean ±SEM will be represented graphically by group and by visit for the 
absolute values and percent change from baseline. Additional plots will be generated by age 
categories as appropriate.   
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Boxplots 
Longitudinal boxplots for absolute values will be provided by group and by visit. Additional plots 
will be generated by age categories as appropriate. 
Heatmaps 
A heatmap representation will be provided for each biomarker data matrix highlighting the 
2 study groups (AD lesional, non-lesional and healthy volunteers) and different study visits. The 
age categories will be represented as appropriate. Biomarkers will be clustered according to an 
unsupervised clustering on Pearson correlation with Ward’s agglomeration technique and a 
dendrogram will be added to the map. Each biomarker will be centered to the mean and reduced 
to the unit standard deviation. To improve the readability a separate heatmap will be generated 
with only the baseline biomarker levels and different groups will be highlighted.   
Principal component plot 
PCA plot will be conducted on log-transformed and scaled data for each biomarker data matrix. 
The data will be visualized on a 2-dimensional plot of first principal component (PC1) versus 
PC2 highlighting potential group differences and change during the study. Confidence ellipses 
will be added as appropriate. A scatterplot with only the baseline samples may be generated to 
ease the readability. Depending on the percentage of variability explained on the PC1, a second 
technique for deriving a composite biomarker will be applied.   
Median polish 
A two-way decomposition (row effect + column effect + overall effect) of the data matrix with 
each biomarker type will be performed using the Tukey's median polish procedure. The biomarker 
will be on columns and the samples on rows. The row effect will be extracted as composite 
biomarker. 
Composite biomarker 
PC1 and the row effect from the median polish algorithm will be analyzed as composite 
biomarkers analog to single biomarker. This includes the correlation with TEWL values, the 
difference between the study groups and the change during the study. 
MDS and t-SNE 
Multidimensional scaling (MDS) and t-distributed stochastic neighbour embedding (t-SNE) will 
be applied for further visualization of the data on 2 dimensions highlighting the study groups.  
2.3 
CLUSTER ANALYSIS 
2.3.1 Patients clustering 
A hierarchical clustering of AD patients will be performed on baseline biomarker data using 
Euclidean distance and Ward agglomeration technique. This will enable the identification of 
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subgroups of homogeneous patients. The identified patients’ subgroups will be further 
investigated regarding the disease activity, disease progression and the response to the treatment 
(eg, longitudinal plots for mean ±SEM of TEWL by cluster, ANOVA model for TEWL at 
baseline with cluster as independent predictor), cross table and Chi2-test for clusters versus 
categorical parameters. 
For clusters definition, an elbow approach (silhouette or inertia by number of clusters) will be 
used for determining the optimal number of subgroups of patients using at least two different 
algorithms to ensure robustness (K-means and agglomerative clustering). 
2.3.2 Biomarker clustering at baseline 
Clustering of biomarker will be performed on biomarker expressions at baseline (using 
correlation-based distance metric). Biomarker clusters may be suggested to pathway analysis as 
appropriate. Heatmaps will be generated considering the biomarker clusters. 
2.4 
CORRELATION ANALYSIS 
2.4.1 Correlation between biomarker and TEWL 
In addition to the correlation analysis between each the composite biomarkers and the TEWL, the 
association between each single biomarker (lipidomics, proteomics, transcriptomics) and TEWL 
will be investigated at baseline in a linear model adjusted for the study group and age. TEWL at 
baseline will be evaluated as TEWL. Biomarker will be ranked according to their importance in 
explaining TEWL using RandomForest for regression.  The Correlation between change in 
biomarker and change in TEWL, the correlation between baseline biomarker and change in 
TEWL will be investigated. 
2.4.2 Correlation between biomarker and clinical and disease parameters 
Analog to TEWL, the correlation analyses will be done between each biomarker and the relevant 
clinical and disease parameters. Analysis of Variance (ANOVA) will be performed for categorical 
variables. 
2.4.3 Intra-class Correlation Coefficient 
Stability of repeated measurements will be assessed for each biomarker (lipids and proteins). For 
each biomarker, its measurement will be modeled as: 
𝑌𝑖𝑗 = 𝜇 + 𝛼𝑖 + 𝛽𝑗 + 𝜖𝑖𝑗 
for subject 𝑖 and visit j of the subject 𝑖 in a single arm (e.g., control arm) (1). Here we assume 
fixed visit effect 𝛽𝑗 but random subject effect 𝛼𝑖 and random error 𝜖𝑖𝑗. If we assume 
𝛼𝑖 ∼ 𝑁(0, 𝜎2 subject) and  𝜖𝑖𝑗 ∼ 𝑁(0, 𝜎2 error) and independence between them, the correlation of 
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measurements within a subject (also known as intra-class correlation coefficient or ICC) can be 
derived as  
 
where 𝜎2 total = 𝜎2 subject + 𝜎2 error. Large ICC value indicates strong stability of repeated 
measurements of the biomarker of a subject. 
