Conditions: Dermatitis Atopic
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: yes

Brief summary:
Primary Objective:

\- Assess change in neuronal architecture following long term treatment with dupilumab in skin biopsies from atopic dermatitis (AD) participants with chronic pruritus.

Secondary Objectives:

* Assess change in neuronal architecture following short term treatment with dupilumab and during follow-up in skin biopsies from AD participants with chronic pruritus.
* To evaluate the efficacy of dupilumab in AD participants with chronic pruritus.
* To evaluate the safety of dupilumab in adult participants with moderate-to-severe AD.

Detailed description:
AD participants: A 20-week Observation Period including 16 weeks of treatment for AD participants and a 4-week follow-up period; Healthy participants: 8 days observation period.

Arms:
arm 1: Healthy participants with site, age, gender, race, location of targeted lesional and non-lesional skin area matched to selected AD participants, received no treatment, and were considered as a control group. arm 2: Participants with moderate to severe AD received dupilumab 600 milligrams (mg) subcutaneous (SC) injection on Day 1, followed by dupilumab 300 mg SC injection every 2 weeks (Q2W) from Week 3 to Week 15.

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

Protocol document:
Prot_000.pdf: 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01  
All  
06 January 2021, version 1 (electronic 1.0) 
Original Protocol 
 
17 August 2020, version 1 (electronic 1.0) 
Amended protocol 01 (06 January 2021) 
This amended protocol (Amendment 01) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT  
This protocol was amended per health authority request in order to remove ankle as a location for 
skin biopsy. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
activities (SOA)-AD 
participants 
Deleted “and ankle” from footnote e.  
To remove ankle as a location for skin biopsy 
per health authority request due to potential 
risk of infection related to this location.  
Section 1.1 Synopsis- 
overall design, Section 4.1 
Overall design, Section 8.3 
Exploratory assessments 
and biomarkers 
Revised in Section 1.1: 
Collection of skin biopsies of lesional skin at 
baseline and post-lesional skin at the end of 
treatment (EoT) (Week 17) is mandatory for all 
AD participants. According to patient 
tolerability to the skin biopsy and at 
Investigators discretion, additional optional 
biopsies of post-lesional skin will be collected 
at Week 3 and Week 21. 
Revised in Section 4.1: 
Collection of skin biopsies of lesional 
skin at baseline and post-lesional skin at the 
end of treatment (EoT) (Week 17) is 
mandatory for all AD participants. If possible, 
a post lesional skin biopsy at Week 3 and 
Week 21. 
To clarify the post-lesional skin biopsies 
collection schedule and to keep consistent 
with Section 1.3 as requested by health 
authority.  
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Section # and Name 
Description of Change 
Brief Rationale 
Revised in Section 8.3: 
Two Skin biopsies will be collected once in 
healthy participants and repeatedly (at least 
twice; baseline and Week 17) from lesional 
and post-lesional skin in AD participants for 
exploratory assessments and a broad panel of 
biomarkers. Further biopsies from post-
lesional and non-lesional skin are optional for 
AD participants. 
Section 1.1 Synopsis 
Changed “2 to 4 weeks” to “up to 4 weeks” 
• 
Screening Period: up to 4 weeks 
before inclusion. 
Changed “21 weeks” to “20 weeks” 
• 
Total duration of Observation 
Period: up to 20 weeks. 
To keep consistent with the schedules in 
Section 1.3.  
Section 1.2 SCHEMA 
Changed Week 2 to Week 3, Week 16 to 
Week 17, and Week 20 to Week 21 in the 
graphical study design.   
Changed “N=40” to “34 AD participants”. 
To keep consistent with the schedules in 
Section 1.3 and study population in Section 5. 
Section 1.3 Schedule of 
activities (SOA)-AD 
participants 
Added an annotation g to Non-lesional skin 
sample collection at baseline to indicate this 
biopsy is optional.  
To keep consistent with the skin biopsy 
sample collection procedures in Section 8.3.1. 
Section 1.3 Schedule of 
activities (SOA)-AD 
participants 
Removed IMP dispense from Visit 5. 
To correct a discrepancy, no IMP dispense is 
planned at EOT visit 
Section 1.3 Schedule of 
activities (SOA)-AD 
participants 
Added a footnote j to archival blood sample 
collection:  
Whole blood sample collected at baseline and 
stored during the study for potential analysis if 
deemed necessary for safety reasons. Will be 
described in study reference manual. 
The subsequent footnote numbers were 
updated accordingly.  
To clarify the purpose of the archival blood 
sample collection  
Section 1.3 Schedule of 
activities (SOA)-AD 
participants and Section 
8.4.2 Vital signs  
Removed pulse rate from Section 1.3 and 
removed both pulse rate and respiratory rate 
from vital sign parameters in Section 8.4.2.  
To correct a discrepancy, heart rate is already 
part of vital signs, and respiratory rate is not 
planned/relevant for this study 
Section 4.1 overall design  
Change 28 days to 21 days: 
Healthy participants will undergo a Screening 
Period of 21 days and a 7 days Observational 
Period following collection of the skin biopsy. 
To keep consistency with Section 1.4  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study 
intervention(s) administered  
Revised from “Week 2 to Week 16” to 
“Week 3 to Week 15”: 
- 
Dose regimen: Participants will 
receive a SC loading dose of 
dupilumab 600 mg on Day 1, 
followed by Q2W SC dosing of 
dupilumab 300 mg (2 mL of a 
150 mg/mL solution) from 
Week 3 to Week 15 
To keep consistency with Section 1.3 
Section 7.1.2 Temporary 
discontinuation 
Removed “and rechallenge” from the section 
title, and added: 
Temporary intervention discontinuation may 
be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial 
due to a regional or national emergency 
declared by a governmental agency 
(eg, natural disaster, pandemic, etc) 
(see Section 6.1). For all temporary 
intervention discontinuations, duration should 
be recorded by the Investigator in the 
appropriate pages of the CRF or eCRF.  
Temporary intervention discontinuation decided 
by the Investigator corresponds to more than 
1 dose not administered to the participant. 
To reflect the update in the protocol template 
regarding regional or national emergency 
declared.  
Section 8.1 Efficacy 
assessments 
Removed “screening or” from the following 
sentence: 
Patient reported outcomes will be collected in an 
appropriate form, for which the respective 
device, diary and/or instruction is handed out to 
the patient at the Screening (or Baseline) Visit. 
To keep consistent with the schedule of 
activities described in Section 1.3.  
Section 8.2 Standardized 
photographs  
Added: photography will be done for healthy 
participants on Day 1. 
To keep consistent with the schedule of 
activities described in Section 1.4. 
Section 8.3.1 Skin Biopsy 
Samples 
Revised the temperature from -80°C to -70°C: 
A) Fixation with paraformaldehyde (PFA) and 
freeze at -70°C 
B) Transfer into RNAlater solution and store at 
-70°C 
To reflect the change from laboratory.  
Section 8.5.4 Regulatory 
reporting requirements for 
SAEs 
Revised “adverse events” to “serious adverse 
events”: 
Serious adverse events that are considered 
expected will be specified in the reference 
safety information (IB). 
Revised the SUSARs reporting process to: 
Investigator safety reports must be prepared 
for suspected unexpected serious adverse 
reactions (SUSARs) according to local 
regulatory requirements and Sponsor policy 
and forwarded to Investigators as necessary. 
To reflect the change in the latest protocol 
template  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.8.1.1 
Definitions 
Removed: 
Their severity will be graded according 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0. 
To correct a discrepancy: the criteria are not 
applicable for this study 
Section 9.4.8.2 Vital signs 
Revised: 
For AD participants, heart rate, systolic and 
diastolic blood pressures (SBP and DBP), and 
body temperature will be analyzed as raw 
parameter value and change from baseline. 
Body weight will be analyzed as raw 
parameter value.  
To keep consistent with the schedule of 
activities described in Section 1.3. 
Section 10.2 Appendix 2: 
Clinical laboratory tests 
Removed:  
Alcohol and urine drug screen (to include at 
minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and 
benzodiazepines)]. 
Removed “or specify other tests” from the 
following sentence: 
Serology (HIV antibody, hepatitis B surface 
antigen [HBsAg], and hepatitis C virus 
antibody or specify other tests). 
Removed: 
The results of each test must be entered into 
the eCRF. 
To keep consistent with the schedule of 
activities described in Section 1.3. 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, and Section 
9.4.7 Description of efficacy 
variables 
Revised “change” or “outcome” from singular 
to plural in several items.  
Editorial changes. 
APPENDIX 8: Protocol 
amendment history 
Added: 
APPENDIX 8: PROTOCOL AMENDMENT 
HISTORY  
The Protocol Amendment Summary of 
Changes Table for the current amendment is 
located before the Table of Contents (TOC). 
To follow the amended protocol process 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) - AD PARTICIPANTS .......................................................... 16 
1.4 
SCHEDULE OF ACTIVITIES - HEALTHY PARTICIPANTS.......................................................... 19 
2 
INTRODUCTION ............................................................................................................................ 20 
2.1 
BACKGROUND ............................................................................................................................. 20 
2.2 
STUDY RATIONALE...................................................................................................................... 21 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 21 
2.3.1 
Risk assessment associated with dupilumab treatment ................................................................ 22 
2.3.2 
Risk assessment associated with other study procedures ............................................................ 23 
2.3.3 
Benefit assessment ........................................................................................................................ 23 
2.3.4 
Benefit/risk assessment related to Coronavirus Disease 2019 (COVID-19) ................................. 23 
2.3.5 
Overall benefit: risk conclusion ...................................................................................................... 24 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 25 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 26 
4 
STUDY DESIGN ............................................................................................................................ 27 
4.1 
OVERALL DESIGN ........................................................................................................................ 27 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 27 
4.2.1 
Participant input into design ........................................................................................................... 28 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 28 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 28 
5 
STUDY POPULATION .................................................................................................................. 29 
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5.1 
INCLUSION CRITERIA .................................................................................................................. 29 
5.1.1 
Atopic dermatitis patients ............................................................................................................... 29 
5.1.2 
Healthy participants........................................................................................................................ 30 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 30 
5.2.1 
Atopic dermatitis patients ............................................................................................................... 30 
5.2.2 
Healthy participants........................................................................................................................ 33 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 34 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 34 
5.4 
SCREEN FAILURES...................................................................................................................... 34 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 35 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 35 
6.1.1 
Devices .......................................................................................................................................... 37 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 37 
6.2.1 
Storage and handling ..................................................................................................................... 37 
6.2.2 
Responsibilities .............................................................................................................................. 37 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 38 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 38 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 39 
6.5.1 
Rescue medicine ............................................................................................................................ 39 
6.5.2 
Prohibited medications and procedures......................................................................................... 39 
6.5.3 
Permitted medications.................................................................................................................... 41 
6.6 
DOSE MODIFICATION .................................................................................................................. 41 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 41 
6.8 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 42 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 43 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 43 
7.1.1 
Definitive discontinuation ............................................................................................................... 43 
7.1.2 
Temporary discontinuation ............................................................................................................. 43 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 43 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 44 
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8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 46 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 46 
8.1.1 
Patient-reported outcome (PRO) scales ........................................................................................ 47 
8.1.1.1 
Peak pruritus assessed by numeric rating scale (NRS) ................................................................ 47 
8.1.1.2 
Patient-reported outcomes measurement information (PROMIS)-itch .......................................... 47 
8.1.1.3 
Patient oriented eczema measure (POEM) ................................................................................... 48 
8.1.1.4 
Dermatology life quality index (DLQI) ............................................................................................ 49 
8.1.1.5 
Atopic dermatitis control tool (ADCT) ............................................................................................. 49 
8.1.1.6 
Skin pain numerical rating scale .................................................................................................... 49 
8.1.1.7 
Skin sensitivity to touch numerical rating scale ............................................................................. 50 
8.1.1.8 
Skin burning numerical rating scale ............................................................................................... 50 
8.1.1.9 
Sleep quality numerical rating scale .............................................................................................. 50 
8.1.2 
Clinician reported outcomes (ClinRO) questionnaires ................................................................... 50 
8.1.2.1 
Investigator global assessment (IGA) ............................................................................................ 50 
8.1.2.2 
Eczema and severity index (EASI) ................................................................................................ 51 
8.1.2.3 
Scoring atopic dermatitis (SCORAD) ............................................................................................. 51 
8.2 
STANDARDIZED PHOTOGRAPHS .............................................................................................. 51 
8.3 
EXPLORATORY ASSESSMENTS AND BIOMARKERS .............................................................. 51 
8.3.1 
Skin biopsy samples ...................................................................................................................... 52 
8.3.2 
Neuroanatomy/Neuronal architecture ............................................................................................ 53 
8.3.3 
Reverse transcription quantitative PCR (qRT-PCR) ...................................................................... 53 
8.3.4 
RNA in situ hybridization (ISH) ...................................................................................................... 54 
8.3.5 
Immunohistochemistry (IHC) ......................................................................................................... 54 
8.3.6 
Nanostring-digital spatial profiling (N-DSP) ................................................................................... 55 
8.4 
SAFETY ASSESSMENTS ............................................................................................................. 55 
8.4.1 
Physical examinations ................................................................................................................... 55 
8.4.2 
Vital signs ....................................................................................................................................... 55 
8.4.3 
Pregnancy testing/Postmenopausal females ................................................................................. 56 
8.5 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 56 
8.5.1 
Time period and frequency for collecting AE and SAE information ............................................... 56 
8.5.2 
Method of detecting AEs and SAEs ............................................................................................... 56 
8.5.3 
Follow-up of AEs and SAEs ........................................................................................................... 57 
8.5.4 
Regulatory reporting requirements for SAEs ................................................................................. 57 
8.5.5 
Pregnancy ...................................................................................................................................... 57 
8.5.6 
Cardiovascular and death events .................................................................................................. 57 
8.5.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 58 
8.5.8 
Adverse event of special interest (AD participants only) ............................................................... 58 
8.5.9 
Guidelines for reporting product complaints .................................................................................. 59 
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8.6 
PHARMACODYNAMICS ............................................................................................................... 59 
8.7 
BLOOD SAMPLE FOR EXPLORATORY RESEARCH ................................................................. 59 
8.8 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 59 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 62 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 62 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 62 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 62 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 63 
9.4.1 
Participant description .................................................................................................................... 63 
9.4.1.1 
Disposition of participants .............................................................................................................. 63 
9.4.2 
Protocol deviations ......................................................................................................................... 63 
9.4.3 
Demographic and baseline characteristics .................................................................................... 64 
9.4.3.1 
Participant demographic characteristics, medical history, and diagnoses .................................... 64 
9.4.3.2 
Baseline efficacy parameters ......................................................................................................... 64 
9.4.3.3 
Baseline safety parameters ........................................................................................................... 64 
9.4.4 
Extent of study treatment exposure and compliance ..................................................................... 64 
9.4.4.1 
Extent of investigational medicinal product exposure .................................................................... 64 
9.4.4.2 
Compliance .................................................................................................................................... 65 
9.4.5 
Prior/Concomitant medication/therapy ........................................................................................... 65 
9.4.6 
Efficacy analyses ........................................................................................................................... 65 
9.4.7 
Description of efficacy variables .................................................................................................... 65 
9.4.8 
Safety analyses .............................................................................................................................. 68 
9.4.8.1 
Adverse events .............................................................................................................................. 68 
9.4.8.2 
Vital signs ....................................................................................................................................... 69 
9.4.8.3 
Physical examination ..................................................................................................................... 70 
9.5 
INTERIM ANALYSES .................................................................................................................... 70 
9.6 
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD ................................. 70 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 71 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 71 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 71 
10.1.2 
Financial disclosure........................................................................................................................ 72 
10.1.3 
Informed consent process .............................................................................................................. 72 
10.1.4 
Data protection ............................................................................................................................... 73 
10.1.5 
Dissemination of clinical study data ............................................................................................... 73 
10.1.6 
Data quality assurance .................................................................................................................. 74 
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10.1.7 
Source documents ......................................................................................................................... 75 
10.1.8 
Study and site start and closure ..................................................................................................... 75 
10.1.9 
Publication policy ........................................................................................................................... 76 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 76 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 77 
10.3.1 
Definition of AE .............................................................................................................................. 77 
10.3.2 
Definition of SAE ............................................................................................................................ 78 
10.3.3 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the 
recording and follow-up of AE and/or SAE .................................................................................... 79 
10.3.4 
Reporting of SAEs.......................................................................................................................... 81 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 82 
10.4.1 
Definitions ...................................................................................................................................... 82 
10.4.2 
Contraception guidance ................................................................................................................. 82 
10.4.3 
Collection of pregnancy information ............................................................................................... 83 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 84 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 85 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................... 85 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY .................................................................. 87 
11 
REFERENCES ............................................................................................................................... 88 
LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 25 
Table 2 - Overview of study interventions administered ............................................................................... 35 
Table 3 - Populations for analyses ................................................................................................................ 62 
Table 4 - Efficacy analyses ........................................................................................................................... 66 
Table 5 - Protocol-required laboratory assessments .................................................................................... 76 
Table 6 - Highly effective contraceptive methods ......................................................................................... 83 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A multi-center, exploratory study to assess dupilumab effect on pruritus 
neuro-mechanisms in patients with atopic dermatitis 
Short title: 
DupIlumab eFFEct on pRuritus nEuro-mechaNismS in paTients with Atopic 
Dermatitis - DIFFEREN-STAD 
Rationale: 
Chronic itch is a defining symptom of atopic dermatitis (AD). Inadequately controlled itch is a 
major burden for AD participants and significantly affects their quality of life (QoL). The basic 
mechanism behind itch in AD is not fully understood, but crosstalk between the nervous system, 
the cutaneous immune system, and keratinocyte populations is central to the development and 
persistence of atopic itch (1). It was also shown that epidermal nerves are aberrantly activated by 
overexposure to environmental stimuli during the development of AD due to the impaired 
protection by the epidermal barrier (2). There is a high medical unmet need to better understand 
the dysregulations of neuromechanistic pathways in AD participants with chronic itch and 
potential effect of treatments on restoration of the neuronal architecture and inflammation.  
The nature of inflammatory pathways in AD is evidenced by the potent therapeutic effects of the 
interleukin(IL)-4 receptor alpha (IL-4Ra) antagonist dupilumab (1) and other cytokines such as 
IL-13 and IL-31. While dupilumab has been investigated clinically in several Type 2 immune 
diseases, including asthma and AD, having shown beneficial impact on itch reduction in Phase 3 
clinical trials in both adult and pediatric AD patients, the underlying itch reduction mechanism in 
AD remains to be elucidated. This exploratory study will assess the effect of dupilumab on both 
chronic pruritus and peripheral neuronal normalization in AD participants. The study will 
contribute to the understanding of the neuromechanistic pathways of itch by evaluating pruritus 
effect on neuronal architecture and neuromarkers. Furthermore, this study will help address a key 
knowledge gap by generating data to allow the formulation of specific hypotheses concerning the 
role of the nervous system in underlying the clinical effects of dupilumab. 
The findings from this study will provide guidance in designing a larger dupilumab clinical study 
to assess the benefits of targeting IL-4 and IL-13 on pruritus neuro-mechanisms. 
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Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
Assess change in neuronal architecture 
following long term treatment with dupilumab in 
skin biopsies from AD participants with chronic 
pruritus 
• 
Change from baseline on Week 17 for intraepidermal 
nerve fiber density by protein gene product 9.5 (PGP9.5) 
antibody staining in lesional skin  
• 
Change from baseline on Week 17 for nerve fiber 
branching by PGP9.5 antibody staining in lesional skin 
Secondary 
• 
Assess change in neuronal architecture 
following short term treatment with dupilumab 
and during follow-up in skin biopsies from AD 
participants with chronic pruritus 
• 
Changes from baseline on Weeks 3 and 21 for 
intraepidermal nerve fiber density by PGP9.5 antibody 
staining in lesional skin  
• 
Changes from baseline on Weeks 3 and 21 for nerve 
fiber branching by PGP9.5 antibody staining in lesional 
skin 
• 
To evaluate the efficacy of dupilumab in AD 
participants with chronic puritus 
• 
Changes from baseline over time and at Weeks 17 and 
21 for the outcomes of the following 
assessments/questionnaires: 
- 
Peak pruritus assessed by numeric rating scale 
(NRS)  
- 
Eczema and severity index (EASI) 
- 
Scoring Atopic Dermatitis (SCORAD) 
- 
Patient-Reported Outcomes Measurement 
Information (PROMIS-itch) 
- 
Patient Oriented Eczema Measure (POEM) 
- 
Dermatology Life Quality Index (DLQI) 
- 
Atopic Dermatitis Control Tool (ADCT) 
- 
Sleep quality NRS 
- 
Skin Pain NRS 
- 
Skin Sensitivity NRS 
- 
Skin Burning NRS 
• 
Proportion of AD participants reaching pruritus NRS 
≥4 point improvement from baseline at Weeks 3, 5, 9, 
17, and 21 
• 
To evaluate the safety of dupilumab in adult 
participants with moderate-to-severe AD 
• 
Incidence of treatment-emergent adverse events during 
the treatment and follow-up period 
Overall design: 
• Open-label, multi-center, single-arm, non-controlled, exploratory study.  
• Moderate-to-severe AD participants with chronic pruritus (N=34) and healthy participants 
(up to N=10, will serve as control group providing normal skin reference for baseline skin 
biopsy derived endpoints; matched for gender, age, race and anatomical site of skin 
biopsy). 
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• A 20-week Observation Period including 16 weeks of treatment for AD participants and a 
4-week follow-up period. 
• Loading dose of 600 mg dupilumab followed by 300 mg every 2 weeks (Q2W). 
This is a 20-week, open-label, multi-center, single-arm exploratory study with a 4-week Screening 
Period, 16-week Treatment Period, and a 4-week post-treatment Follow-up Period designed to 
investigate the effect of dupilumab on neuronal architecture and neuronal markers in skin biopsies 
of lesional skin and compare these results with patient-reported outcomes (PRO) and clinical 
assessments in approximately 34 patients with moderate-to-severe AD. Collection of skin biopsies 
of lesional skin at baseline and post-lesional skin at the end of treatment (EoT) (Week 17) is 
mandatory for all AD participants. According to patient tolerability to the skin biopsy and at 
Investigators discretion, additional optional biopsies of post-lesional skin will be collected at 
Week 3 and Week 21. Collection of skin biopsies of non-lesional skin from AD participants at 
baseline is also optional. 
Skin biopsies taken from healthy skin from healthy donors will serve as control.  
Disclosure statement:  
This is an interventional, exploratory, single-arm study where the primary purpose is advancing 
science (evaluate dupilumab effects on neuronal architecture and neuromarkers) in AD 
participants with a single dupilumab treatment arm and a treatment free control group of healthy 
participants.  
Number of participants:  
A total of 34 AD participant will be enrolled (and treated with dupilumab) and up to 10 healthy 
participants will be enrolled following completion of AD patient enrolment to serve as a control 
group for skin biopsy derived endpoints at baseline. 
Intervention groups and duration: 
Study intervention(s) in AD participants and duration 
Patients with AD who meet the inclusion and exclusion criteria will be part of the following 
investigational medicinal product (IMP) treatment group with the following periods: 
• Screening Period: up to 4 weeks before inclusion. 
• Treatment Period: 16 weeks after inclusion including open-label dupilumab treatment 
starting with a 600 mg loading dose followed by 300 mg Q2W.  
• Follow-up Period: 4 weeks following EoT. 
• Total duration of Observation Period: up to 20 weeks. 
• Total study duration per participant: 22 to 25 weeks. 
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Healthy Participants  
• Screening Period: 1 to 3 weeks before inclusion. 
• Observation Period: 7 days after inclusion and collection of skin biopsy. 
• Total study duration per participant: 2 to 4 weeks. 
Healthy participants will not receive any IMP treatment. 
Investigational medicinal product 
Dupilumab 300 mg: 
• Formulation: Dupilumab 300 mg: A 150 mg/mL dupilumab solution in a prefilled syringe 
to deliver 300 mg in a 2 mL injection. 
• Route of administration: Subcutaneous (SC) injection.  
• Dose regimen: 300 mg Q2W after an initial loading dose of 600 mg (2 injections of 
300 mg) on Day 1. 
• No dose adjustments allowed. 
Statistical considerations: 
• Sample size calculation 
- 
Sample size for this exploratory study was based on medical/clinical judgment and is 
consistent with the sample size from similar studies. No formal sample size calculation 
was performed. Drop-outs 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 and time point for selected parameters 
of interest. Raw data and changes from baseline (absolute and percent changes) for 
selected parameters will be summarized in descriptive statistics and summary plots. 
Data Monitoring Committee: 
Not applicable. 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
*Healthy participants will be recruited as control for normal skin biopsy values performed once at baseline. 
Abbreviations: AD=Atopic dermatitis; HP=healthy participants; Q2W=every 2 weeks.  
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2 
INTRODUCTION  
Dupilumab is a human monoclonal antibody (1) that blocks the shared receptor subunit for 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 (2). 
Dupilumab is approved in the United States (US) for the treatment of patients aged ≥6 years with 
moderate-to-severe AD inadequately controlled with topical prescription therapies or when those 
therapies are not advisable, and for use in adults and adolescents ≥12 with moderate-to-severe AD 
who are candidates for systemic therapy in the European Union (EU). 
2.1 
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 QoL. Additionally, AD places a heavy economic burden on patients and 
their family. Atopic dermatitis is caused by the complex interplay between epithelial dysfunction 
and dysregulated/hyperactivated Type 2 immune response in the skin, with a special role for 
IL-4/IL-13-driven signaling in AD pathogenesis. 
Atopic dermatitis is characterized by disruption of the skin barrier and pruritus (itch), which is the 
hallmark and most burdensome symptom of AD. Itch profoundly affects patients’ daily lives and 
causes sleep disruption. These negative outcomes are worse with more severe itch. Itch occurs 
when sensory nerves are exposed to exogenous and endogenous stimuli (pruritogens) including 
allergens, amines, proteases, neuropeptides, and cytokines. In the peripheral nervous system, the 
ﬁrst event is binding of pruritogens to a sub-set of primary afferent C-ﬁber somatosensory neurons 
(prurito-ceptors) that innervate skin. Individual pruritoceptors are deﬁned by their signaling 
response to speciﬁc pruritogens (1). One system for functionally classifying groups of 
pruritoceptors is by sensitivity to histamine, a common pruritogen. Histamine-responsive 
(histaminergic) and non-histaminergic pruritoceptors use largely distinct receptors and distinct 
cutaneous nerve ﬁbres that follow separate spinothalamic tracts to connect with different neural 
pathways in the central nervous system. Activation of many different pruritogen receptors can 
trigger non-histaminergic pathways relevant to AD. Pruritogens that activate these receptors 
include keratinocyte-derived proteins, mast cell factors, environmental chemicals, 
pathogen-derived molecules, and cytokines. 
Crosstalk between the nervous system, the cutaneous immune system and keratinocyte 
populations is central to the development and persistence of atopic itch (1). Additionally, mast 
cells, eosinophils, and basophils are central effector immune cells in allergic skin inflammation 
(3). These immune cells interact with other cells in the skin to modulate both innate and adaptive 
immunity. There is mounting evidence that mast cells, eosinophils and basophils are central to 
causing pruritus in various skin diseases including AD. These immune cells are considered to be 
the main source of pruritogens, including histamine, neuropeptides (eg, substance P, calcitonin 
gene-related peptide [CGRP], vasoactive intestinal peptide [VIP] and pituitary adenylate 
cyclase-activating polypeptide [PACAP]), interleukins (IL-4, IL-13 and IL-31), cytokines, 
proteases and lipid mediators and can modulate pruritus through interaction with central and 
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peripheral nervous systems. T helper cell 2 (Th2) lymphocytes, eosinophils, neutrophils and mast 
cells amplify inﬂammatory and pruritoceptive pathways in AD by releasing cytokines and 
neurogenic peptides. Some AD-associated cytokines, IL-31 and thymic stromal lymphopoietin 
(TSLP), can directly promote itch via activation of pruritoceptive neurons that express their 
receptors. In addition, IL-4 may potentiate itch by sensitizing itch-sensory neurons to direct 
pruritogens, such as histamine and IL-31. Cytokine-to-neuron signaling by IL-31, TSLP and 
IL-4 - all present in skin during AD ﬂares - may explain the rapid beneﬁt of JAK1/2 and IL-4Rα 
inhibition versus chronic pruritus and pruritus in AD.  
The central nature of inflammatory pathways in AD is also evidenced by the potent therapeutic 
effects of the IL-4Rα antagonist dupilumab (1). Results from several clinical studies in AD 
patients have confirmed dupilumab to significantly improve itch in adult and adolescent patients 
with moderate-to-severe AD (4). Clinical improvements of pruritus in AD patients were observed 
already after 2 weeks of treatment with dupilumab (1, 5).  
2.2 
STUDY RATIONALE  
Currently there is still a medical unmet need to better understand the dysregulations of 
neuromechanistic pathways in AD patients with chronic itch and potential effect of treatments on 
restoration of the neuronal architecture and normalization of itch inducing and pro-inflammatory 
mediators in the lesional and non-lesional skin. Also, the molecular mechanism by which 
dupilumab reduces itch sensations in AD patients is not fully understood. 
Accordingly, the objective of this exploratory study is to get insights into the effect of dupilumab 
on both chronic pruritus and peripheral neuronal normalization of AD. The findings from this 
study will provide guidance in designing a larger dupilumab clinical study to assess the benefits of 
targeting IL-4 and IL-13 on pruritus neuro-mechanisms. 
This study will also contribute to our understanding of the neuromechanistic pathways of itch in AD 
participants by evaluating the effect of dupilumab on neuronal architecture and neuromarkers and 
correlating changes with clinical assessment of itch improvement. Furthermore, this study will help 
addressing a key knowledge gap by generating data to allow formulation of specific hypotheses 
concerning the role of the nervous system in underlying the clinical effects of dupilumab. 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has shown clinically relevant benefit in several Type 2 driven immunological 
disorders, such as AD, bronchial asthma and chronic rhinosinusitis with nasal polyposis 
(CRSwNP) and eosinophilic esophagitis (EoE). A satisfactory safety profile has been observed so 
far in completed and currently ongoing studies, including those in AD, nasal polyposis, and 
asthma patients. 
In asthma and AD indications, studies were also conducted in adolescents and similar benefit to 
adults has been observed. Data showed similar efficacy, safety, and pharmacokinetics (PK) in 
adult and adolescents.  
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More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AE) of dupilumab is available in the Investigator’s Brochure (IB) (6). 
2.3.1 Risk assessment associated with dupilumab treatment  
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies. 
Dupilumab has an extensive safety database. As of 28 March 2020 (Data Lock Point), 
10 191 participants were enrolled into the development program for dupilumab and included in 
the safety population: 382 as healthy participants, 4405 from AD studies, 3614 from asthma 
studies, 782 from CRSwNP studies, 232 from EoE studies, 248 from the grass allergy, 145 peanut 
allergy studies, and 511 from the chronic obstructive pulmonary disease (COPD) study, 5 from 
prurigo nodularis (PN) studies, and 12 from CSU study. The number of participants exposed to 
dupilumab in clinical studies was 8720 (356 in healthy participants studies, 4052 in AD studies, 
3263 in asthma studies, 470 in CRSwNP studies, 166 in EoE studies, 52 in the grass allergy, 96 in 
peanut allergy studies, and 256 from the COPD studies, 3 from PN studies, and 6 from chronic 
spontaneous urticaria studies). 
Based on the sales figure retrieved from Intercontinental Marketing Services Health and using the 
World Health Organization’s defined daily dose for dupilumab of 21.4 mg/day, the cumulative 
post marketing exposure to dupilumab is estimated to be 161 582 patient-years (01 January 
2017 through 31 March 2020).  
Dupilumab was generally well tolerated in all populations tested in clinical development programs 
consistent with a favorable benefit/risk profile. The adverse drug reactions (ADRs) identified to 
date for dupilumab include injection site reactions (ISRs), conjunctivitis (including allergic and 
bacterial), oral herpes, herpes simplex, blepharitis, dry eye, eye pruritus, arthralgia, eosinophilia, 
and serum sickness. These ADRs were generally mild or moderate, transient, and manageable. 
These ADRs were not observed consistently in all indications (see IB for greater details [6]). 
More significant serious allergic reactions were very rare. Importantly, no increased overall 
infection risk was observed in patients treated with dupilumab. 
Systemic hypersensitivity is established as an important identified risk with dupilumab. As protein 
therapeutics, all monoclonal antibodies are potentially immunogenic. Rare serious and systemic 
hypersensitivity reactions have been observed in the dupilumab program including serum 
sickness/serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical trials. 
Patients with known helminth infections were excluded from participation in clinical studies; 
therefore, it is not known if dupilumab will influence the immune response against helminth 
infections. Consequently, patients with pre-existing helminth infections should be treated for their 
helminth infection before initiating therapy with dupilumab.  
The common ADR across all indications is ISRs. Other potential risks based on the safety profile 
in particular indications are discussed in the IB (6). It is anticipated that dupilumab in patients 
with AD will have a favorable safety profile as observed across other Type 2-driven 
immunological disorders. 
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2.3.2 Risk assessment associated with other study procedures  
Punch skin biopsies of 4 mm diameter will be collected at least twice (baseline and Week 17) in a 
subset of AD participants and once in healthy participants. Collection of additional skin biopsies 
at other timepoints (Week 3 and Week 21) and biopsies taken from non-lesional skin are optional 
for AD participants. Complications are uncommon following this simple procedure but can occur 
preoperatively, intraoperative, or postoperative (7). Some of the complications associated with 
punch biopsy include local bleeding and bruising, pain, infection, allergic reaction to the numbing 
medicine used in the procedure, and damage to the structures beneath the skin site (such as an 
artery or a nerve). Delayed wound infection is the most common postoperative complication 
associated with skin biopsy. Later, scarring with or without hypo- or hyperpigmentation is a 
common complication seen after healing of the skin biopsy site. 
2.3.3 Benefit assessment  
Dupilumab solution for injection has demonstrated a positive benefit-risk profile and is approved 
for the treatment of moderate-to-severe AD patients ≥6 years in the US and moderate-to-severe 
AD patients ≥12 in the EU.  
In addition, dupilumab solution for injection is approved for the following indications: 
• In the US for use in adults and adolescents (≥12 years) with moderate-to-severe 
eosinophilic or oral steroid dependent asthma, in the EU for use in adults and adolescents 
with severe asthma with Type 2 inflammation characterized by raised blood eosinophils 
and/or raised fractional exhaled nitric oxide (FeNO). 
• In the US for use in adults with inadequately controlled CRSwNP and in EU as an add-on 
therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for 
whom therapy with systemic corticosteroids and/or surgery do not provide adequate 
disease control. 
Reduction of AD related clinical symptoms including improvement of pruritus have been 
observed already early after start of dupilumab treatment in the majority of patients included (4). 
Change in peak pruritus numeric rating scale (NRS) in AD participants was observed as early as 
1 to 2 weeks after initiation of dupilumab treatment and was significantly better compared to 
placebo. Participants with AD disease in this study will receive dupilumab treatment for a total of 
16 weeks It is thus expected that patients enrolled in this study will have a clear benefit from 
being treated with dupilumab; however, there is no final 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 participants will not benefit directly from participation in this study, other than the 
nominal reimbursements provided for completing study procedures and visits.  
2.3.4 Benefit/risk assessment 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 
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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, the Sponsor does not have sufficient data in patients with Coronavirus Disease 2019 
(COVID-19) and 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 ADRs with 
dupilumab. 
The target population in this study (LPS16763) is patients with moderate-to-severe AD and 
healthy participants as reference. Atopic dermatitis, 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. 
Based on the aforementioned potential benefits for AD patients treated with dupilumab 
(Section 2.3.3), the benefit-risk assessment remains favorable for patient to participate in this trial, 
even under the situation of the current COVID-19 pandemic. The operation of LPS16763 will 
allow enrolled AD patients the opportunity to receive a therapy which may provide benefit in 
improving their itch sensations, overall disease severity, and QoL. 
Healthy participants 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 epidermal defects observed in AD patients. Participating in a clinical trial 
like this may expose healthy subjects to a higher risk to any type of infection including 
COVID-19. Investigators will implement safeguards to reduce the risk for any study participant to 
become infected during the study.  
The Sponsor also recognizes that the “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). 
2.3.5 Overall benefit: risk conclusion  
The potential risks identified in association with dupilumab treatment and skin biopsy collection 
are justified given the measures taken to minimize risk to study participants participating, the 
excellent safety profile and clinical experience with dupilumab and the anticipated benefits that 
may be afforded to participants with AD.  
For healthy participants no benefit is expected, but there is also no relevant risk identified for 
those participants given investigator safeguards. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Assess change in neuronal architecture 
following long term treatment with 
dupilumab in skin biopsies from AD 
participants with chronic pruritus 
• 
Change from baseline on Week 17 for intraepidermal nerve 
fiber density by protein gene product 9.5 (PGP9.5) antibody 
staining in lesional skin  
• 
Change from baseline on Week 17 for nerve fiber branching 
by PGP9.5 antibody staining in lesional skin 
Secondary 
• 
Assess change in neuronal architecture 
following short term treatment with 
dupilumab and during follow-up in skin 
biopsies from AD participants with chronic 
pruritus 
• 
Changes from baseline on Weeks 3 and 21 for 
intraepidermal nerve fiber density by PGP9.5 antibody 
staining in lesional skin  
• 
Changes from baseline on Weeks 3 and 21 for nerve fiber 
branching by PGP9.5 antibody staining in lesional skin 
• 
To evaluate the efficacy of dupilumab in AD 
participants with chronic pruritus 
• 
Changes from baseline over time and at Weeks 17 and 
21 for the outcomes of the following 
assessments/questionnaires: 
- 
Peak pruritus assessed by numeric rating scale (NRS)  
- 
Eczema and severity index (EASI) 
- 
Scoring Atopic Dermatitis (SCORAD) 
- 
Patient-Reported Outcomes Measurement Information 
(PROMIS-itch) 
- 
Patient Oriented Eczema Measure (POEM) 
- 
Dermatology Life Quality Index (DLQI) 
- 
Atopic Dermatitis Control Tool (ADCT) 
- 
Sleep quality NRS 
- 
Skin Pain NRS 
- 
Skin Sensitivity NRS 
- 
Skin Burning NRS 
• 
Proportion of AD participants reaching pruritus NRS ≥4 point 
improvement from baseline at Weeks 3, 5, 9, 17, and 21 
• 
To evaluate the safety of dupilumab in adult 
participants with moderate-to-severe AD 
• 
Incidence of treatment-emergent adverse events during 
treatment and follow-up period 
Exploratory 
• 
Assess change in neuromarkers following 
treatment with dupilumab in skin biopsies 
from AD participants with chronic pruritus 
• 
Nanostring-Digital Spatial Profiling (N-DSP) for epidermal 
proteins and RNA changes from baseline in lesional skin on 
Weeks 3, 17, and 21  
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Objectives 
Endpoints 
• 
Neuromarkersa changes from baseline on Weeks 3, 17, and 
21 in lesional skin (detected by immunohistochemistry, RNA 
in situ hybridization and/or RT-qPCR):  
- 
NGF 
- 
NK-1R 
- 
MRGPRX1/2/4 
- 
TRPV1/A1 
- 
SEMA3A 
- 
integrin alpha 6 
- 
periostin 
- 
ANO1 
- 
NTRK1 
- 
NRTN 
- 
IL-4 
- 
IL-13 
- 
IL-31 
- 
Mast cells, basophils, eosinophils, keratinocytes, 
macrophages and lymphocytes  
• 
Compare the neuronal architecture and 
neuromarkers in skin biopsies of AD 
lesions and normal healthy skin 
• 
Neuronal architecture in lesional skin biopsies from AD 
patients and skin biopsies from healthy controls at baseline 
• 
Neuromarkers in lesional skin biopsies from AD patients and 
skin biopsies from healthy controls at baseline 
• 
Compare the neuronal architecture and 
neuromarkers in skin biopsies of lesional 
skin from AD patients with biopsies from 
non-lesional skin  
• 
Neuronal architecture in lesional and non-lesional skin 
biopsies from AD patients at baseline 
• 
Neuromarkers in lesional and non-lesional skin biopsies from 
AD patients at baseline 
• 
Compare the treatment related outcomes 
for neuronal architecture and 
neuropmarkers with outcomes of clinical 
assessments of AD (clinician- and 
patient-reported outcomes) 
• 
Neuronal architecture, Nanostring derived parameters and 
neuromarkers changes from baseline and clinical 
assessments changes from baseline 
a For gene IDs refering to neuromarkers see Section 8.3.3 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The clinical outcome assessments to be applied in this study are a panel of valid, robust, and 
frequently used questionnaires and PROs scales. The appropriateness of these variables has been 
demonstrated in many clinical studies with dupilumab. 
Skin biopsy collection and processing via RNAlater and formalin fixation/paraffin embedding are 
standard and frequently used practices. Neuromarkers will be assessed through a battery of standard 
molecular biology methods including immunohistochemistry (IHC), RNA in situ hybridization 
(ISH) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the 
appropriateness of these measurements have been described extensively. Nanostring-DSP is a new 
technology that allows for multiplex digital spatial molecular profiling of proteins and/or RNA in 
tissue or blood samples which allows for high resolution, tissue-specific understanding of the way in 
which inflammatory cells and signaling pathways are altered with dupilumab treatment (8). 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is an open-label, interventional, single-arm, non-controlled, multi-center exploratory study to 
evaluate the effect of dupilumab on neuronal architecture and neuronal markers in skin biopsies of 
lesional and non-lesional skin and compare these results with PROs and clinical assessments in 
approximately 34 participants with moderate-to-severe AD. Collection of skin biopsies of lesional 
skin at baseline and post-lesional skin at the end of treatment (EoT) (Week 17) is mandatory for all 
AD participants. If possible, a post-lesional skin biopsy at Week 3 and Week 21 will be collected. 
Skin biopsies taken from healthy skin from healthy donors will serve as a control.  
The maximum study duration for AD participants will be up to 25 weeks. The study will comprise of: 
• Screening Period (Day -28 to -1): Patients will be evaluated according to inclusion and 
exclusion criteria. At Baseline Visit (Day 1), patients who remain eligible will be enrolled 
• Treatment Period (Day 1 to Week 17): Treatment with Q2W dupilumab.  
• Follow-up Period (Week 17 to Week 21): Safety follow-up period to collect data for safety 
and efficacy after the participant has completed the treatment period. 
Atopic Dermatitis participants will be called by the Investigator around 8 weeks after the 
EoS Visit to assess if safety related issues have occurred during this period. 
Healthy participants will undergo a Screening Period of 21 days and a 7 days Observational 
Period following collection of the skin biopsy. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The most suitable population to investigate effects of dupilumab on itch and related neuronal 
changes and neuromarkers are patients with moderate-to-severe AD. This is also the population 
for which dupilumab has been granted a marketing authorization based on positive results on itch 
reduction from several Phase 2 and 3 studies. 
The majority of the clinical assessments (questionnaires, PROs, NRS etc) have been successfully 
applied in other clinical studies, while most of the planned methods and tests to evaluate effects 
on neuronal architecture and most of the neuromarkers have not been investigated in a clinical 
setting with dupilumab. It is thus not known which endpoints will change under treatment with 
dupilumab, as well the magnitude of an effect. Differences in the epidermal micro- and 
neuroanatomy between healthy and AD skin has been described recently. For example, in 
severely lesioned skin areas from AD patients nerve fibers reaching the upper region of the 
thickened epidermis were scarcely found (9). Accordingly, selection of healthy participants to 
serve as a control for non-lesional skin is considered justified. With respect to the study endpoints 
and because of the unknown outcome of dupilumab treatment on selected endpoints, the nature of 
the study is exploratory only. No sample size calculation will be applied nor is it planned to run 
confirmatory statistics for the aforementioned endpoints. 
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Because dupilumab is approved for the treatment of AD participants in the countries or 
participating investigational sites, the inclusion of a placebo group is not considered ethical. In 
addition, the effect on laboratory markers, if detectable, is thought to be unbiased, thus not 
requiring a control group.  
The treatment duration of 16 weeks has been chosen based on clinical results showing evidence of 
itch reduction within this period of time in studies with dupilumab.  
4.2.1 Participant input into design  
Not applicable. 
4.3 
JUSTIFICATION FOR DOSE  
The dose selected in this study is the dose approved for the treatment of moderate-to-severe AD 
patients ≥18 years of age for dupixent in the US and EU. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including end of study (EoS) visit as shown in the schedule of activity (SoA) 
(Section 1.3 and Section 1.4). 
The end of the study is defined as the date of the last visit of the last participant in the study 
shown in the SoA (Section 1.3 and Section 1.4) for the last participant in the trial globally. 
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5 
STUDY POPULATION  
A total of 34 AD participants with moderate-to-severe AD and up to 10 healthy participants are to 
be enrolled in this study. Drop-outs will not be replaced.  
Inclusion of healthy participants should be matched for age, gender, race, and anatomical site of 
skin biopsy. Accordingly, inclusion of healthy participants will start after enrolment of AD 
participants has been completed. The algorithm for matched healthy participants inclusion will be 
provided in a separate document. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA    
Participants are eligible to be included in the study only if all of the following criteria apply. 
5.1.1 Atopic dermatitis patients  
Age 
I 01. 
Male or female of ≥18 years of age inclusive, at the time of signing the informed consent 
form (ICF). 
Type of participant and disease characteristics 
I 02. Diagnosed with moderate-to-severe chronic AD for at least 1 year before screening. 
I 03. Eligible to be treated with dupilumab according to product monograph. 
I 04. Pruritus lasting 6 or more weeks before baseline (Day 1). 
I 05. Eczema Area and Severity Index (EASI) score ≥12 at baseline. 
I 06. Pruritus numerical rating scale (NRS) ≥4 at baseline. 
I 07. Investigator global assessment (IGA) score of ≥3 at screening (on the 0 to 4 scale) at 
baseline. 
I 08. Atopic dermatitis active lesions on the upper limbs or lower limbs suitable for a skin 
biopsy without oozing, bleeding, or infection on upper limbs or trunk. 
I 09. Patients with acute AD lesions as determined by Investigator’s judgment. 
I 10. Participants able to accept skin biopsy procedure. 
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I 11. Participants willing to refrain from applying any emollients or topical medications on the 
target assessment areas (including lesional and non-lesional) throughout the study unless 
necessary to treat intolerable symptoms. 
I 12. Participants willing and able to comply with all site visit and study-related procedures. 
I 13. Participants able to understand and complete all patient related outcome assessments and 
questionnaires. 
Concomitant medication 
I 14. Stable treatment with non-prohibited medication (Section 6.5.2) or therapy during the 
study. 
Informed consent 
I 15. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. In countries where legal 
age of majority is above 18 years, a specific ICF must also be signed by the participant’s 
legally authorized representative. 
5.1.2 Healthy participants  
I 01. 
Male or female of ≥18 years of age inclusive, at the time of signing the ICF. 
I 02. Certified as generally healthy by a comprehensive clinical assessment (detailed medical 
history and complete physical examination). Well-controlled underlying medical 
conditions are allowed as long as they do not interfere with assessments or objectives of 
this study (eg, neurological diseases, neuropathy, skin diseases, chronic pruritus, etc). 
I 03. Participants able to accept skin biopsy procedure. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
5.2.1 Atopic dermatitis patients  
Medical conditions 
E 01. Previous treatment with dupilumab stopped within 6 months of baseline due to inadequate 
response to dupilumab. 
E 02. Skin conditions other than AD that can confound assessments in the opinion of the 
investigator (ie, skin atrophy, severe photo damage). 
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E 03.  Regular use (>2 visits per week) of a tanning booth/parlor within 4 weeks of the Screening 
Visit. 
E 04. 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 participants 
with short life expectancy, participants with uncontrolled diabetes (hemoglobin A1c ≥9%), 
participants with cardiovascular conditions (eg, Class III or IV cardiac failure according to 
the New York Heart Association classification), severe renal conditions (eg, participants 
on dialysis, nephropathy), hepato-biliary conditions (eg, Child-Pugh class B or C), 
neurological conditions (eg, demyelinating diseases), autoimmune diseases (eg, lupus, 
inflammatory bowel disease, rheumatoid arthritis, etc), other severe endocrinological, 
gastrointestinal, metabolic, pulmonary, psychiatric, or lymphatic diseases.  
E 05. Patients with active tuberculosis (TB) or non-TB mycobacterial infection, or a history of 
incompletely treated TB will be excluded from the study unless it is well documented by a 
specialist that the participant has been adequately treated and can now start treatment with 
a biologic agent, in the medical judgment of the Investigator and/or infectious disease 
specialist. Tuberculosis testing will be performed on a country by country basis, according 
to local guidelines if required by regulatory authorities or ethics boards. 
E 06. Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of 
antiparasitic drug within 2 weeks before the Screening Visit (Visit 1) or during the 
Screening Period. 
E 07. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
or antifungals within 2 weeks before the Screening Visit (Visit 1) or during the Screening 
Period. 
E 08. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and 
aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal 
frequency or prolonged duration suggesting an immune compromised status, as judged by 
the Investigator. 
E 09. Active malignancy or history of malignancy within 5 years before the Baseline Visit, 
except completely treated in situ carcinoma of the cervix and completely treated and 
resolved non-metastatic squamous or basal cell carcinoma of the skin. 
E 10. Ocular disorder that in the opinion of the Investigator could adversely affect the 
individual’s risk for study participation. Examples include, but are not limited to, 
individuals with a history of active cases of herpes keratitis, Sjogren’s syndrome, 
keratoconjunctivitis sicca or dry eye syndrome that require daily use of supplemental 
lubrication or individuals with ocular conditions that require the use of ocular 
corticosteroids or cyclosporine. 
E 11. History of systemic hypersensitivity or anaphylaxis to dupilumab or any other biologic 
therapy, including any excipient. 
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E 12. Known or suspected alcohol and/or drug abuse. 
E 13. Participant with any other medical or psychological condition including relevant laboratory 
or electrocardiogram abnormalities at screening that, in the opinion of the Investigator, 
suggest a new and/or insufficiently understood disease, may present an unreasonable risk 
to the study participant as a result of his/her participation in this clinical trial, may make 
patient’s participation unreliable, or may interfere with study assessments. The specific 
justification for participants excluded under this criterion will be noted in study documents 
(chart notes, electronic case report form [eCRF], etc). 
Sex 
E 14. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study. 
E 15. Women of childbearing potential (see Section 10.4.1) unwilling to use adequate birth 
control. 
Adequate birth control is defined as agreement to consistently practice an highly effective 
and accepted method of contraception throughout the duration of the study and for 
12 weeks after last dose of study drug (see Section 10.4.2). 
Prior/concomitant medication or therapy 
E 16. Intake of any prohibited prior or concomitant medication as specified in Section 6.5.2. 
E 17. Planned or anticipated use of any prohibited medications and procedures during screening 
and study treatment period. 
Diagnostic assessments 
E 18. Participants with any of the following result at the Screening Visit (Visit 1): 
- 
Positive (or indeterminate) hepatitis B surface antigen (HBsAg) or,  
- 
Positive total hepatitis B core antibody (HBcAb) confirmed by positive hepatitis B 
virus (HBV) DNA or, 
- 
Positive hepatitis C virus antibody (HCVAb) confirmed by positive hepatitis C virus 
(HCV) RNA. 
- 
Positive human immunodeficiency virus (HIV) 1/2 serology or history of HIV 
infection or at the Screening Visit (Visit 1). 
Other exclusions 
E 19. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
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E 20. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 21. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals 
(in conjunction with Section 1.61 of the ICH-Good Clinical Practice [GCP] Ordinance E6). 
E 22. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 23. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study.  
E 24. Participants suffering from an ailment that makes taking repeat biopsies difficult (blood 
dyscrasias, anticoagulative use, allergy to local anesthetics etc) or if participant has tattoos 
at locations of biopsy.  
5.2.2 Healthy participants   
E 01. Regular use (>2 visits per week) of a tanning booth/ parlor within 4 weeks of the Screening 
Visit. 
E 02. Treatment with the following concomitant medications and procedures is prohibited within 
4 weeks before the Screening Visit or 5 half-lives (whichever is longer) until EoS Visit:  
• Topical medication. 
• Analgesics. 
• Immunomodulators. 
• Antidepressants. 
• Anti-anxiety drugs. 
E 03. Any Type 2 immune disorders (including, but not limited to atopic dermatitis or asthma), 
uncontrolled Type 2 diabetes mellitus, Type 1 diabetes mellitus, neuropathy or any other 
neurological disease. 
E 04. Any concomitant illness(es) or conditions that, in the Investigator’s judgment, would 
adversely affect the subject’s participation in the study or potentially affect any skin biopsy 
related read out. 
E 05. Positive test for immunoglobulin E (IgE) antibodies. 
E 06. Known or suspected alcohol and/or drug abuse. 
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5.3 
LIFESTYLE CONSIDERATIONS  
• Non-prohibited concomitant medication or therapy should be kept stable during the study; 
any changes of concomitant medication should be recorded in the eCRF. 
• Participants should not apply any emollients on or within 5 cm of the predefined skin 
assessment areas during the entire study period. 
5.3.1 Meals and dietary restrictions  
• Participants with a known food allergy should not consume any foods from an outside 
home provider on the day of the dupilumab injection. 
• Alcohol is prohibited for at least 16 hours before each visit and each clinical assessment 
(if done at home). 
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. 
Rescreening may be allowed once during the open screening period and upon the Investigator’s 
decision (for certain circumstances, eg, participants cannot start the study due to private reasons). 
All screening procedures will have to be repeated and a different patient identification number 
will be assigned. There is no requirement for a waiting period between the screen failure date and 
the rescreening date. Participants who are rescreened must sign a new consent form and all Visit 1 
procedures must be repeated. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
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 34 patients with moderate-to-severe AD will receive dupilumab. 
- 
Dose regimen: Participants will receive a SC loading dose of dupilumab 600 mg on 
Day 1, followed by Q2W SC dosing of dupilumab 300 mg (2 mL of a 150 mg/mL 
solution) from Week 3 to Week 15. 
One kit number list is generated centrally by Sanofi and IMP is packaged in accordance with this 
list. 
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 
Intervention name 
Dupilumab 300 mg 
Type  
Biological 
Dose formulation 
A 150 mg/mL dupilumab solution in a prefilled syringe to deliver 300 mg in 2 mL  
Unit dose strength(s) 
300 mg 
Dosage level(s) 
300 mg every 14 ±2 days after an initial loading dose of 600 mg 
Route of administration 
Subcutaneousa 
Use 
Experimental 
IMP 
IMP 
Packaging and labeling 
Each dose of dupilumab will be supplied as 1 glass prefilled syringe packed in a 
patient kit box. Both glass prefilled syringe and the box will be labeled as 
required per country requirement. 
Storage 
2°C to 8°C 
Current/Former name(s) or 
alias(es) 
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. Site of injection should be locally distant from the site of skin 
biopsies. 
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Investigational medicinal product 
The IMP will be administered every 14 ±2 days (Q2W) during the 16-week treatment period 
(with the last IMP administration at Week 15). 
For the doses that are not scheduled to be given at the study site, administration of IMP at 
participant’s home is allowed after appropriate training of the participant (or parent/legally 
authorized representative/caregiver). At Visit 2, the Investigator or delegate will prepare and 
inject the first dose of IMP in front of the participant (or parent/legally authorized participant 
representative/caregiver). The participant (or parent/legally authorized representative/caregiver) 
will prepare and inject the second dose of IMP at Visit 3 under the supervision of the Investigator 
or delegate. The training must be documented in the participant’s study file.  
In case of emergency (eg, natural disaster, pandemic, etc) different methods of IMP injection 
training (eg, training remotely with instructions provided by phone, etc) can be performed (and 
will be documented in the participant’s study file). If the participant (or parent/legally authorized 
representative/caregiver) is unable or unwilling to prepare and inject IMP, injections can be 
performed at the study site by way of unscheduled visits; or arrangements can be made for 
qualified site personnel and/or health care professionals (eg, visiting nurse service) to administer 
IMP at participant’s home.  
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits in case of emergency (eg, natural disaster, pandemic, etc), IMP 
may be supplied from the site to the participant via a Sponsor-approved courier company where 
allowed by local regulations and approved by the participant. 
When the participant has a study visit, the IMP will be administered following clinical procedures 
and blood collection. Participants should be monitored for at least 30 minutes. The monitoring 
period may be extended as per country-specific or local site-specific requirements. 
Participant/parent/legally authorized representative/caregiver should be trained by the site staff to 
recognize potential signs and symptoms of hypersensitivity reaction in order to self 
monitor/monitor at home following injection. In case of hypersensitivity symptoms, the 
participant should contact their healthcare provider or emergency services. 
Subcutaneous injection sites should be alternated among the 4 quadrants of the abdomen 
(avoiding navel and waist areas), the upper thighs or the upper arms, so that the same site is not 
injected between two Q2W injections. Injections in the upper arms could be done only by a 
trained person (parent/legally authorized representative/caregiver trained by Investigator or 
Delegate) or health care professional but not the participants themselves. Site of injection should 
be locally distant from the site of skin biopsies. 
For doses not given at the study site, eDiary will be provided to record information related to the 
injections. The eDiary will be kept as source data in the participant’s study file. 
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6.1.1  Devices  
No devices for administration of study drug will be used in this study. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Storage and handling  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. At 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. 
3. During transportation from the study site to the participant’s home and at the participant’s 
home, study intervention must be handled/stored as per instructions of the Study Drug 
Transportation Guidelines and the Patient User Instruction Manual. Participant/parent/legally 
authorized representative/caregiver should be trained by the site staff to ensure that IMP is 
handled and stored properly at participant’s home. 
4. 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 8.5.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
Direct-to-Patient (DTP) shipment, for which a courier company has been approved by the 
Sponsor), allow the IMP to be used other than as directed by this clinical trial protocol, or dispose 
of IMP in any other manner. 
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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
The study is open-label study without a treatment control or placebo group in patients. To control 
bias, the following measures are taken: 
• Healthy participants will serve as a reference comparator group for interpreting study 
results. 
• PROs will be collected by electronic data capture. 
• Efficacy data will be measured by the same device model. 
• Biomarker data will be measured by an experienced laboratory. 
• Study is limited to 2 to 4 very experienced study centers. 
• Standardized study assessment procedures. 
• Standardized photography for targeted lesional areas, and clinical disease severity and 
PRO evaluations. 
• Reason for screen failures (if any) will be documented. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Investigator or his/her delegate must ensure that IMP will be administered to each participant 
according to the labeling instructions.  
IMP accountability:  
• Intervention units are returned by the participant at the next study visit. In case of DTP 
emergency process, the intervention units can be returned by the carrier (if defined in the 
contract). 
• The Investigator counts the number of remaining unused kits/pre-filled syringes, and fills 
in the IMP accountability and inventory forms. 
• The Investigator or his/her delegate records the dosing information on the appropriate 
page(s) of the eCRF. 
• The monitor in charge of the study then checks the eCRF data by comparing them with the 
IMP which he/she has retrieved and source documents. 
When participants are dosed at the site (see Section 1.3), they will receive study intervention 
directly from the Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. The 
dose of study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention.  
When participants self-administer study intervention(s) at home (see Section 1.3), they will document 
compliance on a home dosing diary. Compliance with study intervention will be assessed at each 
visit. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
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6.5 
CONCOMITANT THERAPY  
Any allowed 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 enrolment or receives during the study must be recorded in the eCRF along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Any change in concomitant medication must be recorded. 
Participants must abstain from taking prohibited prescription drugs within 4 weeks before the 
Screening Visit or 5 half-lives (whichever is longer) until the Week 21 (EoS 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, 
except for 12 hours prior to a visit or clinical assessment to prevent any bias to itch related PRO 
assessments. Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Sponsor representative(s), if required. 
6.5.1 Rescue medicine  
During Treatment Period, if medically necessary (ie, to control intolerable AD symptoms on face 
and genital areas), rescue treatment for AD may be provided to participants at the discretion of the 
Investigator (ie, topical treatment with high potency topical corticosteroids [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.  
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 
AD symptoms. 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. 
6.5.2 Prohibited medications and procedures  
Treatment with the following concomitant medications and procedures is prohibited within 
4 weeks before the Screening Visit or 5 half-lives (whichever is longer) until the Week 21 
(EoS Visit): 
1. Topical treatment used for the treatment of AD or for super-infection: 
- 
Topical calcineurin inhibitors (tacrolimus or pimecrolimus).  
- 
Topical phosphodiesterase inhibitors (crisaborole).  
- 
Topical corticosteroids. 
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2. Topical antibiotics. 
3. Topical immunosuppressive/immunomodulating treatment. 
4. Monoclonal antibodies (mAbs) within 5 half-lives or within 6 months before the Screening 
Visit if the half-life is unknown. 
5. Antihistaminic medication, H2 receptor antagonists. 
6. 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). 
7. Biologic therapy/systemic immunosuppressant to treat inflammatory disease or 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary 
cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc).  
8. 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.  
9. Leukotriene antagonists/modifiers within, unless patient is on a continuous treatment for at 
least 4 weeks before the Screening Visit. 
10. Antifibrinolytic tranexamic acid or epsilon-aminocaproic acid. 
11. Intravenous immunoglobulin (IVIG) therapy and/or plasmapheresis. 
12. Procedures used for the treatment of AD:  
- 
Phototherapy (such as ultraviolet B [UVB], narrowband UVB [NBUVB], ultraviolet 
A1 [UVA1], or psoralen-UVA [PUVA]).  
- 
Bleach baths.  
- 
Use of a tanning booth/parlor.  