2.5 
IDENTIFICATION OF BIOMARKERS 
2.5.1 Differentially expressed biomarkers 
The biomarker potentially linked to the disease status (lesional, non-lesion or healthy skin) and 
the biomarker changing with the treatment will be identified using a linear mixed model. For each 
biomarker, the following model will be used to test for any interaction between group and visit for 
group i, visit j and subject k: 
yijk = μ + groupi + Visitj + groupi Visitij + Subjk + εijk 
with group, visit and interaction between group and visit considered as fixed effects and subject as 
random effect. Baseline will be used as reference visit and healthy skin as reference group. The 
data will be log-transformed. A contrast matrix will be defined for extracted the comparison of 
interest such as group difference at baseline or at Week 16. The fold-changes will be derived, and 
volcano-plots will be provided as appropriate. The intersection between biomarker differentially 
expressed at baseline between lesional vs. non-lesional, lesional vs healthy skin and non-lesional 
vs. healthy skin will be represented graphically using Venn diagrams. The proportion of 
biomarker changing significantly from baseline to Week 16 will be derived for each study group. 
The direction of the changes will be highlighted.   
2.5.2 Discriminative biomarkers 
A multivariate predictive panel will be identified used Elastic-net penalized multinomial logistic 
regression and the predictive value of the panel will be estimated as 10-fold cross-validated as 
accuracy. Biomarkers will be ranked according to their importance in discriminating between 
Lesional, non-lesional and healthy skin groups as provided by RandomForest. 
2.5.3 Predictive biomarkers 
In case of any binary response defined a clinical endpoint, the predictive characteristics for each 
biomarker will be evaluated using a logistic regression model with the baseline biomarker and the 
response variable as binary outcome at Week 16. For the binary response at Week 16, a 
multivariate predictive panel will be identified used Elastic-net penalized logistic regression and 
the predictive value will be estimated as 10-fold cross-validated Area Under the ROC curve. 
These analyses will be computed for AD patients (lesional skin). Biomarkers will be ranked 
according to their importance in discriminating between responders and non-responders as 
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provided by RandomForest. A linear model will be used for change from baseline in clinical 
responses as continue parameters and baseline biomarker level.  
2.6 
MULTIPLICITY ISSUE 
All analyses will be exploratory. No formal hypothesis testing will be conducted. 
2.7 
BIOINFORMATICS METHODS AND RESULTS INTERPRETATION 
2.7.1 Analyses based on biomarkers regulated by treatment from longitudinal analysis of 
RNA-seq 
• Downstream effect analyses (GO terms, biological processes and diseases) of regulated 
gene sets in Ingenuity Pathway Analysis (IPA) to get mechanistic insights into 
disease-affected biological processes. 
• Pathway Enrichment Analyses (Over-representation analysis, t-test based) aimed to the 
identification of curated biological pathways involved in regulated gene patterns 
(MetaCore [Clarivate Analytics], IPA Core Analyses [Qiagen]) 
2.7.2 Functional protein association networks  
For identifying proteins sets, functional protein association networks will be built and interpreted 
using the String database.  
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3 
SOFTWARE DOCUMENTATION 
All analyses of clinical data will be performed under the responsibility of Sanofi Biostatistics 
Department using R software Version 4.0.0 (2). 
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4 
SUPPLEMENTARY INFORMATION 
4.1 
DETAILED BIOMARKER ASSESSMENTS 
4.1.1 Lipidomics 
Skin lipidomics 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 guidelines and requirements 
for samples preparation, handling of skin tapes after stripping, and storage and shipment of such 
skin tapes will be provided in the study reference manual. 
4.1.1.1 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. Filaggrin deficiency leads to impaired lipid profile 
and altered acidification pathways. Lipid abnormalities have been reported in patients with 
FLG mutations. 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. 
4.1.1.2  Analysis of stratum corneum lipids 
It has been reported that lesional and non-lesional skin of AD patients has decreased EOS CER 
and other CER with very long-chain fatty acids (C22-C30) and increased short-chain fatty acids 
NS CER (C16-C22). Highly hydrophobic omega-esterified acid sphingosine CER (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. 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 Liquid Chromatography with tandem Mass 
Spectrometry (LC-MS/MS). All mass spectrometric data will be normalized to the total amount of 
hydrolyzed protein determined. EOS CER and NS CER will be identified and quantified using a 
targeted ultra-high performance liquid chromatography electrospray ionization tandem mass 
spectrometry (UHPLC-ESI-MS/MS). 