For patients having participated recently in a clinical study with an investigational new drug 
which is not approved in the specific country concerned and for which the PK or 
pharmacodynamic half-life is not known, the wash out period between last intake of 
investigational new drug and screening visit should be ≥6 months. 
In addition, participants will be asked to abstain from live (attenuated) vaccinations through 
Week 21. If a participant requires a vaccination prior to 12-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.  
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• 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.  
NOTE: For participants who have vaccination with live attenuated vaccines planned during the 
course of the study (based on national vaccination schedule/local guidelines), it will be 
determined, after consultation with a physician, whether the administration of vaccine can be 
postponed until after the EoS, or preponed to before the start of the study without compromising 
the health of the participant: 
• Patient for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
• Patients who have their vaccination preponed can enroll in the study only after a gap of 
4 weeks following administration of the vaccine. 
6.5.3 Permitted medications  
Other than the prohibited medications and procedures listed in Section 6.5.2, treatment with 
concomitant medications and procedures is permitted during the study. This includes nasal and 
inhaled corticosteroids. The use of these medications should be recorded. 
6.6 
DOSE MODIFICATION  
No change in IMP dose is allowed. Patients who discontinue treatment with IMP will be excluded 
from further participation. 
6.7 
TREATMENT OF OVERDOSE  
The sponsor does not recommend specific treatment for an overdose.  
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In the event of an overdose, the Investigator should  
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities for a 
reasonable period of time. 
3. Document appropriately in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant. 
6.8 
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 be asked to remain in the study to be evaluated for clinical assessments (including 
PRO) and collection of a skin biopsy. 
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 or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (eg, natural disaster, pandemic, etc) (see Section 6.1). For all 
temporary intervention discontinuations, duration should be recorded by the Investigator in the 
appropriate pages of the CRF or eCRF.  
Temporary intervention discontinuation decided by the Investigator corresponds to more than 1 
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.  
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
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• 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. 
Drop-outs will not be replaced.  
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. 
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• 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. 
• 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 (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3 and Section 1.4). 
• Assessments performed only at the Screening and/or Baseline Visit include medical 
history, medication history, serology, demographics, and diagnosis of chronic AD. Atopic 
dermatitis disease characteristics are assessed by clinical and PRO assessments. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 100 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 enrolment criteria due to COVID-19 (or any other 
pandemic) will be granted. All temporary mechanisms utilized, and deviations from 
planned study procedures are to be documented as being related to COVID-19 (or any 
other public health emergency) and will remain in effect only for the duration of the public 
health emergency. 
8.1 
EFFICACY ASSESSMENTS  
Clinical efficacy will be assessed through patient-reported outcome (PRO) and clinician reported 
outcomes (ClinRO) scales in AD participants only.  
The PRO questionnaires (including NRS) should be completed by the patients and before the skin 
biopsy collection and/or any clinical tests, and before the consultation at each visit 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. 
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Patient-reported outcomes will be collected in an appropriate form, for which the respective 
device, diary and/or instruction is handed out to the patient at the Baseline Visit. During the 
Screening Visit the Investigator should inform participants about the PROs and devices used 
during the study and should examine whether the participant is capable to understand and fill out 
the PRO assessments and can follow the instructions provided. This is particularly important if, 
the Investigator has doubts about a participant’s skills to read and understand the PROs eg, in case 
the participant does speak fluently the language used for the PROs.  
Clinician reported outcomes will be completed by the Investigator or sub-investigator. 
8.1.1 Patient-reported outcome (PRO) scales  
8.1.1.1 Peak pruritus assessed by numeric rating scale (NRS)  
The Peak Pruritus NRS is a simple assessment tool that patients will use to report the intensity of 
their pruritus (itch) during a daily recall period. Patients will be asked to rate their worst itch on a 
0 (“No itch”) to 10 (“Worst itch imaginable”) NRS by answering the following question: “On a 
scale of 0 to 10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable’, how would you 
rate your itch at the worst moment during the previous 24 hours?” 
The peak pruritus NRS has been already validated in AD adult patients; a threshold for clinically 
relevant, within-person response was found to be ≥2 to 4-point change (10). 
Peak pruritus NRS will be assessed daily during the first 28 days of treatment and weekly from 
Day 29 onwards until EoS period (see Section 1.3). 
The Pruritus NRS will be provided in the study reference manual. 
8.1.1.2 Patient-reported outcomes measurement information (PROMIS)-itch  
The Patient-Reported Outcomes Measurement Information System ([PROMIS], 
www.healthmeasures.net) for the assessment of itch, was recently developed (11) and represents a 
novel suite of PRO measures for itch. The PROMIS-Itch includes several item domains to assess 
different aspects of the burden of chronic itch. The PROMIS-Itch item domains have good 
concurrent, convergent, and discriminant validity with itch intensity, good internal consistency, 
and no floor or ceiling effects among US adults with chronic itch.  
For this study the following item domains or scales will be used. The short form version will be 
applied, if available.  
• Itch-Severity 
The PROMIS item pool assesses the characteristics of itch, including intensity, frequency 
and time of occurrence. It is universal rather than disease-specific. It includes 8 items, 
each individually scored. There is currently no summary score. 
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• Itch-Activity and Clothing 
The PROMIS-Itch-Activity and Clothing item bank assesses Activity and Clothing related 
QoL impairment from itch (pruritus) in adults. It is universal rather than disease-specific. It 
assesses the impact of itch over the past 7 days. For this item the short version will be used. 
• Itch-Mood and Sleep 
The PROMIS-Itch-Mood and Sleep item bank assesses mood and sleep related QoL 
impairment from itch (pruritus) in adults. It is universal rather than disease-specific. It 
assesses the impact of itch over the past 7 days. For this item the short version will be used. 
• Itch-Interference 
The PROMIS-Itch-Interference item bank assesses general issues related to QoL impairment 
from itch (pruritus) in adults. It is universal rather than disease-specific. It assesses the impact 
of itch over the past 7 days. For this item the short version will be used. 
• Itch-Scratching Behavior 
The PROMIS-Itch-Scratching Behavior scale assesses QoL impairment from scratching 
behavior and the physical manifestations of itch (pruritis) in adults. It is universal rather 
than disease-specific. It assesses the impact of itch over the past 7 days.  
• Itch-Quality 
The PROMIS-Itch-Quality item pool assesses the subjective description of the sensation 
of itch with a 16-item checklist. Respondents can select as many as apply. There is no 
summary score.  
• Itch-Triggers 
The PROMIS-Itch-Triggers item pool assesses the subjective description of the triggers of 
itch with a 13-item checklist. Respondents can select as many as apply. There is no 
summary score. 
The PROMIS-Itch will be assessed at timepoints according to Section 1.3. 
The PROMIS-Itch will be provided in the study reference manual. 
8.1.1.3 Patient oriented eczema measure (POEM)  
The Patient Oriented Eczema Measure (POEM) is a 7-item, PRO questionnaire used in clinical 
practice and clinical trials to assess frequency of disease symptoms in children and adults (28). 
The format is a response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and 
weeping) based on frequency during the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 
4 days, 3 = 5 to 6 days, and 4 = all days) with a scoring system of 0 to 28; the total score reflects 
disease-related severity, with higher score indicating higher severity.  
The POEM will be assessed at time points according to Section 1.3. 
The POEM will be provided in the study reference manual. 
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8.1.1.4 Dermatology life quality index (DLQI)  
The Dermatology Life Quality Index (DLQI) is a 10-item, PRO questionnaire used in clinical 
practice and clinical trials to assess the impact of AD disease symptoms and treatment on QoL 
(12, 13). The questionnaire has a “past week” recall period and has an overall scoring system of 
0 to 30; a high score is indicative of a poor QoL. The questionnaire will be administered only to 
the subset of patients who speak fluently the language in which the questionnaire is presented 
(based on availability of validated translations in participating countries). 
The DLQI will be assessed, at time points according to Section 1.3. 
The DLQI is provided in the study reference manual. 
8.1.1.5 Atopic dermatitis control tool (ADCT)  
The Atopic Dermatitis Control Tool (ADCT) is a PRO questionnaire designed to assess 
patient-self-perceived control of their eczema in clinical practice and in research settings (14). It is 
validated in adult and adolescent patients with AD (15). The ADCT contains 6 items allowing a 
comprehensive coverage of the dimensions defining AD control, ie, overall severity of AD 
symptoms, frequency of intense episodes of itching, extent of AD related bother, impact on sleep, 
impact on daily activities, impact on mood or emotions. Recall period is 1 week. Each item of the 
ADCT is rated from 0 to 4 Likert scale and is equally weighted, thus resulting in a total score 
from 0 to 24; higher scores indicate lower AD control.  
A threshold value equal or at least 7 on the ADCT total score has been established to define the 
cut off for patients with poorly controlled AD (14). A responder definition of 5 points on the 
ADCT total score has been defined as the meaningful within-person change threshold (15).  
The ADCT will be assessed at time points according to Section 1.3. 
The ADCT will be provided in the study reference manual. 
8.1.1.6 Skin pain numerical rating scale  
Skin pain NRS is a one-item PRO measure asking the patients to rate their skin pain using a 
0 (“No pain”) to 10 (“Worst pain possible”) NRS. Patients will be asked the following question:  
“Think about all the areas of your skin with eczema. How would you rate your skin pain at its 
worst in the past 24 hours?” 
The skin pain NRS will be assessed at time points according to Section 1.3.  
The skin pain NRS is provided in the study reference manual. 
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8.1.1.7 Skin sensitivity to touch numerical rating scale  
Skin sensitivity to touch NRS is a 1 item PRO measure asking the patients to rate their skin 
sensitivity to touch using a 0 (“Normal”) to 10 (“Extremely sensitive”) NRS.  
Participant will be asked the following question: "Think about all the areas of your skin with 
eczema. How sensitive was your skin at its worst in the past 24 hours?”  
The skin sensitivity to touch NRS will be assessed at time points according to Section 1.3.  
The skin sensitivity to touch NRS is provided in the study reference manual. 
8.1.1.8 Skin burning numerical rating scale  
Skin burning NRS is a one-item PRO measure asking patients to rate the burning sensation of 
their skin in the past 24 hours using a 0 (“Not at all”) to 10 (“Very much”) NRS.  
Patient will be asked the following question: “Think about all the areas of your skin with eczema. 
How much did your skin burn at its worst in the past 24 hours?” 
The skin burning NRS is provided in the study reference manual. 
8.1.1.9 Sleep quality numerical rating scale  
Sleep quality NRS is a one-item PRO measure asking patients to rate the quality of their sleep 
using a 0 (“Worst possible sleep”) to 10 (“Best possible sleep”) NRS. Patients will be asked to 
complete the following question upon awakening: 
“Select the number that best describes the quality of your sleep last night.”  
The Sleep Quality NRS will be assessed at time points according to Section 1.3.  
The sleep quality NRS is provided in the study reference manual. 
8.1.2 Clinician reported outcomes (ClinRO) questionnaires  
8.1.2.1 Investigator global assessment (IGA)  
The IGA is a ClinRO instrument used in clinical studies to rate the severity of AD globally, based 
on a 5-point scale ranging from 0 (clear) to 4 (severe). The IGA score will be assessed at 
Screening also and is used as one of the inclusion criteria for determining patient’s eligibility. 
The IGA will be provided in the study reference manual. 
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8.1.2.2 Eczema and severity index (EASI)  
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (16). The EASI is a composite index with scores ranging from 0 to 72. Four AD 
disease characteristics (erythema, thickness [induration, papulation, and edema], scratching 
[excoriation], and lichenification) will each be assessed for severity by the Investigator or 
designee on a scale of “0” (absent) through “3” (severe). In addition, the area of AD involvement 
will be assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and 
converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 
2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%).  
The EASI assessment tool will be provided in the study reference manual. 
8.1.2.3 Scoring atopic dermatitis (SCORAD)  
The Scoring Atopic Dermatitis (SCORAD) is a validated tool used in clinical research and clinical 
practice that was developed to standardize the evaluation of the extent and severity of AD (17). 
The extent of AD is assessed as a percentage of each defined body area and reported as the sum of 
all areas, with a maximum score of 100% (assigned as “A” in the overall SCORAD calculation). 
The severity of 6 specific symptoms of AD is assessed using the following scale: none (0), 
mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the 
overall SCORAD calculation). 
Subjective assessment of itch and sleeplessness is recorded for each symptom by the patient or 
relative on a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst 
imaginable itch (or sleeplessness), with a maximum possible score of 20. This parameter is assigned 
as “C” in the overall SCORAD calculation. The SCORAD is calculated as: A/5+7B/2+C.  
The SCORAD will be assessed at time points according to Section 1.3. 
The SCORAD assessment tool will be provided in the study reference manual. 
8.2 
STANDARDIZED PHOTOGRAPHS  
In AD participants, a picture of high resolution will be taken of a representative area of AD 
involvement (the lesional area used for skin biopsy collection) on Day 1 (predose). Subsequent 
pictures of the same area will be taken as described in Section 1.3. 
Photography will be done for healthy participants on Day 1.  
8.3 
EXPLORATORY ASSESSMENTS AND BIOMARKERS  
Two Skin biopsies will be collected once in healthy participants and repeatedly (at least twice; 
baseline and Week 17) from lesional and post-lesional skin in AD participants for exploratory 
assessments and a broad panel of biomarkers. Further biopsies from post-lesional and non-lesional 
skin are optional for AD participants. 
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8.3.1 Skin biopsy samples  
Skin biopsies of 4 mm diameter each will be collected from healthy participants and AD 
participants at time points according to the SoA (Section 1.3). Study staff will provide instructions 
regarding suture removal, if sutures are used for closure. 
Gelfoam®, a hemostatic, can be applied for biopsy closure. Study staff will notify the patient this 
will dissolve and provide instructions regarding wound dressing and care. 
The skin biopsy samples will serve to study the neuronal architecture (neuroanatomy) and 
neuromarkers in the epidermis of pruritic lesional skin before start of treatment with dupilumab 
and localisation matched post-lesional healing skin areas after EoT with dupilumab in AD 
participants. Accordingly, the collection of 4 biopsies in total is mandatory for AD participants at 
the following timepoints: 
• Baseline: 2 biopsies of 4 mm diameter each at baseline before start of treatment from 
pruritic lesional skin.  
• Week 17: 2 biopsies of 4 mm diameter each from non-pruritic, post-lesional healed or 
healing skin, with localisation matched to the baseline pruritic lesional biopsy.  
- 
if post-lesional healed skin that is completely non-pruritic non-lesional is not available 
at later visits, one of the following biopsies should be collected (in the order of 
relevance): 1. lesional non-pruritic skin, 2. Post-lesional pruritic skin or 3. lesional 
pruritic skin. 
Participants who refrain from providing these biopsies at baseline and Week 17 are not eligible 
for this study.  
Collection of the following additional biopsies is optional for AD patients, including 
• 2 biopsies of 4 mm diameter each from non-pruritic, post-lesional healed or healing skin, 
localisation matched to the baseline pruritic lesional biopsy, at week 3 and at the end of 
the observation period at Week 21. 
- 
if post-lesional healed skin that is completely non-pruritic non-lesional is not available 
at later visits, one of the following biopsies should be collected (in the order of 
relevance): 1. lesional non-pruritic skin, 2. Post-lesional pruritic skin or 3. lesional 
pruritic skin. 
• 2 biopsies of 4 mm diameter each from non-lesional skin at baseline. 
Healthy participants will provide 2 biopsies of 4 mm diameter each only. These biopsies serve as 
a control and will allow to investigate differences in neuroanatomy and neuromarkers between 
lesional skin from AD participants and normal skin. Skin biopsies must be taken from 
non-lesional healthy skin. Taking biopsies from an area adjacent to any skin lesion (inflamed skin, 
sun burn, acne, etc) must be avoided.  
Each skin biopsy will be cut and divided in 2 slices of approximately equal size.  
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If 2 biopsies were taken at the same time (which is mandatory for healthy participants and AD 
participants at baseline and Week 17), the corresponding 4 slices (#A, B, C and D) will be 
processed as follows immediately after collection: 
A) Fixation with paraformaldehyde (PFA) and freeze at -70°C 
B) Transfer into RNAlater solution and store at -70°C 
C) Fixation with 10% neutral buffered formalin (NBF), embed into paraffin, and store at 4°C 
D) Fixation with 10% NBF, embed into paraffin, and store at 4°C 
The samples will be processed for RNA-ISH, RT-qPCR, neuroanatomy, IHC, and 
Nanostring-Digital Spatial Profiling (N-DSP).  
Detailed instructions for sample collection and handling are provided in the study reference 
manual. 
Unused skin material will be returned from laboratories assigned for the different methods to a 
facility selected by the sponsor and stored under appropriate conditions for future use 
 (Section 8.8) 
8.3.2 Neuroanatomy/Neuronal architecture  
#A skin biopsy samples will be investigated for epidermal neuroanatomy/neuronal architecture. 
Briefly, the PFA-fixed part of the biopsies will be used to analyze the epidermal nerve fiber 
density and anatomy. Nerve fibers will be visualized by staining consecutive sections for the 
pan-axonal marker protein gene product 9.5 (PGP9.5); the basement membrane will be visualized 
by staining for collagen type 4 in order to determine exactly the point of invasion of nerve fibers 
into the epidermis.  
Quantification of intraepidermal nerve fiber density will be calculated by assessing nerve fibers 
crossing the basement membrane per square millimetre (F/mm2). 
Branching of epidermal nerve fibers will be assessed semi-quantitatively by classifying patients 
into 4 groups comprised of only linear, mainly linear, mainly branched or only branched fibers. 
8.3.3 Reverse transcription quantitative PCR (qRT-PCR)  
 #B skin biopsy samples will be investigated by qRT-PCR for a panel of epidermal neuro- and 
inflammatory markers including (corresponding gene IDs provided in brackets): 
• NK-1R (TACR1) 
• MRGPRX1 (MRGPRX1) 
• MRGPRX2 (MRGPRX2)  
• MRGPRX4 (MRGPRX4) 
• TRPV1 (TRPV1) 
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• TRPA1 (TRPA1) 
• Periostin (POSTN) 
• Integrin alpha 6 (ITGA6) 
• Anoctamin -1 (ANO1) 
• TRKA (NTRK1) 
• Neurturin (NRTN) 
• IL-4 (IL4) 
• IL-13 (IL13) 
• IL-31 (IL31) 
8.3.4 RNA in situ hybridization (ISH)  
#C skin biopsy samples will be investigated by ISH for a panel of epidermal neuro- and 
inflammatory markers including (corresponding gene IDs provided in brackets): 
• MRGPRX1 (MRGPRX1) 
• MRGPRX2 (MRGPRX2) 
• MRGPRX4 (MRGPRX4) 
• TRPV1 (TRPV1) 
• TRPA1 (TRPA1) 
• NK-1R (TACR1) 
8.3.5 Immunohistochemistry (IHC)  
#C skin biopsy samples will be investigated by IHC for a panel of epidermal neuro- and 
inflammatory markers including 
• NGF 
• NK-1R 
• TRPV1 
• TRPA1 
• SEMA3A 
• Integrin alpha 6 
• Periostin 
These markers will be co-localized with cell type markers for mastocytes, basophils, eosinophils, 
macrophages, lymphocytes, and keratinocytes. 
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8.3.6 Nanostring-digital spatial profiling (N-DSP)  
#D skin biopsy samples will be investigated by N-DSP for a broad panel of RNA and protein 
targets. 
The purpose of this study is to characterize the neuroinflammatory response to dupilumab 
treatment in participants with AD. The GeoMx™ digital spatial profiling is a commercial 
technology that allows for the analysis in situ of up to 1,833 immune genes and 92 immune 
protein targets simultaneously in their tissue-based morphological context from formalin fixed 
paraffin embedded or fresh frozen samples (18, 19). This technology will allow us to study the 
spatial association of nerves and immune cells in the skin and deeply profile their phenotypes and 
signalling pathways throughout the course of treatment. Specific RNA and protein expression 
targets will be selected to identify key inflammatory cells implicated in AD pathogenesis, such as 
lymphocytes, eosinophils, mast cells, and macrophages; inflammatory cytokines such as IL-4, 
IL-5, IL-9, IL-13; signalling pathways such as NK-κB and JAK-STAT; and neuromediators and 
their receptors, such as histamine, proteases, opioid receptors, neurotrophins, and sodium 
channels. The target gene and protein list will provide a comprehensive assessment with 
unprecedented resolution of the effect of dupilumab on inflammatory processes in lesional tissue. 
8.4 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3 and 
Section 1.4). 
8.4.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the skin, 
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 each skin biopsy 
assessments at time points according to SoA (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. 
8.4.2 Vital signs  
Vital signs will be measured for AD participants in a semi-supine position after 5 minutes rest and 
will include heart rate,  body temperature (°C), systolic and diastolic blood pressure (mmHg). 
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8.4.3 Pregnancy testing/Postmenopausal females  
Pregnancy testing will be performed for all female AD participants of childbearing potential. 
Urine pregnancy (β-HCG) testing will be performed at time points according to SoA 
(Section 1.3). In case of positive urine test the study treatment will be withheld and a serum 
pregnancy test should be performed as soon as possible, to confirm the pregnancy. 
Women will be tested for their FSH concentration in blood in case their postmenopausal status is 
not confirmed otherwise. 
8.5 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).  
8.5.1 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 
specified in 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 adverse event 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. 
8.5.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
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8.5.3 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 and AEs of 
special interest (as defined in Section 8.5.6), 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). 
8.5.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR, or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB 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. 
8.5.5 Pregnancy  
• Details of all pregnancies in female AD participants will be collected after the start of 
study intervention and until 12 weeks after EoS Visit. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.5.6 Cardiovascular and death events  
Not applicable. 
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8.5.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.5.8 Adverse event of special interest (AD participants only)  
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). 
The following events also require reporting to the Sponsor within 24 hours of learning of the 
event: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP;  
- 
It will be qualified as an SAE only if it fulfills one of the seriousness criteria 
(see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, 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 (See Appendix 4 
[Section 10.4]). 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
• 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 (not based on systematic IMP 
accountability checks) and defined as at least twice the intended dose within the 
intended therapeutic interval, adjusted according to the tested drug. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate adverse event forms. 
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8.5.9 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. 
8.6 
PHARMACODYNAMICS  
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
BLOOD SAMPLE FOR EXPLORATORY RESEARCH  
Venous blood samples will be collected to obtain whole blood, serum and plasma to be stored for 
possible future exploratory research (see Section 8.8), including genetic research. 
A total of approximately 12 to15 mL venous blood will be collected per each timepoint specified 
in the SoA (Section 1.3 and Section 1.4) and split as follows 
• 3 mL whole blood sample for DNA (K2 EDTA tube, collected at baseline only)  
• 2.5 mL whole blood for RNA (Paxgene RNA collection tube) 
• 4 mL whole blood for plasma 
• 5 mL whole blood for serum 
Storage tubes will be labelled and stored under appropriate conditions.  
Blood samples for exploratory research will be collected from participants who have consented to 
participate in the exploratory analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the exploratory research may still participate in the 
study. 
Details on collection, storage and shipment of these samples will be provided in the study 
reference manual. 
Blood samples will be collected as specified in the SoA (Section 1.3 and Section 1.4).  
See Appendix 5 (Section 10.5) for information regarding genetic research.  
8.8 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
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and used for future research (“research substudy”) when consented to by participants 
(see Section 10.1.3) unless prohibited by local laws or IRBs/IECs (in such case, consent for future 
use of sample will not be included in the local ICF).  
Blood samples (see Section 8.7) are explicitly collected for the purpose of future research. In 
addition, while skin biopsies will be collected and processed for the intended use described in 
Section 8.3.1 these studies may not require the entirety of the tissue or processed material. With 
the participants separate consent, blood samples and any residual skin material remaining from 
planned laboratory work will be used for additional exploratory research (“research substudy”) 
related to atopic dermatitis and related inflammatory diseases such as asthma and hidradenitis 
suppurativa, atopic disease processes, interleukin pathway biology, additional drug safety 
assessments or development and validation of bioassay methods beyond those defined in the 
present protocol.  
Analyses of blood and skin samples may include isolating DNA, RNA, proteins or metabolites for 
pharmacogenetic/genomic analysis, RNA transcriptomics (including whole transcriptome RNA 
sequencing), proteomics, metabolomics or lipidomics. DNA/RNA isolated from these samples 
will be used only to determine a possible relationship between genes and response to treatment 
with dupilumab, possible side effects to dupilumab and/or to study genes that may potentially be 
involved in atopic dermatitis and related inflammatory pathways.  
Exploratory analyses may include isolation and analysis of DNA and RNA using whole genome, 
exome, transcriptome or targeted sequencing, or related technologies. If future research on genetic 
material is performed, this will also be limited to the purpose of addressing research questions 
related to the drug, the mechanism of action, the disease or its associated conditions. Additional 
proteomic analysis will utilize techniques such as enzyme-linked immunosorbent assay, Olink, 
mass spectrometry or related protein quantification technologies, to characterize the protein 
changes associated with dupilumab treatment, with AD disease conditions, or to understand 
related inflammatory pathways. Finally, metabolites such as lipids and other small molecules may 
be characterized using mass spectrometry or nuclear magnetic resonance spectroscopy. 
The handling of genetic data is described in Appendix 5 (Section 10.5).  
Each study participant will be informed by the Investigator about the purpose and objectives of 
the research substudy including future use sample storage, research analyses, and the use of coded 
data. In addition, each participant has to sign a separate informed consent form for the research 
substudy-related to future use of samples and research, and will also receive a written subject 
information explaining the matter. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. 
Participants will be told that participation in this research substudy (use of samples for additional, 
exploratory research) and the use of their coded data for this purpose is optional and that they are 
free to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. In that case, biological samples will be destroyed and coded data already 
available will be anonymized unless otherwise required by applicable laws. Data and samples will 
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be used in compliance with the information provided to participants in the ICF dedicated to future 
research and the research substudy. 
Participants who decline to participate in this optional research substudy will not provide this 
separate signature but are still allowed to participate in the main part of the study.  
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. If required by local regularities, all participant’s data and samples required for 
DNA or RNA transcriptome analysis will be double coded following collection of samples. Coded 
data and samples for additional exploratory research will be transferred to and stored by an US 
based central laboratory vendor chosen and contracted by the Sponsor. The Sponsor adopts 
safeguards for protecting participant confidentiality and personal data (see Section 10.1.4). 
The samples will be stored for a maximum of 15 years after the end of the study. Any samples 
remaining at the end of retention period will be destroyed. If a participant requests destruction of 
his/her samples before the end of the retention period, the Investigator must notify the Sponsor 
(or its contract organization) in writing. In such case, samples will be destroyed and related coded 
data will be anonymized unless otherwise required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
No formal hypothesis testing is predefined in this exploratory study. 
9.2 
SAMPLE SIZE DETERMINATION  
Sample size for this exploratory study was determined based on medical experts’ input/clinical 
judgement. No formal sample size estimation was conducted. Approximately 10 to 12 evaluable 
AD participants per site might be enough to provide interpretable data and meet study primary 
objective. 
Neuronal architecture and neuromarkers data collected from skin biopsy in similar settings as 
planned for this study were not available: ie, expected changes from baselines in neuronal 
architecture and neuromarkers after 16-week treatment with dupilumab in AD participants with 
chronic pruritus are unknown. 
Allowing for a drop-out rate of 20%, a total of approximately 34 AD participants with chronic 
pruritus will be enrolled to achieve a minimum of 12 evaluable AD participants per country, 
ie, participants with no major or critical deviations related to IMP and/or biomarker measurements, 
for whom the biomarker data for primary analysis, ie, neuronal architecture and neuromarkers data 
from skin biopsy at baseline and Week 17, are considered sufficient and interpretable.  
Up to 10 healthy participants (with a minimum of 3 per country) serving as a reference comparator 
group will be enrolled. Healthy participants will be matched with AD participants, as far as possible, 
according to site, age, gender, race, location of targeted lesional and non-lesional skin area. 
Drop-out rate in healthy participants is expected to be minimal. 
Any drop-out participant will not be replaced. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 3): 
Table 3 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF 
Intent-to-treat (ITT) 
All enrolled patients, who received at least 1 dose of IMP and all enrolled healthy 
participants who have at least 1 skin biopsy performed, irrespective of compliance 
with the study protocol and procedures. 
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Population 
Description 
Modified ITT (mITT) 
All ITT participants. If prohibited therapies for AD (see Section 6.5.3) are used and 
assessed by the study team as having a significant impact on skin biposy 
assessment, only visits prior to rescue treatment use are considered. 
Safety 
The safety population includes all patients, who actually received at least 1 dose of 
IMP or had at least 1 skin biopsy and all healthy participants who had a skin biopsy 
or another safety assessment performed 
Abbreviations: AD: atopic dermatitis, ICF: informed consent form; IMP: investigational medicinal product; ITT=intent-to-treat, mITT: modified ITT. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be finalized prior to database lock or any interim analysis and it 
will include a more technical and detailed description of the statistical analyses described in this 
section. A specific dedicated SAP might be produced in addition to the main SAP, eg, for some or 
all biomarker analyses. This section is an overview of the planned exploratory statistical analyses 
of the most important endpoints including primary and key secondary endpoints. 
9.4.1 Participant description  
9.4.1.1 Disposition of participants  
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 study groups. 
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. 
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. A pre-defined list of potential protocol deviations will be 
identified by the study team prior to the study start. The protocol deviations will then be reviewed 
by the study team before database lock, including missing data and study drug discontinuations, 
and classified as critical, major, or minor deviations. 
Individual deviations to inclusion and exclusion criteria as reported by the Investigator will be listed. 
If any major and critical deviations other than those involving inclusion/exclusion will be listed by 
participant and/or described in the body of the CSR. 
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9.4.3 Demographic and baseline characteristics  
9.4.3.1 Participant demographic characteristics, medical history, and diagnoses  
Continuous variables (age, weight) and qualitative variables (gender, race, and body mass index 
[BMI]) will be summarized by study groups, 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: eg, ClinRO and PROs will be presented along with the on-
treatment summary statistics in the Section 9.4.6.  
9.4.3.2 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 (Visit 2, Week 1), for AD participants and as the last available and evaluable 
value at Screening or Day 1 (Visit 2) for healthy participants. 
9.4.3.3 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 
screening for healthy participants. 
Baseline safety values will be presented along with subsequent safety values assessed during the 
study. 
9.4.4 Extent of study treatment exposure and compliance  
The extent of study treatment exposure and compliance will be assessed and summarized for 
patient group 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. 
9.4.4.1 Extent of investigational medicinal product exposure  
Duration of IMP exposure is defined as: last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations. 
If the patient’s date of last dose is unknown, his/her last IMP dispensing date will be used in its 
place. 
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Duration of exposure will be summarized in patients’ group using descriptive statistics such as 
mean, standard deviation (SD), median, minimum and maximum. 
9.4.4.2 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 Investigator’s 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. 
9.4.5 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. 
9.4.6 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 nature of the study, missing, or incomplete data 
of efficacy marker will not be imputed. In case a significant number of patients (eg, more than 
20%) using rescue therapy are observed during the study Treatment Period, visit values removed 
due to use of rescue therapy will be imputed. The imputation methods applied will be described in 
the SAP. 
9.4.7 Description of efficacy variables  
Efficacy parameters are described in Section 8.1. The derivation of baseline results is described in 
Section 9.4.3.2. 
The analysis of the efficacy markers 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.  
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Sub-group analyses might be done, if deemed appropriate.  
If relevant, based on results obtained on planned analyses (eg, if any trend or signal is observed), 
further exploratory analyses could be conducted, using statistical models for instance. 
Analysis 
Table 4 - Efficacy analyses  
Endpoint 
Statistical analysis methods 
Primary 
 
• 
Change from baseline on Week 17 for 
intraepidermal nerve fiber density by PGP9.5 
antibody staining in lesional skin  
• 
Change from baseline on Week 17 for 
intraepidermal nerve fiber branching by PGP9.5 
antibody staining in lesional skin  
• 
Raw data and change from baseline to Week 17; 
ie, absolute and percent changes, will be summarized 
with descriptive statistics (such as mean, median, SD, 
minimum, maximum, and 90% confidence interval) and 
plots for AD participants based on the mITT population 
Secondary 
 
• 
Changes from baseline on Weeks 3 and 21 for 
intraepidermal nerve fiber density by PGP9.5 
antibody staining in lesional skin  
• 
Changes from baseline on Weeks 3 and 21 for 
intraepidermal nerve fiber branching by PGP9.5 
antibody staining in lesional skin  
• 
Raw data and changes from baseline to Week 3 and 
Week 21; ie, absolute and percent changes, will be 
summarized with descriptive statistics (such as mean, 
median, SD, minimum, maximum, and 90% confidence 
interval) and plots for AD participants based on the mITT 
population 
• 
Profiles for baseline to Week 21 time points will be 
generated for individual values: eg, spaghetti plot and 
boxplot, and patients’ group means 
• 
Changes from baseline over time and at weeks 
17 and 21 for the outcomes of the following 
assessments/questionnaires 
- 
Peak pruritus assessed by numeric rating 
scale (NRS)  
- 
Eczema and severity index (EASI) 
- 
Scoring Atopic Dermatitis (SCORAD) 
- 
Patient-Reported Outcomes Measurement 
Information (PROMIS-itch) 
- 
Patient Oriented Eczema Measure (POEM) 
- 
Dermatology Life Quality Index (DLQI) 
- 
Atopic Dermatitis Control Tool (ADCT) 
- 
Sleep quality NRS 
- 
Skin Pain NRS 
- 
Skin Sensitivity NRS 
- 
Skin Burning NRS 
• 
Raw data and change from baseline; ie, absolute and 
percent changes, will be summarized with descriptive 
statistics (such as mean, median, SD, minimum, 
maximum, and 90% confidence interval) for AD 
participants based on the mITT population 
• 
Profiles for baseline to Week 17, and baseline to Week 21 
time points will be generated for individual values: 
eg, spaghetti plot and boxplot, and patients’ group means 
• 
Proportion of AD participants reaching pruritus 
NRS ≥4 point improvement from baseline at 
Weeks 3, 5, 9, 17 and 21 
• 
Number and percentage of AD participants reaching 
pruritus NRS ≥4 point improvement from baseline will be 
reported by time points based on the mITT population 
• 
Barplot over time of proportion of AD participants 
reaching pruritus NRS ≥4 point improvement from 
baseline will be produced. 
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Endpoint 
Statistical analysis methods 
Exploratory 
 