4.1.1.3 Quantification of protein bound ceramides 
Protein bound ceramides are formed from EOS CER and represent a portion of EOS CER without 
linoleic acid, thus having a terminal hydroxyl group N-linked fatty acid. Protein-bound ceramides 
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are released from proteins during protein hydrolysis. After protein determination in hydrolysates, 
freed omega-OH CER will be extracted and omega hydroxy fatty acid containing CER will be 
detected by the UHPLC-ESI-MS/MS. Values obtained will be normalized against protein content 
in the samples. 
4.1.2 Proteomics 
The following 3 major functional groups of proteins associated with skin barrier function will be 
examined: 
• 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. 
4.1.3 Transcriptomics 
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 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. 
4.1.4 Optical coherence tomography  
Structural and Angiographic OCT scans using the Vivosight OCT machine 
OCT is a non-invasive imaging modality conceptually similar to ultrasound but uses near-infrared 
radiation rather than sound. It has a 2 to 10 μ depth resolution compared with 100 to 1 000 μ 
typical for clinical ultrasound; and 1 to 2 mm imaging depth vs. 10 to 100 mm for clinical 
ultrasound. It is thus ideal for imaging the surface layers of accessible tissues such as the skin. It is 
attracting interest throughout the medical community as a scanning tool and for diagnosis of 
illnesses such as epithelial cancer, connective tissue disorders, and atherosclerosis. The Vivosight 
OCT device will be used to provide information for both structural and angiographic 
OCT outcomes. 
1. Structural OCT: With a depth focus of 1.0 mm and optical resolution of 7.5 × 5.0 μm the 
Vivosight provides structural images of the skin comparable to histology sections. From 
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these images the thickness of the epidermis, the suprapapillary epidermis, and the papillary 
region can be extrapolated. Epidermal thickness has been identified using histology, as a 
useful biomarker of disease activity and treatment effects in AD. 
2. Angiographic OCT: Structural OCT performed at high image frame rates can map areas of 
temporal decorrelation due to moving red blood cells. Based on this, demonstrated that the 
Vivosight can acquire high-quality maps of the superficial vasculature in living 
participants and is an ideal tool to monitor and quantify erythema, hyperplasia, and 
TCS-induced tissue remodeling. 
 
The OCT assessments will be performed before STS/TEWL assessments at each designated visit 
from Week 0 to Week 28 (see Section 1.3, Section 1.4 and Figure 6 of Clinical Trial Protocol). 
Two scans will be taken from each target area (separate, adjacent, sites for each scan) at each 
designated visit. All images will be checked for quality upon collection, and images with visible 
imaging artifacts will be re-captured. Any part of the device in contact with human skin (the 
stand-off) will be decontaminated between uses.  
Details of OCT operation and OCT data analysis will be provided in a separate study reference 
manual. 
4.1.5 ATR FTIR spectroscopy 
ATR FTIR spectroscopy is a form of molecular spectroscopy useful for the analysis of surfaces, 
including the lipid, water, and carboxylate content of the skin barrier and for analyzing lipid 
arrangement/structure.  
In this study the Agilent 4300 handheld FTIR spectrometer will be used. Measurements will be 
performed by gently but firmly placing the probe in contact with the skin. Duplicate 
measurements will be collected from each target site at the visits indicated in the schedule of 
events. The quality of spectra will be assessed at the point of collection, and any that do not meet 
the established quality parameters (signal to noise ratio) will be discarded. After use in each 
participant the ATR (probe head) will be decontaminated with 70% alcohol wipe.  
The FTIR assessments will be performed before and during the STS assessments at each 
designated visit (see Section 1.3, Section 1.4 and Figure 6 of Clinical Trial Protocol).  
Detailed measurement and data collection from FTIR will be provided in a separate study manual. 
4.1.6 Optional samples for biomarker research 
The following optional serum and plasma samples for biomarker research should be collected 
from participants in the study, where possible: 
• Venous blood samples (not more than 12 mL in total) will be collected at baseline and 
EoT/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 intervention on modulation of 
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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 Clinical Study 
Report (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 in the study at a facility selected by the Sponsor.
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5 
REFERENCES 
1. Diggle P, Heagerty P, Liang KY, Zeger S. Analysis of Longitudinal Data, Oxford University 
Press; 2nd edition 2013:1-400. 
2. Core Team. R: A language and environment for statistical computing. Foundation for 
Statistical Computing (2013). 
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