• 
Nanostring-Digital Spatial Profiling (N-DSP) for 
epidermal proteins and RNA changes from 
baseline in lesional skin on Weeks 3, 17, and 21 
• 
Data will be summarized with descriptive statistics. 
Univariate analysis on raw data and changes from 
baseline for each parameter and multivariate 
unsupervised analysis (eg hierarchical clustering) will be 
performed as appropriate based on the mITT population 
• 
Neuromarkers changes from baseline on Weeks 
3, 17, and 21 in lesional skin (detected by 
immunohistochemistry, RNA in situ hybridization 
and/or RT-qPCR):  
- 
NGF 
- 
NK-1R 
- 
MRGPRX1/2/4 
- 
TRPV1/A1 
- 
SEMA3A 
- 
integrin alpha 6 
- 
periostin 
- 
ANO1 
- 
NTRK1 
- 
NRTN 
- 
IL-4 
- 
IL-13 
- 
IL-31 
- 
Mast celle, basophils, eosinophils, 
keratinocytes, macrophages and lymphocytes 
• 
Data will be summarized with descriptive statistics. 
Univariate analysis on raw data and changes from 
baseline for each parameter and multivariate 
unsupervised analysis (eg hierarchical clustering) will be 
performed as appropriate based on the mITT population 
• 
Neuronal architecture in lesional skin biopsies 
from AD patients and skin biopsies from healthy 
controls at baseline 
• 
Neuromarkers in lesional skin biopsies from AD 
patients and skin biopsies from healthy controls 
at baseline 
• 
Descriptive statistics and plots will be produced for AD 
participants and healthy participants at baseline based on 
the mITT population 
• 
Neuronal architecture in lesional and non-
lesional skin biopsies from AD patients at 
baseline 
• 
Neuromarkers in lesional and non-lesional skin 
biopsies from AD patients at baseline 
• 
Descriptive statistics and plots will be produced for 
lesional and non-lesional skin biopsies from AD 
participants at baseline based on the mITT population 
• 
Neuronal architecture, Nanostring derived 
parameters and neuromarkers changes from 
baseline and clinical assessments changes from 
baseline 
• 
Scatterplot to visualize the form of the relationship 
between changes from baseline will be produced for AD 
participants at specific timepoints, based on the mITT 
population 
• 
Pearson or Spearman’s rank correlation coefficients and 
p-values will be reported at each defined time points 
based on the mITT population 
• 
A heatmap of the change from baseline of some key 
biomarkers could be used to have an overall 
representation of the evolution of those biomarkers over 
time in AD participants 
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Endpoint 
Statistical analysis methods 
• 
As an exploratory analysis repeated measures correlation 
method might be used to assess the overall correlations 
overtime (20) 
Abbreviations: AD: atopic dermatitis; mITT: modified intent-to-treat; SD: standard deviation. 
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 groups 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 AD participants’ group, 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. 
For all healthy participants, 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. 
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9.4.8.1.2 Treatment-emergent adverse events  
The following TEAEs summaries will be provided for the patient’s group 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 participants. 
AEs that occur outside the treatment-emergent period or in healthy participants 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. 
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  
For AD participants, heart rate, systolic and diastolic blood pressures (SBP and DBP), and body 
temperature will be analyzed as raw parameter value and change from baseline. 
Body weight will be analyzed as raw parameter value. BMI will be analyzed as raw parameter 
value. 
Baseline definition 
The values to be used as baselines will be the Day 1 (Visit 2) predose assessment. If any of the 
scheduled baseline tests are repeated for any participant, the last rechecked values will be 
considered as baselines, provided, for patients, they were done before the IMP administration, and 
in the same condition.  
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Abnormalities analyses 
For all 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. Potentially 
clinically significant abnormality (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. 
Potentially clinically significant abnormality (PCSA) Listings 
A listing of individual data from participants with post-baseline PCSAs will be provided; values 
will be flagged when reaching the PCSA criteria. 
9.4.8.3 Physical examination  
Participants with at least 1 clinically significant abnormality in physical examination will be 
summarized and listed by treatment group. 
9.5 
INTERIM ANALYSES  
One or more interim analyses may be performed in case of unexpected safety concerns and/or for 
internal decision making. As it is an open-label study with no predefined hypothesis testing there 
is no issue regarding blinding or multiplicity adjustment. The outcome of this interim analysis 
may lead to early termination of the trial, continuation without any changes, or continuation with 
changes. 
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, IB, 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. 
- 
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. 
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- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• The ICF contains additional separate sections that addresses the use for optional 
exploratory and future research of participants’ data and/or samples of the research 
substudy (remaining mandatory ones or new extra samples collected for optional research, 
see Section 8.8). The Investigator or authorized designee will explain to each participant 
the objectives of the research substudy and why data and samples are important for future 
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. 
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The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told that 
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 these data are required by 
regulatory agencies (eg, on afro American population for the FDA). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
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 electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations) 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
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10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.8 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
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  
• Clinical laboratory safety tests will not be performed during the study.  
However, tests may be performed at any time during the study including screening as 
determined necessary by the Investigator or required by local regulations. 
• Pregnancy testing and test for post menopause 
Refer to Section 5.1 (Inclusion Criteria) for screening pregnancy criteria.  
For details of timing of recommended pregnancy testing see SoA (Section 1.3). 
Table 5 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only). 
• 
Highly sensitive human chorionic gonadotropin (hCG) pregnancy test 
(as needed for women of childbearing potential).  
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody).  
Abbreviations: eCRF=electronic case report form; hCG: human chorionic gonadotropin; HBaAg: hepatitis B surface antigen; HIV: human 
immunodeficiency virus. 
Investigators must document their review of each laboratory safety report. 
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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. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
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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. 
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. 
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• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
• Examples of such events include 
- 
Intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc), or convulsions (seizures, epilepsy, epileptic 
fit, absence, etc). 
- 
Development of drug dependence or drug abuse.  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase 
>10 × ULN (optional). 
- 
Suicide attempt or any event suggestive of suicidality. 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
- 
Bullous cutaneous eruptions. 
- 
Cancers diagnosed during the study or aggravated during the study. 
10.3.3 Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the 
recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested. In 
this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission. 
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• 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. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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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 a copy of any post-mortem findings including 
histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the sponsor by telephone. 
SAE reporting to via paper CRF (if the electronic system is unavailable)  
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
10.4.1 Definitions  
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with >1 FSH measurement (>40 IU/L or mIU/mL) is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrolment. 
10.4.2 Contraception guidance  
Recommended contraceptive methods are listed below in Table 6. 
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Table 6 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
- 
oral 
- 
intravaginal 
- 
transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation 
- 
oral 
- 
injectable 
Highly effective methods that are user independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner:  
Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner 
of the woman of childbearing potential and the absence of sperm has been confirmed. If not and less than 1 year 
after vasectomy, additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies. 
10.4.3 Collection of pregnancy information  
Male AD 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.  
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Female AD 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 8.5.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention  
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA or RNA 
• 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, blood 
samples will be collected for DNA/RNA analysis from study participants consenting to 
participate in the research substudy (Section 8.7). Also, leftover skin biopsies or related 
material will be included in the research substudy. 
• In addition to the planned RT-qPCR, ISH and N-DSP analyses of skin biopsy derived 
RNA described in Section 8.7, biopsy and blood samples from participants consenting to 
future research and from which DNA/RNA could be extracted and analyzed will be used 
for research as described in Section 8.7. The tissue and any isolated DNA/RNA thereof 
may also be used to develop tests/assays including diagnostic tests related to dupilumab 
and AD or related Type 2 immune diseases. Genetic research may consist of the analysis 
of one or more candidate genes or the analysis of genetic markers throughout the genome. 
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• DNA and RNA samples may be used for genetic, transcriptomic and/or expression 
analysis. This analysis may include standard targeted methods, such as qPCR genotyping, 
RT-qPCR, or microarrays, as well as DNA or RNA whole genome, exome or 
transcriptome sequencing. Additional analyses may be conducted if it is hypothesized that 
this may help further understand the clinical data. 
• 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/RNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained while research on dupilumab or Type 2 immune diseases 
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 
ADCT: 
Atopic Dermatitis Control Tool 
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interest 
BMI: 
body mass index 
CGRP: 
calcitonin gene-related peptide 
ClinRO: 
clinician reported outcomes 
COPD: 
chronic obstructive pulmonary disease  
COVID-19: 
Coronavirus Disease 2019 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis  
CSR: 
clinical study report 
DLQI: 
Dermatology Life Quality Index 
DTP: 
Direct to Patient 
EASI: 
Eczema and severity index 
eCRF: 
electronic case report form 
EoE: 
eosinophilic esophagitis 
EoS: 
end of study 
EoT: 
end of treatment 
EU: 
European Union  
GCP: 
Good Clinical Practice 
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HBcAb: 
hepatitis B core antibody 
HBsAg: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
HCVAb: 
hepatitis C virus antibody  
HIV: 
human immunodeficiency virus 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
IGA: 
Investigator Global Assessment 
IgE: 
immunoglobulin E 
IHC: 
immunohistochemistry 
IL: 
interleukin 
IL-4Ra: 
interleukin-4 receptor alpha 
IMP: 
investigational medicinal product 
ISH: 
in situ hybridization 
ISR: 
injection site reaction 
ITT: 
intent-to-treat 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NBF: 
neutral buffered formalin 
N-DSP: 
Nanostring-Digital Spatial Profiling 
NRS: 
numeric rating scale 
PACAP: 
pituitary adenylate cyclase–activating polypeptide 
PCSA: 
potentially clinically significant abnormality 
PFA: 
paraformaldehyde 
PGP9.5: 
protein gene product 9.5 
PK: 
pharmacokinetics 
PN: 
prurigo nodularis  
POEM: 
Patient Oriented Eczema Measure  
PRO: 
patient-reported outcome 
PROMIS: 
Patient-Reported Outcomes Measurement Information  
PT: 
preferred term 
Q2W: 
every 2 weeks 
QoL: 
quality of life 
RT-qPCR: 
reverse transcription quantitative polymerase chain reaction 
SAE: 
serious adverse event 
SC: 
Subcutaneous 
SCORAD: 
Scoring Atopic Dermatitis 
SoA: 
schedule of activity 
SOC: 
system organ class 
TB: 
tuberculosis 
TCS: 
topical corticosteroids 
TEAE: 
treatment-emergent adverse events 
Th2: 
T helper cell 2 
TSLP: 
thymic stromal lymphopoietin 
US: 
United States  
VIP: 
vasoactive intestinal peptide 
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10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
before the Table of Contents (TOC). 
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11 
REFERENCES  
1. Yosipovitch G, Berger T, Fassett MS. Neuroimmune interactions in chronic Itch of atopic 
dermatitis. J Eur Acad Dermatol Venereol. 2020;34(2):239-50. 
2. Takahashi S, Ishida A, Kubo A, Kawasaki H, Ochiai S, Nakayama M, et al. Homeostatic 
pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during 
chronic itch development. Nature. 2019;9(8625):2-15. 
3. Nakashima C, Ishida Y, Kitoh A, Otsuka A, Kabashima K. Interaction of peripheral nerves 
and mast cells, eosinophils, and basophils in the development of pruritus. Exp Dermatol. 
2019;28(12):1405-11. 
4. Silverberg JI, Yosipovitch G, Simpson EL, Graham NM, Patel N, Gadkari A. Dupilumab 
treatment results in early and sustained improvements in itch in adolescents and adults with 
moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and 
SOLO 2, AD ADOL, and CHRONOS. J Am Acad Dermatol. 2020;82(6):1328-36. 
5. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork M, et al. Two Phase 3 
Trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-48. 
6. Dupilumab (SAR231893-REGN668). Atopic dermatitis, Eosinophilic esophagitis, Allergen 
specific immunotherapy: Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road, 
Tarrytown, NY 10591-6707 USA. Asthma, Chronic rhinosinusitis with nasal polyposis: 
Sanofi-aventis Recherche & Développement 1 avenue Pierre Brossolette 91385 Chilly-
Mazarin Cedex FRANCE. Investigator’s Brochure. Edition number:13, Amendment 1, 21-
Aug-2019. 
7. Abhishek K, Khunger N. Complications of skin biopsy. J Cutan Aesthet Surg. 2015;8(4):239-
41. 
8. Merritt CR, Ong GT, Church SE, Barker K, Danaher P, Geiss G, et al. Multiplex Digital 
Spatial Profiling of Proteins and RNA in Fixed Tissue. Nat Biotechnol. 2020;38(5):586-99. 
9. Takahashi S, Ishida A, Kubo A, Kawasaki H, Ochiai S, Nakayama M, et al. Homeostatic 
pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during 
chronic itch development. Sci Rep. 2019;9(1):8625. 
10. Yosipovitch G, Reaney M, Mastey V, Eckert L, Abbé A, Nelson L, et al. Peak Pruritus 
Numerical Rating Scale: Psychometric Validation and Responder Definition for Assessing 
Itch in Moderate-To-Severe Atopic Dermatitis. Br J Dermatol. 2019;181(4):761-9. 
11. Silverberg JI, Lai JS, Kantor RW, Dalal P, Hickey C, Shaunfield S, et al. Development, 
Validation, and Interpretation of the PROMIS Itch Questionnaire: A Patient-Reported 
Outcome Measure for the Quality of Life Impact of Itch. J Invest Dermatol. 2020;140(5):986-
94. 
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12. Badia X, Mascaró JM, Lozano R. Measuring Health-Related Quality of Life in Patients With 
Mild to Moderate Eczema and Psoriasis: Clinical Validity, Reliability and Sensitivity to 
Change of the DLQI. The Cavide Research Group. Br J Dermatol. 1999;141(4):698-702. 
13. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure 
for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6. 
14. Pariser D, Simpson EL, Gadkari A, Bieber T, Margolis D, Brown M, et al. Evaluating Patient-
Perceived Control of Atopic Dermatitis: Design, Validation, and Scoring of the Atopic 
Dermatitis Control Tool (ADCT). Curr Med Res Opin. 2020;36(3):367-76. 
15. Simpson E, Eckert L, Gadkari A, Mallya U, Yang M, Nelson L, et al. Validation of the Atopic 
Dermatitis Control Tool (ADCT©) Using a Longitudinal Survey of Biologic-Treated Patients 
With Atopic Dermatitis. BMC Dermatol. 2019;19(1):15. 
16. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M, et al. The eczema area 
and severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol. 
2001;10:11-8. 
17. European Task Force on Atopic Dermatitis. Severity Scoring of Atopic Dermatitis: The 
SCORAD Index. Consensus Report of the European Task Force on Atopic Dermatitis. 
Dermatology. 1993;186(1):23-31. 
18. Hoang M, Zhou Z, Kriner M, Sorg K, Norgaard Z, Reeves J, et al. In situ RNA expression 
profiling of 1600+ immuno-oncology targets in FFPE tissue using NanoString GeoMx™ 
Digital Spatial Profiler. AGBT conference. 2019 Feb 27.  
19. Merritt CR, Ong GT, Church S, Barker K, Geiss G, Hoang M, et al. High multiplex, digital 
spatial profiling of proteins and RNA in fixed tissue using genomic detection methods. 
BioRxiv. 2019. 
20. Bakdash JZ, Marusich LR. Repeated measures correlation. Front Psychol. 2017;8:456. 
 
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Statistical Technical Document  
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TABLE OF CONTENTS 
STATISTICAL TECHNICAL DOCUMENT ..................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 3 
1 
STATISTICAL AND ANALYTICAL PROCEDURES ...................................................................... 4 
1.1 
INTRODUCTION .............................................................................................................................. 4 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL ............................ 4 
1.2.1 
Observation period definition ........................................................................................................... 4 
1.2.2 
Analysis visits ................................................................................................................................... 5 
1.2.3 
Participant demographic characteristics, medical history, and diagnoses ...................................... 6 
1.2.3.1 
Other baseline characteristics .......................................................................................................... 6 
1.2.3.2 
Medical/surgical history .................................................................................................................... 6 
1.2.4 
Compliance ...................................................................................................................................... 7 
1.2.5 
Prior/Concomitant medication/therapy ............................................................................................. 7 
1.2.6 
Efficacy analyses ............................................................................................................................. 7 
1.2.6.1 
Primary endpoints ............................................................................................................................ 7 
1.2.6.2 
Secondary endpoints ....................................................................................................................... 8 
1.2.6.3 
Exploratory endpoints ...................................................................................................................... 9 
1.2.7 
Safety analyses .............................................................................................................................. 10 
1.2.7.1 
Physical examination ..................................................................................................................... 10 
1.3 
DATA HANDLING CONVENTIONS .............................................................................................. 10 
2 
SOFTWARE DOCUMENTATION ................................................................................................. 12 
3 
APPENDICES ................................................................................................................................ 13 
3.1 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ................................. 13 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADCT: 
atopic dermatitis control tool 
ATC: 
anatomic therapeutic class 
DLQI: 
dermatology life quality index 
EASI: 
eczema and severity index 
EOS: 
end of study 
HLT: 
high level term 
IGA: 
investigator global assessment 
IMP: 
investigational medicinal product  
MedDRA: 
Medical Dictionary for Regulatory Activities 
NRS: 
numeric rating scale 
PCSA: 
potentially clinically significant abnormality 
POEM: 
patient oriented eczema measure 
PROMIS: 
Patient-Reported Outcomes Measurement Information 
PT: 
preferred term 
Q2W: 
every 2 weeks 
QoL: 
quality of life 
SAP: 
statistical analysis plan 
SAS®: 
Statistical Analysis System® 
SC: 
subcutaneous 
SCORAD: 
SCORing Atopic Dermatitis 
SD: 
standard deviation 
SEM: 
standard error of the mean 
SOC: 
system organ class 
STD: 
statistical technical document 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
VAS: 
visual analogue scale 
WHO-DD: 
World Health Organization Drug Dictionary 
 
 
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1 
STATISTICAL AND ANALYTICAL PROCEDURES  
1.1 
INTRODUCTION  
The purpose of this document is to provide additional technical details. 
A comprehensive and detailed description of strategy and statistical technique used to perform the 
analysis of data was provided in Section 9 of the protocol (Version 1 dated on 17AUG2020 and 
Amended version dated on 06JAN2021). 
As specified in the protocol, the biomarker analyses will not be part of this document and 
a specific dedicated statistical analysis plan (SAP) will be produced in addition to this statistical 
technical document (STD). 
Adverse events and medical history terms will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA Version 25.0). 
Previous and concomitant medication records will be coded according to the World Health 
Organization Drug Dictionary (WHO-DD version March 2022). 
The reporting of the 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. For vital signs 
parameters, the analyses of abnormalities will be based on the definitions of potentially clinically 
significant abnormalities (PCSAs) from BTD-009536 “Analysis and reporting of safety data from 
Clinical Trials through the Clinical Study Report” Version 3.0 dated 24-May-2014 (Appendix 3) 
and displayed in Section 3.1. 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL  
Following minor changes and clarifications were made to the statistical section of the protocol 
(amended version dated on 06JAN2021). 
1.2.1 Observation period definition  
For the AD participants, the overall observation period will be divided into 3 segments as follows: 
• The pre-treatment period is defined as the period up to the first investigational medicinal 
product (IMP) administration. 
• The treatment-emergent (TE) period is defined as the period from the IMP administration 
up to the end of treatment (EOT) visit (included).  
• The post-treatment period (ie, the follow-up extension period) is defined as the period 
from the end of the TE period. 
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For the healthy participants, the overall observation period will be divided into 2 segments as 
follows: 
• The screening period is defined as the period of 21 days up to the collection of the skin 
biopsy. 
• The observational period is defined as the period of 7 days following collection of the skin 
biopsy. 
1.2.2 Analysis visits  
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 (home dosing and patient-reported outcome) were linked to 
a unique unscheduled or a missing visit in the SDTM database. To perform the analysis by visit, 
the following visit window algorithm is defined. 
 
VISIT WINDOW ALGORITHM 
Type of data 
Planned visits in the 
protocol 
Time interval for analysed visits 
Home dosing 
Dupilumab administration 
D29 
23 to 36 days after the first IMP administration 
 
D57 
51 to 64 days after the first IMP administration 
 
D71 
65 to 78 days after the first IMP administration 
 
D85 
79 to 92 days after the first IMP administration 
 
D99 
93 to 106 days after the first IMP administration 
Patient-Reported Outcomes 
Peak pruritus NRS 
D1 
Less than 28 days 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 
D43 
40 to 46 days after the first IMP administration 
D50 
47 to 53 days after the first IMP administration 
D57 
54 to 60 days after the first IMP administration 
D64 
61 to 67 days after the first IMP administration 
D71 
68 to 74 days after the first IMP administration 
D78 
75 to 81 days after the first IMP administration 
D85 
82 to 88 days after the first IMP administration 
D92 
89 to 95 days after the first IMP administration 
D99 
96 to 102 days after the first IMP administration 
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VISIT WINDOW ALGORITHM 
Type of data 
Planned visits in the 
protocol 
Time interval for analysed visits 
D106 
103 to 109 days after the first IMP administration 
D113 
110 to 116 days after the first IMP administration 
D120 
117 to 123 days after the first IMP administration 
D127 
124 to 130 days after the first IMP administration 
D134 
131 to 137 days after the first IMP administration 
D141 
138 to 197 days after the first IMP administration 
Sleep quality NRS 
Skin pain NRS 
Skin Sensitivity NRS 
Skin Burning NRS 
D1 
Less than 28 days before the first IMP administration 
D15 
2 to 29 days after the first IMP administration 
D43 
30 to 57 days after the first IMP administration 
D71 
58 to 85 days after the first IMP administration 
D99 
86 to 106 days after the first IMP administration 
D113 
107 to 127 days after the first IMP administration 
D141 
128 to 197 days after the first IMP administration 
POEM 
DLQI 
PROMIS-itch 
D1 
Less than 28 days before the first IMP administration 
D43 
2 to 57 days after the first IMP administration 
D71 
58 to 85 days after the first IMP administration 
D99 
86 to 106 days after the first IMP administration 
D113 
107 to 127 days after the first IMP administration 
D141 
128 to 197 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. Then, for post-treatment assessments, if more than one record 
remain analyzable (ie, two records or more the same day), the first one will be used. 
1.2.3 Participant demographic characteristics, medical history, and diagnoses  
1.2.3.1 Other baseline characteristics  
As there are not any other baseline characteristics, the planned listing will not be produced. 
1.2.3.2 Medical/surgical history  
Medical/surgical histories will be summarized by system organ class (SOC), high level term 
(HLT) and preferred term (PT), and listed. 
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1.2.4 Compliance  
As the exact dose is not recorded in the database for the home dosing, the above-planned and 
under-planned dosing percentages will not be analyzed.  
1.2.5 Prior/Concomitant medication/therapy  
Concomitant medications will be summarized by anatomic category (first digit of the anatomic 
therapeutic class (ATC)) and therapeutic category (first three digits of the ATC). 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. 
A specific listing of rescue medications will also be performed. The rescue medications will be 
identified with “RESCUE THERAPY” as reason for treatment. The following information will be 
added in the listing: demographic data, dose regimen, reason for treatment... 
1.2.6 Efficacy analyses  
No imputation will be performed for the following efficacy analyses. 
1.2.6.1 Primary endpoints  
The two primary endpoints (intraepidermal nerve fiber density and branching by PGP9.5 antibody 
staining in lesional skin) was planned to be analyzed as quantitative endpoints. But the branching 
is a semi-quantitative endpoint with 4 modalities: “only linear”, “mainly linear”, “mainly 
branched” and “only branched” fibers. The statistical method will be updated as follows: 
• The number and percentage of participants for each modality will be described by 
timepoints, by skin type (Lesional pruritic skin, Post-lesional healed skin non-pruritic non-
lesional, Lesional non-pruritic skin and Non-lesional skin) and by treatment group based 
on the mITT and ITT population. Only the evaluable participants will be taken into 
account in the calculation of the percentages. 
• The listing of individual data will be performed, including the following information: 
demographic data, location, laterality and directionality... 
• No plots will be performed. 
To analyze the change from baseline on Week 17 for intraepidermal nerve fiber density by 
PGP9.5 antibody staining in lesional skin, the summary plots for AD participants based on the 
mITT population (and on the ITT population) will be graphs of mean +/- standard error of the 
mean (SEM) for raw data, absolute and percent change from baseline at baseline (ie, 0) and 
Week 17. 
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1.2.6.2 Secondary endpoints  
To analyze the changes from baseline on Weeks 3 and 21 for intraepidermal nerve fiber density 
and branching by PGP9.5 antibody staining in lesional skin, the summary plots for AD 
participants based on the mITT population (and on the ITT population, if applicable) will be 
graphs of mean +/- SEM for raw data, absolute and percent change from baseline at baseline 
(ie, 0), Week 3 and Week 21. 
To analyze the changes from baseline on Weeks 3 and 21 for intraepidermal nerve fiber density 
and branching by PGP9.5 antibody staining in lesional skin and changes from baseline over time 
and at Weeks 17 and 21 for the outcomes of the assessments/questionnaires (peak pruritus 
assessed by numeric rating scale (NRS), eczema and severity index (EASI), scoring atopic 
dermatitis (SCORAD), patient-reported outcomes measurement information (PROMIS-itch), 
patient oriented eczema measure (POEM), dermatology life quality index (DLQI), atopic 
dermatitis control tool (ADCT) and sleep quality/skin pain/skin sensitivity/skin burning NRS), the 
individual profiles over time will be spaghetti plots on raw data with all the AD participants on 
the same graph and the AD group mean. 
To analyze the changes from baseline over time and at Weeks 17 and 21 for the outcomes of the 
assessments/questionnaires, the following variables will be analyzed: 
• Peak pruritus assessed by numeric rating scale (NRS): scale of the worst itch 
(from 0 (“no itch”) to 10 (“Worst itch imaginable”)). 
• Eczema and severity index (EASI): composite index ranging from 0 to 72 calculated as 
follows. The intermediate and total EASI scores will be derived, however, only the total 
EASI score will be analyzed. 
- 
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. 
- 
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 for Head and Neck region, 0.3 for Trunk, 0.2 for 
Upper Limbs, 0.4 for Lower Limbs. 
- 
Total EASI score will be derived as the sum of the 4 region scores. 
• Scoring Atopic Dermatitis (SCORAD): intermediate SCORAD scores (A/B/C) and total 
SCORAD score calculated as follows. The intermediate and total SCORAD scores will be 
derived, however, only the total SCORAD score will be analyzed. 
SCORAD score = A/5 + 7*B/2 + C, where 
A is the sum of each extent of AD (Left and Right Lower Limbs, Left and Right Upper 
Limbs, Anterior Trunk, Head and Neck, Genitalia and Posterior Trunk) in %;  
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B is the sum of severity scales of each symptom of AD (Dryness, Edema/Papulation, 
Erythema, Excoriation, Lichenification and Oozing/Crust) (scale from 0 to 3); 
C is the sum of visual analogue scale (VAS) of itch and sleeplessness (VAS from 0 to 10).  
• Investigator global assessment (IGA): 5-point scale to rate the severity of AD globally 
ranging from 0 (clear) to 4 (severe). 
• Patient-Reported Outcomes Measurement Information (PROMIS-itch):  
- 
Itch-Severity: scores of each of 7 quantitative items and total score. 
- 
Itch-Activity and Clothing: scores of each item. 
- 
Itch-Mood and Sleep: scores of each item. 
- 
Itch-Interference: scores of each item. 
- 
Itch-Scratching Behavior: scores of each item. 
- 
Itch-Quality and Itch-Triggers: not applicable (Yes-No answers). 
• Patient Oriented Eczema Measure (POEM): total score (sum of the 7 items) ranging from 
0 to 28. A high score indicates a high severity. 
• Dermatology Life Quality Index (DLQI): total score (sum of the 10 items) ranging from 
0 to 30. A high score indicates a poor quality of life (QoL). 
• Atopic Dermatitis Control Tool (ADCT): total score (sum of the 6 items) ranging from 
0 to 24. A high score indicates a low AD control. 
• Sleep Quality NRS: scale of the sleep quality [from 0 (“Worst possible sleep”) to 
10 (“Worst pain possible”)]. 
• Skin Pain NRS: scale of the skin pain [from 0 (“No pain”) to 10 (“Worst pain possible”)]. 
• Skin Sensitivity NRS: scale of the skin sensitivity [from 0 (“Normal”)) to 10 (“Extremely 
sensitive”)]. 
• Skin Burning NRS: scale of the skin burning [from 0 (“Not at all”)) to 10 (“Very much”)]. 
To analyse the proportion of AD participants reaching pruritus NRS ≥4 point improvement from 
baseline at Weeks 3, 7, 11, 15, 17 and 21 for each NRS scale (Sleep Quality, Skin Pain, Skin 
Sensitivity and Skin Burning), a participant will be considered to reach a pruritus NRS ≥4 point 
improvement at a given time point if he presents a change from baseline ≥4 at the timepoint. 
1.2.6.3 Exploratory endpoints  
Not applicable (biomarker analyses). 
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1.2.7 Safety analyses  
1.2.7.1 Physical examination  
As the clinically significant abnormality in physical examination is not recorded in the database, 
only the number and percentage of participants with at least one post-baseline abnormality in 
physical examination will be summarized and listed by treatment group. 
1.3 
DATA HANDLING CONVENTIONS  
This section describes the rules and conventions used in the presentation and analysis of data.  
In the statistical appendices and in-text tables, the following study group label will be used: 
• Healthy Participant. 
• Dupilumab (identified as “patient group” in the protocol). 
All individual data for all included participants will be presented in data listings, sorted by study 
group and participant number. 
In listings, no date of assessments/events/medications will be presented but only the relative day. 
It will be calculated as follows: 
• For AD participants: relative day = date of assessments/events/medications – date of first 
IMP administration +1. 
• For healthy participants: relative day = date of assessments/events/medications – date of 
D1 visit +1. 
For parameters with evaluations before administration and in cases of rechecked value(s) for one 
participant, only the last observation will be used as baseline in descriptive statistics and 
derivations of other parameter values. After baseline, only observations planned in the protocol 
will be used in descriptive statistics. 
If not otherwise stated in the statistical section of the protocol:  
• Missing data other than protocol-planned baseline values will not be replaced.  
• Descriptive statistics for quantitative parameters will be provided using number of 
observations (N), mean, standard deviation (SD), SEM, median, minimum and maximum. 
The 95% confidence interval will be added for efficacy analyses. 
• Descriptive statistics for qualitative parameters will be provided using frequencies (N) and 
percent (%).   
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Handling missing data for adverse events 
In case of missing or inconsistent information, an AE will be counted as a treatment-emergent AE 
(TEAE), unless it can clearly be ruled out that it is not a treatment-emergent adverse event (eg, by 
partial dates or other information). 
If the start date (or time) of an AE is incomplete or missing, it will be counted as TEAE except 
if an incomplete date (or time) or comment indicates that it is a pre- or post-treatment event. 
If the relationship to study intervention is missing for an AE, this AE will be assessed as unrelated 
if it started before administration of study medication; in all other cases it will be assumed to be 
related. 
If the severity is missing for one of the treatment-emergent occurrences of an AE, the severity will 
be imputed with the maximal severity of the other occurrences. If the severity is missing for all 
the occurrences, the severity will be left as missing. 
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2 
SOFTWARE DOCUMENTATION  
The analysis of clinical data will be performed under the responsibility of Sanofi Biostatistics 
Department, using SAS® (SAS Institute, NC USA). 
 
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3 
APPENDICES  
3.1 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20 mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
 
 
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